Identification of potential candidate miRNAs related to semen quality in seminal plasma extracellular vesicles and sperms of male duck (Anas Platyrhynchos).

Semen quality is an important indicator that can directly affect fertility. In mammals, miRNAs in seminal plasma extracellular vesicles (SPEVs) and sperms can regulate semen quality. However, relevant regulatory mechanism in duck sperms remains largely unclear. In this study, duck SPEVs were isolated and characterized by transmission electron microscopy (TEM), western blot (WB), and nanoparticle tracking analysis (NTA). To identify the important molecules affecting semen quality, we analysed the miRNA expression in sperms and SPEVs of male ducks in high semen quality group ((DHS, DHSE) and low semen quality group (DLS, DLSE). We identified 94 differentially expressed (DE) miRNAs in the comparison of DHS vs. DLS, and 21 DE miRNAs in DHSE vs. DLSE. Target genes of SPEVs DE miRNAs were enriched in ErbB signaling pathway, glycometabolism, and ECM-receptor interaction pathways (P < 0.05), while the target genes of sperm DE miRNAs were enriched in ribosome (P < 0.05). The miRNA-target-pathway interaction network analyses indicated that 5 DE miRNAs (miR-34c-5p, miR-34b-3p, miR-449a, miR-31-5p, and miR-128-1-5p) targeted the largest number of target genes enriched in MAPK, Wnt and calcium signaling pathways, of which FZD9 and ANAPC11 were involved in multiple biological processes related to sperm functions, indicating their regulatory effects on sperm quality. The comparison of DE miRNAs of SPEVs and sperms found that mir-31-5p and novel-273 could potentially serve as biomarkers for semen quality detection. Our findings enhance the insight into the crucial role of SPEV and sperm miRNAs in regulating semen quality and provide a new perspective for subsequent studies.

Inhibition of Mast Cell Degranulation by Novel Small Molecule MRGPRX2 Antagonists.

BACKGROUND: Mas-related G-protein coupled receptor X2 (MRGPRX2) is a promiscuous receptor on mast cells that mediates IgE-independent degranulation and has been implicated in multiple mast cell-mediated disorders, including chronic urticaria, atopic dermatitis, and pain disorders. Although it is a promising therapeutic target, few potent, selective, small molecule antagonists have been identified, and functional effects of human MRGPRX2 inhibition have not been evaluated in vivo. OBJECTIVE: We identified and characterized novel, potent, and selective orally active small molecule MRGPRX2 antagonists for potential treatment of mast cell-mediated disease. METHODS: Antagonists were identified using multiple functional assays in cell lines overexpressing human MRGPRX2, LAD2 mast cells, human peripheral stem cell-derived mast cells, and isolated skin mast cells. Skin mast cell degranulation was evaluated in Mrgprb2em(-/-) knockout (KO) and Mrgprb2em(MRGPRX2) transgenic human MRGPRX2 knock-in (KI) mice by assessment of agonist-induced skin vascular permeability. Ex vivo skin mast cell degranulation and associated histamine release was evaluated by microdialysis of human skin tissue samples. RESULTS: MRGPRX2 antagonists potently inhibited agonist-induced MRGPRX2 activation and mast cell degranulation in all mast cell types tested, in an IgE-independent manner. Orally administered MRGPRX2 antagonists also inhibited agonist-induced degranulation and resulting vascular permeability in MRGPRX2 KI mice. In addition, antagonist treatment dose dependently inhibited agonist-induced degranulation in ex vivo human skin. CONCLUSION: MRGPRX2 small molecule antagonists potently inhibited agonist-induced mast cell degranulation in vitro and in vivo as well as ex vivo in human skin, supporting potential therapeutic utility as a novel treatment for multiple human diseases involving clinically relevant mast cell activation.

Immunocytes interact directly with cancer cells in the tumor microenvironment: one coin with two sides and future perspectives.

