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Worsening Rash in a Patient With Metastatic Breast Cancer.

A 56-year-old woman with metastatic hormone receptor–positive, ERBB2-negative breast cancer presents with pruritic, erythematous, scaly macules and papules on her forearms, faces, chest, and upper back. What is your diagnosis

Pertuzumab Charge Variant Analysis and Complementarity-Determining Region Stability Assessment to Deamidation.

Pertuzumab is a monoclonal antibody used for the treatment of HER2-positive breast cancer in combination with trastuzumab. Charge variants of trastuzumab have been extensively described in the literature however, little is known about the charge heterogeneity of pertuzumab. Here, changes in the ion-exchange profile of pertuzumab were evaluated by pH gradient cation-exchange chromatography after stressing it for up to 3 weeks at physiological and elevated pH and 37 °C. Isolated charge variants arising under stress conditions were characterized by peptide mapping. The results of peptide mapping showed that deamidation in the Fc domain and N-terminal pyroglutamate formation in the heavy chain are the main contributors to charge heterogeneity. The heavy chain CDR2, which is the only CDR containing asparagine residues, was quite resistant to deamidation under stress conditions according to peptide mapping results. Using surface plasmon resonance, it was shown that the affinity of pertuzumab for the HER2 target receptor does not change under stress conditions. Peptide mapping analysis of clinical samples showed an average of 2-3% deamidation in the heavy chain CDR2, 20-25% deamidation in the Fc domain, and 10-15% N-terminal pyroglutamate formation in the heavy chain. These findings suggest that

Nanomedicine in therapeutic warfront against estrogen receptor-positive breast cancer.

Breast cancer (BC) is the most frequently diagnosed malignancy in women worldwide. Almost 70-80% of cases of BC are curable at the early non-metastatic stage. BC is a heterogeneous disease with different molecular subtypes. Around 70% of breast tumors exhibit estrogen-receptor (ER) expression and endocrine therapy is used for the treatment of these patients. However, there are high chances of recurrence in the endocrine therapy regimen. Though chemotherapy and radiation therapy have substantially improved survival rates and treatment outcomes in BC patients, there is an increased possibility of the development of resistance and dose-limiting toxicities. Conventional treatment approaches often suffer from low bioavailability, adverse effects due to the non-specific action of chemotherapeutics, and low antitumor efficacy. Nanomedicine has emerged as a conspicuous strategy for delivering anticancer therapeutics in BC management. It has revolutionized the area of cancer therapy by increasing the bioavailability of the therapeutics and improving their anticancer efficacy with reduced toxicities on healthy tissues. In this article, we have highlighted various mechanisms and pathways involved in the progression of ER-positive BC. Further, different nanocarriers delivering drugs, genes, and natural therapeutic agents for surmounting BC are the spotlights of this article.

Patient reported improvement in sexual health outcomes following care in a sexual health clinic for women with cancer.

Sexual health concerns are common among female cancer survivors. Few data exist regarding patient-reported outcomes following interventions in this population. We aimed to determine patient-reported adherence and impact of interventions provided in an academic specialty clinic for treatment of sexual health problems. A cross-sectional quality improvement survey regarding sexual problems, adherence with recommended therapies, and improvement following intervention was administered to all women seen at the Womens Integrative Sexual Health (WISH) program at the University of Wisconsin-Madison between November 2013 and July 2019. Descriptive and Kruskal-Wallis tests were used to explore differences between groups. Two hundred twenty women (median age at first visit 50 years, 53.1% breast cancer) were identified N 113 surveys were completed (response rate 49.6%). The most common presenting complaints were pain with intercourse (87.2%), vaginal dryness (85.3%), and low libido (82.6%). Menopausal women were more likely than premenopausal women to present with vaginal dryness (93.4% vs. 69.7%, p .001) and pain with intercourse (93.4% vs. 76.5%, p .02). Nearly all women adhered to recommendations for vaginal moisturizerslubricants (96.9-100%) and vibrating vaginal wands (82.4-92.3%). A majority found recommended interventions helpful regardless of menopausal status or cancer type and reported persistent improvement. Nearly all women had improvement in understanding sexual health (92%) and would recommend the WISH program to others (91%). Women with cancer report integrative sexual health care to address sexual problems that are helpful and result in long-term improvement. Patients are overall highly adherent to recommended therapies, and nearly all would recommend the program to others. Dedicated care to address sexual health in women after cancer treatment improves patient-reported sexual health outcomes across all cancer types.

Association between Consumption of Artificial Sweeteners and Breast Cancer Risk A Systematic Review and Meta-Analysis of Observational Studies.

This study intends to conduct a meta-analysis based on existing research results to further investigate their relationship between artificial sweetener exposure and breast cancer risk. An electronic database literature search was performed up to July 2022, using PubMed, Web of Science, Ovid and Scopus. The relationship between artificial sweetener exposure and breast cancer (BC) incidence was evaluated by odds ratio (OR) and 95% confidence interval (CI). Among the five studies (two case-control studies and three cohort studies) that met the inclusion criteria, 314,056 participants were recruited in the cohort study, 4,043 cancer cases and 3,910 controls were recruited in the case-control study. It was found that exposure of artificial sweeteners was not related to the risk of BC (OR 0.98, 95% CI 0.94-1.03). Subgroup analysis showed that compared with the non-exposurevery-low-dose group, the exposure to low, medium and high doses of artificial sweeteners were not associated with the risk of BC, which were OR 1.01, 95% CI 0.95-1.07, OR 0.98, 95% CI 0.93-1.02, OR 0.88, 95% CI 0.74-1.06, respectively. This study confirmed that there was no relationship between the exposure of artificial sweeteners and the incidence of BC.

Medicaid expansion, chemotherapy delays, and racial disparities among women with early-stage breast cancer.

Medicaid expansion under the Affordable Care Act extends eligibility for participating states has been associated with improved outcomes by facilitating access to care. Delayed initiation of adjuvant chemotherapy is associated with worse outcomes among patients with early-stage breast cancer (BC). The impact of Medicaid expansion in narrowing delays by race and ethnicity has not been studied. Population-based study using the National Cancer Database. Patients diagnosed with primary early-stage BC between 2007-2017 residing in states that underwent Medicaid expansion in January 2014 were included. Time to chemotherapy initiation and proportion of patients experiencing chemotherapy delays (>60 days) were evaluated using difference-in-difference (DID) and Cox proportional hazards models in pre- and post-expansion periods according to race and ethnicity. 100,643 patients included (63,313 pre- and 37,330 post-expansion). After Medicaid expansion, the proportion of patients experiencing chemotherapy initiation delay decreased from 23.4% to 19.4%. The absolute decrease was 3.2, 5.3, 6.4, and 4.8 percentage points (ppt) for White, Black, Hispanic, and Other patients. Compared to White patients, significant adjusted DIDs were observed for Black -2.1ppt (95%CI -3.7% to -0.5% and Hispanic patients -3.2ppt (95%CI -5.6% to -0.9%. Significant reductions in time to chemotherapy between expansion periods were observed among White patients adjusted hazard ratio (aHR)1.11 (95%CI 1.09-1.12) and those belonging to racialized groups (aHR 1.14 95%CI 1.11-1.17). Among patients with early-stage BC, Medicaid expansion was associated with a reduction in racial disparities by decreasing the gap in the proportion of Black and Hispanic patients experiencing delays in adjuvant chemotherapy initiation.

Historical Redlining and Breast Cancer Treatment and Survival among older Women in the US.

Breast cancer (BC) is the most common cancer among US women and institutional racism is a critical cause of health disparities. We investigated impacts of historical redlining on BC treatment receipt and survival in the US. Home Owners Loan Corporation (HOLC) boundaries were used to measure historical redlining. Eligible women in the 2010-2017 SEER-Medicare BC Cohort were assigned an HOLC grade. The independent variable was a dichotomized HOLC grade AB (non-redlined), and CD (redlined). Outcomes of receipt of various cancer treatments, all-cause mortality (ACM), and BC-specific mortality (BCSM) were analyzed using logistic or Cox models. Indirect effects by comorbidity were examined. Among 18,119 women, 65.7% resided in historically redlined areas (HRAs) and 32.6% were deceased at a median follow-up of 58 months. A larger proportion of deceased women resided in HRAs (34.5% vs 30.0%). Of all deceased women, 41.6% died of BC a larger proportion residing in HRAs (43.4% vs 37.8%). Historical redlining significantly predicted poorer survival after BC diagnosis HR 95%CI 1.09 1.03-1.15 for ACM, and 1.26 1.13-1.41 for BCSM. Indirect effects via comorbidity were identified. Historical redlining was associated with a lower likelihood of receiving surgery OR 95%CI 0.74 0.66-0.83, and a higher likelihood of receiving palliative care OR 95%CI 1.41 1.04-1.91. Historical redlining is associated with differential treatment receipt and poorer survival for ACM and BCSM. Relevant stakeholders should consider historical contexts when designingimplementing equity-focused interventions to reduce BC disparities. Clinicians should advocate for healthier neighborhoods while providing care.

The Relationship Between Periodontal Disease and Breast Cancer From Basic Mechanism to Clinical Management and Prevention.

Periodontal disease is potentially related to certain kinds of cancer. This review aimed to summarize the relationship between periodontal disease and breast cancer, providing some strategies for the clinical treatment and periodontal health care of breast cancer patients. Systematic reviews, randomised controlled trials, prospective and retrospective clinical studies, case series and reports were collected using search terms entered into the PubMed, Google Scholar and JSTOR databases. Research has provided some evidence that periodontal disease is related to the occurrence and development of breast cancer. Periodontal disease and breast cancer have some common pathogenic factors. Periodontal disease may affect the initiation and development of breast cancer involving microorganisms and inflammation. Periodontal health is affected by radiotherapy, chemotherapy, and endocrine therapy for breast cancer. Periodontal therapy for breast cancer patients should be performed differently according to the stage of cancer treatment. Adjuvant endocrine treatment (e.g. bisphosphonates) has a great impact on oral treatment. Periodontal therapy contributes to the primary prevention of breast cancer. Periodontal health care of breast cancer patients is worthy of clinician attention.

Prognostic analysis of three forms of Ki-67 in patients with breast cancer with non-pathological complete response before and after neoadjuvant systemic treatment.

Patients who do not achieve a pathological complete response (pCR) after neoadjuvant systemic treatment (NST) have a significantly worse prognosis. A reliable predictor of prognosis is required to further subdivide non-pCR patients. To date, the prognostic role in terms of disease-free survival (DFS) between the terminal index of Ki-67 after surgery (Ki-67 This study aimed to explore the most useful form or combination of Ki-67 that can provide prognostic information to non-pCR patients. We retrospectively reviewed 499 patients who were diagnosed with inoperable breast cancer between August 2013 and December 2020 and received NST with anthracycline plus taxane. Among all the patients, 335 did not achieve pCR (with a follow-up period of ≥1 year). The median follow-up duration was 36 months. The optimal cutoff value of Ki-67 Ki-67

Monocyte chemoattractant protein 1 as a potential biomarker for immune checkpoint inhibitor-associated neurotoxicity.

Oncological patients can benefit substantially from treatment with immune checkpoint inhibitors (ICI). However, there is a growing awareness of immune-related adverse events (irAE). Especially ICI-mediated neurological adverse events (nAE()), are tough to diagnose and biomarkers to identify patients at risk are missing. A prospective register with prespecified examinations was established for ICI treated patients in December 2019. At the time of data cut-off, 110 patients were enrolled and completed the clinical protocol. Herein, cytokines and serum neurofilament light chain (sNFL) from 21 patients were analyzed. nAE of any grade were observed in 31% of the patients (n 34110). In nAE() patients a significant increase in sNFL concentrations over time was observed. Patients with higher-grade nAE had significantly elevated serum-concentrations of monocyte chemoattractant protein 1 (MCP-1) and brain-derived neurotrophic factor (BDNF) at baseline compared to individuals without any nAE (p < 0.01 and p < 0.05). Here, we identified nAE to occur more frequently than previously reported. Increase of sNFL during nAE confirms the clinical diagnosis of neurotoxicity and might be a suitable marker for neuronal damage associated with ICI therapy. Furthermore, MCP-1 and BDNF are potentially the first clinical-class nAE predictors for patients under ICI therapy.

Antitumor therapy for breast cancer Focus on tumor-associated macrophages and nanosized drug delivery systems.

In breast cancer (BC), tumor-associated macrophages (TAMs) are an important component of the tumor microenvironment and are closely related to poor prognosis. A growing number of studies have focused on the role of TAMs in BC progression and therapeutic strategies targeting TAMs. As an emerging treatment, the application of nanosized drug delivery systems (NDDSs) in the treatment of BC by targeting TAMs has attracted much attention. This review is to summarize the characteristics and treatment strategies targeting TAMs in BC and to clarify the applications of NDDSs targeting TAMs in the treatment of BC by targeting TAMs. The existing results related to characteristics of TAMs in BC, BC treatment strategies by targeting TAMs, and the applications of NDDSs in these strategies are described. Through analyzing these results, the advantages and disadvantages of the treatment strategies using NDDSs are discussed, which could provide advices on designing NDDSs for BC treatment. TAMs are one of the most prominent noncancer cell types in BC. TAMs not only promote angiogenesis, tumor growth and metastasis but also lead to therapeutic resistance and immunosuppression. Mainly four strategies have been used to target TAMs for BC therapy, which include depleting macrophages, blocking recruitment, reprogramming to attain an anti-tumor phenotype, and increasing phagocytosis. Since NDDSs can efficiently deliver drugs to TAMs with low toxicity, they are promising approaches for targeting TAMs in tumor therapy. NDDSs with various structures can deliver immunotherapeutic agents and nucleic acid therapeutics to TAMs. In addition, NDDSs can realize combination therapies. TAMs play a critical role in the progression of BC. An increasing number of strategies have been proposed to regulate TAMs. Compared with free drugs, NDDSs targeting TAMs improve drug concentration, reduce toxicity and realize combination therapies. However, in order to achieve better therapeutic efficacy, there are still some disadvantages that need to be considered in the design of NDDSs. TAMs play an important role in the progression of BC, and targeting TAMs is a promising strategy for BC therapy. In particular, NDDSs targeting TAMs have unique advantages and are potential treatments for BC.

Optical coherence tomography for presurgical delineation of basal cell carcinomas on the face - a comparison with histopathology.

In order to minimize the risk of incomplete excision of basal cell carcinomas (BCC) the macroscopic tumor margins should be adequately defined. Optical coherence tomography (OCT) is a non-invasive imaging tool that can provide structural and vascular information about skin cancer lesions. The study objective was to compare the pre-surgical delineation of facial BCC by clinical examination, histopathology and OCT imaging in tumors undergoing full excision. 10 patients with BCC lesions on the face were examined clinically, with OCT and histopathology at 3 mm intervals, from the clinical lesion border and beyond the resection line. The OCT scans were evaluated blinded and a delineation estimate of each BCC lesion was made. The results were compared to the clinical and histopathologic results. OCT evaluations and histopathology were in agreement in 86.6 % of the collected data points. In three cases the OCT scans estimated a reduction of the tumor size compared to the clinical tumor border set by the surgeon. The results of this study support the notion that OCT can have a role in the clinical daily practice by aiding clinicians in delineating BCC lesions prior to surgery. This article is protected by copyright. All rights reserved.

