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Introduction: Berberine (BBR) is an alkaloid found in plants. It has neuroprotective, anti‐inflammatory and lipid‐lowering activity. However, the efficacy of treatment with BBR and the mechanisms through which it acts need further study. Aims: This study investigated the therapeutic effects and the mechanism of action of BBR on obesity‐induced insulin resistance in peripheral tissues. Methods: High‐fat‐fed C57BL/6J mice and low‐fat‐fed C57BL/6J mice with miR‐27a overexpression were given BBR intervention (100 mg/kg, po), and the oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were performed. Palmitic acid‐stimulated hypertrophic adipocyte models were treated with BBR (10 μM). Related indicators and protein expression levels were examined. Results: The AUCs of the OGTT and the ITT in the BBR intervention group were reduced significantly (p < 0.01) (p < 0.05), and the serum biochemical parameters, including FBG, TC, TG and LDL‐C were significantly reduced after BBR intervention. In the in vitro experiments, the triglyceride level and volume of lipid droplets decreased significantly after BBR intervention (p < 0.01) (p < 0.05). Likewise, BBR ameliorates skeletal muscle and pancreas insulin signalling pathways in vivo and in vitro. Discussion: The results showed that BBR significantly ameliorated insulin resistance, reduced body weight and percent body fat and improved serum biochemical parameters in mice. Likewise, BBR reduced triglyceride level and lipid droplet volume in hypertrophic adipocytes, BBR improved obesity effectively. Meanwhile, BBR ameliorated the histomorphology of the pancreas, and skeletal muscle and pancreas insulin related signalling pathways of islets in in vitro and in vivo experiments. The results further demonstrated that BBR inhibited miR‐27a levels in serum from obese mice and supernatant of hypertrophic adipocytes. miR‐27a overexpression in low‐fat fed mice indicated that miR‐27a caused insulin resistance, and BBR intervention significantly improved the miR‐27a induced insulin resistance status. Conclusion: This study demonstrates the important role of BBR in obesity‐induced peripheral insulin resistance and suggest that the mechanism of its effect may be inhibition of miR‐27a secretion. [ABSTRACT FROM AUTHOR]

There is an increasing interest in non-pharmacological treatments for children with attention-deficit/hyperactivity disorder (AD/HD), especially digital techniques that can be remotely delivered, such as neurofeedback (NFT) and computerized cognitive training (CCT). In this study, a randomized controlled design was used to compare training outcomes between remotely delivered NFT, CCT, and combined NFT/CCT training approaches. A total of 121 children with AD/HD were randomly assigned to the NFT, CCT, or NFT/CCT training groups, with 80 children completing the training program. Pre- and post-training symptoms (primary outcome), executive and daily functions were measured using questionnaires as well as resting EEG during eyes-closed (EC) and eyes-open (EO) conditions. After 3 months of training, the inattentive and hyperactive/impulsive symptoms, inhibition, working memory, learning and life skills of the three groups of children were significantly improved. The objective EEG activity showed a consistent increase in the relative alpha power in the EO condition among the three training groups. Training differences were not observed between groups. There was a positive correlation between pre-training EO relative alpha power and symptom improvement scores of inattention and hyperactivity/impulsivity, as well as a negative correlation between pre-training inattention scores and change in EO relative alpha. This study verified the training effects of NFT, CCT, and combined NFT/CCT training in children with AD/HD and revealed an objective therapeutic role for individual relative alpha activity. The verified feasibility and effectiveness of home-based digital training support promotion and application of digital remote training. [ABSTRACT FROM AUTHOR]

Background: V domain Immunoglobulin suppressor of T cell activation (VISTA) has been proved to be a novel immune checkpoint molecule that positively regulates T cell infiltration in several malignancies. However, the clinical impact of VISTA on muscle-invasive bladder cancer (MIBC) patients remains relatively obscure. Methods: This study enrolled 135 MIBC patients from Zhongshan Hospital (ZSHS) and 391 patients from The Cancer Genome Atlas (TCGA) to examine the VISTA expression and immune contexture based on immunohistochemistry (IHC) staining and CIBERSORT algorithm. Additionally, IMvigor210 Cohort included 195 bladder-derived urothelial carcinoma patients to evaluate the efficacy of immunotherapy. Kaplan-Meier curve and Cox regression analyses were conducted to assess clinical outcomes. Results: MIBC patients with high VISTA+ immune cells (ICs) possessed poor overall survival and inferior therapeutic responsiveness to adjuvant chemotherapy (ACT), but superior responsiveness to PD-L1 inhibitor. VISTA+ ICs infiltration shaped an immunoevasive context featured by regulatory T cells (Tregs), M2 macrophages, mast cells and exhausted CD8+ T cells infiltration, with increased interleukin 10 (IL-10), transforming growth factor-β (TGF-β) and interferon-γ (IFN-γ), but also elevated T-cell immunoglobulin mucin-3 (TIM-3), lymphocyte activation gene 3 (LAG-3) and T-cell immunoglobulin and ITIM domain (TIGIT), which was also mainly presented in basal-squamous and luminal-infiltrated subtypes of MIBC. Conclusion: VISTA+ ICs infiltration could be an independent predictor to identify poor prognosis and therapeutic responses (PD-L1 blockade and ACT) in MIBC patients, which was associated with immunoevasive contexture. The novel immune checkpoint VISTA might be utilized as a candidate treatment biomarker in MIBC patients. [ABSTRACT FROM AUTHOR]

Background: Smoking is an established modifying factor for the host immune response of periodontitis patients. However, its exact influence remains unclear. We aimed to compare the cytokine profile of periodontitis patients with and without smoking habits both before and after periodontal therapy to preliminarily explore its influence on the host immune response to periodontitis. Methods: The protocol of the present meta-analysis was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the code CRD42021255656. Meta-analysis was performed for each cytokine if at least three studies were included. We synthesized the evidence to compare the cytokine profile of periodontitis with and without smoking both in gingival cervical fluid (GCF) and serum to explore the impact of smoking on periodontitis both locally and systemically. Moreover, we also compared the cytokine profile of the two groups of patients after periodontal therapy to explore the effect of smoking on the outcome of periodontal therapy. Results: Fifteen studies were included in this meta-analysis. We found that there was no significant difference between the two groups of patients in the baseline cytokine profile. However, after periodontal therapy, smoking periodontitis patients showed significantly higher IL-1β levels in their GCF than nonsmoking patients. Discussion: There was no significant difference between smoking and nonsmoking periodontitis patients in the baseline cytokine profile. However, after periodontal therapy, smoking periodontitis patients showed significantly higher IL-1β levels in their GCF than nonsmoking patients, which indicates that smoking may impair the response of periodontitis to periodontal treatment. [ABSTRACT FROM AUTHOR]

