A Novel Epigenetic Strategy to Concurrently Block Immune Checkpoints PD-1/PD-L1 and CD155/TIGIT in Hepatocellular Carcinoma.

Tumor microenvironment is an intricate web of stromal and immune cells creating an immune suppressive cordon around the tumor. In hepatocellular carcinoma (HCC), Tumor microenvironment is a formidable barrier towards novel immune therapeutic approaches recently evading the oncology field. In this study, the main aim was to identify the intricate immune evasion tactics mediated by HCC cells and to study the epigenetic modulation of the immune checkpoints; Programmed death-1 (PD-1)/ Programmed death-Ligand 1 (PD-L1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT)/Cluster of Differentiation 155 (CD155) at the tumor-immune synapse. Thus, liver tissues, PBMCs and sera were collected from Hepatitis C Virus (HCV), HCC as well as healthy individuals. Screening was performed to PD-L1/PD-1 and CD155/TIGIT axes in HCC patients. PDL1, CD155, PD-1 and TIGIT were found to be significantly upregulated in liver tissues and peripheral blood mononuclear cells (PBMCs) of HCC patients. An array of long non-coding RNAs (lncRNAs) and microRNAs validated to regulate such immune checkpoints were screened. The lncRNAs; CCAT-1, H19, and MALAT-1 were all significantly upregulated in the sera, PBMCs, and tissues of HCC patients as compared to HCV patients and healthy controls. However, miR-944-5p, miR-105-5p, miR-486-5p, miR-506-5p, and miR-30a-5p were downregulated in the sera and liver tissues of HCC patients. On the tumor cell side, knocking down of lncRNAs-CCAT-1, MALAT-1, or H19-markedly repressed the co-expression of PD-L1 and CD155 and accordingly induced the cytotoxicity of co-cultured primary immune cells. On the immune side, ectopic expression of the under-expressed microRNAs; miR-486-5p, miR-506-5p, and miR-30a-5p significantly decreased the transcript levels of PD-1 in PBMCs with no effect on TIGIT. On the other hand, ectopic expression of miR-944-5p and miR-105-5p in PBMCs dramatically reduced the co-expression of PD-1 and TIGIT. Finally, all studied miRNAs enhanced the cytotoxic effects of PBMCs against Huh7 cells. However, miR-105-5p showed the highest augmentation for PBMCs cytotoxicity against HCC cells. In conclusion, this study highlights a novel co-targeting strategy using miR-105-5p mimics, MALAT-1, CCAT-1 and H19 siRNAs to efficiently hampers the immune checkpoints; PD-L1/PD-1 and CD155/TIGIT immune evasion properties in HCC.

A meta-analysis of outcomes of aspiration thrombectomy for high and intermediate-risk pulmonary embolism.

BACKGROUND: Aspiration thrombectomy has gained popularity in patients with massive and sub-massive pulmonary embolism (PE) and having contraindications to thrombolysis. METHODS: A meta-analysis was conducted including studies on aspiration thrombectomy in patients with high-risk and intermediate-risk PE. The pooled odds ratio for efficacy parameters, including change in heart rate, blood pressure and right ventricle/left ventricle (RV/LV) ratio, and safety parameters including major bleeding and stroke, was calculated using a random effects model. RESULTS: The meta-analysis of 24 selected studies revealed that intermediate and high-risk pulmonary embolism (PE) patients demonstrated significant improvements: modified Miller score odds ratio of 10.60, mean pulmonary artery pressure reduction by 0.04 mm Hg, and an overall all-cause mortality odds ratio of 0.10. Considerable heterogeneity was observed in various outcomes. CONCLUSION: Aspiration thrombectomy has success rates in both high-risk and intermediate-risk PE, however, procedural risks, including bleeding, must be anticipated.

Soluble guanylate cyclase stimulators for heart failure: a network meta-analysis and subgroup analyses of reduced and preserved ejection fraction.

