bluuebunny/crossref_metadata_2025 huggingface dataset:
Seismic Fragility of a Multi-Frame Box-Girder Bridge Influenced by Seismic Excitation Angles and Column Height Layouts
Authors: Wu Tong , Wang Luyao , Zhao Liyang , Fan Gangping , Wang Jiahui , Yin Lihui , Zhang Shuang , Liu Shengchun
Published: March 2022

Curved multi-frame box-girder bridges with hinges are widely used in the United States due to the large spanning capacity, construction simplification and construction cost economy. This type of bridge frequently has the characteristics of column height asymmetry, adjacent bridge frames vibrating discrepancy. The combination of curved shape and random seismic excitation angles could aggravate the irregularity of the structural seismic response. In this study, an OpenSees model is established for an example bridge, and the hinge is taken as a key component to observe. The impacts of seismic excitation angles and column height layouts on fragility are investigated through the comparison of the fragility curves. The conclusions list the most unfavorable seismic excitation angles corresponding to the fragilities of bridge system, plug-type concrete elements in hinges, hinge restrainers, columns, abutment bearings as well as the secondary components, respectively. The symmetrical column height layout is proved to be beneficial to mitigate the damage risks of restrainers in intermediate hinges and reduce the fragility of the bridge system. This study can provide a reference for the rapid assessment of the fragile position and damage degree of bridges through structural configuration and shape, as well as the seismic excitation angle.
Low-Sulphur Vacuum Gasoil of Western Siberia Oil: The Impact of Its Structural and Chemical Features on the Properties of the Produced Needle Coke
Authors: Dolomatov Mikhail Y. , Burangulov Daniyar Z. , Dolomatova Milana M. , Osipenko Danil F. , Zaporin Viktor P. , Tukhbatullina Alina A. , Akhmetov Arslan F. , Sabirov Denis S.
Published: March 2022

The specific branches of industry utilize needle coke, a carbon form with a highly anisotropic structure. Searching for novel raw materials for its production is now rigorously studied. In the present work, we use low-sulfur gasoil for this purpose, namely its high-boiling fractions. We study their chemical and physicochemical parameters with the set of physicochemical and spectral methods. The data of FT-IR and UV-Vis spectroscopies with a phenomenological method (that allows assessing average electronic structure parameters) indicate that the gas oil of the West Siberian origin contains polycyclic aromatic hydrocarbons (PAHs) with 3–5 condensed benzene rings. The maximum amount of PAHs with molecular masses of 400–600 a.u. is contained in the fractions with boiling points higher than 450 °C. According to the data of polarized-light optical microscopy, the higher boiling point of the gasoil fraction the higher anisotropy of the produced coke. This occurs as a result of an increase in the amount of PAHs capable of condensation with the formation of a mesophase. Thus, low-sulfur gas oils from thermally processed West Siberian oil are promising raw materials for the production of needle coke in delayed coking processes.
Raman Spectroscopy in Prostate Cancer: Techniques, Applications and Advancements
Authors: Gaba Fortis , Tipping William J. , Salji Mark , Faulds Karen , Graham Duncan , Leung Hing Y.
Published: March 2022

Optical techniques are widely used tools in the visualisation of biological species within complex matrices, including biopsies, tissue resections and biofluids. Raman spectroscopy is an emerging analytical approach that probes the molecular signature of endogenous cellular biomolecules under biocompatible conditions with high spatial resolution. Applications of Raman spectroscopy in prostate cancer include biopsy analysis, assessment of surgical margins and monitoring of treatment efficacy. The advent of advanced Raman imaging techniques, such as stimulated Raman scattering, is creating opportunities for real-time in situ evaluation of prostate cancer. This review provides a focus on the recent preclinical and clinical achievements in implementing Raman-based techniques, highlighting remaining challenges for clinical applications. The research and clinical results achieved through in vivo and ex vivo Raman spectroscopy illustrate areas where these evolving technologies can be best translated into clinical practice.
Applications of Focused Ultrasound in the Treatment of Genitourinary Cancers
Authors: Panzone John , Byler Timothy , Bratslavsky Gennady , Goldberg Hanan
Published: March 2022

Traditional cancer treatments have been associated with substantial morbidity for patients. Focused ultrasound offers a novel modality for the treatment of various forms of cancer which may offer effective oncological control and low morbidity. We performed a review of PubMed articles assessing the current applications of focused ultrasound in the treatment of genitourinary cancers, including prostate, kidney, bladder, penile, and testicular cancer. Current research indicates that high-intensity focused ultrasound (HIFU) focal therapy offers effective short-term oncologic control of localized prostate and kidney cancer with lower associated morbidity than radical surgery. In addition, studies in mice have demonstrated that focused ultrasound treatment increases the accuracy of chemotherapeutic drug delivery, the efficacy of drug uptake, and cytotoxic effects within targeted cancer cells. Ultrasound-based therapy shows promise for the treatment of genitourinary cancers. Further research should continue to investigate focused ultrasound as an alternative cancer treatment option or as a complement to increase the efficacy of conventional treatments such as chemotherapy and radiotherapy.
pncCCND1_B Engages an Inhibitory Protein Network to Downregulate CCND1 Expression upon DNA Damage
Authors: Palombo Ramona , Paronetto Maria Paola
Published: March 2022

