Predictive effect of PD-L1 expression for immune checkpoint inhibitor (PD-1/PD-L1 inhibitors) treatment for non-small cell lung cancer: A meta-analysis

BackgroundProgrammed death-ligand-1 (PD-L1) is a well-known predictive biomarker in non-small cell lung cancer (NSCLC) patients, however, its accuracy remains controversial. Here, we investigated the correlation between PD-L1 expression level and efficacy of its inhibitors, and hence assessed the predictive effect of PD-L1 expression.MethodsStudies that evaluated the efficacy of programmed death-1 (PD-1)/ PD-L1 inhibitors in advanced NSCLC patients according to tumor PD-L1 expression levels were searched for on Medline, Cochrane Library, and Embase. The pooled risk ratio (RR) and 95% confidence intervals (95% CIs) were calculated for the objective response rate (ORR) with overall survival (OS) and progression-free survival (PFS) were measured in terms of hazard ratio (HR) and the corresponding 95% CIs.Results1432 NSCLC patients from six randomized controlled trials (RCTs) were included and three PD-1/PD-L1 inhibitors (atezolizumab, nivolumab, and pembrolizumab) were used to treat the patients. A significantly higher ORR was observed in the high PD-L1 expression group compared to the low expression group (0.35 [95% CI, 0.30–0.40] vs 0.11 [95% CI, 0.09–0.14]). The results of the subgroup analysis, grouped by the type of drugs and antibodies which assess immune checkpoint inhibitors were identical with the pooled result. However, our study showed that PD-L1 expression was neither prognostic nor predictive of overall survival (OS) or progression-free survival (PFS) in patients treated with PD-1/PD-L1 inhibitors compared to chemotherapy.ConclusionsPD-L1 can be a predictive biomarker for ORR. Nevertheless, PD-L1 expression is not a good predictive tool for OS and PFS.     

The role of cancer-related inflammation for prediction of poor survival in postmenopausal female patients with stage II/III colon cancer

ObjectiveCancer-related inflammation (CRI) is thought to be a successful predictor of prognosis in colon cancers (CC), but opinions on how to use it are highly variable. In this study, the role of CRI cells in survival for CC patients was investigated by considering gender and menopausal status.Methods163 stage II/III CC patients who underwent curative surgery between 1995 and 2015 were included in the study. The relationship between CRI cells was examined using a standard methodology.ResultsHigh neutrophil-lymphocyte ratio (NLR) had a better relationship with prognostic factors, especially in postmenopausal women (gender, p = 0.037, positive surgical margin, p = 0.001; MSI, p < 0.001; Crohn’s-like reaction, p = 0.001, etc). Also, the reproducibility of the study was better in postmenopausal women (intra-observer agreement = 0.72, intra-class correlation = 0.722, correlation of estimates = 0.718). In univariate analysis, 5-year survival was worse in postmenopausal women with high NLR (OS, p = 0.001; RFS, p < 0.001). In multivariate analysis, high NLR was independently a worse biomarker for OS (hazard ratio [HR], 1.29; 95% CI, 1.18–2.12; p = 0.001) and RFS (HR, 1.30; 95% CI, 1.21–2.59; p < 0.001) in postmenopausal women.ConclusionsNLR had an independent poor prognostic significance in postmenopausal female patients, and the use of a standard approach for methodology improved successful results.     

Prognostic and clinicopathological utility of PD-L2 expression in patients with digestive system cancers: A meta-analysis