Microtubule Acetylation-Specific Inhibitors Induce Cell Death and Mitotic Arrest via JNKAP-1 Activation in Triple-Negative Breast Cancer Cells.

Microtubule acetylation has been proposed as a marker of highly heterogeneous and aggressive triple-negative breast cancer (TNBC). The novel microtubule acetylation inhibitors GM-90257 and GM-90631 (GM compounds) cause TNBC cancer cell death but the underlying mechanisms are currently unknown. In this study, we demonstrated that GM compounds function as anti-TNBC agents through activation of the JNKAP-1 pathway. RNA-seq and biochemical analyses of GM compound-treated cells revealed that c-Jun N-terminal kinase (JNK) and members of its downstream signaling pathway are potential targets for GM compounds. Mechanistically, JNK activation by GM compounds induced an increase in c-Jun phosphorylation and c-Fos protein levels, thereby activating the activator protein-1 (AP-1) transcription factor. Notably, direct suppression of JNK with a pharmacological inhibitor alleviated Bcl2 reduction and cell death caused by GM compounds. TNBC cell death and mitotic arrest were induced by GM compounds through AP-1 activation

Determinants of posttraumatic growth and quality of life in Ghanaian breast cancer survivors Cancer Investigation.

This study assessed the psychosocial factors associated with posttraumatic growth (PTG) and health-related quality of life (HRQoL) in women breast cancer survivors. Women (

Recent advances in peptide-based therapeutic strategies for breast cancer treatment.

Breast cancer is the leading cause of cancer-related fatalities in female worldwide. Effective therapies with low side effects for breast cancer treatment and prevention are, accordingly, urgently required. Targeting anticancer materials, breast cancer vaccines and anticancer drugs have been studied for many years to decrease side effects, prevent breast cancer and suppress tumors, respectively. There are abundant evidences to demonstrate that peptide-based therapeutic strategies, coupling of good safety and adaptive functionalities are promising for breast cancer therapy. In recent years, peptide-based vectors have been paid attention in targeting breast cancer due to their specific binding to corresponding receptors overexpressed in cell. To overcome the low internalization, cell penetrating peptides (CPPs) could be selected to increase the penetration due to the electrostatic and hydrophobic interactions between CPPs and cell membranes. Peptide-based vaccines are at the forefront of medical development and presently, 13 types of main peptide vaccines for breast cancer are being studied on phase III, phase II, phase III and phase I clinical trials. In addition, peptide-based vaccines including delivery vectors and adjuvants have been implemented. Many peptides have recently been used in clinical treatments for breast cancer. These peptides show different anticancer mechanisms and some novel peptides could reverse the resistance of breast cancer to susceptibility. In this review, we will focus on current studies of peptide-based targeting vectors, CPPs, peptide-based vaccines and anticancer peptides for breast cancer therapy and prevention.

Adverse events of bevacizumab for triple negative breast cancer and HER-2 negative metastatic breast cancer A meta-analysis.

A biodegradable covalent organic framework for synergistic tumor therapy.

Stimulus-responsive biodegradable nanocarriers with tumor-selective targeted drug delivery are critical for cancer therapy. Herein, we report for the first time a redox-responsive disulfide-linked porphyrin covalent organic framework (COF) that can be nanocrystallized by glutathione (GSH)-triggered biodegradation. After loading 5-fluorouracil (5-Fu), the generated nanoscale COF-based multifunctional nanoagent can be further effectively dissociated by endogenous GSH in tumor cells, releasing 5-Fu efficiently to achieve selective chemotherapy on tumor cells. Together with the GSH depletion-enhanced photodynamic therapy (PDT), an ideal synergistic tumor therapy for MCF-7 breast cancer

Seed-derived peptide lunasin suppressed breast cancer cell growth by regulating inflammatory mediators, aromatase, and estrogen receptors.

Breast cancer is one of the most prevalent cancers in women. Its pathology comprises tumor cells and nearby stromal cells, accompanied by cytokines and stimulated molecules, resulting in a favorable microenvironment for tumor progression. Lunasin is a seed peptide with multiple bioactivities derived from seeds. However, the chemopreventive effect of lunasin on different characteristics of breast cancer has not been fully explored. This study aims to explore the chemopreventive mechanisms of lunasin through inflammatory mediators and estrogen-related molecules in breast cancer cells. Estrogen-dependent MCF-7 and independent MDA-MB-231 breast cancer cells were used. The β-estradiol was used to mimic physiological estrogen. The gene expression, mediator secretion, cell vitality, and apoptosis impacting breast malignancy were explored. Lunasin did not affect normal MCF-10A cell growth but inhibited breast cancer cell growth, increased interleukin (IL)-6 gene expression and protein production at 24 h, and decreased its secretion at 48 h. In both breast cancer cells, aromatase gene and activity and estrogen receptor (ER)α gene expression were decreased by lunasin treatment, while ERβ gene levels were significantly increased in MDA-MB-231 cells. Moreover, lunasin decreased vascular endothelial growth factor (VEGF) secretion and cell vitality and induced cell apoptosis in both breast cancer cell lines. However, lunasin only decreased leptin receptor (Ob-R) mRNA expression in MCF-7 cells. Additionally, β-estradiol increased MCF-7-cell proliferation but not the proliferation of other cells in particular, lunasin still inhibited MCF-7-cell growth and cell vitality in the presence of β-estradiol. Seed peptide lunasin inhibited breast cancer cell growth by regulating inflammatory, angiogenic, and estrogen-related molecules, suggesting that lunasin is a promising chemopreventive agent.

Establishment of a Lymph Node Metastasis-Associated Prognostic Signature for Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most common histological subtype of non-small cell lung cancer (NSCLC) with a low 5-year survival rate, which may be associated with the presence of metastatic tumors at the time of diagnosis, especially lymph node metastasis (LNM). This study aimed to construct a LNM-related gene signature for predicting the prognosis of patients with LUAD. RNA sequencing data and clinical information of LUAD patients were extracted from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Samples were divided into metastasis (M) and nonmetastasis (NM) groups based on LNM status. Differentially expressed genes (DEGs) between M and NM groups were screened, and then WGCNA was applied to identify key genes. Furthermore, univariate Cox and LASSO regression analyses were conducted to construct a risk score model, and the predictive performance of model was validated by GSE68465, GSE42127, and GSE50081. The protein and mRNA expression level of LNM-associated genes were detected by human protein atlas (HPA) and GSE68465. A prognostic model based on eight LNM-related genes (ANGPTL4, BARX2, GPR98, KRT6A, PTPRH, RGS20, TCN1, and TNS4) was developed. Patients in the high-risk group had poorer overall survival than those in the low-risk group, and validation analysis showed that this model had potential predictive value for patients with LUAD. HPA analysis supported the upregulation of ANGPTL4, KRT6A, BARX2, RGS20 and the downregulation of GPR98 in LUAD compared with normal tissues. Our results indicated that the eight LNM-related genes signature had potential value in the prognosis of patients with LUAD, which may have important practical implications.

Oncological patient management on the territory the results of a survey in the north-west of Italy.

To investigate the role of community pharmacists in the therapeutic process of oncological patients and to assess these patients state of acceptance of their disease and their relationship with their therapies, we performed a survey in some oncological clinics in Turin (north-west of Italy). The survey was carried out in a three months period by means of a questionnaire. The questionnaire was administered on paper to oncological patients that attended 5 oncological clinics in Turin. The questionnaire was self-administered. 266 patients filled out the questionnaire. More than half of patients reported that their cancer diagnosis interfered with normal life very much or extremely and almost 70% of patients reported that they were accepting of what happened and were trying to fight back. 65% of patients answered that it is important or very important that pharmacists are aware of their health status. About 3 out of 4 patients thought that pharmacists giving information on medicines purchased and on how to use them is important or very important and that it is important to receive information concerning health and the effects of medication taken. Our study underlines the role of territorial health units in the management of oncological patients. It can be said that the community pharmacy is certainly a channel of election, not only in cancer prevention but also in the management of those patients who have already been diagnosed with cancer. More comprehensive and specific pharmacist training is necessary for the management of this type of patient. Furthermore, it is necessary to improve the awareness of this issue in community pharmacists at the local and national levels by creating a network of qualified pharmacies developed in collaboration with oncologists, GPs, dermatologists, psychologists and cosmetics companies.

Exploring neurotransmitters and their receptors for breast cancer prevention and treatment.

While psychological factors have long been linked to breast cancer pathogenesis and outcomes, accumulating evidence is revealing how the nervous system contributes to breast cancer development, progression, and treatment resistance. Central to the psychological-neurological nexus are interactions between neurotransmitters and their receptors expressed on breast cancer cells and other types of cells in the tumor microenvironment, which activate various intracellular signaling pathways. Importantly, the manipulation of these interactions is emerging as a potential avenue for breast cancer prevention and treatment. However, an important caveat is that the same neurotransmitter can exert multiple and sometimes opposing effects. In addition, certain neurotransmitters can be produced and secreted by non-neuronal cells including breast cancer cells that similarly activate intracellular signaling upon binding to their receptors. In this review we dissect the evidence for the emerging paradigm linking neurotransmitters and their receptors with breast cancer. Foremost, we explore the intricacies of such neurotransmitter-receptor interactions, including those that impinge on other cellular components of the tumor microenvironment, such as endothelial cells and immune cells. Moreover, we discuss findings where clinical agents used to treat neurological andor psychological disorders have exhibited preventivetherapeutic effects against breast cancer in either associative or pre-clinical studies. Further, we elaborate on the current progress to identify druggable components of the psychological-neurological nexus that can be exploited for the prevention and treatment of breast cancer as well as other tumor types. We also provide our perspectives regarding future challenges in this field where multidisciplinary cooperation is a paramount requirement.

Dynamic SUMOylation of MORC2 orchestrates chromatin remodelling and DNA repair in response to DNA damage and drives chemoresistance in breast cancer.

SRA inhibition improves antitumor potency of antigen-targeted chaperone vaccine.

We have previously demonstrated that scavenger receptor A (SRA) acts as an immunosuppressive regulator of dendritic cell (DC) function in activating antitumor T cells. Here we investigate the potential of inhibiting SRA activity to enhance DC-targeted chaperone vaccines including one that was recently evaluated in melanoma patients. We show that short hairpin RNA-mediated SRA silencing significantly enhances the immunogenicity of DCs that have captured chaperone vaccines designed to target melanoma (i.e., hsp110-gp100) and breast cancer (i.e., hsp110-HERNeu-ICD). SRA downregulation results in heightened activation of antigen-specific T cells and increased CD8

Locoregional treatment of

Approximately 6% of metastatic breast cancers arise

Review of the status of neoadjuvant therapy in HER2-positive breast cancer.

The development of human epidermal growth factor receptor 2 (HER2)-directed therapies has revolutionized the treatment of HER2-positive breast cancer. The aim of this article is to review the continually evolving treatment strategies in the neoadjuvant setting of HER2-positive breast cancer, as well as the current challenges and future perspectives. Searches were undertaken on PubMed and Clinicaltrials.gov for relevant publications and trials. The current standard of care in high-risk HER2-positive breast cancer is to combine chemotherapy with dual anti-HER2 therapy, for a synergistic anti-tumor effect. We discuss the pivotal trials which led to the adoption of this approach, as well as the benefit of these neoadjuvant strategies for guiding appropriate adjuvant therapy. De-escalation strategies are currently being investigated to avoid over treatment, and aim to safely reduce chemotherapy, while optimizing HER2-targeted therapies. The development and validation of a reliable biomarker is essential to enable these de-escalation strategies and personalization of treatment. In addition, promising novel therapies are currently being explored to further improve outcomes in HER2-positive breast cancer.

The efficacy and safety of epirubicin and cyclophosphamide combined with pyrotinib in neoadjuvant treatment for HER2-positive breast cancer A real-world study.

Long-term survival benefit of anthracyclines for human epidermal growth factor receptor 2 (HER2)-positive breast cancer is clear. In the neoadjuvant treatment, compared with the monoclonal antibody such as trastuzumab and pertuzumab, the clinical benefit of pyrotinib, a new small-molecule tyrosine kinase inhibitor (TKI), as the main anti-HER2 strategy currently requires more research to determine. Our real-world study is the first prospective observational study in China to evaluate the efficacy and safety of epirubicin (E) and cyclophosphamide (C) with pyrotinib as anti-HER2 therapy in the neoadjuvant setting of patients with stage II-III HER2-positive breast cancer. From May 2019 to December 2021, 44 untreated patients with HER2-positive nonspecific invasive breast cancer who received 4 cycles of neoadjuvant EC with pyrotinib. The primary endpoint was pathological complete response (pCR) rate. Secondary endpoints included the overall clinical response, breast pathological complete response rate (bpCR), the rate of axillary lymph nodes pathological negativity and adverse events (AEs). Other objective indicators were the rate of surgical breast-conserving, the negative conversion ratios of tumor markers. Thirty-seven (84.1%) of 44 patients completed this neoadjuvant therapy, and 35 (79.5%) had surgery and were included in the primary endpoint assessment. The objective response rate (ORR) of 37 patients was 97.3%. Two patients reached clinical complete response, 34 obtained clinical partial response, 1 sustained stable disease, and no one had progressive disease. Eleven (31.4%) of 35 patients who had surgery achieved bpCR and the rate of axillary lymph nodes pathological negativity was 61.3%. The tpCR rate was 28.6% (95% CI 12.8-44.3%). Safety was evaluated in all 44 patients. Thirty-nine (88.6%) had diarrhea, and 2 developed grade 3 diarrhea. Four (9.1%) patients had grade 4 leukopenia. All grade 3-4 AEs could be improved after symptomatic treatment. The regimen of 4 cycles of EC combined with pyrotinib presented some feasibility in the neoadjuvant setting for HER2-positive breast cancer with manageable safety. New regimens with pyrotinib should be evaluated for higher pCR in future. chictr.org Identifier ChiCTR1900026061.

Personalized Injury Reduction Strategies in Sports Medicine Lessons Learned from Advances in Breast Cancer Treatment A Clinical Commentary.

Injury rates across sport have risen over the past twenty years, despite increased efforts in training and injury prevention. The rise in injury rates suggest that current approaches to estimating injury risk and risk management are not effective. One factor limiting progress is the inconsistency in screening, risk assessment, and risk management strategies to guide injury mitigation approaches. How can sports physical therapists identify and apply lessons learned from other healthcare fields to improve athlete injury risk and risk management strategies Breast cancer mortality has consistently decreased over the last 30 years, largely attributed to advances in personalizing the prevention and treatment strategies which include modifiable and non-modifiable factors when assessing risk, the transition to personalized medicine, and the systematic approach used to investigate individual risk factors. Three critical phases have facilitated the identification and importance of individual risk factors and developing targeted, personalized strategies for breast cancer risk including 1) Establishing the potential relationship between factors and outcomes 2) Prospectively investigate the strength and direction of the relationship 3) Investigating if intervening on identified factors alters prognosis. Applying lessons learned from other healthcare fields could improve shared decision making between the clinician and athlete concerning risk assessment and management. Examples include calculating only non-modifiable risk, creating individualized screening schedules based on risk assessment, or calculating the influence of each intervention on the athletes injury risk. A systematic approach to identify and intervene on risk is needed to improve athlete outcomes.