Promoter-associated noncoding RNAs (pancRNAs) represent a class of noncoding transcripts driven from the promoter region of protein-coding or non-coding genes that operate as cis-acting elements to regulate the expression of the host gene. PancRNAs act by altering the chromatin structure and recruiting transcription regulators. PncCCND1_B is driven by the promoter region of CCND1 and regulates CCND1 expression in Ewing sarcoma through recruitment of a multi-molecular complex composed of the RNA binding protein Sam68 and the DNA/RNA helicase DHX9. In this study, we investigated the regulation of CCND1 expression in Ewing sarcoma cells upon exposure to chemotherapeutic drugs. Pan-inhibitor screening indicated that etoposide, a drug used for Ewing sarcoma treatment, promotes transcription of pncCCND1_B and repression of CCND1 expression. RNA immunoprecipitation experiments showed increased binding of Sam68 to the pncCCND1_B after treatment, despite the significant reduction in DHX9 protein. This effect was associated with the formation of DNA:RNA duplexes at the CCND1 promoter. Furthermore, Sam68 interacted with HDAC1 in etoposide treated cells, thus contributing to chromatin remodeling and epigenetic changes. Interestingly, inhibition of the ATM signaling pathway by KU 55,933 treatment was sufficient to inhibit etoposide-induced Sam68-HDAC1 interaction without rescuing DHX9 expression. In these conditions, the DNA:RNA hybrids persist, thus contributing to the local chromatin inactivation at the CCND1 promoter region. Altogether, our results show an active role of Sam68 in DNA damage signaling and chromatin remodeling on the CCND1 gene by fine-tuning transitions of epigenetic complexes on the CCND1 promoter.
Isolated Pancreatic Metastases of Renal Cell Cancer: Genetics and Epigenetics of an Unusual Tumour Entity
Authors: Sellner Franz , Thalhammer Sabine , Klimpfinger Martin
Published: March 2022

Isolated pancreatic metastases of renal cell carcinoma (isPMRCC) are a rare manifestation of metastatic renal cell carcinoma (mRCC) characterized by two peculiarities: (1). The definite or at least long-term exclusive occurrence of metastases in the pancreas and (2). an unusual low tumour aggressiveness with slow tumour progression and consecutive, good treatment results. According to current knowledge, the exclusive occurrence of pancreatic metastases is due to a highly specific and highly selective seed and soil mechanism, which does not allow metastases settlement outside the pancreas, and whose detailed genetic/epigenetic causes are not yet elucidated. Recent studies have shed light on some of the pathways involved for the protracted course of the disease and highlighted a special genetic profile (lack of loss of 9p, lower weight genome instability index, low frequency of BAP1 alterations, and a high frequency of PBRM1 loss), which deviates from the conventional mRCC profile. Finally, the question of the reasons for the long-term relative genetic stability of the involved cell clones, which is an essential prerequisite for a favourable prognosis, remains unanswered.
Looking for a Simplified Diagnostic Model to Identify Potentially Lethal Cases of Prostate Cancer at Initial Diagnosis: An ImGO Pilot Study
Authors: Macrini Serena , Francesconi Simona , Caprera Cecilia , Lancia Daniela , Corsi Matteo , Gunnellini Marco , Rocchi Andrea , Pireddu Anjuta , Marziani Fiovo , Mosillo Claudia , Calandrella Maria Letizia , Caserta Claudia , Giannarelli Diana , Guida Annalisa , Ascani Stefano , Bracarda Sergio
Published: March 2022

The recurrent genetic anomalies used to classify prostate cancer (PC) into distinct molecular subtypes have limited relevance for clinical practice. In consideration of WHO 2016 histological classification, which includes the introduction of Gleason Score 4 for patients with cribriform component and the definition of intraductal carcinoma as a new entity, a retrospective pilot study was conducted to investigate, by histological review, if there were any variations of Gleason Score and the incidence of intraductal carcinoma and cribriform pattern, intended as “phenotypic” markers of potentially lethal PC, among metastatic castration-sensitive PC (mCSPC) and metastatic castration-resistant PC (mCRPC) samples. Potentially predictive factors were also assessed. Among 125 cases, a variation in the Gleason Score was reported in 26% of cases. A cribriform (36%) or intraductal (2%) pattern was reported in a higher percentage. Of them, a primary Gleason pattern 4 was reported in 80% of cases. All patients with intraductal carcinoma present a BRCA2 mutation, also found in 80% of cases with a cribriform pattern. This pilot study documented some hypothesis-generating data, as the evaluation of de novo mCSPC and mCRPC as phenotypic/biologic model to be translated in clinical practice. A cribriform pattern/intraductal carcinoma might be a marker of potentially lethal PC. The high incidence of TP53 and BRCA2 mutations in de novo mCSPC may also have a therapeutic implication.
Stem Cell Theory of Cancer: Implications for Drug Resistance and Chemosensitivity in Cancer Care
Authors: Tu Shi-Ming , Guo Charles C. , Chow Diana S. -L. , Zacharias Niki M.
Published: March 2022

When it concerns cancer care and cancer therapy, drug resistance is more than an obstacle to successful treatment; it is a major cause of frustration in our attempts to optimize drug development versus therapy development. Importantly, overcoming the challenges of drug resistance may provide invaluable clues about the origin and nature of cancer. From this perspective, we discuss how chemoresistance and chemosensitivity in cancer therapy could be directly linked to the stem cell origin of cancer. A stem cell theory of cancer stipulates that both normal stem cells and cancer stem cells are similarly endowed with robust efflux pumps, potent antiapoptotic mechanisms, redundant DNA repair systems, and abundant antioxidation reserves. Cancer stem cells, like their normal stem cell counterparts, are equipped with the same drug resistance phenotypes (e.g., ABC transporters, anti-apoptotic pathways, and DNA repair mechanisms). Drug resistance, like other cancer hallmarks (e.g., tumor heterogeneity and cancer dormancy), could be intrinsically ingrained and innately embedded within malignancy. We elaborate that cellular context and the microenvironment may attenuate the effects of cancer treatments. We examine the role of circadian rhythms and the value of chronotherapy to maximize efficacy and minimize toxicity. We propose that a stem cell theory of drug resistance and drug sensitivity will ultimately empower us to enhance drug development and enable us to improve therapy development in patient care.
High-Mannose N-Glycans as Malignant Progression Markers in Early-Stage Colorectal Cancer
Authors: Boyaval Fanny , Dalebout Hans , Van Zeijl René , Wang Wenjun , Fariña-Sarasqueta Arantza , Lageveen-Kammeijer Guinevere S. M. , Boonstra Jurjen J. , McDonnell Liam A. , Wuhrer Manfred , Morreau Hans , Heijs Bram
Published: March 2022

