Histone deacetylase inhibitor and PD­1 blockade synergistically inhibit B­cell lymphoma progression in mice model by promoting T­cell infiltration and apoptosis.

B­cell lymphoma is difficult to cure because of its biological and clinical heterogeneity, and due to native chemoresistance. Immunotherapies that overcome cancer­induced immune evasion have been the center of recent developments in oncology. This is emphasized by the accomplishment of various agents that disrupt programmed cell death protein 1 (PD­1)­mediated immune suppression in diverse tumors. However, while PD­1 blockade has been effective in numerous malignancies, a significant proportion of cancers, including B­cell lymphoma, show certain rates of primary resistance to these therapeutic strategies. Histone deacetylase inhibitors (HDACis) have exhibited anticancer activity though suppressing cell proliferation, inducing differentiation and triggering apoptosis. The present study aimed to explore a therapeutic strategy combining a HDACi (romidepsin) and PD­1 blockade (BMS­1) in B­cell lymphoma, utilizing a constructed mouse model of B­cell lymphoma. The IC50 of the two inhibitors was confirmed by MTT assay, and their inhibitory effects were revealed to be dose­ and time­dependent. The data demonstrated that the combined treatment of romidepsin and BMS­1 synergistically inhibited the growth of B­cell lymphoma. Furthermore, it was revealed that romidepsin and BMS­1 synergistically triggered apoptosis in mouse B­cell lymphoma. The synergistic effect of these agents was capable of activating tumor­infiltrating lymphocytes, particularly CD3+CD4+ and CD3+CD8+ T cells. The results of the present study underscore the potential of HDAC inhibition in conjunction with PD­1 blockade as a novel therapeutic approach for B­cell lymphoma, highlighting the synergistic effects of these two mechanisms in enhancing antitumor immunity.

Vedolizumab plus basiliximab as second-line therapy for steroid-refractory lower gastrointestinal acute graft-versus-host disease.

Background: Steroid-resistant (SR) lower gastrointestinal (LGI) tract graft-versus-host disease (GVHD) is the predominant cause of morbidity and mortality from GVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The role of vedolizumab in the treatment of SR-LGI acute GVHD (aGVHD) remains uncertain. We aimed to assess the efficacy and safety of vedolizumab combined with basiliximab as second-line therapy for SR-LGI-aGVHD. Methods: This study aimed to explore the efficacy of vedolizumab combined with basiliximab for SR-LGI-aGVHD. The primary endpoint was the overall response (OR) on day 28. Secondary and safety endpoints included durable OR at day 56, overall survival (OS), chronic GVHD (cGVHD), non-relapse mortality (NRM), failure-free survival (FFS), and adverse events. Results: Twenty-eight patients with SR-LGI-aGVHD were included. The median time to start of combination therapy after SR-LGI-aGVHD diagnosis was 7 (range, 4-16) days. The overall response rate (ORR) at 28 days was 75.0% (95% CI: 54.8%-88.6%), and 18 achieved a complete response (CR) (64.3%, 95% CI: 44.1%-80.7%). The durable OR at day 56 was 64.3% (95% CI: 44.1%-80.7%). The 100-day, 6-month, and 12-month OS rates for the entire cohort of patients were 60.7% (95% CI: 45.1%-81.8%), 60.7% (95% CI: 45.1%-81.8%), and 47.6% (95% CI: 31.4%-72.1%), respectively. The median failure-free survival was 276 days; (95% CI: 50-not evaluable) 12-month NRM was 42.9% (95% CI: 24.1%-60.3%). The 1-year cumulative incidence of cGVHD was 35.7%. Within 180 days after study treatments, the most common grade 3 and 4 adverse events were infections. Nine (32.1%) patients developed cytomegalovirus (CMV) reactivation complicated with bacterial infections (25.0%, CMV infection; 7.1%, CMV viremia). Epstein-Barr virus (EBV) reactivation occurred in five patients (17.9%, 95% CI: 6.8%-37.6%). Only three patients (10.7%, 95% CI: 2.8%-29.4%) in our study developed pseudomembranous colitis. Conclusions: Vedolizumab plus basiliximab demonstrated efficacy in severe SR-LGI-aGVHD and was well-tolerated. Vedolizumab plus basiliximab may be considered a potential treatment option for patients with LGI-aGVHD.

Graphene/ chitosan tubes inoculated with dental pulp stem cells promotes repair of facial nerve injury.