The tumor microenvironment is closely linked to the initiation, promotion, and progression of solid tumors. Among its constitutions, immunologic cells emerge as critical players, facilitating immune evasion and tumor progression. Apart from their indirect impact on anti-tumor immunity, immunocytes directly influence neoplastic cells, either bolstering or impeding tumor advancement. However, current therapeutic modalities aimed at alleviating immunosuppression from regulatory cells on effector immune cell populations may not consistently yield satisfactory results in various solid tumors, such as breast carcinoma, colorectal cancer, etc. Therefore, this review outlines and summarizes the direct, dualistic effects of immunocytes such as T cells, innate lymphoid cells, B cells, eosinophils, and tumor-associated macrophages on tumor cells within the tumor microenvironment. The review also delves into the underlying mechanisms involved and presents the outcomes of clinical trials based on these direct effects, aiming to propose innovative and efficacious therapeutic strategies for addressing solid tumors.

Participants' perceptions support the coexistence of benefits and burdens of cancer clinical trial participation.

BACKGROUND: To advance oncology treatment for adults, comprehensive understanding of how and why people decide to enroll in, remain in, and withdraw from cancer clinical trials is needed. While quantitative findings provide insights into these benefits and burdens, they provide limited understanding of how adults with cancer appraise their situation and approach decisions to undertake a clinical trial. The goal of this mixed methods analysis was to conceptualize participants' assessment of benefits and burdens related to cancer clinical trial participation. MATERIALS AND METHODS: This sub-group analysis of 21 participants was part of a larger sequential, explanatory mixed methods study. We used Creamer's integrated approach to linking quantitative and qualitative data to assess convergence, with qualitative data explaining quantitative results. Participants were grouped into four categories based on quantitative benefit/burden scores and thematic analysis of their qualitative data was used to describe these categories. RESULTS: Across groups participants varied in descriptions of benefits and burdens of cancer clinical trial participation and reasons for participating. Those reporting high benefit/low burden described "seizing the opportunity to participate;" those reporting low benefit/low burden described "taking responsibility" through trial participation; those reporting low benefit/high burden described how they were "willing to endure," and those with high benefit/high burden emphasized "deciding to act." CONCLUSIONS: Participants' qualitative descriptions of benefits and burdens were more nuanced and dynamic than reflected in their quantitative ratings. Thus, current measures may be missing important concepts, such as logistic challenges of trial participation. Our results have implications for consenting procedures and decisional support guidance offered to patients and their caregivers.

Application of the solution-focused brief strategies via telephone for family caregivers of persons with dementia: the Alzheimer's Association National Helpline.

OBJECTIVES: Nearly 75% of persons living with dementia (PLWD) in the US live at home and are cared for by informal family members who have limited access to supportive and accessible services, indicating an increased need for these types of services (Alzheimer's Association, 2023). The Alzheimer's Association call centers offer free telephone care consultations, but it currently remains unclear which types of brief telephone support benefit caregivers. This study compares outcomes of participants who received traditional care consultation calls via the Alzheimer's Association National Helpline with care consultation calls from Helpline staff trained in Solution-Focused Brief Strategies (SFBS), a client-centered evidence- and resource-based approach. METHOD: Sequential callers were randomly assigned to the "traditional" or "SFBS" care consultation groups and were assessed at the time of call (baseline) and post-call (T1). The outcomes of interest were general self-efficacy (GSE), self-efficacy in managing emotions (PROMIS), caregiver mastery, therapeutic alliance, and goal setting. RESULTS: Of over 500 callers, callers receiving the SFBS scored higher on therapeutic alliance and goal-setting metrics, such as greater sense of collaboration on goals (effect size = 0.280, p = 0.0005, significant with Bonferroni correction), mutual agreement with care consultant on goals (effect size = 0.418, p < 0.0001, significant with Bonferroni correction), and believing the way the problem was resolved was correct (effect size = 0.286, p = 0.0007, significant with Bonferroni correction) than those receiving the traditional care consultation. Both groups reported improvements in the PROMIS measure, but there were no differences between groups. There were no significant differences in GSE or caregiver mastery scores between groups. CONCLUSION: This study provides evidence for the effectiveness of the integration of SFBS in dementia care consultation calls as part of telephone-based supportive services for dementia caregivers.

Tmem30a protects against podocyte injury through suppression of pyroptosis.

