Diagnostic algorithm based on ratio of ascites-serum tumor markers is superior to tumor markers in the differentiation of benign ascites from malignant ascites.

BACKGROUND: Differential diagnosis between benign ascites and malignant ascites remains challenging in clinical practice, the aim of our study is to determine the differential value of the ratio of ascitic-serum tumor markers between benign ascites and malignant ascites. METHODS: 418 patients with new-onset ascites were retrospectively enrolled in this study. The pertinent data of patients enrolled were collected; diagnostic value of tumor markers, ascites-serum tumor marker ratio, and diagnostic algorithm based on ascitic tumor markers and ascites-serum tumor marker ratio in patients with ascites were investigated. RESULTS: 81.25% of the patients with benign ascites had low (<1) ratio of ascites-serum tumor markers (Max [A/S CEA, A/S CA15-3, A/S CA19-9]); and 91.88 % of patients with benign ascites had the ratio of ascites-serum tumor marker less than 1.5. On the other hand, 94.96% of the patients with malignant ascites had high (≥1) ratio of ascites-serum tumor markers; and 97.29% of patients with malignant ascites had the ratio of ascites-serum tumor markers more than 0.67. Finally, diagnostic algorithm based on ascitic tumor markers and ascites-serum tumor marker ratio showed 96.37% of the sensitivity, and 94.37% of the accuracy in the diagnosis of malignant ascites, while ascitic tumor markers with a sensitivity of 78.29%, and an accuracy of 84.93%. CONCLUSIONS: Diagnostic algorithm based on ascitic tumor markers and ascites-serum tumor marker ratio exhibited an excellent performance in distinguishing benign and malignant ascites, which should be recommended in patients with new-onset ascites in clinical practice.

Contrast-enhanced ultrasound for differentiating benign from malignant focal solid renal lesions in pediatric patients.

The contrast-enhanced ultrasound (CEUS) has been mainly applied to adults to differentiate benign and malignant renal lesions, however, the characteristics of CEUS in pediatric has not been as well studied as in adults. In the present work, the eligible pediatric patients who underwent renal CEUS between March 2016 and February 2023 were retrospectively analyzed. It included 20 lesions (median diameter, 8.4 cm; range, 1.8-18.0 cm) from 20 patients (median age, 28.0 months; range, 3.0-212.0 months; 9 boys) in malignant group and 5 lesions (median diameter, 3.8 cm; range, 1.3-7.5 cm) from 5 patients (median age, 25.0 months; range, 0.7-216.0 months; 2 boys) in benign group. The diagnostic performance was assessed. Nonparametric and Chi-square tests were performed. With hyperenhancement plus wash-out, CEUS showed a sensitivity of 95.0% [95% confidence interval (CI): 75.1%, 99.9%], a specificity of 80.0% (CI: 28.4%, 99.5%), a positive predictive value of 95.0% (CI: 75.1%, 99.9%) and a negative predictive value of 80.0% (CI: 28.4%, 99.5%). It suggested that CEUS is a valuable technique for identifying between malignant and benign renal lesions in children.

Association among abnormal glycolipids, reproductive hormones, and cognitive dysfunction in female patients with bipolar disorder.

BACKGROUND: Patients with bipolar disorder (BD) show abnormalities in glucolipid metabolism and reproductive hormone levels, which are of concern in women with BD. This study was dedicated to investigating the glucolipid and reproductive hormone levels of female patients, and to preliminarily investigating their relationships with cognition. METHODS: A total of 58 unmedicated female BD patients, 61 stable-medicated female BD patients, and 63 healthy controls (HC) were recruited in this study. Serum glycolipid indexes and reproductive hormones were measured. Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Stroop Color-Word Test (Stroop test). RESULTS: Patients with BD showed significant cognitive impairment (p < 0.05), which was not affected by medication. Triglycerides (TG), luteinizing hormone (LH), and high-density lipoprotein cholesterol (HDL-c) were altered in stable-medicated BD patients. In addition, regression analysis showed that progesterone (PRGE) and prolactin (PRL) were negatively associated with cognitive performance in stable-medicated BD patients. CONCLUSIONS: Female BD patients may have cognitive deficits and abnormal levels of glycolipids and reproductive hormones. And abnormal levels of glycolipids and reproductive hormones may be associated with cognitive dysfunction in female BD patients.