Introduction: Facial nerve injury significantly impacts both the physical and psychological] wellbeing of patients. Despite advancements, there are still limitations associated with autografts transplantation. Consequently, there is an urgent need for effective artificial grafts to address these limitations and repair injuries. Recent years have witnessed the recognition of the beneficial effects of chitosan (CS) and graphene in the realm of nerve repair. Dental pulp stem cells (DPSCs) hold great promise due to their high proliferative and multi-directional differentiation capabilities. Methods: In this study, Graphene/CS (G/CST) composite tubes were synthesized and their physical, chemical and biological properties were evaluated, then DPSCs were employed as seed cells and G/CST as a scaffold to investigate their combined effect on promoting facial nerve injury repair. Results and Disscussion: The experimental results indicate that G/CST possesses favorable physical and chemical properties, along with good cyto-compatibility. making it suitable for repairing facial nerve transection injuries. Furthermore, the synergistic application of G/CST and DPSCs significantly enhanced the repair process for a 10 mm facial nerve defect in rabbits, highlighting the efficacy of graphene as a reinforcement material and DPSCs as a functional material in facial nerve injury repair. This approach offers an effective treatment strategy and introduces a novel concept for clinically managing facial nerve injuries.

Evaluating the link between immune characteristics and attention deficit hyperactivity disorder through a bi-directional Mendelian randomization study.

Context: Despite the recognition of attention deficit hyperactivity disorder (ADHD) as a multifaceted neurodevelopmental disorder, its core causes are still ambiguous. The objective of this study was to explore if the traits of circulating immune cells contribute causally to susceptibility to ADHD. Methods: By employing a unified GWAS summary data covering 731 immune traits from the GWAS Catalog (accession numbers from GCST0001391 to GCST0002121), our analysis focused on the flow cytometry of lymphocyte clusters, encompassing 3,757 Sardinians, to identify genetically expected immune cells. Furthermore, we obtained summarized GWAS statistics from the Psychiatric Genomics Consortium to evaluate the genetic forecasting of ADHD. The studies employed ADHD2019 (20,183 cases and 35,191 controls from the 2019 GWAS ADHD dataset) and ADHD2022 (38,691 cases and 275,986 controls from the 2022 GWAS ADHD dataset). Through the examination of genome-wide association signals, we identified shared genetic variances between circulating immune cells and ADHD, employing the comprehensive ADHD2022 dataset. We primarily utilized inverse variance weighted (IVW) and weighted median methods in our Mendelian randomization research and sensitivity assessments to evaluate diversity and pleiotropy. Results: After adjusting for false discovery rate (FDR), three distinct immunophenotypes were identified as associated with the risk of ADHD: CD33 in Im MDSC (OR=1.03, CI: 1.01~1.04, P=3.04×10-5, PFDR =0.015), CD8br NKT %T cell (OR=1.08, 95%CI: 1.04~1.12, P=9.33×10-5, PFDR =0.023), and CD8br NKT %lymphocyte (OR=1.08, 95%CI: 1.03~1.12, P=3.59×10-4, PFDR =0.066). Furthermore, ADHD showed no statistical effects on immunophenotypes. It's worth noting that 20 phenotypes exist where ADHD's appearance could diminish 85% of immune cells, including FSC-A in myeloid DC (ß= -0.278, 95% CI: 0.616~0.931, P=0.008), CD3 in CD45RA- CD4+ (ß= -0.233, 95% CI: 0.654~0.960, P=0.017), CD62L- monocyte AC (ß=0.227, 95% CI: 0.038~1.518, P=0.019), CD33 in CD33br HLA DR+ CD14dim (ß= -0.331, 95% CI: 0.543~0.950, P=0.020), and CD25 in CD39+ resting Treg (ß=0.226, 95% CI: 1.522, P=0.022), and FSC-A in monocytes (ß= -0.255, 95% CI: 0.621~0.967, P=0.234), among others. Conclusion: Studies indicate that the immune system's response influences the emergence of ADHD. The findings greatly improve our understanding of the interplay between immune responses and ADHD risk, aiding in the development of treatment strategies from an immunological perspective.

Novel 3D-based deep learning for classification of acute exacerbation of idiopathic pulmonary fibrosis using high-resolution CT.