Long-term Health Risks of Cancer in Ukraine Insights from the 2011 Fukushima Triple Disaster Experience.

The ongoing Russo-Ukrainian War and the Great East Japan Earthquake and the subsequent accident at the Fukushima Daiichi Nuclear Power Plant in Japan have many similarities, such as mass evacuation, family separation, difficulty in accessing necessary medical care, and reduced health priorities. Although several studies have reported concerns about the short-term health impacts of the war on patients with cancer, little has been noted about the long-term effects it may cause. Given the experience of the Fukushima accident, it is important to establish a long-term support system for patients with cancer in Ukraine.

Exploring Predictive Risk Factors of Infusion Reactions with First Pertuzumab Administration in HER2-positive Breast Cancer Patients A Single Institution Experience.

Pertuzumab and trastuzumab are monoclonal antibodies used for treating HER2-positive breast cancer. These anti-HER2 antibodies may induce infusion reactions (IR), mainly upon first administration. We investigated factors predicting IR in the initial pertuzumab treatment for HER2-positive breast cancer. We retrospectively reviewed the medical records of 57 patients who first received pertuzumab-containing treatment in our hospital from January 2014 to February 2021. The frequency of IR during or immediately after pertuzumab administration was examined. We also analyzed patient characteristics that may represent possible risk factors for IR. The incidence rate of IR was 44% (2557). Red blood cell count (P < 0.001), hemoglobin (Hb) concentration (P 0.0011), and hematocrit (P < 0.001) immediately before pertuzumab administration were significantly lower in patients with IR than in those without. In patients with IR, erythrocyte levels immediately before pertuzumab treatment were significantly lower than baseline when having received anthracycline-containing chemotherapy within three months. Logistic regression analysis showed that a decrease in Hb levels was a significant risk factor for IR (log odds ratio -17). According to the receiver-operating characteristic analysis, a 10% decrease in Hb after anthracycline-containing treatment was the best cut-off value for predicting IR (sensitivity 88% specificity 77% area under the curve 0.87). Our study showed a higher incidence of IR after pertuzumab treatment than in clinical trials. There was a strong association between IR occurrence and erythrocyte levels lower than baseline in the group that received anthracycline-containing chemotherapy immediately before.

Cancer-associated fibroblasts The chief architect in the tumor microenvironment.

Stromal heterogeneity of tumor microenvironment (TME) plays a crucial role in malignancy and therapeutic resistance. Cancer-associated fibroblasts (CAFs) are one of the major players in tumor stroma. The heterogeneous sources of origin and subsequent impacts of crosstalk with breast cancer cells flaunt serious challenges before current therapies to cure triple-negative breast cancer (TNBC) and other cancers. The positive and reciprocal feedback of CAFs to induce cancer cells dictates their mutual synergy in establishing malignancy. Their substantial role in creating a tumor-promoting niche has reduced the efficacy of several anti-cancer treatments, including radiation, chemotherapy, immunotherapy, and endocrine therapy. Over the years, there has been an emphasis on understanding CAF-induced therapeutic resistance in order to enhance cancer therapy results. CAFs, in the majority of cases, employ crosstalk, stromal management, and other strategies to generate resilience in surrounding tumor cells. This emphasizes the significance of developing novel strategies that target particular tumor-promoting CAF subpopulations, which will improve treatment sensitivity and impede tumor growth. In this review, we discuss the current understanding of the origin and heterogeneity of CAFs, their role in tumor progression, and altering the tumor response to therapeutic agents in breast cancer. In addition, we also discuss the potential and possible approaches for CAF-mediated therapies.

Inhibitors of Interleukin 4 Induced Protein 1 (IL4I1) as Potential Treatment for Cancer.

The invention in this patent application relates to piperazine-2,3-dione derivatives represented generally by formula 1. These compounds show activities as selective interleukin 4 induced protein 1 (IL4I1) inhibitors and may potentially be useful in preventing and treating IL4Il-related diseases, such as endometrial, ovarian, and triple negative breast cancers.

Suppression of GCH1 Sensitizes Ovarian Cancer and Breast Cancer to PARP Inhibitor.

Breast and ovarian cancers are common malignancies among women, contributing to a significant disease burden, and are characterized by a high level of genomic instability, owing to the failure of homologous recombination repair (HRR). Pharmacological inhibition of poly(ADP-ribose) polymerase (PARP) could elicit the synthetic lethal effect of tumor cells in patients with homologous recombination deficiency, ultimately achieving a favorable clinical benefit. However, primary and acquired resistance remain the greatest hurdle, limiting the efficacy of PARP inhibitors thus, strategies conferring or augmenting tumor cell sensitivity to PARP inhibitors are urgently required. Our RNA-seq data of niraparib-treated and -untreated tumor cells were analyzed by R language. Gene Set Enrichment Analysis (GSEA) was applied to assess the biological functions of GTP cyclohydrolase 1 (GCH1). Quantitative real-time PCR, Western blotting, and immunofluorescence were applied to confirm the upregulation of GCH1 upon niraparib treatment at transcriptional and translational levels. Immunohistochemistry of patient-derived xenograft (PDX)-derived tissue sections further validated that niraparib increased GCH1 expression. Tumor cell apoptosis was detected by flow cytometry, while the superiority of the combination strategy was confirmed in the PDX model. The expression of GCH1 was aberrantly enriched in breast and ovarian cancers and increased after niraparib treatment via JAK-STAT signaling. GCH1 was also demonstrated to be associated with the HRR pathway. Subsequently, the enhancement of the tumor-killing effect of PARP inhibitors induced by GCH1 suppression using siRNA and GCH1 inhibitor was validated by flow cytometry in vitro. Finally, using the PDX model, we further demonstrated that GCH1 inhibitors markedly potentiated PARP inhibitors antitumor efficacy in vivo. Our results illustrated that PARP inhibitors promote GCH1 expression via the JAK-STAT pathway. We also elucidated the potential relationship between GCH1 and the homologous recombination repair pathway and proposed a combination regimen of GCH1 suppression with PARP inhibitors in breast and ovarian cancers.

Overexpression of PKMYT1 associated with poor prognosis and immune infiltration may serve as a target in triple-negative breast cancer.

Breast cancer (BC) is one of the most common malignancies among women worldwide. It is necessary to search for improvement in diagnosis and treatment methods to improve the prognosis. Protein kinase, membrane associated tyrosinethreonine 1 (PKMYT1), a member of the Wee family of protein kinases, has been studied in some tumors except BC. This study has explored that PKMYT1 functional role by bioinformatics methods combined with local clinical samples and experiments. Comprehensive analysis showed that PKMYT1 expression was higher in BC tissues, especially in advanced patients than that in normal breast tissues. The expression of PKMYT1 was an independent determinant for BC patients prognosis when combined with the clinical features. In addition, based on multi-omics analysis, we found that the PKMYT1 expression was closely relevant to several oncogenic or tumor suppressor gene variants. The analysis of single-cell sequencing indicated that PKMYT1 expression was upregulated in triple-negative breast cancer (TNBC), consistent with the results of bulk RNA-sequencing. High PKMYT1 expression was correlated with a poor prognosis. Functional enrichment analysis revealed that PKMYT1 expression was associated with cell cycle-related, DNA replication-related, and cancer-related pathways. Further research revealed that PKMYT1 expression was linked to immune cell infiltration in the tumor microenvironment. Additionally, loss-of-function experiments

Predictors of surgical site infection following reconstructive flap surgery A multi-institutional analysis of 37,177 patients.

Rates of surgical site infection (SSI) following reconstructive flap surgeries (RFS) vary according to flap recipient site, potentially leading to flap failure. This is the largest study to determine predictors of SSI following RFS across recipient sites. The National Surgical Quality Improvement Program database was queried for patients undergoing any flap procedure from years 2005 to 2020. RFS involving grafts, skin flaps, or flaps with unknown recipient site were excluded. Patients were stratified according to recipient site breast, trunk, head and neck (HN), upper and lower extremities (UELE). The primary outcome was the incidence of SSI within 30 days following surgery. Descriptive statistics were calculated. Bivariate analysis and multivariate logistic regression were performed to determine predictors of SSI following RFS. 37,177 patients underwent RFS, of whom 7.5% ( Longer operating time was a significant predictor of SSI regardless of reconstruction site. Reducing operating times through proper surgical planning might help mitigate the risk of SSI following RFS. Our findings should be used to guide patient selection, counseling, and surgical planning prior to RFS.

Model-based prediction of effective target exposure for MEN1611 in combination with trastuzumab in HER2-positive advanced or metastatic breast cancer patients.

MEN1611 is a novel orally bioavailable PI3K inhibitor currently in clinical development for patients with HER2-positive (HER2) PI3KCA mutated advancedmetastatic breast cancer (BC) in combination with trastuzumab (TZB). In this work, a translational model-based approach to determine the minimum target exposure of MEN1611 in combination with TZB was applied. First, pharmacokinetic (PK) models for MEN1611 and TZB in mice were developed. Then, in vivo tumor growth inhibition (TGI) data from seven combination studies in mice xenograft models representative of the human HER2 BC non-responsive to TZB (alterations of the PI3KAkTmTOR pathway) were analyzed using a PK-pharmacodynamic (PD) TGI model for co-administration of MEN1611 and TZB. The established PK-PD relationship was used to quantify the minimum effective MEN1611 concentration, as a function of TZB concentration, needed for tumor eradication in xenograft mice. Finally, a range of minimum effective exposures for MEN1611 were extrapolated to patients with BC, considering the typical steady-state TZB plasma levels in patients with BC following three alternative regimens (i.v. 4 mgkg loading dose 2 mgkg q1w, i.v. 8 mgkg loading dose 6 mgkg q3w or s.c. 600 mg q3w). A threshold of about 2000 ng·hml for MEN1611 exposure associated with a high likelihood of effective antitumor activity in a large majority of patients was identified for the 3-weekly and the weekly i.v. schedule for TZB. A slightly lower exposure (i.e., 25% lower) was found for the 3-weekly s.c. schedule. This important outcome confirmed the adequacy of the therapeutic dose administered in the ongoing phase 1b B-PRECISE-01 study in patients with HER2 PI3KCA mutated advancedmetastatic BC.

Streptococcus agalactiae pyomyositis in a patient with primary biliary cholangitis A case report.

Pyomyositis is an uncommon clinical scenario it is usually associated with predisposing factors, including poorly controlled diabetes mellitus, trauma history, and immunocompromise. We discuss the case of an elderly woman with a 20-year history of diabetes mellitus and remissive breast cancer after modified radical mastectomy and subsequent chemotherapy 28 years previously. The patient presented with severe shoulder pain and gradual swelling. After examination, pyomyositis was diagnosed and debridement surgery was performed. Culture of the wound samples showed the growth of Streptococcus agalactiae. During hospitalization, primary biliary cholangitis (PBC) was diagnosed incidentally, accompanied by poor glycemic control. After treatment with antibiotics for pyomyositis and ursodeoxycholic acid for PBC, the infection resolved in 8 weeks, and her glycemic control was improved after PBC treatment. It is possible that the long-term untreated PBC worsened insulin resistance and aggravated diabetes mellitus in this patient. To the best of our knowledge, this is the first reported case of pyomyositis caused by an unusual pathogen, S. agalactiae, in a patient with newly diagnosed PBC.

Prevalence and correlates of modifiable risk factors for cervical cancer and HPV infection among senior high school students in Ghana a latent class analysis.

While health risk behaviours are likely to co-occur, there is dearth of studies exploring the clustering of cervical cancer and HPV infection risk factors among adolescents. This study aimed to determine 1) the prevalence of modifiable risk factors for cervical cancer and HPV infection, 2) the clustering of modifiable risk factors for cervical cancer and HPV infection, and 3) factors associated with the identified clusters. Female students (aged 16-24 years, N 2400) recruited from 17 randomly selected senior high schools in the Ashanti Region, Ghana completed a questionnaire assessing modifiable risk factors for cervical cancer and HPV infection including sexual experience, early sexual intercourse (< 18 years), unprotected sex, smoking, sexually transmitted infections (STIs) multiple sexual partners (MSP) and smoking. Latent class analysis explored separate classes of students according to their risk factor profiles for cervical cancer and HPV infection. Latent class regression analysis explored factors associated with latent class memberships. Approximately one in three students (34%, 95%CI 32%-36%) reported exposure to at least one risk factor. Two separate classes emerged high-risk and low-risk (cervical cancer 24% and 76% of students, respectively HPV infection 26% and 74% of students, respectively). Compared to participants in the low-risk classes i) the cervical cancer high-risk class were more likely to report exposure to oral contraceptives early sexual intercourse (< 18 years) STIs MSP and smoking and ii) the HPV infection high risk class were more likely to report exposure to sexual intercourse unprotected sex and MSP. Participants with higher risk factor knowledge had significantly higher odds of belonging to cervical cancer and HPV infection high-risk classes. Participants with greater perceived susceptibility to cervical cancer and HPV infection were more likely to belong to the high-risk HPV infection class. Sociodemographic characteristics and greater perceived seriousness about cervical cancer and HPV infection had significantly lower odds of belonging to both high-risk classes. The co-occurrence of cervical cancer and HPV infection risk factors suggests that a single school-based multi-component risk reduction intervention could concurrently target multiple risk behaviours. However, students in the high risk class may benefit from more complex risk reduction interventions.

A systematic review and meta-analysis of psychosocial interventions for immigrant and limited English proficient cancer patients.

Immigrants, particularly those who are less acculturated and limited English proficient (LEP), often lack access to culturally and linguistically appropriate psychosocial care in cancer survivorship. We sought to determine what psychosocial interventions are available for immigrant andor LEP cancer patients and to assess treatment and patient factors that may correlate with better psychosocial outcomes for this population. We conducted a systematic review and meta-analysis of studies published through August 2022 of interventions conducted with immigrant andor LEP cancer patients aimed at improving psychosocial outcomes (i.e., quality of life, depression, cancer-related distress, and anxiety). Using Covidence, a software program for systematic review management, four independent raters screened 16,123 records with a systematic process for reconciling disagreement, yielding 48 articles (45 studies) for systematic review and 21 studies for meta-analysis. Most studies were conducted with Spanish-speaking patients with breast cancer. Study participants (N 5400) were primarily middle-aged (mean53 years old), female (90.0%), and Hispanic (67.0%). The weighted average effect size (g) across studies was 0.14 (95% CI 0.03-0.26) for quality of life (18 studies), 0.04 (95% CI -0.08-0.17) for depression (8 studies), 0.14 (95% CI -0.03-0.31) for cancer-related distress (6 studies), and 0.03 (95% CI -0.11-0.16) for anxiety (5 studies). The interventions under review had small but beneficial effects on psychosocial outcomes for immigrant and LEP cancer patients. Notably, effect sizes were smaller than those found in previous meta-analyses of psychosocial interventions conducted in majority U.S.-born, non-Hispanic White, English-speaking cancer patient samples. More research is needed to identify key components and adaptations of interventions that benefit immigrant and LEP cancer patients to strengthen their effects for this growing yet underserved population. This article is protected by copyright. All rights reserved.

Application value of circulating LncRNA in diagnosis, treatment, and prognosis of breast cancer.

