mTOR inhibitors: A novel class of anti-cancer agents

threonine protein kinase that acts as a master switch between anabolic and catabolic functions of the human body in pathways stimulated by insulin, growth factors and mitogen [1]. mTOR functions as a central controller of growth, proliferation, metabolism and angiogenesis, but its signaling is dysregulated in various human diseases especially certain cancers like renal cell carcinoma and breast cancer [2]. In cancer, mTOR is frequently hyperactivated which promotes cancer development and progression. In certain cancers, resistance to antineoplastic agents such as topoisomerase 1, topoisomerase 2 inhibitors and methotrexate can be overcome with a synergistic combination with mTOR inhibitors [3,4]. Furthermore, mTOR activates the degradation of cyclin dependent kinases such as CDK1 which increases synthesis of dihydrofolate reductases. By decreasing this enzyme, mTOR inhibitors like sirolimus and temsirolimus, promote tumour sensitivity to agents such as methotrexate [4]. Recent development has made cancer treatment move on from conventional cytotoxic drugs to agents that target specific proteins like mTOR called mTOR inhibitors. A very common mTOR inhibitor, rapamycin, is a bacterial product that inhibits mTOR by associating with its intracellular receptor [5]. [Currently, two mTOR inhibitors, temsirolimus and everolimuswhich are derivatives of rapamycin, temsirolimus(Torisel: Wyeth-Ayerst, Charlotte, NC, U.S.A.) and everolimus(Certican: Novarti

IN VITRO CYTOTOXIC ACTIVITY OF CLERODENDRUM INFORTUNATUM L. AGAINST T47D, PC-3, A549 AND HCT-116 HUMAN CANCER CELL LINES AND ITS PHYTOCHEMICAL SCREENING

Objective: Present investigation accounts for scientific evaluation of the plant Clerodendrum infortunatum L. for its medicinal efficacy which includes phytochemical screening and anticancer activities.Methods: Phytochemical screening of Clerodendrum infortunatum extracts was performed for the qualitative detection of reducing sugars, terpenoids, flavonoids, saponins, tannins, alkaloids, phlobatannins, steroids, amino acids and glycosides using standard procedures. The sulforhodamine B (SRB), in vitro cytotoxic assay, was used to investigate the anticancer activity of hexane, chloroform, ethyl acetate and ethanol extracts of leaves and roots of Clerodendrum infortunatum against T47D (Breast), PC-3 (prostate), A549 (lung) and HCT-116 (colon) cancer cell lines.Results: Secondary metabolites including alkaloids, flavonoids, terpenoids, steroids, tannins, and saponins are present in many extracts. Alkaloids and flavonoids found to be present in almost all the extracts. The best cytotoxic activity has been exerted by hexane of root exhibiting growth inhibition of 72.83 ± 0.44, 85.50 ± 0.29 and 68.17 ± 1.36 % against PC-3, A549 and HCT-116 at a concentration of 100 µg/ml. Further, hexane of root showed a moderate cytotoxic effect of 42.17 ± 0.17 % against T47D at 100 µg/ml. At similar concentration, the chloroform extract is also effective against these three cell lines showing 61.50 ± 0.76, 67.00±0.58, and 68.53 ± 0.80% growth inhibition against PC-3, A549 and HCT-116 cell lines respectively, whereas, T47D cancer cell line showed 46.43 ± 0.30 % growth inhibition. The results have indicated that all the leaf extracts, as well as ethyl acetate and ethanol extracts of root, have exhibited a poor response (≤ 40 %).Conclusion: The present ï¬ndings suggest that the Clerodendrum infortunatum extracts are rich in alkaloid, flavonoids and terpenoids. The hexane and chloroform root extracts of Clerodendrum infortunatum possess signiï¬cant anticancer activities which may be due to the presence of these phytochemical groups.Â

Best of Both Worlds: A Pliable and Generalizable Neuro-Symbolic Approach for Relation Classification

