ADAR1 Promotes Invasion and Migration and Inhibits Ferroptosis via the FAK/AKT Pathway in Colorectal Cancer.

The role of adenosine deaminase acting on RNA1 (ADAR1) in colorectal cancer (CRC) is poorly understood. This study investigated the roles and underlying molecular mechanisms of ADAR1 and its isoforms, explored the correlations between ADAR1 expression and the immune microenvironment and anticancer drug sensitivity, and examined the potential synergy of using ADAR1 expression and clinical parameters to determine the prognosis of CRC patients. CRC samples showed significant upregulation of ADAR1, and high ADAR1 expression was correlated with poor prognosis. Silencing ADAR1 inhibited the proliferation, invasion, and migration of CRC cells and induced ferroptosis by suppressing FAK/AKT activation, and the results of rescue assays were consistent with these mechanisms. Both ADAR1-p110 and ADAR1-p150 were demonstrated to regulate the FAK/AKT pathway, with ADAR1-p110 playing a particularly substantial role. In evaluating the prognosis of CRC patients, combining ADAR1 expression with clinical parameters produced a substantial synergistic effect. The in vivo tumorigenesis of CRC was significantly inhibited by silencing ADAR1. Furthermore, ADAR1 expression was positively correlated with tumor mutational burden (TMB) and microsatellite status (p < 0.05), indicating that ADAR1 plays a complex role in CRC immunotherapy. In conclusion, ADAR1 plays oncogenic roles in CRC both in vitro and in vivo, potentially by inhibiting ferroptosis via downregulation of the FAK/AKT pathway. Thus, ADAR1 serves as a potential prognostic biomarker and a promising target for CRC therapy.

Immune status and combined immunotherapy progression in Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant tumors.

Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most frequently mutated oncogene, occurring in various tumor types. Despite extensive efforts over the past 40 years to develop inhibitors targeting KRAS mutations, resistance to these inhibitors has eventually emerged. A more precise understanding of KRAS mutations and the mechanism of resistance development is essential for creating novel inhibitors that target specifically KRAS mutations and can delay or overcome resistance. Immunotherapy has developed rapidly in recent years, and in-depth dissection of the tumor immune microenvironment has led researchers to shift their focus to patients with KRAS mutations, finding that immune factors play an essential role in KRAS-mutant (KRAS-Mut) tumor therapy and targeted drug resistance. Breakthroughs and transitions from targeted therapy to immunotherapy have provided new hope for treating refractory patients. Here, we reviewed KRAS mutation-targeted treatment strategies and resistance issues, focusing on our in-depth exploration of the specific immune status of patients with KRAS mutations and the impact of body immunity following KRAS inhibition. We aimed to guide innovative approaches combining RAS inhibition with immunotherapy, review advances in preclinical and clinical stages, and discuss challenges and future directions.

Profiling the long noncoding RNA interaction network in the regulatory elements of target genes by chromatin in situ reverse transcription sequencing.

Long noncoding RNAs (lncRNAs) can regulate the activity of target genes by participating in the organization of chromatin architecture. We have devised a "chromatin-RNA in situ reverse transcription sequencing" (CRIST-seq) approach to profile the lncRNA interaction network in gene regulatory elements by combining the simplicity of RNA biotin labeling with the specificity of the CRISPR/Cas9 system. Using gene-specific gRNAs, we describe a pluripotency-specific lncRNA interacting network in the promoters of Sox2 and Pou5f1, two critical stem cell factors that are required for the maintenance of pluripotency. The promoter-interacting lncRNAs were specifically activated during reprogramming into pluripotency. Knockdown of these lncRNAs caused the stem cells to exit from pluripotency. In contrast, overexpression of the pluripotency-associated lncRNA activated the promoters of core stem cell factor genes and enhanced fibroblast reprogramming into pluripotency. These CRIST-seq data suggest that the Sox2 and Pou5f1 promoters are organized within a unique lncRNA interaction network that determines the fate of pluripotency during reprogramming. This CRIST approach may be broadly used to map lncRNA interaction networks at target loci across the genome.

