The role of DNA damage response in human embryonic stem cells exposed to atmospheric oxygen tension: Implications for embryo development and differentiation.

Previous retrospective cohort studies have found that, compared with oxygen tension in the uterus and fallopian tubes (2 %-8 %), exposure of pre-implantation embryos to atmospheric oxygen tension (AtmO2, 20 %) during assisted reproductive technology(ART) can affect embryo quality, pregnancy outcomes and offspring health. However, current research on the effects and mechanisms of AtmO2 on the development of embryos and offspring is mainly limited to animal experiments. Human embryonic stem cells (hESCs) play a special and irreplaceable role in the study of early human embryonic development. In this study, we used hESCs as a model to elucidate the possible effects and mechanisms of AtmO2 exposure on human embryonic development. We found that exposure to AtmO2 can reduce cell viability, produce oxidative stress, increase DNA damage, initiate DNA repair, activate autophagy, and increase cell apoptosis. We also noticed that approximately 50 % of hESCs survived, adapted and proliferated through high expression of self-renewal and pluripotency regulatory factors, and affected embryoid body differentiation. These data indicate that hESCs experience oxidative stress, accumulation of DNA damage, and activate DNA damage response under the selective pressure of AtmO2.Some hESCs undergo cell death, whereas other hESCs adapt and proliferate through increased expression of self-renewal genes. The current findings provide in vitro evidence that exposure to AtmO2 during the early preimplantation stage negatively affects hESCs.

Prevalence and prognosis of hypoxia-inducible factor-2α (HIF-2α) pathway gene mutations across advanced solid tumors.

INTRODUCTION: Hypoxia-inducible factor-2α (HIF-2α) modulates the hypoxic response pathway in tumors; however, mutations in pathways (including SDHA, SDHB, SDHC, SDHD, FH, and VHL genes) that are suspected to activate HIF-2α are poorly understood, with limited understanding of the prevalence and clinical prognosis. METHODS: This retrospective observational study used a de-identified nationwide (US-based) clinico-genomic database (CGDB) across 15 available tumor types. RESULTS: Among the 9467 adult patients with advanced/metastatic solid tumors included in the analysis, any mutation at the above-mentioned six genes was observed in 1.8% (95% CI: 1.5-2.1) of patients. The mutation prevalence ranged from 0.05% of SDHD to 0.93% of VHL. When further stratified by tumor type, the prevalence of gene mutation in each tumor type was well below 1%, except for VHL with 44% in renal cell carcinomas (RCC). Excluding RCC, the prevalence of any HIF-2α gene mutations in the study population was 0.9% (95% CI: 0.8-1.2). The median overall survival (OS) from 1 and 2 L therapy among patients with any HIF-2α gene mutation was 14.5 (95% CI: 11.5-24.2) and 9.3 (95% CI: 6.0-18.1) months, respectively, compared with 13.4 (95% CI: 12.9-13.9) and 9.8 (95% CI: 9.3-10.4) months among patients without HIF-2α gene mutations. DISCUSSION AND CONCLUSIONS: The prevalence of HIF-2α related gene mutations was generally low (<1%) across the 15 solid tumor types, except for VHL in RCC. No significant association between HIF-2α gene mutation status and OS was identified among patients evaluated in this study.

Homeostatic measure of insulin resistance is associated with future asthma exacerbations: a 1-year prospective cohort study.

