Incidence of endometrial cancer in BRCA mutation carriers.

OBJECTIVE: Whether or not women who harbor a germline pathogenic variant ('mutation') in the BRCA1 or BRCA2 genes are at elevated risk of developing endometrial cancer is yet to be determined. METHODS: We conducted a prospective analysis of 4959 BRCA mutation carriers with no prior history of cancer (except for breast or melanoma) and an intact uterus. RESULTS: After a mean of 6.7 years of follow-up there were 38 incident cases of endometrial cancer diagnosed; 30 among BRCA1 carriers and eight among BRCA2 carriers. The mean age at diagnosis was 58.4 years (range 46.8-76.1). The majority were of the endometrioid subtype (n = 16), followed by mixed endometroid and serous (n = 4), serous (n = 3) or clear cell (n = 1) (missing = 13). The cumulative incidence from age 40 to age 70 was 3.4% for BRCA1 carriers and was 1.6% for BRCA2 mutation carriers. Prior tamoxifen use was associated with a significant two-fold increased risk (HR = 2.24; 95% CI 1.10-4.55). There was no significant association between exogenous hormone use, oophorectomy, smoking or BMI at age 40 and risk (P ≥ 0.32). CONCLUSIONS: Compared to the general population, we observed higher rates of endometrial cancer among young BRCA1 mutation carriers; however, lifetime risks were similar. Women with prior tamoxifen exposure were at a significantly increased risk. These findings were based. on a small number of incident cases and require confirmation with additional follow-up of our aging cohort.

Two hub genes of bipolar disorder, a bioinformatics study based on the GEO database.

Bipolar disorder is a mood illness that affects many people. It has a high recurrence frequency and will cause significant damage to the patient's social function. At present, the pathogenesis of BD is not clear. The National Center for Biotechnology Information (NCBI) established and maintained the Gene Expression Omnibus (GEO) database, a gene expression database. For bioinformatics analysis, researchers can obtain expression data from the internet. At present, the samples of the dataset used in the research of BD are mostly from brain tissue, and the data containing blood samples are rarely used. GEO databases (GSE46416, GSE5388, and GSE5389) were used to retrieve public data, and utilizing the online tool GEO2R, differentially expressed genes (DEGs) were retrieved. The common DEGs between the samples of patients with BD and the samples of the normal population were screened by Venn diagrams. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used to perform functional annotation and pathway enrichment analysis of DEGs. A protein-protein interaction network (PPI) was built to investigate hub genes on this basis. There were 117 up-regulated DEGs and 38 down-regulated DEGs discovered, with two hub genes [SRC, CDKN1A] among the up-regulated DEGs. These two hub genes were also highly enriched in the oxytocin signaling pathway, proteoglycans in cancer and bladder cancer, according to KEGG analysis. The results of the receiver operating characteristic curve (ROC) of SRC and CDKN1A in the three datasets strongly suggested that SRC and CDKN1A were potential diagnostic markers of BD. The results strongly suggest that SRC and CDKN1A are related to the pathogenesis of BD.

Von Willebrand factor exacerbates heart failure through formation of neutrophil extracellular traps.

BACKGROUND AND AIMS: Heart failure (HF) is a leading cause of mortality worldwide and characterized by significant co-morbidities and dismal prognosis. Neutrophil extracellular traps (NETs) aggravate inflammation in various cardiovascular diseases; however, their function and mechanism of action in HF pathogenesis remain underexplored. This study aimed to investigate the involvement of a novel VWF-SLC44A2-NET axis in HF progression. METHODS: NET levels were examined in patients with HF and mouse models of transverse aortic constriction (TAC) HF. PAD4 knockout mice and NET inhibitors (GSK-484, DNase I, NEi) were used to evaluate the role of NETs in HF. RNA sequencing was used to investigate the downstream mechanisms. Recombinant human ADAMTS13 (rhADAMTS13), ADAMTS13, and SLC44A2 knockouts were used to identify novel upstream factors of NETs. RESULTS: Elevated NET levels were observed in patients with HF and TAC mouse models of HF. PAD4 knockout and NET inhibitors improved the cardiac function. Mechanistically, NETs induced mitochondrial dysfunction in cardiomyocytes, inhibiting mitochondrial biogenesis via the NE-TLR4-mediated suppression of PGC-1α. Furthermore, VWF/ADAMTS13 regulated NET formation via SLC44A2. Additionally, sacubitril/valsartan amplifies the cardioprotective effects of the VWF-SLC44A2-NET axis blockade. CONCLUSIONS: This study established the role of a novel VWF-SLC44A2-NET axis in regulating mitochondrial homeostasis and function, leading to cardiac apoptosis and contributing to HF pathogenesis. Targeting this axis may offer a potential therapeutic approach for HF treatment.