Breast cancer is the malignant tumor with the highest incidence in women worldwide. It is highly heterogeneous, has a high incidence of drug resistance, recurrence, and metastasis, and is one of the malignant tumors with the highest mortality rate. The early diagnosis, treatment monitoring, and prognosis assessment of breast cancer are the key factors affecting the survival of patients. However, due to the lack of specific biomarkers, breast cancer is still an essential factor affecting womens quality of life and physical and mental health. Long non-coding RNA can regulate various genes and different signaling pathways and plays an essential role in the occurrence and development of tumors. Recent studies have found that the abnormal expression of circulating long non-coding RNA in serum, saliva, and other biological body fluids plays a significant role in early diagnosis, pathological classification, stage, therapeutic effect monitoring, and prognosis evaluation of breast cancer. This article will review the potential application value of circulating lncRNA in breast cancer.

Efficient breast cancer mammograms diagnosis using three deep neural networks and term variance.

Breast cancer (BC) is spreading more and more every day. Therefore, a patients life can be saved by its early discovery. Mammography is frequently used to diagnose BC. The classification of mammography region of interest (ROI) patches (i.e., normal, malignant, or benign) is the most crucial phase in this process since it helps medical professionals to identify BC. In this paper, a hybrid technique that carries out a quick and precise classification that is appropriate for the BC diagnosis system is proposed and tested. Three different Deep Learning (DL) Convolution Neural Network (CNN) models-namely, Inception-V3, ResNet50, and AlexNet-are used in the current study as feature extractors. To extract useful features from each CNN model, our suggested method uses the Term Variance (TV) feature selection algorithm. The TV-selected features from each CNN model are combined and a further selection is performed to obtain the most useful features which are sent later to the multiclass support vector machine (MSVM) classifier. The Mammographic Image Analysis Society (MIAS) image database was used to test the effectiveness of the suggested method for classification. The mammograms ROI is retrieved, and image patches are assigned to it. Based on the results of testing several TV feature subsets, the 600-feature subset with the highest classification performance was discovered. Higher classification accuracy (CA) is attained when compared to previously published work. The average CA for 70% of training is 97.81%, for 80% of training, it is 98%, and for 90% of training, it reaches its optimal value. Finally, the ablation analysis is performed to emphasize the role of the proposed networks key parameters.

Studying the connection between SF3B1 and four types of cancer by analyzing networks constructed based on published research.

Splicing factor 3B subunit 1 (SF3B1) is the largest component of SF3b protein complex which is involved in the pre-mRNA splicing mechanism. Somatic mutations of SF3B1 were shown to be associated with aberrant splicing, producing abnormal transcripts that drive cancer development andor prognosis. In this study, we focus on the relationship between SF3B1 and four types of cancer, namely myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and chronic lymphocytic leukemia (CLL) and breast cancer (BC). For this purpose, we identified from the Pubmed library only articles which mentioned SF3B1 in connection with the investigated types of cancer for the period 2007 to 2018 to reveal how the connection has developed over time. We left out all published articles which mentioned SF3B1 in other contexts. We retrieved the target articles and investigated the association between SF3B1 and the mentioned four types of cancer. For this we utilized some of the publicly available databases to retrieve genevariantdisease information related to SF3B1. We used the outcome to derive and analyze a variety of complex networks that reflect the correlation between the considered diseases and variants associated with SF3B1. The results achieved based on the analyzed articles and reported in this article illustrated that SF3B1 is associated with hematologic malignancies, such as MDS, AML, and CLL more than BC. We found that different gene networks may be required for investigating the impact of mutant splicing factors on cancer development based on the target cancer type. Additionally, based on the literature analyzed in this study, we highlighted and summarized what other researchers have reported as the set of genes and cellular pathways that are affected by aberrant splicing in cancerous cells.

Targeting mTOR to overcome resistance to hormone and CDK46 inhibitors in ER-positive breast cancer models.

Resistance to therapy remains a major obstacle in cancer management. Although treatment with hormone and CDK46 inhibitors is successful in luminal breast cancer, resistance to these treatments is frequent, highlighting the need for novel therapeutic strategies to delay disease progression and improve patient survival. Here, we assessed the mechanisms of acquired resistance using T47D and MCF-7 tamoxifen- and palbociclib-resistant cell-line variants in culture and as xenografts, and patient-derived cells (PDCs) obtained from sensitive or resistant patient-derived xenografts (PDXs). In these models, we analyzed the effect of specific kinase inhibitors on survival, signaling and cellular aggressiveness. Our results revealed that mTOR inhibition is more effective than PI3K inhibition in overcoming resistance, irrespective of PIK3CA mutation status, by decreasing cell proliferation and tumor growth, as well as reducing cell migration and stemness. Moreover, a combination of mTOR and CDK46 inhibitors may prevent pathway reactivation downstream of PI3K, interfering with the survival of resistant cells and consequent tumor escape. In conclusion, we highlight the benefits of incorporating mTOR inhibitors into the current therapy in ER breast cancer. This alternative therapeutic strategy not only enhances the antitumor response but may also delay the emergence of resistance and tumor recurrence.

Four-year follow-up on fatigue and sleep quality of a three-armed partly randomized controlled study in breast cancer survivors with cancer-related fatigue.

Cancer-related fatigue (CRF) is a frequent long-term symptom in non-metastasized breast cancer patients (BC). This 4-year follow-up intended to compare the long-term effects of a 10-week multimodal therapy (MT sleep education, psychoeducation, eurythmy- and painting therapy) and combination therapy CT MT plus aerobic training (AT) to AT-control. BC-patients were randomized or allocated by preference to three arms in a comprehensive cohort study. Primary outcome was a composite score including Pittsburgh Sleep Quality Index (PSQI) and Cancer Fatigue Scale (CFS-D), captured at baseline, after 10 weeks of intervention (T1), 6 months later (T2), and after 4 years (T3). We exploratively tested for superiority of MT and CT versus AT after 4 years (T3) based on the statistical model of the main analysis. Of 126 (65 randomized) BC-patients included, 105 started treatments and 79 were re-assessed for long-term effects (T3). MT and CT were superior over AT after 4 years regarding PSQICFS-D and PSQI sum-score, respectively (all p < 0.05), but not for CFS-D. The multimodal and combination treatment for breast cancer patients with CRF indicates sustainable long-term superiority over aerobic training for the outcomes sleep quality and combined sleep qualityfatigue. A confirmative randomized controlled trial is warranted.

Cytotoxic and chemomodulatory effects of Phyllanthus niruri in MCF-7 and MCF-7

The members of the genus Phyllanthus have long been used in the treatment of a broad spectrum of diseases. They exhibited antiproliferative activity against various human cancer cell lines. Breast cancer is the most diagnosed cancer and a leading cause of cancer death among women. Doxorubicin (DOX) is an anticancer agent used to treat breast cancer despite its significant cardiotoxicity along with resistance development. Therefore, this study was designed to assess the potential cytotoxicity of P. niruri extracts (and fractions) alone and in combination with DOX against naïve (MCF-7) and doxorubicin-resistant breast cancer cell lines (MCF-7

Two-Dimensional Analysis Method for Highly Sensitive Detection of Dual MicroRNAs in Breast Cancer Cells.

Multiple biomarker detection is crucial for early clinical diagnosis, and it is significant to achieve the simultaneous detection of multiple biomarkers with the same nanomaterial. In this work, the hairpin DNA strands were selectively modified on the surface of gold nanorods (AuNRs) to construct two kinds of nanoprobes by rational design. When in the presence of dual microRNAs, AuNRs were assembled to form end-to-end (ETE) and side-by-side (SBS) dimers. Compared with a single AuNR, the dark-field scattering intensity and red color percentage variation of dimers were extremely distinguished, which could be developed for dual microRNA detection by combining the red color percentage and scattering intensity with the data processing method of principal component analysis to construct a two-dimensional analysis method. Especially, the fraction of AuNR dimers presented a linear relationship with the amount of microRNAs. Based on this, microRNA-21 and microRNA Let-7a in breast cancer cells were detected with the detection limits of 1.72 and 0.53 fM, respectively. This method not only achieved the sensitive detection of dual microRNAs in human serum but also realized the high-resolution intracellular imaging, which developed a new way for the oriented assembly of nanomaterials and biological detection in living cells.

Do Reader Characteristics Affect Diagnostic Efficacy in Screening Mammography A Systematic Review.

To examine reader characteristics associated with diagnostic efficacy in the interpretation of screening mammograms. A systematic search of the literature was conducted using databases such as Cochrane, Scopus, Medline, Embase, Web of Science, and PubMed. Search terms were combined with AND or OR and included Radiologists characteristics AND performance radiologist experience AND screening mammography annual volume read AND diagnostic efficacy screening mammography performance OR diagnostic efficacy. Studies were included if they assessed reader performance in screening mammography interpretation, breast readers, used a reference standard to assess the performance, and were published in the English language. Twenty-eight studies were reviewed. Increasing readers age was associated with lower false positive rates. No association was found between gender and performance. Half of the studies showed no association between years of reading mammograms and performance. Most studies showed that high reading volume was more likely to be associated with increased sensitivity, cancer detection rates (CDR), lower recall rate, and lower false positive rates. Inconsistent associations were found between fellowship training in breast imaging and reader performance. Specialization in breast imaging was associated with better CDR, sensitivity, and specificity. Limited studies were available to establish the association between performance and factors such as time spent in breast imaging (n 2), screening focus (n 1), formal rotation in mammography (n 1), owner of practice (n 1), and practice type (n 1). No individual characteristics is associated with versatility in diagnostic efficacy, albeit reading volume and specialization in breast imaging appear to be associated with with increased sensitivity and CDR without significantly affecting other performance metrics.

Update on Accelerated Whole Breast Irradiation.

Since the advent of breast conservation, adjuvant radiation therapy (RT) has been standard of care following breast conserving surgery (BCS). Radiation therapy following BCS has traditionally been whole breast irradiation (WBI) studies comparing breast conservation to mastectomy utilized standard fractionation WBI, which delivers treatment daily over 5 to 7 weeks (1.8-2 Gyfraction) and was the standard for decades. More recently, multiple randomized trials have compared standard fractionation WBI to moderately hypofractionated WBI (2.66 Gyfraction, 15-16 fractions), which allows for completion of treatment in 3 to 4 weeks. Results have demonstrated no difference in local control between these two approaches with comparable toxicity and cosmetic outcomes with long-term follow-up. As such, moderately hypofractionated WBI represents the standard of care approach for most patients with early-stage breast cancer following BCS at this time. In the past few years, ultra-hypofractionated WBI (5.2-5.7 Gyfraction, 5 fractions) has emerged with promising outcomes 5-year outcomes from the FAST-Forward randomized trial demonstrated noninferiority between ultra-hypofractionated WBI and moderately hypofractionated WBI. Moving forward, long-term outcomes from ultra-hypofractionated WBI studies are expected, as well as the potential for incorporating moderately hypofractionated regimens into patients requiring regional nodal irradiation following BCS. Finally, the advent of ultra-short regimens may allow clinicians to re-evaluate treatment de-intensification in early-stage breast cancer to consider radiation therapy alone following BCS in lieu of endocrine therapy.

Transitioning From the Traditional Wire Localization to the Wireless Technology for Surgical Guidance at Lumpectomies Part A. Radioseed Localization.

Iodine-125 (I-125) labelled radioactive seeds were the first published wireless pre-operative image-guided breast localization technique. Radioseeds offer benefit to radiologists as a relatively intuitive procedure with precise mammographic or sonographic-guided localization and improved patient experience. Localization and surgical dates can be uncoupled, which facilitates efficient scheduling for radiologists and surgeons. Surgeons can better tailor their surgery with intra-operative localization using a special probe to detect the emitted gamma energy. Due to radioactivity, implementation of a radioseed program requires compliance with the National Regulatory Commission and therefore multidisciplinary involvement. Seeds have a high placement success rate, and comparable surgical success and re-excision rate to wires.

Audit of Prior Screening Mammograms of Screen-Detected Cancers Implications for the Delay in Breast Cancer Detection.

When cancer is detected in a screening mammogram, on occasion retrospective review of prior screening (pre-index) mammograms indicates a likely presence of cancer. These missed cancers during pre-index screens constitute a delay in detection and diagnosis. This study was undertaken to quantify the missed cancer rate by auditing pre-index screens to improve the quality of mammography screening practice. From a cohort of 135 screen-detected cancers, 120 pre-index screening mammograms could be retrieved and served as the study sample. A consensus read by 2 radiologists who interpreted the pre-index screens in an unblinded manner with full knowledge of cancer location, cancer type, lesion type, and pathology served as the truth or reference standard. Five radiologists interpreted the pre-index screens in a blinded manner. Established performance metrics such as sensitivity and specificity were quantified for each reader in interpreting these pre-index screens in a blinded manner. All five radiologists detected lesions in 8120 (6.7%) screens. Excluding the 2 readers whose performance was close to random, all the 3 remaining readers detected lesions in 13 pre-index screens. This indicates that there is a delay in diagnosis by at least one cycle from 8120 (6.7%) to 13120 (10.8%). There were no observable trends in terms of either the cancer type or the lesion type. Auditing prior screening mammograms in screen-detected cancers can help in identifying the proportion of cases that were missed during interpretation and help in quantifying the delay in breast cancer detection.

The Current State of Timeliness in the Breast Cancer Diagnosis Journey Abnormal Screening to Biopsy.

There are several steps involved in a breast cancer diagnosis, starting from the initial abnormal screening mammogram. Each step from the additional imaging to a biopsy provokes anxiety. Timely attention to these appointments will not only help allay anxiety but also provide better care. While breast facilities routinely audit their performance, currently timeliness is not one of the audit parameters. The role of timeliness as a robust quality tool is gaining attention. In this study, we review the timeline of care at our facility over a 1-year period (October 2021- September 2022) and compare them with those reported by National Quality Measures for Breast Centers (NQMBC). Race, ethnicity, location, and type of facility affect the outcome of care and contribute to delays in providing care. In this manuscript, we outline some of the major factors. Societal guidelines outlining some metrics for timeliness may be a useful first step.

High-Risk Lesion Management.

High-risk lesions or lesions of uncertain malignant potential are frequent findings on image-guided needle biopsy of the breast and comprise a number of distinct entities. These lesions are known for having risk of underlying malignancy and are usually associated with an increased lifetime risk for breast cancer. Surgical excision was traditionally recommended for all high-risk lesions but recent studies have demonstrated that vacuum-assisted excision or surveillance may be adequate for some lesions. While management of high-risk lesion varies among institutions, this chapter describes the management recommendations based on recent literature of the most frequent types of lesions.

Mammographic Breast Density Current Assessment Methods, Clinical Implications, and Future Directions.

Mammographic breast density is widely accepted as an independent risk factor for the development of breast cancer. In addition, because dense breast tissue may mask breast malignancies, breast density is inversely related to the sensitivity of screening mammography. Given the risks associated with breast density, as well as ongoing efforts to stratify individual risk and personalize breast cancer screening and prevention, numerous studies have sought to better understand the factors that impact breast density, and to develop and implement reproducible, quantitative methods to assess mammographic density. Breast density assessments have been incorporated into risk assessment models to improve risk stratification. Recently, novel techniques for analyzing mammographic parenchymal complexity, or texture, have been explored as potential means of refining mammographic tissue-based risk assessment beyond breast density.

Updates in Transgender Breast Imaging.