This paper introduces a novel neuro-symbolic architecture for relation classification (RC) that combines rule-based methods with contemporary deep learning techniques. This approach capitalizes on the strengths of both paradigms: the adaptability of rule-based systems and the generalization power of neural networks. Our architecture consists of two components: a declarative rule-based model for transparent classification and a neural component to enhance rule generalizability through semantic text matching. Notably, our semantic matcher is trained in an unsupervised domain-agnostic way, solely with synthetic data. Further, these components are loosely coupled, allowing for rule modifications without retraining the semantic matcher. In our evaluation, we focused on two few-shot relation classification datasets: Few-Shot TACRED and a Few-Shot version of NYT29. We show that our proposed method outperforms previous state-of-the-art models in three out of four settings, despite not seeing any human-annotated training data. Further, we show that our approach remains modular and pliable, i.e., the corresponding rules can be locally modified to improve the overall model. Human interventions to the rules for the TACRED relation \texttt{org:parents} boost the performance on that relation by as much as 26\% relative improvement, without negatively impacting the other relations, and without retraining the semantic matching component

Performance optimization of CH3NH3Pb(I1-xBrx)3 based perovskite solar cells by comparing different ETL materials through conduction band offset engineering

Numerical simulations can provide the physical insights into the carrier transport mechanism in the solar cells, and the factors influencing their performance. In this paper, perovskite solar cell (PSC) based on the mixed perovskite (CH3NH3Pb(I1-xBrx)3 has been numerically simulated using the SCAPS simulator. A comparative analysis of different electron transport layers (ETLs) based on their conduction band offsets (CBO) has been performed, while Spiro-OMeTAD was used as a hole transport layer (HTL). Among the proposed ETLs, CdZnS performed better and demonstrated the power conversion efficiency (PCE) of 25.20%. Also, the PCE of the PSC has been optimized by adjusting the doping concentrations in the ETL, Spiro-OMeTAD layer, and the thickness of the perovskite light absorber layer. It was found that the doping concentration of 1021 cm−3 for the CdZnS based ETL and 1020 cm−3 for Spiro-OMeTAD are the optimum concentrations values for demonstrating enhanced efficiency. A 600 nm thick perovskite layer has found to be appropriate for the efficient PSC design. For the initial guessing and numerical model validation, the photovoltaic data of a very stable (over one year with PCE ~13%) n-i-p structured (ITO/TiO2/CH3NH3Pb(I1-xBrx)3/Spiro-OMeTAD/Au) PSCs was used. These numerically simulated results signify the optimum performance of the photovoltaic device that can be further implemented to develop the highly efficient PSCs.This publication was made possible by the NPRP award [NPRP11S-1210–170080] from Qatar National Research Fund (a member of the Qatar Foundation). The findings made herein are solely the responsibility of the authors. The authors are thankful to Prof. Marc Burgelman, the University of Gent for the SCAPS developments package, and permission to use the SCAPS software

Association of Lowering Low‐Density Lipoprotein Cholesterol With Contemporary Lipid‐Lowering Therapies and Risk of Diabetes Mellitus: A Systematic Review and Meta‐Analysis

Background The relationship between lowering LDL (low‐density lipoprotein) cholesterol with contemporary lipid‐lowering therapies and incident diabetes mellitus (DM) remains uncertain. Methods and Results Thirty‐three randomized controlled trials (21 of statins, 12 of PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitors, and 0 of ezetimibe) were selected using Medline, Embase, and the Cochrane Central Register of Controlled Trials (inception through November 15, 2018). A total of 163 688 nondiabetic patients were randomly assigned to more intensive (83 123 patients) or less intensive (80 565 patients) lipid‐lowering therapy. More intensive lipid‐lowering therapy was defined as the more potent pharmacological strategy (PCSK9 inhibitors, higher intensity statins, or statins), whereas less intensive therapy corresponded to active control group or placebo/usual care of the trial. Metaregression and meta‐analyses were conducted using a random‐effects model. No significant association was noted between 1‐mmol/L reduction in LDL cholesterol and incident DM for more intensive lipid‐lowering therapy (risk ratio: 0.95; 95% CI, 0.87–1.04; P=0.30; R2=14%) or for statins or PCSK9 inhibitors. More intensive lipid‐lowering therapy was associated with a higher risk of incident DM compared with less intensive therapy (risk ratio: 1.07; 95% CI, 1.03–1.11; P\u3c0.001; I2=0%). These results were driven by higher risk of incident DM with statins (risk ratio: 1.10; 95% CI, 1.05–1.15; P\u3c0.001; I2=0%), whereas PCSK9 inhibitors were not associated with incident DM (risk ratio: 1.00; 95% CI, 0.93–1.07; P=0.96; I2=0%; P=0.02 for interaction). Conclusions Among intensive lipid‐lowering therapies, there was no independent association between reduction in LDL cholesterol and incident DM. The risk of incident DM was higher with statins, whereas PCSK9 inhibitors had no association with risk of incident DM