Monocyte Chemoattractant Protein-1, Inflammatory Biomarkers, and Prognosis of Patients With Ischemic Stroke or Transient Ischemic Attack: Fndings From a Nationwide Registry Study.

BACKGROUND: Recent Mendelian randomization and meta-analysis highlight the relevance of MCP-1 (monocyte chemoattractant protein-1) in stroke. We aimed to investigate the associations between MCP-1 and clinical outcomes in patients with ischemic stroke or transient ischemic attack and test whether inflammation mediates or jointly contributes to the relationships. METHODS AND RESULTS: A total of 10 700 patients from the Third China National Stroke Registry study were included. Multivariable Cox regression was used for recurrent stroke and all-cause death, and logistic regression was used for poor functional outcome. Mediation analyses were performed to clarify whether inflammation mediates the associations. After adjusting for potential confounders, low MCP-1 level (<337.6 pg/mL) was associated with a reduced risk of all-cause death (hazard ratio [HR], 0.65 [95% CI, 0.51-0.82]) and poor functional outcome (odds ratio, 0.81 [95% CI, 0.70-0.94]) but was not associated with recurrent stroke (HR, 1.10 [95% CI, 0.95-1.27]), compared with high MCP-1 level (≥337.6 pg/mL). The association between MCP-1 and all-cause death was partially mediated by highly sensitive C-reactive protein, interleukin-6, and YKL-40 (Chitinase-3-like protein 1; mediated proportion: 7.4%, 10.5%, and 7.4%, respectively). The corresponding mediated proportion for poor functional outcome was 9.9%, 17.1%, and 7.1%, respectively. Patients with combined high levels of MCP-1 and inflammatory biomarkers had the highest risks of all-cause death and poor functional outcome. CONCLUSIONS: Low plasma MCP-1 level was associated with decreased risks of all-cause mortality and poor functional outcome after ischemic stroke or transient ischemic attack. Inflammation partially mediated and jointly contributed to the associations.

Vonoprazan and amoxicillin dual therapy for 14 days as the first-line treatment of Helicobacter pylori infection: A non-inferiority, randomized clinical trial.

BACKGROUND: We previously optimized the duration and dose of vonoprazan and amoxicillin dual therapy in China. The efficacy of vonoprazan with b.i.d. amoxicillin in comparison with vonoprazan-containing quadruple therapy as the first-line treatment of Helicobacter pylori infection has not been adequately evaluated. METHODS: In a non-inferiority, randomized clinical trial, H. pylori infected and treatment-naïve patients were randomly assigned to receive 14 days of either vonoprazan dual (vonoprazan 20 mg and amoxicillin 1 g twice daily) or quadruple therapy (vonoprazan 20 mg + amoxicillin 1 g + furazolidone 100 mg + bismuth potassium citrate 600 mg twice daily). H. pylori status was confirmed using 13C-urea breath tests or fecal antigen test. The primary outcome was the H. pylori eradication rate following vonoprazan dual and quadruple therapy at 4-12 weeks. We also compared drug compliance to either regimen and documented their side effect. RESULTS: A total of 190 subjects were randomized. The eradication rate of vonoprazan dual and quadruple therapy were 87.4% and 92.6% (p = 0.23) by intention-to-treat analysis, respectively, and 96.5% and 97.7% (p = 0.63) by per-protocol analysis, respectively. The efficacy of vonoprazan dual therapy was non-inferior to vonoprazan-containing quadruple therapy in per-protocol analysis (p < 0.001; difference: -1.2%; 90% confidence interval: -5.4% to 3.0%). CONCLUSION: Vonoprazan with b.i.d. amoxicillin for 14 days provided similar satisfactory efficacy with vonoprazan-containing quadruple therapy as a first-line H. pylori treatment in China.

