bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Hormones on Breast Development and Breast Cancer Risk in Transgender Women
Authors: Berliere Martine , Coche Maximilienne , Lacroix Camille , Riggi Julia , Coyette Maude , Coulie Julien , Galant Christine , Fellah Latifa , Leconte Isabelle , Maiter Dominique , Duhoux Francois P. , François Aline
Published: January 2023

Transgender women experience gender dysphoria due to a gender assignment at birth that is incongruent with their gender identity. Transgender people undergo different surgical procedures and receive sex steroids hormones to reduce psychological distress and to induce and maintain desired physical changes. These persons on feminizing hormones represent a unique population to study the hormonal effects on breast development, to evaluate the risk of breast cancer and perhaps to better understand the precise role played by different hormonal components. In MTF (male to female) patients, hormonal treatment usually consists of antiandrogens and estrogens. Exogenous hormones induce breast development with the formation of ducts and lobules and an increase in the deposition of fat. A search of the existing literature dedicated to hormone regimens for MTF patients, their impact on breast tissue (incidence and type of breast lesions) and breast cancer risk provided the available information for this review. The evaluation of breast cancer risk is currently complicated by the heterogeneity of administered treatments and a lack of long-term follow-up in the great majority of studies. Large studies with longer follow-up are required to better evaluate the breast cancer risk and to understand the precise mechanisms on breast development of each exogenous hormone.
Pain as a Protective Factor for Alzheimer Disease in Patients with Cancer
Authors: Xia Siqi , Yu Xiaobo , Chen Gao
Published: January 2023

Objective: Alzheimer disease (AD) and cancer have been reported to be inversely correlated in incidence, but the mechanism remains elusive. Methods: A case-control study was conducted, based on the SEER (Surveillance, Epidemiology, and End Results) Research Plus data, to evaluate 12 factors in patients with cancer. Results: Severe pain was related to reduced AD risk, while older age at cancer diagnosis, female, longer survival years after tumor diagnosis, more benign/borderline tumors, less cancer-directed surgery, and more chemotherapy were associated with higher AD risk. In addition, patients of different races or with different cancer sites were associated with different risks of getting AD. Cases had a higher prevalence of severe pain than controls in all race and cancer site subgroups, except for in digestive cancer, where the result was the opposite. Conclusions: This study indicated pain as a novel protective factor for AD in patients with cancer. The mechanism behind it may provide new perspective on AD pathogenesis and AD-cancer association, which we discussed in our own hypothesis of the mechanism of pain action. In addition, digestive cancer pain had an opposite impact on AD risk from other cancer pains, which suggests the uniqueness of digestive system in interacting with the central nervous system.
Multifaceted Pharmacological Potentials of Curcumin, Genistein, and Tanshinone IIA through Proteomic Approaches: An In-Depth Review
Authors: Khan Farheen Badrealam , Singh Parul , Jamous Yahya F. , Ali Syed Azmal , Abdullah  , Uddin Shahab , Zia Qamar , Jena Manoj Kumar , Khan Mohsina , Owais Mohammad , Huang Chih Yang , Chanukuppa Venkatesh , Ardianto Chrismawan , Ming Long Chiau , Alam Waqas , Khan Haroon , Ayoub Mohammad Akli
Published: January 2023

Phytochemicals possess various intriguing pharmacological properties against diverse pathological conditions. Extensive studies are on-going to understand the structural/functional properties of phytochemicals as well as the molecular mechanisms of their therapeutic function against various disease conditions. Phytochemicals such as curcumin (Cur), genistein (Gen), and tanshinone-IIA (Tan IIA) have multifaceted therapeutic potentials and various efforts are in progress to understand the molecular dynamics of their function with different tools and technologies. Cur is an active lipophilic polyphenol with pleiotropic function, and it has been shown to possess various intriguing properties including antioxidant, anti-inflammatory, anti-microbial, anticancer, and anti-genotoxic properties besides others beneficial properties. Similarly, Gen (an isoflavone) exhibits a wide range of vital functions including antioxidant, anti-inflammatory, pro-apoptotic, anti-proliferative, anti-angiogenic activities etc. In addition, Tan IIA, a lipophilic compound, possesses antioxidant, anti-angiogenic, anti-inflammatory, anticancer activities, and so on. Over the last few decades, the field of proteomics has garnered great momentum mainly attributed to the recent advancement in mass spectrometry (MS) techniques. It is envisaged that the proteomics technology has considerably contributed to the biomedical research endeavors lately. Interestingly, they have also been explored as a reliable approach to understand the molecular intricacies related to phytochemical-based therapeutic interventions. The present review provides an overview of the proteomics studies performed to unravel the underlying molecular intricacies of various phytochemicals such as Cur, Gen, and Tan IIA. This in-depth study will help the researchers in better understanding of the pharmacological potential of the phytochemicals at the proteomics level. Certainly, this review will be highly instrumental in catalyzing the translational shift from phytochemical-based biomedical research to clinical practice in the near future.
Present and Future Role of Immune Targets in Acute Myeloid Leukemia
Authors: Damiani Daniela , Tiribelli Mario
Published: January 2023

