Although cisplatin has been a pivotal chemotherapy drug in treating patients with various types of cancer for decades, drug resistance has been a major clinical impediment. In general, cisplatin ...exerts cytotoxic effects in tumor cells mainly through the generation of DNA-platinum adducts and subsequent DNA damage response. Accordingly, considerable effort has been devoted to clarify the resistance mechanisms inside tumor cells, such as decreased drug accumulation, enhanced detoxification activity, promotion of DNA repair capacity, and inactivated cell death signaling. However, recent advances in high-throughput techniques, cell culture platforms, animal models, and analytic methods have also demonstrated that the tumor microenvironment plays a key role in the development of cisplatin resistance. Recent clinical successes in combination treatments with cisplatin and novel agents targeting components in the tumor microenvironment, such as angiogenesis and immune cells, have also supported the therapeutic value of these components in cisplatin resistance. In this review, we summarize resistance mechanisms with respect to a single tumor cell and crucial components in the tumor microenvironment, particularly focusing on favorable results from clinical studies. By compiling emerging evidence from preclinical and clinical studies, this review may provide insights into the development of a novel approach to overcome cisplatin resistance.
BIRC5/Survivin is known as a dual cellular functions protein that directly regulates both apoptosis and mitosis in embryonic cells during embryogenesis and in cancer cells during tumorigenesis and ...tumor metastasis. However, BIRC5 has seldom been demonstrated as a direct macroautophagy/autophagy regulator in cells. ATG7 expression and ATG12-ATG5-ATG16L1 complex formation are crucial for the phagophore elongation during autophagy in mammalian cells. In this study, we observed that the protein expression levels of BIRC5 and ATG7 were inversely correlated, whereas the expression levels of BIRC5 and SQSTM1/p62 were positively correlated in normal breast tissues and tumor tissues. Mechanistically, we found that BIRC5 negatively modulates the protein stability of ATG7 and physically binds to the ATG12-ATG5 conjugate, preventing the formation of the ATG12-ATG5-ATG16L1 protein complex in human cancer (MDA-MB-231, MCF7, and A549) and mouse embryonic fibroblast (MEF) cells. We also observed a concurrent physical dissociation between BIRC5 and ATG12-ATG5 (but not CASP3/caspase-3) and upregulation of autophagy in MDA-MB-231 and A549 cells under serum-deprived conditions. Importantly, despite the fact that upregulation of autophagy is widely thought to promote DNA repair in cells under genotoxic stress, we found that BIRC5 maintains DNA integrity through autophagy negative-modulations in both human cancer and MEF cells under non-stressed conditions. In conclusion, our study reveals a novel role of BIRC5 in cancer cells as a direct regulator of autophagy. BIRC5 may act as a "bridging molecule", which regulates the interplay between mitosis, apoptosis, and autophagy in embryonic and cancer cells.
ACTA1: actin; ATG: autophagy related; BIRC: baculoviral inhibitor of apoptosis repeat-containing; BAF: bafilomycin A
1
; CQ: chloroquine; CASP3: caspase 3; HSPB1/Hsp27: heat shock protein family B (small) member 1/heat shock protein 27; IAPs: inhibitors of apoptosis proteins; IP: immunoprecipitation; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PLA: proximity ligation assay; SQSTM1/p62: sequestosome 1; siRNA: small interfering RNA
The outbreak of COVID-19 caused by SARS-CoV-2 has resulted in more than 50 million confirmed cases and over 1 million deaths worldwide as of November 2020. Currently, there are no effective ...antivirals approved by the Food and Drug Administration to contain this pandemic except the antiviral agent remdesivir. In addition, the trimeric spike protein on the viral surface is highly glycosylated and almost 200,000 variants with mutations at more than 1,000 positions in its 1,273 amino acid sequence were reported, posing a major challenge in the development of antibodies and vaccines. It is therefore urgently needed to have alternative and timely treatments for the disease. In this study, we used a cell-based infection assay to screen more than 3,000 agents used in humans and animals, including 2,855 small molecules and 190 traditional herbal medicines, and identified 15 active small molecules in concentrations ranging from 0.1 nM to 50 μM. Two enzymatic assays, along with molecular modeling, were then developed to confirm those targeting the virus 3CL protease and the RNA-dependent RNA polymerase. Several water extracts of herbal medicines were active in the cell-based assay and could be further developed as plant-derived anti-SARS-CoV-2 agents. Some of the active compounds identified in the screen were further tested in vivo, and it was found that mefloquine, nelfinavir, and extracts of
(RF3),
, and
were effective in a challenge study using hamsters as disease model.