BACKGROUND AND AIMS: Recent evidence suggests that insulin resistance affects asthma outcomes; however, the effect of the homeostatic measure of insulin resistance (HOMA-IR) on airway inflammation and asthma exacerbations (AEs) is poorly understood. OBJECTIVES: To analyze the relationship between HOMA-IR and clinical and inflammatory characteristics in patients with asthma, and the association between HOMA-IR and asthma exacerbations (AEs) in the following year. METHODS: A prospective cohort study recruited participants with asthma, who were classified into the HOMA-IRhigh group and HOMA-IRlow group based on the cutoff value of 3.80 for HOMA-IR and were observed within 12 months. We evaluated the clinical and inflammatory features, and a 1-year follow-up was conducted to study the exacerbations. A negative binomial regression model was used to analyze the association between HOMA-IR and AEs. RESULTS: Compared with the patients in the HOMA-IRlow group (n = 564), patients in the HOMA-IRhigh group (n = 61) had higher levels of BMI, higher waist circumference and waist/hip ratio, higher triglycerides, lower cholesterol high-density lipoproteins (HDL), more neutrophils in the peripheral blood, and elevated IL-5 levels in the induced sputum. Furthermore, patients in the HOMA-IRhigh group had a significantly increased risk for moderate-to-severe AEs (adjusted incidence rate ratio (aIRR) = 2.26, 95% confidence interval (CI) = [1.38, 3.70]), severe AEs (aIRR = 2.42, 95% CI = [1.26, 4.67]), hospitalization(aIRR = 2.54, 95% CI = [1.20, 5.38]), and emergency visits (aIRR = 3.04, 95% CI = [1.80, 8.53]). CONCLUSION: HOMA-IR was associated with asthma-related clinical features, and airway inflammation, as well as being an independent risk factor for future AEs. Therefore, insulin resistance may have important implications for managing asthma as a potential treatable trait.

Lenvatinib plus pembrolizumab for patients with previously treated advanced ovarian cancer: Results from the phase 2 multicohort LEAP-005 study.

OBJECTIVES: The phase 2, multicohort, open-label LEAP-005 study evaluated lenvatinib plus pembrolizumab in patients with previously treated advanced solid tumors. We report outcomes from the ovarian cancer cohort. METHODS: Eligible patients had metastatic/unresectable ovarian cancer and had received 3 previous lines of therapy. Patients received lenvatinib 20 mg/day plus pembrolizumab 200 mg every 3 weeks. Treatment continued until progression, unacceptable toxicity, or (for pembrolizumab) completion of 35 cycles. Primary endpoints were objective response rate (ORR) per RECIST version 1.1 and safety. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). RESULTS: Thirty-one patients were enrolled. 39% had high grade serous ovarian cancer, 23% were platinum-sensitive, 55% were platinum-resistant, 23% were platinum-refractory, and 84% had tumors that had a PD-L1 combined positive (CPS) score ≥1. ORR (95% CI) was 26% (12%-45%) by investigator assessment and 35% (19%-55%) by blinded independent central review (BICR). Per BICR, median DOR was 9.2 (1.5+ to 37.8+) months. ORRs (95% CI) by BICR were 35% (9/26 patients; 17%-56%) for PD-L1 CPS ≥ 1 disease and 50% (2/4 patients; 7%-93%) for PD-L1 CPS < 1 disease. Median (95% CI) PFS by BICR and OS were 6.2 (4.0-8.5) months and 21.3 (11.7-32.3) months, respectively. Treatment-related AEs occurred in 94% of patients (grade 3-4, 77%). One patient died from treatment-related hypovolemic shock. CONCLUSIONS: Lenvatinib plus pembrolizumab demonstrated antitumor activity as fourth line therapy in patients with advanced ovarian cancer, and no unanticipated safety signals were identified. Responses were observed regardless of PD-L1 status.

The yield of SNP microarray analysis for fetal ultrasound cardiac abnormalities.

