Pulsed Electromagnetic Fields Combined With Adipose-Derived Stem Cells Protect Ischemic Myocardium by Regulating miR-20a-5p/E2F1/p73 Signaling.

Myocardial infarction (MI) is a serious threat to human health. Although monotherapy with pulsed electromagnetic fields (PEMFs) or adipose-derived stem cells (ADSCs) has been reported to have positive effect on the treatment of MI, a satisfactory outcome has not yet been achieved. In recent years, combination therapy has attracted widespread interest. Herein, we explored the synergistic therapeutic effect of combination therapy with PEMFs and ADSCs on MI and found that the combination of PEMFs and ADSCs effectively reduced infarct size, inhibited cardiomyocyte apoptosis and protected the cardiac function in mice with MI. In addition, bioinformatics analysis and RT-qPCR showed that the combination therapy could affect apoptosis by regulating the expression of miR-20a-5p. A dual-luciferase reporter gene assay also confirmed that the miR-20a-5p could target E2F transcription factor 1 (E2F1) and inhibit cardiomyocyte apoptosis by regulating the E2F1/p73 signaling pathway. Therefore, our study systematically demonstrated the effectiveness of combination therapy on the inhibition of cardiomyocyte apoptosis by regulating the miR-20a-5p/E2F1/p73 signaling pathway in mice with MI. Thus, our study underscored the effectiveness of the combination of PEMFs and ADSCs and identified miR-20a-5p as a promising therapeutic target for the treatment of MI in the future.

Triglyceride glucose index combined with body mass index and its 4-year change with the risk of hypertension in middle-aged and older Chinese: A prospective cohort study.

BACKGROUND AND AIM: To explore the association of triglyceride glucose index-body mass index (TyG-BMI) and its dynamic changes with the risk of hypertension among middle-aged and older Chinese adults based on a large-sample prospective cohort study. METHODS AND RESULTS: Participants over 45 years old and without a history of hypertension were included from the China Health and Retirement Longitudinal Study registry. Data were collected in 2011 and followed up in 2015. TyG index and TyG-BMI were calculated as ln (triglyceride∗glucose/2) and TyG index∗BMI, respectively. We performed multivariate logistic regression analysis to identify the relationship between the TyG index, TyG-BMI and their dynamic change and the risk of hypertension. In the analyses, 3885 participants were included. After 4 years of follow-up, 1705 (43.89 %) patients developed hypertension. Logistic regression analysis revealed that after adjustments for all potential confounding factors, the highest tertile of baseline TyG index, baseline TyG-BMI, and the dynamic change in TyG-BMI were each associated with higher hypertension incidence than the lowest tertile: OR,1.38, 95 % CI, 1.17-1.63, OR,1.28, 95 % CI, 1.06-1.56, and OR, 1.26, 95 % CI, 1.07-1.48, respectively, whereas TyG index change was not. Moreover, the risk of hypertension increased with increasing levels of baseline TyG index (P for trend < 0.001), baseline TyG-BMI (P for trend = 0.013), and the dynamic change in TyG-BMI (P for trend = 0.006). CONCLUSIONS: The baseline TyG index, baseline TyG-BMI, and the dynamic changes in TyG-BMI were significantly and positively associated with the risk of hypertension in Chinese adults older than 45 years.

