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Yu-Min Yeh,1,2 Chun-Hui Lee,2 Shang-Hung Chen,2,3 Chung-Ta Lee,4 Yi-Lin Chen,4 Bo-Wen Lin,5 Shao-Chieh Lin,5 Ren-Hao Chan,5 Jenq-Chang Lee,5 Meng-Ru Shen,6,7 Peng-Chan Lin21Graduate Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City, Taiwan; 2Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City, Taiwan; 3National Institute of Cancer Research, National Health Research Institutes, Hsinchu, Taiwan; 4Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City, Taiwan; 5Division of Colorectal Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City, Taiwan; 6Department of Pharmacology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City, Taiwan; 7Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City, TaiwanCorrespondence: Peng-Chan LinDepartment of Internal Medicine, National Cheng Kung University Hospital, No. 138, Sheng-Li Road, Tainan 704, TaiwanTel +886 6 235 3535, ext. 4620Email pengchanlin@gmail.comPurpose: Human epidermal growth factor receptor 2 (HER2) is an emerging therapeutic target in colorectal cancer (CRC). Currently, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) have been used to determine HER2-positive CRCs; however, the clinical utility of next-generation sequencing (NGS)-based techniques for determining HER2 status in CRC has been limited. Here, we detail our experience regarding the assessment of HER2 alterations in a CRC cohort.Materials and methods: We prospectively enrolled 73 CRC patients who underwent surgery and received adjuvant oxaliplatin treatment. We then examined HER2 alterations using the Oncomine Comprehensive Assay version 1, as well as clinical outcomes, in this cohort.Results: Using the NGS-based assay, HER2 copy number gains in 12 of 73 CRCs were determined to range from 2.74 to 92.62. Of these 12 tumors, 6 had HER2 high-level copy number gain (92.6, 57.9, 57.0, 52.0, 35.2, and 8.42) and were all defined as HER2-positive CRC using HERACLES Diagnostic Criteria. Nevertheless, other 6 patients with low-level copy number gain (ranging from 2.74 to 3.04) and the remaining 61 patients without increase in HER2 copy number were all HER2-negative. Among the 6 HER2-positive CRCs, KRAS and PIK3CA mutations were detected in 1 (17%; G13D) and 2 (33.3%; 1 Q546R and 1 H1047R) patients, respectively. Moreover, 2 of the 6 (33.3%) HER2-positive patients had recurrent disease, while one patient had a partial response after anti-HER2 therapy.Conclusion: NGS-based tools could assist in the simultaneous detection of HER2 and other genomic alterations in patients with CRC. Only CRCs with HER2 high-level copy number gain were HER2-postive by current diagnostic criteria.Keywords: HER2, colorectal cancer, next generation sequencing, PIK3CA

Purpose: National Comprehensive Cancer Network guidelines suggest chest CT when gastrointestinal stromal tumors are larger than 2 cm. We evaluate the value of screening the chest region during initial and follow-up CT., Method: Single institution retrospective analysis of GIST cancer registry for patients diagnosed between May 2010 and November 2019 with tumor > 2 cm. We collected the patient demographics and clinical data; reviewed all CT scans of the chest region and recorded the lung nodules. Patients were grouped into lung nodule group and non-nodule group. Categorical variables were compared with the Chi square test and continuous variables with the Mann-Whitney U test. The survival probability was determined from Kaplan-Meier survival analysis and log-rank test for comparing differences., Results: The final cohort included 382 patients (median age 61 years-old [interquartile range: 52-71]) and grouped into non-nodule group (n = 284) and lung nodule group (n = 98). The frequency of the CT scan was more in lung nodule group (8 [5-12]) than in non-nodule group (4 [2-9], p < 0.001). The lung nodule group had more CT including the chest region (6 [3-10] vs 3 [1-7], p < 0.001). In progressive lung nodules (8/98 [8 %]), only one patient had confirmed lung metastasis from GIST (1/382 [3 %]). There was no difference in overall survival between nodule groups (p = 0.12)., Conclusions: GIST patients with tumors larger than 2 cm have extremely low risk for lung metastasis. Routine inclusion of chest CT scan in staging and follow up is unnecessary., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The IL6-GP130-STAT3 pathway facilitates lung cancer progression and resistance to tyrosine kinase inhibitors. Although glycosylation alters the stability of GP130, its effect on the ligand IL6 remains unclear. We herein find that N-glycosylated IL6, especially at Asn73, primarily stimulates JAK-STAT3 signaling and prolongs STAT3 phosphorylation, whereas N-glycosylation-defective IL6 (deNG-IL6) induces shortened STAT3 activation and alters the downstream signaling preference for the SRC-YAP-SOX2 axis. This signaling shift induces epithelial-mesenchymal transition (EMT) and migration in vitro and metastasis in vivo, which are suppressed by targeted inhibitors and shRNAs against SRC, YAP, and SOX2. Osimertinib-resistant lung cancer cells secrete a large amount of deNG-IL6 through reduced N-glycosyltransferase gene expression, leading to clear SRC-YAP activation. deNG-IL6 contributes to drug resistance, as confirmed by in silico analysis of cellular and clinical transcriptomes and signal expression in patient specimens. Therefore, the N-glycosylation status of IL6 not only affects cell behaviors but also shows promise in monitoring the dynamics of lung cancer evolution., (© 2024. The Author(s).)

Abstract: Substance use disorder (SUD) continues to be a leading cause of morbidity and mortality with limited treatments. There is interest in expanding the use of GLP-1 agonists in treating SUD. However, evidence for safety and efficacy in humans is limited. This review aims to bridge the existing knowledge gap by establishing a baseline of literature in this area to inform future trials and clinical practice. Our inclusion criteria were English peer-reviewed manuscripts reporting on use of GLP-1, GIP, and/or glucagon receptor agonists in treatment of SUDs, excluding case studies. The literature search was performed in accordance to PRISMA guidelines. Five studies were included in this review examining the use of this medication in tobacco use disorder, alcohol use disorder, and cocaine use disorder. No studies regarding substance withdrawal syndrome were identified. The included studies varied widely in terms of patient selection, dose/formulation of GLP-1 agonists, and follow-up. The results of this scoping review are mixed, with 3 studies demonstrating positive results and 2 studies finding no efficacy of this medication on SUD outcomes. It is premature to prescribe this medication off-label to patients. Further research is needed to determine the efficacy of GLP-1 agonists in treating SUD., Competing Interests: This manuscript is an original work of the aforementioned authors who all have no conflicts of interest to declare. Sources of funding include U54MH118919, U54AG062322, R03MH126143, R01MH128246, and R61MH129331 for Dr Holsen and R21DA056799, R21AA030372, R21DA058119, R21DE033319, and R21DA057545 for Dr Suzuki. None of these funding sources contributed to the creation of this manuscript. No part of this manuscript has been published before, nor is it in any part under consideration for publication at another journal., (Copyright © 2024 American Society of Addiction Medicine.)

