FLT3 inhibitor maintenance after allogeneic stem cell transplantation in FLT3-mutated acute myeloid leukemia (AML) patients.

Background: The somatic mutation of fms-like tyrosine kinase 3 (FLT3) in acute myeloid leukemia (AML) is associated with increased risk of relapse and lower survival rates. FLT3i as maintenance after allogeneic hematopoietic stem cell transplant (allo-HSCT) are under study to prevent disease relapse, but real-world data are lacking. Methods: We performed a single center, retrospective cohort study and analyzed patients who had FLT3-mutated AML and underwent allogeneic-HSCT between January 2011 to June 2022 at the University of Chicago. We identified 23 patients who received FLT3i maintenance therapy post-allo-HSCT and compared their outcomes against 57 patients who did not. Primary outcome was disease-free survival (DFS). Secondary outcomes include overall survival (OS) and relapse rate. Results: FLT3i maintenance therapy was started at a median 59 days (range, 29-216 days) after allo-HSCT with median duration of 287 days (range, 15-1,194 days). Maintenance therapy was well tolerated. Overall, the improvement in DFS rates for patients after they were placed on FLT3i maintenance therapy was not significant [hazard ratio (HR) for relapse or death =0.65, 95% confidence interval (CI): 0.32-1.31, P=0.23]. However, when adjusted for the conditioning regimen and donor status, the differences were statistically significant with improvement in DFS and OS for patients on FLT3i maintenance (HR for OS =0.42, 95% CI: 0.18-0.95, P=0.04). Conclusions: When adjusting for conditioning regimen and donor status, there was a significant improvement in DFS and OS for patients who received FLT3i maintenance therapy compared to those who did not. Randomized prospective studies may provide more insight.

Effect of Histamine H2 Receptor Antagonists on All-Cause Mortality in Critically Ill Patients With Essential Hypertension: A Retrospective Cohort Study.

Previous studies found that histamine H2 receptor antagonists (H2RAs) had blood pressure lowering and cardioprotective effects, but the impact of H2RAs on the survival outcomes of critically ill patients with essential hypertension is still unclear. The aim of this study was to investigate the association of H2RAs exposure with all-cause mortality in patients with essential hypertension based on Medical Information Mart for Intensive Care III database. A total of 17,739 patients were included, involving 8482 H2RAs users and 9257 non-H2RAs users. Propensity score matching (PSM) was performed to improve balance between 2 groups that were exposed to H2RAs or not. Kaplan-Meier survival curves were used to compare the cumulative survival rates and multivariable Cox regression models were performed to evaluate the association between H2RAs exposure and all-cause mortality. After 1:1 PSM, 4416 pairs of patients were enrolled. The results revealed potentially significant association between H2RAs exposure and decreased 30-day, 90-day, and 1-year mortalities in multivariate analyses (HR = 0.783, 95% CI: 0.696-0.882 for 30-day; HR = 0.860, 95% CI: 0.778-0.950 for 90-day; and HR = 0.883, 95% CI: 0.811-0.961 for 1-year mortality, respectively). Covariate effect analyses showed that the use of H2RAs was more beneficial in essential hypertension patients with age ≥ 60, BMI ≥ 25 kg/m2, coronary arteriosclerosis, stroke, and acute kidney failure, respectively. In conclusion, H2RAs exposure was related to lower mortalities in critically ill patients with essential hypertension, which provided novel potential strategy for the use of H2RAs in essential hypertension patients.

The benefit of omeprazole exposure on all-cause mortality and length of ICU/hospital stay might vary with age in critically ill pediatric patients: A cohort study.