Acne vulgaris (AV) is a common dermatosis that causes psychological problems. Isotretinoin is the first-line treatment for moderate-to-severe AV, but its onset of effect is delayed. Although light-based therapy is widely used in the treatment of AV, there is a lack of reports on delicate pulsed light (DPL) which has a narrow therapeutic spectrum (500-600 nm). Low-level light therapy (LLLT) has shown an emerging role in anti-inflammatory effects and skin repair. This study investigates the efficacy and safety of low-dose oral isotretinoin combined with LLLT using DPL in patients with moderate-to-severe AV. Thirty-six patients with moderate-to-severe AV were enrolled and received low-dose oral isotretinoin (10-20 mg/day). The two sides of the face were randomly assigned to receive DPL (6-9 J/cm2) or not at an interval of 2 weeks for 4 treatment sessions (weeks 0, 2, 4, 6). Photos, GAGS score, counts of papules, pustules, comedones, TEWL, melanin and erythema index, side effects, efficacy, and satisfactory score were recorded at each visit and at 4 weeks after the final treatment (week 10). Thirty-three patients completed the study. DPL and oral isotretinoin combined therapy exhibited significantly improved GAGS score as well as the number of the lesions from week 2 and maintained until week 10. At the end of the observation, the improvement of GAGS was 70.88% on the DPL and isotretinoin combined side versus 62.12% on the side with isotretinoin monotherapy (p = 0.0009). The improvement for papule number was 61.58% on the DPL combined side versus 43.33% on the control side (p < 0.0001), for comedone was 63.15% versus 43.30% (p = 0.0008). TEWL and indexes of melanin and erythema also had better outcomes with DPL combined therapy at week 10. All the side effects were temporary and tolerable; no adverse effects were observed. Oral low-dose isotretinoin combined with LLLT by DPL offers a combination with reduced side effects and better outcomes within a limited treatment duration, which advances the onset of effect of isotretinoin monotherapy and improves lesion clearance. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint blockade (ICB) and adjuvant chemotherapy (ACT) have shown clinical benefit in muscle-invasive bladder cancer (MIBC) with only a few predictive biomarkers identified so far. Neuropilin-1 (NRP1) has been identified as a key immune checkpoint and a novel immunotherapeutic target but the clinical significance of NRP1 remains unclear in MIBC. Methods: Three independent cohorts were involved in our study: IMvigor210 Cohort (n = 348), The Cancer Genome Atlas Cohort (TCGA, n = 391), and Zhongshan Hospital Cohort (ZSHS, n = 130). Parallel detection and validation of risk stratification based on NRP1 expression were executed in patients treated with anti-PD-L1 agent and adjuvant chemotherapy (ACT). Results: NRP1 expression conferred poor survival and predicted response to both PD-L1 blockade and cisplatin-based ACT in MIBC. Further exploration revealed high-level NRP1 was extremely associated with infiltration of exhausted CD8+ T cells, immature NK cells and M2 polarized tumor-associated macrophages in MIBC patients. Moreover, elevated NRP1 expression was also correlated with low mutation burden and reduced mutation in cell cycle pathway. Conclusions: Our study firstly identified and validated the clinical implications of NRP1 expression for prognosis and systematic therapeutic responses (PD-L1 blockade and ACT) in MIBC. NRP1 expression was associated with an immunosuppressive microenvironment with dysfunctional effector immune cells. Prospective investigations of its roles in the therapeutic landscape of MIBC warrant more consideration. [ABSTRACT FROM AUTHOR]

To assess the feasibility of motor unit number index (MUNIX) in quantitatively evaluating Hirayama disease (HD) with proximal involvement and to identify the effectiveness of anterior cervical fusion (ACF) in treating atypical HD with proximal involvement. This study included 28 atypical HD patients with proximal involvement (proximal-distal vs. distal-proximal groups: 5 vs. 23) and 41 healthy controls. All patients underwent pre- and postoperative 1-year MUNIX tests on abductor pollicis brevis (APB), abductor digiti minimi (ADM), biceps brachii (BB) and deltoid (Del). The disabilities of arm, shoulder and hand (DASH) and Medical Research Council (MRC) scales were also performed in these patients before and one year after operation. Preoperatively, the patients in the distal-proximal group showed reduced compound muscle action potential (CMAP), decreased MUNIX and increased motor unit size index (MUSIX) in bilateral distal muscles and symptomatic-side proximal muscles (P < 0.05), and similar abnormalities were also observed in ADM, BB and Del on the symptomatic side in the proximal-distal groups (P < 0.05). Postoperative follow-up analysis identified increased MUNIX in the symptomatic-side proximal muscles with improved motor function in the proximal-distal groups (P < 0.05), and distal-proximal group patients showed an increase in both CMAP and MUSIX in the symptomatic-side proximal muscles (P < 0.05). MUNIX may serve as an available supplementary test to quantitatively evaluate the motor dysfunction and treatment outcome in HD with proximal involvement. ACF procedures can effectively treat these atypical HD patients, especially for those whose symptoms started in proximal muscles. [ABSTRACT FROM AUTHOR]

Purpose Methods Results Conclusion Level of Evidence To compare clinical outcomes of autologous osteoperiosteal transplantation versus bone marrow stimulation (BMS) for medium‐sized (100–150 mm2) cystic osteochondral lesions of the talus (OLTs) and assess the correlation between patient demographics and outcomes. It was hypothesised that autologous osteoperiosteal transplantation would provide better clinical outcomes than BMS for medium‐sized cystic OLTs.Patients who underwent autologous osteoperiosteal transplantation or BMS for medium‐sized cystic OLTs between 2014 and 2019 were retrospectively evaluated. According to their characteristics, a 1:1 propensity‐score matching was performed and 33 pairs of patients were matched. The visual analogue scale, American Orthopaedic Foot and Ankle Society (AOFAS) score, Foot Ankle Outcome Score (FAOS) and Ankle Activity Score were collected preoperatively and at the last follow‐up. In addition, a general linear model analysis was performed between patient demographics and clinical outcomes in two groups separately to detect potential risk factors.Finally, 28 patients in the grafted group and 27 patients in the BMS group completed the follow‐up and were enrolled with a mean follow‐up period of 63.5 ± 13.9 months. Both groups showed significant improvement in all patient‐reported outcomes (p < 0.01). At the final follow‐up, no significant differences between groups were found in all postoperative scores except FAOS Pain (p = 0.02). Correlation analysis showed a moderate correlation between cyst depth and the postoperative AOFAS score in the BMS group (r = −0.48, p = 0.01). Based on the regression line, the patients in the BMS group with a cyst deeper than 6 mm showed a lower AOFAS score than the mean score (88.7 ± 9.5) of the grafted group.Autologous osteoperiosteal transplantation and BMS are both safe and effective for medium‐sized cystic OLTs. However, autologous osteoperiosteal transplantation is expected to provide better clinical outcomes than BMS when the cysts are deeper than 6 mm.Level III. [ABSTRACT FROM AUTHOR]