Background: Cardiogenic shock is a clinical syndrome caused by primary heart disease that results in decreased cardiac output and insufficient systemic perfusion. A study was conducted to determine what factors affect survival in patients with cardiogenic shock treated with extracorporeal membrane oxygenation (ECMO)., Methods: A systematic search was conducted across various databases, including CKNI, VIP, Wan Fang, CBM, Embase, PubMed, Cochrane Library, and Web of Science databases, to gather factors linked to the prognosis of patients with cardiogenic shock who underwent ECMO treatment. The search period for each database was set to conclude on April 30, 2024., Results: The findings suggest that, in comparison to the death group, the lactic acid levels of the survival group after treatment were significantly lower (95% confidence interval [CI]: -0.79, -0.58). In addition, the creatinine levels of the survival group after treatment were also significantly lower than those of the death group (95% CI: -0.39, -0.14). Furthermore, the troponin levels in the survival group after treatment were lower than those in the death group (95% CI: -0.32, 0.04), and the total bilirubin levels in the survival group after treatment were also lower than those in the death group (95% CI: -0.62, -0.23)., Conclusions: According to the study, total bilirubin, creatinine, and lactic acid levels were lower in the survival group than in the death group when ECMO was used to treat cardiogenic patients, suggesting a better prognosis for patients with cardiogenic shock. Therefore, total bilirubin, creatinine, and lactic acid could be influential factors in the prognosis of survival in patients with cardiogenic shock., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Sleeve gastrectomy (SG) is the most commonly performed weight loss operation, and its 2 most common complications are postoperative reflux and weight recurrence. There is limited evidence to guide decision-making in treating these conditions., Objectives: To determine the efficacy of conversion of SG to Roux-en-Y gastric bypass (RYGB) for GERD management and weight loss., Setting: Forty-one hospitals in Michigan., Methods: We conducted a retrospective cohort study examining patients who underwent conversion of SG to RYGB from 2014 to 2022. The primary outcomes were changes in GERD-HRQL scores, anti-reflux medication use, and weight from baseline to 1 year after conversion. Secondary outcomes included 30-day postoperative complications and resource utilization., Results: Among 2133 patients undergoing conversion, 279 (13%) patients had baseline and 1-year GERD-HRQL survey data and anti-reflux medication data. GERD-HRQL scores decreased significantly from 24.6 to 6.6 (P < .01). Among these, 207 patients (74%) required anti-reflux medication at baseline, with only 76 patients (27%) requiring anti-reflux medication at 1 year postoperatively (P < .01). Of the 380 patients (18%) with weight loss data, mean weight decreased by 68.4lbs, with a 24.3% decline in total body weight and 51.5% decline in excess body weight. In terms of 30-day complications, 308 (14%) patients experienced any complication and 89 (4%) experienced a serious complication, but there were no leaks, perforations, or deaths. Three-hundred and fifty-five (17%) patients presented to the emergency department and 64 (3%) patients underwent reoperation., Conclusions: This study represents the largest reported experience with conversion from SG to RYGB. We found that conversion to RYGB is associated with significant improvement in GERD symptoms, reduction in anti-reflux medication use, and significant weight loss and is therefore an effective treatment for GERD and weight regain after SG. However, the risks and benefits of conversion surgery should be carefully considered, especially in patients with significant comorbidity burden., (Copyright © 2024 American Society for Metabolic and Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors have no potential conflicts of interest to disclose.

Background: Ovarian carcinoma (OC) is a fatal malignancy, with most patients experiencing recurrence and resistance to chemotherapy. In contrast to hematogenous metastasizing tumors, ovarian cancer cells disseminate within the peritoneal cavity, especially the omentum. Previously, we reported omental crown-like structure (CLS) number is associated with poor prognosis of advanced-stage OC. CLS that have pathologic features of a dead or dying adipocyte was surrounded by several macrophages is well known a histologic hallmark for inflammatory adipose tissue. In this study, we attempted to clarify the interaction between metastatic ovarian cancer cells and omental CLS, and to formulate a therapeutic strategy for advanced-stage ovarian cancer., Methods: A three-cell (including OC cells, adipocytes and macrophages) coculture model was established to mimic the omental tumor microenvironment (TME) of ovarian cancer. Caspase-1 activity, ATP and free fatty acids (FFA) levels were detected by commercial kits. An adipocyte organoid model was established to assess macrophages migration and infiltration. In vitro and in vivo experiments were performed for functional assays and therapeutic effect evaluations. Clinical OC tissue samples were collected for immunochemistry stain and statistics analysis., Results: In three-cell coculture model, OC cells-derived IL-6 and IL-8 could induce the occurrence of pyroptosis in omental adipocytes. The pyroptotic adipocytes release ATP to increase macrophage infiltration, release FFA into TME, uptake by OC cells to increase chemoresistance. From OC tumor samples study, we demonstrated patients with high gasdermin D (GSDMD) expression in omental adipocytes is highly correlated with chemoresistance and poor outcome in advanced-stage OC. In animal model, by pyroptosis inhibitor, DSF, effectively retarded tumor growth and prolonged mice survival., Conclusions: Omental adipocyte pyroptosis may contribute the chemoresistance in advanced stage OC. Omental adipocytes could release FFA and ATP through the GSDMD-mediate pyroptosis to induce chemoresistance and macrophages infiltration resulting the poor prognosis in advanced-stage OC. Inhibition of adipocyte pyroptosis may be a potential therapeutic modality in advanced-stage OC with omentum metastasis., (© 2024. The Author(s).)

Goal : The early diagnosis and treatment of hepatitis is essential to reduce hepatitis-related liver function deterioration and mortality. One component of the widely-used Ishak grading system for the grading of periportal interface hepatitis is based on the percentage of portal borders infiltrated by lymphocytes. Thus, the accurate detection of lymphocyte-infiltrated periportal regions is critical in the diagnosis of hepatitis. However, the infiltrating lymphocytes usually result in the formation of ambiguous and highly-irregular portal boundaries, and thus identifying the infiltrated portal boundary regions precisely using automated methods is challenging. This study aims to develop a deep-learning-based automatic detection framework to assist diagnosis. Methods : The present study proposes a framework consisting of a Structurally-REfined Deep Portal Segmentation module and an Infiltrated Periportal Region Detection module based on heterogeneous infiltration features to accurately identify the infiltrated periportal regions in liver Whole Slide Images. Results : The proposed method achieves 0.725 in F1-score of lymphocyte-infiltrated periportal region detection. Moreover, the statistics of the ratio of the detected infiltrated portal boundary have high correlation to the Ishak grade (Spearman's correlations more than 0.87 with p-values less than 0.001) and medium correlation to the liver function index aspartate aminotransferase and alanine aminotransferase (Spearman's correlations more than 0.63 and 0.57 with p-values less than 0.001). Conclusions : The study shows the statistics of the ratio of infiltrated portal boundary have correlation to the Ishak grade and liver function index. The proposed framework provides pathologists with a useful and reliable tool for hepatitis diagnosis., Competing Interests: VI.No conflict of interest., (© 2024 The Authors.)

Background: Cingulin (CGN) is a pivotal cytoskeletal adaptor protein located at tight junctions. This study investigates the link between CGN mutation and increased cancer susceptibility through genetic and mechanistic analyses and proposes a potential targeted therapeutic approach., Methods: In a high-cancer-density family without known pathogenic variants, we performed tumor-targeted and germline whole-genome sequencing to identify novel cancer-associated variants. Subsequently, these variants were validated in a 222 cancer patient cohort, and CGN c.3560C > T was identified as a potential cancer-risk allele. Both wild-type (WT) (c.3560C > C) and variant (c.3560C > T) were transfected into cancer cell lines and incorporated into orthotopic xenograft mice model for evaluating their effects on cancer progression. Western blot, immunofluorescence analysis, migration and invasion assays, two-dimensional gel electrophoresis with mass spectrometry, immunoprecipitation assays, and siRNA applications were used to explore the biological consequence of CGN c.3560C > T., Results: In cancer cell lines and orthotopic animal models, CGN c.3560C > T enhanced tumor progression with reduced sensitivity to oxaliplatin compared to the CGN WT. The variant induced downregulation of epithelial marker, upregulation of mesenchymal marker and transcription factor, which converged to initiate epithelial-mesenchymal transition (EMT). Proteomic analysis was conducted to investigate the elements driving EMT in CGN c.3560C > T. This exploration unveiled overexpression of IQGAP1 induced by the variant, contrasting the levels observed in CGN WT. Immunoprecipitation assay confirmed a direct interaction between CGN and IQGAP1. IQGAP1 functions as a regulator of multiple GTPases, particularly the Rho family. This overexpressed IQGAP1 was consistently associated with the activation of Rac1, as evidenced by the analysis of the cancer cell line and clinical sample harboring CGN c.3560C > T. Notably, activated Rac1 was suppressed following the downregulation of IQGAP1 by siRNA. Treatment with NSC23766, a selective inhibitor for Rac1-GEF interaction, resulted in the inactivation of Rac1. This intervention mitigated the EMT program in cancer cells carrying CGN c.3560C > T. Consistently, xenograft tumors with WT CGN showed no sensitivity to NSC23766 treatment, but NSC23766 demonstrated the capacity to attenuate tumor growth harboring c.3560C > T., Conclusions: CGN c.3560C > T leads to IQGAP1 overexpression, subsequently triggering Rac1-dependent EMT. Targeting activated Rac1 is a strategy to impede the advancement of cancers carrying this specific variant., (© 2024. The Author(s).)