It is now well known that the bone marrow (BM) cell niche contributes to leukemogenesis, but emerging data support the role of the complex crosstalk between AML cells and the BM microenvironment to induce a permissive immune setting that protects leukemic stem cells (LSCs) from therapy-induced death, thus favoring disease persistence and eventual relapse. The identification of potential immune targets on AML cells and the modulation of the BM environment could lead to enhanced anti-leukemic effects of drugs, immune system reactivation, and the restoration of AML surveillance. Potential targets and effectors of this immune-based therapy could be monoclonal antibodies directed against LSC antigens such as CD33, CD123, and CLL-1 (either as direct targets or via several bispecific T-cell engagers), immune checkpoint inhibitors acting on different co-inhibitory axes (alone or in combination with conventional AML drugs), and novel cellular therapies such as chimeric antigen receptor (CAR) T-cells designed against AML-specific antigens. Though dozens of clinical trials, mostly in phases I and II, are ongoing worldwide, results have still been negatively affected by difficulties in the identification of the optimal targets on LSCs.
Results of PD-L1 Analysis of Women Treated with Durvalumab in Advanced Endometrial Carcinoma (PHAEDRA)
Authors: Smith Deborah , Robledo Kristy P. , Yip Sonia , Cummins Michelle M. , Kok Peey-Sei , Lee Yeh Chen , Friedlander Michael , Baron-Hay Sally , Shannon Catherine , Coward Jermaine , Beale Philip , Goss Geraldine , Meniawy Tarek , Lombard Janine , Spurdle Amanda B. , Andrews John , Stockler Martin R. , Mileshkin Linda , Antill Yoland
Published: January 2023

Women with advanced endometrial carcinoma (EC) with mismatch repair (MMR) deficiency have improved outcomes when treated with immune checkpoint inhibitors; however, additional biomarkers are needed to identify women most likely to respond. Scores for programmed death ligand 1 (PD-L1), immunohistochemical staining of tumor (TC+), immune cells (IC+) and presence of tumor-associated immune cells (ICP) on MMR deficient (n = 34) and proficient (n = 33) EC from women treated with durvalumab in the PHAEDRA trial (ANZGOG1601/CTC0144) (trial registration number ACTRN12617000106336, prospectively registered 19 January 2017) are reported and correlated with outcome. Receiver operating characteristic (ROC) analyses and area under the ROC curve were used to determine optimal cutpoints. Performance was compared with median cutpoints and two algorithms; a novel algorithm derived from optimal cutpoints (TC+ ≥ 1 or ICP ≥ 10 or IC+ ≥ 35) and the Ventana urothelial carcinoma (UC) algorithm (either TC+ ≥ 25, ICP > 1 and IC+ ≥ 25 or ICP = 1 and IC+ = 100). The cutpoint ICP ≥ 10 had highest sensitivity (53%) and specificity (82%), being prognostic for progression-free survival (PFS) (p = 0.01), while the optimal cutpoints algorithm was associated with overall survival (p = 0.02); these results were not significant after adjusting for MMR status. The optimal cutpoints algorithm identified non-responders (p = 0.02) with high sensitivity (88%) and negative predictive value (92%), remaining significant after adjustment for MMR. Although MMR status had the strongest association with response, further work to determine the significance of ICP ≥ 10 and the novel optimal cutpoint algorithm is needed.
Macrophage Resistance to Ionizing Radiation Exposure Is Accompanied by Decreased Cathepsin D and Increased Transferrin Receptor 1 Expression
Authors: Pinto Ana Teresa , Machado Ana Beatriz , Osório Hugo , Pinto Marta Laranjeiro , Vitorino Rui , Justino Gonçalo , Santa Cátia , Castro Flávia , Cruz Tânia , Rodrigues Carla , Lima Jorge , Sousa José Luís R. , Cardoso Ana Patrícia , Figueira Rita , Monteiro Armanda , Marques Margarida , Manadas Bruno , Pauwels Jarne , Gevaert Kris , Mareel Marc , Rocha Sónia , Duarte Tiago , Oliveira Maria José
Published: January 2023

Purpose: To identify a molecular signature of macrophages exposed to clinically relevant ionizing radiation (IR) doses, mirroring radiotherapy sessions. Methods: Human monocyte-derived macrophages were exposed to 2 Gy/ fraction/ day for 5 days, mimicking one week of cancer patient’s radiotherapy. Protein expression profile by proteomics was performed. Results: A gene ontology analysis revealed that radiation-induced protein changes are associated with metabolic alterations, which were further supported by a reduction of both cellular ATP levels and glucose uptake. Most of the radiation-induced deregulated targets exhibited a decreased expression, as was the case of cathepsin D, a lysosomal protease associated with cell death, which was validated by Western blot. We also found that irradiated macrophages exhibited an increased expression of the transferrin receptor 1 (TfR1), which is responsible for the uptake of transferrin-bound iron. TfR1 upregulation was also found in tumor-associated mouse macrophages upon tumor irradiation. In vitro irradiated macrophages also presented a trend for increased divalent metal transporter 1 (DMT1), which transports iron from the endosome to the cytosol, and a significant increase in iron release. Conclusions: Irradiated macrophages present lower ATP levels and glucose uptake, and exhibit decreased cathepsin D expression, while increasing TfR1 expression and altering iron metabolism.
Current State of Immunotherapy and Mechanisms of Immune Evasion in Ewing Sarcoma and Osteosarcoma
Authors: Evdokimova Valentina , Gassmann Hendrik , Radvanyi Laszlo , Burdach Stefan E. G.
Published: January 2023