Virtual Reality-Based Training in Chronic Low Back Pain: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Low back pain is one of the most prevalent pain conditions worldwide. Virtual reality-based training has been used for low back pain as a new treatment strategy. Present evidence indicated that the effectiveness of virtual reality-based training for people with chronic low back pain is inconclusive. OBJECTIVE: This study conducted a meta-analysis to evaluate the immediate- and short-term effects of virtual reality-based training on pain, pain-related fear, and disability in people with chronic low back pain. METHODS: We searched the PubMed, Embase, Web of Science, PEDro, CENTRAL, and CINAHL databases from inception until January 2024. Only randomized controlled trials assessing the effects of virtual reality-based training on individuals with chronic low back pain were selected. The outcomes were focused on pain, pain-related fear measured by the Tampa Scale of Kinesiophobia, and disability measured by the Oswestry Disability Index. The immediate term was defined as the immediate period after intervention, and the short term was defined as 3 to 6 months after intervention. The Cochrane Risk of Bias tool and the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach were used to evaluate the quality of the methodology and evidence, respectively. RESULTS: In total, 20 randomized controlled trials involving 1059 patients were eligible for analysis. Virtual reality-based training showed significant improvements in pain (mean difference [MD] -1.43; 95% CI -1.86 to -1.00; I2=95%; P<.001), pain-related fear using the Tampa Scale of Kinesiophobia (MD -5.46; 95% CI -9.40 to 1.52; I2=90%; P=.007), and disability using the Oswestry Disability Index (MD -11.50; 95% CI -20.00 to -3.01; I2=95%; P=.008) in individuals with chronic low back pain immediately after interventions. However, there were no significant differences observed in pain (P=.16), pain-related fear (P=.10), and disability (P=.43) in the short term. CONCLUSIONS: These findings indicated that virtual reality-based training can be used effectively for individuals with chronic low back pain in the immediate term, especially to reduce pain, alleviate pain-related fear, and improve disability. However, the short-term benefits need more high-quality trials to be demonstrated. TRIAL REGISTRATION: PROSPERO CRD42021292633; http://tinyurl.com/25mydxpz.

Impact of vaginal microecological differences on pregnancy outcomes and endometrial microbiota in frozen embryo transfer cycles.

PURPOSE: This prospective study investigates the correlation between vaginal microecology and pregnancy outcomes and explores their impact on endometrial microbiota composition during frozen embryo transfer (FET) cycles. Additionally, the impact of transvaginal Lactobacillus supplementation on reproductive outcomes in patients with previous failed cycles was assessed. METHODS: A total of 379 patients undergoing FET at a reproductive medicine center were categorized into clinical pregnancy (CP), miscarriage (MISC), and non-pregnant (NP) groups. Vaginal specimens were collected for microecological evaluation prior to embryo transfer. Endometrial microbiota samples were obtained during embryo transfer for 16S rRNA gene sequencing analysis to assess endometrial microbiota composition. Vaginal microecological indicators, including pH, Lactobacillus dominance, and leukocyte esterase activity, were measured. Transvaginal Lactobacillus supplementation was investigated in 60 patients with previous failed cycles. RESULTS: Vaginal microecology significantly correlated with pregnancy outcomes, with normal microecology associated with a higher clinical pregnancy rate. Vaginal pH and leukocyte esterase activity were significantly associated with clinical pregnancy. Furthermore, vaginal microecological differences significantly impacted endometrial microbiota composition. However, no significant differences were observed in endometrial microbiota composition among the CP, MISC, and NP groups. Notably, transvaginal Lactobacillus supplementation increased the clinical pregnancy rate without affecting the miscarriage rate. CONCLUSION: This study highlights that normal vaginal microecology, characterized by lower pH and leukocyte esterase negativity, is associated with a higher likelihood of clinical pregnancy following FET. Importantly, vaginal microecological differences influence endometrial microbiota composition. Moreover, transvaginal Lactobacillus supplementation appears promising in improving clinical pregnancy rates in patients with previous failed cycles. These findings contribute to a better understanding of the interplay between vaginal and endometrial microbiota and offer potential interventions to enhance reproductive success in assisted reproductive technologies.

Bioactive neolignan, iridoid and flavonoid glycosides from the leaves of Vaccinium bracteatum.

Two neolignan glycosides including a new one (1), along with seven iridoid glycosides (3 - 9) and nine flavonoid glycosides (10 - 18), were isolated from the leaves of Vaccinium bracteatum. Their structures were established mainly on the basis of 1D/2D NMR and ESIMS analyses, as well as comparison to known compounds in the literature. The structure of 1 with absolute stereochemistry was also confirmed by chemical degradation and ECD calculation. Selective compounds showed antiradical activity against ABTS and/or DPPH. Moreover, several isolates also suppressed the production of ROS in RAW264.7 cells and exerted neuroprotective effect toward PC12 cells.

Successful secukinumab treatment of generalized pustular psoriasis.