PURPOSE: To investigate the association between proton pump inhibitors (PPIs) administration during hospitalization and mortality and length of stay in critically ill pediatric patients. MATERIALS AND METHODS: This is a retrospective observational cohort study on pediatric ICU patients (0 to 18 years). Propensity score matching (PSM), Kaplan-Meier curves, Cox proportional hazards model and Linear regression model was applied for assessing the effects of PPIs on mortality and other outcomes during hospitalization. RESULTS: A total of 2269 pediatric ICU patients were included, involving 1378 omeprazole (OME) users and 891 non-OME users. The results showed significant association between OME exposure and decreased ICU stay (ß -0.042; 95% CI -0.073--0.011; P = 0.008) but prolonged non-ICU hospital stay (ß 0.121; 95% CI 0.097-0.155; P = 0.040). No statistical significance was observed between OME exposure and reduced mortality, but the OME group had a slightly decreased tendency in 28-day mortality (HR 0.701; 95% CI 0.418-1.176) and in-hospital mortality (HR 0.726; 95% CI 0.419-1.257). Furthermore, subgroup analyses revealed that the decreased tendency of mortality were more obvious in patients less than 1 year old compared with older pediatric patients, although not statistically significant. In addition, we also observed that OME exposure was significantly associated with reduced mortality of general ICU subgroup. CONCLUSIONS: This study provided a sign that PPIs used only in the ICU, rather than throughout hospital stay, might provide more benefit for critically ill pediatric patients. Additionally, younger pediatric patients might gain relatively more benefit than older children when receiving PPIs.

Histamine H2 receptor antagonist exhibited comparable all-cause mortality-decreasing effect as ß-blockers in critically ill patients with heart failure: a cohort study.

Background: Our previous study reported that histamine H2 receptor antagonists (H2RAs) exposure was associated with decreased mortality in critically ill patients with heart failure (HF) through the same pharmacological mechanism as ß-blockers. However, population-based clinical study directly comparing the efficacy of H2RAs and ß-blockers on mortality of HF patients are still lacking. This study aims to compare the association difference of H2RAs and ß-blockers on mortality in critically ill patients with HF using the Medical Information Mart for Intensive Care III database (MIMIC-III). Methods: Study population was divided into 4 groups: ß-blockers + H2RAs group, ß-blockers group, H2RAs group, and Non-ß-blockers + Non-H2RAs group. Kaplan-Meier curves and multivariable Cox regression models were employed to evaluate the differences of all-cause mortalities among the 4 groups. Propensity score matching (PSM) was used to increase comparability of four groups. Results: A total of 5593 patients were included. After PSM, multivariate analyses showed that patients in H2RAs group had close all-cause mortality with patients in ß-blockers group. Furthermore, 30-day, 1-year, 5-year and 10-year all-mortality of patients in ß-blockers + H2RAs group were significantly lower than those of patients in ß-blockers group, respectively (HR: 0.64, 95%CI: 0.50-0.82 for 30-day; HR: 0.80, 95%CI: 0.69-0.93 for 1-year mortality; HR: 0.83, 95%CI: 0.74-0.93 for 5-year mortality; and HR: 0.85, 95%CI: 0.76-0.94 for 10-year mortality, respectively). Conclusion: H2RAs exposure exhibited comparable all-cause mortality-decreasing effect as ß-blockers; and, furthermore, H2RAs and ß-blockers had additive or synergistic interactions to improve survival in critically ill patients with HF.

A meta-analysis of associations of IL-10 gene polymorphisms with acute leukemia susceptibility.

BACKGROUND: Recently, increasing evidence has demonstrated that IL-10 single nucleotide polymorphisms (SNPs) are associated with the risk of acute leukemia (AL), but the findings of different articles remain controversial. Thus, we performed a meta-analysis to further investigate the exact roles of IL-10 SNPs in AL susceptibility. METHODS: Six common Chinese and English databases were utilized to retrieve eligible studies. The strength of the association was assessed by calculating odds ratios and 95 % confidence intervals. All analyses were carried out using Review Manager (version 5.3) and STATA (version 15.1). The registered number of this research is CRD42022373362. RESULTS: A total of 6391 participants were enrolled in this research. The results showed that the AG genotype of rs1800896 increased AL risk in the heterozygous codominant model (AG vs. AA, OR = 1.41, 95 % CI = 1.04-1.92, P = 0.03) and overdominant model (AG vs. AA + GG, OR = 1.32, 95 % CI = 1.04-1.70, P = 0.03). In the subgroup analysis, associations between the G allele, GG genotype, AG genotype, AG + GG genotype of rs1800896 and increased AL risk were also observed in the mixed population based on allelic, homozygote codominant, heterozygous codominant, dominant, and overdominant models. Furthermore, an association between the AC genotype of rs1800872 and increased AL risk was observed in the Caucasian population in the overdominant model. However, the rs1800871, rs3024489 and rs3024493 polymorphisms did not affect AL risk. CONCLUSION: IL-10 rs1800896 and rs1800872 affected the susceptibility of AL and therefore may be biomarkers for early screening and risk prediction of AL.