BACKGROUND: Soluble guanylate cyclase (sGC) stimulators have been investigated for heart failure (HF) in several randomized controlled trials (RCTs). However, its place in the management guidelines of either HFrEF or HfpEF is still inconclusive. METHODS: We conducted a network meta-analysis synthesizing RCTs investigating sGC for HF management, which were retrieved by systematically searching five databases until January 24th, 2023. Dichotomous outcomes were pooled using risk ratio (RR) along with confidence interval (CI). RESULTS: Eight RCTs with a total of 7307 patients were included. Vericiguat 10 mg significantly reduced the composite cardiovascular (CVS) mortality and HF hospitalization in HF (RR: 0.88, 95% CI [0.79; 0.98]) and in HFrEF (RR: 0.87, 95% CI [0.78; 0.97]); however, it was not effective in HFpEF (RR: 0.69, 95% CI [0.15; 3.05]). Also, vericiguat 10 mg showed no difference compared to placebo regarding the incidence of all-cause mortality (RR: 0.96, 95% CI [0.84; 1.10]), any adverse events (AEs) (RR: 0.94, 95% CI [0.83; 1.07]), any serious AEs (RR: 0.91, 95% CI [0.81; 1.01]), and any AEs leading to drug discontinuation (RR: 1.14, 95% CI [0.92; 1.40]). CONCLUSION: Vericiguat 10 mg was effective in reducing the composite CVS mortality and HF hospitalization, with an acceptable safety profile. This was only observed in HFrEF patients, but not in HFpEF patients. However, our data regarding other agents (riociguat and praliciguat) and HFpEF can be underpowered, warranting further RCTs to clarify vericiguat 10 mg place in HFrEF management guidelines and to investigate sGC stimulators for HFpEF in large-scale trials.

Genotype Mutations in Palestinian Children with Familial Mediterranean Fever: Clinical Profile, and Response to Colchicine Treatment: A Retrospective Cohort Study.

Background: Familial Mediterranean fever is a hereditary autoinflammatory disease affecting mainly Arabs, Turks, Armenians, and Jews with genotype-phenotype heterogeneity, presenting as recurrent episodes of fever along with polyserositis and rash. To date, more than 370 mutations in the MEFV gene have been recognized to cause the disease. Methods: We conducted a retrospective cohort study involving 124 patients in Hebron, Palestine, diagnosed with FMF at the Al-Ahli, and Palestinian Red Crescent Society (PRCS) Hospitals. Results: The median age of diagnosis was five years, presenting as abdominal pain (76.6%), fever (67.7%), joint pain and arthritis. Regarding MEFV gene mutations, we had 62 patients (50%) with heterozygous genotypes, 40 patients (32.3%) with homozygous phenotypes, 21 patients (16.9%) with compound heterozygous genotypes, and one was a missing state. Regarding variant frequencies, M694V was the most common one (43.4%), followed by E148Q (15.6%), V726A (5.7%), A744S (4.1%), and R202Q (4.1%). Positive family history was detected in 59 patients (54.6%), and there was no significant difference in zygosity regarding characteristics, consanguinity, and family history. Conclusions: We affirm in this study of 124 children with FMF, abdominal pain, followed by fever, joint pain and arthritis were the main manifestations. Further, M694V, E148Q, V726A, A744S, and R202Q were the most frequent mutations, and carrying the M649V mutations is associated with a predisposition to other comorbidities. We believe that this study gives a pervasive overview of FMF in Palestinian patients. Looking forward, future studies on a larger number of patients could precisely highlight the genotype-phenotype association among FMF patients.

The role of creatine kinase in distinguishing generalized tonic-clonic seizures from psychogenic non-epileptic seizures (PNES) and syncope: a retrospective study and meta-analysis of 1300 patients.