PURPOSE: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is the primary cause of death in patients with IPF, characterised by diffuse, bilateral ground-glass opacification on high-resolution CT (HRCT). This study proposes a three-dimensional (3D)-based deep learning algorithm for classifying AE-IPF using HRCT images. MATERIALS AND METHODS: A novel 3D-based deep learning algorithm, SlowFast, was developed by applying a database of 306 HRCT scans obtained from two centres. The scans were divided into four separate subsets (training set, n=105; internal validation set, n=26; temporal test set 1, n=79; and geographical test set 2, n=96). The final training data set consisted of 1050 samples with 33 600 images for algorithm training. Algorithm performance was evaluated using accuracy, sensitivity, specificity, positive predictive value, negative predictive value, receiver operating characteristic (ROC) curve and weighted κ coefficient. RESULTS: The accuracy of the algorithm in classifying AE-IPF on the test sets 1 and 2 was 93.9% and 86.5%, respectively. Interobserver agreements between the algorithm and the majority opinion of the radiologists were good (κw=0.90 for test set 1 and κw=0.73 for test set 2, respectively). The ROC accuracy of the algorithm for classifying AE-IPF on the test sets 1 and 2 was 0.96 and 0.92, respectively. The algorithm performance was superior to visual analysis in accurately diagnosing radiological findings. Furthermore, the algorithm's categorisation was a significant predictor of IPF progression. CONCLUSIONS: The deep learning algorithm provides high auxiliary diagnostic efficiency in patients with AE-IPF and may serve as a useful clinical aid for diagnosis.

The gene expression of CALD1, CDH2, and POSTN in fibroblast are related to idiopathic pulmonary fibrosis.

Introduction: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive lung dysfunction due to excessive collagen production and tissue scarring. Despite recent advancements, the molecular mechanisms remain unclear. Methods: RNA sequencing identified 475 differentially expressed genes (DEGs) in the TGF-ß1-induced primary lung fibrosis model. Gene expression chips GSE101286 and GSE110147 from NCBI gene expression omnibus (GEO) database were analyzed using GEO2R, revealing 94 DEGs in IPF lung tissue samples. The gene ontology (GO) and pathway enrichment, Protein-protein interaction (PPI) network construction, and Maximal Clique Centrality (MCC) scoring were performed. Experimental validation included RT-qPCR, Immunohistochemistry (IHC), and Western Blot, with siRNA used for gene knockdown. A co-expression network was constructed by GeneMANIA. Results: GO enrichment highlighted significant enrichment of DEGs in TGF-ß cellular response, connective tissue development, extracellular matrix components, and signaling pathways such as the AGE-RAGE signaling pathway and ECM-receptor interaction. PPI network analysis identified hub genes, including FN1, COL1A1, POSTN, KIF11, and ECT2. CALD1 (Caldesmon 1), CDH2 (Cadherin 2), and POSTN (Periostin) were identified as dysregulated hub genes in both the RNA sequencing and GEO datasets. Validation experiments confirmed the upregulation of CALD1, CDH2, and POSTN in TGF-ß1-treated fibroblasts and IPF lung tissue samples. IHC experiments probed tissue-level expression patterns of these three molecules. Knockdown of CALD1, CDH2, and POSTN attenuated the expression of fibrotic markers (collagen I and α-SMA) in response to TGF-ß1 stimulation in primary fibroblasts. Co-expression analysis revealed interactions between hub genes and predicted genes involved in actin cytoskeleton regulation and cell-cell junction organization. Conclusions: CALD1, CDH2, and POSTN, identified as potential contributors to pulmonary fibrosis, present promising therapeutic targets for IPF patients.

Aldo-keto reductase 1B10 as a Carcinogenic but Not a Prognostic Factor in Colorectal Cancer.

Colorectal cancer (CRC) is the leading cause of cancer death, but little is known about its etiopathology. Aldo-keto reductase 1B10 (AKR1B10) protein is primarily expressed in intestinal epithelial cells, but lost in colorectal cancer tissues. This study revealed that AKR1B10 may not be a prognostic but an etiological factor in colorectal tumorigenesis. Using a tissue microarray, we investigated the expression of AKR1B10 in tumor tissues of 592 colorectal cancer patients with a mean follow-up of 25 years. Results exhibited that AKR1B10 protein was undetectable in 374 (63.13%), weakly positive in 146 (24.66%), and positive 72 (12.16%) of 592 tumor tissues. Kaplan-Meier analysis showed that AKR1B10 expression was not correlated with overall survival or disease-free survival. Similar results were obtained in various survival analyses stratified by clinicopathological parameters. AKR1B10 was not correlated with tumor T-pathology, N-pathology, TNM stages, cell differentiation and lymph node/regional/distant metastasis either. However, AKR1B10 silencing in culture cells enhanced carbonyl induced protein and DNA damage; and in ulcerative colitis tissues, AKR1B10 deficiency was associated acrolein-protein lesions. Together this study suggests that AKR1B10 downregulation may not be a prognostic but a carcinogenic factor of colorectal cancer.

CsSPL13A directly binds and positively regulates CsFT and CsBAM to accelerate flowering in cucumber.

