Prognosis of Acute HEV Infection in Patients With Liver Cirrhosis: A Retrospective Study of 628 Chinese Patients.

Acute hepatitis E virus infection is a serious global health problem, which a significant cause of morbidity and mortality. The aim of the present study was to characterise the clinical features and therapeutic response of patients with acute HEV infection and identify risk factors for poor prognosis. In a retrospective study from 01 January 2014 to 01 Januray 2022, we collected baseline data from all patients eligible for acute hepatitis E virus (HEV) infection and followed up with all patients via interviews and medical records. We explored the clinical feature of Chinese patients with acute HEV infection. The follow-up data of patients were used to identify risk factors for poor prognosis. In total, 628 acute hepatitis E (AHE) patients fulfilled the inclusion criteria and did not meet the exclusion criteria. Among them, 452 were males and 176 were females (M:F = 2.57:1). The median age at diagnosis was 57.0 years (interquartile range: 46-64 years). The median baseline serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) were elevated in this cohort (642.3 U/L, 216.2 U/L, 104.1 µmol/L, respectively). The median hospitalisation duration was 16 days. Compared with patients without other liver diseases, patients with liver cirrhosis show lower baseline ALT and AST level, poorer coagulation indices and higher MELD scores. According to multivariate analysis, liver cirrhosis, high MELD score, low albumin concentration was found to be independent predictors of poor prognosis in patients with AHE. Our study used a lager sample size to validate that some demographic and serological features were quite different between patients with/without CLDs. Liver cirrhosis was a significant independent predictor of poor prognosis in acute HEV hepatitis.

Three-dimensional mapping of necrotic lesions for early-stage osteonecrosis of the femoral head.

BACKGROUND: There is a scarcity of evidence regarding the potential relationship between the size and location of necrotic lesions, which must be understood to provide optimal joint-preserving treatment. The purpose of this study was to characterize the distribution patterns of necrotic lesions of varying sizes in early-stage osteonecrosis of femoral head (ONFH) with the use of three-dimensional mapping. METHODS: We retrospectively evaluated clinical CT images of the hips that were performed in the Third Hospital of Hebei Medical University from January 2018 to December 2022 and collected all CT images diagnosed with stage I and II ONFH. Three-dimensional structures that included both necrotic lesions and normal areas of the femoral heads were reconstructed and divided into eight regions to record their size and location. CT images for all lesions were superimposed onto a standard template, and three-dimensional mapping was created to determine the presence of concentrated areas of lesions. RESULTS: In a cohort of 143 patients with stage I and II ONFH, a total of 150 hips were reviewed. For lesions with less than 15% of the femoral head volume, necrotic lesions predominantly involve regions I, III, and V, with region I showing concentration. For lesions with volumes ranging from 15 to 30%, necrotic lesions exhibited a wider distribution across regions I, II, III, IV, V, and VII, with significant concentrations in regions I, III, and V. For lesions exceeding 30% of the femoral head volume, the necrotic lesions were extensively distributed across nearly the entire femoral head, with a notable expansion of the concentrated necrotic areas. CONCLUSIONS: The distribution of necrotic lesions varies with lesion size, with smaller lesions primarily concentrated in the anterior and medial regions of the femoral head, particularly in the anterosuperior region, while larger lesions expand to the lateral and inferior regions. These findings enhance existing classification systems and provide crucial insights for guiding hip-preserving surgical planning and approaches.

Association of MORC2 expression with progression-free survival in cervical cancer patients treated with concurrent chemoradiotherapy.

MORC family CW-type zinc finger 2 (MORC2) is a newly identified chromatin remodeling protein, and has been proposed as a prognostic biomarker associated with survival in some types of human cancer, but the role of MORC2 in cervical cancer remains unknown. Here, we investigated the role of MORC2 expression in predicting the survival outcomes of locally advanced cervical cancer patients treated with cisplatin-based concurrent chemoradiotherapy (CCRT). In this retrospectively study, we detected MORC2 immunohistochemical expression on 55 biopsies from patients who underwent CCRT. The association between the MORC2 expression and various clinicopathological characteristics were analyzed, as were association between MORC2 expression and locoregional failure and progression-free survival (PFS) of cervical cancer patients. MORC2 expression was positively associated with pelvic node metastasis and locoregional failure. Higher MORC2 expression was a significant indicator of worse PFS. Our results suggest that MORC2 expression may be a prognostic indicator in patients with locally advanced cervical cancer undergoing CCRT.