We argue here that in many ways, Ewing sarcoma (EwS) is a unique tumor entity and yet, it shares many commonalities with other immunologically cold solid malignancies. From the historical perspective, EwS, osteosarcoma (OS) and other bone and soft-tissue sarcomas were the first types of tumors treated with the immunotherapy approach: more than 100 years ago American surgeon William B. Coley injected his patients with a mixture of heat-inactivated bacteria, achieving survival rates apparently higher than with surgery alone. In contrast to OS which exhibits recurrent somatic copy-number alterations, EwS possesses one of the lowest mutation rates among cancers, being driven by a single oncogenic fusion protein, most frequently EWS-FLI1. In spite these differences, both EwS and OS are allied with immune tolerance and low immunogenicity. We discuss here the potential mechanisms of immune escape in these tumors, including low representation of tumor-specific antigens, low expression levels of MHC-I antigen-presenting molecules, accumulation of immunosuppressive M2 macrophages and myeloid proinflammatory cells, and release of extracellular vesicles (EVs) which are capable of reprogramming host cells in the tumor microenvironment and systemic circulation. We also discuss the vulnerabilities of EwS and OS and potential novel strategies for their targeting.
Habitat Imaging Biomarkers for Diagnosis and Prognosis in Cancer Patients Infected with COVID-19
Authors: Aminu Muhammad , Yadav Divya , Hong Lingzhi , Young Elliana , Edelkamp Paul , Saad Maliazurina , Salehjahromi Morteza , Chen Pingjun , Sujit Sheeba J. , Chen Melissa M. , Sabloff Bradley , Gladish Gregory , de Groot Patricia M. , Godoy Myrna C. B. , Cascone Tina , Vokes Natalie I. , Zhang Jianjun , Brock Kristy K. , Daver Naval , Woodman Scott E. , Tawbi Hussein A. , Sheshadri Ajay , Lee J. Jack , Jaffray David ,   D3CODE Team, Wu Carol C. , Chung Caroline , Wu Jia
Published: January 2023

Objectives: Cancer patients have worse outcomes from the COVID-19 infection and greater need for ventilator support and elevated mortality rates than the general population. However, previous artificial intelligence (AI) studies focused on patients without cancer to develop diagnosis and severity prediction models. Little is known about how the AI models perform in cancer patients. In this study, we aim to develop a computational framework for COVID-19 diagnosis and severity prediction particularly in a cancer population and further compare it head-to-head to a general population. Methods: We have enrolled multi-center international cohorts with 531 CT scans from 502 general patients and 420 CT scans from 414 cancer patients. In particular, the habitat imaging pipeline was developed to quantify the complex infection patterns by partitioning the whole lung regions into phenotypically different subregions. Subsequently, various machine learning models nested with feature selection were built for COVID-19 detection and severity prediction. Results: These models showed almost perfect performance in COVID-19 infection diagnosis and predicting its severity during cross validation. Our analysis revealed that models built separately on the cancer population performed significantly better than those built on the general population and locked to test on the cancer population. This may be because of the significant difference among the habitat features across the two different cohorts. Conclusions: Taken together, our habitat imaging analysis as a proof-of-concept study has highlighted the unique radiologic features of cancer patients and demonstrated effectiveness of CT-based machine learning model in informing COVID-19 management in the cancer population.
Radiotherapy Fraction in Limited-Stage Small Cell Lung Cancer in the Modern Era: A Systematic Review and Meta-Analysis of 8006 Reconstructed Individual Patient Data
Authors: Zhao Jingjing , Wu Linfang , Hu Chen , Bi Nan , Wang Luhua
Published: January 2023

The optimal thoracic radiotherapy (TRT) dose and fractionation for limited-stage small cell lung cancer (LS-SCLC) using modern techniques remain unclear. We conducted systematic review and meta-analyses of the efficacy and safety differences between definitive hypofractionated TRT (HypoTRT), conventional TRT (ConvTRT) and hyperfractionated TRT (HyperTRT), especially in the modern era. Eligible randomized controlled trials (RCTs), real-world cohorts, and single-arm trials published between 1990 and 2021 were identified. Two meta-analyses of overall survival (OS) were conducted: (i) a random-effects meta-analysis based on reconstructed individual-patient data (IPD) of all studies; and (ii) a Bayesian network meta-analysis based on study-level aggregated data (AD) of RCTs. The incidences of severe radiation-related toxicities were compared using the random-effects meta-regression model. Overall, 53 of the 30,031 publications met the inclusion criteria, and a total of 8006 IPD were reconstructed. After adjusting for key treatment variables and stratification by study type, there were no significant differences in the OS rates between the altered fractionation regimens (HypoTRT vs. HyperTRT, aHR [adjusted HR] = 1.05, 95% CI 0.93–1.19; ConvTRT vs. HyperTRT, aHR = 1.00, 95% CI 0·90–1.11; HypoTRT vs. ConvTRT, aHR = 1.05, 95% CI 0.91–1.20). In the modern era, the survival outcomes of all three schedules, while remaining comparable, have improved significantly. Results of the AD-based network meta-analysis were consistent with those of IPD analysis, and HypoTRT was ranked as the best regimen (SUCRA = 81%). There were no significant differences in toxicities between groups when using modern radiation techniques. In the modern era, no significant differences in OS or severe radiation-related toxicities were observed between altered schedules in LS-SCLC. HypoTRT may be associated with moderate and non-significant OS improvements, which should be further confirmed in prospective randomized phase III trials.
Laparoscopic Cytoreduction Combined with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Peritoneal Surface Malignancies (PSM): Italian PSM Oncoteam Evidence and Literature Review
Authors: Sommariva Antonio , Valle Mario , Gelmini Roberta , Tonello Marco , Carboni Fabio , De Manzoni Giovanni , Sorrentino Lorena , Pasqual Enrico Maria , Bacchetti Stefano , Sassaroli Cinzia , Di Giorgio Andrea , Framarini Massimo , Marrelli Daniele , Casella Francesco , Federici Orietta
Published: January 2023