Background Context: Surgical treatment is indicated for symptomatic thoracic ossification of posterior longitudinal ligament (OPLL), and circumferential decompression (CD) is a promising option. However, the risk of postoperative paralysis in ventral decompression of CD is as high as 30%. Therefore, it is important to balance surgical outcomes and safety of ventral decompression.Purpose: To investigate the role of intraoperative motor-evoked potential (MEP) changes in decision-making of one-staged CD via posterior approach for treating thoracic OPLL.Study Design: A retrospective cohort analysis PATIENT SAMPLE: Twenty-five thoracic OPLL patients in this study underwent posterior decompression (PD) alone, and the other 21 patients accepted CD.Outcome Measures: Intraoperative MEP monitoring from both abductor hallucis and tibialis anterior, and modified Japanese Orthopaedic Association (mJOA) scores.Methods: MEPs were recorded in all patients before and after PD, and patients accepting CD underwent further MEP recordings after ventral decompression. According to MEP changes after PD, patients were divided into MEP improvement, MEP deterioration and no MEP change. Postoperative MEP improvement rates were measured in all tested muscles. Additionally, all patients accepted mJOA scores before and 2 years after operation.Results: Patients in both CD and PD groups exhibited improved mJOA scores after operation (p<.05), and both mJOA and MEP improvement rates were similar between these two groups (p>.05). In no MEP change group, patients accepting CD exhibited increased mJOA improvement rates compared with those accepting PD (p<.05). In MEP deterioration group, higher mJOA improvement rates were observed in PD group than in CD group (p<.05). In MEP improvement group, mJOA improvement rates were similar between CD and PD groups (p>.05).Conclusions: Both CD and PD can effectively treat thoracic OPLL, and which of these two strategies can achieve better functional recovery may be related to different MEP changes after PD. Therefore, monitoring MEP changes may provide additional references in decision-making of one-staged CD for treating thoracic OPLL. [ABSTRACT FROM AUTHOR]

Context: Up to 40% of patients with polycystic ovary syndrome (PCOS) have prediabetes; an optimal pharmacotherapy regimen for diabetes prevention in PCOS is yet to be established.Objective: To evaluate clinical efficacy of exenatide (EX), metformin (MET), or combination (COM) for prediabetes in PCOS.Design: Randomized, open-label, parallel-group controlled trial.Setting: Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine.Patients: PCOS with prediabetes (fasting plasma glucose 5.6-6.9 mmol/L and/or 2 hour post glucose 7.8-11.0 mmol/L on oral glucose tolerance test [OGTT]). A total of 150 out of 183 eligible enrollees completed the study.Intervention: EX (10-20μg daily), MET (1500-2000 mg daily), or COM (EX plus MET) for 12 weeks.Main Outcome Measures: Sustained remission rate of prediabetes (primary endpoint, a normal OGTT after 12 weeks of treatment followed by 12 weeks of washout on no drug treatment) along with anthropometric, hormonal, metabolic, and pancreatic β-cell function parameters (secondary endpoints) and potential mechanisms were assessed.Results: Impaired glucose tolerance was found the dominant prediabetes phenotype. Overall sustained prediabetes remission rate was 50.7%. Remission rate of COM group (64%, 32/50) or EX group (56%, 28/50) was significantly higher than that of the MET group (32%, 16/50) (P = .003 and .027, respectively). EX was associated with superior suppression of 2-hour glucose increment in OGTT. A 2-step hyperglycemic clamp study revealed that EX had led to higher postprandial insulin secretion than MET, potentially explaining the higher remission rate.Conclusions: Compared with MET monotherapy, EX or COM achieved higher rate of remission of prediabetes among PCOS patients by improving postprandial insulin secretion. [ABSTRACT FROM AUTHOR]

Objectives. To verify the protective effect of phosphocreatine on myocardium in an ischemic model and the possible mechanism of action. Methods. The model of myocardial ischemia/reperfusion (I/R) was established by the ligation balloon method. 30 SD rats were randomly divided into three groups, n = 10 in each group. Sham operation group: the coronary artery was not blocked and observed for 120 minutes. The ischemia/reperfusion (I/R) group was given ischemia for 30 minutes and ischemia reperfusion for 90 minutes. Phosphocreatine (PCr) group: after 30 minutes of ischemia, the rats were intraperitoneally injected with PCr (200 mg/kg) for 90 minutes. The animal groups of myocardial ischemia/reperfusion model in vitro were the same as those in vivo. The heart was removed by thoracotomy and washed immediately in H-K buffer solution. Then, the heart was installed on the Langendorff instrument. The concentration of PCr perfusion fluid in the PCr group was 10 mmol/L. The changes in coronary blood flow in isolated myocardium were recorded. The heart rate and electrocardiogram were recorded by RM6240BT. At the end of the experiment, myocardial pathological sections and Cx43 immunofluorescence staining were made, and the contents of malondialdehyde (MDA) in myocardial tissue were detected. Results. Phosphocreatinine treatment improved the myocardial ischemia model, performance in electrocardiogram (ECG) changes (ST segment apparent), and histological changes (decrease in necrotic myocardial cells, inflammatory cell infiltration, and a reduction in myocardial edema). At the same time, MDA decreased, while coronary blood flow and Cx43 expression significantly improved. Conclusions. Phosphocreatine can improve the electrocardiogram and restore histologic changes in ischemic myocardium and coronary blood flow. The postulated mechanism is by inhibiting the generation of free oxygen radicals and restoring the expression of Cx43 protein. [ABSTRACT FROM AUTHOR]