Growing attention is being paid to physician health and behavior, including the occurrence of mental health issues and burnout in medical providers, physician impairment, and alleged disruptive behavior in physicians. In any of these areas, a physician may become the subject of an investigation. Studying the experience of investigated physicians is important to identify and mitigate any potential adverse personal and practice impacts, which in turn can hinder patient care. The purpose of this review is to (1) summarize the published scientific literature to date regarding the experiences of physicians who have been investigated, and (2) based on these findings consider strategies to mitigate any adverse effects of the investigatory process for physicians. A search of the databases PubMed and Ovid MEDLINE was conducted in June 2023 using relevant search terms. After reviewing titles, abstracts, full-length articles, and reference lists, 16 articles were identified and reviewed. Physicians in multiple countries who had been investigated commonly described short-term (feelings of anger, depression, anxiety, shame, powerlessness, isolation, being betrayed, less confidence in clinical decision-making) and long-term (increase in defensive practice, retiring early) impacts of the investigatory process. Physicians found the most difficult aspects of the investigation process to be the length of time involved, lack of transparency/communication regarding the process, feelings of isolation, and dealing with vexatious complaints. While complaints about physicians have the potential to portend constructive individual practice and systemic changes, research suggests that the investigatory process for physicians is associated with negative short- and long-term emotional and practice impacts. Strategies to mitigate the unintended adverse effects of investigatory processes are proposed. Further research is warranted to clarify the investigation experience for physicians, including physicians underrepresented in medicine, and to systematically assess the effectiveness of strategies to mitigate unhealthy or disruptive components of the investigatory process., (© 2023. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Introduction: Comprehensive geriatric assessment (CGA) is used to thoroughly assess and identify complex healthcare problems among older adults. However, administration of CGA is time-consuming and labor intensive. A simple screening tool with the mnemonic "FIND-NEEDS" was developed to quickly identify common geriatric conditions. The present study was to evaluate the clinimetric properties of the FIND-NEEDS., Methods: The participants comprised first-visiting older adults aged 65 years and above (and who were able to communicate by themselves or with the help of a caregiver) who were assessed (October to December, 2021) using the FIND-NEEDS and CGA at geriatric outpatient clinics of a tertiary, referred medical center. The FIND-NEEDS was examined for its criterion-related validity and compared with the CGA results. Two types of scoring (summed score and binary score) of FIND-NEEDS and CGA were analyzed using Spearman correlation, sensitivity and specificity, and area under receiver operating characteristic curve (AUC)., Results: The mean age of the 114 outpatients was 78.3 ± 7.6 years, and 79 (69.3%) were female. The internal consistency was excellent when using all FIND-NEEDS items, and was acceptable when using domain scores. Exploratory factor analysis showed that most of the FIND-NEEDS domain scores had factor loadings higher than 0.3. Intercorrelations of binary scores between domains of FIND-NEEDS and CGA showed most domains were moderately correlated. The overall correlation of summed scores between FIND-NEEDS and CGA was high. The FIND-NEEDS summed score was moderately correlated with CGA score (r = 0.494; p &lt; 0.001), and the binary score showed excellent correlation (r = 0.944; p &lt; 0.001). When using the CGA score as the gold standard, the FIND-NEEDS showed excellent AUC (0.950), sensitivity (1.00), and specificity (0.90)., Discussion/conclusion: The present study demonstrated that the FIND-NEEDS had acceptable clinimetric properties to screen for geriatric problems among older adults. Further in-depth assessment and care plan can then be conducted afterwards., (© 2024 S. Karger AG, Basel.)

Objective: The COVID-19 pandemic has had an enormous impact on society and the medical environment in Taiwan in 2022. As pregnant women with COVID-19 are at higher risk for multiple complications, Taiwan needs a COVID-19 specialized maternity unit to improve the quality of maternal and neonatal care., Materials and Methods: We share our experience with specialized maternity unit for pregnant women with COVID-19 at the National Cheng Kung University Hospital, where we can have careful evaluation, safe birth, and comprehensive postpartum care., Results: Our COVID-19 specialized maternity unit enrolled 253 pregnant women with COVID-19, 90 (35.6%) pregnant women were admitted to the specialized maternity unit, and 71 (28.1%) pregnant women gave birth during hospitalization in two months. All pregnant women recovery well and real-time polymerase chain reaction tests on all infants were negative for COVID-19., Conclusion: A specialized maternity unit can provide pregnant women with a safe birth environment, immediate maternity care, and high medical quality. It can also help health workers in non-specialized maternity units deal with COVID-19-related psychological stress. Therefore, setting up one specialized maternity unit in the city during the pandemic should be guardedly considered., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2023. Published by Elsevier B.V.)

Purpose: This study aimed to investigate differences in cervical lymph node image quality on dual-energy computed tomography (CT) scan with datasets reconstructed using filter back projection (FBP), hybrid iterative reconstruction (IR), and deep learning-based image reconstruction (DLIR) in patients with head and neck cancer., Method: Seventy patients with head and neck cancer underwent follow-up contrast-enhanced dual-energy CT examinations. All datasets were reconstructed using FBP, hybrid IR with 30 % adaptive statistical IR (ASiR-V), and DLIR with three selectable levels (low, medium, and high) at 2.5- and 0.625-mm slice thicknesses. Herein, signal, image noise, signal-to-noise ratio, and contrast-to-noise ratio of lymph nodes and overall image quality, artifact, and noise of selected regions of interest were evaluated by two radiologists. Next, cervical lymph node sharpness was evaluated using full width at half maximum., Results: DLIR exhibited significantly reduced noise, ranging from 3.8 % to 35.9 % with improved signal-to-noise ratio (11.5-105.6 %) and contrast-to-noise ratio (10.5-107.5 %) compared with FBP and ASiR-V, for cervical lymph nodes (p < 0.001). Further, 0.625-mm-thick images reconstructed using DLIR-medium and DLIR-high had a lower noise than 2.5-mm-thick images reconstructed using FBP and ASiR-V. The lymph node margins and vessels on DLIR-medium and DLIR-high were sharper than those on FBP and ASiR-V (p < 0.05). Both readers agreed that DLIR had a better image quality than the conventional reconstruction algorithms., Conclusion: DLIR-medium and -high provided superior cervical lymph node image quality in head and neck CT. Improved image quality affords thin-slice DLIR images for dose-reduction protocols in the future., Competing Interests: Author Ai-Chi Chen and Chia-Wei Lee were employed by General Electric (GE) Healthcare. The remaining authors declare no conflict of interest., (© 2024 The Authors.)