Generalized pustular psoriasis is a rare variant of psoriasis. Evidence recommending generalized pustular psoriasis treatment with secukinumab is limited. This report aims to evaluate the use of secukinumab in two patients with generalized pustular psoriasis. The standard treatment regimen for secukinumab was as follows: 300mg subcutaneously once weekly in weeks 0-4, followed by 300mg every four weeks. The efficacy was evaluated by analyzing the psoriasis area and severity index (PASI) and dermatology life quality index (DLQI). One patient had generalized pustular psoriasis, which had developed from palmoplantar pustulosis over 12 years. The second patient was an adolescent with recurrent generalized pustular psoriasis. The first patient achieved PASI-75 response by week 3 and both PASI-90 and a DLQI score of 0 were observed by week 8. The second patient achieved PASI-75 response by week 4 and complete clinical resolution, except for nail changes, and a DLQI of 0 by week 8, without any adverse events.

Cerebrospinal fluid soluble programmed death-ligand 1 is a useful prognostic biomarker in primary central nervous system lymphoma.

The increased expression of programmed death-ligands 1 and 2 (PD-L1 and PD-L2, respectively) on tumour cells contributes to immune evasion, suggesting that these proteins are attractive therapeutic targets. This study aimed to evaluate the validity of cerebrospinal fluid (CSF) soluble PD-L1 (sPD-L1) and soluble PD-L2 (sPD-L2) as biomarkers for primary central nervous system lymphoma (PCNSL). We determined the CSF concentrations of sPD-L1 and sPD-L2 in 46 patients with PCNSL using enzyme-linked immunosorbent assays (ELISAs). A control group comprised 153 patients with other brain tumours, inflammatory/infectious status, or neurodegenerative diseases. Only CSF sPD-L1 levels were significantly higher in patients with PCNSL relative to the controls. CSF sPD-L1 also exhibited superior overall discrimination performance compared to CSF sPD-L2 in diagnosing PCNSL. Compared with patients with PCNSL with low CSF sPD-L1 levels, more patients with high levels had high serum lactate dehydrogenase levels, leptomeningeal involvement, and deep-brain involvement. Furthermore, CSF sPD-L1 could predict poor survival in PCNSL but CSF sPD-L2 could not. Intriguingly, CSF sPD-L1 levels were correlated with disease status and their dynamic changes post treatment could predict time to relapse. In conclusion, this study identified CSF sPD-L1 as a promising prognostic biomarker, indicating a therapeutic potential of PD-L1 blockade in PCNSL.

Vestibular rehabilitation therapy on balance and gait in patients after stroke: a systematic review and meta-analysis.

BACKGROUND: There is limited evidence to support the use of vestibular rehabilitation therapy (VRT) on improving balance and gait in patients after stroke. This systematic review aimed to evaluate the effects of VRT in addition to usual rehabilitation compared with usual rehabilitation on improving balance and gait for patients after stroke. METHODS: This review followed the Preferred Reporting Items for Systematic reviews and Meta-Analysis statement guidelines. Ten electronic databases were searched up to 1 June 2023 without restrictions in language and publication status. The PEDro scale and the Grading of Recommendations Assessment Development, and Evaluation were used to evaluate the risk of bias and the certainty of evidence. The meta-analysis was conducted with Review Manager 5.3. RESULTS: Fifteen randomised controlled trials with 769 participants were included. PEDro scale was used to assess the risk of bias with a mean score of 5.9 (0.7). VRT was effective in improving balance for patients after stroke (SMD = 0.59, 95% CI (0.40, 0.78), p < 0.00001), particularly for patients after stroke that occurred within 6 months (SMD = 0.56, 95% CI (0.33, 0.79), p < 0.00001) with moderate certainty of evidence. Subgroup analysis showed that VRT provided as gaze stability exercises combined with swivel chair training (SMD = 0.85, 95% CI (0.48, 1.22), p < 0.00001) and head movements (SMD = 0.75, 95% CI (0.43, 1.07), p < 0.00001) could significantly improve balance. Four-week VRT had better effect on balance improvement (SMD = 0.64, 95% CI (0.40, 0.89), p < 0.00001) than the less than 4-week VRT. The pooled mean difference of values of Timed Up-and-Go test showed that VRT could significantly improve gait function for patients after stroke (MD = -4.32, 95% CI (-6.65, -1.99), p = 0.0003), particularly for patients after stroke that occurred within 6 months (MD = -3.92, 95% CI (-6.83, -1.00), p = 0.008) with moderate certainty of evidence. CONCLUSIONS: There is moderate certainty of evidence supporting the positive effect of VRT in improving balance and gait of patients after stroke. TRIAL REGISTRATION: PROSPERO CRD42023434304.