Flowering is an important developmental transition that greatly affects the yield of many vegetable crops. In cucumber (Cucumis sativus), flowering is regulated by various factors including squamosa promoter-binding-like (SPL) family proteins. However, the role of CsSPL genes in cucumber flowering remains largely unknown. In this study, we cloned the squamosa promoter-binding-like protein 13A (CsSPL13A) gene, which encodes a highly conserved SBP-domain protein that acts as a transcription factor and localizes to the nucleus. Quantitative real-time PCR (qRT-PCR) analysis showed that CsSPL13A was mainly expressed in flowers, and its expression level increased significantly nearing the flowering stage. Additionally, compared with the wild type(WT), CsSPL13A-overexpressing transgenic cucumber plants (CsSPL13A-OE) showed considerable differences in flowering phenotypes, such as early flowering, increased number of male flowers, and longer flower stalks. CsSPL13A upregulated the expression of the flowering integrator gene Flowering Locus T (CsFT) and the sugar-mediated flowering gene ß-amylase (CsBAM) in cucumber. Yeast one-hybrid and firefly enzyme reporter assays confirmed that the CsSPL13A protein could directly bind to the promoters of CsFT and CsBAM, suggesting that CsSPL13A works together with CsFT and CsBAM to mediate flowering in cucumber. Overall, our results provide novel insights into the regulatory network of flowering in cucumber as well as new ideas for the genetic improvement of cucumber varieties.

Clinical Significance of FOXP3 Expression in BRCA1/2-Mutant Breast Cancer / 肿瘤防治研究

Objective To investigate the potential significance of FOXP3 expression in BRCA1/2-mutant breast cancer. Methods A total of 48 BRCA mutation carriers (16 with BRCA1 and 32 with BRCA2) and 78 age-matched non-carriers were included in this study. Immunohistochemistry was used to detect the expression of FOXP3 in breast cancer tissues. The FOXP3 RNA expression in 39 BRCA1, 36 BRCA2, and 948 non-carrier breast cancer patients from TCGA-BRCA and the correlation with homologous recombination deficiency scores were evaluated to validate the immunohistochemistry results. Results The FOXP3 positive rate was 43.8% (7/16) in BRCA1 mutation carriers, 59.4% (19/32) in BRCA2 mutation carriers, and 9.0% (7/78) in non-carriers. The FOXP3 positive rates in patients with BRCA1/2 mutant breast cancer were significantly higher than those in non-carriers (P=0.002; P<0.001). TCGA-BRCA results showed that the FOXP3 RNA level in BRCA1/2 mutant breast cancer was significantly higher than that in non-carriers (P=0.02, P=0.004). The FOXP3 RNA level was positively correlated with the homologous recombination deficiency score (Spearman R=0.30, P<2.2e-16). Conclusion Patients with BRCA1/2 mutant breast cancers have higher FOXP3 expression than non-carriers, and may be more sensitive to immunotherapy.

Application of Circulating Tumor DNA in Precision Diagnosis and Treatment of Colorectal Cancer / 肿瘤防治研究

Colorectal cancer (CRC) is one of the most common malignant tumors recorded worldwide. This condition has high morbidity and mortality and seriously endangers people's health. Traditional diagnostic models fail to meet people's current needs for real-time monitoring of tumors. Compared with traditional detection methods, ctDNA detection is not only noninvasive but can also attain real-time detection of comprehensive genomic information of tumors. The advancement of detection technology has gradually highlighted the potential of ctDNA detection in the clinical treatment of CRC. This article reviews the advancements on the clinical application of ctDNA in early screening, minimal residual disease detection, and guidance on individualized treatment of CRC patients.

Case Reports of Adverse Drug Reactions Induced by Tislelizumab in A Hospital and the Literature Review / 医药导报

Objective To investigate the characteristics of adverse drug reactions(ADRs)induced by tislelizumab and to provide reference for clinic drug safety.Methods The ADR of tislelizumab in Beijing Friendship Hospital Affiliated to Capital Medical Univeristy from July 2021 to December 2022 were retrospectively analyzed.The case reports of ADR induced by tislelizumab from January 2019 to December 2022 in PubMed,ScienceDirect,Embase,Wanfang,VIP databases were searched.Age,sex,original diseases,adverse reaction time,clinical manifestation,treatment measures and clinical outcome were analyzed.Results A total of 30 patients including 8 cases in hospital and 22 cases in literature were collected.Among these patients,male accounted for 83.33%(25/30),and the highest proportion was from patients over 60 years old(21 patients,70.00%).Most ADRs occurred in 1-2 dose cycles of medication,mainly including skin toxicity in 8 patients,digestive disease in 6 patients and kidney injury in 4 patients.After the symptomatic treatment,29 patients improved and 1 patient died.Conclusion During the medication with tislelizumab,ADRs of skin,gastrointestinal tract and renal should be vigilant,and the changes of relevant indicators should be closely monitored.