The increase incidence of early colorectal cancer (T1 CRC) last years is mainly due to the introduction of population-based screening for CRC. T1 CRC staging based on histological criteria remains challenging and there is high variability among pathologists in the scoring of these criteria. It is crucial to unravel the biology behind the progression of adenoma into T1 CRC. Glycomic studies have reported extensively on alterations of the N-glycomic pattern in CRC; therefore, investigating these alterations may reveal new insights into the development of T1 CRC. We used matrix-assisted laser desorption ionization (MALDI) mass spectrometry imaging (MSI) to spatially profile the N-glycan species in a cohort of pT1 CRC using archival formalin-fixed and paraffin-embedded (FFPE) material. To generate structural information on the observed N-glycans, CE-ESI-MS/MS was used in conjunction with MALDI-MSI. Relative intensities and glycosylation traits were calculated based on a panel of 58 N-glycans. Our analysis showed pronounced differences between normal epithelium, dysplastic, and carcinoma regions. High-mannose-type N-glycans were higher in the dysplastic region than in carcinoma, which correlates to increased proliferation of the cells. We observed changes in the cancer invasive front, including higher expression of α2,3-linked sialic acids which followed the glycosylation pattern of the carcinoma region.
Long Non-Coding RNA-Based Functional Prediction Reveals Novel Targets in Notch-Upregulated Ovarian Cancer
Authors: Jeong Seonhyang , Park Sunmi , Jo Young Suk , Choi Moon Jung , Lee Gibbeum , Lee Seul Gi , Choi Min Chul , Park Hyun , Joo Won Duk , Jung Sang Geun , Lee Jandee
Published: March 2022

Notch signaling is a druggable target in high-grade serous ovarian cancers; however, its complexity is not clearly understood. Recent revelations of the biological roles of lncRNAs have led to an increased interest in the oncogenic action of lncRNAs in various cancers. In this study, we performed in silico analyses using The Cancer Genome Atlas data to discover novel Notch-related lncRNAs and validated our transcriptome data via NOTCH1/3 silencing in serous ovarian cancer cells. The expression of novel Notch-related lncRNAs was down-regulated by a Notch inhibitor and was upregulated in high-grade serous ovarian cancers, compared to benign or borderline ovarian tumors. Functionally, Notch-related lncRNAs were tightly linked to Notch-related changes in diverse gene expressions. Notably, genes related to DNA repair and spermatogenesis showed specific correlations with Notch-related lncRNAs. Master transcription factors, including EGR1, CTCF, GABPα, and E2F4 might orchestrate the upregulation of Notch-related lncRNAs, along with the associated genes. The discovery of Notch-related lncRNAs significantly contributes to our understanding of the complex crosstalk of Notch signaling with other oncogenic pathways at the transcriptional level.
Vitamin D Metabolites in Nonmetastatic High-Risk Prostate Cancer Patients with and without Zoledronic Acid Treatment after Prostatectomy
Authors: Stephan Carsten , Ralla Bernhard , Bonn Florian , Diesner Max , Lein Michael , Jung Klaus
Published: March 2022

There are limited and discrepant data on prostate cancer (PCa) and vitamin D. We investigated changes in three vitamin D3 metabolites in PCa patients after prostatectomy with zoledronic acid (ZA) treatment regarding their metastasis statuses over four years. In 32 patients from the ZEUS trial, 25(OH)D3, 24,25(OH)2D3, and 1,25(OH)2D3 were measured with liquid chromatography coupled with tandem mass spectrometry at four time points. All the patients received daily calcium and vitamin D3. Bone metastases were detected in 7 of the 17 ZA-treated patients and in 5 of the 15 controls (without ZA), without differences between the groups (p = 0.725). While 25(OH)D3 and 24,25(OH)2D3 increased significantly after the study’s start, with following constant values, the 1,25(OH)2D3 concentrations remained unchanged. ZA treatment did not change the levels of the three metabolites. 25(OH)D3 and 24,25(OH)2D3 were not associated with the development of bone metastases. In contrast, 1,25(OH)2D3 was also higher in patients with bone metastasis before the study’s start. Thus, in high-risk PCa patients after prostatectomy, 25(OH)D3, 24,25(OH)2D3, and 1,25(OH)2D3 were not affected by supportive ZA treatment or by the development of metastasis over four years, with the exception of 1,25(OH)2D3, which was constantly higher in metastatic patients. There might be potential prognostic value if the results can be confirmed.
Identification of a Steroid Hormone-Associated Gene Signature Predicting the Prognosis of Prostate Cancer through an Integrative Bioinformatics Analysis
Authors: Lai Yo-Liang , Liu Chia-Hsin , Wang Shu-Chi , Huang Shu-Pin , Cho Yi-Chun , Bao Bo-Ying , Su Chia-Cheng , Yeh Hsin-Chih , Lee Cheng-Hsueh , Teng Pai-Chi , Chuu Chih-Pin , Chen Deng-Neng , Li Chia-Yang , Cheng Wei-Chung
Published: March 2022

