Identification of isoquinolinone DHODH inhibitor isosteres.

DHODH inhibition represents an attractive approach to overcome differentiation blockade for the treatment of AML. In a previous communication, we described our efforts leading to the discovery of compound 3 (JNJ-74856665), an orally bioavailable, potent, and selective DHODH inhibitor for clinical development. Guided by the co-crystal structures bound to human DHODH, other fused six-membered constructs were explored as isosteric replacements of the isoquinolinone central core.

Discovery of JNJ-74856665: A Novel Isoquinolinone DHODH Inhibitor for the Treatment of AML.

Acute myelogenous leukemia (AML), a heterogeneous disease of the blood and bone marrow, is characterized by the inability of myeloblasts to differentiate into mature cell types. Dihydroorotate dehydrogenase (DHODH) is an enzyme well-known in the pyrimidine biosynthesis pathway and preclinical findings demonstrated that DHODH is a metabolic vulnerability in AML as inhibitors can induce differentiation across multiple AML subtypes. As a result of virtual screening and structure-based drug design approaches, a novel series of isoquinolinone DHODH inhibitors was identified.

Foreign Body in the Male Urinary Bladder: A Case Report.

A foreign body in the urinary bladder is an uncommon finding in urology emergencies. There are several ways in which intravesical foreign bodies can occur, including iatrogenic injuries, self-insertion for pleasure, sexual abuse, assault, and migration from adjacent sites. This case report is about an interesting presentation of a 36-year-old male who presented to the urology outpatient department with a burning sensation and dribbling while urinating for 1 month.

Discovery of Alternative Binding Poses through Fragment-Based Identification of DHODH Inhibitors.

Dihydroorotate dehydrogenase (DHODH) is a mitochondrial enzyme that affects many aspects essential to cell proliferation and survival. Recently, DHODH has been identified as a potential target for acute myeloid leukemia therapy. Herein, we describe the identification of potent DHODH inhibitors through a scaffold hopping approach emanating from a fragment screen followed by structure-based drug design to further improve the overall profile and reveal an unexpected novel binding mode.

Dental aesthetic related popularity and peer pressure, a survey of adolescents in Pakistan.

Objectives: Most research has focused on determining how popularity and peer pressure impact behaviours, rather than identifying a key feature such as dental aesthetics and studying its impacts in relation to popularity and peer pressure.

Methods: A cross sectional study was conducted on a sample of 527 children from four schools located in Lahore, Pakistan. A 14-point questionnaire was developed, using existing measures of peer pressure, and popularity.

Effectiveness of Using Nucleic Acid Amplification Test to Screen Blood Donors for Hepatitis B, Hepatitis C, and HIV: A Tertiary Care Hospital Experience From Pakistan.

Background Ensuring blood safety is the primary goal of transfusion medicine. Despite extensive serological tests and strict safety measures, the risk of transfusion-transmitted infections (TTIs) still exists. As applied to blood screening, Nucleic Acid Amplification Test (NAT) offers much higher sensitivity for detecting viral infections.

Impact of Harvesting Method and Donor Age on the Behavior of Human Osteoblast-Like Cells.

Autogenous particulate bone grafts are being utilized in oral implantology for minor grafting procedures. This study aimed to investigate the influence of the bone-harvesting technique, donor age, and donor site on proliferation and differentiation of human primary osteoblast-like cells in the cell culture. Autogenous bone particles (20 samples) were harvested from the maxilla and mandible during surgery using two different protocols, and two types of particulate bone grafts were collected: bone chips and bone sludge.

Prevalence of periodontitis based on retrospective radiographic evaluation at dental hospital in Eastern Province of Saudi Arabia: A retrospective study.

Objectives: The contemporary information on the prevalence of periodontitis and associated risk factors is deficient in the Kingdom of Saudi Arabia. Our aim was to measure the prevalence of periodontitis and associated risk factors among the Saudi population in the Eastern Province of Saudi Arabia who visited the University Dental Hospital.

Methods: In this retrospective study, the demographic data and medical and dental records of 700 subjects were examined.

Severe aortic regurgitation from aortic valve perforation in Libman-Sacks endocarditis: Incremental value of 3D TEE.

A 43-year-old woman with stroke and systemic lupus erythematosus was found to have severe eccentric aortic regurgitation. Three-dimensional transesophageal echocardiogram further defined the origin of the regurgitant jet through a perforation in the left coronary cusp next to a mass with a tiny stalk attached to the left coronary cusp.

Oral Manifestations: A Reliable Indicator for Undiagnosed Diabetes Mellitus Patients.

Objectives:  This article identifies undiagnosed DM (UDM) cases in the Pakistani population by perceiving the signs and symptoms of DM and associating them with oral manifestations.

Material And Methods:  In this cross-sectional study, patients showing at least three or more classical or warning signs like polydipsia, polyuria, polyphagia, and general weakness were considered UDM cases. Detailed oral examination for gingivitis, periodontitis, halitosis, xerostomia, and tongue manifestations was done followed by the hemoglobin A1c (HbA1c) analysis.

Estimation of the risk of COVID-19 transmission through aerosol-generating procedures.

Background: The outbreak of the coronavirus disease 2019 (COVID-19) pandemic was associated with the provision of multiple guidelines for the dental profession. All elective procedures were restricted, and only emergency procedures were performed. There was fear and anxiety among dentists while performing aerosol-generating procedures (AGPs), as they were considered to pose a high risk of COVID-19 transmission.

