Antimicrobial susceptibility profiles of invasive bacterial infections among children from low- and middle-income countries in the Western Pacific Region (WPRO) - a systematic review and meta-analysis.

Background: Antimicrobial resistance increasingly impacts paediatric mortality, particularly in resource-constrained settings. We aimed to evaluate the susceptibility profiles of bacteria causing infections in children from the Western Pacific region.

Methods: We conducted a systematic review and meta-analysis of bacteria responsible for common infections in children.

Identification of 6-Anilino Imidazo[4,5-]pyridin-2-ones as Selective DNA-Dependent Protein Kinase Inhibitors and Their Application as Radiosensitizers.

The dominant role of non-homologous end-joining in the repair of radiation-induced double-strand breaks identifies DNA-dependent protein kinase (DNA-PK) as an excellent target for the development of radiosensitizers. We report the discovery of a new class of imidazo[4,5-]pyridine-2-one DNA-PK inhibitors. Structure-activity studies culminated in the identification of as a nM DNA-PK inhibitor with excellent selectivity for DNA-PK compared to related phosphoinositide 3-kinase (PI3K) and PI3K-like kinase (PIKK) families and the broader kinome, and displayed DNA-PK-dependent radiosensitization of HAP1 cells.

Coverage gaps in empiric antibiotic regimens used to treat serious bacterial infections in neonates and children in Southeast Asia and the Pacific.

Background: High levels of antimicrobial resistance (AMR) are propagating deaths due to neonatal and paediatric infections globally. This is of particular concern in Southeast Asia and the Pacific, where healthcare resources are constrained and access to newer agents to treat multidrug-resistant pathogens is limited.

Methods: To assess the coverage provided by commonly prescribed empiric antibiotic regimens for children in low- and middle-income countries in Southeast Asia and the Pacific, we built a weighted incidence syndromic combination antibiogram (WISCA), parameterised using data obtained from a systematic review of published literature incorporating WHO-defined SEARO and WPRO regions in Ovid MEDLINE, EMBASE, Global Health and PubMed.

Hypoxia-activated prodrugs of phenolic olaparib analogues for tumour-selective chemosensitisation.

Poly(ADP-ribose)polymerase inhibitors (PARPi) are used for treatment of tumours with a defect in homologous recombination (HR) repair. Combination with radio- or chemotherapy could broaden their applicability but a major hurdle is enhancement of normal tissue toxicity. Development of hypoxia-activated prodrugs (HAPs) of PARPi has potential to restrict PARP inhibition to tumours thereby avoiding off-target toxicity.

Bayesian Network Analysis of Lymphatic Filariasis Serology from Myanmar Shows Benefit of Adding Antibody Testing to Post-MDA Surveillance.

The elimination of lymphatic filariasis (LF) is achieved through repeated mass drug administration (MDA) of anti-filarial medications, which interrupts transmission and prevents new infections. Accurate transmission assessments are critical to deciding when to stop MDA. Current methods for evaluating transmission may be insufficiently sensitive, resulting in post-MDA resurgence.

Radiosensitisation of SCCVII tumours and normal tissues in mice by the DNA-dependent protein kinase inhibitor AZD7648.

Background And Purpose: Inhibitors of DNA-dependent protein kinase (DNA-PK) are effective radiation sensitisers in preclinical tumours, but little is known about risks of normal tissue radiosensitisation. Here, we evaluate radiosensitisation of head and neck squamous cell carcinoma (HNSCC) cells by DNA-PK inhibitor AZD7648 under oxia and anoxia in vitro, and tumour (SCCVII), oral mucosa and small intestine in mice.

Materials And Methods: Radiosensitisation of human (UT-SCC-54C) and murine (SCCVII) HNSCC cells by AZD7648 under oxia and anoxia was evaluated by clonogenic assay.

Risk factors for lymphatic filariasis and mass drug administration non-participation in Mandalay Region, Myanmar.

Background: Myanmar commenced a lymphatic filariasis (LF) elimination programme in 2000. Whilst the country has made considerable progress since then, a number of districts have demonstrated persistent transmission after many rounds of mass drug administration (MDA). The causes of unsuccessful MDA have been examined elsewhere; however, there remains little information on the factors that contribute in Myanmar.

Patient-Derived Xenograft and Organoid Models for Precision Medicine Targeting of the Tumour Microenvironment in Head and Neck Cancer.