BACKGROUND: Chromosomal microarray analysis (CMA) has emerged as a critical instrument in prenatal diagnostic procedures, notably in assessing congenital heart diseases (CHD). Nonetheless, current research focuses solely on CHD, overlooking the necessity for thorough comparative investigations encompassing fetuses with varied structural abnormalities or those without apparent structural anomalies. OBJECTIVE: This study sought to assess the relation of single nucleotide polymorphism-based chromosomal microarray analysis (SNP-based CMA) in identifying the underlying causes of fetal cardiac ultrasound abnormalities. METHODS: A total of 2092 pregnant women who underwent prenatal diagnosis from 2017 to 2022 were included in the study and divided into four groups based on the presence of ultrasound structural abnormalities and the specific type of abnormality. The results of the SNP-Array test conducted on amniotic fluid samples from these groups were analyzed. RESULTS: Findings from the study revealed that the non-isolated CHD group exhibited the highest incidence of aneuploidy, overall chromosomal abnormalities, and trisomy 18, demonstrating statistically significant differences from the other groups (p < 0.001). Regarding the distribution frequency of copy number variation (CNV) segment size, no statistically significant distinctions were observed between the isolated CHD group and the non-isolated CHD group (p > 0.05). The occurrence rates of 22q11.2 and 15q11.2 were also not statistically different between the isolated CHD group and the non-isolated congenital heart defect group (p > 0.05). CONCLUSION: SNP-based CMA enhances the capacity to detect abnormal CNVs in CHD fetuses, offering valuable insights for diagnosing chromosomal etiology and facilitating genetic counseling. This research contributes to the broader understanding of the utility of SNP-based CMA in the context of fetal cardiac ultrasound abnormalities.

Role of Copper Nanoparticles in the Thermal and Mechanical Properties of Expanded Graphite-Reinforced Epoxy Hybrids.

Epoxy resin is extensively applied in the electronics and electrical fields because of its outstanding comprehensive performance. However, the low thermal conductivity (TC) limits its application in thermal interface materials. In the present work, epoxy-based hybrid composites with high TC were prepared by using expanded graphite (EG) and copper (Cu) nanoparticles as thermally conductive hybrid fillers via hot blending and compression-curing processes. Additionally, the influence of the Cu content on the thermal properties, mechanical properties, and morphology of each epoxy/EG/Cu composite was investigated. According to the results, the epoxy/EG/Cu composite showed a maximum TC of 9.74 W/(m·K) at a fixed EG content of 60 wt % owing to the addition of 10 wt % Cu. After the addition of 10 wt % Cu, the flexural strength, flexural modulus, and impact strengths of epoxy/EG/Cu composites were improved from 27.9 MPa, 9.72 GPa, and 0.81 kJ/m2 to 37.5 MPa, 10.88 GPa, and 0.91 kJ/m2, respectively. Hence, this study offers a feasible strategy for the design of epoxy hybrid composites with excellent TC that can be applied to thermal interface materials.

Sensitive Fluorescent Biosensor Reveals Differential Subcellular Regulation of PKC.

The protein kinase C (PKC) family of serine/threonine kinases, which consist of three distinctly regulated subfamilies, have long been established as critical for a variety of cellular functions. However, how PKC enzymes are regulated at different subcellular locations, particularly at emerging signaling hubs such as the ER, lysosome, and Par signaling complexes, is unclear. Here, we present a sensitive Excitation Ratiometric (ExRai) C Kinase Activity Reporter (ExRai-CKAR2) that enables the detection of minute changes in subcellular PKC activity. Using ExRai-CKAR2 in conjunction with an enhanced diacylglycerol (DAG) biosensor capable of detecting intracellular DAG dynamics, we uncover the differential regulation of PKC isoforms at distinct subcellular locations. We find that G-protein coupled receptor (GPCR) stimulation triggers sustained PKC activity at the ER and lysosomes, primarily mediated by Ca2+ sensitive conventional PKC (cPKC) and novel PKC (nPKC), respectively, with nPKC showing high basal activity due to elevated basal DAG levels on lysosome membranes. The high sensitivity of ExRai-CKAR2, targeted to either the cytosol or Par-complexes, further enabled us to detect previously inaccessible endogenous atypical PKC (aPKC) activity in 3D organoids. Taken together, ExRai-CKAR2 is a powerful tool for interrogating PKC regulation in response to physiological stimuli.

From phenotype to mechanism: Prenatal spectrum of NKAP mutation-related disorder and its pathogenesis inducing congenital heart disease.

