Multimechanism biological profiling of tetrahydro-ß-carboline analogues as selective HDAC6 inhibitors for the treatment of Alzheimer's disease.

With the intensive research on the pathogenesis of Alzheimer's disease (AD), inhibition of HDAC6 appears to be a potential therapeutic approach for AD. In this paper, a series of tetrahydro-ß-carboline derivatives with hydroxamic acid group were fast synthesized. Among all, the most potent 15 selectively inhibited HDAC6 with IC50 of 15.2 nM and markedly increased acetylated alpha-tubulin levels. In cellular assay, 15 showed excellent neurotrophic effect by increasing the expression of GAP43 and Beta-3 tubulin markers. Besides, 15 showed neuroprotective effects in PC12 or SH-SY5Y cells against H2O2 and 6-OHDA injury through activation of Nrf2, catalase and Prx II, and significantly reduced H2O2-induced reactive oxygen species (ROS) production. In vivo, 15 significantly attenuated zebrafish anxiety-like behaviour and memory deficits in a SCOP-induced zebrafish model of AD. To sum up, multifunctional 15 might be a good lead to develop novel tetrahydrocarboline-based agents for the treatment of AD.

Identification of platelet-related subtypes and diagnostic markers in pediatric Crohn's disease based on WGCNA and machine learning.

Background: The incidence of pediatric Crohn's disease (PCD) is increasing worldwide every year. The challenges in early diagnosis and treatment of PCD persist due to its inherent heterogeneity. This study's objective was to discover novel diagnostic markers and molecular subtypes aimed at enhancing the prognosis for patients suffering from PCD. Methods: Candidate genes were obtained from the GSE117993 dataset and the GSE93624 dataset by weighted gene co-expression network analysis (WGCNA) and differential analysis, followed by intersection with platelet-related genes. Based on this, diagnostic markers were screened by five machine learning algorithms. We constructed predictive models and molecular subtypes based on key markers. The models were evaluated using the GSE101794 dataset as the validation set, combined with receiver operating characteristic curves, decision curve analysis, clinical impact curves, and calibration curves. In addition, we performed pathway enrichment analysis and immune infiltration analysis for different molecular subtypes to assess their differences. Results: Through WGCNA and differential analysis, we successfully identified 44 candidate genes. Following this, employing five machine learning algorithms, we ultimately narrowed it down to five pivotal markers: GNA15, PIK3R3, PLEK, SERPINE1, and STAT1. Using these five key markers as a foundation, we developed a nomogram exhibiting exceptional performance. Furthermore, we distinguished two platelet-related subtypes of PCD through consensus clustering analysis. Subsequent analyses involving pathway enrichment and immune infiltration unveiled notable disparities in gene expression patterns, enrichment pathways, and immune infiltration landscapes between these subtypes. Conclusion: In this study, we have successfully identified five promising diagnostic markers and developed a robust nomogram with high predictive efficacy. Furthermore, the recognition of distinct PCD subtypes enhances our comprehension of potential pathogenic mechanisms and paves the way for future prospects in early diagnosis and personalized treatment.

Identification of cuproptosis-associated subtypes and signature genes for diagnosis and risk prediction of Ulcerative colitis based on machine learning.