Role-Specific Curricular Needs for Identification and Management of Immune-Related Adverse Events.

Immune checkpoint inhibitors (ICIs) activate the immune system against cancer and have become standard of care for many cancers. With increased ICI use, their toxicities known as immune-related adverse events (irAEs) are becoming more common, but it is unclear how prepared relevant clinicians feel to diagnose and treat irAEs. The objective of this study was to assess irAE knowledge, confidence, and experience among generalists and oncology clinicians to guide future curricular interventions related to irAEs. A 25-item survey with questions assessing knowledge, experience level, confidence, and resource utilization regarding irAE diagnosis and management was sent to University of Chicago-affiliated (UChicago) internal medicine residents and hospitalists (inpatient irAE management) along with UChicago oncology fellows, attendings, nurse practitioners (NPs), and physician assistants (PAs) (inpatient and outpatient) as well as Chicago community oncologists (outpatient) in June 2022. Overall response rate was 37% (171/467). Knowledge scores averaged below 70% for all clinicians. "No idea" responses were most common with knowledge questions on steroid-sparing agent use and ICI use for patients with preexisting autoimmune disease. IrAE experience correlated with higher knowledge for oncology attendings (p = 0.015) and hematology/oncology NPs/PAs (p = 0.031). IrAE experience correlated with higher confidence for residents (p = 0.026), oncology fellows (p = 0.047), and hematology/oncology NPs/PAs (p = 0.042). Most commonly utilized resources were colleagues and UpToDate, and most clinicians were very likely to use online resources in the future. Knowledge and confidence gaps exist, and they were somewhat mitigated by experience. Future irAE curricula can fill these needs through online role-specific resources: irAE identification for generalists versus irAE identification and management for oncologists.

Comparative efficacy and safety of uricosuric agents in the treatment of gout or hyperuricemia: a systematic review and network meta-analysis.

OBJECTIVES: The current world witnesses a greatly increased prevalence and incidence of hyperuricemia and gout with unfortunately the comparative efficacy and safety of present available uricosuric agents remaining uncertain. We herein aimed to investigate the most appropriate uricosuric agent for gout or hyperuricemia patients. METHOD: PubMed, Embase, Cochrane Library databases, and ClinicalTrials.gov from inception to 2 July 2022 were searched to retrieve eligible studies assessing efficacy and safety of uricosuric drugs in hyperuricemia or gout patients. Network meta-analysis was carried out using the Stata 16.0 software. RESULTS: Twelve randomized controlled trials comprising 1851 patients were eventually included. Network meta-analysis showed that dotinurad 4 mg once daily, verinurad, dotinurad 2 mg once daily, dotinurad 1 mg once daily, and benzbromarone were the top 5 effective treatments to achieve target serum uric acid. Furthermore, dotinurad 4 mg once daily was more effective at achieving urate-lowering targets (RR of dotinurad 4 mg once daily vs. probenecid: 1.68, 95% CI [1.13; 2.50]) and safer (RR of probenecid vs. dotinurad 4 mg once daily: 1.77, 95% CI [0.69; 4.56]) than probenecid. CONCLUSIONS: This network meta-analysis demonstrated an important absolute benefit of dotinurad 4 mg once daily to achieve target serum uric acid and low risk of adverse events for drug treatment of gout or hyperuricemia patients. Additionally, verinurad might be used as an alternative uricosuric therapeutic option to dotinurad. These findings provided further comprehensive insight into the treatment value of current uricosuric agents for gout or hyperuricemia. Key Points 1. This is the first systematic review and network meta-analysis examining the efficacy and safety of currently available uricosuric agents in gout or hyperuricemia patients. 2. Recommended doses of dotinurad 4mg once daily used for the treatment of gout or hyperuricemia patients can significantly decrease serum uric acid levels. 3. The present findings will provide further comprehensive insight into the treatment value of certain uricosuric agents for gout or hyperuricemia.