NKAP mutations are associated with Hackmann-Di Donato-type X-linked syndromic intellectual developmental disorder (MRXSHD, MIM: #301039). Here, we elucidate the potential prenatal manifestation of NKAP mutation-associated disorder for the first time, alongside revealing the relationship between NKAP mutations and congenital heart defect (CHD) in the Chinese population. An NKAP mutation (NM_024528.4: c.988C>T, p.Arg330Cys) was identified in two foetuses presenting with CHD. Subsequent mechanistic exploration revealed a marked downregulation of NKAP transcription within HEK293T cells transfected with NKAP p.R330C. However, no significant change was observed at the protein level. Moreover, the mutation led to a dysregulation in the transcription of genes associated with cardiac morphogenesis, such as DHRS3, DNAH11 and JAG1. Additionally, our research determined that NKAP p.R330C affected Nkap protein intra-nuclear distribution, and binding with Hdac3. Summarily, our study strengthens NKAP mutations as a cause of CHD and prompts the reclassification of NKAP p.R330C as likely pathogenic, thereby establishing a prospective prenatal phenotypic spectrum that provides new insight into the prenatal diagnosis of CHD. Our findings also provide evidence of NKAP p.R330C pathogenicity and demonstrate the potential mechanism by which p.R330C dysregulates cardiac developmental gene transcription by altering Nkap intra-nuclear distribution and obstructing the interaction between Nkap and Hdac3, thereby leading to CHD.

Enhanced Electrical Properties and Impact Strength of Phenolic Formaldehyde Resin Using Silanized Graphene and Ionic Liquid.

In this study, to improve the electrical properties and impact strength of phenolic formaldehyde (PF) resin, PF-based composites were prepared by mixing graphene and the ionic liquid 3-decyl-bis(1-vinyl-1H-imidazole-3-ium-bromide) (C10[VImBr]2) via hot blending and compression-curing processes. The graphene surface was modified using a silane coupling agent. The synergistic effect of graphene and C10[VImBr]2 on the electrical properties, electromagnetic shielding efficiency, thermal stability, impact strength, and morphology of PF/graphene and PF/graphene/C10[VImBr]2 composites was then investigated. It was found that the electrical conductivity of the composites significantly increased from 2.3 × 10-10 to 4.14 × 10-3 S/m with an increase in the graphene content from 0 to 15 wt %, increasing further to 0.145 S/m with the addition of 5 wt % C10[VImBr]2. The electromagnetic shielding efficiency of the composite increased from 4.70 to 28.64 dB with the addition of 15 wt % graphene, while the impact strength of the composites rose significantly from 0.59 to 1.13 kJ/m2 with an increase in the graphene content from 0 to 15 wt %, reaching 1.53 kJ/m2 with the addition of 5 wt % C10[VImBr]2. Scanning electron microscopy images of the PF/GNP/C10[VImBr]2 composites revealed a rough morphology with numerous microcracks.

Biomarker Testing Journey Among Patients with Advanced Solid Tumors and Treatment Patterns by Homologous Recombination Repair Status: A Clinico-Genomic Database Study.

INTRODUCTION: Defects in the homologous recombination repair (HRR) pathway can include mutations in BRCA1 and BRCA2 (BRCAm) and other HRR genes (HRRm). These mutations are associated with a homologous recombination deficiency (HRD) phenotype. We evaluated testing journey and treatment patterns by BRCAm, HRRm, and HRD status in a real-world dataset. METHODS: Deidentified data for patients who had undergone comprehensive genomic profiling using FoundationOne®CDx were collected through December 31, 2020, from a real-world multi-tumor clinico-genomic database (CGDB) capturing data from clinics in the United States. Patients eligible for inclusion in this analysis had a confirmed diagnosis with advanced or metastatic disease between January 1, 2018, and December 31, 2019, for 1 of 15 solid tumor types. Objectives were to evaluate patient treatment patterns by BRCAm, HRRm, and HRD status and to describe the timing of when (throughout disease course) comprehensive genomic profiling was performed. RESULTS: Among 9457 patients included in the overall population with evaluable biomarker status, 7856 (83.1%) received ≥ 1 systemic therapy. Among the 7856 patients who received systemic therapy, 2324 (30.0%) underwent testing before first-line therapy, 4114 (52.4%) were tested after receiving first-line therapy and before receiving subsequent therapy (if any), 970 (12.3%) were tested after second-line therapy and before receiving subsequent therapy (if any), and 447 (5.7%) patients underwent testing after receiving third-line therapy. A higher proportion of patients with BRCAm, HRRm, or HRD-positive status were treated with poly(ADP-ribose) polymerase (PARP) inhibitors across all lines of therapy. There was no evidence of a meaningful difference in the proportion of patients who received other treatment (including chemotherapy and immunotherapy) by BRCAm, HRRm, or HRD status. CONCLUSION: The majority of patients from this real-world dataset underwent FoundationOne®CDx testing after initiation of first-line treatment. Testing appeared to influence treatment patterns, with a higher proportion of patients with BRCAm, HRRm, and HRD-positive disease receiving PARP inhibitors.