ObjectiveProgrammed death ligand-2 (PD-L2) has been detected in various cancers. However, its prognostic value in digestive system cancers (DSCs) remains unclear. Accordingly, this meta-analysis investigated the prognostic and clinicopathological utility of PD-L2 in patients with DSCs.MethodsWe systematically searched PubMed, EMBASE, Web of Science, ClinicalTrials.gov., Scopus, and Cochrane Library databases for eligible studies up to April 30, 2020. The hazard ratio (HR), odds ratio (OR), and corresponding 95% confidence interval (CI) of the outcomes were calculated.ResultsTwenty two studies with 4886 patients were included in this meta-analysis. The pooled results showed that PD-L2 overexpression was significantly associated with poor overall survival (OS) (HR 1.470, 95% CI: 1.252–1.728, p < 0.001) and worse disease-free survival (DFS) (HR1.598, 95% CI: 1.398–1.826, p < 0.001). Subgroup analysis revealed that elevated PD-L2 was a significant prognostic indicator of worse OS in hepatocellular carcinoma (HR 1.703, 95% CI: 1.456–1.991, p < 0.001) and colorectal cancer (HR 3.811, 95% CI: 1.718–8.454, p = 0.001). Concerning clinicopathologic factors, PD-L2 overexpression was associated with lymphatic metastasis (OR 1.394., 95% CI: 1.101–1.764, p = 0.006), tumor metastasis (OR 1.599, 95% CI: 1.072–2.383, p = 0.021), and the histopathological stage (OR 0.704, 95% CI: 0.566–0.875, p = 0.002).ConclusionPD-L2 overexpression in DSCs after surgery might predict a poor prognosis, especially in hepatocellular carcinoma and colorectal cancer. Larger patient cohorts are needed to validate its prognostic role.     

Comparison between standard Vs. Escalated dose venous thromboembolism (VTE) prophylaxis in critically ill patients with COVID-19: A two centers,observational study

IntroductionThe risk of mortality in patients with COVID-19 was found to be significantly higher in patients who experienced thromboembolic events. Thus, several guidelines recommend using prophylactic anticoagulants in all COVID-19 hospitalized patients. However, there is uncertainty about the appropriate dosing regimen and safety of anticoagulation in critically ill patients with COVID-19. Thus, this study aims to compare the effectiveness and safety of standard versus escalated dose pharmacological venous thromboembolism (VTE) prophylaxis in critically ill patients with COVID-19.MethodsA two-center retrospective cohort study including critically ill patients aged ≥ 18-years with confirmed COVID-19 admitted to the intensive care unit (ICU) at two tertiary hospitals in Saudi Arabia from March 1st, 2020, until January 31st, 2021. Patients who received either Enoxaparin 40 mg daily or Unfractionated heparin 5000 Units three times daily were grouped under the “standard dose VTE prophylaxis and patients who received higher than the standard dose but not as treatment dose were grouped under ”escalated VTE prophylaxis dose“. The primary outcome was the occurance of thrombotic events, and the secondary outcomes were bleeding, mortality, and other ICU-related complications.ResultsA total of 758 patients were screened; 565 patients were included in the study. We matched 352 patients using propensity score matching (1:1). In patients who received escalated dose pharmacological VTE prophylaxis, any case of thrombosis and VTE were similar between the two groups (OR 1.22;95 %CI 0.52–2.86; P = 0.64 and OR 0.75; 95% CI 0.16–3.38; P = 0.70 respectively). However, the odds of minor bleeding was higher in patients who received escalated VTE prophylaxis dose (OR 3.39; 95% CI 1.08–10.61; P = 0.04). There was no difference in the 30-day mortality nor in-hospital mortality between the two groups (HR 1.17;95 %CI0.79–1.73; P = 0.43 and HR 1.08;95 %CI 0.76–1.53; P = 0.83, respectively).ConclusionEscalated-dose pharmacological VTE prophylaxis in critically ill patients with COVID-19 was not associated with thrombosis, or mortality benefits but led to an increased risk of minor bleeding. This study supports previous evidence regarding the optimal dosing VTE pharmacological prophylaxis regimen for critically ill patients with COVID-19.     

Effectivity and safety of PD-1/PD-L1 inhibitors for different level of PD-L1-positive,advanced NSCLC: A meta-analysis of 4939 patients from randomized controlled trials