Development of a Short-Term Embolic Agent Based on Cilastatin for Articular Microvessels.

Background and Objectives: This study aimed to develop an embolic agent with short-term embolic effects using cilastatin as the basic material. Materials and Methods: The particle size distribution of 25 mg cilastatin-based short-term embolic agents was evaluated microscopically under three different mixing conditions. A total of thirty-six healthy male Sprague Dawley rats were divided into four groups. Each group of six rats was injected once into the tail artery with 0.4 mL each of (A) Cilastatin + D-Mannitol Mixture, (B) Iohexol, (C) Prepenem, and (D) embolization promoter (EGgel). Results: A visual inspection of the tail appearance of rats in each group was performed at 0, 3, 7, 15, and 21 days. At weeks 1 and 3, three rats per group were euthanized, and histopathological analyses were performed on the specimens obtained from each group. No significant differences were observed on day 7, but mild inflammation was observed in Group (D) on day 15. Histopathological inflammation scoring of tail central artery embolization was performed using a six-point scale (from 0 = absent to 5 = marked inflammation). Three groups were formed consisting of six male New Zealand white rabbits each: control, positive control, and test groups. The control group received an Iohexol injection (rabbits: 0.8 mL). The positive control and experimental groups were injected with prepenem and cilastatin/D-mannitol compound, respectively (0.8 mL), and vascular angiography was performed. The order of occlusion progression after embolization was as follows: test group, positive control group, and control group. Conclusions: We developed a cilastatin/D-mannitol compound that exhibits characteristics of short-term embolization by utilizing the pharmacokinetic properties of cilastatin and the crystalline material D-mannitol. We evaluated its particle size distribution microscopically, conducted histopathological evaluation including inflammation via animal experiments, and assessed the embolization effect.

The combined internal and external fixation surgery is effective and safe in treating posterior lateral tibial plateau fractures: An observational study.

To investigate the treatment outcomes of combined internal and external fixation surgery for patients with posterior lateral tibial plateau fractures and explore its safety. The study was conducted from February 2020 to February 2023 and included a total of 77 patients with Schatzker IV and Schatzker V type posterior lateral tibial plateau fractures. Patients were divided into control group and treatment group according to different treatment methods: the control group with 38 cases received treatment with dual-support plates, and the study group with 39 cases received treatment with internal fixation using medial plates combined with lateral locking plates. Clinical indicators during treatment, immediate postoperative and 12-month postoperative radiographic indicators, Rasmussen knee joint function scores before and 3 months after surgery, knee joint function recovery, quality of life, and postoperative complications were recorded and compared between the 2 groups. The inter-group comparisons were made for intraoperative blood loss, surgical duration, and the time to start weight-bearing postoperatively (P > .05). The study group had shorter postoperative hospital stays and fracture healing times compared to the control group (P < .05). Immediately postoperatively, the medial tilt angle and posterior tilt angle in both groups were compared (P > .05). At 12 months postoperatively, the medial tilt angle decreased and the posterior tilt angle increased in both groups compared to immediately postoperative values (P < .05), with no significant difference between the groups (P > .05). However, at 3 months postoperatively, the scores for various dimensions in both groups increased compared to preoperative values, and the study group had higher scores than the control group (P < .05). However, at 3 months postoperatively, the quality of life scores were higher than preoperative values in both groups, with the study group having higher scores (P < .05). The occurrence of complications during the treatment period was compared between the 2 groups (P > .05). The medial and lateral combined plate fixation has a good clinical effect in the treatment of posterolateral tibial plateau fractures, which can shorten the fracture healing time, help the recovery of knee joint function and improve the quality of life of patients after operation, and has high safety in the treatment process.

Circulating tumor DNA-based stratification strategy for chemotherapy plus PD-1 inhibitor in advanced non-small-cell lung cancer.