Direct oral anticoagulants versus low molecular weight heparins for the treatment of cancer-associated thrombosis: a cost-effectiveness analysis.

BACKGROUND: Recently, direct oral anticoagulants (DOACs) have been included in guidelines for the treatment of cancer-associated thrombosis (CAT) to be extended to suitable cancer patients. The purpose of this study was to compare the cost-effectiveness of using DOACs and low molecular weight heparins (LMWHs) for treating CAT from the perspective of the Chinese healthcare system. METHODS: A Markov model was constructed to estimate the cost-effectiveness of the two strategies with a 6-month and 5-year time horizon. Input parameters were either sourced from the clinical trial, published literature. The primary outcome of the model was reported as incremental cost-effectiveness ratios (ICERs). Sensitivity analyses were performed to test model uncertainty. RESULTS: The 6-month cost of DOACs was $ 654.65 with 0.40 quality adjusted life-years (QALYs) while the 6-month cost of LMWHs was $USD 1719.31 with 0.37 QALYs. Similarly, treatment with DOACs had a lower cost ($USD 657.85 vs. $USD 1716.56) and more health benefits (0.40 QALYs vs. 0.37 QALYs) than treatment with LMWHs in a subgroup of patients with gastrointestinal malignancy. We found treatment with DOACs would result in a large reduction in cost ($USD 1447.22 vs. $USD 3374.70) but a small reduction in QALYs (3.07 QALYs vs. 3.09 QALYs) compared with LMWHs over a 5-year time frame, resulting in an ICER of $USD 112895.50/QALYs. Sensitivity analysis confirmed the robustness of the results. CONCLUSION: As compared to LMWHs, DOACs can be a cost-saving anticoagulant choice for the treatment of CAT in the general oncology population and gastrointestinal malignancy population.

Promising targets based on pattern recognition receptors for cancer immunotherapy.

Pattern recognition receptors (PRRs) recognize pathogen-associated as well as endogenous damage-associated molecular patterns. Once ligand binding occurs, signaling cascades develop within the cells to activate effector molecules. Thus, PRRs play key roles in immune surveillance and immune tolerance. Due to their differences in cell localization, stage of action, and ligand recognition, PRRs form a defense network from the cell membrane to the cytoplasm, constituting the regulatory networks of the innate and adaptive immune systems in cancer. However, the activation of PRRs cannot only recruit and activate anti-tumor immune cells, but also promote the release of inflammatory cytokines, which may lead to the formation of the local inflammatory microenvironment in tumors, thus promoting the development of cancer. Therefore, the dual regulation of PRRs in the immune system has attracted much attention, with current research being focused on maximizing their anti-tumor immune activity. In addition to their expression in host cells, PRRs are also expressed in tumor cells; this is closely related to the occurrence and development of cancer. This review attempts to clarify the feasibility and directions for the development of PRR-based applications in cancer immunotherapy by elaborating on the mechanisms underlying the action of PRRs and the current status of immunotherapies.

Molecular classification of small cell lung cancer subtypes: Characteristics, prognostic factors, and clinical translation.

ABSTRACT: Small cell lung cancer (SCLC) is a highly malignant tumor with a very poor prognosis; therefore, more effective treatments are urgently needed for patients afflicted with the disease. In recent years, emerging molecular classifications based on key transcription factors of SCLC have provided more information on the tumor pathophysiology, metastasis, immune microenvironment, and acquired therapeutic resistance and reflected the intertumoral heterogeneity of the various SCLC phenotypes. Additionally, advances in genomics and single-cell sequencing analysis have further revealed the high intratumoral heterogeneity and plasticity of the disease. Herein, we review and summarize these recent lines of evidence and discuss the possible pathogenesis of SCLC.

Association Between Cardiovascular Health and Retinopathy in US Adults: From NHANES 2005-2008.