The importance of anti-androgen therapy for prostate cancer (PC) has been well recognized. However, the mechanisms underlying prostate cancer resistance to anti-androgens are not completely understood. Therefore, identifying pharmacological targets in driving the development of castration-resistant PC is necessary. In the present study, we sought to identify core genes in regulating steroid hormone pathways and associating them with the disease progression of PC. The selection of steroid hormone-associated genes was identified from functional databases, including gene ontology, KEGG, and Reactome. The gene expression profiles and relevant clinical information of patients with PC were obtained from TCGA and used to examine the genes associated with steroid hormone. The machine-learning algorithm was performed for key feature selection and signature construction. With the integrative bioinformatics analysis, an eight-gene signature, including CA2, CYP2E1, HSD17B, SSTR3, SULT1E1, TUBB3, UCN, and UGT2B7 was established. Patients with higher expression of this gene signature had worse progression-free interval in both univariate and multivariate cox models adjusted for clinical variables. The expression of the gene signatures also showed the aggressiveness consistently in two external cohorts, PCS and PAM50. Our findings demonstrated a validated eight-gene signature could successfully predict PC prognosis and regulate the steroid hormone pathway.
Regulation of a Novel Splice Variant of Early Growth Response 4 (EGR4-S) by HER+ Signalling and HSF1 in Breast Cancer
Authors: Drake Jeremy M. , Lang Benjamin J. , Guerrero-Gimenez Martin Eduardo , Bolton Jack , Dow Christopher A. , Calderwood Stuart K. , Price John T. , Nguyen Chau H.
Published: March 2022

The zinc finger transcription factor EGR4 has previously been identified as having a critical role in the proliferation of small cell lung cancer. Here, we have identified a novel, shortened splice variant of this transcription factor (EGR4-S) that is regulated by Heat Shock Factor-1 (HSF1). Our findings demonstrate that the shortened variant (EGR4-S) is upregulated with high EGFR, HER2, and H-Rasv12-expressing breast cell lines, and its expression is inhibited in response to HER pathway inhibitors. Protein and mRNA analyses of HER2+ human breast tumours indicated the novel EGR4-S splice variant to be preferentially expressed in tumour tissue and not detectable in patient-matched normal tissue. Knockdown of EGR4-S in the HER2-amplified breast cancer cell line SKBR3 reduced cell growth, suggesting that EGR4-S supports the growth of HER2+ tumour cells. In addition to chemical inhibitors of the HER2 pathway, EGR4-S expression was also found to be suppressed by chemical stressors and the overexpression of HSF1. Under these conditions, reduced EGR4-S levels were associated with the observed lower cell growth rate, but the augmentation of properties associated with higher metastatic potential. Taken together, these findings identify EGR4-S as a potential biomarker for HER2 pathway activation in human tumours that is regulated by HSF1.
Tumor Treating Fields Concomitant with Sorafenib in Advanced Hepatocellular Cancer: Results of the HEPANOVA Phase II Study
Authors: Gkika Eleni , Grosu Anca-Ligia , Macarulla Mercade Teresa , Cubillo Gracián Antonio , Brunner Thomas B. , Schultheiß Michael , Pazgan-Simon Monika , Seufferlein Thomas , Touchefeu Yann
Published: March 2022

Advanced hepatocellular carcinoma (HCC) is an aggressive disease associated with poor prognosis. Tumor Treating Fields (TTFields) therapy is a non-invasive, loco-regional treatment approved for glioblastoma and malignant pleural mesothelioma. HCC preclinical and abdominal simulation data, together with clinical results in other solid tumors, provide a rationale for investigating TTFields with sorafenib in this patient population. HEPANOVA was a phase II, single arm, historical control study in adults with advanced HCC (NCT03606590). Patients received TTFields (150 kHz) for ≥18 h/day concomitant with sorafenib (400 mg BID). Imaging assessments occurred every 12 weeks until disease progression. The primary endpoint was the overall response rate (ORR). Safety was also evaluated. Patients (n = 27 enrolled; n = 21 evaluable) had a poor prognosis; >50% were Child–Turcotte–Pugh class B and >20% had a baseline Eastern Clinical Oncology Group performance status (ECOG PS) of 2. The ORR was higher, but not statistically significant, for TTFields/sorafenib vs. historical controls: 9.5% vs. 4.5% (p = 0.24), respectively; all responses were partial. Among patients (n = 11) with ≥12 weeks of TTFields/sorafenib, ORR was 18%. Common adverse events (AEs) were diarrhea (n = 15/27, 56%) and asthenia (n = 11/27, 40%). Overall, 19/27 (70%) patients had TTFields-related skin AEs; none were serious. TTFields/sorafenib improved response rates vs. historical controls in patients with advanced HCC, with no new safety concerns or related systemic toxicity.
At the Intersection of Cardiology and Oncology: TGFβ as a Clinically Translatable Therapy for TNBC Treatment and as a Major Regulator of Post-Chemotherapy Cardiomyopathy
Authors: Sulaiman Andrew , Chambers Jason , Chilumula Sai Charan , Vinod Vishak , Kandunuri Rohith , McGarry Sarah , Kim Sung
Published: March 2022

