Effects of statins on the incidence and outcomes of acute kidney injury in critically ill patients: a systematic review and meta-analysis.

Introduction: In critically ill patients, acute kidney injury (AKI) is a common complication with very high mortality rates. Several studies indicated that statin therapy, primarily due to its so-called pleiotropic effects, may beneficially affect the course of the disease, otherwise leading to significant clinical complications. However, both the original research as well as available meta-analyses on these associations report equivocal results. This leaves open a question whether pre- and perioperative statins might prevent AKI and improve overall prognosis in patients undergoing surgery. Material and methods: Following a systematic search of the literature, we performed a meta-analysis of selected clinical studies investigating the impact of statin treatment on the development and the clinical outcomes of AKI among subjects undergoing surgeries. The pooled odds ratios (OR) with 95% confidence intervals (CI) for the development of AKI and AKI-associated mortality, as well as the pooled mean differences (MD) and 95% CI for mean intensive care unit (ICU) stay and overall hospital length of stay were calculated for statin users compared to non-users. Results: Our results showed a highly significant association between statin use and the decrease in mortality of patients with AKI (OR = 0.73, 95% CI: 0.69-0.77; p<0.001). The development of AKI (OR = 0.92, 95% CI: 0.63-1.33; p = 0.659) as well as the ICU stay (MD = -0.02, 95% CI: -0.06 - 0.02; p = 0.321) were not significantly affected, while the overall hospital length of stay (MD = -0.49, 95% CI: -0.91 -0.07; p = 0.020) was reduced. Subgroup analysis showed that both pre- and postoperative statin use were not associated with the risk of AKI. Conclusions: Our analysis showed a significant association between statin therapy and overall mortality of critically ill surgical patients diagnosed with AKI, while at the same time the use of statins did not affect the length of their stay in ICU.

Guillain-Barré/Miller Fisher overlap syndrome in a patient after coronavirus disease-2019 infection: a case report.

BACKGROUND: Beyond the typical respiratory symptoms associated with novel coronavirus, increasing evidence has been reported of the neurological manifestations affecting both the central and peripheral nervous systems. CASE PRESENTATION: We observed a 30-year-old Persian woman developing acute motor sensory axonal neuropathy, a variant of Guillain-Barré syndrome that overlaps Miller Fisher syndrome, 30 days after confirmed coronavirus disease-2019 infection. Our case highlight the rare occurrence of Guillain-Barré syndrome overlapping with Miller Fisher during the coronavirus disease-2019 pandemic. These neurologic manifestations may occur because of an aberrant immune response to coronavirus disease-2019. CONCLUSIONS: The early recognition of Guillain-Barré syndrome symptoms is critical, given the associated severe motor disabilities that may seriously limit the quality of life of these patients. We may still have much to learn about the co-occurrence of Guillain-Barré syndrome and Miller Fisher to improve the quality of life of these patients requiring an accurate evaluation by neurologists.

A Systematic Review and Meta-Analysis on the Significance of TIGIT in Solid Cancers: Dual TIGIT/PD-1 Blockade to Overcome Immune-Resistance in Solid Cancers.

Preclinical studies have indicated that T-cell immunoglobulin and ITIM domain (TIGIT) can substantially attenuate anti-tumoral immune responses. Although multiple clinical studies have evaluated the significance of TIGIT in patients with solid cancers, their results remain inconclusive. Thus, we conducted the current systematic review and meta-analysis based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) to determine its significance in patients with solid cancers. We systematically searched the Web of Science, Embase, PubMed, and Scopus databases to obtain peer-reviewed studies published before September 20, 2020. Our results have shown that increased TIGIT expression has been significantly associated with inferior overall survival (OS) (HR = 1.42, 95% CI: 1.11-1.82, and p-value = 0.01). Besides, the level of tumor-infiltrating TIGIT+CD8+ T-cells have been remarkably associated inferior OS and relapse-free survival (RFS) of affected patients (HR = 2.17, 95% CI: 1.43-3.29, and p-value < 0.001, and HR = 1.89, 95% CI: 1.36-2.63, and p-value < 0.001, respectively). Also, there is a strong positive association between TIGIT expression with programmed cell death-1 (PD-1) expression in these patients (OR = 1.71, 95% CI: 1.10-2.68, and p-value = 0.02). In summary, increased TIGIT expression and increased infiltration of TIGIT+CD8+ T-cells can substantially worsen the prognosis of patients with solid cancers. Besides, concerning the observed strong association between TIGIT and PD-1, ongoing clinical trials, and promising preclinical results, PD-1/TIGIT dual blockade can potentially help overcome the immune-resistance state seen following monotherapy with a single immune checkpoint inhibitor in patients with solid cancers.