Transgender patients are seen in breast imaging centers for routine screening mammography and diagnostic imaging of the symptomatic breast. This comprehensive review of transgender breast imaging aims to update the radiologist on appropriate terminology, breast cancer risk in different patient populations, screening guidelines, and diagnostic scenarios. The chapter concludes with practical tips on how to optimize the patient experience.

Artificial Intelligence in Breast X-Ray Imaging.

This topical review is focused on the clinical breast x-ray imaging applications of the rapidly evolving field of artificial intelligence (AI). The range of AI applications is broad. AI can be used for breast cancer risk estimation that could allow for tailoring the screening interval and the protocol that are woman-specific and for triaging the screening exams. It also can serve as a tool to aid in the detection and diagnosis for improved sensitivity and specificity and as a tool to reduce radiologists reading time. AI can also serve as a potential second reader during screening interpretation. During the last decade, numerous studies have shown the potential of AI-assisted interpretation of mammography and to a lesser extent digital breast tomosynthesis however, most of these studies are retrospective in nature. There is a need for prospective clinical studies to evaluate these technologies to better understand their real-world efficacy. Further, there are ethical, medicolegal, and liability concerns that need to be considered prior to the routine use of AI in the breast imaging clinic.

Savi-Scout Radar Localization Transitioning From the Traditional Wire Localization to Wireless Technology for Surgical Guidance at Lumpectomies.

Breast-conserving surgery or lumpectomy requires localization of the lesion prior to surgery, which is traditionally accomplished by imaging-guided wire localization. Over the last decade, alternatives to wire localization have emerged. This work reviews the literature on one such wireless technology, SaviScout radar (SSR) system, and shares our experience with using this technology for presurgical tumor localization. The SSR surgical guidance system is non-radioactive. The radiologist implants a reflector device in the breast under mammography or ultrasound guidance at any time prior to surgery. The placement of this reflector can be confirmed from the cadence of a handheld percutaneous probe of a handpiece and console system. Results from several studies show that the surgical outcomes from SSR and wire-localization are similar. SSR provides operational advantages as the scheduling for reflector placement by radiologists is decoupled from surgery, but at an increased cost compared to wire-localization.

NIR-II Light Evokes DNA Cross-linking for Chemotherapy and Immunogenic Cell Death.

As a DNA damaging agent, oxaliplatin (OXA) can induce immunogenic cell death (ICD) in tumors to activate the immune system. However, the DNA damage induced by OXA is extremely limited and the ICD effect is not strong enough to enhance anti-tumor efficacy. Here, we propose a strategy to maximize the ICD effect of OXA through the mild hyperthermia generated by nanoparticles with a platinum (IV) prodrug of OXA (Pt(IV)-C16) and a near-infrared-II (NIR-II) photothermal agent IR1061 upon the irradiation of NIR-II laser. The mild hyperthermia (43°C) holds advantages in two aspects 1) increase the Pt-DNA cross-linking, leading to enhanced DNA damage and apoptosis 2) induce stronger ICD effects for cancer immunotherapy. We demonstrated that, compared with OXA and photothermal therapy of IR1061 alone, these nanoparticles under NIR-II light irradiation can significantly improve the anti-cancer efficacy against triple-negative breast cancer 4T1 tumor. This new strategy provides an effective way to improve the therapeutic outcome of OXA. STATEMENT OF SIGNIFICANCE Oxaliplatin could induce immunogenic cell death (ICD) via stimulating immune responses by increasing tumor cell stress and death, which triggers tumor-specific immune responses to achieve immunotherapy. However, due to the insufficient Pt-DNA crosslinks, the ICD effect triggered by oxaliplatin cannot induce robust immune response. Mild hyperthermia has great potential to maximize the therapeutic outcome of oxaliplatin by the following effects 1) increase the Pt-DNA cross-linking, leading to enhanced DNA damage and apoptosis 2) induce stronger ICD effects for cancer immunotherapy.

Tailoring biomimetic dual-redox-responsive nanoplexes for enhanced RNAi-synergized photodynamic cancer immunotherapy.

Despite the strong potential of RNA interference (RNAi) therapies, critical issues, such as poor permeability across biological membranes and efficacy of their delivery into the cytoplasm, remain to be addressed before their successful clinical application. The current study aimed to address these issues by constructing a biomimetic nanoplex with dual redox responsiveness, which is derived from a cationic polymer formed by the condensation of endogenous spermine monomers via diselenide bonds. The developed nanoplexes decomposed in response to the redox microenvironment in cancer cells, thereby avoiding accumulation toxicity and poor transfection efficiency owing to incomplete siRNA release. When co-delivered with siPDL1 and a photosensitizer, the reactive oxygen species generated by irradiated nanoplexes accelerated the cytoplasmic release of siPDL1, which was expected to alleviate the PDT-induced increase in immunosuppressive PD-L1 expression. In a murine model of 4T1 xenografted breast cancer, the fabricated macrophage membrane (MPM)-camouflaged nanoplexes with payloads boosted antitumor immune responses in situ through a self-synergistic immunogenic cell death induced by photodynamic therapy (PDT). Overall, the study reported a new strategy for harnessing photodynamic immunotherapy for treating immunologically cold tumors. STATEMENT OF SIGNIFICANCE This study provides a biomimetic nanoplex with dual redox responsiveness, which is derived from a novel cationic polymer formed by the condensation of endogenous spermine monomers through diselenide bonds. The developed nanoplex disassembles according to the redox microenvironment in cancer cells, thereby avoiding accumulation toxicity and poor transfection efficiency due to incomplete siRNA release. When co-delivery of siPDL1 and photosensitizer in vivo, the ROS generated by irradiated nanoplexes accelerated the cytoplasmic release of siPDL1, and which is expected to alleviate PDT-induced increase in immunosuppressive PD-L1 expression, thereby boosting antitumor immune responses in situ through a self-synergistic immunogenic cell death induced by PDT. Our findings reveal a new strategy of harnessing photodynamic immunotherapy therapy toward immunologically cold tumors.

Targeted Tumor Killing by Pomegranate Polyphenols Pro-oxidant Role of a Classical Antioxidant.

One of the key biochemical features that distinguish a cancer cell from normal cells is its persistent pro-oxidative state that leads to intrinsic oxidative stress. Malignant cells have evolved sophisticated adaptation systems that involve high dependency on antioxidant functions and upregulation of pro-survival molecules to counteract the deleterious effects of reactive species and to maintain dynamic redox balance. This situation renders them vulnerable to further oxidative challenge by exogenous agents. In the present study, we advocated that pomegranate polyphenols act as pro-oxidants and trigger ROS-mediated apoptosis in cancer cells. With the help of both in vitro and in vivo models, we have established that pomegranate fruit extract (PFE) can cause significant reduction in tumor proliferation while leaving normal tissues and cells unharmed. Administration of PFE (0.2% vv) in EAC-bearing mice for 3 weeks, inhibited Nrf2-ARE signaling cascade, increased intracellular ROS content, altered GSH cycle thereby activating ROS-induced apoptotic pathway in EAC cells. Moreover, PFE mitigated epithelial to mesenchymal transition (EMT) and migration in triple negative breast cancer cells (MDA-MB 231 cells) by down-regulating NF-κB. Pre-treatment of tumor cells with N-acetyl cysteine (NAC) protected these cells from undergoing PFE-induced apoptosis while siRNA-mediated silencing of Nrf2 and NF-κB in tumor cells increased the cytotoxic potential and pro-oxidative activity of PFE, indicating a clear role of these transcription factors in orchestrating the anti-cancerpro-oxidative properties of PFE. The seminal findings provided may be exploited to develop potential therapeutic targets for selective killing of malignant cells.

A Review of Biological Targets and Therapeutic Approaches in the Management of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous, aggressive phenotype of breast cancer with associated chemoresistance. The development of chemo- or radioresistance could be attributed to diverse tumor microenvironments, overexpression of membrane proteins (transporters), epigenetic changes, and alteration of the cell signaling pathwaysgenes associated with the development of cancer stem cells (CSCs). Due to the diverse and heterogeneous nature of TNBC, therapeutic response to the existing modalities offers limited scope and thus results in reccurance after therapy. To establish landmark therapeutic efficacy, a number of novel therapeutic modalities have been proposed. In addition, reversal of the resistance that developed during treatment may be altered by employing appropriate therapeutic modalities. This review aims to discuss the plethora of investigations carried out, which will help readers understand and make an appropriate choice of therapy directed toward complete elimination of TNBC. Key Scientific Concepts of Review This manuscript addresses the major contributory factors from the tumor microenvironment that are responsible for the development of chemoresistance and poor prognosis. The associated cellular events and molecular mechanism-based therapeutic interventions have been explained in detail. Inhibition of ABC transporters, cell signaling pathways associated with CSCs, and epigenetic modification offers promising results in this regard. TNBC progression, invasion, metastasis and recurrence can also be inhibited by blocking multiple cell signaling pathways, targeting specific receptorsepigenetic targets, disrupting bioenergetics and generating reactive oxygen species (ROS).

Probabilistic risk assessment of residential exposure to metal(loid)s in a mining impacted community.

The Gold Country region of California is impacted by legacy and active gold mines. Concomitantly, Gold Country has an increased rate of female breast cancer relative to the state average. Using community-based participatory research methods, 40 participants completed surveys and collected a total of 354 water, soil, home-grown foods, and dust samples from their homes, which we compared to state, federal, and international contamination standards for arsenic, cadmium, and lead. All soil samples exceeded U.S. EPA and California EPA soil standards for arsenic. When comparing other media to state, federal and international standards for arsenic, cadmium, and lead, 15 additional exceedances for indooroutdoor dust, drinking water, andor vegetable were documented. A probabilistic risk assessment was conducted to determine an adult females exposure to arsenic, cadmium, and lead and estimated risk. Arsenic exposure, due largely to water (63.5 %) and homegrown food (33.3 %), presents carcinogenic risks in excess of the EPA recommended upper limit for contaminated sites (1 × 10

Factors Associated With False-Positive Recalls in Mammography Screening.

We aimed to identify factors associated with false-positive recalls in mammography screening compared with women who were not recalled and those who received true-positive recalls. We included 29,129 women, aged 40 to 74 years, who participated in the Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) between 2011 and 2013 with follow-up until the end of 2017. Nonmammographic factors were collected from questionnaires, mammographic factors were generated from mammograms, and genotypes were determined using the OncoArray or an Illumina custom array. By the use of conditional and regular logistic regression models, we investigated the association between breast cancer risk factors and risk models and false-positive recalls. Women with a history of benign breast disease, high breast density, masses, microcalcifications, high Tyrer-Cuzick 10-year risk scores, KARMA 2-year risk scores, and polygenic risk scores were more likely to have mammography recalls, including both false-positive and true-positive recalls. Further analyses restricted to women who were recalled found that women with a history of benign breast disease and dense breasts had a similar risk of having false-positive and true-positive recalls, whereas women with masses, microcalcifications, high Tyrer-Cuzick 10-year risk scores, KARMA 2-year risk scores, and polygenic risk scores were more likely to have true-positive recalls than false-positive recalls. We found that risk factors associated with false-positive recalls were also likely, or even more likely, to be associated with true-positive recalls in mammography screening.

In silico and biological activity evaluation of quercetin-boron hybrid compounds, anti-quorum sensing effect as alternative potential against microbial resistance.

Boronic acid compounds and the natural flavonoid compound quercetin were handled to synthesize two novel ligands encoded as B1(2,2-(1,4-phenylenebis (benzo 1,3,2 dioxaborole-2,5-diyl)) bis (3,5,7-trihydroxy-4H- chromen-4-one) and B2(3.3.6. 3,5,7-trihydroxy-2-(2-(6-methoxypyridin-3-yl)benzod1,3,2dioxaborol-5-yl)- 4 H-chromene-4). Antioxidant activities of ligands were investigated by DPPH, ABTS and CUPRAC methods. Cholinesterase inhibition effects of ligands were determined by acetylcholinesterase and butyrylcholinesterase enzyme inhibition methods, cytotoxic effects of ligands were applied to healthy breast and colon cancer cell lines by MTT method, and urease and tyrosinase enzyme activities were determined. Antimicrobial properties of the compounds were analyzed by detecting their anti-QS potentials on Chromobacterium violaceum biosensor strain. Both compounds were found to have significant antioxidant effects compared to controls. It was determined that the compound B1 at 1-10 µgmL was more active than the reference compounds (α-TOC and BHT). Moreover, the enzyme activity studies on ligands demonstrated that acetylchoinesterase and butyrylcholinesterase enzyme inhibitions were higher than the reference compounds. As expected, boron derivatives exhibited respectable activity against the biofilms of Escherichia coli (E. coli) and P. aeruginosa (P. aeruginosa). These results demonstrate the potential applicability of boron derivatives in the treatment of biofilm-associated infections and provide a practical strategy for the design of new boron-based antimicrobial materials. In silico molecular docking studies were performed on ligands to identify newly synthesized compounds. The binding parameter values and binding sites of the compounds were also determined. In conclusion, our studies showed that newly synthesized hybrid compounds could be solutions for antimicrobial resistance and enzyme-related disorders.

Identification of a luminescent platinum(II) complex with BODIPY derivative as novel photodynamic therapy agent for triple negative breast cancer cells.

Triple-negative breast cancer (TNBC) is one of the most malignant breast tumors for its poor prognosis and high tumor recurrence. It is urgent to develop new strategy or effective agents to overcome resistance and improve therapeutic effectiveness. Boron-dipyrromethene (BODIPY) based photosensitizers possess exciting photophysical features suitable for theranostic applications, namely, photodynamic therapy (PDT). We have designed a luminescent monofunctional platinum(II) complex with BODIPY derivative, namely I

Multi-frequency shear modulus measurements discriminate tumorous from healthy tissues.

As far as their mechanical properties are concerned, cancerous lesions can be confused with healthy surrounding tissues in elastography protocols if only the magnitude of moduli is considered. We show that the frequency dependence of the tissues mechanical properties allows for discriminating the tumor from other tissues, obtaining a good contrast even when healthy and tumor tissues have shear moduli of comparable magnitude. We measured the shear modulus G

Near-infrared photoimmunotherapy (NIR-PIT) of bone metastases.

The bones are a common site for metastasis arising from solid tumors such as breast and prostate cancer. Chemotherapy, including immunotherapy, is rarely curative. Radiotherapy with pain palliation can temporize bone metastases but is generally considered a short-term solution and retreatment is difficult. Surgery is often necessary, yet recovery times might exceed life expectancy. Therefore, there is a need to develop new approaches to bone metastases that are effective but minimally invasive. Near-infrared photoimmunotherapy (NIR-PIT) uses antibodies labeled with IRDye700DX (IR700) which is activated by NIR light, resulting in rapid cell membrane damage and immunogenic cell death. NIR-PIT using an anti-epidermal growth factor receptor (EGFR) antibody-IR700 conjugate in patients with recurrent head and neck cancer received qualified approval in Japan in 2020 and is now widely used there. However, no bone metastases have yet been treated. In this study, the efficacy of NIR-PIT for bone metastases was investigated using a bone metastases mouse model successfully established by caudal artery injection of a human triple-negative breast cancer cell line, MDAMB468-GFPluc. The bone metastatic lesions were treated with NIR-PIT using the anti-EGFR antibody, panitumumab-IR700 conjugate. Bioluminescence imaging and histological evaluation showed that EGFR-targeted NIR-PIT has a therapeutic effect on bone metastatic lesions in mice. In addition, micro-CT showed that repeated NIR-PIT led to repair of metastasis-induced bone destruction and restored bone cortex continuity consistent with healing. These data suggest that NIR-PIT has the potential for clinical application in the treatment of bone metastases.