Effectiveness and Safety of Histamine H2 Receptor Antagonists: An Umbrella Review of Meta-Analyses.

Histamine H2 receptor antagonists (H2RAs) were widely used to inhibit gastric acid secretion, but its association with adverse events remains controversial and unclear. We conducted an umbrella review of meta-analyses to systematically assess the quality and credibility of the correlations between H2RA use with the risk of adverse outcomes through searching 4 major databases from inception to April 30, 2022. Forty-six individual meta-analyses were identified, including 29 meta-analyses of observation studies with 32 unique outcomes and 19 meta-analyses of randomized controlled trials with 3 unique outcomes for comparing the H2RA versus non-H2RA group. A Measurement Tool to Assess Systematic Reviews 2 rating for the included meta-analyses showed that 4 of 46 meta-analyses were assigned as high scores, 3 were assigned as "moderate," and 25 were assigned as low scores. Grading of Recommendations Assessment, Development and Evaluation assessment for combined results demonstrated that 6 outcomes were rated as "moderate," 9 outcomes were rated as "low," and 17 outcomes were rated as "very low." We confirmed significant associations of H2RA use with pneumonia, peritonitis, necrotizing enterocolitis, Clostridium difficile infection, liver cancer, gastric cancer, and hip fracture diseases. No associations for colorectal cancer, melanoma, kidney cancer, lung cancer, or common reproductive system cancer or renal, neurological, and cardiovascular system diseases were observed. We found a variety of evidence for the associations between H2RAs and adverse outcomes, which would give clinicians more positive guidance on prescription of H2RAs in clinical practice.

Multiscale Analysis on Changes in Bone Microstructure of Osteoporotic Rats / 医用生物力学

Objective To study changes in bone microstructure of osteoporotic rats by multiscale analysis. Methods A total of 20 5-month-old female SD rats were randomly divided into two groups, i.e., ovariectomy (OVX) group (n=12) and the SHAM group (n=8), respectively. The rats in OVX group were subjected to bilateral ovariectomy and became osteoporosis models after 8 weeks, while sham operation was performed for the SHAM group. Changes in microstructure of cortical bone and cancellous bone at tissue scale, and osteocyte lacunar-canalicular network (LCN) and extracellular matrix (ECM) at cell scale were quantitatively analyzed using Micro-CT and SR-Nano-CT. Results At tissue scale, the cross-sectional area of cortical bone in OVX group was significantly higher than that in SHAM group (P<0.05), and the bone mineral density (BMD) and thickness of cortical bone were not significantly different from those in SHAM group. The trabecular BMD, bone volume fraction, trabecular thickness and trabecular number in OVX group were significantly decreased in comparison with SHAM group (P<0.01), while the trabecular separation was significantly increased (P<0.01). At cell scale, there was no significant difference in the semiaxes of lacunae between OVX group and SHAM group, but the thickness of lacunae and the diameter of canaliculi in OVX group were significantly increased in comparison with SHAM group (P<0.05). At the same time, the porosity of cortical bone in OVX group was significantly higher than that in SHAM group at cell scale (P<0.05). Conclusions The bone microstructure in OVX group varied to different extents at tissue and cell scales. At tissue scale, the cancellous bone loss was severe, while the cortical bone had fewer changes. At cell scale, porosity of the lacunar-canalicular network significantly increased, which directly affected the BMD and strength of cortical bone. Multiscale analysis on changes in bone microstructure of OP rats has potential application value for clinical diagnosis and pathological analysis of osteoporosis.

Cardiovascular effects associated with chimeric antigen receptor T cell therapy in cancer patients: A meta-analysis.