Background: Many methodologies for selecting histopathological images, such as sample image patches or segment histology from regions of interest (ROIs) or whole-slide images (WSIs), have been utilized to develop survival models. With gigapixel WSIs exhibiting diverse histological appearances, obtaining clinically prognostic and explainable features remains challenging. Therefore, we propose a novel deep learning-based algorithm combining tissue areas with histopathological features to predict cancer survival., Methods: The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) dataset was used in this investigation. A deep convolutional survival model (DeepConvSurv) extracted histopathological information from the image patches of nine different tissue types, including tumors, lymphocytes, stroma, and mucus. The tissue map of the WSIs was segmented using image processing techniques that involved localizing and quantifying the tissue region. Six survival models with the concordance index (C-index) were used as the evaluation metrics., Results: We extracted 128 histopathological features from four histological types and five tissue area features from WSIs to predict colorectal cancer survival. Our method performed better in six distinct survival models than the Whole Slide Histopathological Images Survival Analysis framework (WSISA), which adaptively sampled patches using K-means from WSIs. The best performance using histopathological features was 0.679 using LASSO-Cox. Compared to histopathological features alone, tissue area features increased the C-index by 2.5%. Based on histopathological features and tissue area features, our approach achieved performance of 0.704 with RIDGE-Cox., Conclusions: A deep learning-based algorithm combining histopathological features with tissue area proved clinically relevant and effective for predicting cancer survival., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Automatic liver tumor detection from computed tomography (CT) makes clinical examinations more accurate. However, deep learning-based detection algorithms are characterized by high sensitivity and low precision, which hinders diagnosis given that false-positive tumors must first be identified and excluded. These false positives arise because detection models incorrectly identify partial volume artifacts as lesions, which in turn stems from the inability to learn the perihepatic structure from a global perspective. To overcome this limitation, we propose a novel slice-fusion method in which mining the global structural relationship between the tissues in the target CT slices and fusing the features of adjacent slices according to the importance of the tissues. Furthermore, we design a new network based on our slice-fusion method and Mask R-CNN detection model, called Pinpoint-Net. We evaluated proposed model on the Liver Tumor Segmentation Challenge (LiTS) dataset and our liver metastases dataset. Experiments demonstrated that our slice-fusion method not only enhance tumor detection ability via reducing the number of false-positive tumors smaller than 10mm, but also improve segmentation performance. Without bells and whistles, a single Pinpoint-Net showed outstanding performance in liver tumor detection and segmentation on LiTS test dataset compared with other state-of-the-art models.

Background: Heavy metals are considered a global concern because they can deteriorate human health. This guideline aims to scientifically evaluate health risk of heavy metals in TCM and to propose a reference for decision making in developing TCM-related health policies., Methods: Using a multidisciplinary approach, a steering committee oversaw the development of the guideline. To obtain a reasonable and accurate risk assessment, key exposure assessment parameters for TCM, e.g., exposure frequency (EF), exposure duration (ED), and daily ingestion rate (IR) were obtained from surveys. In addition, transfer rates for heavy metals from Chinese medicinal materials (CMM) to decoctions or preparations were examined., Results: Based on the scientific theory of risk control, the guideline was designed systematically, and principles and procedures for the risk assessment of heavy metals in TCM were identified. The guideline can be utilized to assess the risk of heavy metals in CMM and Chinese patent medicines (CPM)., Conclusion: This guideline may help standardize the risk assessment of heavy metals in TCM, advance regulatory standards for heavy metals in TCM, and ultimately improve human health through scientific TCM usage in clinic., (© 2023. The Author(s).)

The sympathetic nervous system (SNS) of the bone marrow regulates the regeneration and mobilization of hematopoietic stem cells. Chemotherapy can damage bone marrow SNS, which impairs hematopoietic regeneration and aggravates hematologic toxicities. This leads to long-term bone marrow niche damage and increases mortality in patients undergoing chemotherapy. Electrical neuromodulation has been used to improve functional recovery after peripheral nerve injury. This study demonstrates that electrical sympathetic neuromodulation (ESN) of bone marrow can protect the bone marrow niche from chemotherapy-induced injury. Using carboplatin-treated rats, the SNS via the sciatic nerve innervating the femoral marrow with the effective protocol for bone marrow sympathetic activation is electrically stimulated. ESN can mediate several hematopoietic stem cells maintenance factors and promote hematopoietic regeneration after chemotherapy. It also activates adrenergic signals and reduces the release of pro-inflammatory cytokines, particularly interleukin-1 β, which contribute to chemotherapy-related nerve injury. Consequently, the severity of chemotherapy-related leukopenia, thrombocytopenia, and mortality can be reduced by ESN. As a result, in contrast to current drug-based treatment, such as granulocyte colony-stimulating factor, ESN can be a disruptive adjuvant treatment by protecting and modulating bone marrow function to reduce hematologic toxicity during chemotherapy., (© 2023 Wiley-VCH GmbH.)

Background: A substantial knowledge gap exists in understanding sex as a biological variable for abdominal wall hernia repair, which also extends to hernia repair practices in females of childbearing age. We sought to determine the incidence of mesh repairs in females of childbearing age and to characterize factors associated with mesh use., Methods: Using a statewide hernia-specific data registry, we conducted a retrospective study identifying females of childbearing age, defined as 18-44 per CDC guidelines, who underwent clean ventral hernia repair between January 2020 and Dec 2021. The primary outcome was mesh use. Multivariable logistic regression was used to examine factors associated with mesh use. To further delineate whether childbearing status may affect decision to use mesh, we also examined mesh practice stratified by age, comparing women 18 to 44 to those 45 and older., Results: Eight hundred and thirty-six females of childbearing age underwent ventral hernia repair with a mean age of 34.8 (6.2) years. Mesh was used in 547 (65.4%) patients. Mesh use was significantly associated with minimally invasive approach [aOR 29.46 (95% CI 16.30-53.25)], greater hernia width [aOR 1.50 (95% CI 1.20-1.88)], and greater BMI [aOR 1.05 (95% CI 1.03-1.08)]. Age was not significantly associated with mesh use [aOR 1.02 (95% CI 0.99-1.05)]. Compared to 1,461 female patients older than 44 years old, there was no significant association between childbearing age and mesh use [aOR 0.77 (95% CI 0.57-1.04)]., Conclusions: Most females of childbearing age had mesh placed during ventral and incisional hernia repair, which was largely associated with hernia size, BMI, and a minimally invasive surgical approach. Neither chronologic patient age nor being of childbearing age were associated with mesh use. Insofar as existing evidence suggests that childbearing status is an important factor in deciding whether to use mesh, these findings suggest that real-world practice may not reflect that evidence., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The metabolome is the best representation of cancer phenotypes. Gene expression can be considered a confounding covariate affecting metabolite levels. Data integration across metabolomics and genomics to establish the biological relevance of cancer metabolism is challenging. This study aimed to eliminate the confounding effect of metabolic gene expression to reflect actual metabolite levels in microsatellite instability (MSI) cancers., Methods: In this study, we propose a new strategy using covariate-adjusted tensor classification in high dimensions (CATCH) models to integrate metabolite and metabolic gene expression data to classify MSI and microsatellite stability (MSS) cancers. We used datasets from the Cancer Cell Line Encyclopedia (CCLE) phase II project and treated metabolomic data as tensor predictors and data on gene expression of metabolic enzymes as confounding covariates., Results: The CATCH model performed well, with high accuracy (0.82), sensitivity (0.66), specificity (0.88), precision (0.65), and F1 score (0.65). Seven metabolite features adjusted for metabolic gene expression, namely, 3-phosphoglycerate, 6-phosphogluconate, cholesterol ester, lysophosphatidylethanolamine (LPE), phosphatidylcholine, reduced glutathione, and sarcosine, were found in MSI cancers. Only one metabolite, Hippurate, was present in MSS cancers. The gene expression of phosphofructokinase 1 (PFKP), which is involved in the glycolytic pathway, was related to 3-phosphoglycerate. ALDH4A1 and GPT2 were associated with sarcosine. LPE was associated with the expression of CHPT1, which is involved in lipid metabolism. The glycolysis, nucleotide, glutamate, and lipid metabolic pathways were enriched in MSI cancers., Conclusions: We propose an effective CATCH model for predicting MSI cancer status. By controlling the confounding effect of metabolic gene expression, we identified cancer metabolic biomarkers and therapeutic targets. In addition, we provided the possible biology and genetics of MSI cancer metabolism., (© 2023. The Author(s).)