Non-pharmacological therapy for chemotherapy-induced peripheral neurotoxicity: a network meta-analysis of randomized controlled trials.

BACKGROUND: Chemotherapy-induced peripheral neurotoxicity (CIPN) is the most common adverse effect in patients undergoing chemotherapy, and no effective interventions are currently available for its prevention and treatment. Non-pharmacological therapies appear to be beneficial for the prevention and treatment of CIPN, but it remains unclear which therapy is most effective. The aim of this study was to identify the most effective non-pharmacological therapy for CIPN patients. METHODS: PubMed, Web of Science, Embase, and Cochrane Library were searched for randomized controlled trials on non-pharmacological therapies for CIPN. The primary outcomes included pain and peripheral neuropathological symptoms, and the secondary outcomes included quality of life, sensory and motor symptoms. The pairwise analysis and a network meta-analysis were performed using a random effects model. RESULTS: A total of 46 articles were included in this study, involving 2,878 participants. Our study showed that massage was more effective in pain-alleviating compared with acupuncture [SMD = 0.81, 95%CI (0.04, 1.57)], vitamin and gabapentin [SMD = 2.56, 95%CI (1.39, 3.74)], and usual care and placebo [SMD = 0.9, 95%CI (0.31, 1.49)]. As for attenuating peripheral neuropathological symptoms, massage was more effective than usual care and placebo [SMD = 0.75, 95%CI (0.33, 1.17)], sensorimotor training [SMD = 1.17, 95%CI (0.24, 2.10)], electrostimulation [SMD=-1.18, 95%CI (-2.14, -0.21)], multimodal exercise [SMD=-0.82, 95%CI (-1.57, -0.08)], and resistance training [SMD = 1.03, 95%CI (0.11, 1.95)]. Massage was also more effective than other non-pharmacological therapies in improving quality of life, sensory and motor symptoms. CONCLUSIONS: According to our study, massage has advantages in alleviating pain, improving quality of life, and improving peripheral neuropathological symptoms and has better effect than other non-pharmacological interventions, representing certain clinical significance. However, the results of this study should be interpreted with caution due to the limitations of the included studies. In the future, more high-quality multi arm randomized controlled trials can be attempted to provide direct comparisons of the relative effects of non-pharmacological interventions.

A Layered Aluminophosphate [C17H21N2]3[Al3(PO4)4]·5H2O with Fluorescent Property Derived from Carbazolyl-Modified Template.

Designing and innovating organic structure-directing agents is the key to synthesizing novel molecular sieve structures. Herein, we design a novel carbazolyl-modified template and further synthesize a two-dimensional layered aluminophosphate with [C17H21N2]3[Al3(PO4)4]·5H2O (denoted as ZHKU-2). ZHKU-2 is composed of AA-stacked [Al3P4O16]3- layers constructed from alternating AlO4 and PO3(=O) tetrahedrons to form a 4.6.8 network featured by capped six-ring secondary building units. Carbazolyl-templated ZHKU-2 exhibits strong purple fluorescence with a high quantum yield of 25.98%. This work expands aluminophosphate materials of the [Al3P4O16]3- family and provides a view for synthesizing new molecular sieves by exploring the organic luminescence structure-directing agents.

HGF-Based CAR-T Cells Target Hepatocellular Carcinoma Cells That Express High Levels of c-Met.