Stratification strategies for chemotherapy plus PD-1 inhibitors in advanced non-small-cell lung cancer (NSCLC) are critically demanded. We performed high-throughput panel-based deep next-generation sequencing and low-pass whole genome sequencing on prospectively collected circulating tumor DNA (ctDNA) specimens from 460 patients in the phase 3 CHOICE-01 study at different time points. We identified predictive markers for chemotherapy plus PD-1 inhibitor, including ctDNA status and genomic features such as blood-based tumor mutational burden, intratumor heterogeneity, and chromosomal instability. Furthermore, we established an integrated ctDNA-based stratification strategy, blood-based genomic immune subtypes (bGIS) scheme, to distinguish patients who benefit from the addition of PD-1 inhibitor to first-line chemotherapy. Moreover, we demonstrated potential applications for the dynamic monitoring of ctDNA. Overall, we proposed a potential therapeutic algorithm based on the ctDNA-based stratification strategy, shedding light on the individualized management of immune-chemotherapies for patients with advanced NSCLC.

Exploring the molecular and immune landscape of cellular senescence in lung adenocarcinoma.

Introduction: The connection between aging and cancer is complex. Previous research has highlighted the association between the aging process of lung adenocarcinoma (LUAD) cells and the immune response, yet there remains a gap in confirming this through single-cell data validation. Here, we aim to develop a novel aging-related prognostic model for LUAD, and verify the alterations in the genome and immune microenvironment linked to cellular senescence. Methods: We integrated a comprehensive collection of senescence genes from the GenAge and CellAge databases and employed the least absolute shrinkage and selection operator (LASSO) Cox analysis to construct and validate a novel prognostic model for LUAD. This model was then utilized to examine the relationship between aging, tumor somatic mutations, and immune cell infiltration. Additionally, we explored the heterogeneity of senescence and intercellular communication within the LUAD tumor microenvironment (TME) through single-cell transcriptomic data analysis. Results: By exploring the expression profiles of 586 cellular senescence-related genes in 428 LUAD patients, we constructed an aging-related genes (ARGs) risk model included 10 ARGs and validated it as an independent prognostic predictor for LUAD patients. Notably, patients with low aging scores (LAS group) exhibited better survival, lower tumor mutation burden (TMB), lower somatic mutation frequency, lower tumor proliferation rate, and an immune activated phenotype compared to patients with high aging scores (HAS group). While the HAS group was enriched in tumor cells and showed a lower infiltration of CD8-CCR7, CD8- CXCL13, CD8-GNLY, FCGR3A NK cells, XCL1 NK cells, plasma cell (PC) and other immune subsets. Furthermore, the SPP1 and TENASCIN pathways, associated with tumor immune escape and tumor progression, were also enriched in the HAS group. Additionally, our study also indicated that senescence levels were heterogeneous in the LUAD tumor microenvironment (TME), especially with tumor cells in the LAS group showing higher age scores compared to those in the HAS group. Conclusions: Collectively, our findings underscore that ARRS through ARGs serves as a robust biomarker for the prognosis in LUAD.

The Role and Underlying Mechanisms of Exercise in Heart Failure.

Heart failure is a prevalent and life-threatening syndrome characterized by structural and/or functional abnormalities of the heart. As a global burden with high rates of morbidity and mortality, there is growing recognition of the beneficial effects of exercise on physical fitness and cardiovascular health. A substantial body of evidence supports the notion that exercise can play a protective role in the development and progression of heart failure and improve cardiac function through various mechanisms, such as attenuating cardiac fibrosis, reducing inflammation, and regulating mitochondrial metabolism. Further investigation into the role and underlying mechanisms of exercise in heart failure may uncover novel therapeutic targets for the prevention and treatment of heart failure.

Recruitment, retention and reporting of variables related to ethnic diversity in randomised controlled trials: an umbrella review.