Background: There is increasing concern about the prevalence and impact of moral distress among healthcare workers. While this body of literature is growing, research specifically examining sources of moral distress among surgeons remains sparse. The unique attributes of the surgeon-patient relationship and the context of surgery may expose surgeons to sources of distress that are distinct from other healthcare providers. To date, a summative assessment of moral distress among surgeons does not exist., Methods: We conducted a scoping review of studies focused on moral distress among surgeons. Using guidelines established by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), relevant articles were identified in EBSCOhost PsycINFO, Elsevier EMBASE, Ovid MEDLINE, and Wiley Cochrane Central Register of Controlled Trials Library from January 1, 2009 to September 29, 2022. Detailed data abstraction was performed on a predetermined instrument and compared across studies. A mixed-methods meta-synthesis was employed for data analysis, and both deductive and inductive methodology was used in our thematic analysis., Results: A total of 1,003 abstracts were screened, and 26 articles (19 quantitative and 7 qualitative) were included for full-text review. Of these, 10 focused only on surgeons. Our analysis revealed numerous definitions of moral distress and 25 instruments used to understand the sources of distress. Moral distress among surgeons is complex and influenced by factors at multiple levels, The most frequent sources originate at the individual and interpersonal levels. However, the environmental, community and policy levels also noted sources of distress., Conclusions: The reviewed articles identified several common themes and sources of moral distress among surgeons. We also found that research investigating sources of moral distress among surgeons is relatively sparse and confounded by various definitions of moral distress, multiple measurement tools, and frequently conflated terms of moral distress, moral injury, and burnout. This summative assessment presents a model of moral distress delineating these distinct terms, which may be applied to other professions at risk for moral distress.

The most popular tools for predicting pathogenicity of single amino acid variants (SAVs) were developed based on sequence-based techniques. SAVs may change protein structure and function. In the context of van der Waals force and disulfide bridge calculations, no method directly predicts the impact of mutations on the energies of the protein structure. Here, we combined machine learning methods and energy scores of protein structures calculated by Rosetta Energy Function 2015 to predict SAV pathogenicity. The accuracy level of our model (0.76) is higher than that of six prediction tools. Further analyses revealed that the differential reference energies, attractive energies, and solvation of polar atoms between wildtype and mutant side-chains played essential roles in distinguishing benign from pathogenic variants. These features indicated the physicochemical properties of amino acids, which were observed in 3D structures instead of sequences. We added 16 features to Rhapsody (the prediction tool we used for our data set) and consequently improved its performance. The results indicated that these energy scores were more appropriate and more detailed representations of the pathogenicity of SAVs.

Background: Although bariatric surgery is the most effective treatment for obesity and weight-related comorbid diseases, utilization rates are disproportionately low among non-white patients. We sought to understand if variation in baseline characteristics or access to care exists between white and non-white patients., Methods: Using a statewide bariatric-specific data registry, we evaluated all patients who underwent bariatric surgery between 2006 and 2020 and completed a preoperative baseline questionnaire, which included a question about self-identification of race. Patient characteristics, co-morbidities, and time from initial preoperative clinic evaluation to date of surgery were compared among racial groups., Results: A total of 73,141 patients met inclusion criteria with 18,741 (25.5%) self-identified as non-white. These included Black/African American (n = 11,904), Hispanic (n = 3448), Asian (n = 121), Native Hawaiian/Pacific Islander (n = 41), Middle Eastern (n = 164), Multiple (n = 2047) and other (n = 608). Non-white males were the least represented group, accounting for only 4% of all bariatric cases performed. Non-white patients were more likely to be younger (43.0 years vs. 46.6 years, p < 0.0001), disabled (16% vs. 11.4%, p < 0.0001) and have Medicaid (8.4% vs. 3.8%, p < 0.0001) when compared to white patients, despite having higher rates of college education (78.0% vs. 76.6, p < 0.0001). In addition, median time from initial evaluation to surgery was also longer among non-white patients (157 days vs. 127 days, p < 0.0001), despite having higher rates of patients with a body mass index above 50 kg/m 2  (39.0% vs. 33.2%, p < 0.0001)., Conclusions: Non-white patients undergoing bariatric surgery represent an extremely diverse group of patients with more socioeconomic disadvantages and longer wait times when compared to white patients despite presenting with higher rates of severe obesity. Current guidelines and referral patterns for bariatric surgery may not be equitable and need further examination when considering the management of obesity within diverse populations to reduce disparities in care-of which non-white males are particularly at risk., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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.

Objective: The taxing nature of surgery residency is well-documented in the literature, with residents demonstrating high rates of burnout, depression, suicidal thoughts, sexual harassment, and racial discrimination. Mentoring has been shown to improve camaraderie, address challenges of underrepresentation in medicine, and be associated with lower burnout. However, existing formal mentoring programs tend to be career-focused and hierarchal without opportunity to discuss important sociocultural issues. An innovative approach is needed to address these cultural and anthropological issues in surgery residencies while creating camaraderie and learning alternative perspectives across different levels of training. We sought to describe the framework we used to fill these needs by creating and implementing a novel mentoring program., Design: A vertical, near-peer mentoring system of 7 groups was created consisting of the following members: 1 to 2 medical students, a PGY-1 general surgery resident, a PGY-4 research resident, and a faculty member. Meetings occur every 3 to 4 months in a casual setting with the first half of the meeting dedicated to intentional reflection and the second half focused on an evidence-based discussion regarding a specific topic in the context of surgery (i.e., burnout, discrimination, allyship, and finding purpose)., Setting: Program implementation took place at the University of Michigan in Ann Arbor, MI., Participants: Medical students, general surgery residents, and general surgery faculty were recruited., Conclusions: We have successfully launched the pilot year of a cross-spectrum formal mentoring program in general surgery. This program emphasizes camaraderie throughout training while providing opportunities for evidence-based discussion regarding sociocultural topics. We have included increased opportunities for community inclusivity and mentoring while allowing trainees and faculty members to discuss sensitive topics in a supportive environment. We plan to continue developing the program with robust evaluation and to expand the program to other surgical specialties and to other institutions., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mary R. Shen, MD, MS is supported by the Health Services Research Training Program (NIH T32HS00053). Kerry Madison, MD is supported by the Surgical Oncology Training Program T32 (NIH 5T32CA009672-30), Brooke C. Bredbeck, MD - Dr. Bredbeck is supported by the Ruth L. Kirschstein Research Service Award from the National Cancer Institute (NCI; T32 CA009672). Michael T. Kemp, MD – No disclosures to report. Jessica R. Santos-Parker, MD, PhD – No disclosures to report. Gurjit Sandhu, PhD - No disclosures to report. Brian C. George, MD, MAEd - No disclosures to report. Paul Gauger, MD – No disclosures to report. David T. Hughes, MD – No disclosures to report. Justin B. Dimick, MD, MPH – Dr. Dimick is supported by the following grants: Using Video Analysis to Improve Outcomes of Laparoscopic Colectomy: National Institute of Health R01HS025365; Long-Term Comparative Effectiveness of Sleeve Gastrectomy: National Institute of Health R01DK115408. He is the co-founder of ArborMetrix, Inc, a venture-capital backed healthcare software company focused on measuring and improving hospital quality and cost-efficiency. He is a consultant for US News and World Report, Medicare Payment Advisory Commission, American College of Surgeons, and The Leapfrog Group. Gifty Kwakye, MD, MPH – No disclosures to report., (Copyright © 2022 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

To provide precision medicine for better cancer care, researchers must work on clinical patient data, such as electronic medical records, physiological measurements, biochemistry, computerized tomography scans, digital pathology, and the genetic landscape of cancer tissue. To interpret big biodata in cancer genomics, an operational flow based on artificial intelligence (AI) models and medical management platforms with high-performance computing must be set up for precision cancer genomics in clinical practice. To work in the fast-evolving fields of patient care, clinical diagnostics, and therapeutic services, clinicians must understand the fundamentals of the AI tool approach. Therefore, the present article covers the following four themes: (i) computational prediction of pathogenic variants of cancer susceptibility genes; (ii) AI model for mutational analysis; (iii) single-cell genomics and computational biology; (iv) text mining for identifying gene targets in cancer; and (v) the NVIDIA graphics processing units, DRAGEN field programmable gate arrays systems and AI medical cloud platforms in clinical next-generation sequencing laboratories. Based on AI medical platforms and visualization, large amounts of clinical biodata can be rapidly copied and understood using an AI pipeline. The use of innovative AI technologies can deliver more accurate and rapid cancer therapy targets.

