Pancras

Resonant electron capture by aza and diaza derivatives of phenanthrene (7,8-benzoquinoline and 1,10-phenanthroline) and anthracene (acridine and phenazine) at incident free electron energies (Ee) in the range of 0-15 eV was studied. All compounds except 7,8-benzoquinoline form long-lived molecular ions (M-) at thermal electron energies (Ee ∼ 0 eV). Acridine and phenazine also form such ions at epithermal electron energies up to Ee = 1.5-2.5 eV. The lifetimes (τa) of M- with respect to electron autodetachment are proportional to the extent of aza-substitution and increase on going from molecules with bent geometry of the fused rings (azaphenanthrenes) to linear isomers (azaanthracenes)...

PAR4 is a promising antithrombotic target with potential for separation of efficacy from bleeding risk relative to current antiplatelet therapies. In an effort to discover a novel PAR4 antagonist chemotype, a quinoxaline-based HTS hit 3 with low μM potency was identified. Optimization of the HTS hit through the use of positional SAR scanning and the design of conformationally constrained cores led to the discovery of a quinoxaline-benzothiazole series as potent and selective PAR4 antagonists. The lead compound 48 , possessing a 2 nM IC50 against PAR4 activation by γ-thrombin in platelet-rich plasma (PRP) and greater than 2500-fold selectivity versus PAR1, demonstrated robust antithrombotic efficacy and minimal bleeding in the cynomolgus monkey models...

BACKGROUND: The present study is analysisof the seeds of buckwheat (Fagopyrum sp.),member of the Polygonaceae family for isolation of rutin and its anticancer property againstOsteosarcoma celllines (SAOS2). The selected plant is traditionally used for diabetes and cancer. It has several biological properties such as antibacterial, antioxidant and anti-aging. PURPOSE: Thirty-five buckwheat cultivars were obtained from Nepal Agriculture Genetic Resources Centre (NAGRC) Khumaltar, Kathmandu, Nepal, and Kumrek Sikkim...

AIMS: The discovery of somatic genetic alterations established many histiocytic disorders as haematologic neoplasms. We aimed to investigate the demographic characteristics and additional haematologic cancers of patients diagnosed with histiocytic disorders in The Netherlands. METHODS AND RESULTS: We retrieved data on histiocytosis patients from the Dutch Nationwide Pathology Databank (Palga). During 1993 to 2022, more than 4000 patients with a pathologist-assigned diagnosis of a histiocytic disorder were registered in Palga...

Transmembrane protein 14A (TMEM14A) is a relatively unknown protein that is now identified to be required for maintaining the integrity of the glomerular filtration barrier. It is an integral transmembrane protein of 99 amino acids with three transmembrane domains. TMEM14A has been implied to suppress Bax-mediated apoptosis in other studies. Other than that, little is currently known of its function. Here, we show that its expression is diminished before onset of proteinuria in a spontaneously proteinuric rat model...

BACKGROUND: The world has come closer than ever to discovering a viable HIV vaccine. However, it remains less certain whether HIV vaccines should be made available to participants and communities in which trials are run no or subsidized cost. Hence the essence of this inquiry. METHODOLOGY: This is a case study design using in-depth interviews (IDI) and focus group discussions (FGD) with researchers of HIV vaccine trials, institutional review board (IRB) members, HIV advocates, a policy maker, and members of community advisory board (CAB) in Tanzania...

Vaccination is one of medicine's greatest achievements; however, its full potential is hampered by considerable variation in efficacy across populations and geographical regions. For example, attenuated malaria vaccines in high-income countries confer almost 100% protection, whereas in low-income regions these same vaccines achieve only 20-50% protection. This trend is also observed for other vaccines, such as bacillus Calmette-Guérin (BCG), rotavirus and yellow fever vaccines, in terms of either immunogenicity or efficacy...

Osteitis fibrosa cystica (OFC) and Brown Tumours are two related but distinct types of bone lesions that result from the overactivity of osteoclasts and are most often associated with chronic kidney disease (CKD). Despite their potential consequences, these conditions are poorly understood because of their rare prevalence and variability in their clinical manifestation. Canonically, OFC and Brown Tumours are caused by secondary hyperparathyroidism in CKD. Recent literature showed that multiple factors, such as hyperactivation of the renin-angiotensin-aldosterone system and chronic inflammation, may also contribute to the occurrence of these diseases through osteoclast activation...

INTRODUCTION: Mentorship is an essential component of research capacity building for young researchers in the health sciences. The mentorship environment in resource-limited settings is gradually improving. This article describes mentees' experiences in a mentorship program for junior academicians amid the COVID-19 pandemic in Tanzania. METHODS: This is a survey study that examined the experiences of mentees who participated in a mentorship program developed as part of the Transforming Health Education in Tanzania (THET) project...

BACKGROUND: For over 35 years, Africa has continued to host HIV vaccine trials geared towards overturning the HIV/AIDs pandemic in the continent. However, the methods of sharing the vaccines, when available remain less certain. Therefore, the study aims to explore stakeholders' perspectives in the global South, in this case, Tanzania, on how HIV vaccines ought to be fairly shared. METHODS: The study deployed a qualitative case study design. Data were collected through in-depth interviews and focus group discussions with a total of 37 purposively selected participants...

