The Role of FOXA1 in Human Normal Development and Its Functions in Sex Hormone-Related Cancers.

Transcription factors (TFs) are essential proteins regulating gene expression by binding to specific nucleotide sequences upstream of genes. Among TF families, the forkhead box (FOX) proteins, characterized by a conserved DNA-binding domain, play vital roles in various cellular processes, including cancer. The FOXA subfamily, encompassing FOXA1, FOXA2, and FOXA3, stands out for its pivotal role in mammalian development. FOXA1, initially identified in the liver, exhibits diverse expression across multiple organ tissues and plays a critical role in cell proliferation, differentiation, and tumor development. Its structural composition includes transactivation domains and a DNA-binding domain, facilitating its function as a pioneer factor, which is crucial for chromatin interaction and the recruitment of other transcriptional regulators. The involvement of FOXA1 in sex hormone-related tumors underscores its significance in cancer biology. This review provides an overview of multifaceted roles of FOXA1 in normal development and its implications in the pathogenesis of hormone-related cancers, particularly breast cancer and prostate cancer.

Post-marketing risk analysis of bendamustine: a real-world approach based on the FAERS database.

Objective: Bendamustine was approved for treating chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma. Despite its therapeutic benefits, the long-term safety of bendamustine in a large population remains inadequately understood. This study evaluates the adverse events (AEs) associated with bendamustine, using a real-world pharmacovigilance database to support its clinical application. Methods: We conducted a post-marketing risk analysis to assess the association between bendamustine and its AEs. Data were extracted from the US FDA's Adverse Event Reporting System (FAERS), covering the period from January 2017 to September 2023. The characteristics of bendamustine-associated AEs and the onset time were further analyzed. Statistical analysis was performed using MYSQL 8.0, Navicat Premium 15, Microsoft EXCEL 2016, and Minitab 21.0. Results: 9,461,874 reports were collected from the FAERS database, 9,131 identified bendamustine as the "primary suspected" drug. We identified 331 significant disproportionality preferred terms (PTs). Common AEs included pyrexia, neutropenia, infusion site reaction, progressive multifocal leukoencephalopathy (PML), injection site vasculitis, and pneumonia-all documented on bendamustine's label. Notably, 16 unexpected and significant AEs were discovered, including hypogammaglobulinemia, which is concerning due to its potential to increase infection susceptibility following bendamustine treatment. Other significant findings were anaphylactic reactions, PML, and cutaneous malignancies, suggesting updates to the drug's label may be necessary. Physicians should monitor for neurological and skin changes in patients and discontinue treatment if PML is suspected. Moreover, the median onset time for bendamustine-associated AEs was 13 days, with an interquartile range [IQR] of 0-59 days, predominantly occurring on the first day post-initiation. The ß of bendamustine-related AEs suggested risk reduction over time. Conclusion: Our study uncovered some potential pharmacovigilance signals for bendamustine, providing important insights for its safe and effective clinical use.

Diagnostic value of dual-source, dual-energy computed tomography combined with the neutrophil-lymphocyte ratio for discriminating gastric signet ring cell from mixed signet ring cell and non-signet ring cell carcinomas.