Background: Although numerous studies confirmed the marked efficacy of chimeric antigen receptor T cells (CAR-T cells) in many hematologic malignancies, severe cardiovascular toxicities remain to be a major obstacle when incorporating this technology. Furthermore, previous individual investigations regarding the cardiovascular toxicities of CAR-T cell therapy also reported controversial conclusions. Therefore, a meta-analysis was performed to further evaluate the impacts of CAR-T cell therapy on cardiovascular toxicities. Methods: The PubMed, Embase, Web of Science, and ClinicalTrials.gov databases were searched for eligible studies up to April 2022. All analyses were carried out using the R 4.1.0 software. Results: Eventually, 25 related studies consisting of 2,059 patients were enrolled in the current meta-analysis. We discovered that the pooled incidence rate of the all-cause mortality rate was 14.1% and that the pooled incidence rates of overall cardiovascular (CV) events and CV events with cytokine release syndrome (CRS) grade ≥ 2 were 25.6% and 14.2%, respectively. The pooled incidence of hypotension was 28.6%. Further analysis showed that the incidence rates of arrhythmias, cardiovascular dysfunction, heart failure (HF), CV deaths, acute coronary syndrome (ACS), cardiomyopathy, cardiac arrest, and other CV events were 19.2%, 8.0%, 5.3%, 1.8%, 2.5%, 2.9%, 1.3%, and 1.9%, respectively. Conclusion: Cancer patients treated with CAR-T cell therapy were at risk for cardiovascular toxicities, of which the most common cardiovascular events were arrhythmias, cardiovascular dysfunction, and heart failure. These findings would contribute to achieving more rational and individualized use of CAR-T cells in clinical treatment.

Proton Pump Inhibitors and Cancer Risk: An Umbrella Review and Meta-analysis of Observational Studies.

OBJECTIVES: Increasing evidence suggested that proton pump inhibitors (PPIs) use might affect the development of cancers, but previous conclusions remain controversial. Therefore, an umbrella review was performed to clarify the associations between PPIs and various types of cancer by summarizing the existing meta-analyses and systematic reviews. METHODS: We searched PubMed, Cochrane Library, Embase, CNKI, Wanfang, and VIP database up to June 2022 for eligible meta-analyses or systematic reviews. The summary effect size, 95% CI, heterogeneity, small study effect, and 95% prediction interval were considered in the present study. A Measurement Tool to Assess Systematic Review 2 and grading of recommendation, assessment, development, and evaluation were used to assess methodological quality and evidence. RESULTS: The umbrella review included 21 meta-analyses containing 65 studies and 10 cancer types with 6.8 million subjects. The results showed that PPI use was significantly associated with increased risks of certain types of cancer, including gastric cancer (odds ratio [OR]: 2.07; 95% CI, 1.30 to 3.29), pancreatic cancer (OR: 1.73; 95% CI, 1.23 to 2.44), colorectal cancer (OR: 1.84; 95% CI, 1.26 to 2.67), and liver cancer (OR: 1.80; 95% CI, 1.27 to 2.54), but was not associated with esophageal cancer. In addition, PPI use was associated with decreased risk of breast cancer (OR: 0.69; 95% CI, 0.50 to 0.96). CONCLUSIONS: These findings suggested that clinicians should pay more attention to the occurrence of gastric cancer, pancreatic cancer, colorectal cancer, and liver cancer in patients who used PPIs, and PPI prescription should be written only when an accurate specific diagnosis has been made. Furthermore, additional PPIs to the treatment regimen may be benefit for women with a higher-than-average risk of breast cancer.

Highly accurate response prediction in high-risk early breast cancer patients using a biophysical simulation platform.

PURPOSE: Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) in early breast cancer (EBC) is largely dependent on breast cancer subtype, but no clinical-grade model exists to predict response and guide selection of treatment. A biophysical simulation of response to NAC has the potential to address this unmet need. METHODS: We conducted a retrospective evaluation of a biophysical simulation model as a predictor of pCR. Patients who received standard NAC at the University of Chicago for EBC between January 1st, 2010 and March 31st, 2020 were included. Response was predicted using baseline breast MRI, clinicopathologic features, and treatment regimen by investigators who were blinded to patient outcomes. RESULTS: A total of 144 tumors from 141 patients were included; 59 were triple-negative, 49 HER2-positive, and 36 hormone-receptor positive/HER2 negative. Lymph node disease was present in half of patients, and most were treated with an anthracycline-based regimen (58.3%). Sensitivity and specificity of the biophysical simulation for pCR were 88.0% (95% confidence interval [CI] 75.7 - 95.5) and 89.4% (95% CI 81.3 - 94.8), respectively, with robust results regardless of subtype. In patients with predicted pCR, 5-year event-free survival was 98%, versus 79% with predicted residual disease (log-rank p = 0.01, HR 4.57, 95% CI 1.36 - 15.34). At a median follow-up of 5.4 years, no patients with predicted pCR experienced disease recurrence. CONCLUSION: A biophysical simulation model accurately predicts pCR and long-term outcomes from baseline MRI and clinical data, and is a promising tool to guide escalation/de-escalation of NAC.