PURPOSE: Investigating the relationship between cardiovascular health (CVH) and retinopathy in the adult population of the United States. DESIGN: The cross-sectional study. METHODS: The study utilized samples, including the diabetes population, from the National Health and Nutrition Examination Survey (NHANES) conducted between 2005 and 2008 (N= 4249), to assess cardiovascular health (CVH) using the Life's Essential 8 (LE8) assessment. Retinopathy is determined through imaging assessment by professionals independently grading fundus photographs. Univariable and multivariable weighted logistic regression models, restricted cubic splines (RCS), subgroup analysis and weighted quantile sum (WQS) regression approaches were employed to assess the association between LE8 score-based CVH status and retinopathy. The mediation analysis was conducted to investigate whether serum albumin levels mediated the relationship between LE8 score and retinopathy. RESULTS: In a fully adjusted logistic regression model, participants in the moderate and high CVH groups had a 39% (odds ratio (OR) 0.61, 95% confidence interval (CI) 0.43-0.87, P-value = 0.01) and 56% (OR 0.44, 95% CI 0.25-0.77, P-value < 0.001) lower odds of developing retinopathy compared to the low CVH group. The RCS model indicates a significant non-linear relationship between CVH and retinopathy. The WQS regression analysis suggests that blood glucose (47.65%) and blood pressure (19.41%) have the highest weights in relation to retinopathy. Mediation analysis suggests that serum albumin partially mediates the relationship between LE8 scores and retinopathy. CONCLUSION: This study demonstrates a significant negative correlation between overall cardiovascular health measured by LE8 scores and retinopathy. Public health strategies that promote achieving optimal cardiovascular health indicators may help reduce the burden of retinal microvascular diseases.

Serum klotho as a novel biomarker for metabolic syndrome: findings from a large national cohort.

Background: Metabolic syndrome is a cluster of metabolic abnormalities that significantly increase the risk of cardiovascular disease and mortality. The identification of novel biomarkers associated with mortality in patients with metabolic syndrome could facilitate early risk stratification and targeted interventions. Methods: We conducted a large prospective cohort study using data from five cycles (2009-2016) of the National Health and Nutrition Examination Survey (NHANES) database, including a total of 40,439 participants. Logistic regression analysis was used to assess the association between serum klotho protein levels and metabolic syndrome, while Cox regression analysis was employed to examine the correlation between serum klotho levels and all-cause mortality. Mortality data were updated until December 31, 2019. Results: After adjusting for demographic and socioeconomic confounders, the logistic regression model demonstrated that higher serum klotho levels were significantly associated with a decreased prevalence of metabolic syndrome (OR [95% CI] Highest vs. lowest quartile: 0.84 [0.70-0.99], P=0.038). In the Cox regression model, elevated klotho levels were found to significantly reduce the risk of all-cause mortality among individuals with metabolic syndrome (HR [95% CI] Highest vs. lowest quartile: 0.68 [0.51-0.90], P=0.006). Conclusion: Serum klotho levels were found to be inversely associated with the prevalence of metabolic syndrome, independent of potential confounding factors such as demographics, socioeconomic status, and lifestyle factors. Furthermore, higher klotho levels strongly indicated a lower risk of all-cause mortality in individuals with metabolic syndrome.

Revisiting the mechanisms linking blood glucose to cognitive impairment: new evidence for the potential important role of klotho.

Background: The association between blood glucose and cognition is controversial. Klotho is an anti-aging protein with neural protective effects. This study aimed to use a population-based study to disentangle the relationship between blood glucose levels and cognitive function in older adults, and to explore the role of klotho in it. Methods: A total of 1445 eligible participants from National Health and Nutrition Examination Survey (NHANES) 2011-2014 were included in our study. Cognitive function was assessed by Digit Symbol Substitution Test (DSST) and categorized into four quartiles (Q1-Q4). General characteristics and laboratory test results including serum klotho concentration and blood glucose levels were collected. Associations of cognitive function and klotho levels with blood glucose concentrations were explored through multivariate linear regression models. Mediation models were constructed to figure out the mediating role of klotho. Results: All three multivariate linear regression models showed a negative correlation between blood glucose and cognitive function. (Model 1, ß=-0.149, 95%CI: -0.202,-0.096, p=0.001; Model 2, ß=-0.116, 95%CI: -0.167,-0.065, p=0.001; Model 3, ß=-0.007, 95%CI: -0.118,-0.023, p=0.003). Mediation analysis showed that klotho mediated the statistical association between blood glucose level and cognitive function with proportions (%) of 12.5. Conclusion: Higher blood glucose levels are associated with poorer cognitive performance in non-diabetic older adults, partially mediated through lower klotho levels.