OBJECTIVE: This umbrella review synthesises evidence on the methods used to recruit and retain ethnically diverse participants and report and analyse variables related to ethnic diversity in randomised controlled trials. DESIGN: Umbrella review. DATA SOURCES: Ovid MEDLINE, Ovid Embase, CINAHL, PsycINFO and Cochrane and Campbell Libraries for review papers published between 1 January 2010 and 13 May 2024. ELIGIBILITY CRITERIA: English language systematic reviews focusing on inclusion and reporting of ethnicity variables. Methodological quality was assessed using the AMSTAR 2 tool. RESULTS: Sixty-two systematic reviews were included. Findings point to limited representation and reporting of ethnic diversity in trials. Recruitment strategies commonly reported by the reviews were community engagement, advertisement, face-to-face recruitment, cultural targeting, clinical referral, community presentation, use of technology, incentives and research partnership with communities. Retention strategies highlighted by the reviews included frequent follow-ups on participants to check how they are doing in the study, provision of incentives, use of tailored approaches and culturally appropriate interventions. The findings point to a limited focus on the analysis of variables relevant to ethnic diversity in trials even when they are reported in trials. CONCLUSION: Significant improvements are required in enhancing the recruitment and retention of ethnically diverse participants in trials as well as analysis and reporting of variables relating to diversity in clinical trials. PROSPERO REGISTRATION NUMBER: CRD42022325241.

Effect of the combined use of ivabradine and metoprolol in patients with acute myocardial infarction early after percutaneous coronary intervention: A randomized controlled study.

Objective: To investigate the effect and safety of the combined use of ivabradine and metoprolol in patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI). Methods: Eighty patients with AMI were randomly divided into the ivabradine group and the control group. The ivabradine group was treated with ivabradine combined with metoprolol after PCI, while the control group was treated with metoprolol only. Both groups were treated continuously for 1 year. Echocardiography-derived parameters, heart rate, cardiopulmonary exercise testing (CPET) data, major adverse cardiac events (MACE) and myocardial markers were analyzed. The primary endpoint was the left ventricular ejection fraction (LVEF). The safety outcomes were blood pressure, liver and kidney function. Results: The LVEF was significantly higher in the ivabradine group than in the control group at 1 week, 3 months and 1 year after PCI. The heart rate of the ivabradine group was significantly lower than that of the control group at 1 week and 1month after PCI. The VO2max, metabolic equivalents, anaerobic threshold heart rate, peak heart rate, and heart rate recovery at 8 min of the ivabradine group were significantly higher than those of the control group at 1 year after PCI. Kaplan-Meier analysis demonstrated the one-year total incidence of MACE in the ivabradine group was significantly lower than that in the control group. The B-type natriuretic peptide of the ivabradine group was significantly lower than that of the control group on Day 2 and Day 3 after PCI. The high-sensitivity cardiac troponin I level of the ivabradine group was significantly lower than that of the control group on Day 5 after PCI. Conclusion: Early use of ivabradine in patients with AMI after PCI can achieve effective heart rate control, reduce myocardial injury, improve cardiac function and exercise tolerance, and may reduce the incidence of major adverse cardiac events. (Clinical research registration number: ChiCTR2000032731).

Oxymatrine Attenuates Ulcerative Colitis through Inhibiting Pyroptosis Mediated by the NLRP3 Inflammasome.

Ulcerative colitis (UC) is difficult to cure and easy to relapse, leading to poor quality of life for patients. Oxymatrine (OMT) is one of the main alkaloids of Sophora flavescens Aiton, which has many effects, such as anti-inflammation, anti-oxidative stress, and immunosuppression. This study aimed to investigate whether OMT could attenuate ulcerative colitis by inhibiting the NOD-like receptor family pyrin domain containing three (NLRP3) inflammasome-mediated pyroptosis. In this study, the UC rat models were established by 2,4,6-Trinitrobenzenesulfonic acid (TNBS) in vivo, while RAW264.7 cells and peritoneal macrophages were stimulated with Lipopolysaccharides/Adenosine Triphosphate (LPS/ATP) in vitro to simulate pyroptosis models, and Western blotting (WB) and other detection techniques were applied to analyze proteins involved in the NLRP3 inflammasome pathway. Our results showed that OMT alleviated colitis ulcers and pathological damage in the TNBS-induced UC rats and exhibited an inhibitory effect on pyroptosis at the early stage of UC. In the model group, the pyroptosis reached the peak at 24 h after modeling with the contents of active-cysteine-aspartic proteases-1 (caspase-1), Gasdermin D (GSDMD)-N, and cleaved-interleukin-1 beta (IL-1ß) to the highest expression level. Meanwhile, we found that OMT (80 mg kg-1) remarkably decreased the expression levels of NLRP3, active-caspase-1, and cleaved-IL-1ß at 24 h in the lesion tissue from UC rats. Further experiments on cells demonstrated that OMT at concentrations of 100 and 250 µM significantly inhibited cell death caused by NLRP3 inflammasome activation (p < 0.05), downregulated caspase-1, GSDMD, and decreased the levels of active-caspase-1, GSDMD-N, cleaved-IL-1ß in RAW326.7 cells, and peritoneal macrophages. In summary, these results indicated that OMT could attenuate ulcerative colitis through inhibiting pyroptosis mediated by the NLRP3 inflammasome. The inhibition of the NLRP3 inflammasome may be a potential strategy for UC.