-Heterocyclic 3-Pyridyl Carboxamide Inhibitors of DHODH for the Treatment of Acute Myelogenous Leukemia.

Acute myelogenous leukemia (AML), a disease of the blood and bone marrow, is characterized by the inability of myeloblasts to differentiate into mature cell types. Dihydroorotate dehydrogenase (DHODH) is an enzyme well-known in the pyrimidine biosynthesis pathway; however, small molecule DHODH inhibitors were recently shown to induce differentiation in multiple AML subtypes. Using virtual screening and structure-based drug design approaches, a new series of N-heterocyclic 3-pyridyl carboxamide DHODH inhibitors were discovered.

Safe protocol of resuming routine dental procedures in a tertiary care hospital setting post COVID-19 lockdown.

Background: The outbreak of the COVID-19 pandemic greatly affected dentistry. Dental procedures are considered one of the modes of transfer of COVID-19 infection due to generation of aerosols. To prevent transmission of this virus through dental procedures, guidelines were issued by the World Health Organisation (WHO), Centers for Disease Control and Prevention (CDC) and Ministry of Health of each country.

A Prospective Randomized Clinical Trial on Radiographic Crestal Bone Loss Around Dental Implants Placed Using Two Different Drilling Protocols: 12-Month Follow-up.

Purpose: There is a substantial need to perform studies to evaluate crestal bone loss (CBL) and implant success when using a newly introduced low-speed drilling protocol. Therefore, this study aimed to evaluate the mean CBL and implant success rate by placing implants utilizing two drilling protocols, ie, standard and low-speed drilling protocols.

Materials And Methods: A randomized controlled clinical trial was carried out in patients who required dental implants to restore their esthetics and function.

Applications and Error Ratios of Calibration Techniques in EOS, Orthoroentgenogram, and Teleoroentgenogram for Length Measurement: A Comparative Study.

Background: Accurate length measurements of extremity bones are essential in treating limb deformities and length discrepancies in children.

Objective: This study aimed to determine errors in common techniques used to measure lower limb lengths in children.

Methods: Precision and instrument errors in length measurements were studied utilizing electro-optical system (EOS), orthoroentgenogram, and teleoroentgenogram The goal was to measure a 70-cm metallic rod phantom (average length of the lower extremity of a 10-year-old boy in the 50th percentile) in 3 phases.

The Novel Nucleoside Analogue ProTide NUC-7738 Overcomes Cancer Resistance Mechanisms and in a First-In-Human Phase I Clinical Trial.

Purpose: Nucleoside analogues form the backbone of many therapeutic regimens in oncology and require the presence of intracellular enzymes for their activation. A ProTide is comprised of a nucleoside fused to a protective phosphoramidate cap. ProTides are easily incorporated into cells whereupon the cap is cleaved and a preactivated nucleoside released.

A Phase 2a cohort expansion study to assess the safety, tolerability, and preliminary efficacy of CXD101 in patients with advanced solid-organ cancer expressing HR23B or lymphoma.

Background: This Phase 2a dose expansion study was performed to assess the safety, tolerability and preliminary efficacy of the maximum tolerated dose of the oral histone de-acetylase (HDAC) inhibitor CXD101 in patients with relapsed / refractory lymphoma or advanced solid organ cancers and to assess HR23B protein expression by immunohistochemistry as a biomarker of HDAC inhibitor sensitivity.

Methods: Patients with advanced solid-organ cancers with high HR23B expression or lymphomas received CXD101 at the recommended phase 2 dose (RP2D). Key exclusions: corrected QT > 450 ms, neutrophils < 1.

Ecological impacts of climate change on the snow leopard (Panthera unica) in South Asia.

Snow leopard (Panthera unica) is a felid which lives in the highly rugged areas of alpine regions in different mountain ranges of South and Central Asia. This solitary animal needs large spaces for its ranges but due to climate change and relatively faster rate of global warming in South Asian mountain ranges, its habitat is going to shrink and fragment by tree-line shifts and change in hydrology of the area. Vegetative modification of montane flora and competition with domestic goats will create its prey's population to decline along with a chance of a direct conflict and competition with the common leopard.

A Phase Ib Open-Label, Dose-Escalation Study of NUC-1031 in Combination with Carboplatin for Recurrent Ovarian Cancer.

Purpose: NUC-1031 is a first-in-class ProTide modification of gemcitabine. In PRO-002, NUC-1031 was combined with carboplatin in recurrent ovarian cancer.

Patients And Methods: NUC-1031 was administered on days 1 and 8 with carboplatin on day 1 every 3 weeks for up to six cycles.

Infantile Tibia Vara (Blount Disease) with Iatrogenic Changes Causing Residual Tibial Deformities.

Treatment of infantile tibia vara or Blount disease (ITV/BD) in patients < 3 years old and Langenskiold stages I-III consists of orthosis and, in relapsing cases, proximal tibial osteotomy and/or proximal tibial guided growth laterally with a tension band plate. Our aim was to evaluate the results of treatments in a consecutive group. After Institutional Review Board approval, data from 2002 to 2018 were collected.

A carboxylic acid isostere screen of the DHODH inhibitor Brequinar.

Dihydroorotate dehydrogenase (DHODH) enzymatic activity impacts many aspects critical to cell proliferation and survival. Recently, DHODH has been identified as a target for acute myeloid differentiation therapy. In preclinical models of AML, the DHODH inhibitor Brequinar (BRQ) demonstrated potent anti-leukemic activity.