Rationale, aims, and objectives: Acute postoperative pain can result in immune dysfunction, which can be partly mitigated by efficient pain management. Opioids that have been widely applied to analgesia have been shown to suppress immune function, which has a negative impact on the treatment of patients with cancer. This study investigated the effects of perioperative fentanyl analgesia alone or in combination with parecoxib sodium on postoperative pain, immune function, and prognosis in patients undergoing hepatectomy of hepatocellular carcinoma (HCC). Methods: A total of 80 patients scheduled for hepatectomy between October 2013 and August 2014 were included. Patients were randomly divided into two groups (n = 40) and allocated to receive parecoxibsodium 40 mg (group P) or placebo (group C) 30 minutes before induction of anaesthesia, followed by 40 mg every 12 hours for 48 hours after the operation. All patients had access to patient‐controlled analgesia with intravenous fentanylpostoperatively. Venous blood samples were collected at the following time points: 30 minutes before induction of anaesthesia (T0), the end of the surgery (T1), 24 hours after surgery (T2), and 72 hours after surgery (T3). The percentages of CD3+, CD4+, CD8+, CD4+/CD8+ T cells, and CD3+CD16+CD56+ (NK) cells at these time points were quantified by flow cytometry (FCM).Visual analogue scale (VAS) scores, total fentanyl consumption, and adverse effects were recorded. The prognostic differences in overall survival (OS) and disease‐free survival (DFS) between the two groups was also investigated. Results: For both groups, the percentages of CD3+, CD4+ T cells, and the ratio of CD4+/CD8+ significantly decreased at T1 and T2 (P <.05). The percentages of CD3+ T cells were significantly lower in group C than that in group P at T2 (P <.05). In group C, the amount of CD3+ T cells was lower at T3 compared with T0 (P <.05). The percentages of NK cells significantly decreased at T1 in both groups (P <.05). The percentages of NK in group P were recovered nearly to baseline (T0) at T2, which was higher than that of group C (P <.05). In group C, the percentages of NK cells have not recovered nearly to baseline at T3 compared with T0 (P <.05). VAS scores at rest and on cough in group P were significantly lower than those in group C at 2, 6, 12, and 24 hours after operation (P <.05), and there were no significant differences in VAS scores between the two groups at 48 hours after surgery (P >.05). There were no significant differences regarding the incidence of adverse effects between the two groups (P >.05). Kaplan‐Meier analysis indicated that the DFS time in group P was significantly longer than in group C (19.0 months, 95% confidence interval [CI], 9.8–28.2 vs 14.0 months, 95% CI, 8.1–19.9; P <.05). There was no significant difference in OS time (36.0 months, 95% CI, 13.4–58.9 vs 14.0 months, 95% CI, 10.6–25.4; P >.05) between two groups. Conclusions: The present study indicated that perioperative analgesia of parecoxib sodium combined with patient‐controlled analgesic fentanyl resulted in better preserved immune function with enhancement of the analgesic efficacy to fentanyl alone of HCC patients undergoing hepatectomy and helped postpone postoperative tumour recurrence. [ABSTRACT FROM AUTHOR]

Pathological hypoxia-induced organ dysfunction contributes to the high mortality of sepsis. Because of the microcirculation dysfunction following severe sepsis, it is difficult for erythrocytes to transport oxygen to hypoxic tissues. Haemoglobin-based oxygen carriers (HBOCs) are capable of delivering oxygen to hypoxic tissues. The aim of this study is to observe the potential benefits of a novel bovine-derived, non-polymerized, cell-free HBOC solution, YQ23, on sepsis in rats. Cecum ligation and puncture was performed to induce sepsis in Sprague-Dawley rats. Effects of Lactate Ringer's solution (LR), YQ23, and whole blood on oxygen delivery and consumption, mitochondrial function, organ protection and animal survival were observed. LR failed to restore oxygen delivery and the therapeutic effects were limited, whereas low dosage of YQ23 and whole blood significantly increased the tissue oxygen delivery and consumption, improved the mitochondrial function of heart, liver, kidney and intestine, prevented the vital organs injuries and improved the animal survival. The effects of 0.15 g·kg−1 YQ23 resembled that of the whole blood. In addition, YQ23 did not induce renal toxicity, severe oxidative effect and acute vasoconstriction. Thus, YQ23 is a safe and effective resuscitation fluid for sepsis. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the protective effects of Shexiang Tongxin Dropping Pill (麝香通心滴丸, STP) on Na2S2O4-induced hypoxia-reoxygenation injury in cardiomyoblast H9c2 cells. Methods: The cell viability and levels of mRNA and protein expression in H9c2 cells were determined following Na2S2O4-induced hypoxia using Hoechst staining, annexin V/propidium iodide (PI) flow cytometry, real-time polymerase chain reaction and Western blot analysis. Results: STP pretreatment significantly increased the viability and inhibited aberrant morphological changes in H9c2 cardiomyoblast cells induced by Na2S2O4 treatment (P<0.05). In addition, STP pretreatment attenuated Na2S2O4-induced hypoxic damage, down-regulated the expression of pro-apoptotic Bax, and up-regulated the expression of anti-apoptotic Bcl-2 in H9c2 cells (P<0.05). Conclusions: STP was strongly cardioprotective in hypoxia-reoxygenation injury by preventing hypoxic damage and inhibiting cellular apoptosis. These results further support the use of STP as an effective drug for the treatment of ischemic heart disease. [ABSTRACT FROM AUTHOR]

Objective To report the efficacy and safety of lamotrigine in the treatment of one case of Becker myotonia congenita. Methods and Results A 17 - year - old male had muscle stiffness in the limbs as the first symptom, which could be alleviated after repeated exercise. The creatine kinase (CK) level was normal. Genetic testing showed there were two missense mutations c.1205C > T (p.Ala402Val) and c.896T > C (p.Val299Ala) located in exon 11 and 8 of CLCN1 gene respectively in the proband. The missense mutation c.1205C > T (p.Ala402Val) in exon 11 was found out in his mother and c.896T > C (p. Val299Ala) located in exon 8 was found out in his father. The latter, exon 8 c.896T > C of CLCN1 gene has not been reported. The proband was clearly diagnosed as Becker myotonia congenita, and his family was diagnosed as Becker myotonia congenita pedigree. After 5 years' treatment with lamotrigine, the symptom of myotonia was significantly improved and no adverse reactions was observed. Conclusions The missense mutation in exon 8 c.896T > C in this patient further expanded the CLCN1 gene mutation spectrum. Lamotrigine is effective in treating Becker myotonia congenita, providing a new idea for the treatment of myotonia congenita. [ABSTRACT FROM AUTHOR]

Aims: To assess predictors of glycemic control after patients with type 2 diabetes mellitus (T2DM), inadequately controlled with oral antidiabetic drugs (OADs), were initiated basal insulin (BI) in the Observational Registry of BI Treatment study in China. Materials and Methods: This multicenter, 6-month prospective registry study included patients, ages 18–80 years, who enrolled in secondary and tertiary hospitals, representative of the eight geographic regions in China. In this subgroup analysis of patients who completed the 6-month follow-up, relationship between several variables and glycemic control (glycosylated hemoglobin [HbA1c] <7%) at 6 months was examined using logistic regression. Results: Overall, 16,271 completed the 6-month visit and were included in this subgroup analysis. At 6 months, mean HbA1c was 7.4% ± 1.4%. Multivariate logistic regression analysis showed significant independent associations between a higher HbA1c control rate with frequent self-monitoring of blood glucose (SMBG) at baseline (odds ratio [OR] = 1.02; P < 0.0001), continuous use of BI (OR = 1.56; P < 0.05), and increased SMBG frequency at 6 months (OR = 1.02; P < 0.0001). Large insulin dose at 6 months [0.25–0.35 IU/(kg·day): OR = 0.64 and ≥0.35 IU/(kg·day): OR = 0.63; P < 0.05], higher HbA1c levels at baseline (OR = 0.80; P < 0.0001), longer duration of diabetes (OR = 0.97; P = 0.0002), and more OADs at baseline (2 OADs: OR = 0.81 and ≥3 OADs: OR = 0.63; P < 0.0001) were associated with a lower HbA1c control rate. Conclusions: The major predictors of good glycemic control after the initiation of BI therapy in T2DM patients were lower baseline HbA1c levels, consistent use of BI, frequent SMBG at baseline and increase in the frequency of SMBG, shorter duration of diabetes, and fewer OADs at baseline. [ABSTRACT FROM AUTHOR]