Organic solvents-free and ambient-pressure drying melamine formaldehyde resin aerogels with homogeneous structures, outstanding mechanical strength and flame retardancy.

Atmospheric drying method for fabricating aerogels is considered the most promising way for casting aerogels on a large scale. However, the organic solvent exchange, remaining environmental pollution risk, is a crucial step in mitigating the impact of surface tension during the atmospheric drying process, especially for wet gel formed through the alkoxy-derived sol-gel process, such as melamine-formaldehyde resin (MF) aerogel. Herein, a tough polymer-assisted in situ polymerization was proposed to fabricate MF resin aerogel with a combination of mechanical toughness and strength, enabling it to withstand the capillary force during water evaporation. The monolithic MF resin aerogel through the sol-gel method can be directly prepared without additional network strengthening or organic solvent exchange. The resulting MF resin aerogel exhibits a homogeneous as well as hierarchical structure with macropores and mesopores (~6 µm and ~5 nm), high compressive modulus of 31.8 MPa, self-extinguishing property, and high-temperature thermal insulation with 97 % heat decrease for butane flame combustion. This work presents a straightforward and environmentally friendly method for fabricating MF resin aerogels with nanostructures and excellent performance in open conditions, exhibiting various applications.

The risk of skin cancer in women who carry BRCA1 or BRCA2 mutations.

BACKGROUND: It has not been clearly established if skin cancer or melanoma are manifestations of BRCA1 or BRCA2 mutation carrier status. Estimating the risk of skin cancer is an important step towards developing screening recommendations. METHODS: We report the findings of a prospective cohort study of 6,207 women from North America who carry BRCA1 or BRCA2 mutations. Women were followed from the date of baseline questionnaire to the diagnosis of skin cancer, to age 80 years, death from any cause, or the date of last follow-up. RESULTS: During the mean follow-up period of eight years, 3.7% of women with a BRCA1 mutation (133 of 3,623) and 3.8% of women with a BRCA2 mutation (99 of 2,584) reported a diagnosis of skin cancer (including both keratinocyte carcinomas and melanoma). The cumulative risk of all types of skin cancer from age 20 to 80 years was 14.1% for BRCA1 carriers and 10.7% for BRCA2 carriers. The cumulative risk of melanoma was 2.5% for BRCA1 carriers and 2.3% for BRCA2 carriers, compared to 1.5% for women in the general population in the United States. The strongest risk factor for skin cancer was a prior diagnosis of skin cancer. CONCLUSION: The risk of non-melanoma skin cancer in women who carry a mutation in BRCA1 or BRCA2 is similar to that of non-carrier women. The risk of melanoma appears to be slightly elevated. We suggest that a referral to a dermatologist or primary care provider for BRCA mutation carriers for annual skin examination and counselling regarding limiting UV exposure, the use of sunscreen and recognizing the early signs of melanoma might be warranted, but further studies are necessary.

Differential contributions of G protein- or arrestin subtype-mediated signalling underlie urocortin 3-induced somatostatin secretion in pancreatic δ cells.