Podocytopathies, such as focal segmental glomerulosclerosis (FSGS), are characterized by podocyte injury and can easily progress to end-stage kidney disease. However, the mechanisms underlying podocyte injury remain unclear. We observed podocyte injury along with pyroptosis in patients with FSGS. Bioinformatic analysis of public datasets revealed that transmembrane protein 30a (Tmem30a) might be associated with FSGS. The expression of Temem30a and the podocyte-related protein, nephrin, were significantly downregulated in patients with FSGS, adriamycin (ADR)-induced mice, and podocyte-specific Tmem30a lox P /loxP ; NPHS2-Cre mice, whereas the expression of NLR family pyrin domain containing 3 (NLRP3) and ASC, two pyroptosis-related proteins, were significantly upregulated. Meanwhile, the pyroptosis inhibitor MCC950 and disulfiram (DSF) increased Tmem30a and podocyte-related proteins expression, and inhibited pyroptosis-related proteins expression in ADR-induced mouse podocytes and Tmem30a knockdown (KD) mouse podocytes. Therefore, Tmem30a might protect against podocyte injury by inhibiting pyroptosis, suggesting a potential therapeutic target for podocytopathies.

Long-term surgical outcomes of bile duct tumor thrombus versus portal vein tumor thrombus for hepatocellular carcinoma: a propensity score matching analysis.

Background: Portal vein tumor thrombus (PVTT) seriously affects the prognosis of hepatocellular carcinoma (HCC). However, whether bile duct tumor thrombus (BDTT) significantly affects the prognosis of HCC as much as PVTT remains unclear. We aimed to compare the long-term surgical outcomes of HCC with macroscopic PVTT (macro-PVTT) and macroscopic BDTT (macro-BDTT). Methods: The data of HCC patients with macro-BDTT or macro-PVTT who underwent hemihepatectomy were retrospectively reviewed. A propensity score matching (PSM) analysis was performed to reduce the baseline imbalance. The recurrence-free survival (RFS) and overall survival (OS) rates were compared between the cohorts. Results: Before PSM, the PVTT group had worse RFS and OS rates than the BDTT group (P = 0.043 and P = 0.008, respectively). Multivariate analyses identified PVTT (hazard ratio [HR] = 1.835, P = 0.016) and large HCC (HR = 1.553, P = 0.039) as independent risk factors for poor OS and RFS, respectively. After PSM, the PVTT group had worse RFS and OS rates than the BDTT group (P = 0.037 and P = 0.004, respectively). The 3- and 5-year OS rates were significantly higher in the BDTT group (59.5% and 52.1%, respectively) than in the PVTT group (33.3% and 20.2%, respectively). Conclusion: Aggressive hemihepatectomy provides an acceptable prognosis for HCC patients with macro-BDTT. Furthermore, the long-term surgical outcomes of HCC patients with macro-BDTT were significantly better than those of HCC patients with macro-PVTT.

PRODH safeguards human naive pluripotency by limiting mitochondrial oxidative phosphorylation and reactive oxygen species production.

Naive human embryonic stem cells (hESCs) that resemble the pre-implantation epiblasts are fueled by a combination of aerobic glycolysis and oxidative phosphorylation, but their mitochondrial regulators are poorly understood. Here we report that, proline dehydrogenase (PRODH), a mitochondria-localized proline metabolism enzyme, is dramatically upregulated in naive hESCs compared to their primed counterparts. The upregulation of PRODH is induced by a reduction in c-Myc expression that is dependent on PD0325901, a MEK inhibitor routinely present in naive hESC culture media. PRODH knockdown in naive hESCs significantly promoted mitochondrial oxidative phosphorylation (mtOXPHOS) and reactive oxygen species (ROS) production that triggered autophagy, DNA damage, and apoptosis. Remarkably, MitoQ, a mitochondria-targeted antioxidant, effectively restored the pluripotency and proliferation of PRODH-knockdown naive hESCs, indicating that PRODH maintains naive pluripotency by preventing excessive ROS production. Concomitantly, PRODH knockdown significantly slowed down the proteolytic degradation of multiple key mitochondrial electron transport chain complex proteins. Thus, we revealed a crucial role of PRODH in limiting mtOXPHOS and ROS production, and thereby safeguarding naive pluripotency of hESCs.

Anthropometric indicators may explain the high incidence of follicular lymphoma in Europeans: Results from a bidirectional two-sample two-step Mendelian randomisation.