PURPOSE: To explore the diagnostic value of dual-source computed tomography (DSCT) and neutrophil to lymphocyte ratio (NLR) for differentiating gastric signet ring cell carcinoma (SRC) from mixed SRC (mSRC) and non-SRC (nSRC). METHODS: This retrospective study included patients with gastric adenocarcinoma who underwent DSCT between August 2019 and June 2021 at our Hospital. The iodine concentration in the venous phase (ICvp), standardized iodine concentration (NICVP), and the slope of the energy spectrum curve (kVP) were extracted from DSCT data. NLR was determined from laboratory results. DSCT (including ICVP, NICVP, and kVP) and combination (including DSCT model and NLR) models were established based on the multinomial logistic regression analysis. The receiver operator characteristic (ROC) curve and area under the curve (AUC) were used to evaluate the diagnostic value. RESULTS: A total of 155 patients (SRC [n = 45, aged 61.22 ± 11.4 years], mSRC [n = 60, aged 61.09 ± 12.7 years], and nSRC [n = 50, aged 67.66 ± 8.76 years]) were included. There were significant differences in NLR, ICVP, NICVP, and kVP among the SRC, mSRC, and nSRC groups (all P < 0.001). The AUC of the combination model for SRC vs. mSRC + nSRC was 0.964 (95% CI: 0.923-1.000), with a sensitivity of 98.3% and a specificity of 86.7%, higher than with DSCT (AUC: 0.959, 95% CI: 0.919-0.998, sensitivity: 90.0%, specificity: 89.9%) or NLR (AUC: 0.670, 95% CI: 0.577-0.768, sensitivity: 62.2%, specificity: 61.8%). CONCLUSION: DSCT combined with NLR showed high diagnostic efficacy in differentiating SRC from mSRC and nSRC.

KCNH6 is essential for insulin secretion by regulating intracellular ER Ca2+ store.

Appropriate Ca2+ concentration in the endoplasmic reticulum (ER), modulating cytosolic Ca2+ signal, serves significant roles in physiological function of pancreatic ß cells. To maintaining ER homeostasis, Ca2+ movement across the ER membrane is always accompanied by a simultaneous K+ flux in the opposite direction. KCNH6 was proven to modulate insulin secretion by controlling plasma membrane action potential duration and intracellular Ca2+ influx. Meanwhile, the specific function of KCNH6 in pancreatic ß-cells remains unclear. In this study, we found that KCNH6 exhibited mainly ER localization and Kcnh6 ß-cell-specific knockout (ßKO) mice suffered from abnormal glucose tolerance and impaired insulin secretion in adulthood. ER Ca2+ store was overloaded in islets of ßKO mice, which contributed to ER stress and ER stress-induced apoptosis in ß cells. Next, we verified that ethanol treatment induced increases in ER Ca2+ store and apoptosis in pancreatic ß cells, whereas adenovirus-mediated KCNH6 overexpression in islets attenuated ethanol-induced ER stress and apoptosis. In addition, tail-vein injections of KCNH6 lentivirus rescued KCNH6 expression in ßKO mice, restored ER Ca2+ overload and attenuated ER stress in ß cells, which further confirms that KCNH6 protects islets from ER stress and apoptosis. These data suggest that KCNH6 on the ER membrane may help to stabilize intracellular ER Ca2+ stores and protect ß cells from ER stress and apoptosis. In conclusion, our study reveals the protective potential of KCNH6-targeting drugs in ER stress-induced diabetes.

LINC01234 promoted malignant behaviors of breast cancer cells via hsa-miR-30c-2-3p/CCT4/mTOR signaling pathway.

OBJECTIVE: Despite continuous progress in treatment, recurrence and metastasis limit further improvement in the prognosis of breast cancer (BC) patients. Our aim was to search for a crucial prognostic biomarker of BC. MATERIALS AND METHODS: Patient data were selected from The Cancer Genome Atlas (TCGA) and GTEx databases. Several online public databases, including Gene Expression Profiling Interactive Analysis (GEPIA), miRWalk, miRDB, and LncBase Predicted v.2, were used to identify potential upstream miRNAs and lncRNAs. These findings were validated through in vitro experiments. RESULTS: A total of 1, 097 invasive BC samples and 572 normal breast tissues (including 113 samples from TCGA and 459 samples from GTEx) were collected for the study. CCT4 was not only significantly overexpressed in BC compared with normal breast tissues but also had important prognostic significance (P < 0.001). By intersecting miRWalk and miRDB and conducting correlation analysis, hsa-miR-30c-2-3p was identified as the most probable upstream miRNA of CCT4. Following an extensive assessment that included survival analysis, correlation analysis, and common binding-site prediction, LINC01234 was chosen as the most likely upstream lncRNA. In vitro experiments showed that LINC01234-siRNA inhibited the proliferation, invasion, and migration abilities of BC cells. Western blot analysis further confirmed that LINC01234 promoted malignant behaviors of BC cells via the CCT4/mTOR signaling pathway. CONCLUSION: The LINC01234/hsa-miR-30c-2-3p/CCT4/mTOR axis was identified as a potential ceRNA regulatory mechanism in BC. These findings established the foundation for systematically unveiling the pathological mechanisms of BC and provided new insights for targeted therapy of BC patients.