Improved COVID-19 Outcomes following Statin Therapy: An Updated Systematic Review and Meta-analysis.

BACKGROUND: Although vaccine rollout for COVID-19 has been effective in some countries, there is still an urgent need to reduce disease transmission and severity. We recently carried out a meta-analysis and found that pre- and in-hospital use of statins may improve COVID-19 mortality outcomes. Here, we provide an updated meta-analysis in an attempt to validate these results and increase the statistical power of these potentially important findings. METHODS: The meta-analysis investigated the effect of observational and randomized clinical studies on intensive care unit (ICU) admission, tracheal intubation, and death outcomes in COVID-19 cases involving statin treatment, by searching the scientific literature up to April 23, 2021. Statistical analysis and random effect modeling were performed to assess the combined effects of the updated and previous findings on the outcome measures. Findings. The updated literature search led to the identification of 23 additional studies on statin use in COVID-19 patients. Analysis of the combined studies (n = 47; 3,238,508 subjects) showed no significant effect of statin treatment on ICU admission and all-cause mortality but a significant reduction in tracheal intubation (OR = 0.73, 95% CI: 0.54-0.99, p = 0.04, n = 10 studies). The further analysis showed that death outcomes were significantly reduced in the patients who received statins during hospitalization (OR = 0.54, 95% CI: 0.50-0.58, p < 0.001, n = 7 studies), with no such effect of statin therapy before hospital admission (OR = 1.06, 95% CI = 0.82-1.37, p = 0.670, n = 29 studies). CONCLUSION: Taken together, this updated meta-analysis extends and confirms the findings of our previous study, suggesting that in-hospital statin use leads to significant reduction of all-cause mortality in COVID-19 cases. Considering these results, statin therapy during hospitalization, while indicated, should be recommended.

Improved COVID-19 ICU admission and mortality outcomes following treatment with statins: a systematic review and meta-analysis.

INTRODUCTION: Approximately 1% of the world population has now been infected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19). With cases still rising and vaccines just beginning to rollout, we are still several months away from seeing reductions in daily case numbers, hospitalisations, and mortality. Therefore, there is a still an urgent need to control the disease spread by repurposing existing therapeutics. Owing to antiviral, anti-inflammatory, immunomodulatory, and cardioprotective actions, statin therapy has been considered as a plausible approach to improve COVID-19 outcomes. MATERIAL AND METHODS: We carried out a meta-analysis to investigate the effect of statins on 3 COVID-19 outcomes: intensive care unit (ICU) admission, tracheal intubation, and death. We systematically searched the PubMed, Web of Science, Scopus, and ProQuest databases using keywords related to our aims up to November 2, 2020. All published observational studies and randomised clinical trials on COVID-19 and statins were retrieved. Statistical analysis with random effects modelling was performed using STATA16 software. RESULTS: The final selected studies (n = 24 studies; 32,715 patients) showed significant reductions in ICU admission (OR = 0.78, 95% CI: 0.58-1.06; n = 10; I 2 = 58.5%) and death (OR = 0.70, 95% CI: 0.55-0.88; n = 21; I 2 = 82.5%) outcomes, with no significant effect on tracheal intubation (OR = 0.79; 95% CI: 0.57-1.11; n = 7; I 2= 89.0%). Furthermore, subgroup analysis suggested that death was reduced further by in-hospital application of stains (OR = 0.40, 95% CI: 0.22-0.73, n = 3; I 2 = 82.5%), compared with pre-hospital use (OR = 0.77, 95% CI: 0.60-0.98, n = 18; I 2 = 81.8%). CONCLUSIONS: These findings call attention to the need for systematic clinical studies to assess both pre- and in-hospital use of statins as a potential means of reducing COVID-19 disease severity, particularly in terms of reduction of ICU admission and total mortality reduction.