Current situation and future countermeasures of mobile internet remote teaching of pediatric imaging / 中华医学教育探索杂志

Due to the limitations professional status and training channels, the training of pediatric imaging talents in China is seriously insufficient. Pediatric imaging doctors are concentrated in children's hospitals. Pediatric imaging knowledge and talents in primary medical institutions are scarce, which is not conducive to the construction of hierarchical diagnosis and treatment system. Large-scale telemedicine and online medical treatment based on mobile Internet have become the mainstream platforms for medical consultation and teaching, providing a good opportunity for remote teaching of pediatric imaging, and are expected to become a powerful tool for training pediatric imaging talents. The analysis of literature, mobile phone application market software and cost-effectiveness shows that the current large-scale telemedicine construction cycle is long, the construction and maintenance costs are high, and it is vulnerable to geographical and environmental constraints. It is still a long way to go for remote teaching in hospitals below the county level. The use of mobile terminals and mobile Internet is very convenient. It is an excellent choice to realize the remote teaching of pediatric imaging. It is expected to solve the problem of pediatric imaging talent training and skill dissemination.

Quality-of-life and associated factors after pediatric liver transplantation: based upon CHU9D scale / 中华器官移植杂志

Objective:To explore health utility value, evaluate health-related quality-of-life(QOL)of pediatric liver transplantation(LT)recipients and examine its influencing factors to provide rationales for related health economic evaluations.Methods:This cross-sectional QOL was conducted through a questionnaire in pediatric LT recipients aged 5-17 years.The interviewees undergoing initial LT from June 2013 to September 2021 were reviewed regularly.Those children and their parents unwilling to participate or failing to understand the contents of questionnaire were excluded.The questionnaire was designed on the basis of Child Health Utility 9D Instrument(CHU9D)and answered online by one of primary caregiver.Chinese score system of CHU9D was employed for converting the responses into health utility values and the influencing factors were analyzed.Univariate analysis was performed by nonparametric tests and multivariate analysis by multiple linear regression model. P<0.05 was deemed as statistically significant. Results:A total of 140 valid questionnaires were obtained.Mean age of pediatric LT recipients was(7.95±2.74)years and mean postoperative time(4.90±2.17)years.Among them, 19 cases had experienced acute rejection and 101(72.1%)cases were living-related LT recipients.CHU9D scale indicated that average health utility value was(0.85±0.14)points.Univariate analysis revealed that age( P=0.008), education level( P<0.001)and primary disease( P=0.010)influenced the postoperative level of QOL.Multivariate analysis indicated that QOL was correlated with education level(behind schedule: 95% CI: -0.146, -0.034, P=0.002; leave of absence: 95% CI: -0.251, -0.068, P=0.001). Conclusions:Health utility of pediatric LT recipients is high with an excellent QOL.Poor QOL is associated with absence from school or dropping out of school.

Association between plasma uric acid and hypertension and the gender difference in community-dwelling middle-aged and elderly population / 中华全科医师杂志

Objective:To investigate the association between plasma uric acid and hypertension and the gender difference in community-dwelling middle-aged and elderly population.Methods:A community-based cross-sectional study was conducted in Beijing Tongzhou Yongshun Community Health Service Center from June to December 2021, among residents aged 45 years or older selected by cluster sampling method. According to plasma uric acid (UA) level in quartiles, the subjects were divided into 4 groups; and stratified by gender, the subjects were further divided into subgroups. Multivariate logistic regression model was used to analyze the related factors of hypertension, and restricted cubic spline fitting logistic regression model was used to analyze the nonlinear association between uric acid and hypertension and the cut-off values of uric acid.Results:A total of 6 229 residents with the age of (63.2±7.3) years were enrolled in the study. In 1 874 male participants (30.1%), 946 participants (50.5%) had hypertension, and the uric acid level was 359 (309, 418)μmol/L; in 4 355 female participants (69.9%), 2 003 participants (46.0%) had hypertension, and the uric acid level was 306 (261, 359)μmol/L. Multivariate logistic regression analysis showed that after adjusting for factors that were statistically significant in univariate analyses or potentially clinically relevant (including age, body mass index, diabetes mellitus, coronary heart disease, cerebrovascular disease, albumin, estimated glomerular filtration rate, and cholesterol), uric acid was independently associated with hypertension ( P<0.001), for total participants the risk of hypertension in Q4 group was 1.33 times of that in Q1 group ( OR=1.33,95% CI 1.13-1.56, P=0.001); while for females the risk of hypertension in Q4 group was 1.38 times of that in Q1 group ( OR=1.38,95% CI 1.13-1.68, P=0.002), but no significant association was observed for males ( P>0.05). The results of restricted cubic spline fitting logistic regression analysis showed that there was a linear association between uric acid level and hypertension in the total population and males, and the risk of hypertension increased with uric acid level ( P<0.001 for the total population, P=0.016 for male). However, there was a non-linear association in females. When uric acid>307 μmol/L in females, the risk of hypertension increased significantly as the level of uric acid increased ( P<0.001). Conclusions:Uric acid level was independently associated with hypertension in the community-dwelling middle-aged and elderly population, and there was a gender difference in the correlation. The association was nonlinear in females and the cut-off value of uric acid in females was 307 μmol/L.