Objectives. To evaluate the effect and safety of 5-hydroxytryptamine (5-HT) receptor antagonist in alleviating the pain of patients under general anesthesia induced by rocuronium injection and preemptive analgesia. Methods. Meta-analysis was conducted with RevMan 5.1 software by electronically retrieving the databases of PubMed, Embase, the Cochrane Library, WanFang Data, and CNKI and collecting the published random control tests (RCTs) where 5-hydroxytryptamine receptor antagonist was used to alleviate the pain/limb shrinkage reaction associated with rocuronium injection. Results. Seven RTCs, including 556 patients, were included. The results of meta-analysis showed the following. (1) Compared to the control group, 5-HT receptor antagonist could prevent the total pain/limb shrinkage reaction associated with rocuronium injection [RR=0.62, 95% CI (0.54, 0.71), P<0.00001] and reduce the incidence rate of mild and moderate pain/limb shrinkage reaction associated with rocuronium injection [RR=0.46, 95% CI (0.33, 0.63), P<0.00001; RR=0.18, 95% CI (0.11, 0.31), P<0.000 01]. (2) Compared to the lidocaine group, the incidence rate was higher in preventing the pain/limb shrinkage reaction associated with rocuronium injection by 5-HT receptor antagonist, which was statistically significant [RR=1.33, 95% CI (1.05, 1.68), P=0.02]. Conclusion. 5-hydroxytryptamine receptor antagonist may be effective in preventing the pain/limb shrinkage reaction associated with rocuronium injection. [ABSTRACT FROM AUTHOR]

Background: The expression alterations of B4GALT1 have been noted in some types of cancer and they are related to cancer cell proliferation, invasiveness, metastasis, and drug resistance. We aimed to establish the expression of B4GALT1 in bladder cancer and its connection to patient outcomes, as well as forecasting the advantages of adjuvant chemotherapy (ACT) in patients with muscle-invasive bladder cancer (MIBC).Methods: There were 142 and 112 MIBC patients who were consecutively recruited and treated via radical cystectomy from 2008 to 2012 in Shanghai Zhongshan Hospital and Fudan University Shanghai Cancer Center (FUSCC), respectively. Tissue microarrays (TMAs) were constructed in triplicate from specimens that had been fixed in formalin and embedded in paraffin samples. Immunohistochemistry was conducted to evaluate B4GALT1 expression in tumor cores, the connection between B4GALT1 expression and patients' clinical characteristics, and clinical results.Results: B4GALT1 expression was not connected to clinical prognosis markers, but it was linked to overall survival (OS) (P = 0.013 and P = 0.010, respectively) in the two groups. Moreover, the high levels of B4GALT1 expression were independent indicators of poor OS (P = 0.026 and P = 0.046, respectively). Inclusion of B4GALT1 in the prognostic model revealed a greater predictive accuracy than the primary models. In addition, no differences were observed between B4GALT1 expression (low vs. high) and CD8+ T cell infiltration density (number/cm2) within tumor cores, but there was a positive Pearson correlation between B4GALT1 expression and expression of inhibitory receptor ligands, such as PD-L1 and CTLA4. Most significantly, the advantage of ACT noted in pT3/4 or N+ bladder cancer patients with low B4GALT1 expression was greater than in patients with a high B4GALT1 expression.Conclusions: Our evaluation indicated that B4GALT1 may be a possible prognosticator of MIBC, and it may be a predictive marker for the choice of ACT in pT3/4 or N+ patients. [ABSTRACT FROM AUTHOR]

Background: Complementary and alternative medicines (CAM) are sometimes used by individuals who desire to improve the outcomes of their fertility treatment and/or mental health during fertility treatment. However, there is little comprehensive information available that analyzes various CAM methods across treatment outcomes and includes information that is published in languages other than English. Method: This scoping review examines the evidence for 12 different CAM methods used to improve female and male fertility outcomes as well as their association with improving mental health outcomes during fertility treatment. Using predefined key words, online medical databases were searched for articles (n = 270). After exclusion criteria were applied, 148 articles were analyzed in terms of their level of evidence and the potential for methodological and author bias. Results: Surveying the literature on a range of techniques, this scoping review finds a lack of high quality evidence that complementary and alternative medicine (CAM) improves fertility or mental health outcomes for men or women. Acupuncture has the highest level of evidence for its use in improving male and female fertility outcomes although this evidence is inconclusive. Conclusion: Overall, the quality of the evidence across CAM methods was poor not only because of the use of research designs that do not yield conclusive results, but also because results were contradictory. There is a need for more research using strong methods such as randomized controlled trials to determine the effectiveness of CAM in relation to fertility treatment, and to help physicians and patients make evidence-based decisions about CAM use during fertility treatment. [ABSTRACT FROM AUTHOR]

Background: Posterior cervical pedicle screw (CPS) internal fixation has better biomechanical stability than other posterior cervical fixation methods. However, this technique is limited in clinical practice due to the complex anatomical structure and the adjacent relationship of the cervical pedicle, and the high risk of neurovascular injury. The purpose of this study was to describe a novel subaxial CPS insertion technique assisted by a special angular scale using lateral mass as a reference marker and to evaluate the accuracy of CPS placement and the distribution characteristics of CPS misplacement. Methods: A total of 36 patients with subaxial cervical spine diseases who underwent posterior CPS fixation were consecutively selected. The optimal entry point on the posterior surface of the lateral mass was identified on the three-dimensional cervical model reconstructed from preoperative computed tomography (CT) images. The pedicle transverse angle (PTA) and pedicle-lateral mass angle (PLMA) were measured on the transverse and sagittal CT images respectively. The pedicle screws were inserted according to the preoperatively planned entry point and angles. We analysed the postoperative CT images for CPS misplacement rates and perforation directions following the Lee classification. Results: Overall, 177 pedicle screws were inserted, of which 119 (67.2%) were classified as grade 0, 43 (24.3%) as grade 1, 12 (6.8%) as grade 2 and 3 (1.7%) as grade 3 by the postoperative CT images. The accuracy rate of CPS placement was 91.5%. Of the 15 misplaced pedicle screws (grades 2 and 3), 11 were lateral pedicle perforations, 3 were superior perforations and 1 was an inferior perforation. There were no neurovascular injuries related to CPS misplacement. Conclusions: With our technique, the optimal entry point and two angles (PTA and PLMA) were identified for CPS insertion. The novel CPS insertion technique assisted by a special angular scale provides high accuracy and few complications. [ABSTRACT FROM AUTHOR]