All-potassium channel CRISPR screening reveals a lysine-specific pathway of insulin secretion.

OBJECTIVE: Genome-scale CRISPR-Cas9 knockout coupled with single-cell RNA sequencing (scRNA-seq) has been used to identify function-related genes. However, this method may knock out too many genes, leading to low efficiency in finding genes of interest. Insulin secretion is controlled by several electrophysiological events, including fluxes of KATP depolarization and K+ repolarization. It is well known that glucose stimulates insulin secretion from pancreatic ß-cells, mainly via the KATP depolarization channel, but whether other nutrients directly regulate the repolarization K+ channel to promote insulin secretion is unknown. METHODS: We used a system involving CRISPR-Cas9-mediated knockout of all 83 K+ channels and scRNA-seq in a pancreatic ß cell line to identify genes associated with insulin secretion. RESULTS: The expression levels of insulin genes were significantly increased after all-K+ channel knockout. Furthermore, Kcnb1 and Kcnh6 were the two most important repolarization K+ channels for the increase in high-glucose-dependent insulin secretion that occurred upon application of specific inhibitors of the channels. Kcnh6 currents, but not Kcnb1 currents, were reduced by one of the amino acids, lysine, in both transfected cells, primary cells and mice with ß-cell-specific deletion of Kcnh6. CONCLUSIONS: Our function-related CRISPR screen with scRNA-seq identifies Kcnh6 as a lysine-specific channel.

Development and evaluation of a risk assessment tool for the personalized screening of breast cancer in Chinese populations: A prospective cohort study.

INTRODUCTION: Breast cancer is a significant contributor to female mortality, exerting a public health burden worldwide, especially in China, where risk-prediction models with good discriminating accuracy for breast cancer are still scarce. METHODS: A multicenter screening cohort study was conducted as part of the Cancer Screening Program in Urban China. Dwellers aged 40-74 years were recruited between 2014 and 2019 and prospectively followed up until June 30, 2021. The entire data set was divided by year of enrollment to develop a prediction model and validate it internally. Multivariate Cox regression was used to ascertain predictors and develop a risk-prediction model. Model performance at 1, 3, and 5 years was evaluated using the area under the curve, nomogram, and calibration curves and subsequently validated internally. The prediction model incorporates selected factors that are assigned appropriate weights to establish a risk-scoring algorithm. Guided by the risk score, participants were categorized into low-, medium-, and high-risk groups for breast cancer. The cutoff values were chosen using X-tile plots. Sensitivity analysis was conducted by categorizing breast cancer risk into the low- and high-risk groups. A decision curve analysis was used to assess the clinical utility of the model. RESULTS: Of the 70,520 women enrolled, 447 were diagnosed with breast cancer (median follow-up, 6.43 [interquartile range, 3.99-7.12] years). The final prediction model included age and education level (high, hazard ratio [HR], 2.01 [95% CI, 1.31-3.09]), menopausal age (≥50 years, 1.34 [1.03-1.75]), previous benign breast disease (1.42 [1.09-1.83]), and reproductive surgery (1.28 [0.97-1.69]). The 1-year area under the curve was 0.607 in the development set and 0.643 in the validation set. Moderate predictive discrimination and satisfactory calibration were observed for the validation set. The risk predictions demonstrated statistically significant differences between the low-, medium-, and high-risk groups (p < .001). Compared with the low-risk group, women in the high- and medium-risk groups posed a 2.17-fold and 1.62-fold elevated risk of breast cancer, respectively. Similar results were obtained in the sensitivity analyses. A web-based calculator was developed to estimate risk stratification for women. CONCLUSIONS: This study developed and internally validated a risk-adapted and user-friendly risk-prediction model by incorporating easily accessible variables and female factors. The personalized model demonstrated reliable calibration and moderate discriminative ability. Risk-stratified screening strategies contribute to precisely distinguishing high-risk individuals from asymptomatic individuals and prioritizing breast cancer screening. PLAIN LANGUAGE SUMMARY: Breast cancer remains a burden in China. To enhance breast cancer screening, we need to incorporate population stratification in screening. Accurate risk-prediction models for breast cancer remain scarce in China. We established and validated a risk-adapted and user-friendly risk-prediction model by incorporating routinely available variables along with female factors. Using this risk-stratified model helps accurately identify high-risk individuals, which is of significant importance when considering integrating individual risk assessments into mass screening programs for breast cancer. Current clinical breast cancer screening lacks a constructive clinical pathway and guiding recommendations. Our findings can better guide clinicians and health care providers.

