Identification of Small-Molecule Inhibitors against Meso-2, 6-Diaminopimelate Dehydrogenase from Porphyromonas gingivalis

Species-specific antimicrobial therapy has the potential to combat the increasing threat of antibiotic resistance and alteration of the human microbiome. We therefore set out to demonstrate the beginning of a pathogen-selective drug discovery method using the periodontal pathogen Porphyromonas gingivalis as a model. Through our knowledge of metabolic networks and essential genes we identified a “druggable” essential target, meso-diaminopimelate dehydrogenase, which is found in a limited number of species. We adopted a high-throughput virtual screen method on the ZINC chemical library to select a group of potential small-molecule inhibitors. Meso-diaminopimelate dehydrogenase from P. gingivaliswas first expressed and purified in Escherichia coli then characterized for enzymatic inhibitor screening studies. Several inhibitors with similar structural scaffolds containing a sulfonamide core and aromatic substituents showed dose-dependent inhibition. These compounds were further assayed showing reasonable whole-cell activity and the inhibition mechanism was determined. We conclude that the establishment of this target and screening strategy provides a model for the future development of new antimicrobials

Hereditary diffuse gastric cancer therapeutic roadmap: current and novel approaches in a nutshell

Hereditary diffuse gastric cancer (HDGC) is a rare malignancy characterized by autosomal dominant inheritance of pathological variants of the CDH1 gene encoding E-cadherin, which is involved in cell–cell adhesion, maintenance of epithelial architecture, tumor suppression, and regulation of intracellular signaling pathways. Late-stage recognition of HDGC is typically associated with a poor clinical outcome due to its metastatic potential and risk of lobular breast cancer (LBC) development. The American College of Gastroenterology issued guidelines to evaluate HDGC, test for CDH1 genetic variants, and recommend prophylactic gastrectomy for carriers of CDH1 mutations. If surgery is not pursued, endoscopy is a surveillance alternative, although it carries a limited ability to detect malignant foci. As part of clinical research efforts, novel endoscopy advances are currently studied, and a center of excellence for HDGC was created for a comprehensive multidisciplinary team approach. Within this review, we cover current conventional treatment modalities such as gastrectomy and chemotherapy, as the mainstay treatments, in addition to Pembrolizumab, an immune checkpoint inhibitor, as the last therapeutic resort. We also shed light on novel and promising approaches with emphasis on immunotherapy to treat HDGC. We further break down the therapeutic paradigms to utilize molecular tools, antibodies against checkpoint inhibitors, TGF-β and tyrosine kinase inhibitors, cell-based adoptive therapies, and oncolytic viral therapies. We aim to expand the understanding on how to modulate the tumor microenvironment to tip the balance towards an anti-tumor phenotype, prevent metastasis of the primary disease, and potentially alter the therapeutic landscape for HDGC

Pengaruh Penambahan Kolin Klorida Pada Pakan Terhadap Kadar Kolesterol Dan Lipoprotein Darah Sapi Perah Laktasi

The purpose of this study was to evaluate the effects of choline chloride addition in feed on cholesterol, low density lipoprotein (LDL), and high density lipoprotein (HDL) levels in blood of lactating dairy cow, as indicator of lipid anabolism in the body. Eight of lactating dairy cows (61 to 91 days in milk; 2nd lactation period and 456 ± 31 kg of BW average as equal to 99 ± 5 kg BW0.75) were fed total mixed diet containing Napier grass and concentrate (40:60) and additive 30 g/d choline chloride 60% corn-cob as 18 g/d choline chloride (as equal to 0.02 % BW0.75). The experiment was set as cross-over designs with two experiments and eight replications. The treatments were T0 = 0 g/d choline chloride and T1= 30 g/d choline chloride, within 2 periods in which each period was 4 weeks and the data was analyzed using analysis of variance (ANOVA). The results showed that the addition of 30 g/d choline chloride in feed did not affect (P>0,05) the cholesterol, LDL and HDL levels in blood of lactating dairy cows. The conclusion of this study was the choline chloride addition in feed did not increase cholesterol, LDL, and HDL levels in blood of lactating dairy cows as the indicator of lipid anabolism

A Systems Biology Approach For Predicting Essential Genes and Deciphering Their Dynamics Under Stress In Streptococcus sanguinis