Y chromosome polymorphisms contribute to an increased risk of non-obstructive azoospermia: a retrospective study of 32,055 Chinese men.

PURPOSE: To investigate the prevalence of Y chromosome polymorphisms in Chinese men and analyze their associations with male infertility and female adverse pregnancy outcomes. METHODS: The clinical data of 32,055 Chinese men who underwent karyotype analysis from October 2014 to September 2019 were collected. Fisher's exact test, chi-square test, or Kruskal-Wallis test was used to analyze the effects of Y chromosome polymorphism on semen parameters, azoospermia factor (AZF) microdeletions, and female adverse pregnancy outcomes. RESULTS: The incidence of Y chromosome polymorphic variants was 1.19% (381/32,055) in Chinese men. The incidence of non-obstructive azoospermia (NOA) was significantly higher in men with the Yqh- variant than that in men with normal karyotype and other Y chromosome polymorphic variants (p < 0.050). The incidence of AZF microdeletions was significantly different among the normal karyotype and different Y chromosome polymorphic variant groups (p < 0.001). The detection rate of AZF microdeletions was 28.92% (24/83) in the Yqh- group and 2.50% (3/120) in the Y ≤ 21 group. The AZFb + c region was the most common AZF microdeletion (78.57%, 22/28), followed by AZFc microdeletion (7.14%,2/28) in NOA patients with Yqh- variants. There was no significant difference in the distribution of female adverse pregnancy outcomes among the normal karyotype and different Y chromosome polymorphic variant groups (p = 0.528). CONCLUSIONS: Patients with 46,XYqh- variant have a higher incidence of NOA and AZF microdeletions than patients with normal karyotype and other Y chromosome polymorphic variants. Y chromosome polymorphic variants do not affect female adverse pregnancy outcomes.

Clinical Study on the Thoracodorsal Artery Perforator Flap in Breast-Conserving Reconstruction of T2 Breast Cancer.

BACKGROUND: Breast-conserving surgery combined with oncoplastic breast surgery has become the standard surgical treatment for early breast cancer. OBJECTIVE: The purpose of this study was to investigate the safety and efficacy of the thoracodorsal artery perforator flap (TDAPF) in breast-conserving reconstruction of T2 breast cancer. METHODS: Thirty patients with T2 breast cancer admitted to our hospital from January 2019 to December 2020 were enrolled to receive pedicled TDAPF for repairing breast defects after breast-conserving surgery. Intraoperative conditions, postoperative complications, and shape satisfaction after breast reconstruction were recorded. RESULTS: The operation was successfully completed in all 30 patients, with an operation time of 177.77 ± 24.39 min, bleeding of 44.17 ± 7.67 mL, and length of hospital stay of 5.23 ± .97 d. There was no deformity or seroma at the donor site. Breast shape recovered well after operation. After operation, one patient had fat liquefaction in the recipient site, which healed well after wound treatment. The incidence of postoperative complications was 3.33%. Postoperative follow-up lasted 16-28 months, with a median of 22 months. The Breast-Q score for breast satisfaction was 61.83 ± 12.87 at 6 months after operation, compared to 62.07 ± 11.78 before operation (P > .05). CONCLUSIONS: TDAPF, featuring a high survival rate, moderate flap area, fewer postoperative complications, and high satisfaction with breast shape after operation. For east asian women with moderate breast size, TDAPF is a safe, effective choice for repairing defects in breast-conserving surgery for T2 breast cancer.