Mechanism of Compound Fuling Granule Regulating Glucose Metabolism Reprogramming and Inhibiting Ovarian Cancer Me-tastasis through DRP1 / 浙江中医药大学学报

[Objective]To investigate the mechanism of Compound Fuling Granule(CFG)in inhibiting the glucose metabolism and metastasis of ovarian cancer cells.[Methods]Ovarian cancer cell HEY-T30 were cultured in vitro and incubated with different concentration(0.25,0.5,1,1.5,2 mg·mL-1)of CFG for 24 h.Cell counting kit-8(CCK-8)assay was performed to detect the effect of CFG on the cell proliferation,Transwell assay was used to investigate cell migration ability,lactic acid detection kit and glucose detection kit were used to detect lactic acid production and glucose consumption,the expressions of dynamin-related protein 1(DRP1),some key glycolysis-related proteins and metastasis-related proteins were detected by Western blot,Mito-Tracker Red was used to label mitochondria to observe mitochondria morphology.Lentivirus transfection technique was used to achieve the stable DRP1 knockdown HEY-T30 cells.Real-time quantitative polymerase chain reaction(Real-time qPCR)was used to detect the expression of DRP1 mRNA,the effect of CFG on lactic acid production and glucose consumption of HEY-T30 after DRP1 knockdown was detected by lactic acid detection kit and glucose detection kit,Transwell assay was used to investigate the migration ability of HEY-T30 with DRP1 knockdown after treated with CFG,the effect of CFG on the expression of glycolysis-related proteins and metastasis-related proteins in HEY-T30 with DRP1 knockdown was detected by Western blot.[Results]Compared with control group,the cell survival rate in 0.5,1,1.5,2 mg·mL-1 CFG groups reduced significantly(P＜0.01).The average length of mitochondria in 0.5,1 mg·mL-1 group was markedly increased(P＜0.01),the protein expression of DRP1 was significantly reduced(P＜0.05,P＜0.01),and the lactate production and glucose consumption in 0.5 and 1 mg·mL-1 groups were significantly decrease(P＜0.01).The number of migration cell was significantly reduced in 0.25,0.5 and 1 mg·mL-1 concentration groups(P＜0.05,P＜0.01).After knockdown of DRP1,the glycolysis level and migration of HEY-T30 were decreased(P＜0.05,P＜0.01),and the expressions of glycolysis-related proteins and metastasis-related proteins were decreased(P＜0.05,P＜0.01).The inhibitory effect of CFG on glycolysis and metastasis of ovarian cancer cells was also weakened.[Conclusion]By targeting DRP1 to regulate glucose metabolism reprogramming,CFG could inhibit the metastasis of ovarian cancer.

Correlation analysis between prenatal exposure of per-/polyfluoroalkyl compounds and neonatal outcome / 中华预防医学杂志

Objective: To investigate the correlation between the prenatal exposure of per-/polyfluoroalkyl substances (PFASs) and the neonatal outcome. Methods: A total of 506 maternal infant cohort samples were collected in Hangzhou, Zhejiang province from 2020 to 2021. The exposure levels of seven PFASs in maternal serum before delivery were detected by solid-phase extraction-ultra performance liquid chromatography tandem mass spectrometry. Multivariable linear regression model was used to analyze the influence of prenatal exposure of PFASs on birth weight, birth length and Apgar score. Results: The maternal age, prenatal body mass index and gestation age were (31.3±4.3) years old, (26.7±3.2) kg/m2 and (265.0±28.3) days, respectively. The birth weight, birth length and scores of Apgar-1 and Apgar-5 were (3.1±0.8) kg, (49.3±2.9) cm, (9.88±0.47) points and (9.99±0.13) points, respectively. PFASs were widely distributed in maternal serum, with the highest concentration of (18.453±19.557) ng/ml, (6.756±9.379) ng/ml and (5.057±8.555) ng/ml for perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS) and 6∶2 chlorinated polyfluorinated ether sulfonate (Cl-PFESA), respectively. Maternal age, parity and delivery mode were associated with the exposure level of PFASs (P<0.05). Subgroup analysis showed that PFOS had negative effects on birth weight (β=-0.958), birth length (β=-0.073) and Apgar-5 score (β=-0.288) for neonates in the low birth weight (LBW) group. 6∶2 Cl-PFESA and 8∶2 Cl-PFESA inhibited the birth weight (β=-0.926; β=-0.552) and length (β=-0.074; β=-0.045) of newborn in the LBW group. In addition, 4∶2 fluorotelomer sulfonate (FTS) was associated with increased birth weight (β=0.111) and decreased Apgar-5 score (β=-0.030) in the normal weight group. Conclusion: Prenatal exposure to PFASs is associated with birth weight, birth length and Apgar-5 score. It is necessary to continue to pay attention to the impact of PFASs on fetal growth and development through maternal-fetal transmission.