The pyroptosis-related gene signature predicts prognosis and reveals characterization of the tumor immune microenvironment in acute myeloid leukemia.

Background: Pyroptosis is a novel inflammatory form of programmed cell death and a prospective target for cancer therapy. Nevertheless, little is known about the association between pyroptosis-related genes (PRGs) and acute myeloid leukemia (AML) prognosis. Herein, we systematically investigated the specific functions and clinical prognostic value of multiple PRGs in AML. Methods: Univariate and LASSO Cox regression analyses based on TCGA and GTEx databases were used to generate the PRG signature, whose predictive efficacy of survival was evaluated using survival analysis, ROC, univariate and multivariate Cox analyses as well as subgroup analysis. The BeatAML cohort was used for data validation. The association between risk score and immune cell infiltration, HLA, immune checkpoints, cancer stem cell (CSC), tumor mutation burden (TMB), and therapeutic drug sensitivity were also analyzed. Results: Six -PRG signatures, namely, CASP3, ELANE, GSDMA, NOD1, PYCARD, and VDR were generated. The high-risk score represented a poorer prognosis and the PRG risk score was also validated as an independent predictor of prognosis. A nomogram including the cytogenetic risk, age, and risk score was constructed for accurate prediction of 1-, 3-, and 5-year survival probabilities. Meanwhile, this risk score was significantly associated with the tumor immune microenvironment (TIME). A high-risk score is characterized by high immune cell infiltration, HLA, and immune checkpoints, as well as low CSC and TMB. In addition, patients with low-risk scores presented significantly lower IC50 values for ATRA, cytarabine, midostaurin, doxorubicin, and etoposide. Conclusion: Our findings might contribute to further understanding of PRGs in the prognosis and development of AML and provide novel and reliable biomarkers for its precise prevention and treatment.

Histamine H2 receptor antagonist exposure was related to decreased all-cause mortality in critical ill patients with heart failure: a cohort study.

AIMS: Previous studies reported that histamine H2 receptor antagonists (H2RAs) had cardioprotective effects. However, the effect of H2RAs on mortality of critical ill patients with heart failure (HF) remains unclear. The aim of this study was to clarify the association between H2RAs and all-cause mortality of critical ill patients with HF based on Medical Information Mart for Intensive Care III database (MIMIC-III). METHODS AND RESULTS: Propensity score matching (PSM) was applied to account for the baseline differences between two groups that were exposed to H2RAs or not. The study primary outcome was all-cause mortality. Kaplan-Meier curves and multivariable Cox regression models were employed to estimate the effects of H2RAs on mortality of critical ill patients with HF. A total of 10 387 patients were included, involving 4440 H2RAs users and 5947 non-H2RAs users. After matching, 3130 pairs of patients were matched between H2RAs users and non-H2RAs users. The results showed significant association between H2RAs exposure and decreased 30-day, 90-day, and 1-year mortality in both univariate analyses and multivariate analyses [hazard ratio (HR) = 0.73, 95% confidence interval (CI): 0.65-0.83 for 30-day; HR = 0.80, 95%CI: 0.72-0.89 for 90-day; and HR = 0.83, 95%CI: 0.76-0.90 for 1-year mortality, respectively] by Cox regression after PSM. Furthermore, stratified analyses revealed that the 30-day, 90-day, and 1-year mortality of ranitidine users were significantly lower than those of famotidine users, respectively. CONCLUSION: Histamine H2 receptor antagonists exposure was associated with lower mortality in critical ill patients with HF. Furthermore, ranitidine might be superior to famotidine in reducing mortality of critical ill patients with HF.