Research progress on the regulation of oxidative stress by phenolics: the role of gut microbiota and Nrf2 signaling pathway.

In recent years, the increase in high-calorie diets and sedentary lifestyles has made obesity a global public health problem. An unbalanced diet promotes the production of proinflammatory cytokines and causes redox imbalance in the body. Phenolics have potent antioxidant activity and cytoprotective ability. They can scavenge free radicals and reactive oxygen species, and enhance the activity of antioxidant enzymes, thus combating the body's oxidative stress. They can also improve the body's inflammatory response, enhance the enzyme activity of lipid metabolism, and reduce the contents of cholesterol and triglyceride. Most phenolics are biotransformed and absorbed into the blood after the action by gut microbiota; these metabolites then undergo phase I and II metabolism and regulate oxidative stress by scavenging free radicals and increasing expression of antioxidant enzymes. Phenolics induce the expression of genes encoding antioxidant enzymes and phase II detoxification enzymes by stimulating Nrf2 to enter the nucleus and bind to the antioxidant response element after uncoupling from Keap1, thereby promoting the production of antioxidant enzymes and phase II detoxification enzymes. The absorption rate of phenolics in the small intestine is extremely low. Most phenolics reach the colon, where they interact with the microbiota and undergo a series of metabolism. Their metabolites will reach the liver via the portal vein and undergo conjugation reactions. Subsequently, the metabolites reach the whole body to exert biological activity by traveling with the systemic circulation. Phenolics can promote the growth of probiotics, reduce the ratio of Firmicutes/Bacteroidetes (F/B), and improve intestinal microecological imbalance. This paper reviews the nutritional value, bioactivity, and antioxidant mechanism of phenolics in the body, aiming to provide a scientific basis for the development and utilization of natural antioxidants and provide a reference for elucidating the mechanism of action of phenolics for regulating oxidative stress in the body. © 2023 Society of Chemical Industry.

Endosome positioning coordinates spatially selective GPCR signaling.

G-protein-coupled receptors (GPCRs) can initiate unique functional responses depending on the subcellular site of activation. Efforts to uncover the mechanistic basis of compartmentalized GPCR signaling have concentrated on the biochemical aspect of this regulation. Here we assess the biophysical positioning of receptor-containing endosomes as an alternative salient mechanism. We devise a strategy to rapidly and selectively redistribute receptor-containing endosomes 'on command' in intact cells without perturbing their biochemical composition. Next, we present two complementary optical readouts that enable robust measurements of bulk- and gene-specific GPCR/cyclic AMP (cAMP)-dependent transcriptional signaling with single-cell resolution. With these, we establish that disruption of native endosome positioning inhibits the initiation of the endosome-dependent transcriptional responses. Finally, we demonstrate a prominent mechanistic role of PDE-mediated cAMP hydrolysis and local protein kinase A activity in this process. Our study, therefore, illuminates a new mechanism regulating GPCR function by identifying endosome positioning as the principal mediator of spatially selective receptor signaling.

Interaction effect of chronic cough and ageing on increased risk of exacerbation in patients with asthma: a prospective cohort study in a real-world setting.