BACKGROUND: Non-Hodgkin's lymphoma incidence rates vary between European and Asian populations. The reasons remain unclear. This two-sample two-step Mendelian randomisation (MR) study aimed to investigate the causal relationship between anthropometric indicators (AIs) and diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) and the possible mediating role of basal metabolic rate (BMR) in Europe. METHODS: We used the following AIs as exposures: body mass index (BMI), whole-body fat mass (WBFM), whole-body fat-free mass (WBFFM), waist circumference(WC), hip circumference(HC), standing height (SH), and weight(Wt). DLBCL and FL represented the outcomes, and BMR was a mediator. A two-sample MR analysis was performed to examine the association between AIs and DLBCL and FL onset. We performed reverse-MR analysis to determine whether DLBCL and FL interfered with the AIs. A two-step MR analysis was performed to determine whether BMR mediated the causality. FINDINGS: WBFFM and SH had causal relationships with FL. A causal association between AIs and DLBCL was not observed. Reverse-MR analysis indicated the causal relationships were not bidirectional. Two-step MR suggested BMR may mediate the causal effect of WBFFM and SH on FL. CONCLUSIONS: We observed a causal relationship between WBFFM and SH and the onset of FL in Europeans, Which may explain the high incidence of follicular lymphoma in Europeans.

Novel small molecule inhibitors targeting renal cell carcinoma: Status, challenges, future directions.

Renal cell carcinoma (RCC) is the most common renal malignancy with a rapidly increasing morbidity and mortality rate gradually. RCC has a high mortality rate and an extremely poor prognosis. Despite numerous treatment strategies, RCC is resistant to conventional radiotherapy and chemotherapy. In addition, the limited clinical efficacy and inevitable resistance of multiple agents suggest an unmet clinical need. Therefore, there is an urgent need to develop novel anti-RCC candidates. Nowadays many promising results have been achieved with the development of novel small molecule inhibitors against RCC. This paper reviews the recent research progress of novel small molecule inhibitors targeting RCC. It is focusing on the structural optimization process and conformational relationships of small molecule inhibitors, as well as the potential mechanisms and anticancer activities for the treatment of RCC. To provide a theoretical basis for promoting the clinical translation of novel small molecule inhibitors, we discussed their application prospects and future development directions. It could be capable of improving the clinical efficacy of RCC and improving the therapy resistance for RCC.

The function of Bazhen decoction in rescuing progeroid cell senescence via facilitating G-quadruplex resolving and telomere elongation.

ETHNOPHARMACOLOGICAL RELEVANCE: The Bazhen decoction is one of the most extensively used Traditional Chinese medicine (TCM) prescriptions for treatment of aging related diseases. However, due to the complexity of the components, the pharmacological mechanism of Bazhen decoction is still limited. AIM OF THE STUDY: In this study, with the aim of helping the clinical precision medicine of TCM, we try out a systematic analysis for dissecting the molecular mechanism of complicated TCM prescription: Bazhen decoction. We identify the pharmacological mechanism of Bazhen decoction in telomere elongation as revealed by systematic analysis. MATERIALS AND METHODS: By RNA sequencing and transcriptome analysis of Bazhen decoction treated wild type cells, we reveal the transcriptome profile induced by Bazhen decoction. We utilized the cells derived from Werner syndrome (WS) mice, which is known to be dysfunctional in telomere elongation due to the deficiency of DNA helicase Wrn. By Western blot, qPCR, Immunofluorescence, flow cytometry, telomere FISH, and SA-ß-Gal staining, we verify the transcriptome data and confirm the pharmacological function of Bazhen decoction and its drug containing serum in telomere elongation and reversing progeroid cell senescence. RESULTS: We reveal that Bazhen decoction may systematically regulate multiple anti-aging pathways, including stem cell regulation, protein homeostasis, cardiovascular function, neuronal function, anti-inflammation, anti-DNA damage induced stress, DNA helicase activity and telomere lengthening. We find that Bazhen decoction and its drug containing serum could up-regulate multiple DNA helicases and telomere regulating proteins. The increased DNA helicases promote the resolving of G-quadruplex (G4) structures, and facilitate DNA replication and telomere elongation. These improvements also endow the cellular resistance to DNA damages induced by replication stress, and rescue the WS caused cellular senescence. CONCLUSIONS: Together these data suggest that Bazhen decoction up-regulate the expression of DNA helicases, thus facilitate G4 resolving and telomere maintenance, which rescue the progeroid cellular senescence and contribute to its anti-aging properties. Our data reveal a new molecular mechanism of Bazhen decoction in anti-aging related diseases via elongating telomere, this may shed light in the application of Bazhen decoction in multiple degenerative diseases caused by telomere erosion.