BACKGROUND AND PURPOSE: Pancreatic islets are modulated by cross-talk among different cell types and paracrine signalling plays important roles in maintaining glucose homeostasis. Urocortin 3 (UCN3) secreted by pancreatic ß cells activates the CRF2 receptor (CRF2R) and downstream pathways mediated by different G protein or arrestin subtypes in δ cells to cause somatostatin (SST) secretion, and constitutes an important feedback circuit for glucose homeostasis. EXPERIMENTAL APPROACH: Here, we used Arrb1-/-, Arrb2-/-, Gsfl/fl and Gqfl/fl knockout mice, the G11-shRNA-GFPfl/fl lentivirus, as well as functional assays and pharmacological characterization to study how the coupling of Gs, G11 and ß-arrestin1 to CRF2R contributed to UCN3-induced SST secretion in pancreatic δ cells. KEY RESULTS: Our study showed that CRF2R coupled to a panel of G protein and arrestin subtypes in response to UCN3 engagement. While RyR3 phosphorylation by PKA at the S156, S2706 and S4697 sites may underlie the Gs-mediated UCN3- CRF2R axis for SST secretion, the interaction of SYT1 with ß-arrestin1 is also essential for efficient SST secretion downstream of CRF2R. The specific expression of the transcription factor Stat6 may contribute to G11 expression in pancreatic δ cells. Furthermore, we found that different UCN3 concentrations may have distinct effects on glucose homeostasis, and these effects may depend on different CRF2R downstream effectors. CONCLUSIONS AND IMPLICATIONS: Collectively, our results provide a landscape view of signalling mediated by different G protein or arrestin subtypes downstream of paracrine UCN3- CRF2R signalling in pancreatic ß-δ-cell circuits, which may facilitate the understanding of fine-tuned glucose homeostasis networks.

[Ligusticum cycloprolactam inhibits IL-1ß-induced apoptosis and inflammation of rat chondrocytes via HMGB1/TLR4/NF-κB signaling pathway].

Chondrocytes are unique resident cells in the articular cartilage, and the pathological changes of them can lead to the occurrence of osteoarthritis(OA). Ligusticum cycloprolactam(LIGc) are derivatives of Z-ligustilide(LIG), a pharmacodynamic marker of Angelica sinensis, which has various biological functions such as anti-inflammation and inhibition of cell apoptosis. However, its protective effect on chondrocytes in the case of OA and the underlying mechanism remain unclear. This study conducted in vitro experiments to explore the molecular mechanism of LIGc in protecting chondrocytes from OA. The inflammation model of rat OA chondrocyte model was established by using interleukin-1ß(IL-1ß) to induce. LIGc alone and combined with glycyrrhizic acid(GA), a blocker of the high mobility group box-1 protein(HMGB1)/Toll-like receptor 4(TLR4)/nuclear factor-kappa B(NF-κB) signaling pathway, were used to intervene in the model, and the therapeutic effects were systematically evaluated. The viability of chondrocytes treated with different concentrations of LIGc was measured by the cell counting kit-8(CCK-8), and the optimal LIGc concentration was screened out. Annexin V-FITC/PI apoptosis detection kit was employed to examine the apoptosis of chondrocytes in each group. The enzyme-linked immunosorbent assay(ELISA) was employed to measure the expression of cyclooxygenase-2(COX-2), prostaglandin-2(PGE2), and tumor necrosis factor-alpha(TNF-α) in the supernatant of chondrocytes in each group. Western blot was employed to determine the protein levels of B-cell lymphoma-2(Bcl-2), Bcl-2-associated X protein(Bax), caspase-3, HMGB1, TLR4, and NF-κB p65. The mRNA levels of HMGB1, TLR4, NF-κB p65, and myeloid differentiation factor 88(MyD88) in chondrocytes were determined by real-time fluorescent quantitative PCR(RT-qPCR). The safe concentration range of LIGc on chondrocytes was determined by CCK-8, and then the optimal concentration of LIGc for exerting the effect was clarified. Under the intervention of IL-1ß, the rat chondrocyte model of OA was successfully established. The modeled chondrocytes showed increased apoptosis rate, promoted expression of COX-2, PGE2, and TNF-α, up-regulated protein levels of Bax, caspase-3, HMGB1, TLR4, and NF-κB p65 and mRNA levels of HMGB1, TLR4, NF-κB p65, and MyD88, and down-regulated protein level of Bcl-2. However, LIGc reversed the IL-1ß-induced changes of the above factors. Moreover, LIGc combined with GA showed more significant reversal effect than LIGc alone. These fin-dings indicate that LIGc extracted and derived from the traditional Chinese medicine A. sinensis can inhibit the inflammatory response of chondrocytes and reduce the apoptosis of chondrocytes, and this effect may be related to the HMGB1/TLR4/NF-κB signaling pathway. The pharmacological effect of LIGc on protecting chondrocytes has potential value in delaying the progression of OA and improving the clinical symptoms of patients, and deserves further study.