BACKGROUND/AIM: As the clinical differentiation between epileptic seizures, psychogenic non-epileptic seizures (PNES), and syncope depends mainly on a detailed report of the event, which may not be available, an objective assessment of a potential biochemical analysis is needed. We aimed to investigate whether serum creatine kinase (CK) could be used to differentiate epileptic seizure from PNES and syncope and to assess the strength of evidence present. METHODS: We directed a retrospective cohort study coupled with a systematic review and meta-analysis of studies that measured CK in patients with epilepsy, PNES, syncope, and healthy controls. RESULTS: The cohort study, which traced 202 patients, showed that the CK level was significantly higher 48 h after the event in the epilepsy group versus patients with syncope (p < 0.01) Along with 1086 patients obtained through a database search for meta-analysis, CK level compared to different types of seizures from PNES was higher in epileptic seizure patients with a mean difference of 568.966 mIU/ml (95% CI 166.864, 971.067). The subgroup analysis of CK showed that it was higher in GTCS compared to syncope with a mean difference of 125.39 mIU/ml (95% CI 45.25, 205.52). DISCUSSION: Increased serum levels of CK have been associated mainly with epileptic seizures in relation to non-epileptic events. However, further studies would try to explore the variation in measurements and any other potential diagnostic marker. CONCLUSION: The cohort study shows that the CK level in epilepsy seizures is higher after 48 h from the event compared to syncope. Moreover, the meta-analysis results show the present diagnostic utility of CK and its importance to be used in accordance with a detailed report of the event.

SGLT2 inhibitors among patients with heart failure with preserved ejection fraction: A meta-analysis of randomised controlled trials.

BACKGROUND: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been recommended in the practice guidelines for the treatment of patients with heart failure with reduced ejection fraction; however, their effects among patients with preserved ejection fraction have been debatable. OBJECTIVE: We aim to evaluate the SGLT2 inhibitor effect among patients with heart failure with reduced ejection fraction, including DELIVER and EMPEROR-Preserved trials. METHODS: We performed a systematic literature search using the PubMed, Embase, Scopus, and Cochrane libraries for relevant articles from inception until August 30th, 2022. Statistical analysis was performed by calculating hazard ratio (HR) using the random effect model with a 95% confidence interval (CI) and probability value (P). Statistical significance was met if 95% CI does not cross numeric "1" and P < .05. RESULTS: Six studies with a total of 15,989 total patients were included in the final analysis. The mean age of patients enrolled in SGLT2 inhibitors and placebo was 69.13 and 69.37 years, respectively. The median follow-up duration was 2.24 years. SGLT2 inhibitors reduced composite cardiovascular mortality or first hospitalization for heart failure (HR, 0.80 [95% CI: 0.74-0.87], P < .001, I2 = 0%), heart failure hospitalization (HR, 0.74 [95% CI: 0.67-0.82], P < .001, I2 = 0%) compared with placebo. However, all-cause mortality (HR, 0.97 [95% CI: 0.89-1.06], P = .54, I2 = 0%) and cardiovascular mortality (HR, 0.96 [95% CI: 0.82-1.13), P = .66, I2 = 35.09%] were comparable between both groups. CONCLUSION: Our study finding shows that SGLT2 inhibitors significantly reduced the risk of first HF hospitalization or cardiovascular death and HF hospitalization; however, all-cause mortality was comparable between the groups.

Transcatheter vs Surgical Aortic Valve Replacement Outcomes Among Solid Organ Transplant Patients: A Systematic Review and Meta-Analysis.