Maintenance therapy with anlotinib after induction therapy with platinum-based chemotherapy for advanced non-small-cell lung cancer: A pooled analysis of 2 single-arm trials.

BACKGROUND: Maintenance therapy could significantly improve the prognosis of patients with advanced non-small cell lung cancer (NSCLC) receiving chemotherapy. Anlotinib is effective, tolerable, and convenient in administration as a third-line treatment for NSCLC. This study aimed to evaluate the efficacy and safety of maintenance therapy with anlotinib after platinum-based induction chemotherapy for patients with advanced NSCLC. METHODS: This pooled analysis of 2 multicenter, open-label, single-arm, phase 2 clinical trials (ALTER-L014 and ALTER-L011) enrolled patients with locally advanced or metastatic NSCLC and without known sensitive mutations in China between September 2018 and January 2021. The primary outcome was progression-free survival. The secondary outcomes were objective response rate, disease control rate, overall survival, and safety. RESULTS: The data of 23 patients were pooled, with 15 from ALTER-L014 and 8 from ALTER-L011. At the cutoff date of June 13, 2021, the median progression-free survival since the start of maintenance therapy was 5.95 (95% confidence interval, 4.30-8.80) months. Nineteen patients had stable disease, 1 had a partial response and 3 had progressive disease. The objective response rate was 4.35%, while disease control rate was 86.96%. The median overall survival of the patients since the start of maintenance therapy was 18.60 (95% confidence interval, 6.87-22.80) months. The incidence of adverse events of grade ≥ 3 was 21.7%. CONCLUSION: Anlotinib might offer a new option for maintenance treatment in patients with locally advanced or metastatic NSCLC without known sensitive mutations after standard first-line platinum-based chemotherapy.

Chimeric Antigen Receptor T Cells Targeting CD19 and GCC in Metastatic Colorectal Cancer: A Nonrandomized Clinical Trial.

Importance: Chimeric antigen receptor (CAR) T-cell therapy (CART) has transformed the treatment landscape of hematologic cancer, but has negligible effects for adult solid cancers. In this trial, an autologous CAR T-cell product demonstrated antitumor activity in heavily pretreated patients with metastatic colorectal cancer (mCRC). Objective: To evaluate the safety and efficacy of guanylate cyclase-C (GCC19) CART in participants with metastatic colorectal cancer (mCRC). Design, Setting, and Participants: This single-arm, nonrandomized, phase 1 trial was conducted at the First Hospital of Jilin University from December 3, 2020, to April 13, 2022. Data analysis was conducted from May 2022 to April 2024. Adults with relapsed and refractory mCRC expressing GCC were treated with GCC19CART, a mixture of autologous CAR T cells transduced with lentiviral vectors expressing genes that encode either CD-19 CAR or GCC CAR. Main Outcomes and Measures: Safety and tolerability of CAR T-cell therapy targeting GCC in patients with mCRC without therapeutic options is capable of conferring a reasonable likeliness of clinical benefit. Other outcomes included objective response rate, progression-free survival, overall survival, and immune activation. Results: Of 15 patients 9 (60%) were women, and the median (range) age was 44 (33-61) years. Treatment with GCC19CART was associated with the development of cytokine release syndrome and diarrhea in most patients, all of which were self-limited and manageable. The objective response rate was 40%, with a partial response in 2 of 8 and 4 of 7 patients treated with either 1 × 106 cells/kg or 2 × 106 cells/kg. Median overall survival was 22.8 months (95% CI, 13.4-26.1) at data cutoff; the median progress-free survival was 6.0 months in the high dose level group (95% CI, 3.0 to not available). Conclusions and Relevance: The results of this nonrandomized clinical trial suggest that GCC19CART was safe and tolerable in heavily pretreated patients with mCRC and is the first CAR T-cell therapy known to produce objective clinical activity in refractory cancer. Given the paucity of effective therapeutics developed for colorectal cancer in recent decades, the observation that CD-19 CART target engagement can robustly induce GCC19CART target engagement sufficient to produce objective activity may serve as a foundation to develop effective cellular therapy in mCRC and other solid cancers. Trial Registration: Chinese Clinical Trial Registry: ChiCTR2000040645.