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that accounts for the majority of breast cancer-related deaths due to the lack of specific targets for effective treatments. While there is immense focus on the development of novel therapies for TNBC treatment, a persistent and critical issue is the rate of heart failure and cardiomyopathy, which is a leading cause of mortality and morbidity amongst cancer survivors. In this review, we highlight mechanisms of post-chemotherapeutic cardiotoxicity exposure, evaluate how this is assessed clinically and highlight the transforming growth factor-beta family (TGF-β) pathway and its significance as a mediator of cardiomyopathy. We also highlight recent findings demonstrating TGF-β inhibition as a potent method to prevent cardiac remodeling, fibrosis and cardiomyopathy. We describe how dysregulation of the TGF-β pathway is associated with negative patient outcomes across 32 types of cancer, including TNBC. We then highlight how TGF-β modulation may be a potent method to target mesenchymal (CD44+/CD24−) and epithelial (ALDHhigh) cancer stem cell (CSC) populations in TNBC models. CSCs are associated with tumorigenesis, metastasis, relapse, resistance and diminished patient prognosis; however, due to plasticity and differential regulation, these populations remain difficult to target and continue to present a major barrier to successful therapy. TGF-β inhibition represents an intersection of two fields: cardiology and oncology. Through the inhibition of cardiomyopathy, cardiac damage and heart failure may be prevented, and through CSC targeting, patient prognoses may be improved. Together, both approaches, if successfully implemented, would target the two greatest causes of cancer-related morbidity in patients and potentially lead to a breakthrough therapy.
Addressing the Elephant in the Immunotherapy Room: Effector T-Cell Priming versus Depletion of Regulatory T-Cells by Anti-CTLA-4 Therapy
Authors: Hong Megan M Y , Maleki Vareki Saman
Published: March 2022

Cytotoxic T-lymphocyte Associated Protein 4 (CTLA-4) is an immune checkpoint molecule highly expressed on regulatory T-cells (Tregs) that can inhibit the activation of effector T-cells. Anti-CTLA-4 therapy can confer long-lasting clinical benefits in cancer patients as a single agent or in combination with other immunotherapy agents. However, patient response rates to anti-CTLA-4 are relatively low, and a high percentage of patients experience severe immune-related adverse events. Clinical use of anti-CTLA-4 has regained interest in recent years; however, the mechanism(s) of anti-CTLA-4 is not well understood. Although activating T-cells is regarded as the primary anti-tumor mechanism of anti-CTLA-4 therapies, mounting evidence in the literature suggests targeting intra-tumoral Tregs as the primary mechanism of action of these agents. Tregs in the tumor microenvironment can suppress the host anti-tumor immune responses through several cell contact-dependent and -independent mechanisms. Anti-CTLA-4 therapy can enhance the priming of T-cells by blockading CD80/86-CTLA-4 interactions or depleting Tregs through antibody-dependent cellular cytotoxicity and phagocytosis. This review will discuss proposed fundamental mechanisms of anti-CTLA-4 therapy, novel uses of anti-CTLA-4 in cancer treatment and approaches to improve the therapeutic efficacy of anti-CTLA-4.
The Impact of Cognitive Impairment on Treatment Toxicity, Treatment Completion, and Survival among Older Adults Receiving Chemotherapy: A Systematic Review
Authors: Sattar Schroder , Haase Kristen , Tejero Isabel , Bradley Cara , Mariano Caroline , Kilgour Heather , Verma Ridhi , Amir Eitan , Alibhai Shabbir
Published: March 2022

Cognitive impairment (CI) is common among older adults with cancer, but its effect on cancer outcomes is not known. This systematic review sought to identify research investigating clinical endpoints (toxicity risk, treatment completion, and survival) of chemotherapy treatment in those with baseline CI. A systematic search of five databases (inception to March 2021) was conducted. Eligible studies included randomized trials, prospective studies, and retrospective studies in which the sample or a subgroup were older adults (aged ≥ 65) screened positive for CI prior to receiving chemotherapy. Risk of bias assessment was performed using the Quality in Prognosis Studies (QUIPS) tool. Twenty-three articles were included. Sample sizes ranged from n = 31 to 703. There was heterogeneity of cancer sites, screening tools and cut-offs used to ascertain CI, and proportion of patients with CI within study samples. Severity of CI and corresponding proportion of each level within study samples were unclear in all but one study. Among studies investigating CI in a qualified multivariable model, statistically significant findings were found in 4/6 studies on survival and in 1/1 study on nonhematological toxicity. The lack of robust evidence indicates a need for further research on the role of CI in predicting survival, treatment completion, and toxicity among older adults receiving chemotherapy, and the potential implications that could shape treatment decisions.
The Role of ROS as a Double-Edged Sword in (In)Fertility: The Impact of Cancer Treatment
Authors: Mendes Sara , Sá Rosália , Magalhães Manuel , Marques Franklim , Sousa Mário , Silva Elisabete
Published: March 2022

Tumor cells are highly resistant to oxidative stress resulting from the imbalance between high reactive oxygen species (ROS) production and insufficient antioxidant defenses. However, when intracellular levels of ROS rise beyond a certain threshold, largely above cancer cells’ capacity to reduce it, they may ultimately lead to apoptosis or necrosis. This is, in fact, one of the molecular mechanisms of anticancer drugs, as most chemotherapeutic treatments alter redox homeostasis by further elevation of intracellular ROS levels or inhibition of antioxidant pathways. In traditional chemotherapy, it is widely accepted that most therapeutic effects are due to ROS-mediated cell damage, but in targeted therapies, ROS-mediated effects are mostly unknown and data are still emerging. The increasing effectiveness of anticancer treatments has raised new challenges, especially in the field of reproduction. With cancer patients’ life expectancy increasing, many aiming to become parents will be confronted with the adverse effects of treatments. Consequently, concerns about the impact of anticancer therapies on reproductive capacity are of particular interest. In this review, we begin with a short introduction on anticancer therapies, then address ROS physiological/pathophysiological roles in both male and female reproductive systems, and finish with ROS-mediated adverse effects of anticancer treatments in reproduction.
Considerations and Challenges in the Management of the Older Patients with Gastric Cancer
Authors: Loizides Sotiris , Papamichael Demetris
Published: March 2022