The safety and clinical outcomes of transcatheter aortic valve replacement (TAVR) compared to surgical aortic valve replacement (SAVR) among patients with solid organ transplants is not well understood. This study aimed to evaluate the clinical outcomes of TAVR and SAVR among patients with a history of solid organ transplantation. We performed a systematic literature search of databases for relevant articles from inception until May 1st, 2022. Unadjusted odds ratios (OR) were pooled using a random-effect model, and a P-value of <0.05 was considered statistically significant. A total of 3240 studies were identified of which 3 studies with a total of 2960 patients were included in the final analysis. For solid organ transplants patients, the odds of in-hospital mortality (OR 0.37, 95% CI 0.20-0.71, P < 0.001), 30-day mortality (OR 0.51, 95% CI 0.35-0.74, P < 0.001), acute kidney injury (OR 0.45, 95% CI 0.35-0.59, P < 0.001), and bleeding (OR 0.35, 95% CI 0.27-0.46, P < 0.001) were significantly lower in patients undergoing TAVR compared to SAVR. In contrast, the odds of pacemaker implantation (OR 2.60, 95% CI 0.36-18.90, P = 0.34), postprocedural stroke (OR 0.36, 95% CI 0.13-1.03, P = 0.06) were similar between both groups of patients. Length of hospital stay was significantly lower in TAVR compared to SAVR patients (SMD -0.82, 95% CI -0.95 to -0.70, P < 0.001). In solid organ transplant patients, TAVR appeared to be a safe procedure with fewer postprocedure complications, shorter length of hospital stay, and lower in hospital mortality compared with SAVR.

MALAT-1: Immunomodulatory lncRNA hampering the innate and the adaptive immune arms in triple negative breast cancer.

BACKGROUND: Triple negative breast cancer (TNBC) is known as hot immunogenic tumor. Yet, it is one of the most aggressive BC subtypes. TNBC evolve several tactics to evade the immune surveillance phenomena, one of which is shedding of natural killer (NK) cells activating immune ligands such as MICA/B and/or by inducing the expression of the immune checkpoints such as PD-L1 and B7-H4. MALAT-1 is an oncogenic lncRNA. MALAT-1 immunogenic profile is not well investigated. AIM: The study aims at exploring the immunogenic role of MALAT-1 in TNBC patients and cell lines and to identify its molecular mechanism in altering both innate and adaptive immune cells present at the tumor microenvironment of TNBC METHODS: BC patients (n = 35) were recruited. Primary NK cells and cytotoxic T lymphocytes were isolated from normal individuals using the negative selection method. MDA-MB-231 cells were cultured and transfected by several oligonucleotides by lipofection technique. Screening of ncRNAs was performed using q-RT-PCR. Immunological functional analysis experiments were performed upon co-culturing primary natural killer cells and cytotoxic T lymphocytes using LDH assay. Bioinformatics analysis was performed to identify potential microRNAs targeted by MALAT-1. RESULTS: MALAT-1 expression was significantly upregulated in BC patinets with a profound expression in TNBC patients compared to their normal counterparts. Correlation analysis revealed a positive correlation between MALAT-1, tumor size and lymph node metastasis. Knocking down of MALAT-1 in MDA-MB-231 cells resulted in a significant induction of MICA/B, repression of PD-L1 and B7-H4 expression levels. Enhancement of cytotoxic activity of co-cultured NK and CD8+ cells with MALAT-1 siRNAs transfected MDA-MB-231 cells. In silico analysis revealed that miR-34a and miR-17-5p are potential targets to MALAT-1; accordingly, they were found to be downregulated in BC patients. Forcing the expression of miR-34a in MDA-MB-231 cells resulted in a significant induction in MICA/B levels. Ectopic expression of miR-17-5p in MDA-MB-231 cells significantly repressed the expression of PD-L1 and B7-H4 checkpoints. Validations of MALAT-1/miR-34a" and "MALAT-1/miR-17-5p axes were performed by a series of co-transfections and functional assessment of cytotoxic profile of primary immune cells. CONCLUSION: This study proposes a novel epigenetic alteration exerted by TNBC cells mainly by inducing the expression of MALAT-1 lncRNA. MALAT-1 mediates innate and adaptive immune suppression events partially via targeting miR-34a/MICA/B and miR-175p/PD-L1/B7-H4 axes in TNBC patients and cell lines.

Neutrophil-lymphocyte ratio and platelet-lymphocyte ratio as markers of stable ischemic heart disease in diabetic patients: An observational study.