Chemotherapy plus therapeutic plasmapheresis with 4% human albumin solution in multiple myeloma patients with acute kidney injury: a prospective, open-label, proof-of-concept study.

As no unified treatment protocol or evidence yet exists for plasmapheresis without plasma, this study explored the outcomes of using 4% human albumin (ALB) solution as a replacement solution in patients undergoing plasma exchange for multiple myeloma (MM) patients with acute kidney injury (AKI). This study was prospectively registered (ChiCTR2000030640 and NCT05251896). Bortezomib-based chemotherapy plus therapeutic plasmapheresis (TPP) with 4% human ALB solution was assessed for three years in patients with MM aged >18 years, with AKI according to the Kidney Disease Improving Global Outcomes criteria, and without previous renal impairment from other causes. The primary endpoints were changes in renal function over 18 weeks and survival outcomes at 36 months. The secondary endpoints were the incidence of adverse reactions and symptom improvement. Among the 119 patients included in the analysis, 108 experienced renal reactions. The M protein (absolute changes: median -12.12%, interquartile ranges (IQRs) -18.62 to -5.626) and creatine (median -46.91 µmol/L, IQR -64.70 to -29.12) levels decreased, whereas the estimated glomerular filtration rate (eGFR) increased (median 20.66 mL/(min·1.73 m2), IQR 16.03-25.29). Regarding patient survival, 68.1% and 35.3% of patients survived for >12 and >36 months, respectively. The three symptoms with the greatest relief were urine foam, poor appetite, and blurred vision. All 11 patients (7.6%) who experienced mild adverse reactions achieved remission. In conclusion, in MM patients with AKI, plasma-free plasmapheresis with 4% human ALB solution and bortezomib-based chemotherapy effectively alleviated light chain damage to kidney function while improving patient quality of life.

Associations of BRAFV600E mutation with the American College of Radiology Thyroid Imaging Reporting and Data System and clinicopathological characteristics in pediatric patients with papillary thyroid carcinoma.

BACKGROUND: Identifying the associations between BRAFV600E mutation, the American College of Radiology Thyroid Imaging Reporting and Data System (TI-RADS) and clinicopathological characteristics could assist in making appropriate treatment strategies for pediatric patients with papillary thyroid carcinoma. OBJECTIVE: To retrospectively assess the associations between BRAFV600E mutation, TI-RADS, and clinicopathological characteristics in pediatric patients with papillary thyroid carcinoma. MATERIALS AND METHODS: Between May 2013 and May 2023, pediatric patients with papillary thyroid carcinoma who underwent thyroidectomy were retrospectively evaluated. Univariate and multivariate logistic regression analyses were performed to determine the associations between BRAFV600E mutation, TI-RADS, and clinicopathological characteristics. The diagnostic performance of TI-RADS to predict BRAFV600E mutation was assessed. RESULTS: The BRAFV600E mutation was found in 59.1% (39/66) of pediatric patients with papillary thyroid carcinoma. Multivariate analyses showed that hypoechoic/very hypoechoic [odds ratio (OR) = 8.48; 95% confidence interval (CI) = 1.48-48.74); P-value = 0.02] and punctate echogenic foci (OR = 24.3; 95% CI = 3.80-155.84; P-value = 0.001) were independent factors associated with BRAFV600E mutation. In addition, BRAFV600E mutation was significantly associated with TI-RADS 5 (OR = 12.61; 95% CI = 1.28-124.49; P-value = 0.03). There were no associations between BRAFV600E mutation and nodule size, composition, shape, margin, cervical lymph node metastasis, or Hashimoto's thyroiditis (P-value > 0.05). Combined with hypoechoic/very hypoechoic and punctate echogenic foci, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 89.7%, 85.2%, 89.7%, 85.2%, and 87.9%, respectively. CONCLUSIONS: Hypoechoic/very hypoechoic, punctate echogenic foci, and TI-RADS 5 are independently associated with BRAFV600E mutation in pediatric patients with papillary thyroid carcinoma.

Photoacoustic trace gas detection of OCS using a 2.45 mL Helmholtz resonator and a 4823.3 nm ICL light source.