Development and validation of a prognostic nomogram for breast cancer patients who underwent chemoradiotherapy and surgery: a retrospective cohort study based on the SEER database and two Chinese cohorts.

There is no strong evidence indicating the optimal treatment for breast cancer (BC) and no specific prognostic model. The aim of this study was to establish nomograms to predict the overall survival (OS) of BC patients receiving chemoradiotherapy and surgery, thereby quantifying survival benefits and improving patient management. A total of 1877 patients with primary nonmetastatic BC who received chemoradiotherapy and surgery from 2010 to 2019 were identified from the Surveillance, Epidemiology and End Results (SEER) database as the training cohort, 804 as the internal validation cohort, and 796 patients from the First Affiliated Hospital of Zhengzhou University (n=324) and Jiaxing Maternal and Child Health Hospital (n=472) as the external validation cohort. Least absolute shrinkage and selection operator (LASSO), univariate, and multivariate Cox regression analyses were performed in the training cohort to determine independent prognostic factors for BC, and a nomogram was constructed to predict 3-year, 5-year, and 8-year OS. The final model incorporated 7 factors that significantly affect OS: race, location, positive regional nodes, T stage, N stage, subtype, and grade. The calibration curves showed good consistency between the predicted survival and actual outcomes. Time-dependent receiver operating characteristic (ROC) curves and the time-dependent area under the curve (AUC) confirmed that the accuracy and clinical usefulness of the constructed nomograms were favorable. Decision curve analysis (DCA) and net reclassification improvement (NRI) also demonstrated that this nomogram was more suitable for clinical use than the 7th American Joint Committee on Cancer (AJCC) tumor node metastasis (TNM) staging system and the previous prediction model. In the training cohort and the internal validation cohort, the concordance indices (C-index) of the nomogram for predicting OS (0.723 and 0.649, respectively) were greater than those of the 7th AJCC TNM staging system and the previous prediction model. In addition, based on Kaplan-Meier (K-M) survival curves, the survival differences among different risk stratifications were statistically significant, indicating that our risk model was accurate. In this study, we determined independent prognostic factors for OS in patients with primary nonmetastatic BC treated with chemoradiotherapy and surgery. A new and accurate nomogram for predicting 3-, 5-, and 8-year OS in this patient population was developed and validated for potential clinical applicability.

Effects of perioperative electroacupuncture on postoperative gastrointestinal recovery after thoracoscopic lung surgery.