Chinese Pharmacopoeia is an important part of drug standards in China, and it is also a legal basis that must be strictly followed in drug development, production, operation, application, and management. The information on prescriptions, preparation methods, properties, identification, inspection, content determination, functions and indications, usage and dosage, precautions, specifications, and storage of Chinese patent medicine preparations included in the Chinese Pharmacopoeia(Vol.Ⅰ) was clarified. The &quot;Preparation Method&quot; section describes the preparation process of Chinese patent medicine from decoction pieces to finished preparations in detail and specifies the preparation production methods and parameters, which has a good guiding and standardizing effect on the production of Chinese patent medicine in China. The present study summarized the preparation methods of Chinese patent medicine preparations and single drug preparations contained in the Chinese Pharmacopoeia(2020 edition, Vol.Ⅰ) in stages and analyzed the common preparation methods and technical parameters of Chinese patent medicine preparations, which is helpful to understand the current situation of Chinese patent medicine production technology in China and can provide references for the development of new Chinese medicine, the transformation of large varieties of Chinese patent medicine, and the optimization of preparation process of Chinese patent medicine in the market.

The incidence of breast cancer is increasing, and is one of the leading causes of cancer death worldwide. Dysregulation of NOTCH1 signaling is reported in breast cancer. In present study, bioinformatics was utilized to study the expression of NOTCH1 gene in breast cancer from public databases, including the Kaplan-Meier Plotter, PrognoScan, Human Protein Atlas, and cBioPortal. The relationship between NOTCH1 mRNA expression and survival of patients was inconsistent in public databases. In addition, we performed immunohistochemistry (IHC) staining of 135 specimens from our hospital. Lower cytoplasmic staining of NOTCH1 protein was correlated with cancer recurrence, bone metastasis, and a worse disease-free survival of patients, especially those with estrogen receptor-positive and human epidermal growth factor receptor 2-positive (HER2 + ) cancers. In TCGA breast cancer dataset, lower expression of NOTCH1 in breast cancer specimens was correlated with higher level of CCND1 (protein: cyclin D1). Decreased expression of NOTCH1 was correlated with lower level of CCNA1 (protein: cyclin A1), CCND2 (protein: cyclin D2), CCNE1 (protein: cyclin E1), CDK6 (protein: CDK6), and CDKN2C (protein: p18). In conclusion, NOTCH1 mRNA expression is not consistently correlated with clinical outcomes of breast cancer patients. Low cytoplasmic expression of NOTCH1 in IHC study is correlated with poor prognosis of breast cancer patients. Cytoplasmic localization of NOTCH1 protein failed to initial oncogenic signaling in present study. Expression of NOTCH1 mRNA was discordant with cell cycle-related genes. Regulation of NOTCH1 in breast cancer involves gene expression, protein localization and downstream signaling., Competing Interests: None., (AJCR Copyright © 2022.)

Background: Multidisciplinary rounds (MDRs) are scheduled, patient-focused communication mechanisms among multidisciplinary providers in the intensive care unit (ICU)., Objective: i-Dashboard is a custom-developed visualization dashboard that supports (1) key information retrieval and reorganization, (2) time-series data, and (3) display on large touch screens during MDRs. This study aimed to evaluate the performance, including the efficiency of prerounding data gathering, communication accuracy, and information exchange, and clinical satisfaction of integrating i-Dashboard as a platform to facilitate MDRs., Methods: A cluster-randomized controlled trial was performed in 2 surgical ICUs at a university hospital. Study participants included all multidisciplinary care team members. The performance and clinical satisfaction of i-Dashboard during MDRs were compared with those of the established electronic medical record (EMR) through direct observation and questionnaire surveys., Results: Between April 26 and July 18, 2021, a total of 78 and 91 MDRs were performed with the established EMR and i-Dashboard, respectively. For prerounding data gathering, the median time was 10.4 (IQR 9.1-11.8) and 4.6 (IQR 3.5-5.8) minutes using the established EMR and i-Dashboard (P<.001), respectively. During MDRs, data misrepresentations were significantly less frequent with i-Dashboard (median 0, IQR 0-0) than with the established EMR (4, IQR 3-5; P<.001). Further, effective recommendations were significantly more frequent with i-Dashboard than with the established EMR (P<.001). The questionnaire results revealed that participants favored using i-Dashboard in association with the enhancement of care plan development and team participation during MDRs., Conclusions: i-Dashboard increases efficiency in data gathering. Displaying i-Dashboard on large touch screens in MDRs may enhance communication accuracy, information exchange, and clinical satisfaction. The design concepts of i-Dashboard may help develop visualization dashboards that are more applicable for ICU MDRs., Trial Registration: ClinicalTrials.gov NCT04845698; https://clinicaltrials.gov/ct2/show/NCT04845698., (©Chao-Han Lai, Kai-Wen Li, Fang-Wen Hu, Pei-Fang Su, I-Lin Hsu, Min‑Hsin Huang, Yen‑Ta Huang, Ping-Yen Liu, Meng-Ru Shen. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 13.05.2022.)

To evaluate whether adjusted computed tomography (CT) scan image-based radiomics combined with immune genomic expression can achieve accurate stratification of cancer recurrence and identify potential therapeutic targets in stage III colorectal cancer (CRC), this cohort study enrolled 71 patients with postoperative stage III CRC. Based on preoperative CT scans, radiomic features were extracted and selected to build pixel image data using covariate-adjusted tensor classification in the high-dimension (CATCH) model. The differentially expressed RNA genes, as radiomic covariates, were identified by cancer recurrence. Predictive models were built using the pixel image and immune genomic expression factors, and the area under the curve (AUC) and F1 score were used to evaluate their performance. Significantly adjusted radiomic features were selected to predict recurrence. The association between the significantly adjusted radiomic features and immune gene expression was also investigated. Overall, 1037 radiomic features were converted into 33 × 32-pixel image data. Thirty differentially expressed genes were identified. We performed 100 iterations of 3-fold cross-validation to evaluate the performance of the CATCH model, which showed a high sensitivity of 0.66 and an F1 score of 0.69. The area under the curve (AUC) was 0.56. Overall, ten adjusted radiomic features were significantly associated with cancer recurrence in the CATCH model. All of these methods are texture-associated radiomics. Compared with non-adjusted radiomics, 7 out of 10 adjusted radiomic features influenced recurrence-free survival. The adjusted radiomic features were positively associated with PECAM1 , PRDM1 , AIF1 , IL10 , ISG20 , and TLR8 expression. We provide individualized cancer therapeutic strategies based on adjusted radiomic features in recurrent stage III CRC. Adjusted CT scan image-based radiomics with immune genomic expression covariates using the CATCH model can efficiently predict cancer recurrence. The correlation between adjusted radiomic features and immune genomic expression can provide biological relevance and individualized therapeutic targets.

Sarcopenia is defined as the loss of skeletal muscle mass and muscle function. It is common in patients with malignancies and often associated with adverse clinical outcomes. The presence of sarcopenia in patients with cancer is determined by body composition, and recently, radiologic technology for the accurate estimation of body composition is under development. Artificial intelligence- (AI-) assisted image measurement facilitates the detection of sarcopenia in clinical practice. Sarcopenia is a prognostic factor for patients with cancer, and confirming its presence helps to recognize those patients at the greatest risk, which provides a guide for designing individualized cancer treatments. In this review, we examine the recent literature (2017-2021) on AI-assisted image assessment of body composition and sarcopenia, seeking to synthesize current information on the mechanism and the importance of sarcopenia, its diagnostic image markers, and the interventions for sarcopenia in the medical care of patients with cancer. We concluded that AI-assisted image analysis is a reliable automatic technique for segmentation of abdominal adipose tissue. It has the potential to improve diagnosis of sarcopenia and facilitates identification of oncology patients at the greatest risk, supporting individualized prevention planning and treatment evaluation. The capability of AI approaches in analyzing series of big data and extracting features beyond manual skills would no doubt progressively provide impactful information and greatly refine the standard for assessing sarcopenia risk in patients with cancer., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Ying-Tzu Huang et al.)