Associations of multiple toxic metal exposures with metabolic dysfunction-associated fatty liver disease: NHANES 2011-2018.

Background: The occurrence of metabolic dysfunction-associated fatty liver disease (MASLD) is driven by multiple factors including obesity, hypertension, dyslipidemia, and insulin resistance. However, epidemiological research investigating the association between metal exposure and MASLD occurrence remains limited. Methods: We conducted a large cross-sectional study with 6,520 participants who were involved in the National Health and Nutrition Examination Survey (NHANES) between 2011 and 2018. Using generalized linear regression, we examined the relationship between five heavy metals (mercury, manganese, lead, selenium, cadmium) and MASLD. Furthermore, restricted cubic spline models and weighted quantile sum (WQS) analysis were employed to characterize the exposure-response relationship between the five metals and MASLD. Results: Higher blood selenium levels were associated with an increased likelihood of MASLD among US adults. Blood lead exposure was also positively correlated with MASLD risk. However, there was no significant association observed between blood cadmium, mercury, manganese levels, and MASLD risk. Among the five metals, blood cadmium exposure accounted for the highest proportion of MASLD risk. Conclusion: Our study indicated the significant association between blood cadmium and lead exposure levels and the occurrence of MASLD in a representative sample of US adults.

Erratum: Genome-wide target interactome profiling reveals a novel EEF1A1 epigenetic pathway for oncogenic lncRNA MALAT1 in breast cancer.

[This corrects the article on p. 714 in vol. 9, PMID: 31105998.].

A bacteriocyte symbiont determines whitefly sex ratio by regulating mitochondrial function.

Nutritional symbionts influence host reproduction, but the underlying molecular mechanisms are largely unclear. We previously found that the bacteriocyte symbiont Hamiltonella impacts the sex ratio of the whitefly Bemisia tabaci. Hamiltonella synthesizes folate by cooperation with the whitefly. Folate deficiency by Hamiltonella elimination or whitefly gene silencing distorted whitefly sex ratio, and folate supplementation restored the sex ratio. Hamiltonella deficiency or gene silencing altered histone H3 lysine 9 trimethylation (H3K9me3) level, which was restored by folate supplementation. Genome-wide chromatin immunoprecipitation-seq analysis of H3K9me3 indicated mitochondrial dysfunction in symbiont-deficient whiteflies. Hamiltonella deficiency compromised mitochondrial quality of whitefly ovaries. Repressing ovary mitochondrial function led to distorted whitefly sex ratio. These findings indicate that the symbiont-derived folate regulates host histone methylation modifications, which thereby impacts ovary mitochondrial function, and finally determines host sex ratio. Our study suggests that a nutritional symbiont can regulate animal reproduction in a way that differs from reproductive manipulators.

A Neutrophil Extracellular Traps Signature Predicts the Clinical Outcomes and Immunotherapy Response in Head and Neck Squamous Cell Carcinoma.