A miniaturized photoacoustic spectroscopy-based gas sensor is proposed for the purpose of detecting sub-ppm-level carbonyl sulfide (OCS) using a tunable mid-infrared interband cascade laser (ICL) and a Helmholtz photoacoustic cell. The tuning characteristics of the tunable ICL with a center wavelength of 4823.3 nm were investigated to achieve the optimal driving parameters. A Helmholtz photoacoustic cell with a volume of ∼2.45 mL was designed and optimized to miniaturize the measurement system. By optimizing the modulation parameters and signal processing, the system was verified to have a good linear response to OCS concentration. With a lock-in amplifier integration time of 10 s, the 1σ noise standard deviation in differential mode was 0.84 mV and a minimum detection limit (MDL) of 409.2 ppbV was achieved at atmospheric pressure and room temperature.

Current Status of Cognition and Clinical Practice of Refractory Cancer Pain in Shanghai: A Questionnaire Survey.

Purpose: This study aimed to assess the current status of clinical practice of refractory cancer pain (RCP) among a sample of physicians specializing in cancer pain management in Shanghai. Methods: From 2019 to 2021, a questionnaire survey was conducted among physicians engaged in diagnosis and treatment of cancer pain through the questionnaire WJX network platform in Shanghai, China. Results: A total of 238 responses participated in the survey. This survey reports physicians' understanding and incidence rate of breakthrough cancer pain (BTCP). The choice of analgesics and satisfaction of analgesic effect were investigated. We also investigated doctors' knowledge of the diagnostic criteria for RCP and their tendency to choose analgesics. Oral immediate-release morphine and intravenous or subcutaneous morphine injection have been the common treatment approach for transient cancer pain exacerbations. The main barriers to pain management are lack of standardized treatment methods for RCP, lack of knowledge related to RCP, and single drug dosage form. Doctors believe the most necessary measures to improve the current situation of poor cancer pain control include improving medical staff's understanding and treatment techniques for RCP, updating treatment techniques and methods, and improving the configuration of drug types in medical institutions. Clinicians expect to improve understanding and treatment techniques through systematic training. Conclusion: Despite multiple available analgesic measures, the treatment of RCP remains challenging. Improving the understanding of medical staff towards RCP, improving treatment techniques, and increasing the accessibility of multiple drug types are important ways to improve the satisfaction of cancer pain management in the future.

Comprehensive analysis of zinc and ring finger 3 in prognostic value and pan-cancer immunity.

Zinc and ring finger 3 (ZNRF3) is a negative suppressor of Wnt signal and newly identified as an important regulator in tumorigenesis and development. However, the pan-cancer analysis of ZNRF3 has not been reported. We found that ZNRF3 was significantly decreased in six tumors including CESC, KIRP, KIRC, SKCM, OV, and ACC, but increased in twelve tumors, namely LGG, ESCA, STES, COAD, STAD, LUSC, LIHC, THCA, READ, PAAD, TGCT, and LAML. Clinical outcomes of cancer patients were closely related to ZNRF3 expression in ESCA, GBM, KIRC, LUAD, STAD, UCEC, LGG, and SARC. The highest genetic alteration frequency of ZNRF3 occurred in ACC. Abnormal expression of ZNRF3 could be attributed to the differences of copy number variation (CNV) and DNA methylation as well as ZNRF3-interacting proteins. Besides, ZNRF3 were strongly associated with tumor heterogeneity, tumor stemness, immune score, stromal score and ESTIMATE score in certain cancers. In terms of immune cell infiltration, ZNRF3 was positively correlated to infiltration of cancer-associated fibroblasts in CESC, HNSC, OV, PAAD, PRAD, and THYM, but negatively associated with infiltration of CD8 T cells in HNSC, KIRC, KIRP and THYM. Moreover, ZNRF3 expression was correlated with most immune checkpoint genes in SARC, LUSC, LUAD, PRAD, THCA, UVM, TGCT, and OV, and associated with overwhelming majority of immunoregulatory genes in almost all cancers. Most RNA modification genes were also remarkably related to ZNRF3 level in KIRP, LUAD, LUSC, THYM, UVM, PRAD, and UCEC, indicating that ZNRF3 might have an important effect on cancer epigenetic regulation. Finally, we verified the expression and role of ZNRF3 in clinical specimens and cell lines of renal cancer and liver cancer. This study provides a comprehensive pan-cancer analysis of ZNRF3 and reveals the complexity of its carcinogenic effect.