The role of hypoxia-inducible factors in breast cancer stem cell specification.

Breast tumor is heterogeneous cancer with high morbidity and mortality rates, particularly in developing countries. Despite new efforts to reduce the breast cancer implications, the number of newly diagnosed cases is increasing worldwide. It is believed that cancer stem cells (CSCs) are responsible for the implication of cancers including breast cancer. Although CSCs compose a small population in tumor bulks, they play a crucial role in tumor initiation, progression, metastasis, and chemotherapeutic resistance. These events are mediated by the hypoxia-inducible factor (HIF) pathway which regulates the transcription of genes involved in CSC maintenance and tumorigenesis. In this review, we discussed the mechanisms by which hypoxia- or chemotherapy-induced HIFs promote breast CSC specification.

Amyloid fibril-based thixotropic hydrogels for modeling of tumor spheroids in vitro.

Biomaterials mimicking extracellular matrices (ECM) for three-dimensional (3D) cultures have gained immense interest in tumor modeling and in vitro organ development. Here, we introduce a new class of amyloid fibril-based peptide hydrogels as a versatile biomimetic ECM scaffold for 3D cell culture and homogenous tumor spheroid modeling. We show that these amyloid fibril-based hydrogels are thixotropic and allow cancer cell adhesion, proliferation, and migration. All seven designed hydrogels support 3D cell culture with five different cancer cell lines forming spheroid with necrotic core and upregulation of the cancer biomarkers. We further developed the homogenous, single spheroid using the drop cast method and the data suggest that all hydrogels support the tumor spheroid formation but with different necrotic core diameters. The detailed gene expression analysis of MCF7 spheroid by microarray suggested the involvement of pro-oncogenes and significant regulatory pathways responsible for tumor spheroid formation. Further, using breast tumor tissue from a mouse xenograft model, we show that selected amyloid hydrogels support the formation of tumor spheroids with a well-defined necrotic core, cancer-associated gene expression, higher drug resistance, and tumor heterogeneity reminiscent of the original tumor. Altogether, we have developed an easy-to-use, rapid, cost-effective, and scalable platform for generating in vitro cancer models for the screening of anti-cancer therapeutics and developing personalized medicine.

Dual kinase inhibitor for EGFR mutants and ErbB2 limit breast cancer.

Mutations in the epidermal growth factor receptor (EGFR) have been found in more than 10% of non-small cell lung cancer (NSCLC) patients in North America. The vast majority of these differences are L858R point mutations in Exon 21. Currently, monoclonal antibodies directed against the extracellular domain of EGFR or small moleculetyrosine kinase inhibitors (TKI) are the stalwarts of NSCLC therapy. Resistance, however, gradually develops because of the T790 mutation towards first and second generation TKIs. The third generation TKI AZD9291 (Osimertinib) has a high affinity for both activating and the acquired resistant mutation (T790 M) in EGFR, with a low affinity towards wild-type EGFR. Recent research, however, suggests that the EGFR (C797S) mutation in the tyrosine kinase domain is a likely cause of resistance to AZD9291. Another significant transformation mechanism associated with this resistance is erbB2 amplification. Our laboratory has developed a small kinase inhibitor, ER121 (MW ∼500), that inhibits the erbB2HER2 tyrosine kinases in addition to the EGFR C797S mutations. We have identified a TKI, ER121 targeting the mutant EGFR(T790 M). Using in vitro and in vivo models, examined the efficacy of ER121 on mutant EGFR cell lines. This has enabled us to establish that ER121 is well tolerated when administered orally and produces significant inhibitory activity against human cancers generated by mutant EGFR and amplified ErbB2.

Quantitative Characterization of Clinically Relevant Drug-Metabolizing Enzymes and Transporters in Rat Liver and Intestinal Segments for Applications in PBPK Modeling.

Rats are extensively used as a preclinical model for assessing drug pharmacokinetics (PK) and tissue distribution however, successful translation of the rat data requires information on the differences in drug metabolism and transport mechanisms between rats and humans. To partly fill this knowledge gap, we quantified clinically relevant drug-metabolizing enzymes and transporters (DMETs) in the liver and different intestinal segments of Sprague-Dawley rats. The levels of DMET proteins in rats were quantified using the global proteomics-based total protein approach (TPA) and targeted proteomics. The abundance of the major DMET proteins was largely comparable using quantitative global and targeted proteomics. However, global proteomics-based TPA was able to detect and quantify a comprehensive list of 66 DMET proteins in the liver and 37 DMET proteins in the intestinal segments of SD rats without the need for peptide standards. Cytochrome P450 (Cyp) and UDP-glycosyltransferase (Ugt) enzymes were mainly detected in the liver with the abundance ranging from 8 to 6502 and 74 to 2558 pmolg tissue. P-gp abundance was higher in the intestine (124.1 pmolg) as compared to that in the liver (26.6 pmolg) using the targeted analysis. Breast cancer resistance protein (Bcrp) was most abundant in the intestinal segments, whereas organic anion transporting polypeptides (Oatp) 1a1, 1a4, 1b2, and 2a1 and multidrug resistance proteins (Mrp) 2 and 6 were predominantly detected in the liver. To demonstrate the utility of these data, we modeled digoxin PK by integrating protein abundance of P-gp and Cyp3a2 into a physiologically based PK (PBPK) model constructed using PK-Sim software. The model was able to reliably predict the systemic as well as tissue concentrations of digoxin in rats. These findings suggest that proteomics-informed PBPK models in preclinical species can allow mechanistic PK predictions in animal models including tissue drug concentrations.

Clinical Features and Outcomes of Triple-Negative Breast Cancer Among Latin American Adolescents and Young Adults Compared to Middle-Aged and Elder Females A Cohort Analysis Over 15 Years.

The liver kinase B1 supports mammary epithelial morphogenesis by inhibiting critical factors that mediate epithelial-mesenchymal transition.

The liver kinase B1 (LKB1) controls cellular metabolism and cell polarity across species. We previously established a mechanism for negative regulation of transforming growth factor β (TGFβ) signaling by LKB1. The impact of this mechanism in the context of epithelial polarity and morphogenesis remains unknown. After demonstrating that human mammary tissue expresses robust LKB1 protein levels, whereas invasive breast cancer exhibits significantly reduced LKB1 levels, we focused on mammary morphogenesis studies in three dimensional (3D) acinar organoids. CRISPRCas9-introduced loss-of-function mutations of STK11 (LKB1) led to profound defects in the formation of 3D organoids, resulting in amorphous outgrowth and loss of rotation of young organoids embedded in matrigel. This defect was associated with an enhanced signaling by TGFβ, including TGFβ auto-induction and induction of transcription factors that mediate epithelial-mesenchymal transition (EMT). Protein marker analysis confirmed a more efficient EMT response to TGFβ signaling in LKB1 knockout cells. Accordingly, chemical inhibition of the TGFβ type I receptor kinase largely restored the morphogenetic defect of LKB1 knockout cells. Similarly, chemical inhibition of the bone morphogenetic protein pathway or the TANK-binding kinase 1, or genetic silencing of the EMT factor SNAI1, partially restored the LKB1 knockout defect. Thus, LKB1 sustains mammary epithelial morphogenesis by limiting pathways that promote EMT. The observed downregulation of LKB1 expression in breast cancer is therefore predicted to associate with enhanced EMT induced by SNAI1 and TGFβ family members.

Brain network deficits in breast cancer patients after early neoadjuvant chemotherapy A longitudinal MRI study.

Breast cancer (BC) patients who undergo chemotherapy are likely to develop chemotherapy-related cognitive impairment (CRCI). Recent studies of BC patients after chemotherapy have used graph theory to investigate the topological properties of the brain functional connectome. However, little is known about structural morphological networks in BC patients after early neoadjuvant chemotherapy (NAC). Brain morphological network organization in 47 female participants with BC was investigated before and after NAC. Topological properties of brain networks were ascertained based on morphological similarities in regional gray matter using a graph theory approach based on 3D T1-weighted MRI data. Nonparametric permutation testing was used to assess longitudinal-group differences in topological metrics. Compared with BC patients before NAC, BC patients after early NAC showed significantly increased global efficiency (p .048), decreased path length (p .033), and abnormal nodal properties and connectivity, mainly located in the central executive network (CEN). The change in the network efficiency of the right caudate was negatively correlated with the change in the Self-Rating Anxiety Scale score (r -.435, p .008), and the change in the nodal degree of the left superior frontal gyrus (dorsolateral part) was positively correlated with the change in the Functional Assessment of Cancer Therapy score (r .547, p .002). BC participants showed randomization in global properties and dysconnectivity in the CEN after early NAC. NAC may disrupt the cognitive balance of the brain morphological network in individuals with BC.

Breast-Conserving Surgery with or without Irradiation in Early Breast Cancer.

Limited level 1 evidence is available on the omission of radiotherapy after breast-conserving surgery in older women with hormone receptor-positive early breast cancer receiving adjuvant endocrine therapy. We performed a phase 3 randomized trial of the omission of irradiation the trial population included women 65 years of age or older who had hormone receptor-positive, node-negative, T1 or T2 primary breast cancer (with tumors ≤3 cm in the largest dimension) treated with breast-conserving surgery with clear excision margins and adjuvant endocrine therapy. Patients were randomly assigned to receive whole-breast irradiation (40 to 50 Gy) or no irradiation. The primary end point was local breast cancer recurrence. Regional recurrence, breast cancer-specific survival, distant recurrence as the first event, and overall survival were also assessed. A total of 1326 women were enrolled 658 were randomly assigned to receive whole-breast irradiation and 668 to receive no irradiation. The median follow-up was 9.1 years. The cumulative incidence of local breast cancer recurrence within 10 years was 9.5% (95% confidence interval CI, 6.8 to 12.3) in the no-radiotherapy group and 0.9% (95% CI, 0.1 to 1.7) in the radiotherapy group (hazard ratio, 10.4 95% CI, 4.1 to 26.1 P<0.001). Although local recurrence was more common in the group that did not receive radiotherapy, the 10-year incidence of distant recurrence as the first event was not higher in the no-radiotherapy group than in the radiotherapy group, at 1.6% (95% CI, 0.4 to 2.8) and 3.0% (95% CI, 1.4 to 4.5), respectively. Overall survival at 10 years was almost identical in the two groups, at 80.8% (95% CI, 77.2 to 84.3) with no radiotherapy and 80.7% (95% CI, 76.9 to 84.3) with radiotherapy. The incidence of regional recurrence and breast cancer-specific survival also did not differ substantially between the two groups. Omission of radiotherapy was associated with an increased incidence of local recurrence but had no detrimental effect on distant recurrence as the first event or overall survival among women 65 years of age or older with low-risk, hormone receptor-positive early breast cancer. (Funded by the Chief Scientist Office of the Scottish Government and the Breast Cancer Institute, Western General Hospital, Edinburgh ISRCTN number, ISRCTN95889329.).

The SET oncoprotein promotes estrogen-induced transcription by facilitating establishment of active chromatin.

SET is a multifunctional histone-binding oncoprotein that regulates transcription by an unclear mechanism. Here we show that SET enhances estrogen-dependent transcription. SET knockdown abrogates transcription of estrogen-responsive genes and their enhancer RNAs. In response to 17β-estradiol (E2), SET binds to the estrogen receptor α (ERα) and is recruited to ERα-bound enhancers and promoters at estrogen response elements (EREs). SET functions as a histone H2 chaperone that dynamically associates with H2A.Z via its acidic C-terminal domain and promotes H2A.Z incorporation, ERα, MLL1, and KDM3A loading and modulates histone methylation at EREs. SET depletion diminishes recruitment of condensin complexes to EREs and impairs E2-dependent enhancer-promoter looping. Thus, SET boosts E2-induced gene expression by establishing an active chromatin structure at ERα-bound enhancers and promoters, which is essential for transcriptional activation.

Impact of multidisciplinary team meetings on the management of patients with breast cancer in a large private healthcare facility.

Multidisciplinary meetings (MDMs) play a crucial role in decision-making in breast cancer patient care. This study aimed to firstly assess the impact of breast cancer MDMs in decision-making for breast cancer patients and secondly to determine the concordance between MDM recommendations and implementation of clinical practice. Patient cases to be presented at the weekly breast cancer MDMs were identified and prospectively enrolled. Management plans were predicted by the treating surgeon with the pre-MDM management plans then compared to MDM recommendations. Changes in decision-making were assessed in the following domains further surgery, systemic therapy (endocrine, chemotherapy or targeted), radiotherapy, enrolment in a clinical trial, further investigations, and referral to other specialists or services. Patient records were subsequently reviewed at 3 months post-MDM to assess the rate of implementation of MDM recommendations and any reasons for discordance. Out of 50 cases, 66% (CI 53-79% p < .005) experienced a change in management plan as a result of MDM discussion, with a total of 66 episodes of recorded change per decision-making domain affecting the following further surgery (7.6%), endocrine therapy (4.5%), chemotherapy (19.7%), targeted therapy (4.5%), radiotherapy (18.2%), enrolment for a clinical trial (12.1%), additional investigations (22.7%), and further referrals (10.6%). MDM recommendations were implemented in 83.7% of cases. The breast cancer MDMs were found to substantially impact on the management plans for breast cancer patients, with 83.7% of MDM recommendations being implemented into clinical practice. This study reinforces the importance of MDMs in the management of these patients, as well as highlighting the need for further investigating and addressing the potential barriers to the implementation of MDM recommendations.

Protocol for the Pilot Study of Group Video Yogic Breathing App in Breast Cancer Survivors.

Breast cancer remains a leading cause of cancer deaths however, recent improvements in treatment have improved survivorship. As a result of this improvement, more individuals are living with the long-term side effects of cancer treatment. Therefore, methods that incorporate lifestyle and mind-body approaches are becoming increasingly used in the patient treatment pathway. In this study, PranaScience Institute will develop and test a group video mobile application for Yogic Breathing (YB). YB is shown to reduce symptomatic conditions associated with several conditions including breast cancer. For this initial feasibility study, PranaScience will collaborate with the Medical University of South Carolina to implement the study app-based program in breast cancer survivors. This research is aimed to understand if the YB could be delivered via an app, if participants are able to practice it satisfactorily, and if there is any symptom relief by the YB practice. In the control group, participants will be directed to the Attention Control (AC) feature of the app, which guides users to focus on a mindfulness activity not involving YB. Participants will be randomly assigned to the YB or AC study plan (N 20 per group). Breast cancer survivors who have completed radiation therapy within last 2 months will be recruited for this study and provided access to the app for a 12-weeks program. The study app will record total practice times. Virtual visits by a study yoga instructor during group video sessions will measure participant compliance with proper technique. Feasibility will be examined by evaluating intervention delivery factors and resource needs. Acceptability of using the mobile study app to support symptom management will be evaluated using a satisfaction and system usability scale. Behavioral survey measures will help guide effect sizes and power calculations for the next larger-scale study. Biomarkers in the saliva (tumor suppressors, cytokines), and fingernails (cortisol, differential proteomics) will be measured at baseline and end of study at 12 weeks. All findings from this pilot study will be synthesized to refine the mobile study app in preparation for large-scale evaluation in Phase II involving all-study site participants with cancer. ClinicalTrials.gov Identifier NCT05161260.