Association of Lowering Low�Density Lipoprotein Cholesterol With Contemporary Lipid�Lowering Therapies and Risk of Diabetes Mellitus: A Systematic Review and Meta�Analysis

Background The relationship between lowering LDL (low�density lipoprotein) cholesterol with contemporary lipid�lowering therapies and incident diabetes mellitus (DM) remains uncertain. Methods and Results Thirty�three randomized controlled trials (21 of statins, 12 of PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitors, and 0 of ezetimibe) were selected using Medline, Embase, and the Cochrane Central Register of Controlled Trials (inception through November 15, 2018). A total of 163 688 nondiabetic patients were randomly assigned to more intensive (83 123 patients) or less intensive (80 565 patients) lipid�lowering therapy. More intensive lipid�lowering therapy was defined as the more potent pharmacological strategy (PCSK9 inhibitors, higher intensity statins, or statins), whereas less intensive therapy corresponded to active control group or placebo/usual care of the trial. Metaregression and meta�analyses were conducted using a random�effects model. No significant association was noted between 1�mmol/L reduction in LDL cholesterol and incident DM for more intensive lipid�lowering therapy (risk ratio: 0.95; 95% CI, 0.87–1.04; P=0.30; R2=14%) or for statins or PCSK9 inhibitors. More intensive lipid�lowering therapy was associated with a higher risk of incident DM compared with less intensive therapy (risk ratio: 1.07; 95% CI, 1.03–1.11; P<0.001; I2=0%). These results were driven by higher risk of incident DM with statins (risk ratio: 1.10; 95% CI, 1.05–1.15; P<0.001; I2=0%), whereas PCSK9 inhibitors were not associated with incident DM (risk ratio: 1.00; 95% CI, 0.93–1.07; P=0.96; I2=0%; P=0.02 for interaction). Conclusions Among intensive lipid�lowering therapies, there was no independent association between reduction in LDL cholesterol and incident DM. The risk of incident DM was higher with statins, whereas PCSK9 inhibitors had no association with risk of incident DM

Complex partial non-convulsive status epilepticus masquerading as hepatic encephalopathy: a case report

INTRODUCTION: Hepatic encephalopathy is usually suspected in patients who are cirrhotic with neuropsychiatric manifestations. We present a case of suspected hepatic encephalopathy that did not respond to standard empiric therapy and was eventually diagnosed as non-convulsive status epilepticus of complex partial type. Our patient responded dramatically to anti-convulsive therapy. CASE PRESENTATION: We report the case of a 45-year-old African-American man with hepatitis C virus cirrhosis and human immunodeficiency virus who presented to our facility with a one-day history of confusion and a variable mental status. Our patient’s vital signs were stable and all his electrolytes were within normal range. A clinical diagnosis of hepatic encephalopathy was made and our patient was started on empiric therapy with lactulose and rifaximin. Our patient did not respond to therapy. After five days of treatment, alternative diagnoses were sought and a neurology consult was requested. An electroencephalogram was eventually performed which showed seizure activity in the right parietal lobe. A diagnosis of non-convulsive status epilepticus was made and our patient was started on oral levetiracetam. On day two of therapy, our patient was alert and oriented. He continues to do well on follow-up approximately one year after discharge. CONCLUSIONS: Non-convulsive status epilepticus should be considered in the differential diagnosis of patients with suspected hepatic encephalopathy who do not respond to empirical treatment. Further studies are needed to investigate the incidence of this entity in patients with persistent hepatic encephalopathy

Gastro-intestinal stromal tumor (GIST) complicating a colonic interposition: a novel case report