Background: Neutrophil extracellular traps (NETs) play an important role in the occurrence, metastasis and immune escape of cancers. This study aimed to investigate NET-related genes, their clinical prognostic value and their correlation with immunotherapy and anticancer drugs in patients with head and neck squamous cell carcinoma (HNSCC). Methods: Differentially expressed NET-related genes in HNSCC were identified based on multiple public databases. To improve the clinical practicability and avoid overfitting, univariable, least absolute shrinkage and selection operator (LASSO) and multivariable Cox algorithms were used to construct a prognostic risk model. A nomogram was further used to explore the clinical value of the model. Internal and external validation were conducted to test the model. Furthermore, the immune microenvironment, immunophenoscore (IPS) and sensitivity to anticancer drugs in HNSCC patients with different prognostic risks were explored. Results: Six NET-related genes were screened to construct the risk model. In the training cohort, Kaplan-Meier (K-M) analysis showed that the overall survival (OS) of low-risk HNSCC patients was significantly better than that of high-risk HNSCC patients (p < 0.001). The nomogram also showed a promising prognostic value with a better C-index (0.726 vs 0.640) and area under the curve (AUC) (0.743 vs 0.706 at 3 years, 0.743 vs 0.645 at 5 years) than those in previous studies. Calibration plots and decision curve analysis (DCA) also showed the satisfactory predictive capacity of the nomogram. Internal and external validation further strengthened the credibility of the clinical prognostic model. The level of tumor mutational burden (TMB) in the high-risk group was significantly higher than that in the low-risk group (p = 0.017), and the TMB was positively correlated with the risk score (R = 0.11; p = 0.019). Moreover, the difference in immune infiltration was significant in HNSCC patients with different risks (p < 0.05). Furthermore, the IPS analysis indicated that anti-PD-1 (p < 0.001), anti-CTLA4 (p < 0.001) or combining immunotherapies (p < 0.001) were more beneficial for low-risk HNSCC patients. The response to anticancer drugs was also closely correlated with the expression of NET-related genes (p < 0.001). Conclusion: This study identified a novel prognostic model that might be beneficial to develop personalized treatment for HNSCC patients.

Association between the CASC16 rs4784227 polymorphism and breast cancer risk and prognosis in a northeast Chinese Han population.

Background: Breast cancer (BC) poses a serious threat to women worldwide. This research was designed to explore the association between the rs4784227 polymorphism of cancer susceptibility candidate gene 16 (CASC16) and BC susceptibility and prognosis, aiming to provide further information for the early detection of BC and to accelerate comprehensive cancer management. Methods: A total of 1,733 subjects were recruited for this case-control study, of which 828 are BC patients and 905 are healthy individuals. The relevance between SNP rs4784227 and BC risk in diverse genetic models was analyzed by using the SNPStats analysis program and was assessed by odds ratios (ORs) and 95% confidence intervals (CIs) using the binary logistic regression model. Pearson's χ 2 test was used to determine the correlation between the polymorphism and clinical characteristics of BC patients. Additionally, univariate survival analysis was performed by the Kaplan-Meier method and log-rank test, and multivariate survival analysis was performed by Cox regression. Results: SNP rs4784227 was significantly associated with susceptibility to BC in the dominant model (CT/TT versus CC, OR = 1.237, 95% CI = 1.012-1.513, P = 0.038). The minor allele of SNP rs4784227 was significantly linked to an increased risk of BC (OR = 1.197, 95% CI = 1.022-1.401, P = 0.026). In addition, the rs4784227 polymorphism of CASC16 was associated with perineural invasion (P = 0.030), menstrual status (P = 0.016) and histological grade (P = 0.001, P = 0.003, P = 0.025; respectively) of BC patients. There was no significant association between the genotypes of rs4784227 and disease-free survival (DFS) or overall survival (OS) of breast cancer patients (P > 0.05). Conclusions: The rs4784227 polymorphism of CASC16 may affect susceptibility to breast cancer and is associated with perineural invasion, menstrual status and histological grade in BC patients. Additionally, our results could not confirm that this polymorphism was related to breast cancer prognosis.

Targeted therapy combined with immunotherapy in patients with breast infiltrating ductal carcinoma with axillary lymph node metastasis of metaplastic SCC.

At present, the clinicopathological features, optimal treatment patterns, and prognosis of breast metaplastic squamous cell carcinoma (SCC) are not fully understood and are still controversial. Here, we report a 56-year-old female patient with breast infiltrating ductal carcinoma with axillary lymph node metastasis of metaplastic SCC admitted to our hospital. Their homology was clarified by comparing the gene mutation results of the two lesions, that is, the axillary lymph node lesion was a metastasis of breast metaplastic SCC. We treated the patient with Poly ADP-ribose Polymerase (PARP) inhibitors in combination with immune checkpoint inhibitors (ICIs) and found that she could achieve clinical benefit from the combination regimen. We reported a successful diagnosis and treatment of this rare refractory disease and reviewed the literature on the characteristics, pathogenesis, and advances in the diagnosis and treatment of breast metaplastic SCC.