Tobacco as bioenergy and medical plant for biofuels and bioproduction.

Tobacco, a widely cultivated crop, has been extensively utilized by humans for an extended period. However, the tobacco industry generates a significant amount of organic waste, and the effective utilization of this tobacco waste has been limited. Currently, most tobacco waste is either recycled as reconstituted tobacco sheets or disposed of in landfills. However, tobacco possesses far more potential value than just these applications. This article provides an overview of the diverse uses of tobacco waste in agriculture, medicine, chemical engineering, and energy sectors. In the realm of agriculture, tobacco waste finds primary application as fertilizers and pesticides. In medical applications, the bioactive compounds present in tobacco are fully harnessed, resulting in the production of phenols, solanesol, polysaccharides, proteins, and even alkaloids. These bioactive compounds exhibit beneficial effects on human health. Additionally, the applications of tobacco waste in chemical engineering and energy sectors are centered around the utilization of lignocellulosic compounds and certain fuels. Chemical platform compounds derived from tobacco waste, as well as selected fuel sources, play a significant role in these areas. The rational utilization of tobacco waste represents a promising prospect, particularly in the present era when sustainable development is widely advocated. Moreover, this approach holds significant importance for enhancing energy utilization.

Characterization techniques for tobacco and its derivatives: a systematic review.

Biomass and its derivatives have broad applications in the fields of bio-catalysis, energy storage, environmental remediation. The structure and components of biomass, which are vital parameters affecting corresponding performances of derived products, need to be fully understood for further regulating the biomass and its derivatives. Herein, tobacco is taken as an example of biomass to introduce the typical characterization techniques in unraveling the structural information, chemical components, and properties of biomass and its derivatives. Firstly, the structural information, chemical components and application for biomass are summarized. Then the characterization techniques together with the resultant structural information and chemical components are introduced. Finally, to promote a wide and deep study in this field, the perspectives and challenges concerning structure and composition charaterization in biomass and its derivatives are put forward.

A viroid-derived small interfering RNA targets bHLH transcription factor MdPIF1 to regulate anthocyanin biosynthesis in Malus domestica.

Fruit colour is a critical determinant for the appearance quality and commercial value of apple fruits. Viroid-induced dapple symptom severely affects the fruit coloration, however, the underlying mechanism remains unknown. In this study, we identified an apple dimple fruit viroid (ADFVd)-derived small interfering RNA, named vsiR693, which targeted the mRNA coding for a bHLH transcription factor MdPIF1 (PHYTOCHROME-INTERACTING FACTOR 1) to regulate anthocyanin biosynthesis in apple. 5' RLM-RACE and artificial microRNA transient expression system proved that vsiR693 directly targeted the mRNA of MdPIF1 for cleavage. MdPIF1 positively regulated anthocyanin biosynthesis in both apple calli and fruits, and it directly bound to G-box element in the promoter of MdPAL and MdF3H, two anthocyanin biosynthetic genes, to promote their transcription. Expression of vsiR693 negatively regulated anthocyanin biosynthesis in both apple calli and fruits. Furthermore, co-expression of vsiR693 and MdPIF1 suppressed MdPIF1-promoted anthocyanin biosynthesis in apple fruits. Infiltration of ADFVd infectious clone suppressed coloration surrounding the injection sites in apple fruits, while a mutated version of ADFVd, in which the vsiR693 producing region was mutated, failed to repress fruit coloration around the injection sites. These data provide evidence that a viroid-derived small interfering RNA targets host transcription factor to regulate anthocyanin biosynthesis in apple.

Global, regional, and national burden of female cancers in women of child-bearing age, 1990-2021: analysis of data from the global burden of disease study 2021.