BackgroundEffective improvement for the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors had been shown in advanced non-small cell lung cancer (NSCLC) patients compared with traditional therapy. However, we do not have ample evidences to demonstrate the safety and effectivity in the treatment of PD-L1-positive, advanced NSCLC. The relation was controversial about the expression of PD-L1 and survival outcomes of PD-1/PD-L1 inhibitors.Materials and methodsElectronic databases (PubMed, EMBASE, and the Cochrane library) and major conference proceedings were systematically searched for all clinical trials in NSCLC using PD-1/PD-L1 inhibitors. Randomized controlled trials (RCTs) were included to compare PD-1/PD-L1 inhibitors with chemotherapy in advanced NSCLC patients reporting adverse events (AEs) and immune-related AEs (irAEs). The incidence, Hazard Ratio (HR), Odds Ratio (OR), and corresponding 95% confidence interval (CI) of outcomes were calculated.ResultsA total of 4939 patients from 10RCTs were included. In the group of PD-L1 ≥ 1%, PD-L1 ≥ 5%, PD-L1 ≥ 10%, PD-L1 ≥ 50%, the HR of OS is 0.31(95%CI 0.38–0.23; p < 0.0001), 0.47(95%CI 0.82–0.12; p = 0.008), 0.85(95%CI 1.17–0.53; p < 0.0001), 0.47(95%CI 0.59–0.36; p < 0.0001) respectively. The HR of PFS is 0.13(95%CI 0.01–0.24; p = 0.027), 0.31(95%CI 0.00–0.62; p < 0.0001), 0.62(95%CI 0.30–0.93; p < 0.0001), 0.40(95% CI 0.20–0.59; p < 0.0001) respectively. In terms of summary adverse events, PD-1/PD-L1 inhibitors groups had a significant lower risks in any treat-realated AEs than chemotherapy. About irAEs, PD-1/PD-L1 inhibitors groups had a significant higher risks in irAEs than chemotherapy.ConclusionPD-1/PD-L1 inhibitors are generally effected and safer than chemotherapy for patients with PD-L1-positive, advanced NSCLC. However, PD-1/PD-L1 inhibitors can generate a unique spectrum of irAEs, and even life-threatening.     

Assessment of genetic polymorphism associated with ATP-binding cassette transporter A1 (ABCA1) gene and fluctuations in serum lipid profile levels in patients with coronary artery disease

BackgroundCoronary artery disease (CAD) is one of the common genetic and clinical risk factors associated with cardiovascular and multifactorial disorder. ATP-binding cassette transporter A1 (ABCA1) gene plays an important role in lipid metabolism and in multiple studies associated with CAD. However, more studies are needed to identify the exact role of single nucleotide polymorphisms which may cause CAD.ObjectivesThe aim of this study is to investigate the genetic association of polymorphism g.1051G > A in the ABCA1 gene with CAD patients in the Saudi population.MethodsWe included 315 confirmed CAD cases, and 205 non-CAD or control subjects in this case-control study. DNA isolation was carried out for all registered participants and the polymorphism g.1051G > A was genotyped with Polymerase Chain Reaction followed by Restriction Fragment Length Polymorphism analysis with EcoNI restriction enzyme.ResultsModifiable risk factors such as Body Mass Index, smoking and diabetes were strongly associated and non-modifiable risk factors such as hypertension (Systolic Blood Pressure and Diastolic Blood Pressure) and serum analysis such as Fasting Blood Glucose, Total cholesterol (TC), Triglyceride (TG) and LDL-c were significantly associated in CAD cases (p < 0.05). Allele (OR-1.73;95% CI:1.33–2.26; p = 0.0004), GA vs GG (OR-2.26; 95% CI: 1.53–3.35; p = 0.0003 and dominant inheritance pattern (OR-2.23; 95% CI:1.56–3.20; p = 0.00009 was strongly associated with CAD cases and control subjects. The frequency level of use of atorvastatin was significantly different among GG, GA and AA subjects. Additionally, TC and TG levels were influenced by the presence of g.1051G > A polymorphism.ConclusionThe polymorphism g.1051G > A in the gene ABCA1 is closely associated with the existence of the CAD subjects. This polymorphism could also affect the serum levels of the lipid profile, suggesting a possible occurrence of CAD in the Saudi population.     