OBJECTIVE: To study whether perioperative electroacupuncture (EA) can improve postoperative gastrointestinal recovery in patients receiving thoracoscopic lung surgery. METHODS: This study was a single-center, prospective, randomized open-label trial. 180 patients who underwent video-assisted thoracoscopic segmentectomy or lobectomy were randomized to EA group (three sessions, 24 h prior to surgery, postoperative 4 h and 24 h) or usual care group (UC group). The primary outcomes were time to first flatus and defecation. Secondary outcomes included incidence and degree of abdominal distention, postoperative nausea and vomiting (PONV) and pain scores within 72 h after surgery, postoperative morphine use, time to ambulation, and length of hospital stay. RESULTS: Time to first flatus (15.4 ± 3.2 h vs. 17.0 ± 3.7 h, P = 0.004) and time to first defecation (75.9 ± 7.9 vs. 79.7 ± 8.1 h, P = 0.002) in the EA group were significantly shorter than the UC group. The incidences of abdominal distension and PONV postoperative 24 h were significantly reduced in the EA group (P < 0.05). There was no difference in postoperative pain intensity, morphine use, time to ambulation, and length of hospital stay between the two groups (P>0.05). CONCLUSION: Electroacupuncture is a simple intervention for accelerating postoperative gastrointestinal recovery and may be considered as an adjunct strategy in enhanced recovery protocols in thoracoscopic lung surgery.

The value of total tumor diameter in unilateral multifocal papillary thyroid carcinoma: a propensity score matching analysis.

Background: Tumor multifocality is frequently observed in papillary thyroid carcinoma (PTC). However, the maximum tumor diameter (MTD), currently utilized in various staging schemes, might not accurately indicate the level of aggressiveness exhibited by multifocal tumors. We aimed to investigate the relationship between total tumor diameter (TTD) and clinicopathological features of papillary thyroid carcinoma. Methods: Retrospective data analysis was done on 1936 individuals who underwent complete thyroidectomy for PTC. Patients were classified into subgroups according to unilateral multifocality, central lymph node metastasis (CLNM) and lateral lymph node metastasis (LLNM). The relationships of clinicopathological features among these groups were analyzed. Results: Unilateral multifocality was observed in 117 patients. The clinicopathological features of the unilateral multifocal PTC were similar to the unifocal PTC with approximate TTD. The unilateral multifocality played no independent role in CLNM and LLNM. Moreover, the efficiency of TTD in predicting CLNM and LLNM was significantly higher than that of MTD. Conclusion: In the case of unilateral multifocal PTC, TTD is a more accurate indicator of the biological characteristics of the tumor than MTD.

RNA N6-methyladenosine of DHAPAT and PAP involves in regulation of diapause of Bombyx mori via the lipid metabolism pathway.

Environment-induced epigenetics are involved in diapause regulation, but the molecular mechanism that epigenetically couples nutrient metabolism to diapause regulation remains unclear. In this study, we paid special attention to the significant differences in the level of N6-adenosine methylation (m6A) of dihydroxyacetone phosphate acyltransferase (DHAPAT) and phosphatidate phosphatase (PAP) genes in the lipid metabolism pathway of the bivoltine silkworm (Bombyx mori) strain Qiufeng developed from eggs incubated at a normal temperature (QFHT, diapause egg producer) compared to those from eggs incubated at a low temperature (QFLT, non-diapause egg producer). We knocked down DHAPAT in the pupal stage of the QFLT group, resulting in the non-diapause destined eggs becoming diapausing eggs. In the PAP knockdown group, the colour of the non-diapause destined eggs changed from light yellow to pink 3 days after oviposition, but they hatched as normal. Moreover, we validated that YTHDF3 binds to m6A-modified DHAPAT and PAP mRNAs to promote their stability and translation. These results suggest that RNA m6A methylation participates in the diapause regulation of silkworm by changing the expression levels of DHAPAT and PAP and reveal that m6A epigenetic modification can be combined with a lipid metabolism signal pathway to participate in the regulation of insect diapause traits, which provides a clearer image for exploring the physiological basis of insect diapause.

Current application status and structure-activity relationship of selective and non-selective JAK inhibitors in diseases.