Background: Ulcerative colitis (UC) is a chronic and debilitating inflammatory bowel disease that impairs quality of life. Cuproptosis, a recently discovered form of cell death, has been linked to many inflammatory diseases, including UC. This study aimed to examine the biological and clinical significance of cuproptosis-related genes in UC. Methods: Three gene expression profiles of UC were obtained from the Gene Expression Omnibus (GEO) database to form the combined dataset. Differential analysis was performed based on the combined dataset to identify differentially expressed genes, which were intersected with cuproptosis-related genes to obtain differentially expressed cuproptosis-related genes (DECRGs). Machine learning was conducted based on DECRGs to identify signature genes. The prediction model of UC was established using signature genes, and the molecular subtypes related to cuproptosis of UC were identified. Functional enrichment analysis and immune infiltration analysis were used to evaluate the biological characteristics and immune infiltration landscape of signature genes and molecular subtypes. Results: Seven signature genes (ABCB1, AQP1, BACE1, CA3, COX5A, DAPK2, and LDHD) were identified through the machine learning algorithms, and the nomogram built from these genes had excellent predictive performance. The 298 UC samples were divided into two subtypes through consensus cluster analysis. The results of the functional enrichment analysis and immune infiltration analysis revealed significant differences in gene expression patterns, biological functions, and enrichment pathways between the cuproptosis-related molecular subtypes of UC. The immune infiltration analysis also showed that the immune cell infiltration in cluster A was significantly higher than that of cluster B, and six of the characteristic genes (excluding BACE1) had higher expression levels in subtype B than in subtype A. Conclusions: This study identified several promising signature genes and developed a nomogram with strong predictive capabilities. The identification of distinct subtypes of UC enhances our current understanding of UC's underlying pathogenesis and provides a foundation for personalized diagnosis and treatment in the future.

Metastatic Small Bowel Adenocarcinoma Mimicking a Primary Ovarian Mucinous Tumour - Clinical, Radiologic, Pathologic and Molecular Correlation.

We describe an interesting case of a patient who presented with a large adnexal mass, first favored to be mucinous carcinoma of the gynecologic origin. The primary tumour site was ascertained after the patient's small bowel was resected by identifying an adenomatous component evolving into an invasive adenocarcinoma identical in morphology and immunophenotype to the ovarian tumour. Notably, both tumours were found to harbor a BRAF K601E mutation, which is extremely rare for a primary of the ovary. BRAF mutations are present in a subset of large bowel and small bowel adenocarcinoma, but our case shows the first instance of a BRAF K601E mutation being present in a small bowel adenocarcinoma, to the best of our knowledge. This case serves as a great illustration of the pivotal role of molecular diagnostics in modern pathology in arriving at the correct diagnosis. Additionally, it is an excellent example of how clinical-radiologic-pathologic-molecular correlation plays into the landscape of molecular pathology to deliver optimal care for the patient.

Patterns of First-Line Systemic Therapy Delivery and Outcomes in Advanced Epithelial Ovarian Cancer in Ontario.

BACKGROUND: First-line treatment of epithelial ovarian cancer (EOC) consists of a combination of cytoreductive surgery and platinum-based chemotherapy. Recently, targeted therapies such as bevacizumab have been shown to improve oncologic outcomes in a subset of a high-risk population. The objective of this study is to evaluate the patterns of practice and outcomes of first-line systemic treatment of advanced EOC, focusing on the adoption of bevacizumab. METHODS: A population cohort study was conducted using administrative data in Ontario, Canada. Patients diagnosed with advanced stage non-mucinous EOC between 2014 and 2018 were identified. Datasets were linked to obtaining information on first-line treatment including surgery, systemic therapy, providers of care, systemic therapy facilities, and acute care utilization (emergency department (ED) visits and hospitalizations) during systemic treatment. Multivariate logistic regression was used to determine factors associated with systemic therapy utilization. RESULTS: Among 3726 patients with advanced EOC, 2838 (76%) received chemotherapy: 1316 (47%) received neoadjuvant chemotherapy, 1060 (37%) underwent primary cytoreductive surgery followed by chemotherapy, and 462 (16%) received chemotherapy only. The median age was 67 (range: 20-100). Most chemotherapies were prescribed by gynecologic oncologists (60%) and in level 1 academic cancer centres (58%). Only 54 patients (3.1%) received bevacizumab in the first-line setting after its approval in Ontario in 2016. Bevacizumab was more likely to be administered by medical oncologists compared to gynecologic oncologists (OR 3.95, 95% CI 2.11-7.14). In total, 1561 (55%) and 1594 (56%) patients had at least one ED visit and/or hospitalization during systemic treatment, respectively. The most common reasons for ED visits were fever and bowel obstruction. CONCLUSION: Patterns of care for EOC in Ontario differed between care providers. The uptake of bevacizumab for first-line treatment of EOC was low. Acute care utilization related to EOC was high.