Background: The global status of women's health is underestimated, particularly the burden on women of child-bearing age (WCBA). We aim to investigate the pattern and trend of female cancers among WCBA from 1990 to 2021. Methods: We retrieved data from the Global Burden of Disease Study (GBD) 2021 on the incidence and disability-adjusted life-years (DALYs) of four major female cancers (breast, cervical, uterine, and ovarian cancer) among WCBA (15-49 years) in 204 countries and territories from 1990 to 2021. Estimated annual percentage changes (EAPC) in the age-standardised incidence and DALY rates of female cancers, by age and socio-demographic index (SDI), were calculated to quantify the temporal trends. Spearman correlation analysis was used to examine the correlation between age-standardised rates and SDI. Findings: In 2021, an estimated 1,013,475 new cases of overall female cancers were reported globally, with a significant increase in age-standardised incidence rate (EAPC 0.16%), and a decrease in age-standardised DALY rate (-0.73%) from 1990 to 2021. Annual increase trends of age-standardised incidence rate were observed in all cancers, except for that in cervical cancer. Contrary, the age-standardised DALY rate decreased in all cancers. Breast and cervical cancers were prevalent among WCBA worldwide, followed by ovarian and uterine cancers, with regional disparities in the burden of four female cancers. In addition, the age-standardised incidence rates of breast, ovarian, and uterine cancers basically showed a consistent upward trend with increasing SDI, while both the age-standardised incidence and DALY rates in cervical cancer exhibited downward trends with SDI. Age-specific rates of female cancers increased with age in 2021, with the most significant changes observed in younger age groups, except for uterine cancer. Interpretation: The rising global incidence of female cancers, coupled with regional variations in DALYs, underscores the urgent need for innovative prevention and healthcare strategies to mitigate the burden among WCBA worldwide. Funding: This study was supported by the Science Foundation for Young Scholars of Sichuan Provincial People's Hospital (NO. 2022QN44 and NO. 2022QN18); the Key R&D Projects of Sichuan Provincial Department of Science and Technology (NO. 2023YFS0196); the National Natural Science Foundation of China (No. 82303701).

The regulation pathways of biochar and microorganism in soil-plant system by multiple statistical methods: The forms of carbon participation in coastal wetlands.

Coastal wetlands possess significant carbon storage capabilities. However, in coastal soil-plant systems augmented with biochar and microorganisms, the mechanisms of these amendments and carbon participation remain unclear. This study utilized pot experiments to explore how Enteromorpha prolifera biochar and Arbuscular mycorrhizal fungi (AMF) affect soil organic carbon (SOC), carbon-related microbes, photosynthetic and osmotic system of Suaeda salsa. The results showed biochar reduced exchangeable sodium percentage by 6.9% through adsorption and ion exchange, and increased SOC content by 34.4%. The abundance of carbon-related microorganisms (Bacteroidota and Chloroflexi) was increased and carbon metabolizing enzyme (cellulase and sucrase) activity in the soil was enhanced. AMF significantly improved plant growth compared with CK, as evidenced by the enhanced dry weight by 2.34 times. A partial least squares pathway model (PLS-PM) and correlation analysis suggested that the combined effect of biochar and AMF could be outlined as two pathways: soil and plant. Biochar increased SOC, improved the growth of soil carbon metabolizing microorganisms, and further promoted the activity of carbon-related enzymes. Additionally, AMF facilitated nutrient absorption by plants through root symbiosis, with biochar further enhancing this process by acting as a nutrient adsorber. These combined effects of biochar and AMF at soil and plant level enhanced the photosynthetic process of Suaeda salsa. The transport of photosynthetic products to the roots can increase the carbon storage in the soil. This study provides quantitative evidence supporting the increase of carbon storage in coastal wetland soil-plant systems through a combined application of biochar and AMF.

