MicroRNAs Regulate Cell Cycle and Cell Death Pathways in Glioblastoma

Glioblastoma (GBM), a grade IV brain tumor, is known for its heterogenicity and its resistance to the current treatment regimen. Over the last few decades, a significant amount of new molecular and genetic findings has been reported regarding factors contributing to GBM’s development into a lethal phenotype and its overall poor prognosis. MicroRNA (miRNAs) are small non-coding sequences of RNA that regulate and influence the expression of multiple genes. Many research findings have highlighted the importance of miRNAs in facilitating and controlling normal biological functions, including cell differentiation, proliferation, and apoptosis. Furthermore, miRNAs’ ability to initiate and promote cancer development, directly or indirectly, has been shown in many types of cancer. There is a clear association between alteration in miRNAs expression in GBM’s ability to escape apoptosis, proliferation, and resistance to treatment. Further, miRNAs regulate the already altered pathways in GBM, including P53, RB, and PI3K-AKT pathways. Furthermore, miRNAs also contribute to autophagy at multiple stages. In this review, we summarize the functions of miRNAs in GBM pathways linked to dysregulation of cell cycle control, apoptosis and resistance to treatment, and the possible use of miRNAs in clinical settings as treatment and prediction biomarkers.

Discovery of Novel Antituberculosis Compounds Using an Intra-Macrophage Assay

<p>The causative agent of tuberculosis (TB) is Mycobacterium tuberculosis, which affects 2 billion of the world population and kills 1.8 million people annually. It is among the top three infectious killers in the world human immuno deficiency virus, TB and Malaria. Every year among 300-400 new cases of TB are reported in New Zealand according to a recent WHO 2008 report. The current treatment regimen for TB is very long and results in significant toxicity, development of resistant strains and is unable to eliminate the latent bacilli. The above reasons demonstrate the growing need of research for novel antimycobacterial compounds and novel targets for the treatment of TB. Many in vitro and biochemical screens are available for testing against different mycobacterium strains but none of these screens can be considered comprehensive. The reason for this can be the lack of resemblance of the in vitro screen model with the biological systems. Hence we chose the intra-macrophage infection screening model to look for novel antimycobacterial prodrugs which are not active in an in vitro screen but selectively active inside macrophage cell lines. We were successful in establishing and validating such an intra-macrophage infection model using the non-pathogenic M. smegmatis. The model was validated using common anti-tuberculosis drugs. A preliminary high throughput screen was then set up using a mini-library demo model, followed by screening with an actual Lopac synthetic library.</p>

Discovery of Novel Antituberculosis Compounds Using an Intra-Macrophage Assay

<p>The causative agent of tuberculosis (TB) is Mycobacterium tuberculosis, which affects 2 billion of the world population and kills 1.8 million people annually. It is among the top three infectious killers in the world human immuno deficiency virus, TB and Malaria. Every year among 300-400 new cases of TB are reported in New Zealand according to a recent WHO 2008 report. The current treatment regimen for TB is very long and results in significant toxicity, development of resistant strains and is unable to eliminate the latent bacilli. The above reasons demonstrate the growing need of research for novel antimycobacterial compounds and novel targets for the treatment of TB. Many in vitro and biochemical screens are available for testing against different mycobacterium strains but none of these screens can be considered comprehensive. The reason for this can be the lack of resemblance of the in vitro screen model with the biological systems. Hence we chose the intra-macrophage infection screening model to look for novel antimycobacterial prodrugs which are not active in an in vitro screen but selectively active inside macrophage cell lines. We were successful in establishing and validating such an intra-macrophage infection model using the non-pathogenic M. smegmatis. The model was validated using common anti-tuberculosis drugs. A preliminary high throughput screen was then set up using a mini-library demo model, followed by screening with an actual Lopac synthetic library.</p>

The promising oncostatic effects of melatonin against ovarian cancer

Melatonin is a pineal hormone, secreted at the subjective night. It is involved in the regulation of many physiological functions, including the sleep-wake cycle, gonadal activity, free radical scavenging, immunomodulation, neuro-protection, and cancer progression. Melatonin acts through cell surface receptors (MT1 and MT2) as well as nuclear receptors. Circadian dysfunction can alter the secretion of melatonin. Inappropriate melatonin level promotes the initiation of many pathologies including cancer. Ovarian cancer is a common form of gynecological disease. Several studies indicate the profound link between impaired melatonin secretion and the progression of ovarian cancer. Melatonin exerts oncostatic effects in multiple ways; it acts as a potent antioxidant, induces apoptosis, and regulates metabolism, and chronic inflammatory response in ovarian cancer cells. Moreover, melatonin improves the efficacy of the current treatment regimen of ovarian cancer and can be used as an adjuvant.

Obesity in Children with Acute Promyelocytic Leukemia: What is its Incidence and Prognostic Significance?

Objective: To compare outcomes data of obese and non-obese pediatric patients with acute promyelocytic leukemia from the Cancer and Leukemia Group B trial C9710 and the Children’s Oncology Group trial AAML0631. Methods: Data including demographics, adverse events, overall survival and event free survival was analyzed, with a focus on mortality in obese patients. Results: The incidence of obesity was 34% on C9710 and 35% on AAML0631. There was significantly lower overall survival in the obese population on AAML0631. Thirteen patients died during therapy or in follow up; seven of these occurred during induction. Conclusion: The incidence of obesity is higher in patients with APL compared to the general population. The presence and degree of obesity can influence OS on the most current treatment regimen. This implies the need for close management of obese patients at diagnosis as well as reinforces the need for further research on obesity driven APL

Glby, is a PBP with β-lactamase activity and is required for in vivo viability of M. abscessus