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has gained increasing acceptance in clinical practice. Performing CRS and HIPEC laparoscopically represents a challenging and intriguing technical evolution. However, the experiences are limited, and the evidence is low. This retrospective analysis was performed on patients treated with laparoscopic CRS-HIPEC within the Italian Peritoneal Surface Malignancies Oncoteam. Clinical, perioperative, and follow-up data were extracted and collected on prospectively maintained databases. We added a systematic review according to the PRISMA method for English-language articles through April 2022 using the keywords laparoscopic, hyperthermic, HIPEC, and chemotherapy. From 2016 to 2022, fourteen patients were treated with Lap-CRS-HIPEC with curative intent within the Italian centers. No conversion to open was observed. The median duration of surgery was 487.5 min. The median Peritoneal Cancer Index (PCI) was 3, and complete cytoreduction was achieved in all patients. Two patients (14.3%) had major postoperative complications, one requiring reintervention. After a median follow-up of 16.9 months, eleven patients were alive without disease (78.6%), two patients developed recurrence (14.3%), and one patient died for unrelated causes (7.1%). The literature review confirmed these results. In conclusion, current evidence shows that Lap-CRS-HIPEC is feasible, safe, and associated with a favorable outcome in selected patients. An accurate patient selection will continue to be paramount in choosing this treatment.
Genomic and Transcriptional Profiling of Chinese Melanoma Patients Enhanced Potentially Druggable Targets: A Multicenter Study
Authors: Li Yue , Wang Baoming , Wang Chunyang , Zhao Dandan , Liu Zhengchuang , Niu Yanling , Wang Xiaojuan , Li Wei , Zhu Jianhua , Tao Houquan , Ma Tonghui , Li Tao
Published: January 2023

Background: In contrast to Caucasian melanoma, which has been extensively studied, there are few studies on melanoma in Asian populations. Sporadic studies reported that only 40% of Asian melanoma patients could be druggable, which was much lower than that in Caucasians. More studies are required to refine this conclusion. Methods: Chinese melanoma patients (n = 469) were sequentially sequenced by DNA-NGS and RNA-NGS. The genomic alterations were determined, and potentially actionable targets were investigated. Results: Patients with potential druggable targets were identified in 75% of Chinese melanoma patients by DNA-NGS based on OncoKB, which was much higher than in a previous Asian study. NRG1 fusions were first identified in melanoma. In addition, up to 11.7% (7/60) of patients in the undruggable group could be recognized as actionable by including RNA-NGS analysis. By comparing the fusion detection rate between DNA-NGS and RNA-NGS, all available samples after DNA-NGS detection were further verified by RNA-NGS. The use of RNA-NGS enhanced the proportion of druggable fusions from 2.56% to 17.27%. In total, the use of RNA-NGS increased the druggable proportion from 75% to 78%. Conclusions: In this study, we systemically analyzed the actionable landscape of melanoma in the largest Asian cohort. In addition, we first demonstrated how DNA and RNA sequential sequencing is essential in bringing clinical benefits to more patients with melanoma.
Decoding Roles of Exosomal lncRNAs in Tumor-Immune Regulation and Therapeutic Potential
Authors: Zhang Wenqin , Yan Yuanliang , Peng Jinwu , Thakur Abhimanyu , Bai Ning , Yang Keda , Xu Zhijie
Published: January 2023

Exosomes are nanovesicles secreted into biofluids by various cell types and have been implicated in different physiological and pathological processes. Interestingly, a plethora of studies emphasized the mediating role of exosomes in the bidirectional communication between donor and recipient cells. Among the various cargoes of exosomes, long non-coding RNAs (lncRNAs) have been identified as crucial regulators between cancer cells and immune cells in the tumor microenvironment (TME) that can interfere with innate and adaptive immune responses to affect the therapeutic efficiency. Recently, a few major studies have focused on the exosomal lncRNA-mediated interaction between cancer cells and immune cells infiltrated into TME. Nevertheless, a dearth of studies pertains to the immune regulating role of exosomal lncRNAs in cancer and is still in the early stages. Comprehensive mechanisms of exosomal lncRNAs in tumor immunity are not well understood. Herein, we provide an overview of the immunomodulatory function of exosomal lncRNAs in cancer and treatment resistance. In addition, we also summarize the potential therapeutic strategies toward exosomal lncRNAs in TME.
Circulating Tumor Cells as Biomarkers for Renal Cell Carcinoma: Ready for Prime Time?
Authors: Couto-Cunha Anabela , Jerónimo Carmen , Henrique Rui
Published: January 2023