Assessment of a medication management program targeting hypertension and diabetes patients: Impact on medication adherence

BackgroundThe National Health Insurance Service in South Korea has conducted a telephone outreach program to improve medication adherence for hypertension and diabetes patients since 2014.ObjectivesTo evaluate the direct outcomes of the program.MethodsPatients were identified among those who visited an outpatient clinic at least twice or used an inpatient service at least once for hypertension or diabetes during 6-month intervals and who were nonadherent based on the proportion of days covered (PDC) calculated. As a preliminary intervention, participants were mailed an information leaflet on their own medication adherence and other tips for effective self-management of chronic diseases. For the intervention, two phone calls and three phone messages were made to patients by 24 participating regional offices. Ultimately, 2,428 hypertension patients and 884 diabetes patients received the intervention. Propensity matching was used based on age, sex, and the Charlson Comorbidity Index to select 12,140 hypertension and 4,420 diabetes patients as controls in the non-participating regions. The outcome was PDC. Multivariate ordinary least squares or logistic regression analysis were used with difference-in-difference specification.ResultsThe adjusted quarterly PDC increased by 1.96%p for hypertension (p = 0.023) and by 7.79%p for diabetes patients (p < 0.001). Approximately 40.6% and 51.7% of hypertension and diabetes patients in the treatment arm (p = 0.0069) became adherent after the intervention, whereas the corresponding proportions were 37.7% and 41.4% (p < 0.001) in the control group. Both treatment groups showed a higher likelihood of good medication adherence (hypertension: odds ratio = 1.157, 95% CI [1.058, 1.265]; diabetes: odds ratio = 1.532, 95% CI [1.323, 1.774]). The control group, who received only a print intervention with a mailed leaflet, also showed a dramatic increase in medication adherence.ConclusionsAn insurer-coordinated telephone-administered program resulted in improvement of medication adherence among patients with hypertension and diabetes.     

Epigenetically silenced PD-L1 confers drug resistance to anti-PD1 therapy in gastric cardia adenocarcinoma

ObjectivesThe anti-PD-1/PD-L1 therapy has been demonstrated safe and effective for cancer patients. However, our previous data showed that it had no obvious effects on gastric cardia adenocarcinoma (GCA). Thus, we investigated how the expression level of the PD-L1 was affected by the anti-PD-1 therapy, because it has been demonstrated that the PD-L1 level affects the therapeutic efficient of the anti-PD-1 therapy.Materials and methodsThe mRNA and protein levels of PD-L1 in the GCA tissues and corresponding normal tissues were determined by qPCR and ELISA. Promoter methylation was analyzed by bisulfite sequencing. Finally the methylation of PD-L1 promoter was confirmed in the mice.ResultsThe level of PD-L1 was up-regulated in the GCA tissues when compared to the adjacent non-tumor tissues. The anti-PD1 therapy could reduce the PD-L1 levels in patients with cancer recurrence. The promoter of PD-L1 was more hypermethylated in the secondary GCA after the anti-PD-1 therapy when compared with the adjacent non-tumor tissues or the primary GCA without the anti-PD-1 therapy. Furthermore, the promoter methylation of PD-L1 could be induced by the anti-PD-1 therapy in the mice model. Finally, the anti-PD-1 plus DNA hypomethylating agent azacytidine could significantly suppressed the tumor growth better than the anti-PD-1 therapy.ConclusionsHere we demonstrated that the unresponsiveness of GCA to the anti-PD-1 therapy might result from the promoter methylation and down-regulation of PD-L1. The anti-PD-1 plus azacytidine might be a more promising approach to treat GCA.     

Combined evaluation of the expression status of CD155 and TIGIT plays an important role in the prognosis of LUAD (lung adenocarcinoma)

The interaction between CD155 and its high-affinity ligand TIGIT is being increasingly investigated in various solid tumors. However, the prognostic significance of CD155 and TIGIT in lung adenocarcinoma (LUAD) remains unclear. In this study, immunohistochemistry was applied in 334 LUAD cases to evaluate the expression of CD155 and TIGIT. Western blotting was conducted in 5 paired primary LUAD and adjacent normal lung tissues. Our results reveal that CD155 and TIGIT are overexpressed in LUAD tissues and that aberrant overexpression is closely correlated with poor clinical outcomes (P < 0.01). The multivariate model also shows that CD155 expression is an independent risk factor for LUAD (RR, 1.34; P = 0.036). Moreover, patients expressing high CD155 and TIGIT simultaneously presented shorter overall survival (OS) (P < 0.01) and progression-free survival (PFS) (P < 0.01). These findings suggest that CD155 and TIGIT can make up a prognosticating tool to predict clinical outcomes, thereby contributing to personalized medical care in LUAD.     