Causal associations between gastroesophageal reflux disease and essential hypertension: A bidirectional Mendelian randomization study.

BACKGROUND: Clinical studies have reported that patients with gastroesophageal reflux disease (GERD) have a higher prevalence of hypertension. AIM: To performed a bidirectional Mendelian randomization (MR) analysis to investigate the causal link between GERD and essential hypertension. METHODS: Eligible single nucleotide polymorphisms (SNPs) were selected, and weighted median, inverse variance weighted (IVW) as well as MR egger (MR-Egger) regression were used to examine the potential causal association between GERD and hypertension. The MR-Pleiotropy RESidual Sum and Outlier analysis was used to detect and attempt to reduce horizontal pleiotropy by removing outliers SNPs. The MR-Egger intercept test, Cochran's Q test and "leave-one-out" sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneities, and stability of single instrumental variable. RESULTS: IVW analysis exhibited an increased risk of hypertension (OR = 1.46, 95%CI: 1.33-1.59, P = 2.14E-16) in GERD patients. And the same result was obtained in replication practice (OR = 1.002, 95%CI: 1.0008-1.003, P = 0.000498). Meanwhile, the IVW analysis showed an increased risk of systolic blood pressure (ß = 0.78, 95%CI: 0.11-1.44, P = 0.021) and hypertensive heart disease (OR = 1.68, 95%CI: 1.36-2.08, P = 0.0000016) in GERD patients. Moreover, we found an decreased risk of Barrett's esophagus (OR = 0.91, 95%CI: 0.83-0.99, P = 0.043) in essential hypertension patients. CONCLUSION: We found that GERD would increase the risk of essential hypertension, which provided a novel prevent and therapeutic perspectives of essential hypertension.

Exploration of kiwi root on non-small cell lung cancer based on network pharmacology and molecular docking.

BACKGROUND: Kiwi root is a Chinese herb clinically used in the treatment of lung neoplasm; however, the multi-target mechanism of kiwi root in the treatment of non-small cell lung cancer (NSCLC) remains to be elucidated. Thus, this study aimed to investigate the molecular mechanisms of kiwi root in the treatment of NSCLC through network pharmacology and molecular docking techniques. METHODS: The active components and targets of kiwi root were obtained from the TCMSP database, and NSCLC-related targets were obtained from the GeneCards, OMIM, and DrugBank databases. The intersection targets of NSCLC and kiwi root were obtained from VENNY 2.1.0. Then, the common targets were imported into the STRING database, and by using the Cytoscape 3.7.1 software, drug-disease network diagrams were created. Afterwards, the DAVID database was utilized to perform bioinformatic annotation. Finally, molecular docking of key components and key targets was performed by Autodock Tools. RESULTS: A total of 4083 NSCLC-related disease genes were collected from the GeneCards, OMIM,and DrugBank databases, and 177 non-duplicated drug targets were acquired from the TCMSP database. A total of 138 intersection target genes were obtained, in which TP53, AKT1, and TNF were the key targets. CONCLUSION: Through network pharmacology techniques, the mechanism of kiwi root in the treatment of NSCLC has been uncovered and provides a theoretical basis for the clinical treatment of NSCLC with kiwi root, which requires further experimental validation.

Seven preoperative factors have strong predictive value for postoperative pneumonia in patients undergoing thoracoscopic lung cancer surgery.