Renal cell carcinoma (RCC) is among the 15 most common cancers worldwide, with rising incidence. In most cases, this is a silent disease until it reaches advance stages, demanding new effective biomarkers in all domains, from detection to post-therapy monitoring. Circulating tumor cells (CTC) have the potential to provide minimally invasive information to guide assessment of the disease’s aggressiveness and therapeutic strategy, representing a special pool of neoplastic cells which bear metastatic potential. In some tumor models, CTCs’ enumeration has been associated with prognosis, but there is a largely unexplored potential for clinical applicability encompassing screening, diagnosis, early detection of metastases, prognosis, response to therapy and monitoring. Nonetheless, lack of standardization and high cost hinder the translation into clinical practice. Thus, new methods for collection and analysis (genomic, proteomic, transcriptomic, epigenomic and metabolomic) are needed to ascertain the role of CTC as a RCC biomarker. Herein, we provide a critical overview of the most recently published data on the role and clinical potential of CTCs in RCC, addressing their biology and the molecular characterization of this remarkable set of tumor cells. Furthermore, we highlight the existing and emerging techniques for CTC enrichment and detection, exploring clinical applications in RCC. Notwithstanding the notable progress in recent years, the use of CTCs in a routine clinical scenario of RCC patients requires further research and technological development, enabling multimodal analysis to take advantage of the wealth of information they provide.
Robust Performance of the Novel Research-Use-Only Idylla GeneFusion Assay Using a Diverse Set of Pathological Samples with a Proposed 1-Day Workflow for Advanced NSCLC Evaluation
Authors: Leone Alvaro , Muscarella Lucia Anna , Graziano Paolo , Tornese Andrea , Grillo Lucia Rosalba , Di Lorenzo Angela , Bronzini Monica , Scarpino Stefania , Sparaneo Angelo , Rossi Giulio
Published: January 2023

A range of different techniques are available for predictive biomarker testing for non-small-cell lung cancer (NSCLC) clinical management. International guidelines suggest next-generation sequencing (NGS) as the preferred procedure, but other reverse transcriptase-polymerase chain reaction (RT-PCR)-based methods are rapidly evolving. In this study, we evaluated the reliability and accuracy of the IdyllaTM GeneFusion assay, a rapid and fully automated platform able to simultaneously detect ALK, ROS1, RET and NTRK1/2/3 and MET ex14 skipping mutations and compared its performance with routine reference methods. The cohort included thirty-seven NSCLCs plus two parotid gland carcinomas, previously characterized for the above alterations through either IHC, FISH, RT-PCR or NGS. In 36 of 39 cases, the Idylla GeneFusion assay and the reference methods were concordant (overall agreement: 92.3%). Tumor sections stored at room temperature for up to 60 days and 17 cases older than 2 years were successfully characterized. Our results suggest that the Idylla GeneFusion assay is a reliable tool to define gene fusion status and may be a valuable stand-alone diagnostic test when time efficiency is needed or NGS is not feasible.
A Survey of Naturally Occurring Molecules as New Endoplasmic Reticulum Stress Activators with Selective Anticancer Activity
Authors: Correia da Silva Daniela , Valentão Patrícia , Pereira David M.
Published: January 2023

The last century has witnessed the establishment of neoplastic disease as the second cause of death in the world. Nonetheless, the road toward desirable success rates of cancer treatments is still long and paved with uncertainty. This work aims to select natural products that act via endoplasmic reticulum (ER) stress, a known vulnerability of malignant cells, and display selective toxicity against cancer cell lines. Among an in-house chemical library, nontoxic molecules towards noncancer cells were assessed for toxicity towards cancer cells, namely the human gastric adenocarcinoma cell line AGS and the lung adenocarcinoma cell line A549. Active molecules towards at least one of these cell lines were studied in a battery of ensuing assays to clarify the involvement of ER stress and unfolded protein response (UPR) in the cytotoxic effect. Several natural products are selectively cytotoxic against malignant cells, and the effect often relies on ER stress induction. Berberine was the most promising molecule, being active against both cell models by disrupting Ca2+ homeostasis, inducing UPR target gene expression and ER-resident caspase-4 activation. Our results indicate that berberine and emodin are potential leads for the development of more potent ER stressors to be used as selective anticancer agents.
Special Techniques of Adjuvant Breast Carcinoma Radiotherapy
Authors: Kolářová Iveta , Melichar Bohuslav , Vaňásek Jaroslav , Sirák Igor , Petera Jiří , Horáčková Kateřina , Pohanková Denisa , Šinkorová Zuzana , Hošek Oldřich , Vošmik Milan
Published: January 2023

Modern radiotherapy techniques are designed to permit reduced irradiation of healthy tissue, resulting in a diminished risk of adverse effects and shortened recovery times. Several randomized studies have demonstrated the benefits of increased dosage to the tumor bed area in combination with whole breast irradiation (WBI). Conventional WBI treatment following breast-conserving procedures, which required 5–7 weeks of daily treatments, has been reduced to 3–4 weeks when using hyperfractionated regimens. The dosage administration improves local control, albeit with poorer cosmesis. The method of accelerated partial breast irradiation (APBI) shortens the treatment period whilst reducing the irradiated volume. APBI can be delivered using intraoperative radiation, brachytherapy, or external beam radiotherapy. Currently available data support the use of external beam partial breast irradiation in selected patients. Modern radiotherapy techniques make it possible to achieve favorable cosmesis in most patients undergoing immediate breast reconstruction surgery, and studies confirm that current methods of external beam radiation allow an acceptable coverage of target volumes both in the reconstructed breast and in the regional lymphatic nodes.
The Research Advances of Aptamers in Hematologic Malignancies
Authors: Liao Yongkang , Xiong Shijun , Ur Rehman Zaid , He Xiaoli , Peng Hongling , Liu Jing , Sun Shuming
Published: January 2023