Background: The video laryngoscope is recommended for intubating difficult airways. The present study aimed to determine whether the video laryngoscope can further improve intubation success rates compared with the direct laryngoscope in patients with non-difficult airways. Methods: In total, 360 patients scheduled for elective abdominal surgeries were randomly assigned to undergo intubation using either a video laryngoscope (n = 179) or a direct laryngoscope (n = 181). The following parameters were measured: mouth opening; thyromental distance; sternomental distance; shape angle of the tracheal catheter; and glottic exposure grade. Results: The percentage of patients with level I-II of total glottic exposure in the video laryngoscope group was 100% versus 63.5% in the direct laryngoscope group (P < 0.001). The one-attempt success rate of intubation was 96.1% using a video laryngoscope versus 90.1% using a direct laryngoscope (P = 0.024). The intubation success rate using a video laryngoscope was 100% versus 94.5% using a direct laryngoscope (P = 0.004). Immediate oropharyngeal injury occurred in 5.1% of patients intubated using a direct laryngoscope versus 1.1% using a video laryngoscope (P = 0.033). On postoperative day 1, obvious hoarseness was exhibited by 7.9% of patients intubated using a direct laryngoscope versus 2.8% using a video laryngoscope (P = 0.035). The grade of glottic exposure and catheter shape angle were independent risk factors for tracheal intubation failure. Thyromental distance, shape angle, glottic exposure time, and surgical position were independent risk factors for postoperative complications. Thyromental distance and glottic exposure time were independent risk factors for complications lasting > 2 days. Conclusions: Intubation using a video laryngoscope yielded significantly higher intubation success rates and significantly fewer postoperative complications than direct laryngoscopy in patients with non-difficult airways. Trial registration: Chinese Clinical Trial Registry. No: ChiCTR-IOR-16009023. Prospective registration. [ABSTRACT FROM AUTHOR]

• Acute traumatic central cord syndrome (ATCCS) has adverse downstream effect on distal motor axons. • Early surgical treatment can immediately ameliorate downstream excitability abnormalities in ATCCS. • Distal axonal excitability abnormalities after ATCCS may partly contribute to motor unit loss. To investigate the impact of early vs. delayed surgical decompression on peripheral motor axonal dysfunction following acute traumatic central cord syndrome (ATCCS). Both axonal excitability testing and motor unit number estimation (MUNE) were performed in 30 ATCCS patients (early- vs. delayed-surgical treatment: 12 vs. 18) before operation and 28 healthy subjects. Axonal excitability testing was repeated 3–5 days and 1-year after operation, and MUNE was re-evaluated 1-year after operation. Preoperatively, an obvious modification in membrane potentials was observed in ATCCS patients that mostly coincided with depolarization-like features, and MUNE further revealed reduced motor units in tested muscles (P < 0.05). Unlike delayed-surgical cases, early-surgical cases showed recoveries of most measurements of axonal excitabilities soon after operation (P < 0.05). Postoperative one-year follow-up demonstrated that greater motor unit numbers in tested muscles were obtained in early-surgical cases than in delayed-surgical cases (P < 0.05). ATCCS has adverse downstream effects on peripheral nervous system, even in the early stage of ATCCS. Early surgical treatment can ameliorate both excitability abnormalities and motor unit loss in distal motor axons. Optimizing axonal excitability in the early phases of ATCCS may alleviate peripheral nerve injury secondary to lesions of upper motor neuron and improve clinical outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Deep vein thrombosis (DVT) is a major cause of cardiovascular disease-related deaths worldwide and is considered a thrombotic inflammatory disorder. IL-1β, as a key promoter of venous thrombus inflammation, is a potential target for DVT treatment. Constructing a nanocarrier system for intracellular delivery of siIL-1β to silence IL-1β may be an effective strategy for alleviating DVT. Methods: ELISA was used to detect the expression levels of IL-1β and t-PA in the serum of DVT patients and healthy individuals. In vitro, HUVEC cells were treated with IL-1β, and changes in VWF and t-PA expression levels were assessed. PBAE/MCM-41@siIL-1β (PM@siIL-1β) nano-complexes were synthesized, the characterization and biocompatibility of PM@siIL-1β were evaluated. A rat hind limb DVT model was established, and PM@siIL-1β was used to treat DVT rats. Morphology of the inferior vena cava, endothelial cell count, IL-1β, vWF, and t-PA levels, as well as changes in the p38 MAPK and NF-κB pathways, were examined in the different groups. Results: IL-1β and t-PA were highly expressed in DVT patients, and IL-1β treatment induced a decrease in VWF levels and an increase in t-PA levels in HUVEC cells. The synthesized PM@siIL-1β exhibited spherical shape, good stability, high encapsulation efficiency, and high drug loading capacity, with excellent biocompatibility. In the DVT model rats, the inferior vena cava was filled with blood clots, endothelial cells increased, IL-1β and VWF levels significantly increased, while t-PA levels were significantly downregulated. Treatment with PM@siIL-1β resulted in reduced thrombus formation, decreased endothelial cell count, and reversal of IL-1β, VWF, and t-PA levels. Furthermore, PM@siIL-1β treatment significantly inhibited p38 phosphorylation and upregulation of NF-κB expression in the DVT model group. Conclusion: IL-1β can be considered a therapeutic target for suppressing DVT inflammation. The synthesized PM@siIL-1β achieved efficient delivery and gene silencing of siIL-1β, demonstrating good therapeutic effects on rat hind limb DVT, including anti-thrombotic and anti-inflammatory effects, potentially mediated through the p38 MAPK and NF-κB pathways. [ABSTRACT FROM AUTHOR]

B7-H4, a sibling to PD-L1 in B7 family, has been reported to be a novel immune checkpoint that is prevalent among non-inflamed tumors. Herein, we attempt to explore the potential of B7-H4 in survival prediction and therapeutic guidance in muscle-invasive bladder cancer (MIBC) patients. This study included 391 patients from The Cancer Genome Atlas (TCGA) database and 122 patients from Zhongshan (ZS) Hospital. The evaluation of response to PD-L1 inhibitors was based on 270 patients in IMvigor210 cohort. Kaplan–Meier survival and multivariate analyses were performed to assess clinical outcomes in three cohorts. The correlation of B7-H4 expression with immune contexture and genomic alterations was analyzed based on immunohistochemistry, Microenvironment Cell Populations-counter (MCP-counter) tool, and whole-exome sequencing. MIBC patients with the high level of B7-H4 expression (B7-H4high) were found to possess an inferior overall and recurrence-free survival. Nonetheless, substantial clinical benefits of cisplatin-based chemotherapy and anti-PD-L1 immunotherapy were observed in these patients. After identifying a positive correlation between B7-H4 and tumor mutation burden (TMB), clinical benefits in B7-H4high TMBhigh subgroup were found to be the most upon PD-L1 blockade. Further studies revealed that B7-H4high subgroup was featured by non-inflamed immune contexture and cell cycle-related gene alterations. Despite adverse clinical outcomes, B7-H4high patients possessed superior responsiveness to chemotherapy and immunotherapy. B7-H4 stratification could also synergize with TMB to pinpoint the patients who benefited most from immunotherapy. The clinical exploration of B7-H4 as a companion predictor could allow clinicians to direct proper therapeutic agents to patients. • B7-H4 expression was proved to be an adverse prognosticator in MIBC. • B7-H4high patients had prolonged survival after chemotherapy or immunotherapy. • B7-H4high TMBhigh patients might benefit most from PD-L1 blockade. • B7-H4 correlated with non-inflamed immune contexture in MIBC. [ABSTRACT FROM AUTHOR]