Background: Postoperative pneumonia (POP) is a hospital acquired pneumonia that occurs >48 hours after tracheal intubation. The diagnosis of POP should be based on clinical and radiological findings within 30 days after surgery. It is a common complication after thoracoscopic surgery for lung cancer patients. However, the specific impact of preoperative comorbidities on the incidence of POP remains unclear. This study aimed to analyze the preoperative data of patients with lung cancer to help surgeons predict the risk of incidence of POP after thoracoscopic lung resection. Methods: This study is a prospective study that included patients with lung cancer who were scheduled for thoracoscopic surgery in 1 year. All cases came from two medical centers. Preoperative demographic information, tumor information, preoperative comorbidities, quality of life scores, and incidence of POP were collected. Variables were screened by univariate analysis and multivariate regression. Finally, a prediction model was constructed. A total of 53 preoperative factors were included as candidate predictors. The binary outcome variable was defined as the presence or absence of POP. The incidence of POP was the primary outcome variable. The predictive performance of the model was verified internally through 1,000 iterations of bootstrap resampling. Results: A total of 1,229 patients with lung cancer who underwent thoracoscopic surgery were enrolled. In addition, 196 cases (15.95%) had POP; 1,025 (83.40%) patients had comorbid conditions. The total number of comorbidity diagnosed in all samples was 2,929. The prediction model suggested that patients with advanced age, high body mass index (BMI), smoking, poor physical condition, respiratory diseases, diabetes, and neurological diseases were more likely to develop POP. The area under the curve (AUC) and Brier scores were 0.851 and 0.091, respectively. The expected and observed results were in strong agreement, according to the likelihood of POP calibration curve. Conclusions: The constructed model is capable of evaluating the probability of POP occurrence in patients with lung cancer. Seven preoperative factors in patients with lung cancer were found to be associated with increased probability of having pneumonia after thoracoscopic lung resection. This model can help predict the incidence of POP after surgery.

Comparison of the diagnostic efficiency between the O-RADS US risk stratification system and doctors' subjective judgment.

BACKGROUND: This study aimed to compare the diagnostic efficiency of Ovarian-Adnexal Reporting and Data System (O-RADS) and doctors' subjective judgment in diagnosing the malignancy risk of adnexal masses. METHODS: This was an analysis of 616 adnexal masses between 2017 and 2020. The clinical findings, preoperative ultrasound images, and pathological diagnosis were recorded. Each adnexal mass was evaluated by doctors' subjective judgment and O-RADS by two senior doctors and two junior doctors. A mass with an O-RADS grade of 1 to 3 was a benign tumor, and a mass with an O-RADS grade of 4-5 was a malignant tumor. All outcomes were compared with the pathological diagnosis. RESULTS: Of the 616 adnexal masses, 469 (76.1%) were benign, and 147 (23.9%) were malignant. There was no difference between the area under the curve of O-RADS and the subjective judgment for junior doctors (0.83 (95% CI: 0.79-0.87) vs. 0.79 (95% CI: 0.76-0.83), p = 0.0888). The areas under the curve of O-RADS and subjective judgment were equal for senior doctors (0.86 (95% CI: 0.83-0.89) vs. 0.86 (95% CI: 0.83-0.90), p = 0.8904). O-RADS had much higher sensitivity than the subjective judgment in detecting malignant tumors for junior doctors (84.4% vs. 70.1%) and senior doctors (91.2% vs. 81.0%). In the subgroup analysis for detecting the main benign lesions of the mature cystic teratoma and ovarian endometriosic cyst, the junior doctors' diagnostic accuracy was obviously worse than the senior doctors' on using O-RADS. CONCLUSIONS: O-RADS had excellent performance in predicting malignant adnexal masses. It could compensate for the lack of experience of junior doctors to a certain extent. Better performance in discriminating various benign lesions should be expected with some complement.

Identification of a novel endocytosis­associated gene signature for prognostic prediction in lung adenocarcinoma.

Lung cancer is one of the most common malignant solid tumors and the leading cause of cancer-associated mortality worldwide. Endocytosis is an essential physiological activity for cells to maintain membrane homeostasis, and has been reported to serve an important role in tumorigenesis and progression. In the present study, the aim was to construct a prognostic prediction model of endocytosis-associated genes for patients with lung adenocarcinoma (LUAD). The endocytosis-associated gene signature was established using Lasso Cox regression analysis using the training set of the LUAD cohort from The Cancer Genome Atlas (TCGA) database, and verified using two datasets from the Gene Expression Omnibus (GEO) database. Kaplan-Meier survival curves were used to evaluate the effectiveness of the prognostic evaluation of patients with LUAD. Differentially expressed genes were screened in the tumor tissue of patients compared with paired paracancerous tissues. A series of candidate genes associated to the prognosis of patients with LUAD was obtained using univariate Cox's regression analysis. Using the Lasso Cox regression analysis, an appropriate risk model with 18 endocytosis-associated genes was established. A high-risk score was positively correlated with a higher tumor stage and pathologic grade. Patients with LUAD and high-risk scores had shorter survival times, increased intratumor heterogeneities and immune cell infiltration into tumor tissues, compared with those patients with LUAD and low-risk scores. The endocytosis inhibitor chloroquine could repress proliferation and increase the apoptosis of lung cancer cells. In summary, a novel endocytosis-associated gene signature was constructed using TCGA and GEO datasets. Patients with LUAD and high-risk scores, as calculated by the signature, had a poor prognosis and short survival time.