The liquid-liquid phase separation signature predicts the prognosis and immunotherapy response in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common and fatal malignancy characterized by poor patient prognosis and treatment outcome. The process of liquid-liquid phase separation in tumour cells alters the dysfunction of biomolecular condensation in tumour cells, which affects tumour progression and treatment. We downloaded the data of HCC samples from TCGA database and GEO database, and used a machine learning method to build a new liquid-liquid phase separation index (LLPSI) by liquid-liquid phase separation related genes. The LLPSI-related column line Figure was constructed to provide a quantitative tool for clinical practice. HCC patients were divided into high and low LLPSI groups based on LLPSI, and clinical features, tumour immune microenvironment, chemotherapeutic response, and immunotherapeutic response were systematically analysed. LLPSI, which consists of five liquid-liquid phase separation-associated genes (MAPT, WDR62, PLK1, CDCA8 and TOP2A), is a reliable predictor of survival in patients with HCC and has been validated in multiple external datasets. We found that the high LLPSI group showed higher levels of immune cell infiltration and better response to immunotherapy compared to the low LLPSI group, and LLPSI can also be used for prognostic prediction in various cancers other than HCC. In vitro experiments verified that knockdown of MAPT could inhibit the proliferation and migration of HCC. The LLPSI identified in this study can accurately assess the prognosis of patients with HCC and identify patient populations that will benefit from immunotherapy, providing valuable insights into the clinical management of HCC.

TMEM176B Promotes EMT via FGFR/JNK Signalling in Development and Tumourigenesis of Lung Adenocarcinoma.

Lung cancer, the leading cause of cancer-related incidence and mortality worldwide, is characterised by high invasiveness and poor prognosis. Novel therapeutic targets are required, especially for patients with inoperable metastatic disease requiring systemic therapies to improve patients' welfare. Recently, studies indicated that TMEM176B is a positive regulator in breast and gastric cancers, and it could be a potential target for treatment. In this study, we used single-cell sequencing, proteomics, Co-IP, and in vivo and in vitro experimental models to investigate the role of TMEM176B in lung adenocarcinoma development. Our study indicated that TMEM176B expression was enhanced in lung adenocarcinoma tissues, and it was associated with shorter overall survival (OS). TMEM176B promoted cellular functions, including cell proliferation, invasion, migration and adhesion in vitro and tumour growth in vivo. Moreover, the tube formation ability of endothelial cells was enhanced by treating with the tumour cell-conditioned medium. We have also demonstrated that TMEM176B regulated EMT via the FGFR1/JNK/Vimentin/Snail signalling cascade. Overall, our study suggests TMEM176B could be a potential therapeutic target in lung adenocarcinoma.

PARP inhibitor-related acute renal failure: a real-world study based on the FDA adverse event reporting system database.

BACKGROUND: Current clinical trial data on PARP inhibitors (PARPis)-related acute renal failure (ARF) are not entirely representative of real-world situations. Therefore, in this study, the US Food and Drug Administration Adverse Event Reporting System (FAERS) was used to evaluate PARPis-related ARF. RESEARCH DESIGN AND METHODS: Data were obtained from 1 January 2015, to 30 September 2023. ARF event reports were analyzed based on four algorithms. The time-to-onset (TTO) and clinical outcomes of PARPis-associated ARF were assessed. RESULTS: The total included cases were 2726. Significant signals were observed for olaparib, niraparib, and rucaparib (reporting odds ratio (ROR): 1.62, 95% confidence interval (CI): 1.49-1.78, 1.25, 95% CI: 1.19-1.32 and 1.59, 95% CI: 1.47-1.72 respectively). The median TTO of ARF onset was 57, 36, and 85 days for olaparib, niraparib, and rucaparib, respectively. The proportion of deaths with olaparib (9.88%) was significantly higher than for niraparib (2.52%) and rucaparib (2.94%) (p < 0.005). The proportion of life-threatening adverse events associated with niraparib (4.89%) was significantly higher than for rucaparib (0.98%) (p < 0.005). CONCLUSIONS: ARF and PARPi were related, with the exception of talazoparib. More emphasis should be given to PARPis-related ARF due to the high proportion of serious AEs and delayed adverse reactions.

Elucidating the nature of acinic cell carcinoma of the breast with high-grade morphology: evidence from case report.