Ischemic heart disease (IHD) is a pressing public health concern with high prevalence, mortality, and morbidity. Although the value of neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) as markers of the acute coronary syndrome are well recognized, there is a paucity of data deciphering their role in screening for stable ischemic heart disease (SIHD) in the presence of type 2 diabetes mellitus (T2DM). The present study investigates the value of NLR and PLR as markers of SIHD in T2DM. We evaluated the predictive value of NLR and PLR for SIHD by comparing T2DM patients having angiographically proven SIHD to T2DM patients without IHD at different cutoff levels by evaluating the area under the curve (AUC) obtained from receiver-operating-characteristic analysis. Raised NLR and PLR were significantly associated with SIHD ( P < .001 for each). On performing AUC-receiver-operating-characteristic analysis, NLR of > 2.39 and PLR of > 68.80 were associated with the highest prevalence of SIHD (NLR, AUC: 0.652 [0.605-0.699]; CI: 95%; P < .001, PLR, AUC: 0.623 [0.575-0.671] CI: 95%; P < .001). The sensitivities and specificities for these cutoff values were 50% and 73% for NLR and 73% and 46% for PLR, respectively. NLR and PLR were significantly higher in SIHD compared to those without; however, these markers had limited predictive potential in the setting of T2DM.

Efficacy of lenvatinib versus sorafenib in the primary treatment of advanced hepatocellular carcinoma: A meta-analysis.

Background and Aim: Molecular-targeted agents such as lenvatinib and sorafenib have been approved to treat hepatocellular carcinoma (HCC). However, the choice between these two agents in the primary treatment for advanced HCC is still under debate with conflicting results. We sought to evaluate the efficacy of lenvatinib and sorafenib in patients with HCC. Methods: We performed a systematic literature search using PubMed, Embase, and Scopus for relevant articles from inception until February 10, 2023. The primary outcome of this meta-analysis was overall survival (OS). The secondary outcomes were progression-free survival (PFS), time to progression, objective response rate (ORR), and disease control rate (DCR). Results: A total of 13 studies with 3705 patients (1635 on lenvatinib and 2070 on sorafenib) were included in our analysis. The mean age of the patients in both groups was comparable (66.81 vs 65.9 years). Pooled analysis of primary outcomes showed that, compared with sorafenib, lenvatinib was associated with significantly better OS in patients treated with these drugs (HR 0.82, 95% CI: 0.69-0.97, P = 0.02). Pooled analysis also showed that PFS (HR 0.67, 95% CI: 0.57-0.78, P < 0.00001) and time to progression (HR 0.49, 95% CI: 0.31-0.79; P = 0.004) were significantly better in the lenvatinib group compared to the sorafenib group. It also showed that the lenvatinib group had significantly better ORR (odds ratio [OR] 5.43, 95% CI: 3.71-7.97; P < 0.00001) and DCR (OR 2.35, 95% CI: 1.75-3.16; P < 00001) than the sorafenib group. Conclusion: Our study shows that lenvatinib is superior to sorafenib regarding OS and PFS in patients with advanced HCC.

Changes in physical activity during COVID-19 pandemic among Saudi Arabians: Results from a cross-sectional study.

Background and Aims: The COVID-19 pandemic and the resultant change in sedentary behaviors have had immense health, economic, and social implications globally. As governments worldwide imposed lockdowns and curfews, the amount of time spent indoors greatly increased. This lead to a dramatic change in physical activity (PA) levels and profound consequences on daily routines. Our study aimed to investigate patterns of PA during the COVID-19 pandemic among adults residing in Saudi Arabia. Methods: This cross-sectional survey-based study aimed to investigate patterns of PA during the COVID-19 pandemic among adults residing in Saudi Arabia. The International Physical Activity Questionnaire was utilized to measure participants' PA levels between April 2021 and May 2021. Participants were then classified into three groups according to their PA level, and their PA levels and sedentary behaviors were analyzed. Results: We surveyed 463 participants, 315 (68%) of which were female and 134 (32%) of which were male with a median age of 23 (interquartile range, 21-35) years. Moderate-to-high PA was reported by 257 (55.7%) of the participants. There was a significant decrease in PA during the COVID-19 pandemic and resultant lockdowns among the participants (p = 0.04), with higher rates of sedentary behavior among males than females (p = 0.14). Conclusions: The decline in PA is a profound challenge of the COVID-19 pandemic that needs to be addressed by health practitioners and policymakers. Our study highlights the decline in PA levels seen during the COVID-19 pandemic and the importance of promotional programs and interventions to increase PA among the Saudi Arabian population without compromising the essential health restrictions and social distancing.