Currently, research for hematological malignancies is very intensive, with many breakthroughs. Among them, aptamer-based targeted therapies could be counted. Aptamer is a targeting tool with many unique advantages (easy synthesis, low toxicity, easy modification, low immunogenicity, nano size, long stability, etc.), therefore many experts screened corresponding aptamers in various hematological malignancies for diagnosis and treatment. In this review, we try to summarize and provide the recent progress of aptamer research in the diagnosis and treatment of hematologic malignancies. Until now, 29 aptamer studies were reported in hematologic malignancies, of which 12 aptamers were tested in vivo and the remaining 17 aptamers were only tested in vitro. In this case, 11 aptamers were combined with chemotherapeutic drugs for the treatment of hematologic malignancies, 4 aptamers were used in combination with nanomaterials for the diagnosis and treatment of hematologic malignancies, and some studies used aptamers for the targeted transportation of siRNA and miRNA for targeted therapeutic effects. Their research provides multiple approaches to achieve more targeted goals. These findings show promising and encouraging future for both hematological malignancies basic and clinical trials research.
Long Non-Coding RNAs Associated with Mitogen-Activated Protein Kinase in Human Pancreatic Cancer
Authors: Ishikawa Tomohiko , Fukushige Shinichi , Saiki Yuriko , Hirose Katsuya , Hiyoshi Takako , Ogawa Takenori , Katori Yukio , Furukawa Toru
Published: January 2023

Long non-coding RNAs (lncRNAs) have emerged as a significant player in various cancers, including pancreatic cancer. However, how lncRNAs are aberrantly expressed in cancers is largely unknown. We hypothesized that lncRNAs would be regulated by signaling pathways and contribute to malignant phenotypes of cancer. In this study, to understand the significance of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), which is a major aberrant signaling pathway in pancreatic cancer, for the expression of lncRNAs, we performed comparative transcriptome analyses between pancreatic cancer cell lines with or without activation of MAPK. We identified 45 lncRNAs presumably associated with MAPK in pancreatic cancer cells; among these, LINC00941 was consistently upregulated by MAPK. The immediate genomic upstream region flanking LINC00941 was identified as a promoter region, the activity of which was found to be preferentially associated with MAPK activity via ETS-1 binding site. LINC00941 promoted cell proliferation in vitro. Moreover, TCGA data analysis indicated that high expression of LINC00941 was associated with poor prognosis of patients with pancreatic cancer. Transcriptomes comparing transcriptions between cells with and without LINC00941 knockdown revealed 3229 differentially expressed genes involved in 44 biological processes, including the glycoprotein biosynthetic process, beta-catenin-TCF complex assembly, and histone modification. These results indicate that MAPK mediates the aberrant expression of lncRNAs. LINC00941 is the lncRNA by MAPK most consistently promoted, and is implicated in the dismal prognosis of pancreatic cancer. MAPK-associated lncRNAs may play pivotal roles in malignant phenotypes of pancreatic cancer, and as such might represent both potentially valid therapeutic targets and diagnostic biomarkers.
Perspective: Is a Closer Interaction between Experimental and Clinical Research Paradigms in Chronic Neurodegeneration, Such as Parkinson’s Disease, Necessary Again?
Authors: Müller Thomas
Published: January 2023

This editorial discusses the current standstill in research in Parkinson’s disease from a clinician’s point of view [...]
Platelet Aggregation, Mitochondrial Function and Morphology in Cold Storage: Impact of Resveratrol and Cytochrome c Supplementation
Authors: Ekaney Michael L. , Carrillo-Garcia Juan Carlos , Gonzalez-Gray Gabrielle , Wilson Hadley H. , Jordan Mary M. , McKillop Iain H. , Evans Susan L.
Published: January 2023

Donated platelets are critical components of hemostasis management. Extending platelet storage beyond the recommended guidelines (5 days, 22 °C) is of clinical significance. Platelet coagulation function can be prolonged with resveratrol (Res) or cytochrome c (Cyt c) at 4 °C. We hypothesized that storage under these conditions is associated with maintained aggregation function, decreased reactive oxygen species (ROS) production, increased mitochondrial respiratory function, and preserved morphology. Donated platelets were stored at 22 °C or 4 °C supplemented with 50 μM Res or 100 μM Cyt c and assayed on days 0 (baseline), 5, 7 and 10 for platelet aggregation, morphology, intracellular ROS, and mitochondrial function. Declining platelet function and increased intracellular ROS were maintained by Res and Cyt c. Platelet respiratory control ratio declined during storage using complex I + II (CI + CII) or CIV substrates. No temperature-dependent differences (4 °C versus 22 °C) in respiratory function were observed. Altered platelet morphology was observed after 7 days at 22 °C, effects that were blunted at 4 °C independent of exposure to Res or Cyt c. Storage of platelets at 4 °C with Res and Cyt c modulates ROS generation and platelet structural integrity.
Antibody-Mediated Delivery of VEGF-C Promotes Long-Lasting Lymphatic Expansion That Reduces Recurrent Inflammation
Authors: Cousin Nikola , Bartel Sophie , Scholl Jeannette , Tacconi Carlotta , Egger Annina , Thorhallsdottir Gudrun , Neri Dario , Dieterich Lothar C. , Detmar Michael
Published: January 2023