Angiogenesis: A Pivotal Therapeutic Target in the Drug Development of Gynecologic Cancers.

Since the discovery of angiogenesis and its relevance to the tumorigenesis of gynecologic malignancies, a number of therapeutic agents have been developed over the last decade, some of which have become standard treatments in combination with other therapies. Limited clinical activity has been demonstrated with anti-angiogenic monotherapies, and ongoing trials are focused on combination strategies with cytotoxic agents, immunotherapies and other targeted treatments. This article reviews the science behind angiogenesis within the context of gynecologic cancers, the evidence supporting the targeting of these pathways and future directions in clinical trials.

Impact of care by gynecologic oncologists on primary ovarian cancer survival: A population-based study.

OBJECTIVES: Timely treatment of epithelial ovarian cancer (EOC) by gynecologic oncologists (GOs) with a combination of surgery and/or chemotherapy has been advocated. Nonetheless, some patients are not assessed by GOs prior to starting their treatment or have surgery by non-GOs. This study aims to determine trends over time in non-mucinous EOC care and to evaluate the impact of care on survival. METHODS: Using province-wide administrative data, patients diagnosed with non-mucinous EOC between 2007 and 2018 were identified. Multivariate Cox proportional hazards regression models were used to evaluate the impact of GO assessment prior to initiating treatment or having surgery done by a non-GO on mortality. RESULTS: A total of 10,086 EOC patients were included between 2007 and 2018. During the study period, there was an 8% increase in GO assessment (79% in 2007 to 87% in 2018-19, p ≤  0.001) and a 19% increase in surgeries performed by GOs (69% in 2007 to 88% in 2018-19, p ≤ 0.001). On multivariate analysis, there was an increased hazard of all-cause mortality for patients not assessed by GOs before first treatment (Hazard ratio (HR): 1.61; 95% CI 1.46-1.79). There was an increased hazard of all-cause mortality if ovarian cancer surgery was performed by non-GOs (HR 2.03; 95% CI 1.80-2.30). CONCLUSION: Assessment by GO before starting initial treatment is associated with improved survival in women with non-mucinous EOC as the type of surgeon performing primary ovarian cancer surgery. Assessment by GO for all patients with new or suspected ovarian cancer diagnosis before initiation of primary treatment should be advocated.

Ethical frameworks in clinical research processes during COVID-19: a scoping review.

OBJECTIVES: In response to the COVID-19 pandemic there have been significant developments in research, its conduct and the supporting ethical framework. While many protocols have been delayed, halted or modified, other research efforts have been accelerated, generating controversy. The goal of this paper is to determine the rates of references surrounding the ethical oversight of research as reported in current COVID-19-related research publications. DESIGN: Scoping review. SETTING: Population-based observational or interventional studies from December 2019 to May 2020 with sample size of two or more. Studies were searched through electronic databases including Medline, EMBASE, and Cochrane CENTRAL Register of Controlled Trials. PARTICIPANTS: Eligibility criteria included participants within published studies who tested positive for COVID-19. MAIN OUTCOMES AND MEASURES: Data were extracted and charting methods included taking note of references to ethical frameworks, institutional review board (IRB), ethics committee (EC) or research ethics board (REB) involvement, consent processes, and other variables. RESULTS: 11 556 articles were screened, with 656 included in the final analysis. References to ethics were present in 530 (80.8%) studies, with 491 (74.8%) involving IRB/ECs/REBs and 126 (19.2%) not referencing ethics. Consent processes were outlined in 201 (30.6%) studies, with 198 (30.2%) reporting that they obtained consent waivers, however, 257 (39.2%) did not mention consent at all. Differences (p<0.001) in ethics-related references were apparent when analysed by continent, publication type, sample size and IF. CONCLUSIONS: The majority of published articles pertaining to COVID-19 research made mention of ethical considerations, however, national and regional variations in research ethics review requirements introduce heterogeneity between studies and raise important questions about the conduct of scientific research during global public emergencies. TRIAL REGISTRATION NUMBER: Open Science Framework: https://osfio/z67wb.