Comparison of Clinicopathological Characteristics Between Primary and Contralateral Cancers in BRCA1/2 Carriers with Metachronous Bilateral Breast Cancers / 肿瘤防治研究

Objective To compare the clinicopathological characteristics between primary and contralateral cancers in patients with metachronous bilateral breast cancer (MBBC) who carried a BRCA1/2 germline pathogenic variant. Methods A total of 496 BRCA1/2 carriers with primary unilateral breast cancer were included (196 with BRCA1 and 300 with BRCA2). Clinicopathological information of patients was collected, and the median follow-up for the entire cohort was 10.4 years (0.4-20.8 years). Results Among all patients, 31 (15.8%) of the 196 BRCA1 carriers and 49 (16.3%) of the 300 BRCA2 carriers had MBBC, respectively. Among the 31 BRCA1 carriers who developed MBBC, the proportion of triple-negative breast cancer (TNBC) in primary cancer and contralateral cancer was 61.3% and 67.7%, respectively. If the primary cancer of BRCA1-mutated MBBC was TNBC, the probability of the contralateral breast cancer with TNBC was 89.5% (17/19), which was significantly higher than that if the primary cancer was non-TNBC (33.3%, 4/12) (P=0.004). Among the 49 BRCA2 carriers who developed MBBC, the predominant molecular phenotype of the primary and contralateral cancers was HR+ & HER2- (77.6% and 67.3%, respectively; P=0.53). Conclusion Approximately 60% of BRCA1 carriers exhibit TNBC. If a BRCA1 carrier with a TNBC primary breast cancer had an MBBC, the probability of the contralateral breast cancer being TNBC phenotype is almost 89.5%.

Short-course radiotherapy combined with CAPOX and PD-1 inhibitor for the total neoadjuvant therapy of locally advanced rectal cancer: the preliminary single-center findings of a prospective, multicentre, randomized phase II trial (TORCH) / 中华胃肠外科杂志