BACKGROUND: Acinic cell carcinoma (AciCC) of the breast is a rare subtype of breast cancer. It was considered a low-grade triple-negative breast cancer (TNBC) with the potential to progress or transform into a high-grade lesion because of the molecular similarities with conventional aggressive TNBC in several genetic studies. Microscopically, the coexistence of classical low-grade and high-grade triple-negative components in breast AciCC is not uncommon. However, there is a scarcity of research on the comparative histopathological and genetic aspects of both components. CASE PRESENTATION: A 34-year-old woman with a nontender mass in the upper outer quadrant of the left breast was initially diagnosed with a malignant small round cell tumor (undifferentiated or poorly differentiated carcinoma) based on a preoperative biopsy, which was later identified as breast AciCC with a high-grade solid component. Left breast-conserving surgery with sentinel lymph node biopsy was performed. Microscopically, the breast AciCC consisted of a classical acinic component and a high-grade component. The latter demonstrated a solid sheet-like pattern characterized by large, round, pleomorphic or vesicular nuclei, prominent nucleoli, and frequent mitotic activities. Classical acinic architectures focally merged together to form solid nests and transited into high-grade areas. Remarkably, in the high-grade lesion, conventional immunochemical markers for breast AciCC, such as α1-antitrypsin (AAT), Lysozyme (LYS), Epithelial membrane antigen (EMA), S100 protein (S100), and cytokeratin (CK) were negative, whereas cell cycle protein D1 (cyclin D1) and vimentin showed diffuse expression. Next­generation sequencing (NGS) revealed that 43.5% of variants were identical in both components. Furthermore, PAK5 mutation; copy number (CN) loss of CDH1, CHEK1, and MLH1; and CN gains of CDK6, HGF, and FOXP1 were identified in the high-grade lesion. The patient was treated with eight cycles of adjuvant chemotherapy (epirubicin combined with cyclophosphamide) and radiotherapy after surgery, and she is currently alive for 43 months with no metastases or recurrences. CONCLUSIONS: This case demonstrates a comparative analysis of the histopathological and genetic characteristics of classical low-grade and high-grade components of AciCC within the same breast. This information may serve as a morphological and molecular basis for further investigation into the molecular mechanisms underlying high-grade lesions in breast AciCC.

Low-intensity pulsed ultrasound improves myocardial ischaemia‒reperfusion injury via migrasome-mediated mitocytosis.

During myocardial ischaemia‒reperfusion injury (MIRI), the accumulation of damaged mitochondria could pose serious threats to the heart. The migrasomes, newly discovered mitocytosis-mediating organelles, selectively remove damaged mitochondria to provide mitochondrial quality control. Here, we utilised low-intensity pulsed ultrasound (LIPUS) on MIRI mice model and demonstrated that LIPUS reduced the infarcted area and improved cardiac dysfunction. Additionally, we found that LIPUS alleviated MIRI-induced mitochondrial dysfunction. We provided new evidence that LIPUS mechanical stimulation facilitated damaged mitochondrial excretion via migrasome-dependent mitocytosis. Inhibition the formation of migrasomes abolished the protective effect of LIPUS on MIRI. Mechanistically, LIPUS induced the formation of migrasomes by evoking the RhoA/Myosin II/F-actin pathway. Meanwhile, F-actin activated YAP nuclear translocation to transcriptionally activate the mitochondrial motor protein KIF5B and Drp1, which are indispensable for LIPUS-induced mitocytosis. These results revealed that LIPUS activates mitocytosis, a migrasome-dependent mitochondrial quality control mechanism, to protect against MIRI, underlining LIPUS as a safe and potentially non-invasive treatment for MIRI.

Finite-time compensation control with dead-zone estimation for a rehabilitative walker considering internal disturbance forces.

This study discusses a finite-time compensation tracking control method for a rehabilitative training walker. The dynamic model with input dead zone was constructed to describe the walker, and a finite-time disturbance forces observation method was proposed based on the impact mechanism on tracking performance. This approach is novel in that the disturbance forces were observed in reverse through their effects on tracking performance, thus successfully obtaining the disturbance forces of the walker. To ensure the practical finite-time stability of the system, the nonlinear finite-time compensation tracking controller with stochastic configuration networks (SCN) dead-zone estimation was built for the rehabilitative walker. Simulation results and comparative analyses confirmed that the proposed compensation control method effectively restrains dead zone and internal disturbance forces.