Apatinib added when NSCLC patients get slow progression with EGFR-TKI: A prospective, single-arm study.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) acquired resistance was an inevitably events in NSCLC treatment. AIMS: Intending to overcome the acquired resistance of EGFR-TKI. MATERIALS & METHODS: A clinical trial was, we enrolled 12 patients who were slowly progressing on first-generation EGFR-TKI, and added apatinib when the patients got slow progression. RESULTS: Seven patients were included in the efficacy analysis. The median PFS2 of apatinib combined with EGFR-TKI was 8.2 months (95% CI, 7.3 m-NA), and the total PFS reached 20.9 months (95% CI, 17.3 m-NA) when plus PFS1. All the adverse events were manageable. The median PFS was significantly longer for circulating tumor DNA (ctDNA)-cleared patients (8.4 months; 95% CI, 8.2-NA) than for those ctDNA not cleared (7.1 months; 95% CI, 6.9-NA) (p = 0.0082). DISCUSSION: The addition of apatinib did improve the duration of first-generation EGFR-TKI use, and the duration was better than the first-line use of third-generation EGFR-TKI. CONCLUSION: The addition of apatinib when the patients got slow progression after initial EGFR-TKI therapy may be a good treatment option and the side effects are controllable. It is possible to monitor treatment efficacy using ctDNA.

KRAS inhibition activates an actionable CD24 'don't eat me' signal in pancreas cancer.

KRAS G12C inhibitor (G12Ci) has produced encouraging, albeit modest and transient, clinical benefit in pancreatic ductal adenocarcinoma (PDAC). Identifying and targeting resistance mechanisms to G12Ci treatment is therefore crucial. To better understand the tumor biology of the KRAS G12C allele and possible bypass mechanisms, we developed a novel autochthonous KRAS G12C -driven PDAC model. Compared to the classical KRAS G12D PDAC model, the G12C model exhibit slower tumor growth, yet similar histopathological and molecular features. Aligned with clinical experience, G12Ci treatment of KRAS G12C tumors produced modest impact despite stimulating a 'hot' tumor immune microenvironment. Immunoprofiling revealed that CD24, a 'do-not-eat-me' signal, is significantly upregulated on cancer cells upon G12Ci treatment. Blocking CD24 enhanced macrophage phagocytosis of cancer cells and significantly sensitized tumors to G12Ci treatment. Similar findings were observed in KRAS G12D -driven PDAC. Our study reveals common and distinct oncogenic KRAS allele-specific biology and identifies a clinically actionable adaptive mechanism that may improve the efficacy of oncogenic KRAS inhibitor therapy in PDAC. Significance: Lack of faithful preclinical models limits the exploration of resistance mechanisms to KRAS G12C inhibitor in PDAC. We generated an autochthonous KRAS G12C -driven PDAC model, which revealed allele-specific biology of the KRAS G12C during PDAC development. We identified CD24 as an actionable adaptive mechanisms in cancer cells induced upon KRAS G12C inhibition and blocking CD24 sensitizes PDAC to KRAS inhibitors in preclinical models.

Association of serum 25-hydroxyvitamin D concentrations with all-cause mortality among individuals with kidney stone disease: the NHANES database prospective cohort study.