Chemotherapy-induced neurotoxicity is a common adverse effect of cancer treatment. No medication has been shown to be effective in the prevention or treatment of chemotherapy-induced neurotoxicity. Using minoxidil as an initial template for structural modifications in conjunction with an in vitro neurite outgrowth assay, an image-based high-content screening platform, and mouse behavior models, an effective neuroprotective agent CN016 was discovered. Our results showed that CN016 could inhibit paclitaxel-induced inflammatory responses and infiltration of immune cells into sensory neurons significantly. Thus, the suppression of proinflammatory factors elucidates, in part, the mechanism of action of CN016 on alleviating paclitaxel-induced peripheral neuropathy. Based on excellent efficacy in improving behavioral functions, high safety profiles (MTD > 500 mg/kg), and a large therapeutic window (MTD/MED > 50) in mice, CN016 might have great potential to become a peripherally neuroprotective agent to prevent neurotoxicity caused by chemotherapeutics as typified by paclitaxel.

Purpose: Research has shown that barriers to career success in academic medicine disproportionately affect women. These barriers include inadequate mentoring, which may perpetuate the underrepresentation of women in senior leadership positions. The purpose of this review was to summarize the qualitative and quantitative evidence of the impact of mentoring on women's career outcomes and to inform future interventions to support the promotion and retention of women in academic medicine., Method: The authors conducted a systematic review of original research published in English-language, peer-reviewed journals through March 20, 2020. Search terms related to mentorship, women, and academic medicine. The authors searched MEDLINE, Embase, Scopus, Current Contents Connect via Web of Science, Cochrane Library, and PsycINFO. They excluded studies not specifically addressing women and those without gender-stratified outcomes. They extracted and analyzed the following data: study design, population, sample size, response rate, participant age, percentage of women, mentoring prevalence, and outcomes., Results: Of 2,439 citations identified, 91 studies met the inclusion criteria, including 65 quantitative and 26 qualitative studies. Mentoring was associated with objective and subjective measures of career success. Women perceived mentorship to be more valuable to their career development yet were more likely to report having no mentor. Additionally, women were more likely to report lower levels of research productivity, less career satisfaction, and greater barriers to promotion. Qualitative results indicated that women had less access to informal mentoring and family responsibilities had a greater effect on their career outcomes. Professional networking, female mentors, and relational aspects of mentoring were common themes., Conclusions: This review examined gender disparities in mentoring and the impact on research productivity, promotion success, and career satisfaction for women in academic medicine. Institution-supported mentoring programs are needed to facilitate identification of appropriate mentors and promotion of a more equitable academic career environment for women., (Copyright © 2021 by the Association of American Medical Colleges.)

The impact of germline variants on the regulation of the expression of tumor microenvironment (TME)-based immune response genes remains unclear. Expression quantitative trait loci (eQTL) provide insight into the effect of downstream target genes (eGenes) regulated by germline-associated variants (eVariants). Through eQTL analyses, we illustrated the relationships between germline eVariants, TME-based immune response eGenes, and clinical outcomes. In this study, both RNA sequencing data from primary tumor and germline whole-genome sequencing data were collected from patients with stage III colorectal cancer (CRC). Ninety-nine high-risk subjects were subjected to immune response gene expression analyses. Seventy-seven subjects remained for further analysis after quality control, of which twenty-two patients (28.5%) experienced tumor recurrence. We found that 65 eQTL, including 60 germline eVariants and 22 TME-based eGenes, impacted the survival of cancer patients. For the recurrence prediction model, 41 differentially expressed genes (DEGs) achieved the best area under the receiver operating characteristic curve of 0.93. In total, 19 survival-associated eGenes were identified among the DEGs. Most of these genes were related to the regulation of lymphocytes and cytokines. A high expression of HGF , CCR5 , IL18 , FCER1G , TDO2 , IFITM2 , and LAPTM5 was significantly associated with a poor prognosis. In addition, the FCER1G eGene was associated with tumor invasion, tumor nodal stage, and tumor site. The eVariants that regulate the TME-based expression of FCER1G , including rs2118867 and rs12124509, were determined to influence survival and chromatin binding preferences. We also demonstrated that FCER1G and co-expressed genes in TME were related to the aggregation of leukocytes via pathway analysis. By analyzing the eQTL from the cancer genome using germline variants and TME-based RNA sequencing, we identified the eQTL in immune response genes that impact colorectal cancer characteristics and survival.

Cervical cancer is a significant gynecological cancer and causes cancer-related deaths worldwide. Human papillomavirus (HPV) is implicated in the etiology of cervical malignancy. However, much evidence indicates that HPV infection is a necessary but not sufficient cause in cervical carcinogenesis. Therefore, the cellular pathophysiology of cervical cancer is worthy of study. This review summarizes the recent findings concerning the ion transport processes involved in cell volume regulation and intracellular Ca 2+ homeostasis of epithelial cells and how these transport systems are themselves regulated by the tumor microenvironment. For cell volume regulation, we focused on the volume-sensitive Cl - channels and K + -Cl - cotransporter (KCC) family, important regulators for ionic and osmotic homeostasis of epithelial cells. Regarding intracellular Ca 2+ homeostasis, the Ca 2+ store sensor STIM molecules and plasma membrane Ca 2+ channel Orai proteins, the predominant Ca 2+ entry mechanism in epithelial cells, are discussed. Furthermore, we evaluate the potential of these membrane ion transport systems as diagnostic biomarkers and pharmacological interventions and highlight the challenges.

Systemic characterization of genomic alterations into signaling pathways helps to understand the molecular pathogenies of colorectal cancer; however, their clinical implications remain unclear. Here, 128 patients with metastatic colorectal cancer (mCRC) receiving targeted next generation sequencing were retrospectively enrolled to analyze the impact of altered oncogenic pathways on clinical outcome. The datasets from Memorial Sloan Kettering Cancer Center were used for validation. In 123 patients with non-MSI-high tumor, the most common mutated gene was TP53 (84.6%), followed by APC (78.0%), KRAS (49.6%), and SMAD4 (22.8%). When mutated genes were allocated into signaling pathways defined as The Cancer Genome Atlas Pan-Cancer Analysis Project, alterations of cell cycle, Wnt, p53, RTK-RAS, PI3K, TGF-β, Notch, and Myc pathways were identified in 88%, 87%, 85%, 75%, 28%, 26%, 17%, and 10% of mCRC tissues, respectively. The survival analyses revealed that Myc and TGF-β pathway alterations were associated with a shorter overall survival (OS) (hazard ratio [HR]: 2.412; 95% confidence interval [CI]: 1.139-5.109; p = 0.018 and HR: 2.754; 95% CI: 1.044-7.265; p = 0.033, respectively). The negative prognostic impact of altered TGF-β pathway was maintained in patients receiving an anti-EGFR antibody. The OS of patients with mCRC carrying MYC and BRAF mutation was shorter than those with either MYC or BRAF mutation (HR: 4.981, 95% CI: 0.296-83.92; p = 0.02). These findings have clinical implications, such as prognosis prediction, treatment guidance, and molecular-targeted therapy development.

Colony-stimulating factor 1 receptor (CSF-1R) acts as the receptor for colony stimulating factor 1, a cytokine that controls the production, differentiation, and function of macrophages. Prior studies showed cancer patients harboring germline CSF1R c.1085A>G genetic variant had better survival. Here, primary tumor samples from a stage III colorectal cancer (CRC) cohort were analyzed by a targeted gene expression assay containing 395 immune-related genes to study the immune mechanism underlying the different outcomes. CRC patients with CSF1R c.1085 genotype A&#95;G had a better disease-free and overall survival than those with CSF1R genotype A&#95;A. Compared to the group of patients without CSF1R variant, higher CD40LG expression, a surface marker of T cells, was found in the tumor tissues of patients with CSF1R c.1085 variant. In parallel with the higher CD40LG gene expression, immunofluorescent staining also showed more CD3 + CD40L + T cell infiltrates in tumors with CSF1R c.1085 genotype A&#95;G. Moreover, higher IL-2 expression, known to be regulated by CD40 pathway, was also observed in tumors with CSF1R c.1085 genotype A&#95;G than genotype A&#95;A. Higher IL-2 expression generated by the interaction of CD40 ligand and CD40 between T cells and macrophages with CSF1R c.1085A>G variant is the potential mechanism explaining the different outcomes.