IFN regulatory Factor-1 induced macrophage pyroptosis by modulating m6A modification of circ_0029589 in patients with acute coronary syndrome

BackgroundPyroptosis is identified as a novel form of inflammatory programmed cell death and has been recently found to be closely related to atherosclerosis (AS). We found that IFN regulatory factor-1(IRF-1) effectively promotes macrophage pyroptosis in patients with acute coronary syndrome (ACS). Subsequent studies have demonstrated that circRNAs are implicated in AS. However, the underlying mechanisms of circRNAs in macrophage pyroptosis remain elusive.MethodsWe detected the RNA expression of hsa_circ_0002984, hsa_circ_0010283 and hsa_circ_0029589 in human PBMC-derived macrophages from patients with coronary artery disease (CAD). The lentiviral recombinant vector for hsa_circ_0029589 overexpression (pLC5-GFP-circ_0029589) and small interference RNAs targeting hsa_circ_0029589 and METTL3 were constructed. Then, macrophages were transfected with pLC5-GFP-circ_0029589, si-circ_0029589 or si-METTL3 after IRF-1 was overexpressed and to explore the potential mechanism of hsa_circ_0029589 involved in IRF-1 induced macrophage pyroptosis.ResultsThe relative RNA expression level of hsa_circ_0029589 in macrophages was decreased, whereas the N6-methyladenosine (m6A) level of hsa_circ_0029589 and the expression of m6A methyltransferase METTL3 were validated to be significantly elevated in macrophages in patients with ACS. Furthermore, overexpression of IRF-1 suppressed the expression of hsa_circ_0029589, but induced its m6A level along with the expression of METTL3 in macrophages. Additionally, either overexpression of hsa_circ_0029589 or inhibition of METTL3 significantly increased the expression of hsa_circ_0029589 and attenuated macrophage pyroptosis.ConclusionOur observations suggest a novel mechanism by which IRF-1 facilitates macrophage pyroptosis and inflammation in ACS and AS by inhibiting circ_0029589 through promoting its m6A modification.     

Identification of the collagen family as prognostic biomarkers and immune-associated targets in gastric cancer

BackgroundGastric cancer has extremely high morbidity and mortality. Currently, it is lack of effective biomarkers and therapeutic targets for guiding clinical treatment. In this study, we aimed to identify novel biomarkers and therapeutic targets for gastric cancer.MethodsDifferentially expressed genes (DEGs) between gastric cancer and normal tissues were obtained from Gene Expression Omnibus (GEO). Core genes were identified by constructing protein-protein interaction network of DEGs. The expression of core genes was verified in Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN and clinical samples. Further, the mutation, DNA methylation, prognostic value, and immune infiltration of core genes were validated by cBioPortal, MethSurv, Kaplan-Meier plotter, and Tumor Immune Estimation Resource (TIMER) databases. Additionally, drug response analysis was performed by Cancer Therapy Response Portal (CTRP).ResultsA total of seven collagen family members were identified as core genes among upregulated genes. And copy number amplification may be involved in the upregulation of COL1A1 and COL1A2. Importantly, the collagen family was associated with the poor prognosis of patients with metastasis. Among them, COL1A1 had a higher hazard ratio (HR) for overall survival than other members (HR = 2.33). The correlation between DNA methylation levels at CpG sites of collagen family members and the prognosis was verified in gastric cancer. Besides, collagen family expression was positively correlated with macrophages infiltration and the expression of M2 macrophages markers. Further, collagen expression was related to the sensitivity and resistance of gastric cancer cell lines to certain drugs.ConclusionsThe collagen family, especially COL1A1, COL1A2, and COL12A1, may act as potential prognostic biomarkers and immune-associated therapeutic targets in gastric cancer.     