Gastric cancer is one of the commonest malignancies with high rates of mortality worldwide. Older patients represent a substantial proportion of cases with this diagnosis. However, there are very few ‘elderly-specific’ trials in this setting. In addition, the inclusion rate of such patients in randomised clinical trials is poor, presumably due to concerns about increased toxicity, co-existing comorbidities and impaired performance status. Therapeutic strategies for this patient group are therefore mostly based on retrospective subgroup analysis of randomised clinical trials. Review of currently available evidence suggests that older gastric cancer patients who are fit for trial inclusion may benefit from surgical intervention and peri-operative systemic chemotherapy strategies. For patients with metastatic disease, management has been revolutionized by the use of anti-HER2 directed therapies as well as immune checkpoint inhibitors with or without chemotherapy. Early data suggest that fit older patients may also benefit from these therapeutic interventions. However, once again there may be limitations in extrapolating these data to everyday clinical practice with older patients being less likely to have a good performance status and an intact immune system. Therefore, determining the functional age and not just the chronological age of a patient prior to initiating therapy becomes very important. The functional decline including reduced organ function that may occur in older patients makes the integration of some form of geriatric assessment in routine clinical practice very relevant.
The Multi-Kinase Inhibitor EC-70124 Is a Promising Candidate for the Treatment of FLT3-ITD-Positive Acute Myeloid Leukemia
Authors: Lopez-Millan Belen , Costales Paula , Gutiérrez-Agüera Francisco , Díaz de la Guardia Rafael , Roca-Ho Heleia , Vinyoles Meritxell , Rubio-Gayarre Alba , Safi Rémi , Castaño Julio , Romecín Paola Alejandra , Ramírez-Orellana Manuel , Anguita Eduardo , Jeremias Irmela , Zamora Lurdes , Rodríguez-Manzaneque Juan Carlos , Bueno Clara , Morís Francisco , Menendez Pablo
Published: March 2022

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Patients with AML harboring a constitutively active internal tandem duplication mutation (ITDMUT) in the FMS-like kinase tyrosine kinase (FLT3) receptor generally have a poor prognosis. Several tyrosine kinase/FLT3 inhibitors have been developed and tested clinically, but very few (midostaurin and gilteritinib) have thus far been FDA/EMA-approved for patients with newly diagnosed or relapse/refractory FLT3-ITDMUT AML. Disappointingly, clinical responses are commonly partial or not durable, highlighting the need for new molecules targeting FLT3-ITDMUT AML. Here, we tested EC-70124, a hybrid indolocarbazole analog from the same chemical space as midostaurin with a potent and selective inhibitory effect on FLT3. In vitro, EC-70124 exerted a robust and specific antileukemia activity against FLT3-ITDMUT AML primary cells and cell lines with respect to cytotoxicity, CFU capacity, apoptosis and cell cycle while sparing healthy hematopoietic (stem/progenitor) cells. We also analyzed its efficacy in vivo as monotherapy using two different xenograft models: an aggressive and systemic model based on MOLM-13 cells and a patient-derived xenograft model. Orally disposable EC-70124 exerted a potent inhibitory effect on the growth of FLT3-ITDMUT AML cells, delaying disease progression and debulking the leukemia. Collectively, our findings show that EC-70124 is a promising and safe agent for the treatment of AML with FLT3-ITDMUT.
Selective Targeting of Protein Kinase C (PKC)-θ Nuclear Translocation Reduces Mesenchymal Gene Signatures and Reinvigorates Dysfunctional CD8+ T Cells in Immunotherapy-Resistant and Metastatic Cancers
Authors: Dunn Jenny , McCuaig Robert D. , Tan Abel H. Y. , Tu Wen Juan , Wu Fan , Wagstaff Kylie M. , Zafar Anjum , Ali Sayed , Diwakar Himanshu , Dahlstrom Jane E. , Bean Elaine G. , Forwood Jade K. , Tsimbalyuk Sofiya , Cross Emily M. , Hardy Kristine , Bain Amanda L. , Ahern Elizabeth , Dolcetti Riccardo , Mazzieri Roberta , Yip Desmond , Eastgate Melissa , Malik Laeeq , Milburn Peter , Jans David A. , Rao Sudha
Published: March 2022

Protein kinase C (PKC)-θ is a serine/threonine kinase with both cytoplasmic and nuclear functions. Nuclear chromatin-associated PKC-θ (nPKC-θ) is increasingly recognized to be pathogenic in cancer, whereas its cytoplasmic signaling is restricted to normal T-cell function. Here we show that nPKC-θ is enriched in circulating tumor cells (CTCs) in patients with triple-negative breast cancer (TNBC) brain metastases and immunotherapy-resistant metastatic melanoma and is associated with poor survival in immunotherapy-resistant disease. To target nPKC-θ, we designed a novel PKC-θ peptide inhibitor (nPKC-θi2) that selectively inhibits nPKC-θ nuclear translocation but not PKC-θ signaling in healthy T cells. Targeting nPKC-θ reduced mesenchymal cancer stem cell signatures in immunotherapy-resistant CTCs and TNBC xenografts. PKC-θ was also enriched in the nuclei of CD8+ T cells isolated from stage IV immunotherapy-resistant metastatic cancer patients. We show for the first time that nPKC-θ complexes with ZEB1, a key repressive transcription factor in epithelial-to-mesenchymal transition (EMT), in immunotherapy-resistant dysfunctional PD1+/CD8+ T cells. nPKC-θi2 inhibited the ZEB1/PKC-θ repressive complex to induce cytokine production in CD8+ T cells isolated from patients with immunotherapy-resistant disease. These data establish for the first time that nPKC-θ mediates immunotherapy resistance via its activity in CTCs and dysfunctional CD8+ T cells. Disrupting nPKC-θ but retaining its cytoplasmic function may offer a means to target metastases in combination with chemotherapy or immunotherapy.
Continuous Flow Biocatalysis: Synthesis of Coumarin Carboxamide Derivatives by Lipase TL IM from Thermomyces lanuginosus
Authors: Du Li-Hua , Yang Meng-Jie , Pan Yue , Zheng Ling-Yan , Zhang Shi-Yi , Sheng Zhi-Kai , Chen Ping-Feng , Luo Xi-Ping
Published: March 2022