Background: Older adults with asthma have the greatest burden and worst outcomes, and there is increasing evidence that chronic cough (CC) is associated with asthma severity and poor prognosis. However, the clinical characteristics of older adult patients with both asthma and CC remain largely unknown. Methods: Participants with stable asthma underwent two cough assessments within 3 months to define the presence of CC. Patients were divided into four groups based on CC and age (cut-off ≥60 years). Multidimensional assessment was performed at baseline, followed by a 12-month follow-up to investigate asthma exacerbations. Logistic regression models were used to explore the interaction effect of CC and age on asthma control and exacerbations. Results: In total, 310 adult patients were prospectively recruited and divided into four groups: older CC group (n=46), older non-CC group (n=20), younger CC group (n=112) and younger non-CC group (n=132). Compared with the younger non-CC group, the older CC group had worse asthma control and quality of life and increased airflow obstruction. The older CC group showed an increase in moderate-to-severe exacerbations during the 12-month follow-up. There was a significant interaction effect of CC and ageing on the increased moderate-to-severe exacerbations (adjusted risk ratio 2.36, 95% CI 1.47-3.30). Conclusion: Older asthma patients with CC have worse clinical outcomes, including worse asthma control and quality of life, increased airway obstruction and more frequent moderate-to-severe exacerbations, which can be partly explained by the interaction between CC and ageing.

Association Between Homologous Recombination Repair Biomarkers and Survival in Patients With Solid Tumors.

PURPOSE: Mutations in BRCA1 and/or BRCA2 (BRCAm), other homologous recombination repair genes (HRRm), and homologous recombination deficiency (HRD) lead to an accumulation of genomic alterations that can drive tumorigenesis. The prognostic impact of these HRR pathway defects on overall survival (OS) in patients not receiving poly (ADP-ribose) polymerase inhibitors (PARPi) or immunotherapy is unclear. We evaluated the association of HRR biomarkers with OS in patients with advanced solid tumors receiving therapy excluding PARPi and immunotherapy. METHODS: Deidentified data were collected through December 31, 2020, from a real-world clinicogenomic database (CGDB) with data originating from approximately 280 cancer clinics in the United States. Patients age 18 years and older with an advanced/metastatic diagnosis between 2018 and 2019 for 1 of 15 solid tumors and available data in the CGDB were included. The primary analysis evaluated the association between HRR pathway biomarkers and OS, using start of second-line therapy as the index date (to reduce immortal time bias). RESULTS: A total of 9,457 patients had available data for BRCA/HRR and 5,792 for HRD status; 4,890 (51.7%) were women and mean (SD) age was 65.9 (11.5) years. For the primary analysis, adjusted hazard ratios for OS were BRCAm (n = 156) versus BRCA wild-type (wt; n = 3,131; 0.83 [95% CI, 0.60 to 1.17]); for HRRm (n = 467) versus HRRwt (n = 282; 0.95 [95% CI, 0.79 to 1.14]); and for HRD-positive (n = 447) versus -negative (n = 1,687; 1.22 [95% CI, 1.02 to 1.47]). Results were similar using start of first-line and start of third-line therapy as index dates. CONCLUSION: This large, real-world study found no association between OS and either BRCA or HRR status but identified a possible linkage between HRD positivity and shorter median OS in patients with advanced solid tumors who did not receive PARPi or immunotherapy.

Conference report for the 10th China Bioanalysis Forum annual meeting.

The 10th China Bioanalysis Forum annual conference was held in Suzhou between 9 and 11 June 2023. This year a full range of bioanalytical topics were discussed such as new technology and bioanalytical approaches for biotherapeutics and biomarkers, particularly in the areas of gene and cell therapy. Another research area covered extensively at the conference was drug metabolism, including new drug metabolism and pharmacokinetic methods; absorption, distribution, metabolism and excretion of new modality drugs, recent regulatory guidance such as human mass balance study and preclinical study of antibody-drug conjugates and case studies of drug metabolism support to newly approved drugs.

Dual Suture Versus Suture and Plug Closure Devices for Large Bore Access Haemostasis During Percutaneous Access Endovascular Aneurysm Repair.