Oral squamous cell carcinoma (SCC) is a prevalent malignant disease worldwide, especially so in Taiwan. Early- or even preclinical-stage detection is critical for reducing morbidity and mortality ...from oral SCC. Epidemiological and genome association studies are useful for identifying clinicopathological risk factors for preventive, diagnostic, and therapeutic approaches of oral SCC. For advanced oral SCC, effective treatments are critical to prolonging survival and enhancing quality of life. As oral SCC is characteristic of regional invasion with lymph node metastases, understanding the aggressive features of oral SCC, particularly in lymphangiogenesis, is essential for determining effective treatments. Emerging evidence has demonstrated that the tumor microenvironment (TME) plays a pivotal role in tumor growth, invasion, and metastases. Recent clinical successes in immune checkpoint inhibitors either alone or combined with chemotherapy have also supported the therapeutic value of immunotherapy in oral SCC. This review summarizes critical advances in basic knowledge of oral SCC from the perspective of clinicopathological risk factors, molecular tumorigenesis, and the TME. We also highlight our recent investigations on the microbiome, genome association studies, lymphangiogenesis, and immunomodulation in oral SCC. This review may provide new insights for oral SCC treatment by systematically interpreting emerging evidence from various preclinical and clinical studies.
The coronavirus disease 2019 (COVID-19) pandemic has greatly affected medical education in addition to clinical systems. Residency training has probably been the most affected aspect of medical ...education during the pandemic, and research on this topic is crucial for educators and clinical teachers. The aim of this study was to understand the effect of the COVID-19 pandemic comprehensively through a systematic review and analysis of related published articles.
A systematic review was conducted based on a predesigned protocol. We searched MEDLINE and EMBASE databases until November 30, 2020, for eligible articles. Two independent reviewers extracted data by using a customized form to record crucial information, and any conflicts between the two reviewers were resolved through discussion with another independent reviewer. The aggregated data were summarized and analyzed.
In total, 53 original articles that investigated the effect of the COVID-19 pandemic on residency training were included. Studies from various regions were included in the research, with the largest percentage from the United States (n = 25, 47.2%). Most of these original articles were questionnaire-based studies (n = 44, 83%), and the research target groups included residents (79.55%), program directors (13.64%), or both (6.82%). The majority of the articles (n = 37, 84.0%) were published in countries severely affected by the pandemic. Surgery (n = 36, 67.92%) was the most commonly studied field.
The COVID-19 pandemic has greatly affected residency training globally, particularly surgical and interventional medical fields. Decreased clinical experience, reduced case volume, and disrupted education activities are major concerns. Further studies should be conducted with a focus on the learning outcomes of residency training during the pandemic and the effectiveness of assisted teaching methods.
Background: In modern critical care, extracorporeal membrane oxygenation (ECMO) is crucial in the management of severe respiratory and cardiac failure. Nationwide studies of the relationship between ...hospital volume and outcomes of ECMO use are unavailable.Methods and Results: Using Taiwan’s National Health Insurance Research Database, we identified 11,734 adult patients who received ECMO support in 101 hospitals between January 1, 2001, and December 31, 2017. Outcomes included in-hospital mortality, 1-year mortality, and ECMO-related complications. Cox proportional hazards model, locally estimated scatterplot smoothing, and restricted cubic spline regression were used to analyze the volume–outcome relationship. The overall in-hospital mortality rate was 65.5%, and the 1-year mortality rate was 70.6% in this database. The 101 hospitals were divided into 4 groups based on annual volume. The in-hospital and 1-year mortality rates were significantly lower in the high-volume group (annual volume >40) than in the low-volume group (annual volume <10).Conclusions: For critical care, high-volume hospitals have superior short-term and mid-term outcomes. To make the medical system equitable and reasonable, establishing a rapid and efficient nationwide referral system should be considered.
The Omicron variant of concern (VOC) has surged in many countries and replaced the previously reported VOC. To identify different Omicron strains/sublineages on a rapid, convenient, and precise ...platform, we report a novel multiplex real‐time reverse transcriptase polymerase chain reaction (RT‐PCR) method in one tube based on the Omicron lineage sequence variants' information. Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) subvariants were used in a PCR‐based assay for rapid identification of Omicron sublineage genotyping in 1000 clinical samples. Several characteristic mutations were analyzed using specific primers and probes for the spike gene, del69–70, and F486V. To distinguish Omicron sublineages (BA.2, BA.4, and BA.5), the NSP1:141–143del in the ORF1a region and D3N mutation in membrane protein occurring outside the spike protein region were analyzed. Results from the real‐time PCR assay for one‐tube accuracy were compared to those of whole genome sequencing. The developed PCR assay was used to analyze 400 SARS‐CoV‐2 positive samples. Ten samples determined as BA.4 were positive for NSP1:141–143del, del69–70, and F486V mutations; 160 BA.5 samples were positive for D3N, del69–70, and F486V mutations, and 230 BA.2 samples were without del69–70. Screening these samples allowed the identification of epidemic trends at different time intervals. Our novel one‐tube multiplex PCR assay was effective in identifying Omicron sublineages.