The prevalence of Mycobacteroides abscessus, Mab, (also known as Mycobacterium abscessus) has been increasing steadily globally. Patients with structural lung conditions such as bronchiectasis, cystic fibrosis and chronic obstructive pulmonary disease are at high risk of developing pulmonary Mab disease. The disease is often recurrent as the current treatment regimen is considered sub-efficacious. The cell wall peptidoglycan of bacteria is required for their viability and its biosynthetic pathway is enriched in proteins whose inhibition is the basis for two of the most widely used classes of antibiotics to treat bacterial infections. The peptidoglycan of Mab is distinct from that of most bacteria as its synthesis involves penicillin binding proteins (PBP) and L,D-transpeptidases. Here, we demonstrate that Mab gene locus MAB_3167c encodes a PBP (hereafter referred to as Glby) and is required for normal planktonic growth in liquid broth. Glby exhibits a strong β-lactamase activity and is sensitive to β-lactamase inhibitors. In a mouse model of pulmonary Mab disease, mutant lacking this gene was unable to proliferate, gradually cleared and undetectable after three weeks. In a collection of 1.046 Mab clinical isolates, there is evidence that changes in amino acid sequence that compromise Glby function are not favored. These evidences suggest that an agent that can inhibit Glby in vivo has the potential to be an efficacious treatment against Mab disease.

Hydroxychloroquine and SARS-CoV-2 (COVID-19): An Old Problem and New Considerations in Ophthalmology

The antimalarial hydroxychloroquine (HCQ) has been suggested as a potential drug for treatment and prevention against severe acute respiratory syndrome–coronavirus 2 (SARS–CoV-2). Currently, there is insufficient scientific evidence available on HCQ retinal toxicity associated with the current treatment regimen and dosing for COVID-19 patients. In the sight of the current public health crisis, our recommendations aim to reduce the probability of unfavorable HCQ treatment outcomes and emphasize the importance of monitoring and early detection for HCQ retinopathy by simple means and the need for correlating clinical observations with multimodal imaging. We, therefore, recommend the use of Threshold Amsler grid (TAG) as a screening tool for high risk COVID-19 patients as well as treated patients with visual symptoms. Clinical decisions should be made on an individual basis, taking into consideration any pre-existing liver and kidney disease as well as macular pathology.

VIRTUAL SCREENING TO IDENTIFY POTENTIAL INHIBITOR OF ARGINASE OF LEISHMANIASIS

Leishmaniasis is caused by Leishmania protozoan parasites transmitted by the female phlebotomine sandfly. The current treatment regimen of leishmaniasis is not up to the mark and there is a huge scope of improvement. Hence, the need to approve new drugs, a complete understanding of the pathophysiology of the parasite is required. Since polyamines are required by the parasites for their infection cycle, inhibitors of polyamine pathway can be targeted by the new drugs for restricting the infection. In Leishmania, the polyamine biosynthetic pathway comprises of four compounds: arginase (ARG), ornithine decarboxylase (ODC), spermidine synthase (SPD), and S-adenosylmethionine decarboxylase (ADOMETDC). To identify these novel medicines like compounds, a structure-based screening system was utilized against downloaded drug-like compounds. In total, 1279 compounds were downloaded from the ZINC database dependent on the properties like the known inhibitor nor-NOHA [N(omega)- hydroxy-nor-L-arginase]. Virtual-ligand screening approaches were applied to identify drug-related like compounds utilizing sub-atomic docking program AutoDockVina in PyRx 0.8, and five best novel medication like compounds were chosen and their hydrogen ties with the receptor were decided.ZINC84057569, ZINC87440467, ZINC04617649, ZINC33978586, ZINC01677572 and ZINC35794928, ZINC33978586, ZINC84057569. ZINC53751324, ZINC00204059 were finalized as inhibitors against Human Arginase I and L. mexicana arginase individually contrasted with nor-NOHA, based on their binding efficiency. These inhibitors may become the base for formulating new drugs against Leishmania's, focusing on both the protein for example Human Arginase I and L. mexicana arginase. Keywords: Leishmaniasis, Human Arginase I, Leishmania mexicana arginase, nor-NOHA, Polyamine pathway, Molecular docking, Virtual screening.

Assessment and associated factors of suicidal behaviour among cancer patients visiting the oncology outpatient unit in Mekelle oncologic clinics, Tigray, Ethiopia: a cross−sectional study

Background Cancer is a group of diseases characterized by the uncontrolled growth and spread of abnormal cells. According to estimates from the International Agency for Research on Cancer, there will be 17.0 million new cancer cases in 2018 worldwide. Depression, age, sex, divorced, and hopelessness are of most factors can patient with cancer result in suicidal behaviour. The purpose of this study is to identify and associated factors of suicidal behaviour among cancer patients in Mekelle, Ethiopia. Methods The cross-sectional study design was employed with a total of 345 study subjects in Mekelle, Ethiopia. Suicidal behaviour was measured by the Suicidal Behavior Questionnaire-Revised (SBQ-R) scale. Bivariate and multiple logistic regression analyses were performed to determine between the explanatory and outcome variables. Results The magnitude of suicidal behaviour was 20%. Previously suicidal attempt [AOR = 31.466, 95% CI (14.552, 68.042), P < 0.0001] was associated factor whereas no comorbid physical illness [AOR = .0.363, 95% (0. 164, 0.806)] and current treatment regimen (surgery, radiotherapy and palliative care) were significantly protective factors for suicidal behavior. Conclusion No comorbid physical illness, suicide attempt and current treatment regimen were significant factors of suicidal behaviour. Oncologic professionals should assess patient suicidal risk assessment routinely and every professional focuses on management besides the medication.