Culture filtrate ether extracted metabolites from Streptomyces levis ABRIINW111 increased apoptosis and reduced proliferation in acute lymphoblastic leukemia.

Despite the advances in the discovery of various types of anticancer drugs for curing acute lymphoblastic leukemia (ALL), their toxicity and unfavorable side effects remained as big limitations for therapeutical applications. In this regard, natural products such as Streptomyces -derived agents have shown potential applications as anticancer drugs. The present study deals with evaluating the anti-carcinogenic activity of the ether extracted metabolites derived from Streptomyces on nalm-6 and molt-4 ALL cell lines. MTT assay was performed to evaluate the cytotoxicity effect of Streptomyces sp on nalm-6 and molt-4 cell lines. Apoptosis and proliferation were evaluated by Flow cytometry. Quantitative real-time RT-PCR (qRT-PCR) and western blot were performed to investigate the effect of these metabolites on the mRNA and protein expression levels of P53, Bax, and Bcl2. In both cell lines, extracted metabolites significantly inhibited cell growth and increased apoptosis. Although P53, Bax mRNA and protein expressions were increased, Bcl-2 expression decreased in treated cells compared with control. In addition, the G0/G1 arrest of Nalm-6 cells was induced. These findings of this work show that the ether-extracted metabolites from Streptomyces levis ABRIINW111 can be used as an anti-carcinogenic for acute lymphoblastic leukemia cells.

Extracted metabolite from Streptomyces Levis ABRIINW111 altered the gene expression in colon cancer.

AIM: In this study we attempt to indicate anti-carcinogenic influence of ether extracted metabolites of Streptomyces Levis sp. on gene expression in colon cancer. BACKGROUND: Colon cancer is one of the most prevalent cancers worldwide. In recent decades, researchers have been seeking the treatment for cancer. Natural products are valuable compounds with fewer side effects in comparison to chemotherapy drugs. METHODS: Secondary metabolites were extracted with the inoculation of bacterial sample in Mueller Hinton Broth. MTT assay was done to evaluate the cytotoxicity effect of metabolites on SW480 cells. qRT-PCR was performed to observe effects of metabolites on Bcl-2, P53, SOX2, KLF4, ß-Catenin, SMAD4, K-ras, BRAF genes expression in colon cancer. RESULTS: The metabolites exhibited cytotoxic effects on colon cancer in a dose/time dependent manner (P < 0.001). After 48 h treatment, fold expression of Bcl-2, SOX2, ß-catenin, K-ras, BRAF genes fold of expression were decreased, whereas P53, KLF4, SMAD4 genes were increased in treated cells (P < 0.001). CONCLUSION: These findings indicate that ether extracted metabolites of Streptomyces Levis ABRIINW111 have anti-carcinogenic effects on colon cancer.

Streptomyces Levis ABRIINW111 Inhibits SW480 Cells Growth by Apoptosis Induction.

Purpose: Streptomyces sp., a dominant genus in Actinomycetes, is the source of a wide variety of secondary metabolites. Microbial metabolites can be utilized as novel anticancer agents; with fewer side effects. The present article illustrated the anti-carcinogenic effect of the ether extracted organic metabolites derived from Streptomyces bacteria on SW480 colon cancer cell line. Methods: MTT assay was performed in order to investigate the cytotoxicity effect of metabolites on SW480 cells. Apoptosis and cell cycle arrests were measured by flowcytometry. Morphological changes were indicated by Propidium iodide staining andP53 gene expression was evaluated by real-time PCR. Results: Streptomyces Levis ABRIINW111 inhibited cell growth, increased Caspases 3 and reduced Ki67 expression in a concentration/time-dependent manner in SW40 cells. Metabolites increased subG1 phase (apoptosis) and also cell cycle arrest in G1, G---2/M and S phase. P53 gene expression followed Sw480 cells treatment significantly. Conclusion: Streptomyces sp. metabolites have anti-carcinogenic effect on colon cancer cells. Streptomyces Levis ABRIINW111 metabolites are a candidate for Colon cancer treatment.