JAK kinase includes four family members: JAK1, JAK2, JAK3, and TYK2. It forms the JAK-STAT pathway with signal transmitters and activators of subscription (STAT). This pathway is one of the main mechanisms by which many cytokine receptors transduce intracellular signals, it is associated with the occurrence of various immune, inflammatory, and tumor diseases. JAK inhibitors block the signal transduction of the JAK-STAT pathway by targeting JAK kinase. Based on whether they target multiple subtypes of JAK kinase, JAK inhibitors are categorized into pan-JAK inhibitors and selective JAK inhibitors. Compared with pan JAK inhibitors, selective JAK inhibitors are associated with a specific member, thus more targeted in therapy, with improved efficacy and reduced side effects. Currently, a number of JAK inhibitors have been approval for disease treatment. This review summarized the current application status of JAK inhibitors that have been marketed, advances of JAK inhibitors currently in phase Ш clinical trials, and the structure-activity relationship of them, with an intention to provide references for the development of novel JAK inhibitors.

An ileal gastrointestinal stromal tumor misdiagnosed as pelvic metastases from rectal cancer: a case report.

With the advancement of imaging and pathological diagnostic methods, it is not uncommon to see synchronous gastrointestinal stromal tumors (GIST) and other primary cancers, the most common of which are synchronous gastric cancer and gastric GIST. However, synchronous advanced rectal cancer and high-risk GIST in the terminal ileum are extremely rare, and they are easily misdiagnosed as rectal cancer with pelvic metastases due to their special location near iliac vessels. Herein, we report a 55-year-old Chinese woman with rectal cancer. Preoperative imaging revealed a middle and lower rectal lesion with a right pelvic mass (considered possible metastasis from rectal cancer). Through multidisciplinary discussions, we suspected the possibility of rectal cancer synchronous with a GIST in the terminal ileum. Intraoperative exploration by laparoscopy revealed a terminal ileal mass with pelvic adhesion, a rectal mass with plasma membrane depression, and no abdominal or liver metastases. Laparoscopic radical proctectomy (DIXON) plus partial small bowel resection plus prophylactic loop ileostomy was performed, and the pathological report confirmed the coexistence of advanced rectal cancer and a high-risk ileal GIST. The patient was treated with the chemotherapy (CAPEOX regimen) plus targeted therapy(imatinib) after surgery, and no abnormalities were observed on the follow-up examination. Synchronous rectal cancer and ileal GIST are rare and easily misdiagnosed as a rectal cancer with pelvic metastases, and careful preoperative imaging analysis and prompt laparoscopic exploration are required to determine the diagnosis and prolong patient survival.

Exorista sorbillans (Diptera: Tachinidae) parasitism shortens host larvae growth duration by regulating ecdysone and juvenile hormone titers in Bombyx mori (Lepidoptera: Bombycidae).

The tachinid fly, Exorista sorbillans, is a notorious ovolarviparous endoparasitoid of the silkworm, Bombyx mori, causing severe damage to silkworm cocoon industry. Silkworm larvae show typically precocious wandering behavior after being parasitized by E. sorbillans; however, the underlying molecular mechanism remains unexplored. Herein, we investigated the changes in the levels of 20-hydroxyecdysone (20E) and juvenile hormone (JH) titer, and they both increased in the hemolymph of parasitized silkworms. Furthermore, we verified the expression patterns of related genes, which showed an upregulation of 20E signaling and biosynthesis genes but a significant downregulation of ecdysone oxidase (EO), a 20E inactivation enzyme, in parasitized silkworms. In addition, related genes of the JH signaling were activated in parasitized silkworms, while related genes of the JH degradation pathway were suppressed, resulting in an increase in JH titer. Notably, the precocious wandering behavior of parasitized silkworms was partly recoverable by silencing the transcriptions of BmCYP302A1 or BmCYP307A1 genes. Our findings suggest that the developmental duration of silkworm post parasitism could be shortened by regulation of 20E and JH titers, which may help silkworm to resist the E. sorbillans infestation. These findings provide a basis for deeper insight into the interplay between silkworms and E. sorbillans and may serve as a reference for the development of a novel approach to control silkworm myiasis.

m6A-dependent mevalonate kinase in juvenile hormone synthesis pathway regulates the diapause process of bivoltine silkworm (Bombyx mori).