The lymphatic vascular system plays a fundamental role in inflammation by draining interstitial fluid, immune cells, antigens, and inflammatory mediators from peripheral tissues. Site-specific delivery of the lymphangiogenic growth factor VEGF-C alleviates acute inflammation in mouse models of psoriasis and chronic colitis by enhancing local drainage. However, it is unclear whether therapeutically induced lymphangiogenesis is transient or long-lasting and whether it might prevent relapses of inflammation. Here, we investigated the long-term effects of targeted VEGF-C delivery in a chronic dermatitis model in mice. Congruent with our previous results, intravenous injection with a VEGF-C fusion protein targeted to the EDA domain of fibronectin initially resulted in reduced inflammation. Importantly, we found that targeted VEGF-C-mediated expansion of lymphatic vessels in the skin persisted for more than 170 days, long after primary inflammation had resolved. Furthermore, the treatment markedly decreased tissue swelling upon inflammatory re-challenge at the same site. Simultaneously, infiltration of leukocytes, including CD4+ T cells, macrophages, and dendritic cells, was significantly reduced in the previously treated group. In conclusion, our data show that targeted delivery of VEGF-C leads to long-lasting lymphatic expansion and long-term protection against repeated inflammatory challenge, suggesting that it is a promising new approach for the treatment of chronic, recurrent inflammatory diseases.
Modeling the Differentiation of Embryonic Limb Chondroprogenitors by Cell Death and Cell Senescence in High Density Micromass Cultures and Their Regulation by FGF Signaling
Authors: Duarte-Olivenza Cristina , Hurle Juan M. , Montero Juan A. , Lorda-Diez Carlos I.
Published: January 2023

Considering the importance of programmed cell death in the formation of the skeleton during embryonic development, the aim of the present study was to analyze whether regulated cell degeneration also accompanies the differentiation of embryonic limb skeletal progenitors in high-density tridimensional cultures (micromass cultures). Our results show that the formation of primary cartilage nodules in the micromass culture assay involves a patterned process of cell death and cell senescence, complementary to the pattern of chondrogenesis. As occurs in vivo, the degenerative events were preceded by DNA damage detectable by γH2AX immunolabeling and proceeded via apoptosis and cell senescence. Combined treatments of the cultures with growth factors active during limb skeletogenesis, including FGF, BMP, and WNT revealed that FGF signaling modulates the response of progenitors to signaling pathways implicated in cell death. Transcriptional changes induced by FGF treatments suggested that this function is mediated by the positive regulation of the genetic machinery responsible for apoptosis and cell senescence together with hypomethylation of the Sox9 gene promoter. We propose that FGF signaling exerts a primordial function in the embryonic limb conferring chondroprogenitors with their biological properties.
Biofabrication of Silver Nanoparticles Using Teucrium Apollinis Extract: Characterization, Stability, and Their Antibacterial Activities
Authors: Abdussalam-Mohammed Wanisa , Mohamed Laila , Abraheem Mohammed S. , Mansour Mohmeed M.A , Sherif Akram Mansour
Published: January 2023

Medical science has paid a great deal of attention to green synthesis silver nanoparticles (AgNPs) because of their remarkable results with multidrug-resistant bacteria. This study was conducted on the preparation of AgNPs, using the teucrium apollinis extract as a reducing agent and a capping ligand. The AgNP produced was stable in room condition up to 10 weeks. The AgNP was characterized using UV-visible absorption spectroscopy (UV-Vis), attenuated Fourier transform infrared (ATR-FTIR), transmission electron microscopy (TEM), and dynamic light scattering (DLS). The study confirms the ability of teucrium apollinis to produce AgNPs with high stability. The influence of pH was studied over a pH range of (2–12) on the stability of synthesized AgNPs. The best value of pH was 7.2, where AgNP showed a good stability with high antibacterial activity against Pseudomonas aeruginosa. AgNP synthesis is confirmed by a strong peak in the UV-Vis due to surface plasmon resonance (SPR) at 379 nm. Based on TEM findings, monodispersed AgNP has a spherical shape with a small size of 16 ± 1.8 nm. In this study, teucrium apollinis extract was used for the first time, which could be a good environmental method for synthesizing AgNP, which offers a possible alternative to chemical AgNPs.
Molecularly Imprinted Plasmonic-Based Sensors for Environmental Contaminants—Current State and Future Perspectives
Authors: Lazarević-Pašti Tamara , Tasić Tamara , Milanković Vedran , Potkonjak Nebojša
Published: January 2023

The increase of production and consumption persistently introduce different pollutants into the environment. The constant development and improvement of analytical methods for tracking environmental contaminants are essential. The demand for high sample throughput analysis has hit the spotlight for developing selective sensors to avoid time-consuming sample preparation techniques. In addition, the sensor’s sensitivity should satisfy the rigorous demands of harmful compound tracking. Molecularly imprinted plasmonic-based sensors are excellent candidates to overcome selectivity and sensitivity issues. Molecularly imprinted polymers are robust, stable in aqueous and organic solvents, stable at extreme pHs and temperatures, and include a low-cost synthesis procedure. Combined with plasmonic-based techniques, they are the perspective choice for applications in the field of environmental protection. Plasmonic-based sensors offer a lower limit of detection, a broad linearity range, high sensitivity, and high selectivity compared to other detection techniques. This review outlines the optical plasmonic detection of different environmental contaminants with molecularly imprinted polymers as sensing elements. The main focus is on the environmental pollutants affecting human and animal health, such as pesticides, pharmaceuticals, hormones, microorganisms, polycyclic aromatic hydrocarbons, dyes, and metal particles. Although molecularly imprinted plasmonic-based sensors currently have their application mostly in the biomedical field, we are eager to point them out as a highly prospective solution for many environmental problems.
A Preterm Infant with Feeding Aspiration Diagnosed with BOR Syndrome, Confirmed Case by Whole-Genome Sequencing and Structural Variant Calling
Authors: Kim Da Hyeon , Yang Misun , Jo Heui Seung , Park JongHo , Jang JaHyun , Shin Sunghwan , Son SeHyung
Published: January 2023