Coumarin carboxamide derivatives are important building blocks for organic synthesis and chemical biology due to their excellent biopharmaceutical properties. In this paper, we demonstrate for the first time a two-step enzymatic synthesis of coumarin carboxamide derivatives. Salicylaldehyde and dimethyl malonate were reacted to obtain coumarin carboxylate methyl derivatives, which were then reacted with various amines under the catalysis of lipase TL IM from Thermomyces lanuginosus to obtain coumarin carboxamide derivatives in continuous flow reactors. We studied various reaction parameters on the yields. The important features of this method include mild reaction conditions, a short reaction time (40 min), reduced environmental pollution, higher productivity (STY = 31.2941 g L−1 h−1) and enzymes being relatively easy to obtain.
Mesenchymal Stromal Cells in Ischemic Brain Injury
Authors: Brooks Beverly , Ebedes Dominique , Usmani Ahsan , Gonzales-Portillo Joaquin Vega , Gonzales-Portillo Daniel , Borlongan Cesario V.
Published: March 2022

Ischemic brain injury represents a major cause of death worldwide with limited treatment options with a narrow therapeutic window. Accordingly, novel treatments that extend the treatment from the early neuroprotective stage to the late regenerative phase may accommodate a much larger number of stroke patients. To this end, stem cell-based regenerative therapies may address this unmet clinical need. Several stem cell therapies have been tested as potentially exhibiting the capacity to regenerate the stroke brain. Based on the long track record and safety profile of transplantable stem cells for hematologic diseases, bone marrow-derived mesenchymal stromal cells or mesenchymal stromal cells have been widely tested in stroke animal models and have reached clinical trials. However, despite the translational promise of MSCs, probing cell function remains to be fully elucidated. Recognizing the multi-pronged cell death and survival processes that accompany stroke, here we review the literature on MSC definition, characterization, and mechanism of action in an effort to gain a better understanding towards optimizing its applications and functional outcomes in stroke.
Impact of Anti PD-1 Immunotherapy on HIV Reservoir and Anti-Viral Immune Responses in People Living with HIV and Cancer
Authors: Baron Marine , Soulié Cathia , Lavolé Armelle , Assoumou Lambert , Abbar Baptiste , Fouquet Baptiste , Rousseau Alice , Veyri Marianne , Samri Assia , Makinson Alain , Choquet Sylvain , Mazières Julien , Brosseau Solenn , Autran Brigitte , Costagliola Dominique , Katlama Christine , Cadranel Jacques , Marcelin Anne-Geneviève , Lambotte Olivier , Spano Jean-Philippe , Guihot Amélie ,   The French Cooperative Thoracic Intergroup (IFCT) CHIVA-2 Investigators,   The ANRS Co 24 OncoVIHAC Study Group
Published: March 2022

The role of immune checkpoints (ICPs) in both anti-HIV T cell exhaustion and HIV reservoir persistence, has suggested that an HIV cure therapeutic strategy could involve ICP blockade. We studied the impact of anti-PD-1 therapy on HIV reservoirs and anti-viral immune responses in people living with HIV and treated for cancer. At several timepoints, we monitored CD4 cell counts, plasma HIV-RNA, cell associated (CA) HIV-DNA, EBV, CMV, HBV, HCV, and HHV-8 viral loads, activation markers, ICP expression and virus-specific T cells. Thirty-two patients were included, with median follow-up of 5 months. The CA HIV-DNA tended to decrease before cycle 2 (p = 0.049). Six patients exhibited a ≥0.5 log10 HIV-DNA decrease at least once. Among those, HIV-DNA became undetectable for 10 months in one patient. Overall, no significant increase in HIV-specific immunity was observed. In contrast, we detected an early increase in CTLA-4 + CD4+ T cells in all patients (p = 0.004) and a greater increase in CTLA-4+ and TIM-3 + CD8+ T cells in patients without HIV-DNA reduction compared to the others (p ≤ 0.03). Our results suggest that ICP replacement compensatory mechanisms might limit the impact of anti-PD-1 monotherapy on HIV reservoirs, and pave the way for combination ICP blockade in HIV cure strategies.
Salvia miltiorrhiza Extract and Individual Synthesized Component Derivatives Induce Activating-Transcription-Factor-3-Mediated Anti-Obesity Effects and Attenuate Obesity-Induced Metabolic Disorder by Suppressing C/EBPα in High-Fat-Induced Obese Mice
Authors: Wu Yueh-Lin , Lin Heng , Li Hsiao-Fen , Don Ming-Jaw , King Pei-Chih , Chen Hsi-Hsien
Published: March 2022

Pharmacological studies indicate that Salvia miltiorrhiza extract (SME) can improve cardiac and blood vessel function. However, there is limited knowledge regarding the effects (exerted through epigenetic regulation) of SME and newly derived single compounds, with the exception of tanshinone IIA and IB, on obesity-induced metabolic disorders. In this study, we administered SME or dimethyl sulfoxide (DMSO) as controls to male C57BL/J6 mice after they were fed a high-fat diet (HFD) for 4 weeks. SME treatment significantly reduced body weight, fasting plasma glucose, triglyceride levels, insulin resistance, and adipogenesis/lipogenesis gene expression in treated mice compared with controls. Transcriptome array analysis revealed that the expression of numerous transcriptional factors, including activating transcription factor 3 (ATF3) and C/EBPα homologous protein (CHOP), was significantly higher in the SME group. ST32db, a novel synthetic derivative similar in structure to compounds from S. miltiorrhiza extract, ameliorates obesity and obesity-induced metabolic syndrome in HFD-fed wild-type mice but not ATF3−/− mice. ST32db treatment of 3T3-L1 adipocytes suppresses lipogenesis/adipogenesis through the ATF3 pathway to directly inhibit C/EBPα expression and indirectly inhibit the CHOP pathway. Overall, ST32db, a single compound modified from S. miltiorrhiza extract, has anti-obesity effects through ATF3-mediated C/EBPα downregulation and the CHOP pathway. Thus, SME and ST32db may reduce obesity and diabetes in mice, indicating the potential of both SME and ST32db as therapeutic drugs for the treatment of obesity-induced metabolic syndrome.
Activation of Calpain Contributes to Mechanical Ventilation-Induced Depression of Protein Synthesis in Diaphragm Muscle
Authors: Hyatt Hayden W. , Ozdemir Mustafa , Bomkamp Matthew P. , Powers Scott K.
Published: March 2022