BACKGROUND: Research has shown that epigenetic modification are involved the regulation of diapause in bivoltine silkworms (Bombyx mori), but it remains unclear how epigenetic modification in response to environmental signals precisely to regulate the diapause processing of bivoltine B. mori. METHODS AND RESULTS: In this study, the diapause terminated eggs of bivoltine B. mori, Qiufeng (QF) were divided into two groups: a QFHT group incubated at 25 °C with a natural day/night cycle to produce diapause eggs, and a QFLT group incubated at 16.5 °C in darkness to produce non-diapause eggs. On the 3rd day of the pupal stage, the total RNAs of the eggs were extracted and their N6-adenosine methylation (m6A) abundances were analyzed to explore the effects of m6A methylation on diapause in the silkworm. The results showed that 1984 m6A peaks are shared, 1563 in QFLT and 659 in QFHT. The m6A methylation level of the QFLT group was higher than that of the QFHT one in various signaling pathways. The m6A methylation rate of mevalonate kinase (MK) in the insect hormone synthesis pathway was significantly different between the two groups. The knockdown of MK by RNA interference in the pupae of QFLT resulted in females laying diapause eggs rather than non-diapause eggs after mating. CONCLUSIONS: m6A methylation involves in the diapause regulation of bivoltine B. mori by changing the expression levels of MK. This result provides a clearer image of the environmental signals on the regulation of diapause in bivoltine silkworms.

Current Status in Rechallenge of Immunotherapy.

The treatment of malignant tumors has entered the era of immunotherapy, and immune checkpoint inhibitors (ICIs) have brought significant benefits to patients. However, some patients are required to discontinue treatment with ICIs owing to factors such as disease progression and intolerable side effects. Faced with limited subsequent treatment options and complex medical needs, we searched PubMed, Embase, Cochrane library, and the NIH clinical trials database and found that ICI rechallenge could be a relevant clinical strategy. The factors that could affect the rechallenge efficacy include the patients' characteristics, therapeutic strategy selection, and the timing of treatment. Multiple factors are used to identify target population, of which clinical features and PD-L1 expression are more potential. Both single ICI rechallenge and combination therapy may have survival benefits. Patients who have tolerated initial immunotherapy well could undergo ICI rechallenge, while patients who have experienced grade 3 or higher immune-related adverse events should be carefully assessed prior to rechallenge. Interventions and the interval between two courses of ICI will clearly have an impact on the efficacy of subsequent treatment. Preliminary data evaluation supports further investigation on ICI rechallenge to identify the factors that could contribute to its efficacy.

Thrombus formation in the suprahepatic inferior vena cava after microwave ablation in patients with hepatic metastasis: a case report.

BACKGROUND: Microwave ablation (MWA) via ultrasound guidance is an important tool in the treatment of liver metastases. The most common postoperative complications are abdominal hemorrhage and bile leakage, whereas thrombosis in the suprahepatic inferior vena cava (IVC) is very rare, and clinical management is very difficult when the head end of the thrombus reaches the right atrium. CASE PRESENTATION: This is a case report of a 52-year-old man with hepatic metastasis 21 months after radical resection of rectal cancer. After chemotherapy combined with targeted therapy, metastasis in segment IV (S4) of the liver was treated with microwave ablation. Two months after treatment, the hepatic metastasis in S4 showed a microwave ablation zone on MRI.Enhanced MRI showed venous thrombosis located in the left hepatic vein and IVC, and the head of the thrombus reached the right atrium. After two weeks of anticoagulation and thrombolytic treatment, the follow-up MRI showed that the venous thrombus had nearly disappeared. CONCLUSION: When liver metastases are close to the hepatic vein, clinicians should pay attention to the occurrence of hepatic vein and IVC thrombosis following MWA; through early diagnosis and anticoagulation, pulmonary thromboembolism (PTE) can be minimized.