Background and Aim: Osteoporotic vertebral compression fractures (OVCFs) are acknowledged to be common fractures, especially in the elderly population. Minimally invasive percutaneous methods of treatment for these fractures such as kyphoplasty (KP) and vertebroplasty (VP) have been valid and effective tools for decreasing clinical problems, which are associated with more beneficial effects compared with traditional methods such as open surgery or conservative treatment. Hence, we conducted the current meta-analysis in order to gather updated evidence for the systematic assessment of clinical and radiographic outcomes of KP compared with VP.Methods: We searched articles published based on the electronic databases, including PubMed, EMBASE, and Cochrane Library. Publications of studies comparing KP with VP in the treatment of OVCFs were collected. After rigorous and thorough review of study quality, we extracted the data on the basis of eligible trials, which analyzed the summary hazard ratios (HRs) of the end points of interest.Results: Our inclusion criteria involved a total of 6 studies. In total, data from 644 patients, 330 who received VP and 284 who received KP, were included in the review. There was no significant difference in either group in terms of visual analog scale (VAS) scores (MD = 0.17; 95% CI, -0.39 to 0.73; P = .56), risk of cement leakage (odds ratio [OR] = 1.31; 95% CI, 0.62 to 2.74; P = .47) or Oswestry Disability Index (ODI) scores (MD = 0.51; 95% CI, -1.87 to 2.88; P = .68). Nevertheless, the injected cement volume (MD = -0.52; 95% CI, -0.88 to -0.15; P = .005) in the VP group was linked to a markedly lower statistically significant trend compared with the KP group.Conclusion: This meta-analysis evaluated acceptable efficacy levels across the involved trials. VP injected cement volume had several advantages in this meta-analysis. Yet, no significant differences were observed in terms of VAS scores, ODI scores, or cement leakage when KP was compared to VP therapy. Given the combined results of our study, the optimal treatment for patients with OVCFs should be determined by further high-quality multicenter randomized controlled trials with longer follow-up and larger sample sizes. [ABSTRACT FROM AUTHOR]

Hepatocyte lipid accumulation is the main feature in the early stage of nonalcoholic fatty liver disease (NAFLD). Highland barley Monascus purpureus Went (HBMPW), a fermentation product of Hordeum vulgare Linn. var. nudum Hook. f. has traditionally been used as fermented foods in Tibet with the effect of reducing blood lipid in folk medicine. This study investigated the protective effects and molecular mechanism of highland barley Monascus purpureus Went extract (HBMPWE) on NAFLD in syrian golden hamster fed with high-fat, high-fructose, high-cholesterol diet (HFFCD). HFFCD-induced NAFLD golden hamster model was established and treated with HBMPWE. Liver index, biochemical index, and hematoxylin and eosin (HE) staining were observed. Liver metabolomics and western blot analysis were employed. Our study found that HBMPWE ameliorated HFFCD induced dyslipidemia, weight gain and elevated the liver index. In addition, HBMPWE treatment significantly attenuated lipid accumulation in the liver and modulated lipid metabolism (sphingolipid, glycerophospholipid). Our data demonstrated that HBMPWE not only regulated the expression of proteins related to fatty acid synthesis and decomposition (SREBP-1/ACC/FAS/AceS1, PPARα/ACSL/CPT1/ACOX1), but also regulated the expression of proteins related to cholesterol synthesis and clearance (HMGCR, LDLR, CYP7A1). HBMPWE improved NAFLD through multiple pathways and multiple targets in body metabolism and could be used as a functional food to treat NAFLD and other lipid metabolic disorders. [Display omitted] • Evaluation for anti-NAFLD effect of highland barley Monascus purpureus Went (HBMPW). • Providing the insight into the anti-NAFLD mechanism of HBMPW. • Finding for HBMPW significantly increase the amount of ACSL1 in mitochondria. [ABSTRACT FROM AUTHOR]

Study Design: A retrospective cohort analysis.Objective: The aim of this study was to investigate the impact of piecemeal versus en bloc laminectomies on spinal cord in thoracic ossification of ligamentum flavum (TOLF) through intraoperative changes of motor-evoked potentials (MEPs) and somatosensory-evoked potentials (SEPs).Summary Of Background Data: Surgical treatment is indicated for symptomatic TOLF, and both piecemeal and en bloc laminectomies are commonly used methods. However, few studies compared both intraoperative interference and prognostic impact of these two laminectomies on spinal cord in TOLF patients.Methods: MEPs were recorded from abductor hallucis (AH) and tibialis anterior, and SEPs were performed on tibial nerve in 55 TOLF patients (piecemeal vs. en bloc: 23 vs. 32). Patients were categorized based on MEP/SEP improvement, deterioration, and no change, and MEP/SEP improvement rates were measured in the improvement group. Additionally, all patients were assessed by American Spinal Injury Association (ASIA) scores, Ashworth scores, and modified Japanese Orthopedic association (mJOA) scores before and after operation.Results: The incidences of both MEP/SEP improvement and deterioration were similar between the two laminectomy groups (P > 0.05), and no significant difference is noted in both MEP and SEP amplitudes between the baseline and different critical manipulations in both laminectomy groups (P > 0.05). In the improvement group, patients receiving en bloc laminectomy exhibited increased improvement rates of both MEPs in bilateral AH and left-side SEPs compared to piecemeal laminectomy (P < 0.05). Clinically, all functional scales clearly improved in both laminectomy groups after operation (P < 0.05), and postoperative 1-year mJOA improvement rates were highly correlated with MEP improvement rates (P < 0.05).Conclusion: Intraoperative changes of MEPs and SEPs potentially provide a valid method for quantitatively evaluating the safety of different intraoperative manipulations and their prognostic impacts on spinal cord. Both laminectomies are safe and effective methods to treat TOLF, and en bloc laminectomy may cause relatively better spinal cord functional recovery.Level of Evidence: 3. [ABSTRACT FROM AUTHOR]