Validation of an assessment,medical problem-oriented plan,and care plan tools for demonstrating the clinical pharmacist's activities

BackgroundIdentifying, preventing, and resolving medical problems are some of the most central functions of clinical pharmacy (CP) and pharmaceutical care (PC) practitioners. Usually, the practitioners and researchers find a challenging to link the problem and the appropriate intervention to be included in the care plan. A comprehensive, well-structured, validated, simple use and standardized tool, which fulfill these requirements in daily clinical practice, are currently rare.PurposeTo design and validate a comprehensive medical problem-oriented plan (MPOP) classification system in addition to assessment and care plan tools for use in practicing, researching, and teaching CP and PC.Materials and methodsThe methodology was composed of five steps: literature searching and classification of the problems; developing the assessment of treatments and care plan templates; implementing the tutorial; validation; completion and evaluation of the final version.ResultsThe classification system (MPOP tool) is an open hierarchical structure, where higher levels are broadly defined, consisting of 5 main categories, and lower levels become more specific. In the MPOP tool's final version, a total of 24 major subcategories were distributed to the major five categories as 4 (Indication), 5 (Effectiveness), 7 (Safety), 3 (Patient), and 5 (Miscellaneous). Different minor subcategories (subcategory 2, n = 62) and 95 plans (interventions) were determined. Each of the subcategories and plans includes a notes section that represents a specific detail. There was strong agreement on using the MPOP tool between the two authors (κ = 1.000, p < 0.0005) and between three random clinical pharmacists out of 17 (κ = 0.947, 95% CI, 0.840 to 1.055, p < 0.0005). The validity and reliability statistics demonstrate that the Alsayed_v1 tools are extremely appropriate. The majority of users expressed high satisfaction with all the assessment, MPOP, and care plan tools.ConclusionThe Alsayed_v1 tools introduced in this paper were applied to actual patient cases and were validated. These tools include: assessment of treatments, MPOP, and care plan. Including the interventions in the classification system is important especially in PC research where the type of recommendations should be documented to assess the value and impact of the service and saves the time of practitioners in typing the appropriate interventions. By applying the steps within these Alsayed tools, the clinical pharmacists can actively provide the best practice to achieve the optimal patient outcome.     

Evaluation of the efficacy and safety of home treatment with the recombinant human C1-inhibitor in hereditary angioedema resulting from C1-inhibitor deficiency

ObjectiveConestat alpha, a C1-inhibitor produced by recombinant technology (rhC1-INH) is an acute treatment for edematous attacks occurring in hereditary angioedema (HAE) with C1-inhibitor deficiency (C1-INH-HAE). Our study evaluated the efficacy and safety of rhC1-INH administered during HAE attacks, and for short-term prophylaxis (STP).Materials & methodOur prospective study analyzed the course of 544 HAE attacks experienced by the 21 C1-INH-HAE patients treated, as well as the outcome of 97 instances of STP implemented with rhC1-INH. Using a purpose-designed questionnaire, the patients recorded relevant, treatment-related information.ResultsTime to the administration of rhC1-INH was 90.0 min (median) after the onset of HAE attacks. The symptoms started to improve as early as 60 min after the injection of rhC1-INH, and the attack resolved 730.0 min after treatment. The interval between the onset of the HAE attack and the administration of rhC1-INH correlated with time until the onset of improvement (R = 0.2053 p < 0.0001), and with time to the complete resolution of symptoms (R = 0.2805, p < 0.0001). Nine patients received STP with rhC1-INH in 97 instances. STP successfully prevented the HAE attack within 72 h of the event on 93/97 occasions. No local and serious systemic adverse events/effects were observed.ConclusionsTreatment with rhC1-INH is effective and safe both for acute management, and for STP. Following the onset of an HAE attack, early administration of rhC1-INH may reduce time to the improvement and to the complete resolution of symptoms. Repeated administration of rhC1-INH does not impair its efficacy.     