GCN5 regulates ZBTB16 through acetylation, mediates osteogenic differentiation, and affects orthodontic tooth movement.

In the process of orthodontic tooth movement (OTM), periodontal ligament fibroblasts (PDLFs) must undergo osteogenic differentiation. OTM increased the expression of Zinc finger and BTB domain-containing 16 (ZBTB16), which is implicated in osteogenic differentiation. Our goal was to investigate the mechanism of PDLF osteogenic differentiation mediated by ZBTB16. The OTM rat model was established, and PDLFs were isolated and exposed to mechanical force. Hematoxylin-eosin staining, Alizarin Red staining, immunofluorescence, and immunohistochemistry were carried out. The alkaline phosphatase (ALP) activity was measured. Dual-luciferase reporter gene assay and chromatin immunoprecipitation assay were conducted. In OTM models, ZBTB16 was significantly expressed. Additionally, there was an uneven distribution of PDLFs in the OTM group, as well as an increase in fibroblasts and inflammatory infiltration. ZBTB16 interference hindered PDLF osteogenic differentiation and decreased Wnt and ß-catenin levels. Meanwhile, ZBTB16 activated the Wnt/ß-catenin pathway. ZBTB16 also enhanced the expression of the osteogenic molecules osterix, osteocalcin (OCN), osteopontin (OPN), and bone sialo protein (BSP) at mRNA and protein levels. The interactions between Wnt1 and ZBTB16, as well as GCN5 and ZBTB16, were also verified. The adeno-associated virus-shZBTB16 injection also proved to inhibit osteogenic differentiation and reduce tooth movement distance in in vivo tests. ZBTB16 was up-regulated in OTM. Through acetylation modification of ZBTB16, GCN5 regulated the Wnt/ß-catenin signaling pathway and further mediated PDLF osteogenic differentiation.

Oseltamivir phosphate for suspension is bioequivalent to TAMIFLU in healthy volunteers: a randomized, open-label clinical study.

PURPOSE: The study was aimed at evaluating the bioequivalence and safety of oseltamivir phosphate for suspension, provided by Shenzhen Beimei Pharmaceutical Co. Ltd. and manufactured by Hetero Labs Limited, and the reference product TAMIFLU® in healthy Chinese subjects. METHODS: A single-dose, randomized, two-phase, self-crossed model was adopted. Among 80 healthy subjects, 40 subjects in the fasting group and 40 subjects in the fed group. Subjects in the fasting group were randomized into two sequences according to the proportion of 1:1, each given 75 mg/12.5 mL of Oseltamivir Phosphate for Suspension or TAMIFLU®, and cross-administered after 7 days. Postprandial group is the same as fasting group. RESULTS: The Tmax of TAMIFLU® and Oseltamivir Phosphate for Suspension in the fasting group were 1.50 h and 1.25 h, which in the fed group were both 1.25 h. Geometrically adjusted mean ratios of the PK parameters of Oseltamivir Phosphate for Suspension along with TAMIFLU® under fasting and postprandial conditions were in the range of 80.00-125.00% at the 90% confidence interval (CI). The 90% CI of Cmax, AUC0-t, AUC0-∞ for fasting group and postprandial group were (92.39,106.50), (94.26,100.67), (94.32,100.89) and (93.61,105.83),(95.64,100.19),(96.06,102.66). Among the subjects on medication, a total of 18 subjects reported 27 adverse events, all of which were treatment-emergent adverse events (TEAEs), six of these TEAEs were rated as grade 2 in severity and the rest were as grade 1. The number of TEAEs in the test product and the reference product were 14,13 respectively. CONCLUSION: Two Oseltamivir phosphate for suspensions are safe and bioequivalent.