Mechanical ventilation (MV) is a clinical tool that provides respiratory support to patients unable to maintain adequate alveolar ventilation on their own. Although MV is often a life-saving intervention in critically ill patients, an undesired side-effect of prolonged MV is the rapid occurrence of diaphragmatic atrophy due to accelerated proteolysis and depressed protein synthesis. Investigations into the mechanism(s) responsible for MV-induced diaphragmatic atrophy reveal that activation of the calcium-activated protease, calpain, plays a key role in accelerating proteolysis in diaphragm muscle fibers. Moreover, active calpain has been reported to block signaling events that promote protein synthesis (i.e., inhibition of mammalian target of rapamycin (mTOR) activation). While this finding suggests that active calpain can depress muscle protein synthesis, this postulate has not been experimentally verified. Therefore, we tested the hypothesis that active calpain plays a key role in the MV-induced depression of both anabolic signaling events and protein synthesis in the diaphragm muscle. MV-induced activation of calpain in diaphragm muscle fibers was prevented by transgene overexpression of calpastatin, an endogenous inhibitor of calpain. Our findings indicate that overexpression of calpastatin averts MV-induced activation of calpain in diaphragm fibers and rescues the MV-induced depression of protein synthesis in the diaphragm muscle. Surprisingly, deterrence of calpain activation did not impede the MV-induced inhibition of key anabolic signaling events including mTOR activation. However, blockade of calpain activation prevented the calpain-induced cleavage of glutaminyl-tRNA synthetase in diaphragm fibers; this finding is potentially important because aminoacyl-tRNA synthetases play a central role in protein synthesis. Regardless of the mechanism(s) responsible for calpain’s depression of protein synthesis, these results provide the first evidence that active calpain plays an important role in promoting the MV-induced depression of protein synthesis within diaphragm fibers.
On the Cutting Edge of Oral Cancer Prevention: Finding Risk-Predictive Markers in Precancerous Lesions by Longitudinal Studies
Authors: Crawford Madeleine , Johnson Eliza H. , Liu Kelly Y. P. , Poh Catherine , Tsai Robert Y. L.
Published: March 2022

Early identification and management of precancerous lesions at high risk of developing cancers is the most effective and economical way to reduce the incidence, mortality, and morbidity of cancers as well as minimizing treatment-related complications, including pain, impaired functions, and disfiguration. Reliable cancer-risk-predictive markers play an important role in enabling evidence-based decision making as well as providing mechanistic insight into the malignant conversion of precancerous lesions. The focus of this article is to review updates on markers that may predict the risk of oral premalignant lesions (OPLs) in developing into oral squamous cell carcinomas (OSCCs), which can logically be discovered only by prospective or retrospective longitudinal studies that analyze pre-progression OPL samples with long-term follow-up outcomes. These risk-predictive markers are different from those that prognosticate the survival outcome of cancers after they have been diagnosed and treated, or those that differentiate between different lesion types and stages. Up-to-date knowledge on cancer-risk-predictive markers discovered by longitudinally followed studies will be reviewed. The goal of this endeavor is to use this information as a starting point to address some key challenges limiting our progress in this area in the hope of achieving effective translation of research discoveries into new clinical interventions.
The Atypical Chemerin Receptor GPR1 Displays Different Modes of Interaction with β-Arrestins in Humans and Mice with Important Consequences on Subcellular Localization and Trafficking
Authors: Degroot Gaetan-Nagim , Lepage Valentin , Parmentier Marc , Springael Jean-Yves
Published: March 2022

Atypical chemokine receptors (ACKRs) have emerged as a subfamily of chemokine receptors regulating the local bioavailability of their ligands through scavenging, concentration, or transport. The biological roles of ACKRs in human physiology and diseases are often studied by using transgenic mouse models. However, it is unknown whether mouse and human ACKRs share the same properties. In this study, we compared the properties of the human and mouse atypical chemerin receptor GPR1 and showed that they behave differently regarding their interaction with β-arrestins. Human hGPR1 interacts with β-arrestins as a result of chemerin stimulation, whereas its mouse orthologue mGPR1 displays a strong constitutive interaction with β-arrestins in basal conditions. The constitutive interaction of mGPR1 with β-arrestins is accompanied by a redistribution of the receptor from the plasma membrane to early and recycling endosomes. In addition, β-arrestins appear mandatory for the chemerin-induced internalization of mGPR1, whereas they are dispensable for the trafficking of hGPR1. However, mGPR1 scavenges chemerin and activates MAP kinases ERK1/2 similarly to hGPR1. Finally, we showed that the constitutive interaction of mGPR1 with β-arrestins required different structural constituents, including the receptor C-terminus and arginine 3.50 in the second intracellular loop. Altogether, our results show that sequence variations within cytosolic regions of GPR1 orthologues influence their ability to interact with β-arrestins, with important consequences on GPR1 subcellular distribution and trafficking.