The use of bevacizumab in the modern era of targeted therapy for ovarian cancer: A systematic review and meta-analysis.

OBJECTIVES: The optimal systemic therapy strategy for advanced epithelial ovarian cancer (EOC) remains unclear. We performed a systematic review and meta-analysis to assess oncologic outcomes and toxicity of bevacizumab combination treatment in advanced EOC. METHODS: We conducted an electronic search of all phase 2 and 3 clinical trials involving bevacizumab combination therapy in advanced-stage EOC between 2010 and March 2020, using Embase, Medline, Epub Ahead of Print, Cochrane for clinical trials, Cochrane Database of Systematic Reviews, Web of Science and clinicaltrials.gov databases. Progression-free survival (PFS), overall survival (OS), and their hazard ratios (HR) when available were extracted. Pooled HR were calculated for each efficacy endpoint in the meta-analysis using inverse variance weighted method. Bias was assessed using the Cochrane Collaboration Risk of Bias I (ROB1) tool for randomized controlled trials. RESULTS: Thirty-five studies were included in the qualitative analysis and eight studies in the quantitative synthesis. In the first-line setting, bevacizumab combined with chemotherapy revealed a significant improvement in PFS (pooled HR = 0.72, 95% CI 0.65-0.81) when compared to chemotherapy alone but no significant OS benefit (pooled HR = 0.88, 95% CI 0.72-1.06). In the recurrent setting, bevacizumab combinations showed significant PFS (pooled HR = 0.52, 95% CI 0.47-0.58) and OS benefits (pooled HR = 0.88, 95% CI 0.79-0.99) compared with non-bevacizumab regimens. Rate of bowel perforation was low at 1.24% (range 0-4.2%). CONCLUSIONS: Bevacizumab-containing regimens are associated with significant PFS benefit in advanced and recurrent epithelial ovarian cancer. While the difference in OS did not reach statistical significance in the first-line setting, bevacizumab was associated with improved survival in the recurrent setting.

The Impact of Geography in Hepatocellular Carcinoma: A Retrospective Population Based Study.

BACKGROUND: The treatment of hepatocellular carcinoma (HCC) includes different therapeutic modalities and multidisciplinary tumor board reviews. The impact of geography and treatment center type (quaternary vs. non-quaternary) on access to care is unclear. METHODS: A retrospective chart review was performed on HCC patients who received sorafenib in British Columbia from 2008 to 2016. Patients were grouped by Statistics Canada population center (PC) size criteria: large PC (LPC), medium PC (MPC), and small PC (SPC). Access to specialists, receipt of liver-directed therapies, and survival outcomes were compared between the groups. RESULTS: Of 286 patients, the geographical distribution was: LPC: 75%; MPC: 16%; and SPC: 9%. A higher proportion of Asians (51% vs. 9% vs. 4%; p < 0.001), Child-Pugh A (94% vs. 83% vs. 80%; p = 0.022), and hepatitis B (37% vs. 15% vs. 4%; p < 0.001) was observed in LPC vs. MPC vs. SPC, respectively. LPC patients were more likely referred to a hepatologist (62% vs. 48% vs. 40%; p = 0.031) and undergo transarterial chemoembolization (TACE) (43% vs. 24% vs. 24%; p = 0.018). Sixty percent were treated at a quaternary center, and the median overall survival (OS) was higher for patients treated at a quaternary vs. non-quaternary center (28.0 vs. 14.6 months, respectively; p < 0.001) but similar when compared by PC size. Treatment at a quaternary center predicted an improved survival on multivariate analysis (hazard ratio (HR): 0.652; 95% confidence interval (CI): 0.503-0.844; p = 0.001). CONCLUSIONS: Geography did not appear to impact OS but patients from LPC were more likely to be referred to hepatology and undergo TACE. Treatment at a quaternary center was associated with an improved survival.