Infectious diseases are the top leading cause of death worldwide. Identifying essential genes, genes indispensable for survival, has been proven indispensable in defining new therapeutic targets against pathogens, major elements of the minimal set genome to be harnessed in synthetic biology, and determinants of evolutionary relationships of phylogenetically distant species. Thus, essentiality studies promise valuable revenues that can decipher much of biological complexities. Taking advantage of the available microbial sequences and the essentiality studies conducted in various microbial models, we proposed a framework for the prediction of essential genes based on our experimentally verified knowledge of the pathways involved in three essential xiv functions: genetic information processing, cell wall biosynthesis, and energy metabolism. We investigated physiological pathways in Kyoto Encyclopedia of Genes and Genomes (KEGG) database and developed a bioinformatics approach to predict essential genes in 13 different microbial species. Our in silico findings matched to a high degree the experimental data derived from essentiality studies conducted on the same microbial models, providing insights about the microbial lifestyles, including energy resources, cell wall structure, and ecological preferences, but not virulence tools and mechanisms. Furthermore, we believe that essential genes have survived the evolutionary purifying selection due to their evolved capacity to re-wire genetic and protein networks in response to any emerging stress. In this sense, an environmental specificity (stress) provides a dominant determinant of an essential gene set. The new challenge was understanding the contribution of the essential genome in S. sanguinis to the coping mechanisms to different clinically relevant stress factors, namely temperature elevation (43oC) and sub-inhibitory concentration of ampicillin, an abundantly prescribed antibiotic for prophylaxis and treatment against S. sanguinis. The current project investigated the transcriptomic and proteomic profiles of essential genes and proteins, using RNA-seq and mass spectrometry respectively, under the impact of the two stressors separately, to elucidate the essential genome and proteome dynamics on a temporal basis and define “pathogenesis signatures” as potential therapeutic targets. We believe that the current findings will help characterize a bacterial model for studying the dynamics of essential genes and assist in designing evidence-based guidelines for drug prescription in clinical practice

Incidence of sepsis following transrectal ultrasound guided prostate biopsy at a tertiary-care medical center in Lebanon

ABSTRACT Background Urosepsis is a rare but life-threatening complication following transrectal ultrasound (TRUS) guided needle prostate biopsy. Despite the technological and pharmacological improvements, the problem of bacterial urosepsis after prostate biopsy remains. A strategy for preventing urosepsis following TRUS prostate biopsy in areas with high prevalence of resistant strains or patients presenting risk factors is lacking. Objectives The aim of this study was to assess the prevalence of urosepsis, as well its predictors, following TRUS guided needle biopsy of the prostate in a tertiary care medical center in Lebanon. Materials and Methods We carried out a retrospective study on all patients who underwent TRUS prostate biopsy at the American University of Beirut Medical Center between January 1, 2011 and June 31, 2013. Patients’ hospital charts were reviewed. Data collected included demographic information, pre-procedure disease specific information, as well as post-procedure information. Predictors of urosepsis following TRUS were assessed. Results In total, 265 patients were included in this study, where the prevalence of urosepsis following TRUS prostate biopsy was found to be 9.4%. The significant independent predictors of urosepsis were found to be: age with an OR=0.93 (95% CI: 0.88–1.00, p-value=0.03), and hypertension comorbidity with an OR=3.25 (95% CI: 1.19–8.85, p-value=0.02). Conclusion We found a high prevalence of urosepsis among patients who have undergone TRUS prostate biopsy, and identified two significant risk factors. The results of this study highlight the importance of implementing strategies for prevention of urosepsis following TRUS prostate biopsy

Bellini Duct Carcinoma Misdiagnosed with Urothelial Papillary Carcinoma

Background. Collecting (Bellini) duct carcinoma (CDC) or Bellini duct carcinoma (BDC) is a rare subtype of kidney tumors, accounting for less than 3% and known to have the worst prognosis. It is known to have multiple clinical presentations; this is why it can be easily misdiagnosed. The aim of this article is to present a case of CDC that was initially misdiagnosed with urothelial papillary carcinoma (UPC) in a 41-year-old male. Case Presentation. Our patient presented with a left flank pain evolving for one month and one episode of gross macroscopic hematuria. Upon presentation, he had left costovertebral angle tenderness. Initial lab tests were normal. Computed tomography revealed a 5 cm solid mass of the left renal pelvis and multiple infracentimetric perihilar lymph nodes. Subsequently, the patient had left nephroureterectomy. Microscopic examination showed the presence of a high-grade urothelial papillary carcinoma of the renal pelvis’ lumen. All four of the dissected lymph nodes showed disease metastasis. Three years after establishing the diagnosis, the patient presented again for chronic abdominal pain, with a recent history of weight loss. CT scan showed a left paraaortic mass infiltrating the left psoas muscle over a length of 12 cm. Immunohistochemical profiling of this mass confirmed the diagnosis of Bellini duct carcinoma, rejecting the initial diagnosis of UPC. Therefore, the patient required a cisplatin-gemcitabine-based chemotherapy regimen. Conclusion. BDC remains one of the rare aggressive subtypes of RCC, having a multitude of initial clinical presentations and an unfavorable prognosis. In this patient, CDC was masquerading as a transitional cell carcinoma that should always be kept in mind as a possible presentation. Corresponding early imaging and histopathology exams are primordial for a correct diagnosis and thus a better prognosis