Hospitalizations, Emergency Department Visits, and Home Health Use Among Older Adults With Sensory Loss.

Objectives: This study examines healthcare resource use (hospitalizations, emergency department [ED] visits, and home health episodes) among adults 65 and older diagnosed with hearing, vision, or dual sensory loss (SL) seen in the primary care setting of an academic health system. Methods: Multivariable logistic regression models were used to examine the relationship between SL (identified using ICD-10 codes) and healthcare resource use for 45,000 primary care patients. Results: The sample included 5.5% (N = 2479) with hearing loss, 10.4% (N = 4697) with vision loss, and 1.0% with dual SL (N = 469). Hearing loss increased the likelihood of having an ED visit (OR = 1.22, CI: 1.07-1.39), and home health services (OR = 1.27, CI: 1.07-1.51) compared to older adults without any SL. Vision loss reduced the likelihood of having a hospitalization (OR = .81, CI: .73-.91). Discussion: Findings support research into the drivers of healthcare use among older adults with sensory loss.

A New "Mix and Measure" Method for Rapid Quantitative Determination of Alkalinity Based on Proton Equilibrium and Definite Integral of Buffer Capacity.

Alkalinity is crucial in environmental control of ecosystems, wastewater and drinking water treatment, and industrial process control. In this work, we reported a new equation for calculating alkalinity based on the definition of buffer capacity in acid-base buffer solutions and the quantitative relationship between the buffer capacity and pH changes. A "mix and measure" method was developed using this new equation, involving mixing a solution with unknown alkalinity and a standard solution in a specific volume ratio, followed by measuring the pH after mixing. The alkalinity of the solution can be calculated using the newly developed equation. The "mix and measure" method is much more efficient than traditional titration methods for determination of alkalinity because it is restricted by the titration stoichiometric point. Additionally, we demonstrated the rapid determination of the alkalinity for a series of solutions using a portable detection system. This system exhibited precision and accuracy comparable to those of traditional titration methods. The portable system offers great potential for the on-site and real-time determination of alkalinity for industrial control and environmental monitoring purposes.

Surgical outcomes of hepatocellular carcinoma with extrahepatic bile duct tumor thrombus: a multicenter study.

Background: The long-term prognosis after surgery of patients with hepatocellular carcinoma (HCC) and extrahepatic bile duct tumor thrombus (Ex-BDTT) remains unknown. We aimed to identify the surgical outcomes of patients with HCC and Ex-BDTT. Methods: A total of 138 patients with Ex-BDTT who underwent hepatectomy with preservation of the extrahepatic bile duct from five large hospitals in China between January 2009 and December 2017 were included. The Cox proportional hazards model was used to analyze overall survival (OS) and recurrence-free survival (RFS). Results: With a median follow-up of 60 months (range, 1-127.8 months), the median OS and RFS of the patients were 28.6 and 8.9 months, respectively. The 1-, 3-, and 5-year OS rates of HCC patients with Ex-BDTT were 71.7%, 41.2%, and 33.5%, respectively, and the corresponding RFS rates were 43.5%, 21.7%, and 20.0%, respectively. Multivariate analysis identified that major hepatectomy, R0 resection, and major vascular invasion were independent prognostic factors for OS and RFS. In addition, preoperative serum total bilirubin ≥ 4.2 mg/dL was an independent prognostic factor for RFS. Conclusion: Major hepatectomy with preservation of the extrahepatic bile duct can provide favorable long-term survival for HCC patients with Ex-BDTT.

Circulating tumor biomarkers in early-stage breast cancer: characteristics, detection, and clinical developments.