Patients perceived challenges, competencies, and supportive care needs during acute clinical treatment of breast or gynecological cancer.

This study aimed to examine challenges, competencies, and supportive care needs (SCN) of women with breast or gynecological cancer during acute cancer treatment and associations to other health-related variables. We surveyed 120 patients with breast or gynecological cancer at the end of acute cancer treatment, either directly after surgery or during adjuvant chemotherapy. We assessed challenges, subjective competencies, and SCN using a self-developed measure comprising 25 items referring to coping tasks assigned to six domains. In addition, patients competencies and health literacy (HL) were assessed. Most patients felt at least moderately challenged by coping tasks concerning psychological distress (e.g., dealing with fears and insecurities, 70.2% coping with cancer diagnosis, 69.6%) and physical complaints (e.g., dealing with a reduced physical capacity, 56.6%). About 42.5% to 71.4% of patients who evaluated coping tasks as highly challenging felt competent to deal with these challenges themselves. Less than half of patients reported SCN, mainly regarding psychological concerns. The extent of challenging coping tasks, patients perceived ability to overcome challenges themselves, and SCN showed associations to patient competencies and HL. SCN regarding psychological concerns and health behavior should be addressed in acute cancer care and rehabilitation programs. In addition, promoting HL might be essential in strengthening patients subjective competencies related to various coping tasks. This article is protected by copyright. All rights reserved.

Erythrocyte membrane-camouflaged Prussian blue nanocomplexes for combinational therapy of triple-negative breast cancer.

Although combined photodynamicphotothermal therapy (PDTPTT) has been used for cancer theranostics recently, their therapeutic efficacy has been compromised by the low O

Computed Tomography-Based Radiomics Analysis for Prediction of Response to Neoadjuvant Chemotherapy in Breast Cancer Patients.

Previous studies have pointed out that magnetic resonance- and fluorodeoxyglucose positron emission tomography-based radiomics had a high predictive value for the response of the neoadjuvant chemotherapy (NAC) in breast cancer by respectively characterizing tumor heterogeneity of the relaxation time and the glucose metabolism. However, it is unclear whether computed tomography (CT)-based radiomics based on density heterogeneity can predict the response of NAC. This study aimed to develop and validate a CT-based radiomics nomogram to predict the response of NAC in breast cancer. A total of 162 breast cancer patients (110 in the training cohort and 52 in the validation cohort) who underwent CT scans before receiving NAC and had pathological response results were retrospectively enrolled. Grades 4 to 5 cases were classified as response to NAC. According to the Miller-Payne grading system, grades 1 to 3 cases were classified as nonresponse to NAC. Radiomics features were extracted, and the optimal radiomics features were obtained to construct a radiomics signature. Multivariate logistic regression was used to develop the clinical prediction model and the radiomics nomogram that incorporated clinical characteristics and radiomics score. We assessed the performance of different models, including calibration and clinical usefulness. Eight optimal radiomics features were obtained. Human epidermal growth factor receptor 2 status and molecular subtype showed statistical differences between the response group and the nonresponse group. The radiomics nomogram had more favorable predictive efficacy than the clinical prediction model (areas under the curve, 0.82 vs 0.70 in the training cohort 0.79 vs 0.71 in the validation cohort). The Delong test showed that there are statistical differences between the clinical prediction model and the radiomics nomogram (z 2.811, P 0.005 in the training cohort). The decision curve analysis showed that the radiomics nomogram had higher overall net benefit than the clinical prediction model. The radiomics nomogram based on CT radiomics signature and clinical characteristics has favorable predictive efficacy for the response of NAC in breast cancer.

The Cost of Doing Business An Appraisal of Relative Value Units in Plastic Surgery and Other Surgical Subspecialties.

The relationship between procedural complexity and RVUs awarded has been previously studied within some specialties, but it has not yet been compared across different surgical disciplines. This study aims to analyze the association of RVUs with operative time as a surrogate for complexity across surgical specialties, with a focus on plastic surgery. A retrospective review of surgical cases was conducted with the 2019 NSQIP database. The top 10 most performed procedures per surgical specialty were identified based on case volume. Only cases with a single CPT code were analyzed. A sub-analysis of plastic surgery procedures was also conducted to include unilateral and bilateral procedures with a frequency of greater than 20. Overall, operative time correlated strongly with work RVU (R 0.86). Orthopedic surgery had one of the shortest average operative times with the greatest wRVU per hour, in contrast to plastic surgery with the greatest average operative time and one of the lowest wRVU per hour. Of the plastic surgery procedures analyzed, only 5 were valued on par with the average calculated from all other specialties. The most poorly rewarded procedure for time spent is the unilateral free flap breast reconstruction. Of all the specialties, plastic surgery has the lowest RVU per hour and the highest average operative time, leading to severe potential undervaluation compared to other specialties. Our study suggests that further reevaluation of the current RVU system may be needed to account for complexity more equitably as well as encourage value-based care.

The prognostic value of DAAM2 in lower grade glioma, liver cancer, and breast cancer.

Dishevelled-associated activator of morphogenesis 2 (DAAM2) is a formin protein and has a potential role in the tumor metastasis. The prognostic value of DAAM2 in pan-cancer is investigated in this study. TCGA and GTEx database were downloaded to perform bioinformatics analysis and ROC curves. Then we explored protein-protein interaction and GO-KEGG enrichment to figure out the protein pathways associated with DAAM2 and studied DAAM2-related immune infiltration and methylation. Fifteen pairs of BRCA clinical samples were enrolled to determine the expression and distribution of DAAM2 in BRCA sections by immunohistochemistry. Finally, BRCA cells were transfected with siRNA targeting DAAM2 and subsequently subject to cell proliferation, migration, and invasion assays. DAAM2 was closely related to the diagnosis and clinical characteristics of lower grade glioma (LGG), liver hepatocellular carcinoma (LIHC), and breast cancer (BRCA). Survival curve analysis demonstrated DAAM2 served as a potential prognostic indicator of LGG and LIHC (P 0.0029 and P 0.025, respectively). DAAM2 was mainly participated in signaling pathways mediating cytoskeleton regulation and tumor development. The correlation of DAAM2 with tumor-infiltrating immune cells (TIICs) and methylation levels was conducive to the prediction of novel biomarkers of pan-carcinoma. DAAM2 was highly expressed in BRCA tissues than that in paracancerous tissues. The proliferation, invasion, and migration of BRCA cells were inhibited by DAAM2 siRNA. DAAM2 had a specific value in foretelling the prognosis of LGG, LIHC, and BRCA. High expression level of DAAM2 has longer survival rates in LGG and LIHC. The knockdown of DAAM2 retards the proliferation, invasion, and migration of BRCA cells. This study provides a novel sight of DAAM2 into the exploration of a potential biomarker in pan-cancer.

Cyclin-dependent kinase (CDK) 46 inhibition in non-small cell lung cancer with epidermal growth factor receptor (EGFR) mutations.

Lung cancer is the leading cause of cancer death worldwide, and EGFR mutation is the most common genetic alteration among Asian patients with lung adenocarcinoma. While osimertinib has been shown to be effective in lung cancer patients with EGFR mutation, the majority of patients eventually develop acquired resistance to treatment. We explored the significance of the cyclin D1 expression in patients with EGFR mutation and the potential efficacy of adding abemaciclib, a cyclin-dependent kinase (CDK) 46 inhibitor, simultaneously with osimertinib in vitro. Immunohistochemical staining, using an anti-cyclin D1 antibody, of specimens from 83 patients with EGFR mutation (male, n 27 pStage 0-I, n 71) who were treated by surgical resection between 2017 and 2020, and the relationship between the cyclin D1 expression and clinicopathological factors was analyzed. Additionally, the combined effect of osimertinib and abemaciclib in lung cancer cell lines were analyzed using a growth inhibition test, and the signaling pathway underlying the combined effect was investigated. Cyclin D1 was negative in 18.1% of patients with EGFR mutation, and cyclin D1 negativity was associated with pStage ≥ II (p 0.02), lymph node metastasis (p 0.001), and lymphatic invasion (p 0.01). The cyclin D1-negative group had significantly shorter recurrence-free survival (p 0.02), although this difference disappeared when limited to pN0 patients. In EGFR mutated cell lines, the combination of osimertinib and abemaciclib demonstrated synergistic effects, which were thought to be mediated by the inhibition of AKT phosphorylation. Combination therapy with CDK46 inhibitors and EGFR-TKIs may be a promising approach.

New antiproliferative 3-substituted oxindoles inhibiting EGFRVEGFR-2 and tubulin polymerization.

New 3-substituted oxindole derivatives were designed and synthesized as antiproliferative agents. The antiproliferative activity of compounds 6a-j was evaluated against 60 NCI cell lines. Among these tested compounds, compounds 6f and 6g showed remarkable antiproliferative activity, specifically against leukemia and breast cancer cell lines. Compound 6f was the most promising antiproliferative agent against MCF-7 (human breast cancer) with an IC

Clinical and pathological characterization of 158 consecutive and unselected oligometastatic breast cancers in a single institution.

Data about incidence, biological, and clinical characteristics of oligometastatic breast cancer (OMBC) are scarce. However, these data are essential in determining optimal treatment strategy. Gaining knowledge of these elements means observing and describing large, recent, and consecutive series of OMBC in their natural history. We collected data retrospectively at our institution from 998 consecutive patients diagnosed and treated with synchronous or metachronous metastatic breast cancer (MBC) between January 2014 and December 2018. The only criterion used to define OMBC was the presence of one to five metastases at diagnosis. Of 998 MBC, 15.8% were classified OMBC. Among these, 88% had one to three metastases, and 86.7% had only one organ involved. Bone metastases were present in 52.5% of cases, 20.9% had progression to lymph nodes, 14.6% to the liver, 13.3% to the brain, 8.2% to the lungs, and 3.8% had other metastases. 55.7% had HRHER2- OMBC, 25.3% had HER2OMBC, and 19% had HR-HER2- OMBC. The HRHER2- subtype statistically correlated with bone metastases (p 0.001), the HER2subtype with brain lesions (p 0.001), and the HR-HER2- subtype with lymph node metastases (p 0.008). Visceral metastases were not statistically associated with any OMBC subtypes (p 0.186). OMBC-SBR grade III was proportionally higher than in the ESME series of 22,109 MBC (49.4% vs. 35.1%, p < 0.001). OMBC is a heterogeneous entity whose incidence is higher than has commonly been published. Not an indolent disease, each subgroup, with its biological and anatomical characteristics, merits specific management.

The PER3

Dyschromatosis universalis hereditaria (DUH) is a pigmentary genodermatosis characterized by a mixture of hyperpigmented and hypopigmented macules distributed randomly over the body. Although Sterile Alpha motif- and SH3 domain-containing protein 1 (SASH1) and ATP-binding cassette subfamily B, member 6 (ABCB6) have been identified as causative genes for this disorder, some cases involve unknown pathogenic genes. In this study, whole-exome sequencing, data analysis, and Sanger sequencing were utilized for a four-generation extended Chinese family with DUH. A single-nucleotide polymorphism (SNP) (c. 517C > T (p.P173S), rs772027021) variant in exon 5 of Period Circadian Regulator 3 (PER3) (NM001289861) was detected in each affected individual of the DUH family the c. 517C > T SNP of PER3 (PER3

mTOR pathway candidate genes and obesity interaction on breast cancer risk in black women from the Womens Circle of Health Study.

Obesity is known to stimulate the mammalian target of rapamycin (mTOR) signaling pathway and both obesity and the mTOR signaling pathway are implicated in breast carcinogenesis. We investigated potential gene-environment interactions between mTOR pathway genes and obesity in relation to breast cancer risk among Black women. The study included 1,655 Black women (821 incident breast cancer cases and 834 controls) from the Womens Circle of Health Study (WCHS). Obesity measures including body mass index (BMI) central obesity i.e., waist circumference (WC) and waisthip ratio (WHR) and body fat distribution (fat mass, fat mass index and percent body fat) were obtained by trained research staff. We examined the associations of 43 candidate single-nucleotide polymorphisms (SNPs) in 20 mTOR pathway genes with breast cancer risk using multivariable logistic regression. We next examined interactions between these SNPs and measures of obesity using Wald test with 2-way interaction term. The variant allele of BRAF (rs114729114 C > T) was associated with an increase in overall breast cancer risk odds ratio (OR) 1.81, 95% confidence interval (CI) 1.10-2.99, for each copy of the T allele and the risk of estrogen receptor (ER)-defined subtypes (ER tumors OR 1.83, 95% CI 1.04,3.29, for each copy of the T allele ER- tumors OR 2.14, 95% CI 1.03,4.45, for each copy of the T allele). Genetic variants in AKT, AKT1, PGF, PRKAG2, RAPTOR, TSC2 showed suggestive associations with overall breast cancer risk and the risk of, ER and ER- tumors (range of p-values 0.040-0.097). We also found interactions of several of the SNPs with BMI, WHR, WC, fat mass, fat mass index and percent body fat in relation to breast cancer risk. These associations and interactions, however, became nonsignificant after correction for multiple testing (FDR-adjusted p-value > 0.05). We found associations between mTOR genetic variants and breast cancer risk as well as gene and body fatness interactions in relation to breast cancer risk. However, these associations and interactions became nonsignificant after correction for multiple testing. Future studies with larger sample sizes are required to confirm and validate these findings.

Stromal grading predicts pathologic complete response and prognosis in triple-negative breast cancer.

Do traditional prognostic factors fully account for the diversity of clinical behavior in breast cancer Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer seen to have a poor prognosis, although there is great variation in clinical outcomes. Most recently, novel approaches have targeted the tumoral microenvironment (TME) to determine prognosis and tumor-associated stroma has become increasingly recognized as a potential biomarker to predict treatment response and prognosis in TNBC. The principle aim of this paper is to demonstrate an approach to stromal grading in TNBC, with consideration of its utility for predicting pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) and clinical survival outcomes. We evaluated 152 TNBC cases from the Firehose Legacy TCGA Cohort and validated our findings in a series of 110 patients from our health system. Stromal grading correlated with clinical outcomes related to prognosis and response to NAC, advanced pathologic stage, as well as clinical demographics like age over 50 years with good interobserver reliability (83.6-89.1%). Looking forward, the TME could carve out a more precision-based care in TNBC and breast cancer generally.

Effectiveness of a novel gene nanotherapy based on putrescine for cancer treatment.

Gene therapy has long been proposed for cancer treatment. However, the use of therapeutic nucleic acids presents several limitations such as enzymatic degradation, rapid clearance, and poor cellular uptake and efficiency. In this work we propose the use of putrescine, a precursor for higher polyamine biosynthesis for the preparation of cationic nanosystems for cancer gene therapy. We have formulated and characterized putrescine-sphingomyelin nanosystems (PSN) and studied their endocytic pathway and intracellular trafficking in cancer cells. After loading a plasmid DNA (pDNA) encoding the apoptotic Fas Ligand (FasL), we proved their therapeutic activity by measuring the cell death rate after treatment of MDA-MB-231 cells. We have also used xenografted zebrafish embryos as a first

Mass Nanotags Mediate Parallel Amplifications on Nanointerfaces for Multiplexed Profiling of RNAs.