ISO-alpha-acids improve the hematoma resolution and prevent peri-hematoma inflammations by transforming microglia via PPARgamma-CD36 axis in ICH rats

ObjectiveTo elucidate the effects of ISO-α-acids (IAAs), a PPAR-γ agonist, on ICH rats and its potential mechanism.Material and methodsThe Sprague Dawley rats ICH model was induced by stereotactic injecting of 100 μl autologous artery blood. Ninety male rats were randomly allocated to five groups: autologous blood and IAAs (IAA); received autologous blood, IAAs and PPAR-γ inhibitor (IAA + GW9662); autologous blood and normal Saline (Saline); only autologous blood (Mock); and only needle injection (Sham). Neurological functions were assessed by mNSS. Hematoma volume, brain water content, surface proteins and inflammatory factors were detected. The microglia anti-inflammatory abilities were also evaluated.ResultsIAAs were able to significantly decrease ICH rat’s mNSS scores, alleviate brain water content, improve hematoma resolution than Saline, Mock (p < 0.05). More “M2” microglial/macrophage can be induced by IAAs. The expression of CD 36 was statistically higher in IAA than other groups (p < 0.05). Injection of IAAs led to a greatly increasing in CD 11b and CD 206 double-positive anti-inflammatory type microglial/macrophage, moreover, a reduction of inflammatory cytokines expression (p < 0.05). Such protective effects can be relieved by GW9662.ConclusionsThis is the first study to elucidate the relationship between IAAs and ICH. IAAs were able to accelerate hematoma absorption, alleviate brain edema, suppress peri-hematoma inflammations and finally improved the outcome of ICH rats. The phenotype was due to the IAAs induction of “M2” microglial/macrophage via activating of PPAR-γ and increasing CD 36 expression.     

The relative and absolute benefit of programmed death receptor-1 vs programmed death ligand 1 therapy in advanced non-small-cell lung cancer: A systematic review and meta-analysis

IntroductionProgrammed death receptor-1 (PD-1) and its ligand (PD-L1) inhibitors have shown promising results in treating advanced non-small-cell lung cancer (NSCLC). Our objective was to compare the relative and absolute benefits between PD-1 and PD-L1 inhibitors in advanced NSCLC.Materials and methodsPubMed, EMBASE and the Cochrane Library were searched up to Dec 1, 2019, for randomized controlled trials of PD-1/PD-L1 inhibitors that had available overall survival (OS) data in NSCLC. Random-effects models were used to calculate the pooled estimates.ResultsTwenty-three randomized controlled trials (15,797 patients) of PD-1/PD-L1 inhibitors were included in the analysis. PD-1 inhibitors significantly extended OS compared with standard of care therapy (difference in means, 4.80 months, 95% CI 3.41–6.18; HR 0.72, 95% CI 0.66–0.78; P < 0.01 for both). PD-L1 inhibitors also significantly improved OS compared with standard of care therapy (difference in means, 2.59 months 95% CI 1.47–3.71; HR 0.83, 95% CI 0.79–0.88; P < 0.01 for both). More importantly, PD-1 inhibitors had significantly higher OS than PD-L1 inhibitors (difference in means, P = 0.015; HR, P = 0.006). The same increased OS benefit was observed in patients with PD-L1 ≥1% (P = 0.035) and PD-L1 <1% (P = 0.007). However, OS did not differ between PD-1 and PD-L1 inhibitors in patients with an EGFR mutation-positive status (P = 0.724) and who were never smokers (P = 0.999).ConclusionsPD-1 inhibitors showed superior relative and absolute OS benefits compared with PD-L1 inhibitors in the treatment of advanced NSCLC. These findings have implications for treatment selection in current clinical practice and future study design.     

Safety and efficacy of Rituximab in systemic sclerosis: A systematic review and meta-analysis

