On the role of bioactive sphingolipids and their metabolizing enzymes in cancer

Ceramide is a family of closely related molecules, which are presumed to be in the center of sphingolipid metabolism. Among sphingolipid metabolites, several ceramide subspecies and sphingosine induce apoptosis, cell cycle arrest and death, whereas sphingosine 1-phosphate (S1P) mediates cell proliferation, invasion, angiogenesis and metastasis. Cell fate is largely dependent on the balance of ceramide and sphingosine versus S1P. The sphingosine kinases (SKs) are responsible for maintaining this balance, which leans towards S1P in many cancers. Thereby SKs have been suggested as targets for cancer therapy. The overall aim of this thesis was to target SKs in order to enhance the effects of anti-cancer agents in hepatocellular carcinoma (HCC) and bladder cancer cells. In study I, we have treated HCC cell lines with selenite in combination with pharmacological inhibitors of sphingolipid-metabolizing enzymes. Selenite treatment induced the activity of neutral sphingomyelinase and increased the levels of long chain ceramides. Moreover, the sphingosine kinase 1 inhibitor 2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole (SKI-II) sensitized HCC cells to selenite treatment by increasing the levels of ceramide subspecies, inducing reactive oxygen species formation and apoptosis, and inhibiting cell cycle progression and cell viability. In study II, HCC cell lines were co-treated with the multi-tyrosine kinase inhibitor sorafenib and the sphingosine agonist FTY720 in order to improve the efficacy of sorafenib treatment. We have shown that a marginally toxic dose of FTY720 synergistically increased the cytotoxicity of sorafenib towards the Huh7 and HepG2 cell lines. Combined treatment with FTY720 and sorafenib mediated cell cycle arrest, caspase-dependent and –independent apoptosis, autophagy blockage and cell death in Huh7 cells. In study III, the treatment effects of supernatant from Bacillus Calmette-Guérin -activated macrophages (SupBCG) and SKI-II on murine bladder cancer cell lines were studied. Combined treatment with SKI-II and SupBCG mediated a decrease in cell viability compared to SupBCG treatment alone. There was a transient increase in Sphk1 mRNA level following SupBCG treatment, but the SK1 protein level was unaffected. SupBCG and SKI-II individually induced PARP-cleavage. The level of dihydro C16-ceramide was increased following SKI-II treatment alone, and was further enhanced after combined treatment with SupBCG. In our studies we have observed that inhibition of SKs enhanced the cytotoxicity of treatment with selenite or sorafenib in HCC cell lines, and of BCG in bladder cancer cell lines. Therefore, we conclude that targeting these enzymes could potentiate other treatment effects in HCC and bladder cancer cells

Selección de cepa de Bacillus Spp probiótica autóctona con mayor actividad enzimática

El presente estudio se enfocó en la determinación de actividad enzimática de cepas de Bacillus spp autóctonas (XSCD-9, xsc-9, X2-10) previamente estudiadas, estas cepas fueron procesadas mediante técnicas de laboratorio para esto se realizaron pruebas probióticas de halos de hidrólisis, unidades de Anson, a si como también la determinación de un medio de cultivo industrial económico y efectivo para la optima reproducción y producción de enzimas proteolíticas de los microorganismos candidatos, en donde resulto como mayor productora de enzimas proteolíticas con 17.5336 UA y 30 mm de halo de hidrólisis, fue la cepa X2-10 que corresponde a un Bacillus cereus según su secuenciación, con la composición de la corrida #3 (Melaza: 75 g/1, Levadura torula: 50 g/1, Calcio: 1.5 g/1, Temperatura: 39°C.) la cual fue evaluada atreves del método estadístico coeficiente de variación, presentando el porcentaje más bajo de las 3 cepas candidatas estudiadas

Clinical Profile of HIV/AIDS-infected Patients Admitted to a New Specialist Unit in Dhaka, Bangladesh\u2014A Low-prevalence Country for HIV