Multiplexed profiling of RNAs aids in a comprehensive understanding of multiparameter-defined cellular processes and pathological states. We herein present a mass nanotags-enabled interfacial assembly system (MNTs-AS) with parallel amplification motors for simultaneous assaying of multiple RNAs in biosystems by matrix-assisted laser desorptionionization mass spectrometry (MALDI MS). Four kinds of MNTs encoding corresponding RNA can be cyclically assembled on magnetic beads by target-triggered catalytic hairpin assembly (CHA) machineries on nanointerfaces, generating multiplexed and amplified characteristic ion signals assigned to target RNAs upon MALDI MS interrogation. By virtue of high sensitivity and multiplexing capability, the MNTs-AS-based MS assay allows precision subtyping of diverse breast cancer cells and their exosomes by multiplexed profiling of miRNA-21, miRNA-373, miRNA-155, and manganese superoxide dismutase mRNA via a single MS inquiry. This method provides a promising tool for unraveling multiple RNA-involved biological events in fundamental research and distinguishing different cancer subtypes in clinical practice.

Fine needle aspirational cytology of metastatic tumours to the thyroid.

Metastasis to the thyroid gland from non-thyroid sites is relatively rare and often poses a diagnostic difficulty on fine-needle aspiration cytology as it often mimics primary thyroid neoplasms. All cases of fine needle aspiration cytology (FNAC) of metastasis to the thyroid gland ( 2014 to 2022) were selected from the pathology database. The detailed cytopathological features and histopathology of the cases were studied. There was a total of 18 cases of secondary tumours of the thyroid. All cases had confirmed histopathological data. The commonest sites of the primary tumours in our study were squamous cell carcinoma of the oesophagus (9) followed by infiltrating ductal carcinoma of the breast (4), and one case each of renal cell carcinoma, neuroendocrine carcinoma of the lung, carcinoma stomach and malignant melanoma and squamous cell carcinoma from vallecula. Metastasis to thyroid carcinoma is relatively uncommon. The history of malignancy, the presence of malignant cells amid benign thyroid follicular cells, unusual malignancy in FNAC smear and immunocytochemistry are helpful in diagnosing such cases.

T-type Ca2 channels and their relationship with pre-neoplastic and neoplastic lesions in the human breast.

The expression of T-type voltage-dependent Ca2 channels (Cav3) has been previously observed in breast cancer, but their expression and subcellular localization were not evaluated in pre-neoplastic lesions. Therefore, this work aimed to evaluate protein expression and subcellular localization of T-type channel isoforms in human breast tissue samples. Protein expressions of CaV3.1, CaV3.2, and CaV3.3 were evaluated by immunohistochemistry in breast without alteration, in proliferative non-neoplastic lesions, and in neoplastic ductal epithelial lesions of the human breast. CaV3.1, CaV3.2, and CaV3.3 nuclear expressions were decreased in advanced stages of neoplastic transformation, whereas CaV3.1 and CaV3.2 cytoplasmic expression increased. Also, the decrease in nuclear expression was correlated with an increase in cytoplasmic expression for CaV3.1 isoform. The change in CaV3 protein expression and subcellular localization are consistent with the neoplastic transformation stages of mammary epithelial cells, evident in early neoplastic lesions, such as ductal carcinomas in situ. These results suggest a possible involvement of CaV3 in the carcinogenic processes and could be considered as a potential pharmacological target in new therapies for breast cancer treatment.

Seasonal effects on cancer incidence and prognosis.

It is unknown if the reduction in the expected number of cancer cases diagnosed during Swedish holidays are due to diagnostic delays, how different cancers are affected, and if the season of diagnosis influences long-term cancer survival. We aimed to quantify seasonal trends in incidence and excess mortality for a wide range of malignancies, requiring more or less urgent clinical management. This nationwide cohort study included all Swedish residents aged 20-84 in 1990-2019. Incidence and relative survival in pancreatic, colorectal, lung, urothelial, breast, and prostate cancer, together with malignant melanoma, non-Hodgkin lymphoma, and acute leukemia diagnosed during holiday and post-holiday were compared to working (reference) season. Incidence rate ratios (IRR) were estimated using Poisson regression and excess (cancer) mortality rate ratios using flexible parametric models. We identified 882,980 cancer cases. Incidence declined during holiday season for all malignancies and the IRR ranged from 0.58 (95% CI 0.57-0.59 in breast to 0.92 (95% CI 0.89-0.94) in pancreatic cancer. A post-holiday increase was noted for acute leukemia, pancreatic, and lung cancer. For all malignancies except lung cancer, non-Hodgkin lymphoma, and acute leukemia, the excess mortality at 2 years from diagnosis was higher among those diagnosed during the holiday season. A tendency toward elevated short-term (0.5 years) excess mortality was noted in the post-holiday group, but long-term effects only persisted in breast cancer. This study demonstrates lower holiday detection rates and higher mortality rates in various cancer types diagnosed during holiday season. Healthcare systems should offer a uniform level of cancer care independent of calendar season.

Sexual well-being in patients with early-stage breast cancer at 1- and 2-year follow-up.

Sexual well-being (SWB) is an important aspect of overall quality of life and should therefore be considered when measuring the effect of breast cancer on daily life. To identify positive and negative predictive factors associated with change in SWB 1 year after diagnosis (T12 hereafter, ∆SWB) and whether SWB changes the year after. All data were derived from an online patient-reported outcome measure that included patients aged >18 years who were treated for breast cancer between October 2015 and March 2022 at the Erasmus University Medical Center. Multivariable linear regression was used to analyze the association between demographic- and disease-specific variables and change in SWB between time of diagnoses (T0) and one year after (T12) (∆SWB). For defining the clinical relevance of ∆SWB, patients were divided into 3 groups based on their SWB score at T12 decreased, stable, and improved. Wilcoxon signed rank test was used to test the difference in SWB between T12 and T24 (2 years after diagnosis) in all 3 groups. Outcomes included the associations between demographic- and disease-specific variables and ∆SWB (T0 vs T12) and change in SWB the year after (T12 vs T24). An overall 204 patients were included, with a mean age of 51.7 years (SD, 12.8) and a mean SWB score of 64.3 (SD, 20.9) at T0. Body mass index >30 kgm2 at T0 had a significant negative association (β -8.369, P .019) with ∆SWB. Reconstruction (β 20.136, P < .001) and mastectomy (β 11.157, P < .001) had a significant positive association with ∆SWB vs lumpectomy. Change in psychological well-being had a significant positive relation to ∆SWB (β 0.349, P < .001). Patients with decreased SWB at T12 did not improve the year after (P .376). By identifying the variables that are associated with decreased SWB during the trajectory of breast cancer treatment and by defining the clinical relevance of decreased SWB, patient groups can be targeted and offered extra support. This study is one of the first to analyze the development of SWB, instead of sexual function, over time in patients with breast cancer, and it uses data over a longer period. However, only one-third of the patients responded to the SWB domains at both time points. Type of operation, body mass index >30, and change in psychological well-being were associated with ∆SWB. Patients with decreased SWB 1 year after diagnosis tended not to improve or normalize the year after, indicating that intervention is needed to restore SWB in this specific group.

Potential of Lesion-to-Fat Elasticity Ratio Measured by Shear Wave Elastography to Reduce Benign Biopsies in BI-RADS 4 Breast Lesions.

We evaluated whether lesion-to-fat ratio measured by shear wave elastography in patients with Breast Imaging Reporting and Data System (BI-RADS) 3 or 4 lesions has the potential to further refine the assessment of B-mode ultrasound alone in breast cancer diagnostics. This was a secondary analysis of an international diagnostic multicenter trial (NCT02638935). Data from 1288 women with breast lesions categorized as BI-RADS 3 and 4a-c by conventional B-mode ultrasound were analyzed, whereby the focus was placed on differentiating lesions categorized as BI-RADS 3 and BI-RADS 4a. All women underwent shear wave elastography and histopathologic evaluation functioning as reference standard. Reduction of benign biopsies as well as the number of missed malignancies after reclassification using lesion-to-fat ratio measured by shear wave elastography were evaluated. Breast cancer was diagnosed in 368 (28.6%) of 1288 lesions. The assessment with conventional B-mode ultrasound resulted in 53.8% (495 of 1288) pathologically benign lesions categorized as BI-RADS 4 and therefore false positives as well as in 1.39% (6 of 431) undetected malignancies categorized as BI-RADS 3. Additional lesion-to-fat ratio in BI-RADS 4a lesions with a cutoff value of 1.85 resulted in 30.11% biopsies of benign lesions which correspond to a reduction of 44.04% of false positives. Adding lesion-to-fat ratio measured by shear wave elastography to conventional B-mode ultrasound in BI-RADS 4a breast lesions could help reduce the number of benign biopsies by 44.04%. At the same time, however, 1.98% of malignancies were missed, which would still be in line with American College of Radiology BI-RADS 3 definition of <2% of undetected malignancies.

Correction Evaluation of the effects of newly synthesized metallophthalocyanines on breast cancer cell lines with photodynamic therapy.

Correction for Evaluation of the effects of newly synthesized metallophthalocyanines on breast cancer cell lines with photodynamic therapy by Hayrani Eren Bostancı

Risk and incidence of breast cancer in transgender individuals a systematic review and meta-analysis.

The risk of developing breast cancer in transgender individuals male-to-female (MtF) or female-to-male (FtM) is still inadequately quantified. We aimed to evaluate the impact of breast cancer in this population. We conducted a systematic literature search and review using the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines through the PUBMED and SCOPUS databases. We identified six cohort studies (for both populations) plus 35 case reports. Incidence and breast cancer risk quantification were the main outcomes considered. FtM individuals had a higher risk of developing breast cancer in comparison to cisgender men standardized incidence ratio (SIR) 63.4 95% confidence interval (CI), 32.2-124.9 but a lower risk than cisgender women (SIR 0.42 95% CI, 0.07-2.41). Similarly, MtF individuals were at higher risk of developing breast cancer in comparison to cisgender men (SIR 22.5 95% CI, 5.54-91.8) and at lower risk than cisgender women (SIR 0.30 95% CI, 0.22-0.42). In this systematic study and meta-analysis, we identified that FtM and MtF individuals are at substantially higher risk of developing breast cancer in comparison to cisgender men, though at lower risk than cisgender women. These individuals, in the absence of defined guidelines for breast cancer prevention, should periodically undergo breast or chest examinations.

Stratifying the risk of ovarian cancer incidence by histologic subtypes in the Korean Epithelial Ovarian Cancer Study (Ko-EVE).

This study aimed to verify the association between ovarian cancer (OC) and reproductive- and lifestyle-related risk factors stratified by the subtype of OC. In this matched case-control study derived from the Korean epithelial ovarian cancer study (Ko-EVE), we calculated the risk of OC subtypes using odds ratios (ORs) and 95% confidence intervals (95% CIs) in a logistic regression model. As a result of matching, 531 cases and 2,124 controls were selected. Smoking had positive association with high-grade serous (HGS) OC (OR 2.69, 95% CI 1.15-6.30), whereas alcohol consumption had positive association with mucinous type (MUC) (OR 3.63, 95% CI 1.39-9.49). Obesity (≥30 kgm A heterogeneous association between some risk factors and the incidence of each subtype of epithelial OC was observed, suggesting that the carcinogenic mechanisms of each subtype may be partly different.

Variation in second breast cancer risk after primary invasive cancer by time since primary cancer diagnosis and estrogen receptor status.

In women with previously treated breast cancer, occurrence and timing of second breast cancers have implications for surveillance. The authors examined the timing of second breast cancers by primary cancer estrogen receptor (ER) status in the Breast Cancer Surveillance Consortium. Women who were diagnosed with American Joint Commission on Cancer stage I-III breast cancer were identified within six Breast Cancer Surveillance Consortium registries from 2000 to 2017. Characteristics collected at primary breast cancer diagnosis included demographics, ER status, and treatment. Second breast cancer events included subsequent ipsilateral or contralateral breast cancers diagnosed >6 months after primary diagnosis. The authors examined cumulative incidence and second breast cancer rates by primary cancer ER status during 1-5 versus 6-10 years after diagnosis. At 10 years, the cumulative second breast cancer incidence was 11.8% (95% confidence interval CI, 10.7%-13.1%) for women with ER-negative disease and 7.5% (95% CI, 7.0%-8.0%) for those with ER-positive disease. Women with ER-negative cancer had higher second breast cancer rates than those with ER-positive cancer during the first 5 years of follow-up (16.0 per 1000 person-years PY 95% CI, 14.2-17.9 per 1000 PY vs. 7.8 per 1000 PY 95% CI, 7.3-8.4 per 1000 PY, respectively). After 5 years, second breast cancer rates were similar for women with ER-negative versus ER-positive breast cancer (12.1 per 1000 PY 95% CI, 9.9-14.7 vs. 9.3 per 1000 PY 95% CI, 8.4-10.3 per 1000 PY, respectively). ER-negative primary breast cancers are associated with a higher risk of second breast cancers than ER-positive cancers during the first 5 years after diagnosis. Further study is needed to examine the potential benefit of more intensive surveillance targeting these women in the early postdiagnosis period.

ZNF3 regulates proliferation, migration and invasion through MMP1 and TWIST in colorectal cancer.

Colorectal cancer (CRC) is a malignant tumor with a high incidence and mortality worldwide. Currently, the underlying molecular mechanisms of CRC are still unclear. Zinc finger protein 3 (ZNF3) is a zinc-finger transcription factor that has been reported as a candidate for breast cancer prognosis, suggesting its involvement in the regulation of tumorigenesis. However, the association between ZNF3 and CRC remains unknown. To investigate the role of ZNF3 in CRC, we first analyze the correlation between ZNF3 expression and CRC, and the results demonstrate that ZNF3 is highly expressed in CRC tissue and cells, which is associated with the age of CRC patients.

Excellent response of refractory triple-negative breast cancer to sintilimab plus chemotherapy a case report.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a high propensity for invasion and a high incidence of lymph node metastasis. Systemic chemotherapy is considered the primary treatment for patients with TNBC however, immune checkpoint inhibitors in addition to chemotherapy have been associated with better outcomes. Sintilimab, an anti-PD-1 antibody, was developed in China. Herein, the authors report a 49-year-old woman diagnosed with TNBC with extensive lung and sternal metastases. Treatment with sintilimab plus paclitaxel and carboplatin was found highly effective after failure of first-line chemotherapy. This combinational therapy can be considered for the treatment of TNBC after necessary investigations and clinical trials. Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that has no target for endocrine or targeted therapy, and the standard treatment for patients with TNBC was chemotherapy alone. Recent studies have suggested that immune checkpoint inhibitors plus chemotherapy might be effective and safe for advanced TNBC. Pembrolizumab and atezolizumab have been approved by the US FDA for the treatment of PD-L1-positive TNBC patients. Sintilimab, a Chinese immune checkpoint inhibitor, has not been reported in the treatment of TNBC. This case report presents excellent outcomes of a patient with TNBC who received sintilimab plus chemotherapy after the failure of standard chemotherapy. This combinational therapy can be considered for the treatment of TNBC after necessary investigations and clinical trials.