Omission of adjuvant therapy in stage I clear cell ovarian cancer: Review of the BC Cancer experience.

BACKGROUND: Since 2012, the BC Cancer provincial treatment guideline for surgically staged stage IA/B and IC1 (defined by intraoperative rupture only) clear cell ovarian cancer (CCOC) has been to offer observation only. We reviewed the clinical outcomes of all stage I CCOC patients since policy implementation. METHODS: A retrospective, population-based cohort study of all stage I CCOC patients operated on between April 2012 and December 2017 was conducted. Patient, tumor, surgical and clinical outcome data were collected. Survival analysis was conducted using Kaplan-Meier methods. RESULTS: 78 patients with stage I disease were identified. 40 patients with stages IA/B and IC1, who underwent post-operative observation, were included in the analysis. Lymph node dissection was omitted in 20 patients (50%). Median duration of follow-up was 36 months. There were 4 recurrences (10%), 3 metastatic. The 5-year disease-free survival is 90%, and the 5-year overall survival is 95% for stage IA/B and 90% for stage IC1 (p = 0.645). In comparison, 5-year overall survival for stage IC2 (surface involvement) and IC1 with sharp dissection (all received adjuvant chemotherapy) is 82% (p < 0.001) and for stage IC3 (positive washings) was 23% (p < 0.001). CONCLUSION: Adjuvant therapy can be safely omitted in patients with stage I A/B and IC1 CCOC. Recurrence rates are low and survival is >90% at 5 years. Stage IC2 /IC3 had worse outcomes, thus stage I substage is instrumental in predicting clinical outcomes for CCOC. Lymph node metastases are rare in stage IA/B/C1 CCOC as absence of lymphadenectomy did not increase the risk of disease recurrence.

Role of surveillance imaging and endoscopy in colorectal cancer follow-up: Quality over quantity?

Colorectal cancer (CRC) is a prevalent disease and represents a major cause of morbidity and mortality in the developed world. Intensive post-treatment surveillance is routinely recommended by major expert groups for early stage (II and III) CRC survivors because previous meta-analyses showed a modest, but significant survival benefit. This practice has been recently challenged based on data emerging from several large phase III randomized trials that demonstrated a lack of survival benefit from intensive surveillance strategies. In addition, findings from cost-effectiveness analyses of such an approach are inconsistent. Data on real-world practice, specifically adherence to these follow-up guidelines, are also limited. The debate is especially controversial in resected stage IV patients where there are currently no clear guidelines for follow-up. In an era of personalized medicine, there may be a shift towards a more risk-adapted approach to better define the optimal follow-up strategy. In this article, we review the evidence and highlight the role of surveillance in CRC survivors.

The adhesion energy measured by a stress accumulation-peeling mechanism in the exfoliation of graphite.

The mechanical exfoliation of graphite using tape is one way to obtain high-quality graphene samples. However, the amount of graphene obtained is negligible due to the unclear exfoliation mechanism. In this paper, we present a stress accumulation-peeling mechanism, which can be applied to measure the adhesion energy of graphite. This mechanism is different from a wriggle or a creep. First, we obtained a simple universal formula to measure the adhesion energy Ga = (Fmax-Fmin)/3b, where Fmax and Fmin are the maximum and minimum values, respectively, of the external stretch force in the peeling process, and b is the width of the peeling arm. Second, the reliability of the method was demonstrated by measuring the adhesion energy between polydimethylsiloxane and glass. Using the simple universal formula, the adhesion energies of three graphite slices were determined to be 0.34 ± 0.03, 0.33 ± 0.06 and 0.34 ± 0.02 J m-2. These adhesion energies were consistent with the other measured result of 0.33 J m-2, which was based on the self-retraction phenomenon of graphite. The macroscopic method is very simple and easy to implement. It can be used to measure the adhesion energy of any van der Waals material and any biomaterial with adhesion interaction, as well as prepare excellent 2D material samples by optimizing the experimental conditions.