BACKGROUND: CAR-T is emerging as an effective treatment strategy for hematologic malignancies, however its effectiveness for treating solid tumors, such as Hepatocellular Carcinoma (HCC) is limited. Here, we screened a variety of CAR-T cells that target c-Met to investigate their potential to induce HCC cell death in vitro. METHODS: Human T cells were transduced to express CARs by lentiviral vector transfection. c-Met expression in human HCC cell lines and CARs expression were monitored by flow cytometry. Tumor cell killing was evaluated by Luciferase Assay System Kit. The concentrations of cytokine were tested by Enzyme-linked immunosorbent assays. Knock down and overexpression studies targeting c-Met were conducted to assess the targeting specificity of CARs. RESULTS: We found that CAR T cells expressing a minimal amino-terminal polypeptide sequence comprising the first kringle (kringle 1) domain (denoted as NK1 CAR-T cells), efficiently killed HCC cell lines that expressed high levels of the HGF receptor c-Met. Furthermore, we report that while NK1 CAR-T cells were efficient at targeting SMMC7221 cells for destruction, and its potency was significantly attenuated in parallel experiments with cells stably expressing short hairpin RNAs (shRNAs) that suppressed c-Met expression. Correspondingly, overexpression of c-Met in the embryonic kidney cell line HEK293T led to their enhanced killing by NK1 CAR-T cells. CONCLUSION: Our studies demonstrate that a minimal amino-terminal polypeptide sequence comprising the kirngle1 domain of HGF is highly relevant to the design of effective CAR-T cell therapies that kill HCC cells expressing high levels of c-Met.

The search for a maximum of the D-π-A paradigm for second order nonlinear optical molecular materials.

Push-pull π-conjugated molecules are one of the paradigms of second order nonlinear optical (NLO) materials and have been extensively explored. However, high-performance second order NLO materials with an optimum electron donor (D), π-bridge (π) and acceptor (A) under this paradigm are still the most sought-after. In the present work, D-π-A molecules with optimal D, π and A combination for strong second order NLO properties are proposed based on molecular orbital theories. The optimal D-π-A push-pull molecule achieves an unprecedentedly strong NLO response under the D-π-A paradigm, i.e., the static first hyperpolarizability reaches -453.92 × 10-30 esu per heavy atom using azulene as part of the π-bridge and acceptor to synergistically reinforce the strength of the acceptor. The protocols of D-π-A NLO molecule design through frontier molecular orbital matching of D, π and A with optimal combination of electron donating and accepting strengths shed light on future molecular NLO materials exploration. The simulated two-dimensional second order spectra provide useful information (e.g., sum frequency generation) on the applications of those D-π-A push-pull molecules in nonlinear optics.

Monocyte to high-density lipoprotein ratio is associated with mortality in patients with coronary artery diseases.

BACKGROUND: Whether the monocyte to high-density lipoprotein ratio (MHR) is associated with the prognosis of coronary artery disease (CAD) is inconclusive. METHODS: Patients with CAD were enrolled and their data were collected. Blood was sampled within 24 h after admission. Multivariate Cox regression analysis was performed to determine the relationship between the MHR and all-cause mortality as well as complications during hospitalization. RESULTS: We included 5371 patients in our cohort study. Among them, 114 (2.12%) patients died in hospital. MHR was independently associated with all-cause mortality (hazard ratio [HR], 1.81; 95% confidence interval [CI] 1.35, 2.42), cardiovascular mortality (1.69; 1.17, 2.45) and non-cardiovascular mortality (2.04; 1.27, 3.28). This association was only observed in patients with hypertension (P for interaction = 0.003). Patients with higher MHR levels also have a higher risk of complications, including infection, pneumonia, electrolyte disturbance, gastrointestinal bleeding, multiple organ dysfunction syndrome, and disturbance of consciousness. The receiver operating characteristic (ROC) analysis showed that the MHR had higher prognostic values than monocytes and high-density lipoprotein. CONCLUSION: MHR was an independent predictor of all-cause mortality and in-hospital complications in patients with CAD, especially in patients with hypertension.

Effects of home-based cardiac telerehabilitation programs in patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis.