Pulsatile gonadotropin-releasing hormone therapy induces spermatogenesis in pituitary stalk interruption syndrome: A case report and review of the literature.

BACKGROUND: Pituitary stalk interruption syndrome (PSIS) is a rare anatomical defect of the pituitary gland falling under the spectrum of holoprosencephaly phenotypes. It is characterized by a deficiency in anterior pituitary hormones, such as growth hormone, gonadotropins, and thyroid hormones. Due to the syndrome's rarity and nonspecific manifestations, there is a lack of standardized treatment strategies. Consequently, early diagnosis through imaging and on-time intervention are crucial for improving patients' outcomes. CASE SUMMARY: A 30-year-old man presented with absent secondary sexual characteristics and azoospermia. Laboratory evaluation revealed a deficiency in gonadotropins, while thyroid function was mostly within normal ranges. Magnetic resonance imaging of the pituitary gland showed pituitary stalk agenesis, hypoplasia of the anterior pituitary, and ectopic posterior pituitary, leading to the diagnosis of PSIS. Initially, the patient underwent 6 mo of gonadotropin therapy without significant changes in hormone levels and secondary sexual characteristics. Pulsatile gonadotropin-releasing hormone therapy was then administered, resulting in the detection of sperm in the semen analysis within 3 mo. After 6 mo, routine semen tests showed normal semen quality. The couple faced challenges in conceiving due to abstinence and underwent three cycles of artificial insemination, which was unsuccessful. They also attempted in vitro fertilization, but unfortunately, the woman experienced a miscarriage 10 wk after the embryo transfer. CONCLUSION: Early detection, accurate diagnosis, and timely treatment are crucial in improving the quality of life and fertility of PSIS patients.

A comprehensive approach to lifestyle intervention based on a calorie-restricted diet ameliorates liver fat in overweight/obese patients with NAFLD: a multicenter randomized controlled trial in China.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a globally increasing health epidemic. Lifestyle intervention is recommended as the main therapy for NAFLD. However, the optimal approach is still unclear. This study aimed to evaluate the effects of a comprehensive approach of intensive lifestyle intervention (ILI) concerning enhanced control of calorie-restricted diet (CRD), exercise, and personalized nutrition counseling on liver steatosis and extrahepatic metabolic status in Chinese overweight and obese patients with NAFLD. METHODS: This study was a multicenter randomized controlled trial (RCT) conducted across seven hospitals in China. It involved 226 participants with a body mass index (BMI) above 25. These participants were randomly assigned to two groups: the ILI group, which followed a low carbohydrate, high protein CRD combined with exercise and intensive counseling from a dietitian, and a control group, which adhered to a balanced CRD along with exercise and standard counseling. The main measure of the study was the change in the fat attenuation parameter (FAP) from the start of the study to week 12, analyzed within the per-protocol set. Secondary measures included changes in BMI, liver stiffness measurement (LSM), and the improvement of various metabolic indexes. Additionally, predetermined subgroup analyses of the FAP were conducted based on variables like gender, age, BMI, ethnicity, hyperlipidemia, and hypertension. RESULTS: A total of 167 participants completed the whole study. Compared to the control group, ILI participants achieved a significant reduction in FAP (LS mean difference, 16.07 [95% CI: 8.90-23.25] dB/m) and BMI (LS mean difference, 1.46 [95% CI: 1.09-1.82] kg/m2) but not in LSM improvement (LS mean difference, 0.20 [95% CI: -0.19-0.59] kPa). The ILI also substantially improved other secondary outcomes (including ALT, AST, GGT, body fat mass, muscle mass and skeletal muscle mass, triglyceride, fasting blood glucose, fasting insulin, HbA1c, HOMA-IR, HOMA-ß, blood pressure, and homocysteine). Further subgroup analyses showed that ILI, rather than control intervention, led to more significant FAP reduction, especially in patients with concurrent hypertension (p < 0.001). CONCLUSION: In this RCT, a 12-week intensive lifestyle intervention program led to significant improvements in liver steatosis and other metabolic indicators in overweight and obese Chinese patients suffering from nonalcoholic fatty liver disease. Further research is required to confirm the long-term advantages and practicality of this approach. TRIAL REGISTRATION: This clinical trial was registered on ClinicalTrials.gov (registration number: NCT03972631) in June 2019.