Early surgery vs conservative management among asymptomatic aortic stenosis: A systematic review and meta-analysis.

Introduction: Although aortic valve replacement in severe symptomatic Aortic Stenosis (AS) are clearly outlined, the role of surgical intervention in asymptomatic severe AS remains unclear with limited evidence. The aim of our meta-analysis is to evaluate the efficacy and safety of early surgical aortic valve repair compared to conservative management. Methods: A systematic literature search was performed in PubMed, Scopus, Embase and Cochrane databases for studies comparing the early surgery versus conservative management among asymptomatic aortic stenosis patients. Unadjusted odds ratios (OR) were pooled using a random-effect model, and a p-value of < 0.05 was considered statistically significant. Results: A total of 5 articles (3 observational studies and 2 randomized controlled trials) were included. At a median followup of 4.1 years, here were significantly lower odds of all-cause mortality [OR = 0.30 (95 %CI:0.17-0.53), p < 0.0001], cardiovascular mortality [OR = 0.35 (95 %CI:(0.17-0.72), p = 0.005], and sudden cardiac death (OR = 0.36 (95 %CI: 0.15-0.89), p = 0.03) among early surgery group compared with conservative care. There was no significant difference between incidence of major bleeding, clinical thromboembolic events, hospitalization due to heart failure, stroke and myocardial infarction between the conservative care groups and early surgery. Conclusion: Among asymptomatic patients with AS, early surgery shows better outcomes in reducing all-cause mortality and cardiovascular mortality compared with conservative management approaches.

Demographic, clinical, and laboratory characteristics of patients with COVID-19 during the second and third waves of the pandemic in Egypt.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel virus that belongs to the coronaviruses and causes coronavirus disease 2019 (COVID-19). In this study, we explored the demographic details, clinical features, and routinely conducted laboratory investigations of patients with COVID-19 during the second and third waves of the pandemic to understand their possible diagnostic and prognostic values in Egypt. METHODS: In this retrospective cohort study, the demographic characteristics, detailed medical history, laboratory findings, and symptoms of all enrolled patients with SARS-CoV-2 were collected from the medical records of Beni Suef University Hospitals between December 15, 2020, and April 15, 2021. RESULTS: This retrospective study included 473 patients, almost all of whom were elderly. The median age of the patients was 48 years, and those with moderate and severe disease were older than those with mild infections. The proportion of females was higher (63.4%) than males (36.6%). Diabetes mellitus (DM) was the most common comorbidity (17.3%), and fever was the most typical manifestation of COVID-19 (62.6%). Those with severe disease showed a higher C-reactive protein level (CRP) than those with moderate (p-value 0.009) or mild (p-value 0.01) diseases. Serum ferritin levels were significantly higher in patients with severe disease than in those with moderate disease (p-value 0.018). In contrast, d-dimer and serum creatinine were normal and showed no significant difference in all comparisons (p-value overall 0.21). CONCLUSION: This study observed several variations in COVID-19 patients' characteristics. The new manifestations included skin rash, bone and low back pains, and rigors. In contrast to females, most males had moderate-to-severe illness. Old age and higher body mass index was associated with increasing severity. d-dimer and complete blood count were normal and could not identify potential COVID-19 patients. Patients who had mild illness were still at risk of developing post-COVID complications.