Breast cancer is the most common form of cancer in women, contributing to high rates of morbidity and mortality owing to the ability of these tumors to metastasize via the vascular system even in the early stages of progression. While ultrasonography and mammography have enabled the more reliable detection of early-stage breast cancer, these approaches entail high rates of false positive and false negative results Mammograms also expose patients to radiation, raising clinical concerns. As such, there is substantial interest in the development of more accurate and efficacious approaches to diagnosing breast cancer in its early stages when patients are more likely to benefit from curative treatment efforts. Blood-based biomarkers derived from the tumor microenvironment (TME) have frequently been studied as candidate targets that can enable tumor detection when used for patient screening. Through these efforts, many promising biomarkers including tumor antigens, circulating tumor cell clusters, microRNAs, extracellular vesicles, circulating tumor DNA, metabolites, and lipids have emerged as targets that may enable the detection of breast tumors at various stages of progression. This review provides a systematic overview of the TME characteristics of early breast cancer, together with details on current approaches to detecting blood-based biomarkers in affected patients. The limitations, challenges, and prospects associated with different experimental and clinical platforms employed in this context are also discussed at length.

Impact of combining photodynamic diagnosis with reflectance confocal microscopy, on tumor margin detection and surgical outcomes in patients with extramammary Paget disease.

Background The recurrence rate of extramammary Paget disease after surgical resection is high due to the lesions' poorly delineated and unclear margins. Aims To evaluate the impact of non-invasive tumour margin detection via photodynamic diagnosis plus reflectance confocal microscopy on the surgical outcomes of patients with extramammary Paget disease. Methods Thirty-six patients with histopathologically confirmed primary extramammary Paget disease between January 2017 and June 2018 were included in this study. The skin lesion margins were preoperatively observed using the naked eye, photodynamic diagnosis, and reflectance confocal microscopy. An incision was made 0.5-2 cm from the outermost non-invasive detection marker line. The incision depth was more significant than the follicle level or the deepest level affected by the tumour in the biopsy specimens. After the skin lesions were removed, a pathological examination of the specimens was conducted to ensure clear margins to prevent tumour recurrence and metastases. Results A total of 166 good-quality tissue sections were selected from 36 patients. The tumour surfaces and deep margins were within the scope of resection. Six patients (6/36, 15.4%) experienced local recurrence 2-12 months postoperatively. One patient (1/36, 2.8%) had lymph node metastasis without local recurrence 36 months postoperatively and died 50 months postoperatively (1/36, 2.8%). Limitations This study is limited by the small patient population, especially the number of patients with mucous membrane involvement. Conclusion Using photodynamic diagnosis plus reflectance confocal microscopy to detect the margins of extramammary Paget disease lesions non-invasively reduces the postoperative tumour recurrence rate and is a valuable guide for tumour treatment.

Informed Consent among Clinical Trial Participants with Different Cancer Diagnoses.

IMPORTANCE: Informed consent is essential to ethical, rigorous research and is important to recruitment and retention in cancer trials. OBJECTIVE: To examine cancer clinical trial (CCT) participants' perceptions of informed consent processes and variations in perceptions by cancer type. DESIGN AND SETTING AND PARTICIPANTS: Cross-sectional survey from mixed-methods study at National Cancer Institute-designated Northeast comprehensive cancer center. Open-ended and forced-choice items addressed: (1) enrollment and informed consent experiences and (2) decision-making processes, including risk-benefit assessment. Eligibility: CCT participant with gastro-intestinal or genitourinary, hematologic-lymphatic malignancies, lung cancer, and breast or gynecological cancer (N = 334). MAIN OUTCOME MEASURES: Percentages satisfied with consent process and information provided; and assessing participation's perceptions of risks/benefits. Multivariable logistic or ordinal regression examined differences by cancer type. RESULTS: Most patient-participants felt well informed by the consent process (more than 90% overall and by cancer type) and. most (87.4%) reported that the consent form provided all the information they wanted, although nearly half (44.8%) reported that they read the form somewhat carefully or less. More than half (57.9%) said that talking to research staff (i.e., the consent process) had a greater impact on participation decisions than reading the consent form (2.1%). A third (31.1%) were very sure of joining in research studies before the informed consent process (almost half of lung cancer patients did-47.1%). Most patients personally assessed the risks and benefits before consenting. However, trust in physicians played an important role in the decision to enroll in CCT. CONCLUSIONS AND RELEVANCE: Cancer patients rely less on written features of the informed consent process than on information obtained from the research staff and their own physicians. Research should focus on information and communication strategies that support informed consent from referring physicians, researchers, and others to improve patient risk-benefit assessment and decision-making.