Background: Sex differences in the long-term prognosis of symptomatic hypertrophic obstructive cardiomyopathy (HOCM) patients undergoing alcohol septal ablation (ASA) remain unclear, especially in the Chinese Han population.Method: This cohort study included 320 HOCM Chinese Han patients who underwent ASA because of symptomatic left ventricular outflow tract (LVOT) obstruction. Patients were grouped according to sex: females (mean±standard deviation age [SD] 50.7±6.8 years) and males (mean±SD age 52.6±7.3 years). Individuals were followed over the long term.Results: Pre-procedure, women had more symptoms (New York Heart Association [NYHA] class III-IV 67.3% vs 56.3%, p=0.03), more atrial fibrillation (23.5% vs 14.6%, p=0.047) than men. Transient complete atrioventricular block after ASA was more common in woman than in men (34.0 vs 23.4%; p=0.048). Residual LVOT gradient, post-procedural residual left ventricular wall thickness, NYHA functional class, and adverse arrhythmic events were comparable between the two groups. The 10-year survival rate (77% vs 89%, p=0.037) and the annual adverse arrhythmic event rate (1.3% vs 0.4%, p<0.01) following ASA were significantly worse in women compared with men. Kaplan-Meier analysis showed a significantly lower survival in women compared with men (p=0.023). In multivariable modelling, female sex remained independently associated with higher all-cause mortality (hazard ratio, 1.12; 95% confidence interval, 1.08-1.27; p=0.03) when adjusted for age, NYHA class III-IV symptoms, and other cardiovascular comorbidities.Conclusions: Female patients with HOCM undergoing ASA tended to have more severe symptoms and adverse arrhythmic events. The 10-year survival rate after ASA was significantly worse in women compared with men with HOCM. Sex may need to be considered as an important factor in the clinical management of patients with symptomatic HOCM. [ABSTRACT FROM AUTHOR]

Background: Previous studies have shown the prognostic value of PAK1 expression in different tumor patients, including nonmetastatic renal cell carcinoma. In this study, we explored the prognostic and drug predictive value of PAK1 expression in metastatic renal cell carcinoma (mRCC) patients treated with tyrosine kinase inhibitors (TKIs).Materials and Methods: We retrospectively enrolled 138 mRCC patients treated with TKIs from a single institution from 2005 to 2014. Analyses were based on 111 patients who met our inclusion criteria. The validation set enrolled 538 RCC patients from The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma cohort (TCGA KIRC) between 1998 and 2013 in North America. PAK1 expression was assessed by immunohistochemistry (IHC) on tissue microarrays.Results: High PAK1 expression was associated with short overall survival (OS) (P < 0.001) and progression-free survival (PFS) (P = 0.008). Multivariate analyses further indicated that PAK1 expression was an independent prognostic factor for OS (hazard ratio 3.301 [95% confidence interval 2.579-10.899], P < 0.001) and PFS (hazard ratio 3.108 [95% confidence interval 1.795-5.381], P < 0.001). Subgroup analyses suggested that PAK1 was more significant in patients with the intermediate risk group of Heng risk criteria (OS, P = 0.004). Of note, patients treated with Sunitinib showed improved outcome in the low PAK1 subgroup (OS, P = 0.002; PFS, P = 0.013). Finally, relationship was found between PAK1 expression and natural killer cell-mediated cytotoxicity according to gene profile investigation.Conclusions: High PAK1 expression predicted dismal prognosis in mRCC patients treated with TKIs. Besides, PAK1 was a potential predictor for TKIs treatments. [ABSTRACT FROM AUTHOR]

Background: CD47 has been identified as a phagocytosis checkpoint conferring poor clinical outcomes in various cancer types. A flurry of clinical trials designed to evaluate agents that block CD47 have been initiated. We aimed to explore the clinical significance of CD47 and its correlation with immune infiltration and molecular features in clear cell renal cell carcinoma (ccRCC).Methods: 235 tumor tissue microarray specimens of ccRCC patients from Zhongshan Hospital, 530 ccRCC patients from The Cancer Genome Atlas and 726 ccRCC patients from JAVELIN Renal 101 study were analyzed. CD47 expression and immune contexture were examined by immunohistochemistry and CIBERSORT algorithm. Survival analyses were conducted through Kaplan-Meier curves and Cox regression model.Results: We demonstrated that ccRCC patients with high CD47 expression exhibited inferior overall survival and recurrence-free survival. CD47 expression associated with heavily immune infiltrated but immunosuppressed microenvironment. CD8+ T cells infiltration had discordant prognostic value based on CD47 expression, where high CD8+ T cell infiltration was associated with worse clinical outcome in CD47hi patients and with favorable prognosis in CD47lo patients. Patients with mutated PBRM1 and SETD2 correlated with decreased CD47 mRNA expression. Patients with higher CD47 expression possessed improved PFS in ICI + VEGFR TKI combination therapy.Conclusions: CD47 expression was an independent prognosticator of clinical outcome for ccRCC patients. CD47 expression correlated with ccRCC molecular classification and response to combination therapy. The phagocytosis checkpoint CD47 could be applied as an attractive candidate for immunotherapeutic approach in ccRCC. [ABSTRACT FROM AUTHOR]

Objectives: In tumor immune microenvironment, the functions of tumor-associated macrophages (TAMs), including phagocytosis and immunomodulatory, have attracted increasing attention recently. With the discovery of CD47-signal regulatory protein-α (SIRPα) as "don't eat me" signaling pathway, the role of novel subpopulation of TAMs expressing SIRPα has not been fully elucidated in a wide spectrum of solid tumors including bladder cancer. In this study, we investigated the prognostic and predictive implication of SIRPα+ TAMs regarding clinical outcomes and adjuvant chemotherapeutic benefit in muscle-invasive bladder cancer (MIBC), and preliminarily characterized the phenotypic features of SIRPα+ TAMs and its relationship with immune contexture.Materials and Methods: A total of 141 histochemical MIBC samples from Zhongshan Hospital (ZS), 45 fresh tissue samples, and 391 MIBC patients from TCGA database were enrolled in this study. SIRPα+ TAMs was evaluated by immunohistochemical staining of CD68 and SIRPα, and flow cytometry fluorescence staining.Results: Our results illustrated that SIRPα+ TAMs were enriched in MIBC specimens. Patients with high SIRPα+ TAMs infiltration suffered significant poor overall survival and recurrence-free survival (P = 0.0030 and P = 0.0282). SIRPα+ TAMs infiltration was an independent prognosticator in multivariate Cox model. Moreover, adjuvant chemotherapy (ACT) application showed significantly survival benefit in patients with low SIRPα+ TAMs infiltration (P = 0.0135). SIRPα+ TAMs with suppressive phenotype exhibited a positive correlation with immune tolerance and dysfunctional CD8+ T cells in MIBC.Conclusions: SIRPα+ TAMs infiltration indicated poor prognosis and ACT resistance in MIBC. Immunosuppressive SIRPα+ TAMs is closely related to immune evasion with exhausted T cells states, suggesting the prospect of SIRPα+ TAMs as a potential therapeutic target in MIBC. [ABSTRACT FROM AUTHOR]