Rapamycin Inhibits Expansion of Cord Blood Derived NK and T Cell.

BACKGROUND: The mammalian target of rapamycin (mTOR) is important in hematopoiesis. Despite the central role of mTOR in regulating the differentiation of immune cells, the effect of mTOR function on cord blood mononuclear cells is yet to be defined. OBJECTIVES: To evaluate the effect of mTOR inhibition, using rapamycin on the proliferation and apoptosis of cord blood mononuclear cells, as well as on the B and T cell expansion. METHODS: Cord blood mononuclear cells were cultured in the presence of IL-2, IL-7 and IL-15 cytokines and inhibited by rapamycin for 14 days. The harvested cells were evaluated at distinct time points by flow cytometry. RESULTS: The mTOR expression decreased in the presence of rapamycin on day 14. Inhibition of mTOR reduced the proliferation of the cord blood mononuclear cells, yet did not influence apoptosis. Moreover, the number of T and NK cells was significantly reduced in the presence of rapamycin, while no change was observed in the B cell expansion. CONCLUSION: mTOR signaling plays a crucial part in cord blood derived NK and T cells expansion.

Terminal Deoxynucleotidyl Transferase (TdT) Inhibiti on of Cord Blood Derived B and T Cells Expansion.

Purpose: Terminal deoxynucleotidyl transferase(TdT) is a DNA polymerase that is present in immature pre-B and pre-T cells. TdT inserts N-nucleotides to the V (D) J gene segment during rearrangements of genes, therefore, it plays a vital role in the development and variation of the immune system in vertebrates. Here we evaluated the relationship between cytokines like interleukin-2 (IL-2), interleukin-7 (IL-7), and interleukin-15 (IL-15) and TdT expression in cord blood mononuclear cells and also effect of inhibition in the expansion of B and T cells derived from cord blood. Methodes: The cord blood mononuclear cells were cultured with different combination of cytokines for 21days, which they were harvested in definite days (7, 14 and 21) and evaluated by flow cytometry. Results: Our data indicated that TdT expression increased in cord blood mononuclear cells using immune cell key cytokines without being dependent on the type of cytokines. TdT inhibition reduced both the expansion of B and T cells derived from cord blood and also declined the apoptosis and proliferation. Considered together, TdT played an important role in the control of the expansion of B and T cells derived from cord blood. Conclusion: considered together, it was observed that TdT expression was increased by cytokines and TdT inhibition not only reduced B and Tcells derived from cord blood, but it also affected the rate of apoptosis and proliferation.

Copper sulfate pentahydrate reduced epithelial cytotoxicity induced by lipopolysaccharide from enterogenic bacteria.

The over usage of multiple antibiotics contributes to the emergence of a whole range of antibiotic-resistant strains of bacteria causing enterogenic infections in poultry science. Therefore, finding an appropriate alternative natural substance carrying an antibacterial capacity would be immensely beneficial. It has been previously discovered that the different types of cupric salts, especially copper sulfate pentahydrate (CuSO4·5H2O), to carry a potent bactericidal capacity. We investigated the neutralizing effect of CuSO4·5H2O (6.25µg/ml) on the reactive oxygen species generation, and expression of MyD88, an essential adaptor protein of Toll-like receptor, and NF-κB in three intestinal epithelial cell lines exposed to 50ng/ml lipopolysaccharide. In order to find the optimal cupric sulfate concentration without enteritis-inducing toxicity, broiler chickens were initially fed with water containing 0.4, 0.5, and 1mg/l during a period of 4days. After determination of appropriate dosage, two broiler chickens and turkey flocks with enteritis were fed with cupric compound for 4days. We found that cupric sulfate can lessen the cytotoxic effect of lipopolysaccharide by reducing the reactive oxygen species content (p<0.05). Additionally, the expression of MyD88 and NF-κB was remarkably down-regulated in the presence of lipopolysaccharide and cupric sulfate. The copper sulfate in doses lower than 0.4mg/ml expressed no cytotoxic effect on the liver, kidney, and the intestinal tract while a concentration of 0.5 and 1mg/ml contributed to a moderate to severe tissue injuries. Pearson Chi-Square analysis revealed the copper cation significantly diminished the rate of mortality during 4-day feeding of broiler chicken and turkey with enteritis (p=0.000). Thus, the results briefed above all confirm the potent anti-bactericidal feature of cupric sulfate during the course of enteritis.