BACKGROUND: Recent advances in telecommunications technology have raised the possibility of telehealth intervention delivering cardiac telerehabilitation, which may provide the efficacy of health services in patients after percutaneous coronary intervention (PCI). This study aimed to investigate the effects of home-based cardiac telerehabilitation (HBCTR) in patients undergoing PCI. METHODS: We performed a comprehensive search of the following electronic databases: PubMed, Cochrane Central, Web of Science, Embase, CNKI, and WANFANG. For the prespecified outcomes, the primary outcomes were results of physical function (the six-minute walking test, 6MWT) and quality of life (QoL) of the participants. The secondary outcomes were results of (1) blood pressure; (2) full lipid profile (3) reliable assessment of anxiety and depression in patients. RESULTS: All studies were conducted between 2013 and 2022, and a total of 5 articles could be included in the quantitative meta-analysis. The results showed that there was a statistically significant difference between the HBCTR intervention group and the control group in 6WMT (MD 16.59, 95%CI 7.13 to 26.06, P = 0.0006), but there was no difference in QoL (SMD - 0.25, 95%CI - 1.63 to 1.13, P = 0.73). According to the fixed effects model, there was a statistically significant difference between the HBCTR group versus the control group (MD - 2.88, 95%CI - 5.19 to - 0.57, P = 0.01), but not in diastolic blood pressure. Likewise, significant improvements of triglycerides and in low-density lipoprotein cholesterol were observed in HBTCR groups, but no significant differences were observed regarding total cholesterol and high-density lipoprotein cholesterol. CONCLUSION: This systematic review and meta-analysis have proven that the HBCTR is one of the promisingly effective cardiac rehabilitation strategies that improve cardiorespiratory fitness and reduce cardiovascular disease risk factors. With the continuous improvement of the telerehabilitation network, it is expected to serve in clinical.

Effectiveness of robotic-assisted gait training on cardiopulmonary fitness and exercise capacity for incomplete spinal cord injury: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To determine the effects of robotic-assisted gait training on cardiopulmonary fitness and exercise capacity for people with incomplete spinal cord injury. METHODS: PubMed, Embase, Web of Science, PEDro, CENTRAL and CINAHL were searched from inception until September 4, 2022. Randomized controlled trials that evaluated the effects of robotic-assisted gait training on cardiopulmonary fitness and exercise capacity for individuals with incomplete spinal cord injury were selected. Mean differences (MD) with 95% confidence interval (CI) were calculated. The methodological quality was evaluated by the Cochrane Risk of Bias 2.0 tool. Subgroup analyses were conducted according to the time since injury. RESULTS: In total 19 studies involving 770 patients were eligible for analysis. Individuals with acute incomplete spinal cord injury in robotic-assisted gait training groups showed significantly greater improvements in 6-minute walking test (MD 53.32; 95% CI 33.49 to 73.15; P < 0.001), lower extremity motor scale (MD 5.22; 95% CI 3.63 to 6.80; P < 0.001) and walking index for spinal cord injury II (MD 3.18; 95% CI 1.34 to 5.02; P < 0.001). Robotic-assisted gait training improved peak oxygen consumption to a greater degree for chronic incomplete spinal cord injury patients (MD 4.90; 95% CI 0.96 to 8.84; P = 0.01). CONCLUSION: Robot-assisted gait training may be a feasible and effective intervention in terms of cardiopulmonary fitness and exercise capacity for individuals with incomplete spinal cord injury.

Association between neutrophil percentage-to-albumin ratio and pneumonia in patients with traumatic spinal cord injury.

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: To investigate the association between neutrophil percentage-to-albumin ratio (NPAR) and pneumonia in patients with SCI. SETTING: Department of Rehabilitation Medicine Center, West China Hospital, Sichuan University. METHODS: SCI patients admitted to West China Hospital within 24 h of injury were consecutively enrolled. Blood samples were collected on admission. Pneumonia was diagnosed based on chest radiography and clinician records of patient symptoms and laboratory tests. Multivariable logistic regression analysis was performed to determine the relationship between NPAR and pneumonia. Receiver operating characteristic (ROC) curves were generated to assess the predictive value of NPAR. RESULTS: A total of 264 SCI patients were included, of whom 65 (24.6%) developed pneumonia. NPAR was positively correlated with pneumonia (OR 2.66, 95% CI, 1.06-6.71, p = 0.038). Patients in the upper NPAR tertile (2.35-3.71) had a higher risk of pneumonia than patients in the lower tertile (1.66-2.12) after adjustment for potential confounders (OR 2.55, 95% CI, 1.05-6.19, p = 0.039). The risk of pneumonia increased stepwise across NPAR tertiles (p for trend = 0.031). The optimal cutoff value of NPAR for predicting pneumonia was 2.17 with a sensitivity of 0.82 and a specificity of 0.50. There was a significant interaction between NPAR and neurological level of injury (p for interaction = 0.034), with no significant association between NPAR and pneumonia in patients with cervical SCI. CONCLUSIONS: A higher NPAR was independently associated with higher risk of pneumonia in a dose-dependent manner in patients with non-cervical SCI.