Identification of a RAD51B enhancer variant for susceptibility and progression to glioma.

BACKGROUND: RAD51B plays a significant role in homologous recombination-mediated repair of DNA double-strand breaks. Many enhancer variants are involved in cancer development and progression. However, the significance of enhancer variants of RAD51B in glioma susceptibility and progression remains unclear. METHODS: A case-control study consisting of 1056 individuals was conducted to evaluate the associations of enhancer variants of RAD51B with glioma susceptibility and progression. Sequenom MassARRAY technology was used for genotyping. The function of enhancer variants was explored by biochemical assays. RESULTS: A significantly decreased risk of glioma was associated with rs6573816 GC genotype compared with rs6573816 GG genotype (OR = 0.66, 95% CI 0.45-0.97; P = 0.034). Multivariable Cox regression revealed that rs6573816 was significantly associated with glioma progression in a sex-dependent manner. Worse PFS was found in the male patients with high grade glioma carrying rs6573816 GC or CC genotype (HR = 2.28, 95% CI 1.14-4.57; P = 0.020). The rs6573816 C allele repressed enhancer activity by affecting transcription factor POU2F1 binding, which resulted in lower expression of RAD51B. Remarkably attenuated expression of RAD51B was observed following POU2F1 knockdown. Consistently, positive correlation between the expression of POU2F1 and RAD51B was found in lymphoblastic cells and glioma tissues. CONCLUSIONS: These results indicate that an enhancer variant of RAD51B rs6573816 influences enhancer activity by changing a POU2F1 binding site and confers susceptibility and progression to glioma.

A nomogram prediction model for treatment failure in primary membranous nephropathy.

BACKGROUND: Primary membranous nephropathy (PMN) has a heterogeneous natural course. Immunosuppressive therapy is recommended for PMN patients at moderate or high risk of renal function deterioration. Prediction models for the treatment failure of PMN have rarely been reported. METHODS: This study retrospectively studied patients diagnosed as PMN by renal biopsy at Sichuan Provincial People's Hospital from January 2017 to December 2020. Information on clinical characteristics, laboratory test results, pathological examination, and treatment was collected. The outcome was treatment failure, defined as the lack of complete or partial remission at the end of 12 months. Simple logistic regression was used to identify candidate predictive variables. Forced-entry stepwise multivariable logistic regression was used to develop the prediction model, and performance was evaluated using C-statistic, calibration plot, and decision curve analysis. Internal validation was performed by bootstrapping. RESULTS: In total, 310 patients were recruited for this study. 116 patients achieved the outcome. Forced-entry stepwise multivariable logistic regression indicated that PLA2Rab titer (OR = 1.002, 95% CI: 1.001-1.004, p = 0.003), inflammatory cells infiltration (OR = 2.753, 95% CI: 1.468-5.370, p = 0.002) and C3 deposition on immunofluorescence (OR = 0.217, 95% CI: 0.041-0.964, p = 0.049) were the three independent risk factors for treatment failure of PMN. The final prediction model had a C-statistic (95% CI) of 0.653 (0.590-0.717) and a net benefit of 23%-77%. CONCLUSIONS: PLA2R antibody, renal interstitial inflammation infiltration, and C3 deposition on immunofluorescence were the three independent risk factors for treatment failure in PMN. Our prediction model might help identify patients at risk of treatment failure; however, the performance awaits improvement.

Treatment of nasal squamous cell carcinoma with combination of surgery and photodynamic therapy.

Cutaneous squamous cell carcinoma (cSCC) is a common malignant skin tumor. Some invasive cSCC can cause severe cosmetic damage; therefore, comprehensive measures should be taken. Here, we present a case of a 48-year-old male patient with invasive cSCC on the nose. The lesion recurred twice after excision in the other hospital. After admission, the patient underwent surgical excision; however, the tumor remained because of its deep infiltration, and we left the wound exposed without repair. During the period of open-wound, the patient received 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT) to completely clear the residual tumors, and multipoint biopsies were performed to monitor the tumor remission process. We reconstructed the defect by using bilateral flaps after complete remission. The tumor did not recur in 63 months of follow-up after reconstruction. Open-wound treatment should be considered for tumors that occur at high-risk sites such as the nose. Surgery combined with PDT may be an efficient method for treating cSCC.