Human umbilical cord-derived mesenchymal stem cells promote repair of neonatal brain injury caused by hypoxia/ischemia in rats.

Administration of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) is believed to be an effective method for treating neurodevelopmental disorders. In this study, we investigated the possibility of hUC-MSCs treatment of neonatal hypoxic/ischemic brain injury associated with maternal immune activation and the underlying mechanism. We established neonatal rat models of hypoxic/ischemic brain injury by exposing pregnant rats to lipopolysaccharide on day 16 or 17 of pregnancy. Rat offspring were intranasally administered hUC-MSCs on postnatal day 14. We found that polypyrimidine tract-binding protein-1 (PTBP-1) participated in the regulation of lipopolysaccharide-induced maternal immune activation, which led to neonatal hypoxic/ischemic brain injury. Intranasal delivery of hUC-MSCs inhibited PTBP-1 expression, alleviated neonatal brain injury-related inflammation, and regulated the number and function of glial fibrillary acidic protein-positive astrocytes, thereby promoting plastic regeneration of neurons and improving brain function. These findings suggest that hUC-MSCs can effectively promote the repair of neonatal hypoxic/ischemic brain injury related to maternal immune activation through inhibition of PTBP-1 expression and astrocyte activation.

Sintilimab plus autologous NK cells as second-line treatment for advanced non-small-cell lung cancer previous treated with platinum-containing chemotherapy.

This pilot study (NCT03958097; https://www.clinicaltrials.gov/ct2/show/NCT03958097) was aimed to evaluate the efficacy and safety of PD-1 antibody combined autologous NK cells in the treatment of patients with stage IIIB/IIIC or IV non-small-cell lung cancer (NSCLC) who failed the first-line platinum-based chemotherapy. All patients received both sintilimab 200mg and 3×109 NK cells every 3 weeks. 20 patients were enrolled, median follow up time was 22.6 months. The median PFS was 11.6 months, ORR was 45%. Median OS was 17.7 months, 6-month OS rate and 12-month OS rate was 95.0% and 80.0%. Unexpected adverse events were not observed. 2 patients reported grade 3 adverse events (hypertriglyceridemia, neutropenia and increased creatine kinase). The autologous NK cells did not add extra adverse events to the ICI treatment. Autologous NK plus sintilimab showed promising antitumor activity and an acceptable safety profile in advanced driven-mutation negative NSCLC who failed on the first line treatment.

Effect of non-pharmacological interventions on anxiety, depression, sleep quality, and pain after orthopedic surgery: A protocol for systematic review and network meta-analysis.

BACKGROUND: Patients after orthopedic surgery often experience the pain, anxiety, depression, and sleep disturbances, which can be greatly reduced by non-pharmacologic interventions as alternative therapies. Randomized controlled trials of nonpharmacologic interventions for anxiety, depression, sleep quality, and pain in patients after orthopedic surgery have been reported, but the results may be conflicting. Evidence to determine the optimal non-pharmacological intervention with a high efficacy is limited. This study aims to assess the effects of non-pharmacologic interventions on the bone anxiety, depression, sleep quality, and pain in patients after orthopedic surgery through a network meta-analysis, thus providing guidance in clinical application. METHODS: A systematic search of randomized controlled trials reporting the effects of non-pharmacological interventions on anxiety, depression, sleep quality and pain after orthopedic surgery published before October 2021 will be searched in Wanfang, VIP Information Chinese Journal Service Platform, China National Knowledge Infrastructure, Chinese BioMedicine Literature Database, Pubmed, Embase, Cochrane, and Web of science. Two reviewers will be independently responsible for study selection, quality appraisal, and data extraction. Stata 14.0 software will be used to perform the network meta-analysis. RESULTS: The findings of this research will be reported in a recognized journal. CONCLUSION: This meta-analysis will provide the stronger evidence for non-pharmacological interventions on alleviating bone anxiety, depression, sleep quality, and pain in patients after orthopedic surgery, which will help clinicians and decision makers in their choices.Open Science Framework registration number: DOI 10.17605/OSF.IO/2SCBD.