Branchiootorenal (BOR) syndrome is a rare autosomal dominant inherited disease with a prevalence of approximately 1 in 40,000 newborns. This disease is characterized by hearing loss, preauricular pits, branchial fistulas or cysts, and renal dysplasia. We discovered a case of BOR syndrome in a premature 2-week-old female infant with a gestational age of 32 weeks and two days. She and her family had major symptoms and a family history of BOR. BOR syndrome was confirmed by whole-genome sequencing and structural variant calling, which revealed an EYA1 exon 5–6 deletion. The infant had recurrent sleep and feeding cyanosis with second branchial anomalies. Via videofluoroscopic swallowing study and a modified barium swallow test, penetration into the vocal cords was observed before and during swallowing when bottle feeding. This is the first report of a preterm infant early diagnosed with BOR syndrome in which deletion margin was accurately identified by whole-genome sequencing and structural variant calling in Republic of Korea.
Neurodevelopmental Disorders, Schizophrenia Spectrum Disorders and Catatonia: The “Iron Triangle” Rediscovered in a Case Report
Authors: Fantozzi Pamela , Del Grande Claudia , Berloffa Stefano , Tolomei Greta , Salluce Carmen , Narzisi Antonio , Salarpi Gianluca , Capovani Barbara , Masi Gabriele
Published: January 2023

Catatonia is a complex neuropsychiatric syndrome, occurring in the context of different psychiatric and neurodevelopmental disorders, in neurological and medical disorders, and after substance abuse or withdrawal. The relationship between Autism Spectrum Disorder (ASD), Schizophrenia Spectrum Disorders (SSDs) and catatonia has been previously discussed, with the three disorders interpreted as different manifestations of the same underlying brain disorder (the “Iron Triangle”). We discuss in this paper the diagnostic, clinical and therapeutic implications of this complex relationship in an adolescent with ASD, who presented an acute psychotic onset with catatonia, associated with mixed mood symptoms. Second-generation antipsychotics were used to manage psychotic, behavioral and affective symptoms, with worsening of the catatonic symptoms. In this clinical condition, antipsychotics may be useful at the lowest dosages, with increases only in the acute phases, especially when benzodiazepines are ineffective. Mood stabilizers with higher GABAergic effects (such as Valproate and Gabapentin) and Lithium salts may be more useful and well tolerated, given the frequent association of depressive and manic symptoms with mixed features.
Early Phase Increase in Serum TIMP-1 in Patients with Acute Encephalopathy with Biphasic Seizures and Late Reduced Diffusion
Authors: Kasai Ayaka , Kobayashi Jun , Nishioka Makoto , Kubota Noriko , Inaba Yuji , Motobayashi Mitsuo
Published: January 2023

Background: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is the most frequent subtype of acute encephalopathy syndrome among Japanese children. Exanthem subitum is the most common causative infectious disease of AESD. We herein retrospectively analyzed serum and cerebrospinal fluid (CSF) concentrations of matrix metalloproteinase-9 (MMP-9), tissue inhibitor matrix metalloproteinase-1 (TIMP-1), and seven cytokines in patients with AESD or prolonged febrile seizure (FS) to assess the pathophysiology of AESD and detect biomarkers for diagnosing AESD in the early phase. Methods: Serum and CSF samples were obtained from 17 patients with AESD (1st seizure phase group, n = 7; 2nd seizure phase group, n = 10) and 8 with FS. The concentrations of MMP-9, TIMP-1, and seven cytokines were measured by enzyme-linked immunosorbent assays or cytometric bead arrays. Results: Serum concentrations of TIMP-1 were significantly higher in the 1st seizure phase group than in the 2nd seizure phase group. No significant differences were observed in serum concentrations of MMP-9 or the MMP-9/TIMP-1 ratio. Conclusions: The MMP-9-independent increase in circulating TIMP-1 concentrations observed in the present study may be associated with the pathophysiology of AESD in the 1st seizure phase.
Evaluation of Intraligamentous and Intraosseous Computer-Controlled Anesthetic Delivery Systems in Pediatric Dentistry: A Randomized Controlled Trial
Authors: Prol Castelo Andrea , García Mato Eliane , Varela Aneiros Iván , Sande López Lucía , Outumuro Rial Mercedes , Abeleira Pazos María Teresa , Rivas Mundiña Berta , Limeres Posse Jacobo
Published: January 2023

Computer-controlled local anesthetic delivery systems (CDS) represent one of the resources that have progressed the most in recent years, but their efficacy and applicability in pediatric dentistry is still the subject of certain controversies. This randomized, controlled, split-mouth clinical trial assessed two CDS in children (n = 100) with deep caries in the temporary dentition that required invasive therapeutic procedures, using inferior alveolar nerve block as the gold standard. Half of the patients (n = 50) underwent the intraligamentary technique (Wand STA®) on one side of the mouth and conventional inferior alveolar nerve block on the contralateral side, while the other half (n = 50) underwent the intraosseous technique (QuickSleeper®) on one side of the mouth and conventional inferior alveolar nerve block on the contralateral side. The following were considered covariates: age, sex, type of dental procedure and the applied local anesthesia system. The outcome variables were the pain caused by the anesthesia injection, the physical reaction during the anesthesia injection, the need for anesthetic reinforcement, pain during the therapeutic procedure, the overall behavior during the visit, the postoperative morbidity and, lastly, the patient’s preference. In conclusion, we confirmed the efficacy of intraligamentary and intraosseous techniques administered using a CDS for conducting invasive dental treatments in children, their advantages compared with inferior alveolar nerve block in terms of less pain generated by the anesthesia injection and less postoperative morbidity, as well as the pediatric patients’ preference for CDS versus conventional techniques.