Background: The purpose of this study was to investigate the correlation between serum 25(OH)D concentrations and all-cause mortality in patients with kidney stone disease (KSD) as the effects of a deficiency in 25-hydroxyvitamin D on KSD patients are currently unclear. Methods: For our prospective cohort study, we included 2,916 participants from the National Health and Nutrition Examination Survey (NHANES) 2007-2018. The National Death Index (NDI) was utilized to identify all causes of death and cause-specific mortality until December 31, 2018. We calculated hazard ratios (HR) and 95% confidence intervals (CIs) using multivariate Cox regression models. Results: During the 18,859 person-years of follow-up, a total of 375 fatalities occurred, including 83 deaths from cardiovascular disease (CVD) and 79 deaths from cancer. At baseline, individuals with higher blood 25(OH)D concentrations had lower levels of glucose, glycohemoglobin, CRP, and insulin, as well as higher levels of HDL cholesterol (P < 0.01). In the fully adjusted model (Model 3), compared to the group with the lowest 25(OH)D concentrations, those with serum 25(OH)D concentrations ≥75 nmol/L had hazard ratios (HRs) and 95% confidence intervals (CIs) of 0.48 (0.26, 0.87) for all-cause mortality (P=0.02, P for trend = 0.02). The association between serum 25(OH)D concentrations and all-cause mortality in KSD patients was found to be significantly non-linear. A 7% decrease in the risk of death from all causes was observed for each unit-nmol/L increase in serum 25(OH)D concentrations when the concentrations were below 27.7 nmol/L (P < 0.05). Conclusion: Based on the findings, KSD patients with insufficient serum 25(OH)D concentrations were at a higher risk of all-cause mortality. Therefore, it is crucial to maintain sufficient blood 25(OH)D concentrations and prevent 25(OH)D insufficiency in order to extend the lifespan of KSD patients.

Benzophenanthridine Alkaloid Chelerythrine Elicits Necroptosis of Gastric Cancer Cells via Selective Conjugation at the Redox Hyperreactive C-Terminal Sec498 Residue of Cytosolic Selenoprotein Thioredoxin Reductase.

Targeting thioredoxin reductase (TXNRD) with low-weight molecules is emerging as a high-efficacy anti-cancer strategy in chemotherapy. Sanguinarine has been reported to inhibit the activity of TXNRD1, indicating that benzophenanthridine alkaloid is a fascinating chemical entity in the field of TXNRD1 inhibitors. In this study, the inhibition of three benzophenanthridine alkaloids, including chelerythrine, sanguinarine, and nitidine, on recombinant TXNRD1 was investigated, and their anti-cancer mechanisms were revealed using three gastric cancer cell lines. Chelerythrine and sanguinarine are more potent inhibitors of TXNRD1 than nitidine, and the inhibitory effects take place in a dose- and time-dependent manner. Site-directed mutagenesis of TXNRD1 and in vitro inhibition analysis proved that chelerythrine or sanguinarine is primarily bound to the Sec498 residue of the enzyme, but the neighboring Cys497 and remaining N-terminal redox-active cysteines could also be modified after the conjugation of Sec498. With high similarity to sanguinarine, chelerythrine exhibited cytotoxic effects on multiple gastric cancer cell lines and suppressed the proliferation of tumor spheroids derived from NCI-N87 cells. Chelerythrine elevated cellular levels of reactive oxygen species (ROS) and induced endoplasmic reticulum (ER) stress. Moreover, the ROS induced by chelerythrine could be completely suppressed by the addition of N-acetyl-L-cysteine (NAC), and the same is true for sanguinarine. Notably, Nec-1, an RIPK1 inhibitor, rescued the chelerythrine-induced rapid cell death, indicating that chelerythrine triggers necroptosis in gastric cancer cells. Taken together, this study demonstrates that chelerythrine is a novel inhibitor of TXNRD1 by targeting Sec498 and possessing high anti-tumor properties on multiple gastric cancer cell lines by eliciting necroptosis.

Lifestyle factors, serum parameters, metabolic comorbidities, and the risk of kidney stones: a Mendelian randomization study.