A novel phosphodiesterase 9A inhibitor LW33 protects against ischemic stroke through the cGMP/PKG/CREB pathway.

BACKGROUND: Ischemic stroke is one of the leading causes of mortality worldwide. The available treatments are not effective. Phosphodiesterase 9A (PDE9A) is an intracellular cyclic guanosine monophosphate (cGMP) hydrolase considered to be a promising therapeutic target for brain diseases. This study explored neuroprotective effects and the underlying mechanism of LW33, a novel PDE9A inhibitor, on ischemic stroke in vitro and in vivo. METHODS: A middle cerebral artery occlusion (MCAO) model was established in adult male Sprague-Dawley rats and an oxygen-glucose deprivation/reoxygenation (OGD/R) model was established in human SH-SY5Y cells to mimic ischemia-reperfusion injury in vitro. RESULTS: LW33 increased cell viability, reduced lactate dehydrogenase activity, and OGD/R-induced apoptosis of SH-SY5Y cells. The protective effects of LW33 against stroke occurred in the recovery phase. LW33 administration significantly reduced cerebral infarction volume in MCAO rats, without causing significant deformation or necrosis of neurons in the cortex. LW33 also improved learning and cognitive dysfunction and reduced other pathological changes in MCAO rats in the recovery period. Moreover, LW33 stimulated the cGMP/PKG/CREB pathway and up-regulated the expression of the apoptosis-related proteins, and this effect was reversed by KT5823 treatment. CONCLUSION: LW33 inhibited cell apoptosis and promoted neuronal repair to alleviate OGD/R and MCAO induced pathological alterations via the cGMP/PKG/CREB pathway, indicating that LW33 may be a promising therapeutic target for ischemic stroke.

Associations of FOXP3 gene polymorphisms with susceptibility and severity of preeclampsia: A meta-analysis.

OBJECTIVE: FOXP3 single nucleotide polymorphisms (SNPs) were recently elucidated to influence the development of preeclampsia (PE), but the results on this issue still remained controversial. Thus, a meta-analysis was implemented to systematically investigate the roles of FOXP3 SNPs in PE. METHODS: Eligible publications were identified by retrieving relevant electronic databases. Meanwhile, the association intensity was estimated by calculating odds ratios (ORs) and 95% confidence intervals (CIs) in various genetic models. RESULTS: Totally eight investigations involving 3446 subjects were enrolled in the final meta-analysis. The AC and AC + CC genotypes of FOXP3 rs3761548 were related to the susceptibility of PE in over-dominant (OR = 1.19, 95%CI = 1.02-1.38, P = 0.03) and recessive (OR = 0.59, 95% CI: 0.36-0.97, P = 0.04) models. Furthermore, correlation between rs2232365 and PE was observed in recessive model (GG vs. GA + AA) (OR = 0.79, 95%CI: 0.65-0.97, P = 0.03). Moreover, rs2232365 GA and GG + GA genotypes were associated with the severity of PE. However, rs4824747, rs3761547 and rs2280883 polymorphisms had no significant impact on PE susceptibility. CONCLUSIONS: FOXP3 rs3761548 and rs2232365 SNPs influenced the PE susceptibility and therefore may be potential biomarkers for prediction of PE risk.

The emerging role of immune checkpoint inhibitors for the treatment of breast cancer.

INTRODUCTION: Breast cancer has traditionally been viewed as immunogenically 'cold,' but two immune checkpoint inhibitors have been approved in combination with chemotherapy for PD-L1 positive advanced triple-negative breast cancer (TNBC), and pembrolizumab was also recently approved for early stage TNBC. As the landscape is rapidly evolving, a comprehensive review of checkpoint inhibitors in breast cancer is needed to aid clinicians in selecting appropriate candidates for therapy, and to highlight ongoing promising studies in this area and topics in need of further investigation. AREA COVERED: This review summarizes the latest evidence from completed and ongoing trials of immune checkpoint inhibitors. Ongoing studies were identified using a search of ClinicalTrials.gov with the term 'breast cancer' along with specific checkpoint inhibitor agents. EXPERT OPINION: A number of novel combination strategies are under investigation to enhance response and overcome resistance to immunotherapy, with promising preliminary data from checkpoint inhibitors targeting TIGIT, combinations with small molecule inhibitors such as lenvatinib, and injectable agents directly influencing the immune microenvironment. As immunotherapy enters into the curative setting, biomarkers predictive of immunotherapy benefit are needed, as PD-L1 status has not been a helpful discriminator in completed trials in early-stage breast cancer.