Programmed death-ligand 1 (PD-L1) is an immune checkpoint molecule that can regulate immune responses in the tumor microenvironment (TME); however, the clinical applications of PD-L1 in early-stage ...colorectal cancer (CRC) remain unclear. In this study, we aimed to investigate the relationship between PD-L1 expression and survival outcome and explore its relevant immune responses in CRC. PD-L1 expression was evaluated by immunohistochemical staining to determine the tumor proportion score and combined positive score (CPS) in a Taiwanese CRC cohort. The oncomine immune response research assay was conducted for immune gene expression analyses. CRC datasets from the TCGA database were reappraised for PD-L1-associated gene enrichment analyses using GSEA. The high expression of PD-L1 (CPS ≥ 5) was associated with longer recurrence-free survival (p = 0.031) and was an independent prognostic factor as revealed by multivariate analysis. High PD-L1 expression was related to six immune-related gene signatures, and CXCL9 is the most significant overexpressed gene in differential analyses. High CXCL9 expression correlated with increased infiltration levels of immune cells in the TME, including CD8+ T lymphocytes and M1 macrophages. These findings suggest that high PD-L1 expression is a prognostic factor of early-stage CRC, and CXCL9 may play a key role in regulating PD-L1 expression.
This review comprehensively covers the electrospun nanofiber, structural and morphological effects on optical sensing, and sensing characters towards environmental toxicants including recent trends, ...breakthroughs and future perspectives.
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•Electrospun optical nanofiber serves better for toxicant sensing.•Optical nanofiber membranes morphology governs the toxicant sensing.•Optical sensory nanofibers work promising with good sensitivity.•Sensing modes and easy readouts contributes for rapid toxicant detection.
Heavy metal and other toxicant detection in natural resources like water, air, soil and food is vital for environmental safety, personal hygiene, and public health care. Abundant number of sensor has acquired its wide and pivotal role in establishing the peaceful and healthy environments. The reliable features such as detection range, response/recovery time, stability and portability is in its urgency for achieving its lifetime applicability. For ultrasensitive chemosensory applications, colorimetric and fluorescent nanofibers engender a linear range, the lowest detection limit, and faster response toward harmful toxic pollutants such as heavy metals and other toxicants including gases, pH, temperature, humidity, and cancer cells. In this review, we surveyed various modes of sensing, sensor fabrication and the evolution of naked eye visible color optical sensors developed with electrospun nanofibrous membranes along with their strength and weaknesses. The review outlines the obstacles, trends and breakthroughs achieved in optical sensory nanofibers and it will definitely inspire the research community in recognizing and overcoming the interdisciplinary challenges to achieve the cleaner greener environment.
Atrial fibrosis is an essential contributor to atrial fibrillation (AF). It remains unclear whether atrial endocardial endothelial cells (AEECs) that undergo endothelial-mesenchymal transition ...(EndMT) are among the sources of atrial fibroblasts. We studied human atria, TGF-β–treated human AEECs, cardiac-specific TGF-β–transgenic mice, and heart failure rabbits to identify the underlying mechanism of EndMT in atrial fibrosis. Using isolated AEECs, we found that miR-181b was induced in TGF-β–treated AEECs, which decreased semaphorin 3A (Sema3A) and increased EndMT markers, and these effects could be reversed by a miR-181b antagomir. Experiments in which Sema3A was increased by a peptide or decreased by a siRNA in AEECs revealed a mechanistic link between Sema3A and LIM-kinase 1/phosphorylated cofilin (LIMK/p-cofilin) signaling and suggested that Sema3A is upstream of LIMK in regulating actin remodeling through p-cofilin. Administration of the miR-181b antagomir or recombinant Sema3A to TGF-β–transgenic mice evoked increased Sema3A, reduced EndMT markers, and significantly decreased atrial fibrosis and AF vulnerability. Our study provides a mechanistic link between the induction of EndMT by TGF-β via miR-181b/Sema3A/LIMK/p-cofilin signaling to atrial fibrosis. Blocking miR-181b and increasing Sema3A are potential strategies for AF therapeutic intervention.
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