Background and objective: The early identification of modifiable risk factors is important for preventing kidney stones but determining causal associations can be difficult with epidemiological data. We aimed to genetically assess the causality between modifiable factors (lifestyle factors, serum parameters, and metabolic comorbidities) and the risk of kidney stones. Additionally, we aimed to explore the causal impact of education on kidney stones and its potential mediating pathways. Methods: We conducted a two-sample Mendelian randomization (MR) study to explore the causal association between 44 modifiable risk factors and kidney stones. The FinnGen dataset initially explored the causal relationship of risk factors with kidney stones and the UK Biobank dataset was used as the validation set. Then, a meta-analysis was conducted by combining discovery and validation datasets. We used two-step MR to assess potential mediators and their mediation proportions between education and kidney stones. Results: The combined results indicated that previous exposures may increase the risk of kidney stones, including sedentary behavior, urinary sodium, the urinary sodium/potassium ratio, the urinary sodium/creatinine ratio, serum calcium, 25-hydroxyvitamin D (25OHD), the estimated creatinine-based glomerular filtration rate (eGFRcrea), GFR estimated by serum cystatin C (eGFRcys), body mass index (BMI), waist circumference, type 2 diabetes mellitus (T2DM), fasting insulin, glycated hemoglobin, and hypertension. Coffee intake, plasma caffeine levels, educational attainment, and the urinary potassium/creatinine ratio may decrease the risk of kidney stones. Ranked by mediation proportion, the effect of education on the risk of kidney stones was mediated by five modifiable risk factors, including sedentary behavior (mediation proportion, 25.7%), smoking initiation (10.2%), BMI (8.2%), T2DM (5.8%), and waist circumference (3.2%). Conclusion: This study provides MR evidence supporting causal associations of many modifiable risk factors with kidney stones. Sedentary lifestyles, obesity, smoking, and T2DM are mediating factors in the causal relationship between educational attainment and kidney stones. Our results suggest more attention should be paid to these modifiable factors to prevent kidney stones.

Case Report: ALK rearranged locally advanced lung adenocarcinoma showing inconsistent radiographic findings and pathological responses during neoadjuvant alectinib therapy.

Alectinib has been approved as first-line treatment for anaplastic lymphoma kinase (ALK)-positive non-small cell lung carcinoma. Oncologists are also exploring the possibility of applying alectinib in the perioperative period. Here, we present a patient with locally advanced lung adenocarcinoma associated with EML4-ALK fusion mutation, who received neoadjuvant chemotherapy and alectinib treatment, and then underwent thoracoscopic left lower lung lobectomy. The patient initially received eight chemotherapy cycles and achieved partial remission. After eight cycles of chemotherapy, the lymph nodes in the hilar region again enlarged. The patient was then switched to 4 months of alectinib therapy, but no significant lesion changes were detected on imaging during this period. This raised the question of whether the patient developed alectinib resistance. The pathological findings of the postoperative lung lobe specimens indicated extensive necrosis in the tumor area with no residual tumor cells and massive chronic inflammatory cell infiltration around the tumor area, confirming inconsistency between the imaging findings and pathological results. Multi-point tumor specimen sampling was postoperatively performed. Tumor immune-related gene expression was detected in the sample with the help of the PanCancer IO360™ panel based on the nCounter platform. This is a rare case of a patient who was treated with neoadjuvant alectinib and had paradoxical radiographic findings and pathological responses. The possibility that intratumoral immune heterogeneity was responsible for this phenomenon has been discussed. Based on the findings, it is argued that the pathological response should be an important basis for assessing the effectiveness of neoadjuvant alectinib therapy.

Prevalence and characteristics of polycystic ovarian syndrome in patients with bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is frequently accompanied by endocrine disturbances. We compared the prevalence of polycystic ovary syndrome (PCOS) and related reproductive disorders between drug-naïve BD patients and matched healthy controls (HCs) and between drug-naïve BD patients and BD patients with long-term medication, as well as the clinical metabolic correlates among BD patients. METHODS: 72 drug-naïve BD patients, 98 HCs, and 72 BD patients with long-term medication were recruited in the study. Menstruation was recorded, reproductive hormone levels and metabolic indicators were measured, and a pelvic ultrasound examination was performed via transvaginal sensor for each participant. PCOS was defined using the Rotterdam criteria. RESULTS: After controlling for demographic variables, drug-naïve BD patients presented higher rates of PCOS than the HCs (OR: 3.02, 95 % CI: 1.09-8.36). Regression analysis showed that long-term treatment with valproate (OR: 3.89, 95 % CI: 1.13-13.37), age (OR: 0.37, 95 % CI: 0.14-0.95), and insulin resistance index (OR: 1.73, 95 % CI: 1.10-12.71) were correlated with PCOS in BD patients. CONCLUSIONS: Drug-naïve BD patients are susceptible to developing PCOS, and valproate is correlated with increased occurrence and development of PCOS. Therefore, PCOS in BD patients, especially those who use valproate, needs to be investigated and monitored closely by medical personnel.