Patient survival from head and neck squamous cell carcinoma (HNSCC), the seventh most common cause of cancer, has not markedly improved in recent years despite the approval of targeted therapies and immunotherapy agents. Precision medicine approaches that seek to individualise therapy through the use of predictive biomarkers and stratification strategies offer opportunities to improve therapeutic success in HNSCC. To enable precision medicine of HNSCC, an understanding of the microenvironment that influences tumour growth and response to therapy is required alongside research tools that recapitulate the features of human tumours.

Hypoxia-selective radiosensitisation by SN38023, a bioreductive prodrug of DNA-dependent protein kinase inhibitor IC87361.

DNA-dependent protein kinase (DNA-PK) plays a key role in repair of radiation-induced DNA double strand breaks (DSB) by non-homologous end-joining. DNA-PK inhibitors (DNA-PKi) are therefore efficient radiosensitisers, but normal tissue radiosensitisation represents a risk for their use in radiation oncology. Here we describe a novel prodrug, SN38023, that is metabolised to a potent DNA-PKi (IC87361) selectively in radioresistant hypoxic cells.

Radiosensitization of head and neck squamous cell carcinoma lines by DNA-PK inhibitors is more effective than PARP-1 inhibition and is enhanced by SLFN11 and hypoxia.

Poly(ADP-ribose)polymerase-1 (PARP1) and DNA-dependent protein kinase (DNA-PK) play key roles in the repair of radiation-induced DNA double strand breaks, but it is unclear which is the preferred therapeutic target in radiotherapy. Here we compare small molecule inhibitors of both as radiosensitizers of head and neck squamous cell carcinoma (HNSCC) cell lines. Two PARP1 inhibitors (olaparib, veliparib) and two DNA-PK inhibitors (KU57788, IC87361) were tested in 14 HNSCC cell lines and two non-tumorigenic lines (HEK-293 and WI-38/Va-13), with drug exposure for 6 or 24 h post-irradiation, using regrowth assays.

Studies Towards Hypoxia-Activated Prodrugs of PARP Inhibitors.

Poly(ADP-ribose)polymerase (PARP) inhibitors (PARPi) have recently been approved for the treatment of breast and ovarian tumors with defects in homologous recombination repair (HRR). Although it has been demonstrated that PARPi also sensitize HRR competent tumors to cytotoxic chemotherapies or radiotherapy, normal cell toxicity has remained an obstacle to their use in this context. Hypoxia-activated prodrugs (HAPs) provide a means to limit exposure of normal cells to active drug, thus adding a layer of tumor selectivity.

The prevalence of lymphatic filariasis infection and disease following six rounds of mass drug administration in Mandalay Region, Myanmar.

Lymphatic filariasis is widely endemic in Myanmar. Despite the establishment of an elimination program in 2000, knowledge of the remaining burden of disease relies predominantly on programmatic information. To assist the program, we conducted an independent cross-sectional household cluster survey to determine the prevalence of filariasis infection, morbidity and mass-drug administration coverage in four townships of the Mandalay Region: Amarapura, Patheingyi, Tada-U and Wundwin.

RETRACTED: Straticyte demonstrates prognostic value over oral epithelial dysplasia grade for oral potentially malignant lesion assessment.

Objectives: Straticyte™ was previously shown to be a more effective prognostic assessment than the current standard of care, histopathological dysplasia grading, to assess progression risk of oral epithelial dysplasia to invasive cancer [Hwang JT, Gu YR, Shen M, Ralhan R, Walfish PG, Pritzker KP, et al. Individualized five-year risk assessment for oral premalignant lesion progression to cancer. Oral Surg Oral Med Oral Pathol Oral Radiol.

Lymphatic Filariasis in Mainland Southeast Asia: A Systematic Review and Meta-Analysis of Prevalence and Disease Burden.

Accurate prevalence data are essential for the elimination of lymphatic filariasis (LF) as a public health problem. Despite it bearing one of the highest burdens of disease globally, there remains limited reliable information on the current epidemiology of filariasis in mainland Southeast Asia. We conducted a systematic review and meta-analysis of available literature to assess the recent and current prevalence of infection and morbidity in the region.

Neural responses to free field and virtual acoustic stimulation in the inferior colliculus of the guinea pig.

Virtual auditory space (VAS) stimuli based on outer ear transfer functions became increasingly important in spatial hearing research. However, few studies have investigated the match between responses of auditory neurons to VAS and free-field (FF) stimulation. This study validates acoustic spatial receptive fields (SRFs) of 183 individual midbrain units using both VAS and FF stimuli.