Necroptosis-Mediated Synergistic Photodynamic and Glutamine-Metabolic Therapy Enabled by a Biomimetic Targeting Nanosystem for Cholangiocarcinoma.

Targeted delivery of glutamine metabolism inhibitors holds promise for cholangiocarcinoma therapy, yet effective delivery vehicles remain a challenge. This study reports the development of a biomimetic nanosystem, termed R-CM@MSN@BC, integrating mesoporous organosilicon nanoparticles with reactive oxygen species-responsive diselenide bonds for controlled release of the glutamine metabolism inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) and the photosensitizer Ce6. Erythrocyte membrane coating, engineered with Arg-Gly-Asp (RGD) peptides, not only enhanced biocompatibility but also improved tumor targeting and tissue penetration. Upon laser irradiation, R-CM@MSN@BC executed both photodynamic and glutamine-metabolic therapies, inducing necroptosis in tumor cells and triggering significant immunogenic cell death. Time-of-flight mass cytometry analysis revealed that R-CM@MSN@BC can remodel the immunosuppressive tumor microenvironment by polarizing M1-type macrophages, reducing infiltration of M2-type and CX3CR1+ macrophages, and decreasing T cell exhaustion, thereby increasing the effectiveness of anti-programmed cell death ligand 1 immunotherapy. This strategy proposed in this study presents a viable and promising approach for the treatment of cholangiocarcinoma.

EGFR mutation testing, treatment and survival in stage I-III non-small cell lung cancer: CancerLinQ Discovery database retrospective analysis.

Aim: To describe real-world biomarker testing, treatment and survival in stage IA-IIIC non-small cell lung cancer (NSCLC). Methods: Electronic records of USA-based patients in the CancerLinQ Discovery® database with stage IA-IIIC NSCLC (diagnosed between 2014 and 2018) were screened; a curated cohort of 14,452 records was identified for further analysis. Results: Of 3121 (21.6%) patients who had EGFR testing, 493 (15.8%) were EGFR-mutation positive. Of 974 patients who underwent surgical resection, 513 (52.7%) received adjuvant therapy. A quarter of patients with EGFR-mutation positive NSCLC received targeted adjuvant therapy. Conclusion: Approximately a fifth of patients underwent EGFR testing; biomarker testing is important to ensure optimal outcomes for patients with stage I-III NSCLC.

A study investigating how many patients with early-stage non-small cell lung cancer (NSCLC) had mutations in a protein called EGFR and which treatments they received in routine clinical practice: The treatment recommended by medical experts for stage IA­IIIA non-small cell lung cancer (NSCLC) is surgical removal of the growth (tumor). Patients with stage II or III, and some with stage IB disease, are recommended to receive treatment with medications such as chemotherapy or oral cancer treatments after surgery (adjuvant treatment). In some lung cancers, there are mutations in a protein called EGFR. Osimertinib, a drug that blocks the activity of mutated EGFR on cancer cells, reducing their growth and spread, is recommended as an adjuvant treatment for patients with EGFR-mutated, stage IB­IIIA NSCLC. This study aimed to understand how many patients with stage I­III NSCLC have tumors with EGFR mutations, and which treatments patients received in everyday clinical practice, before new medicines such as osimertinib (that treat EGFR-mutated NSCLC) were recommended. We looked at anonymous data from 14,452 patients with stage I­III NSCLC treated at cancer clinics in the USA between 2014 and 2018. We found that 3121 (21.6%) patients had an EGFR mutation test and 493 (15.8%) had EGFR-mutation positive NSCLC. Of patients who had surgery to remove the tumor, 55% received adjuvant therapy (treatment after surgery). It is important to perform EGFR mutation testing in patients with stage IB­IIIA NSCLC so that patients with EGFR-mutation positive NSCLC can receive appropriate treatment.