Background: Gastrointestinal stromal tumor (GIST) is a rare tumor comprising 0.1-0.3% of all gastrointestinal (GI) malignancies. Stomach followed by small intestine is the most common sites of involvement, implicated in 95% of the cases. We present a case of GIST complicating a colonic interposition. To the best of the author's knowledge, this is the first reported case of GIST complicating a colonic interposition. Case presentation: A 47 year old African American male presented to the emergency department with intermittent, severe chest pain. Past medical history was significant for alkali (NaOH) ingestion during 1980 for which esophageal resection and a colonic pull-through was performed. A CXR revealed a widened mediastinum and CT scan chest revealed showed a large (11.4 ˟ 8.3 ˟ 12.1 cm) vascular mediastinal mass. At endoscopy, a large, ulcerated, cratered and friable mass was found at 29cm extending to 36cm at which point the lower anastomosis of the colonic pull through was present. Multiple endoscopic biopsies were obtained which showed that the tumor was immunoreactive with CD117, CD34 and DOG1 while markers of carcinoma, melanoma and lymphoma were negative. In light of the pathology report, the immunohistochemistry and the CT scans, the tumor was classified as a stage 4 GIST of colonic interposition. Conclusions: GIST can complicate unusual locations such as colonic interposition and should be kept in the differential diagnosis of such unusual presentations

Serum ferritin levels, socio-demographic factors and desferrioxamine therapy in multi-transfused thalassemia major patients at a government tertiary care hospital of Karachi, Pakistan

<p>Abstract</p> <p>Background</p> <p>Beta thalassemia is the most frequent genetic disorder of haemoglobin synthesis in Pakistan. Recurrent transfusions lead to iron-overload manifested by increased serum Ferritin levels, for which chelation therapy is required.</p> <p>Findings</p> <p>The study was conducted in the Pediatric Emergency unit of Civil Hospital Karachi after ethical approval by the Institutional Review Board of Dow University of Health Sciences. Seventy nine cases of beta thalassemia major were included after a written consent. The care takers were interviewed for the socio-demographic variables and the use of Desferrioxamine therapy, after which a blood sample was drawn to assess the serum Ferritin level. SPSS 15.0 was employed for data entry and analysis.</p> <p>Of the seventy-nine patients included in the study, 46 (58.2%) were males while 33 (41.8%) were females. The mean age was 10.8 (± 4.5) years with the dominant age group (46.2%) being 10 to 14 years. In 62 (78.8%) cases, the care taker education was below the tenth grade. The mean serum Ferritin level in our study were 4236.5 ng/ml and showed a directly proportional relationship with age. Desferrioxamine was used by patients in 46 (58.2%) cases with monthly house hold income significant factor to the use of therapy.</p> <p>Conclusions</p> <p>The mean serum Ferritin levels are approximately ten times higher than the normal recommended levels for normal individuals, with two-fifths of the patients not receiving iron chelation therapy at all. Use of iron chelation therapy and titrating the dose according to the need can significantly lower the iron load reducing the risk of iron-overload related complications leading to a better quality of life and improving survival in Pakistani beta thalassemia major patients.</p> <p>Conflicts of Interest: None</p

Colorimetric sensing of uric acid based on sawdust-deposited silver nanoparticles via an eco-friendly and cost-effective approach

Uric acid is directly linked to gout, arthritis, neurological, cardiovascular, and kidney-related disorders. It is a byproduct obtained from the breakdown of purines and a significant indicator of hyperuricemia observed in both urine and blood. In the absence of any enzyme, it's quite difficult to develop a novel, cost-effective, and clinical method for uric acid detection. Herein, we report a very simple, low-cost, and non-enzymatic method for the selective identification and quantification of uric acid using green synthesized silver nanoparticles (Ag NPs). The desired Ag NPs were synthesized by the hydrothermal method using Erythrina suberosa sawdust as a deagglomeration agent and Psidium guajava extract as a reductant. The synthesis of the sensing platform, i.e., sawdust-deposited Ag NPs, was confirmed through different techniques such as UV-Vis spectrophotometer, FTIR, XRD, EDX, and scanning electron microscopy (SEM). Sawdust can offer a good, environmentally friendly, and cost-effective strategy to overcome the problem of agglomeration in nanoparticles. The enzyme mimic, with the help of H2O2, oxidizes the colorless 3,3′,5,5′-tetramethylbenzidine (TMB) to oxidized TMB with a blue-green color. The addition of uric acid reduces the oxidized TMB to a colorless product, resulting in a colorimetric change. For quality improvement, different reaction parameters, including pH, time, TMB, and NPs concentration, were optimized. Our proposed sensor responds in linear ranges of 0.04–0.360 μM, with a limit of quantification of 0.01 μM and a limit of detection of 0.004 μM. The suggested enzyme mimic detected uric acid in blood samples, with particular specificity in the presence of competitive analytes