PURPOSE: This study aimed to compare a dual Proglide strategy versus a combination of one Proglide and dual Exoseal for large-bore access closure during percutaneous access endovascular aneurysm repair (pEVAR). MATERIALS AND METHODS: We retrospectively analyzed 97 patients who underwent pEVAR at our center between January 2021 and February 2023. The patients were divided into two groups: dual Proglide (P + P) and one Proglide with dual Exoseal (P + E). The primary outcome measures were technical success and access-related vascular complications. Technical success was defined as achieving complete hemostasis without a bailout strategy. Postprocedural follow-up for access-related vascular complications was evaluated at 30 and 60 days using computed tomography angiography and ultrasonography. Severity was graded according to the Cardiovascular Interventional Radiological Society of Europe (CIRSE) Classification. RESULTS: Overall, a dual Proglide strategy was used in 46 patients (47.4%) with 65 groins (46.4%), and a combination of one Proglide and dual Exoseal was used in 51 patients (52.6%) with 75 groins (53.6%). The baseline characteristics were similar between the groups. The total technical success rate was 96.4%, and no significant differences were observed (95.4% vs. 97.3%; p = 0.870). Minor bleeding treatable through compression occurred significantly more often in the P group (CIRSE 1, 10.8% vs. 1.3%, p = 0.042). Hemostasis time, procedural time, length of stay in the hospital, closure device failure, and incidence of unplanned intervention did not differ significantly between the groups. CONCLUSIONS: A combined Proglide and Exoseal strategy is safe and effective for large-bore access closure during pEVAR and can be considered an alternative. However, it should be supported by larger prospective studies.

X-linked RBBP7 mutation causes maturation arrest and testicular tumors.

Maturation arrest (MA) is a subtype of non-obstructive azoospermia, and male infertility is a known risk factor for testicular tumors. However, the genetic basis for many affected individuals remains unknown. Here, we identified a deleterious hemizygous variant of X-linked retinoblastoma-binding protein 7 (RBBP7) as a potential key cause of MA, which was also found to be associated with the development of Leydig cell tumors. This mutation resulted in premature protein translation termination, affecting the sixth WD40 domain of the RBBP7 and the interaction of the mutated RBBP7 with histone H4. Decreased BRCA1 and increased γH2AX were observed in the proband. In mouse spermatogonial and pachytene spermatocyte-derived cells, deprivation of rbbp7 led to cell cycle arrest and apoptosis. In Drosophila, knockdown of RBBP7/Caf1-55 in germ cells resulted in complete absence of germ cells and reduced testis size, whereas knockdown of RBBP7/Caf1-55 in cyst cells resulted in hyperproliferative testicular cells. Interestingly, male infertility caused by Caf1-55 deficiency was rescued by ectopic expression of wild-type human RBBP7 but not mutant variants, suggesting the importance of RBBP7 in spermatogenesis. Our study provides insights into the mechanisms underlying the co-occurrence of MA and testicular tumors and may pave the way for innovative genetic diagnostics of these 2 diseases.

Impact of Entanglement on Folding of Semicrystalline Polymer during Crystallization.

Upon cooling, semicrystalline polymers experience crystallization and form alternatively stacked layers consisting of thin crystal lamellae and amorphous ones. The unique morphology, crystallinity, and crystallization kinetics highly depend on the molecular weight. Therefore, it is deduced that entanglement impacts crystallization kinetics, as well as hierarchically crystalline structures. However, the impact of entanglement on folded crystalline chains has not been well understood due to experimental difficulties. In this work, chain-folding structures for seven 13C CH3 labeled poly(l-lactic acid)s with various molecular weights (Mws) were investigated by 13C-13C double quantum NMR spectroscopy. As a result, chain-folding events were categorized into three different Mw regimes: (i) The lowest Mw sample (2K g/mol) adopts an extended chain conformation (folding number, n = 0) (regime I); (ii) Intermediate Mw ones possess mixtures of non- and once-folded structures, and the once-folded fraction suddenly increases above the entanglement length (Me), up to Mw = 45K g/mol (regime II); (iii) The high Mw ones (Mw > 45K g/mol) adopt the highest chance for an adjacent re-entry structure with n = 1.0 in the well-developed entangled network (regime III). It was suggested that entanglement induces folding of the semicrystalline polymer.