Smoke emissions produced by firearms contain hazardous chemicals, but little is known if their properties change depending on firearm and ammunition type and whether such changes affect toxicity outcomes. Pulmonary toxicity was assessed in mice exposed by oropharyngeal aspiration to six different types of smoke-related particulate matter (PM) samples; (1) handgun PM, (2) rifle PM, (3) copper (Cu) particles (a surrogate for Cu in the rifle PM) with and without the Cu chelator penicillamine, (4) water-soluble components of the rifle PM, (5) soluble components with removal of metal ions, and (6) insoluble components of the rifle PM...

The neoplastic "stromal" cells in giant cell tumor of bone (GCTB) harbor a mutation in the H3F3A gene, which causes alterations in the epigenome. Current systemic targeted therapies, such as denosumab, do not affect the neoplastic cells, resulting in relapse upon treatment discontinuation. Therefore, this study examined whether targeting the epigenome could eliminate the neoplastic cells from GCTB. We established four novel cell lines of neoplastic "stromal" cells that expressed the H3F3A p.G34W mutation. These cell lines were used to perform an epigenetics compound screen ( n = 128), which identified histone deacetylase (HDAC) inhibitors as key epigenetic regulators in the neoplastic cells...

Protease-activated receptor 4 (PAR4) is a G-protein coupled receptor that is expressed on human platelets and activated by the coagulation enzyme thrombin. PAR4 plays a key role in blood coagulation, and its importance in pathological thrombosis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of imidazothiadiazole PAR4 antagonists to a first-in-class clinical candidate, BMS-986120 ( 43 ), and a backup clinical candidate, BMS-986141 ( 49 ). Both compounds demonstrated excellent antithrombotic efficacy and minimal bleeding time prolongation in monkey models relative to the clinically important antiplatelet agent clopidogrel and provide a potential opportunity to improve the standard of care in the treatment of arterial thrombosis...

Debates about what constitutes benefits in human research continue to be less informed due to a lack of empirical evidence from the developing world. This study aimed to explore what constitutes benefits in HIV vaccine trials in Tanzania and examine inherent ethical implications. A qualitative case study design was deployed and a total of 29 purposively selected study participants comprising of experienced researchers, institutional review board members and community advisory board members were included. Collected data were analyzed by thematic analysis aided by computer software: MAXQDA version 20...

Apixaban is a factor Xa (FXa) inhibitor and standard-of-care anticoagulant with FXa Ki and plasma protein binding (free fraction) averages 0.08 nM and 0.13 in humans and 0.16 nM and 0.37 in rabbits, respectively. Apixaban at the approved dose of 5 mg BID achieved maximum and minimum plasma concentration of 373 nM (95% CI: 198 - 699 nM) and 224 nM (95% CI 89-501 nM), respectively, in patients with nonvalvular atrial fibrillation (AF). We calibrated the rabbit model of electrolytic-mediated arterial thrombosis (ECAT) against apixaban and correlated the potencies derived from the rabbit ECAT to in vivo efficacious exposure levels in AF patients...

The phase III clinical study of adjuvant liposomal muramyl tripeptide (MTP-PE) in resected high-grade osteosarcoma (OS) documented positive results that have been translated into regulatory approval, supporting initial promise for innate immune therapies in OS. There remains, however, no new approved treatment such as MTP-PE for either metastatic or recurrent OS. Whilst the addition of different agents, including liposomal MTP-PE, to surgery for metastatic or recurrent high-grade osteosarcoma has tried to improve response rates, a mechanistic hiatus exists in terms of a detailed understanding the therapeutic strategies required in advanced disease...

In this study, the effect of heterozygous germline mutations in the heparan sulfate (HS) glycosaminoglycan chain co-polymerases EXT1 and EXT2 on glomerular barrier function and the endothelial glycocalyx in humans is investigated. Heparan sulfate (HS) glycosaminoglycans are deemed essential to the glomerular filtration barrier, including the glomerular endothelial glycocalyx. Animal studies have shown that loss of HS results in a thinner glycocalyx. Also, decreased glomerular HS expression is observed in various proteinuric renal diseases in humans...

BACKGROUND: Community Advisory Boards (CAB) have become essential organs of involving communities in HIV clinical trials especially in developing countries. However, limited empirical evidence exists on the role of CABs in low and middle-income countries including Tanzania. This study aims at exploring the role of CABs in community-based HIV clinical trials conducted in Tanzania. METHODOLOGY: We adopted a phenomenological approach to purposefully select HIV clinical trial stakeholders...

UNLABELLED: GCTB is an osteolytic, locally-aggressive, rarely-metastasizing tumour, characterized by abundance of osteoclast-like giant cells, induced by neoplastic mononuclear cells expressing high-levels of the receptor activator of nuclear factor Kappa-B ligand (RANKL), a mediator of osteoclast activation. Although the mainstay of treatment is complete tumour removal with preservation of bone, therapy with denosumab, an inhibitor of RANKL, has been introduced for selected cases. OBJECTIVES: Denosumab-treated GCTB (DT-GCTB) was reported to show a wide spectrum of histological changes such as depletion of osteoclast-like giant cells and intralesional bone deposition, which may lead to diagnostic difficulties...

BACKGROUND: Milvexian (BMS-986177/JNJ-70033093) is an orally bioavailable factor XIa (FXIa) inhibitor currently in phase 2 clinical trials. OBJECTIVES: To evaluate in vitro properties and in vivo characteristics of milvexian. METHODS: In vitro properties of milvexian were evaluated with coagulation and enzyme assays, and in vivo profiles were characterized with rabbit models of electrolytic-induced carotid arterial thrombosis and cuticle bleeding time (BT)...