"We are not invited": Australian focus group results on how to improve ethnic diversity in trials.

OBJECTIVES: Lack of ethnic diversity in trials may contribute to health disparities and to inequity in health outcomes. The primary objective was to investigate the experiences and perspectives of ethnically diverse populations about how to improve ethnic diversity in trials. STUDY DESIGN AND SETTING: Qualitative data were collected via 16 focus groups with participants from 21 ethnically diverse communities in Australia. Data collection took place between August and September 2022 in community-based settings in six capital cities: Sydney, Melbourne, Perth, Adelaide, Brisbane, and Darwin, and one rural town: Bordertown (South Australia). RESULTS: One hundred and fifty-eight purposively sampled adults (aged 18-85, 49% women) participated in groups speaking Tamil, Greek, Punjabi, Italian, Mandarin, Cantonese, Karin, Vietnamese, Nepalese, and Arabic; or English-language groups (comprising Fijian, Filipino, African, and two multicultural groups). Only 10 participants had previously taken part in medical research including three in trials. There was support for medical research, including trials; however, most participants had never been invited to participate. To increase ethnic diversity in trial populations, participants recommended recruitment via partnering with communities, translating trial materials and making them culturally accessible using audiovisual ways, promoting retention by minimizing participant burden, establishing trust and rapport between participants and researchers, and sharing individual results. Participants were reluctant to join studies on taboo topics in their communities (eg, sexual health) or in which physical specimens (eg, blood) were needed. Participants said these barriers could be mitigated by communicating about the topic in more culturally cognizant and safe ways, explaining how data would be securely stored, and reinforcing the benefit of medical research to humanity. CONCLUSION: Participants recognized the principal benefits of trials and other medical research, were prepared to take part, and offered suggestions on recruitment, consent, data collection mechanisms, and retention to enable this to occur. Researchers should consider these community insights when designing and conducting trials; and government, regulators, funders, and publishers should allow for greater innovation and flexibility in their processes to enable ethnic diversity in trials to improve.

The Tumor Microenvironment Mediates the HIF-1α/PD-L1 Pathway to Promote Immune Escape in Colorectal Cancer.

The unsatisfactory efficacy of immunotherapy for colorectal cancer (CRC) remains a major challenge for clinicians and patients. The tumor microenvironment may promote CRC progression by upregulating the expression of hypoxia-inducing factor (HIF) and PD-L1. Therefore, this study explored the expression and correlation of HIF-1α and PD-L1 in the CRC microenvironment. The expression and correlation of HIF-1α and PD-L1 in CRC were analyzed using bioinformatics and Western blotting (WB). The hypoxia and inflammation of the CRC microenvironment were established in the CT26 cell line. CT26 cells were stimulated with two hypoxia mimics, CoCl2 and DFO, which were used to induce the hypoxic environment. Western blotting was used to assess the expression and correlation of HIF-1α and PD-L1 in the hypoxic environment.LPS stimulated CT26 cells to induce the inflammatory environment. WB and bioinformatics were used to assess the expression and correlation of TLR4, HIF-1α, and PD-L1 in the inflammatory environment. Furthermore, the impact of curcumin on the inflammatory environment established by LPS-stimulated CT26 cells was demonstrated through MTT, Transwell, molecular docking, network pharmacology and Western blotting assays. In this study, we found that the HIF-1α/PD-L1 pathway was activated in the hypoxic and inflammatory environment and promoted immune escape in CRC. Meanwhile, curcumin suppressed tumor immune escape by inhibiting the TLR4/HIF-1α/PD-L1 pathway in the inflammatory environment of CRC. These results suggest that combination therapy based on the HIF-1α/PD-L1 pathway can be a promising therapeutic option and that curcumin can be used as a potent immunomodulatory agent in clinical practice.