PurposeRituximab is widely prescribed to treat systemic sclerosis (SSc) by the depletion of pathogenic B cells. Nonetheless, the clinical benefit of Rituximab in SSc remains contentious. This meta-analysis was conducted to systematically evaluate the safety and efficacy profile of Rituximab in SSc patients.Patients and methodsWe performed a systematic online query in PubMed, Cochrane, and Web of Science. The available studies on the use of Rituximab in SSc patients were comprehensively reviewed and investigated.ResultsIn total, 14 studies, including 597 participants, were analyzed. Pooled results showed the long-term improvement in the modified Rodnan skin score (mRSS) for skin function (ΔmRSS: 7.00 at 6 months, 9.70 at 12 months, and 10.93 at 24 months), while forced vital capacity (FVC) (ΔFVC: −0.69 at 6 months, −2.62 at 12 months, and −0.67 at 24 months) and diffusing capacity of the lungs for carbon monoxide (DLCO) (ΔDLCO: −2.39 at 6 months, −3.28 at 12 months, and −0.79 at 24 months) for lung function remained stable in SSc patients after Rituximab treatment. The rate of Rituximab-related adverse events was 12% in the pooled results.ConclusionThe pooled results of this meta-analysis indicated that Rituximab is well tolerated, and it is able to improve cutaneous function and stabilize pulmonary function in SSc patients.     

Association of serum macrophage-mannose receptor CD206 with mortality in idiopathic pulmonary fibrosis

BackgroundAcute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is attracting considerable attention due to disease acceleration and substantial mortality. Macrophages are known to regulate the fibrotic process in idiopathic pulmonary fibrosis.ObjectiveWe investigated if two new macrophage-specific serum biomarkers, soluble mannose receptor (MR, sCD206) and soluble CD163 (sCD163), increased in serum obtained from patients with AE-IPF compared to stable IPF (S-IPF).MethodsA total of 36 IPF patients with AE status, 54 IPF patients with stable status, and 27 normal controls were enrolled in this study. The levels of serum sCD206 and sCD163 were compared among the three groups and analysed with the clinical features and mortality of IPF.ResultsThe serum concentrations of both markers were higher in patients with AE-IPF than in those with S-IPF (580.0 ng/ml vs 335 ng/ml for sCD206 and 69.2 ng/ml vs 37.9 ng/ml for sCD163). The level of sCD206 was related to an increased risk of mortality (HR = 1.002, p < 0.001). The best separation between decedents and survivors was obtained by sCD206 (area under the receiver operating characteristic curve [AUC] 0.712 and 95% confidence interval 0.595–0.830).ConclusionOur data demonstrated that the macrophage-related markers sCD206 and sCD163 were significantly higher in patients with IPF, especially sCD206 in AE-IPF patients. The high level of serum sCD206 was associated with mortality in idiopathic pulmonary fibrosis.     

In-vitro and in-vivo anti-breast cancer activity of synergistic effect of berberine and exercise through promoting the apoptosis and immunomodulatory effects

PurposeBreast cancer is the most common reason of cancer death in women. Berberine (BBR), a main alkaloid in Coptis chinensis, exerted anti-cancer activities. Exercise is a new immunotherapy treatment against cancer. However, it is unclear whether exercise has effects on breast cancer and whether exercise has synergistic anti-cancer effect when co-treated with BBR. Thus, it is assumed that exercise might exert an anti-cancer effect through the immune way.MethodThe anti-tumor effect of exercise and BBR in vivo was studied in mice. The MTT method, hoechst staining and cell morphology were performed to determine the synergistic effect of exercise and BBR on breast cancer in vitro. At the same time, Western blotting, intestinal microbial and SCFA detection, Q-PCR and other methods were used to study the anti-cancer molecular mechanism.ResultsThe study found that exercise and BBR co-treatment significantly slowed the progression of breast cancer in 4T1 tumor-bearing mice (p < 0.01). Compared with the TC group, the infiltration of NK cells increased in the combined group of BBR and exercise (p < 0.01), and the expression of immune factors and cytokines was also regulated. At the same time, the synergistic effect significantly increased the level of short chain fatty acids (SCFA). SCFA can promote apoptosis of 4T1 cells and change the inflammatory factors in vitro. The expression of bcl-2 and XIAP was reduced in tumor tissues, and the expression of Fas, Fadd, Bid, Cyto-C, and Caspase-3/8/9 was also increased in vitro experiments (p < 0.05).ConclusionsThese results indicate that the synergistic treatment of exercise and BBR can improve the immune system, regulate intestinal microbial metabolite (SCFA), activate the mitochondrial apoptosis pathway and Fas death receptor apoptosis pathway, and thus play an anticancer role. This may provide a new method for the treatment of breast cancer.