Epidermal growth factor receptor inhibitors as adjuvant treatment for patients with resected non-small cell lung cancer harboring EGFR mutation: a meta-analysis of randomized controlled clinical trials.

BACKGROUND: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is still under investigation as adjuvant treatment for early-stage disease. Here, we performed a meta-analysis to evaluate the efficacy of adjuvant EGFR-TKI versus non-EGFR-TKI treatment in patients with completely resected non-small cell lung cancer (NSCLC) harboring EGFR mutation. METHODS: Two investigators independently extracted data from databases. A meta-analysis was performed following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The protocol was registered in PROSPERO (ID: CRD42022316481). The primary outcome was disease-free survival (DFS) in patients with EGFR mutation, measured as the hazard ratio (HR). Other outcomes (of subgroup analyses) included overall survival (OS) and DFS. RESULTS: After the systematic screening, eight studies with a total of 3098 patients with stage IB-IIIA NSCLC were included. The results show that in patients with EGFR mutation, the DFS in the adjuvant EGFR-TKI group was significantly superior to that in the control group, with a HR of 0.47 (95% confidence interval [CI]: 0.30-0.74; P = 0.001). In subgroup analyses of DFS, the benefit was observed in the EGFR-TKI group versus the chemotherapy group (HR 0.50, 95% CI 0.30-0.84; P = 0.009), the EGFR-TKI combined with chemotherapy group versus the chemotherapy group (HR 0.37, 95% CI 0.16-0.85; P = 0.02), and in stage IIA-IIIA NSCLC (HR 0.45, 95% CI 0.27-0.74; P = 0.002). However, the benefit of DFS did not translate into improved OS in the whole population (HR 0.79, 95% CI 0.54-1.14; P = 0.20). CONCLUSION: EGFR-TKIs prolonged DFS but not OS in patients with completely resected stage II-IIIA NSCLC harboring EGFR mutation. Longer follow-ups and new clinical trials that can result in changes in clinical practice are needed.

A multicenter, randomized controlled study on the efficacy of agomelatine in ameliorating anhedonia, reduced motivation, and circadian rhythm disruptions in patients with major depressive disorder (MDD).

OBJECTIVE: To evaluate the clinical efficacy and safety of Agomelatine in improving symptoms in patients with major depressive disorder (MDD), providing more scientific evidence for the treatment of depression, and offering more effective therapeutic options for patients. METHODS: A total of 180 MDD patients in acute phase from 10 psychiatric hospitals of Grade three in Zhejiang Province were enrolled in this 12-week study with the competitive and consecutive pattern, and they were randomized into two different groups treated with flexible-dosage antidepressants of selective serotonin reuptake inhibitors (SSRI) or agomelatine, respectively. The subjects were evaluated with psychological scales of HAMD-17, HAMA, SHAPS for anhedonia, MFI-20 for fatigue, PQSI for sleep quality and MEQ for disturbances in chronobiologic rhythms at baseline, 2, 4, 8 and 12-weekend points, and TESS was used for side-effect. The results were analyzed with repeated measurement analysis of variance. RESULTS: The two groups each had 90 participants, and there were no significant differences at baseline. The scores of various assessment scales showed statistically significant time main effects during the visits (P < 0.01). The Agomelatine group demonstrated faster efficacy within 2 weeks, with better improvement in SHAPS, MEQ, and PSQI compared to the SSRIs group. However, the remission rate at 12 weeks was lower in the Agomelatine group than in the SSRIs group (63.3% and 72.2%), but the difference between the groups was not statistically significant. The Agomelatine group had fewer adverse reactions (14.4% and 16.7%), but there was a slightly higher incidence of liver function impairment (6.7% and 4.4%), with no statistically significant difference between the groups. CONCLUSION: Agomelatine, as a novel antidepressant, shows certain advantages in improving depression and anxiety symptoms and is comparable to SSRIs in terms of safety. However, its long-term efficacy and safety on MDD or other depressive subtypes still require further observation and research.