Effects of Total Hip Arthroplasty on Proximal Femoral Bone Remodeling / 医用生物力学

Objective To analyze the influence of total hip arthroplasty (THA) on the process of proximal femoral bone remodeling by using the Wolff bone remodeling theory. Methods According to control equation of bone remodeling, the program of bone remodeling was written in Python language. Preoperative femur model and postoperative femur and prosthesis finite element models were established respectively in ABAQUS software. The process of bone reconstruction before and after THA operation was compared to analyze the effect of prosthesis implantation on mechanical properties of the femur in the middle and long term after THA operation. Results The stress in proximal femur continued to decrease after prosthesis implantation, and the stress site was transferred from the femoral head to the prosthesis, resulting in an obvious stress shielding phenomenon. Bone loss in the stress shielding area was serious. The femoral shaft cortical bone became thinner and the stress shielding was relieved. The medial side at the bottom of the prosthesis was compressed, and the stress was significantly higher than that of the lateral side, where the bone was unevenly distributed. Conclusions After THA operation, obvious stress shielding occured at proximal medial side of the femur, leading to bone loss and prosthesis loosening. The difference in stress levels on both sides at the bottom of the prosthesis resulted in an uneven bone distribution, causing the discordance between the prosthesis and the femur, as well as postoperative pain in the middle part of the thigh.

Research Advances in Musculoskeletal Biomechanical Modeling in 2021 / 医用生物力学

Biomechanical model of musculoskeletal system has accurate human anatomy and good biological fidelity. It can accurately and effectively reveal the biomechanical state and predict the internal mechanical response of musculoskeletal system. Therefore, it has been widely used in biomechanical study of musculoskeletal system, diagnosis and treatment of bone diseases, implant optimization design and preoperative planning. In 2021, the latest advances in biomechanical modeling method of musculoskeletal system mainly included three aspects, i.e., individualized finite element modeling, statistical model modeling and musculoskeletal system modeling. On this basis, the latest relevant literatures were summarized in this review to illustrate the progress and main applications of the above modeling method, and the future development direction of musculoskeletal modeling was discussed.

Association between TNF-α gene polymorphisms and susceptibility of myelodysplastic syndromes: a meta-analysis.

OBJECTIVE: Myelodysplastic syndromes (MDS) constitute a heterogeneous group of clonal hematological diseases. Previous investigations reported that tumor necrosis factor-alpha (TNF-α) gene polymorphisms were associated with MDS susceptibility, but the results remained controversial. Thus, we conducted a meta-analysis to higher elucidate the correlation between TNF-α gene polymorphisms and MDS susceptibility. METHODS: The PubMed, Cochrane Library, Embase, Chinese National Knowledge Infrastructure (CNKI), and Wan Fang databases were searched for eligible literatures published up to July 2021. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were applied to evaluate the strength of association. RESULTS: Eight studies involving 1180 MDS patients and 1387 controls were included in this meta-analysis. For the TNF-α G308A polymorphism, we confirmed that the G allele (G versus A: P = 0.001), GG genotypes (GG versus GA: P = 0.005; GG versus GA + AA: P = 0.002), and GG + AA genotypes (GG + AA versus GA: P = 0.008) was significantly associated with decreased MDS susceptibility according to different genetic models. Furthermore, the G308A polymorphism was significantly correlated with decreased occurrence risk of MDS in the Caucasian population as compared with Asians in the above four genetic models (P < 0.05). However, no significant association was observed between the TNF-α G238A polymorphism and MDS risk. CONCLUSION: This research showed that TNF-α G308A polymorphism might be a potential biomarker in early clinical screening of MDS, which would contribute to improving the individualized prevention of MDS patients in clinic.