Impact of C-rel inhibition of cord blood-derived B-, T-, and NK cells.

The c-Rel transcription factor is a unique member of the nuclear factor (NF)-κB family that has a role in curtailing the proliferation, differentiation, cytokine production, and overall activity of B- and T-cells. In addition, c-Rel is a key regulator of apoptosis in that it influences the expression of anti-apoptotic genes such as Bcl-2 and Bcl-xL; conversely, inhibition of c-Rel increases cell apoptosis. To better understand the relationship between c-Rel expression and effects on B- and T-cell expansion, the current study evaluated c-Rel expression in cord blood mononuclear cells. This particular source was selected as cord blood is an important source of cells used for transplantation and immunotherapy, primarily in treating leukemias. As stem cell factor (SCF) and FLT3 are important agents for hematopoietic stem cell expansion, and cytokines like interleukin (IL)-2, -7, and -15 are essential for T- and B- (and also NK) cell development and proliferation, the current study evaluated c-Rel expression in cord blood mononuclear cells and CD34+ cells, as well as effects on B-, T-, and NK cells associated with alterations in c-Rel expression, using flow cytometry and PCR. The results showed c-Rel expression increased among cells cultured in the presence of SCF and FLT3 but was reduced when IL-2, IL-7, and IL-15 were used all together. Further, inhibition of c-Rel expression by siRNA reduced cord blood-derived B-, T-, and NK cell differentiation and expansion. These results indicated that with cells isolated from cord blood, c-Rel has an important role in B-, T-, and NK cell differentiation and, further, that agents (select cytokines/growth factors) that could impact on its expression might not only affect immune cell profiles in a host but could potentially also limit apoptotic activities in (non-)immune cells in that host. In the context of cancer (immuno)therapy, in particular, when cord blood is used an important source in stem cell transplantation in leukemia patients, such down-regulating changes in c-Rel levels could be counter-productive.

Key Immune Cell Cytokines Affects the Telomere Activity of Cord Blood Cells In vitro.

PURPOSE: Telomere is a nucleoprotein complex at the end of eukaryotic chromosomes and its length is regulated by telomerase. The number of DNA repeat sequence (TTAGGG)n is reduced with each cell division in differentiated cells. The aim of this study was to evaluate the effect of SCF (Stem Cell Factor), Flt3 (Fms- Like tyrosine kinase-3), Interleukin-2, 7 and 15 on telomere length and hTERT gene expression in mononuclear and umbilical cord blood stem cells (CD34+ cells) during development to lymphoid cells. METHODS: The mononuclear cells were isolated from umbilical cord blood by Ficoll-Paque density gradient. Then cells were cultured for 21 days in the presence of different cytokines. Telomere length and hTERT gene expression were evaluated in freshly isolated cells, 7, 14 and 21 days of culture by real-time PCR. The same condition had been done for CD34+ cells but telomere length and hTERT gene expression were measured at initial and day 21 of the experiment. RESULTS: Highest hTERT gene expression and maximum telomere length were measured at day14 of MNCs in the presence of IL-7 and IL-15. Also, there was a significant correlation between telomere length and telomerase gene expression in MNCs at 14 days in a combination of IL-7 and IL-15 (r = 0.998, p =0.04). In contrast, IL-2 showed no distinct effect on telomere length and hTERT gene expression in cells. CONCLUSION: Taken together, IL-7 and IL-15 increased telomere length and hTERT gene expression at 14 day of the experiment. In conclusion, it seems likely that cells maintain naïve phenotype due to prolonged exposure of IL-7 and IL-15.

Feasibility, reliability and validity of the Iranian version of the Diabetes Quality of Life Brief Clinical Inventory (IDQOL-BCI).