CD44 promotes angiogenesis in myocardial infarction through regulating plasma exosome uptake and further enhancing FGFR2 signaling transduction.

BACKGROUND: Since angiogenesis occurs as the pathological process following myocardial infarction to alleviate ischemia, therapeutic angiogenesis has been proposed to be a cardioprotective strategy. CD44 has been implicated in endothelial cell functions and its role has been well established in angiogenesis for years. Although recent studies indicate the close correlation between CD44 and exosome, as well as the two being implicated in myocardial ischemia pathological processes, the effect and the underlying mechanism of CD44 and its regulated plasma exosome in pathological angiogenesis post-myocardial infarction have not been fully elucidated. METHODS: In this study, we used CD44 knockout mice to study the in vivo impacts of CD44 on ischemic angiogenesis in myocardial infarction. Mouse cardiac function was measured by echocardiography, histological changes were observed by Evans Blue and TTC-double staining and Masson's trichrome staining, and molecular changes were detected by immunofluorescence. In the in vitro study, CD44 knockout HUVECs were generated and CD44 inhibitor was used to study the mechanism of CD44 on angiogenesis. We performed the immunoprecipitation, proximity ligation assay, and super-resolution imaging to study the mechanistic regulation of FGFR2 signaling transduction by CD44. Importantly, we also isolated plasma exosomes from myocardial infarction model mice and studied the effect of plasma exosomes on the activation of the FGFR2 signaling pathway and the related phenotypic alterations, including exosomes uptake and angiogenic function in primary mouse microvascular endothelial cells, and further discovered the regulation mechanism of exosomal miRNAs. RESULTS: We observed that the expression of CD44 in the border zone of the infarcted heart was tightly related to pathological angiogenesis following myocardial ischemia. The depletion of CD44 impaired angiogenesis and impacts biogenesis and proangiogenic function of plasma exosomes. Subsequently, we found that CD44 mediated the activation of the FGFR2 signaling pathway as well as the caveolin 1-dependent uptake of exosomes in vascular endothelial cells. Most importantly, the proangiogenic therapeutic effect of plasma exosomal miRNAs depended upon the participation of CD44/FGFR2 signaling transduction in vascular endothelial cells. CONCLUSION: CD44 and its regulated plasma exosomes have crucial potent angiogenic activity. Our studies elucidate that CD44 plays a key role in plasma exosomal miRNA-enhanced angiogenic FGFR2 singling transduction and ischemic angiogenesis in the early stage of myocardial infarction.

Induction of COX-2 by feline calicivirus via activation of the MEK1-ERK1/2 pathway, and attenuation of feline lung inflammation and injury by MEK1 inhibitor AZD6244 (selumetinib).

Feline calicivirus (FCV) is an important and highly prevalent pathogen of cats that causes acute infectious respiratory disease. Here it is shown in vitro that FCV induces the production of cyclooxygenase-2 (COX-2) through the MEK1-ERK1/2 signaling pathway. Screening of FCV proteins revealed that FCV non-structural protein VPg enhanced COX-2 mRNA expression and protein production in CRFK cells in a concentration-dependent manner. Regions 24-54aa and 84-111aa in FCV VPg were essential for up-regulation. In vivo, COX-2 and IL-6 production caused by FCV infection of kittens was significantly suppressed by the MEK1 inhibitor AZD6244 (selumetinib) and lung inflammation and injury were practically eliminated, with body temperature being returned to normal. AZD6244 may therefore find application as an effective therapeutic agent for the treatment of FCV infection.