Store-operated Ca 2+ entry (SOCE) is an essential pathway for Ca 2+ signaling, and regulates various vital cellular functions. It is triggered by the endoplasmic reticulum Ca 2+ sensor stromal interaction molecule 1 (STIM1). Illustration of STIM1 spatiotemporal structure at the nanometer scale during SOCE activation provides structural and functional insights into the fundamental Ca 2+ homeostasis. In this study, we used direct stochastic optical reconstruction microscopy (dSTORM) to revisit the dynamic process of the interaction between STIM1, end-binding protein (EB), and microtubules to the ER-plasma membrane. Using dSTORM, we found that"powder-like"STIM1 aggregates into "trabecular-like" architectures toward the cell periphery during SOCE, and that an intact microtubule network and EB1 are essential for STIM1 trafficking. After thapsigargin treatment, STIM1 can interact with EB1 regardless of undergoing aggregation. We generated STIM1 variants adapted from a real-world database and introduced them into SiHa cells to clarify the impact of STIM1 mutations on cancer cell behavior. The p.D76G and p.D84Y variants locating on the Ca 2+ binding domain of STIM1 result in inhibition of focal adhesion turnover, Ca 2+ influx during SOCE and subsequent cell migration. Inversely, the p.R643C variant on the microtubule interacting domain of STIM1 leads to dissimilar consequence and aggravates cell migration. These findings imply that STIM1 mutational patterns have an impact on cancer metastasis, and therefore could be either a prognostic marker or a novel therapeutic target to inhibit the malignant behavior of STIM1-mediated cancer cells. Altogether, we generated novel insight into the role of STIM1 during SOCE activation, and uncovered the impact of real-world STIM1 variants on cancer cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Huang, Hsu, Chen and Shen.)

The new generation, i.e., second- and third-generation, drug-eluting stents (DESs) remain a risk of in-stent restenosis (ISR). We evaluated the power of a genetic risk score (GRS) model to identify high-risk populations for new generation DES ISR. We enrolled patients with coronary artery disease (CAD) treated with new generations DESs by a single-center cohort study in Taiwan and evaluated their genetic profile. After propensity score matching, there were 343 patients and 153 patients in the derivation and validation cohorts, respectively. Five selected single-nucleotide polymorphisms (SNPs), i.e., SNPs in CAMLG , GALNT2 , C11orf84 , THOC5 , and S AMD11 , were included to calculate the GRS for new generation DES ISR. In the derivation and the validation cohorts, patients with a GRS greater than or equal to 3 had significantly higher new generation DES ISR rates. We provide biological information for interventional cardiologists prior to percutaneous coronary intervention by specific five SNP-derived GRS., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Tumor heterogeneity results in more than 50% of hypermutated cancers failing to respond to standard immunotherapy. There are numerous challenges in terms of drug resistance, therapeutic strategies, and biomarkers in immunotherapy. In this study, we analyzed primary tumor samples from 533 cancer patients with six different cancer types using deep targeted sequencing and gene expression data from 78 colorectal cancer patients, whereby driver mutations, mutational signatures, tumor-associated neoantigens, and molecular cancer evolution were investigated. Driver mutations, including RET , CBL , and DDR2 gene mutations, were identified in the hypermutated cancers. Most hypermutated endometrial and pancreatic cancer patients carry genetic mutations in EGFR , FBXW7 , and PIK3CA that are linked to immunotherapy resistance, while hypermutated head and neck cancer patients carry genetic mutations associated with better treatment responses, such as ATM and BRRCA2 mutations. APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) and DNA repair defects are mutational drivers that are signatures for hypermutated cancer. Cancer driver mutations and other mutational signatures are associated with sensitivity or resistance to immunotherapy, representing potential genetic markers in hypermutated cancers. Using computational prediction, we identified NF1 p.T700I and NOTCH1 p.V2153M as tumor-associated neoantigens, representing potential therapeutic targets for immunotherapy. Sequential mutations were used to predict hypermutated cancers based on genomic evolution. Using a logistic model, we achieved an area under the curve (AUC) = 0.93, accuracy = 0.93, and sensitivity = 0.81 in the testing set. The sequential patterns were distinct among the six cancer types, and the sequential mutation order of MSH2 and the coexisting BRAF genetic mutations influenced the hypermutated phenotype. The TP53 ~ MLH1 and NOTCH1 ~ TET2 sequential mutations impacted colorectal cancer survival ( p -value = 0.027 and 0.0001, respectively) by reducing the expression of PTPRCAP ( p -value = 1.06 × 10 -6 ) and NOS2 ( p -value = 7.57 × 10 -7 ) in immunity. Sequential mutations are significant for hypermutated cancers, which are characterized by mutational heterogeneity. In addition to driver mutations and mutational signatures, sequential mutations in cancer evolution can impact hypermutated cancers. They characterize potential responses or predictive markers for hypermutated cancers. These data can also be used to develop hypermutation-associated drug targets and elucidate the evolutionary biology of cancer survival. In this study, we conducted a comprehensive analysis of mutational patterns, including sequential mutations, and identified useful markers and therapeutic targets in hypermutated cancer patients.

An optimal therapeutic regimen for endometrial cancer with extra-uterine metastasis is unavailable. This study aims to improve our understanding of the genomic landscape of advanced endometrial cancer and identify potential therapeutic targets. The clinical and genomic profiles of 81 patients with stage III or IV endometrial cancer were integrated. To identify genomic aberrations associated with clinical outcomes, Cox proportional hazard regression was used. The impacts of the genomic aberrations were validated in vitro and in vivo. The mutation status of MET , U2AF1 , BCL9 , PPP2R1A , IDH2 , CBL , BTK, and CHEK2 were positively correlated with poor clinical outcomes. MET mutations occurred in 30% of the patients who presented with poor overall survival (hazard ratio, 2.606; 95% confidence interval, 1.167~5.819; adjusted p -value, 0.067). Concurrent MET and KRAS mutations presented with the worst outcomes. MET mutations in hepatocyte growth factor (HGF)-binding (58.1%) or kinase (16.2%) domains resulted in differential HGF-induced c-MET phosphorylation. Different types of MET mutations differentially affected tumor growth and displayed different sensitivities to cisplatin and tyrosine kinase inhibitors. MET N375S mutation is a germline variant that causes chemoresistance to cisplatin, with a high incidence in Eastern Asia. This study highlights the ethnic differences in the biology of the disease, which can influence treatment recommendations and the genome-guided clinical trials of advanced endometrial cancer.

Chemotherapy-induced cognitive impairment (CICI) is an adverse side effect of cancer treatment with increasing awareness. Hippocampal damage and related neurocognitive impairment may mediate the development of CICI, in which altered neurogenesis may play a role. In addition, increased inflammation may be related to chemotherapy-induced hippocampal damage. Memantine, an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that may enhance neurogenesis and modulate inflammation, may be useful for treating CICI. To test this hypothesis, paclitaxel was administered to eight-week-old male B6 mice to demonstrate the relationship between CICI and impaired neurogenesis, and then, we evaluated the impact of different memantine regimens on neurogenesis and inflammation in this CICI model. The results demonstrated that both the pretreatment and cotreatment regimens with memantine successfully reversed impaired neurogenesis and spatial memory impairment in behavior tests. The pretreatment regimen unsuccessfully inhibited the expression of peripheral and central TNF-α and IL-1β and did not improve the mood alterations following paclitaxel treatment. However, the cotreatment regimen led to a better modulatory effect on inflammation and restoration of mood disturbance. In conclusion, this study illustrated that impaired neurogenesis is one of the mechanisms of paclitaxel-induced CICI. Memantine may serve as a potential treatment for paclitaxel-induced CICI, but different treatment strategies may lead to variations in the treatment efficacy.