AIMS: To validate and culturally adapt the Diabetes-specific Quality of Life Brief Clinical Inventory (DQOL-BCI) for the Iranian population. METHODS: After translation - back translation, content validity was assessed utilizing a panel of six experts. Based on a sample of 180 diabetic patients referred to two Diabetics Clinic Centers from September to May 2011 in Karaj, Iran, construct validity via detecting the factor structure, and convergent and discriminant validity were evaluated by scale-item correlations and known group analyses. Internal consistency and test-retest reliability were assessed in sample of 30 patients by Cronbach's and intraclass correlation coefficient (ICC). RESULTS: The IDQOL-BCI showed good content validity (CVI values>0.75 and CVR values>0.99), internal consistency (α=0.75) and test-retest reliability (ICC=0.81). A 3-factor solution was found. In addition, high values of item-scale correlations confirmed the convergence validity, and some subscales and total scores differentiate between groups defined by sex, disease duration, income levels, drug using status and physical activity demonstrated the discriminant validity. CONCLUSIONS: Our findings demonstrate the initial feasibility, reliability and validity of the Iranian version of the IDQOL-BCI as a measure of diabetic-specific QOL measure in Iranian patients.

Patterns of survival for anatomical sites of colorectal cancer with shift to advanced lesions in Iran.

BACKGROUND: With a background of disparities in colorectal cancer (CRC) incidences/mortality across countries due to differences in exposure to various prognostic factors, this study aimed to evaluate the site-specific pattern for the survival of colon and rectal patients. METHODS: A total of 1,283 patients with CRC diagnosis according to the pathology report of cancer registry of RCGLD from 1 January 2002 to 1 October 2007, were entered into the study. Data were analyzed using univariate and multivariate competing risk survival analysis. RESULTS: Survival proportion of patients showed a significant trend for 1, 3 and 5 year survival in colon cancer (P< 0.001) but this wasn't significant for rectal cancer (P=0.078). Tumor grade and pathologic stage were the most important factors predicting the survival in colon and rectal cancers with stronger hazard in the rectal site for grade and stronger hazard in the colon site for stage. For colon site, in the well and moderate categories of tumor grade, shifting from early to advance stage and also shifting in tumor grade from well and moderate categories to poor tumor grade had a considerable effect in hazard ratios. For rectum site, well to moderate shifting in tumor grade increased the hazard of death and shifting from early to advance stage increased the hazard equal to 2.54 and 4.36 times within the well and moderate tumor differentiation, respectively. In shifting to advance CRC, colon site had generally worse hazard than the rectum. CONCLUSION: Due to the worse conditions of CRC patients as shifting to advance cancer, to improve the effectiveness of treatment and hence the survival of Iranian patients, we should pay more attention to early detection, in particular by implementing population based screening programmes.

Does the prognosis of colorectal cancer vary with tumor site?

AIM: The aim of this study was to compare prognostic factors between colon and rectal cancers. BACKGROUND: Prognosis of Colorectal Cancer (CRC) may depend on the anatomical site. PATIENTS AND METHODS: A total of 1219 patients with CRC diagnosis according to the pathology report of RCGLD cancer registry, from 1 January 2002 to 1 October 2007, were entered into the study. Demographic and clinico-pathological factors were analyzed using survival analysis. RESULTS: From age at diagnosis, colon cancer had significantly better survival than rectal cancer (Multivariate Hazard Ratio (MVHR)=0.24; 95% Confidence Interval (CI) =(0.074-0.77)). Other factors, including marital status (MVHR =1.78; 95% CI =(0.33-9.62)), body mass index (BMI) (MVHR =1.21 and 1.54; 95% CI =(.30-4.85) and (.44-5.4) respectively for < 18.5 and >30 BMI groups), pathologic stage (MVHR =.64; 95% CI =(.21-1.98)) and alcohol history (MVHR =4.86; 95% CI =(.67-35.14)) were not significantly different between the two patient group but suggested a possible effect upon prognosis. Overall survival in rectum was better than that of colon. CONCLUSION: Our findings support this hypothesis that prognosis of CRC varies with tumor site.