Objective: Total neoadjuvant therapy has been used to improve tumor responses and prevent distant metastases in patients with locally advanced rectal cancer (LARC). Patients with complete clinical responses (cCR) then have the option of choosing a watch and wait (W&W) strategy and organ preservation. It has recently been shown that hypofractionated radiotherapy has better synergistic effects with PD-1/PD-L1 inhibitors than does conventionally fractionated radiotherapy, increasing the sensitivity of microsatellite stable (MSS) colorectal cancer to immunotherapy. Thus, in this trial we aimed to determine whether total neoadjuvant therapy comprising short-course radiotherapy (SCRT) combined with a PD-1 inhibitor improves the degree of tumor regression in patients with LARC. Methods: TORCH is a prospective, multicenter, randomized, phase II trial (TORCH Registration No. NCT04518280). Patients with LARC (T3-4/N+M0, distance from anus ≤10 cm) are eligible and are randomly assigned to consolidation or induction arms. Those in the consolidation arm receive SCRT (25Gy/5 Fx), followed by six cycles of toripalimab plus capecitabine and oxaliplatin (ToriCAPOX). Those in the induction arm receive two cycles of ToriCAPOX, then undergo SCRT, followed by four cycles of ToriCAPOX. Patients in both groups undergo total mesorectal excision (TME) or can choose a W&W strategy if cCR has been achieved. The primary endpoint is the complete response rate (CR, pathological complete response [pCR] plus continuous cCR for more than 1 year). The secondary endpoints include rates of Grade 3-4 acute adverse effects (AEs) etc. Results: Up to 30 September 2022, 62 patients attending our center were enrolled (Consolidation arm: 34, Induction arm:28). Their median age was 53 (27-69) years. Fifty-nine of them had MSS/pMMR type cancer (95.2%), and only three MSI-H/dMMR. Additionally, 55 patients (88.7%) had Stage III disease. The following important characteristics were distributed as follows: lower location (≤5 cm from anus, 48/62, 77.4%), deeper invasion by primary lesion (cT4 7/62, 11.3%; mesorectal fascia involved 17/62, 27.4%), and high risk of distant metastasis (cN2 26/62, 41.9%; EMVI+ 11/62, 17.7%). All 62 patients completed the SCRT and at least five cycles of ToriCAPOX, 52/62 (83.9%) completing six cycles of ToriCAPOX. Finally, 29 patients achieved cCR (46.8%, 29/62), 18 of whom decided to adopt a W&W strategy. TME was performed on 32 patients. Pathological examination showed 18 had achieved pCR, four TRG 1, and 10 TRG 2-3. The three patients with MSI-H disease all achieved cCR. One of these patients was found to have pCR after surgery whereas the other two adopted a W&W strategy. Thus, the pCR and CR rates were 56.2% (18/32) and 58.1% (36/62), respectively. The TRG 0-1 rate was 68.8% (22/32). The most common non-hematologic AEs were poor appetite (49/60, 81.7%), numbness (49/60, 81.7%), nausea (47/60, 78.3%) and asthenia (43/60, 71.7%); two patients did not complete this survey. The most common hematologic AEs were thrombocytopenia (48/62, 77.4%), anemia (47/62, 75.8%), leukopenia/neutropenia (44/62, 71.0%) and high transaminase (39/62, 62.9%). The main Grade III-IV AE was thrombocytopenia (22/62, 35.5%), with three patients (3/62, 4.8%) having Grade IV thrombocytopenia. No Grade V AEs were noted. Conclusions: SCRT-based total neoadjuvant therapy combined with toripalimab can achieve a surprisingly good CR rate in patients with LARC and thus has the potential to offer new treatment options for organ preservation in patients with MSS and lower-location rectal cancer. Meanwhile, the preliminary findings of a single center show good tolerability, the main Grade III-IV AE being thrombocytopenia. The significant efficacy and long-term prognostic benefit need to be determined by further follow-up.

Serum mitochondrial tsRNA serves as a novel biomarker for hepatocarcinoma diagnosis / 医学前沿

Hepatocellular carcinoma (HCC), which makes up the majority of liver cancer, is induced by the infection of hepatitis B/C virus. Biomarkers are needed to facilitate the early detection of HCC, which is often diagnosed too late for effective therapy. The tRNA-derived small RNAs (tsRNAs) play vital roles in tumorigenesis and are stable in circulation. However, the diagnostic values and biological functions of circulating tsRNAs, especially for HCC, are still unknown. In this study, we first utilized RNA sequencing followed by quantitative reverse-transcription PCR to analyze tsRNA signatures in HCC serum. We identified tRF-Gln-TTG-006, which was remarkably upregulated in HCC serum (training cohort: 24 HCC patients vs. 24 healthy controls). In the validation stage, we found that tRF-Gln-TTG-006 signature could distinguish HCC cases from healthy subjects with high sensitivity (80.4%) and specificity (79.4%) even in the early stage (Stage I: sensitivity, 79.0%; specificity, 74.8%; 155 healthy controls vs. 153 HCC patients from two cohorts). Moreover, in vitro studies indicated that circulating tRF-Gln-TTG-006 was released from tumor cells, and its biological function was predicted by bioinformatics assay and validated by colony formation and apoptosis assays. In summary, our study demonstrated that serum tsRNA signature may serve as a novel biomarker of HCC.

Progress of miR-196 in the development and diagnosis of non-small cell lung cancer / 国际外科学杂志

Microribonucleic acid (miRNAs) is a widely existing endogenous single-stranded non-coding small RNA, which is stably expressed in tissues and body fluids. By complementing messenger RNA(mRNA) sequences, miRNAs degrade target mRNA and block the expression of protein-coding genes, playing a key role in post-transcriptional regulation and different biological processes. In recent years, more and more studies have shown that miRNAs are closely related to the occurrence and development of tumors. Among them, as a member of the miRNAs family, microribonucleic acid-196 (miR-196) is abnormally expressed in the serum, tissues and cells of patients with non-small cell lung cancer, participating in the occurrence and development of non-small cell lung cancer and playing an important regulatory role in various biological processes such as proliferation, invasion and metastasis, providing diagnostic evidence for early screening of non-small cell lung cancer.This paper reviews the progress of miR-196 in the development and diagnosis of non-small cell lung cancer.