This paper describes the clinical features of a series of patients admitted to the specialist HIV/AIDS unit (Jagori) of the Dhaka Hospital, ICDDR,B (International Centre for Diarrhoeal Disease Research, Bangladesh) during May 2008\u2013February 2010. Data were collected from a review of documents and electronic case-records and collation of laboratory results with respect to CD4 counts. One hundred and nine patients were admitted during this period. Their mean age was 33.4 years, and 62% were male. On admission, the mean CD4 count\ub1standard deviation (SD) was 244\ub1245 (range 2-1,549). The death rate was 12%. The patients were classified as World Health Organization clinical stage 1: 23%, stage 2: 30%, stage 3: 23%, and stage 4: 24% during the admission. The commonest diagnosis recorded was tuberculosis (TB) (23%), which was also the commonest cause of death (38%). Even for those clinicians with limited experience of managing AIDS cases, the commonest problem encountered in this patient group was TB, reflecting the continued high burden of TB on health services in Bangladesh. Additional challenges to managing TB/HIV co-infection include atypical presentations in HIV-infected persons and the complex drug interaction with antiretroviral therapy

Setting Reading Fluency Benchmark in Bangla for the Students of Grade III and Grade V

Reading is one of the most significant media of learning. Reading with comprehension mostly depends on reading fluency. It is necessary to measure students fluency through the reading rate of words per minute to know the level of comprehension. There was no benchmark in Bangla reading fluency at the primary level, which is necessary to check students\u27 reading performances regarding the targeted level. This study aims to set a reading fluency benchmark for grade III and grade V in Bangla. This study followed quantitative approaches with a cross-sectional survey design. A total of 1536 students from both grades were selected through a multistage cluster sampling procedure. Two types of texts for each grade were developed and finalized alter piloting to administer. The median method was used for setting the fluency benchmark as many countries already had used it for the same purpose. This study recommended setting the reading fluency benchmark for grade III in Bangla at 46 CWPM and 54 CWPM for grade V. It also recommended that policymakers need to take the necessary teaching-learning interventions to achieve this benchmark

Pneumonia mortality and healthcare utilization in young children in rural Bangladesh: a prospective verbal autopsy study

BackgroundThe present study aimed to examine the risk factors for death due to pneumonia in young children and healthcare behaviors of the guardians for children in rural Bangladesh. A prospective autopsy study was conducted among guardians of children aged 4 weeks to 59 months in Mirzapur, Bangladesh, from 2008 to 2012.ResultsPneumonia was the primary cause of death, accounting for 26.4% (n = 81) of all 307 deaths. Of the pneumonia deaths, 58% (n = 47) deaths occurred in younger infants (aged 4 weeks to < 6 months) and 24.7% (n = 20) in older infants (aged 6–11 months). The median duration of illness before pneumonia death was 8 days (interquartile range [IQR] 3–20 days). Prior to death, 91.4% (n = 74) children with pneumonia sought treatment, and of those who sought treatment, 52.7% (n = 39) sought treatment ≥ 2 days after the onset of disease. Younger infants of 4 weeks to < 6 months old were at 5.5-time (95% confidence interval [CI] 2.5, 12.0) and older infants aged 6–11 months were at 3-time (1.2, 7.5) greater risk of dying from pneumonia than older children aged 12–59 months. Children with a prolonged duration of illness (2–10 days) prior to death were at more risk for death by pneumonia than those who died from other causes (5.8 [2.1, 16.1]). Children who died from pneumonia sought treatment 3.4-time more than children who died from other causes. Delayed treatment seeking (≥ 2 days) behavior was 4.9-time more common in children who died from pneumonia than those who died from other causes. Children who died from pneumonia more often had access to care from multiple sources (5.7-time) than children who died from other causes.ConclusionsDelay in seeking appropriate care and access to multiple sources for treatment are the underlying risk factors for pneumonia death in young children in Bangladesh. These results indicate the perplexity in guardians’ decisions to secure appropriate treatment for children with pneumonia. Therefore, it further underscores the importance of focusing on mass media coverage that can outline the benefits of seeking care early in the progression of pneumonia and the potential negative consequences of seeking care late

Diarrhea in young children from low-income countries leads to large-scale alterations in intestinal microbiota composition

Acknowledgments This work was funded in part by the William and Melinda Gates Foundation, award 42917 to JPN and OCS; US National Institutes of Health grants 5R01HG005220 to HCB, 5R01HG004885 to MP; US National Science Foundation Graduate Research Fellowship award DGE0750616 to JNP; AWW and JP are funded by The Wellcome Trust (Grant No. WT098051).Peer reviewedPublisher PD

Factors affecting the micronutrient status of adolescent girls living in complex agro-aquatic ecological zones of Bangladesh

Acknowledgements The study was conducted in collaboration with Noakhali Science and Technology University (NSTU), icddr,b, University of Stirling, University of Copenhagen, University of Aberdeen, and the University of Glasgow. We acknowledge with gratitude the commitment of all investigators from all of the collaborating institutes. icddr,b is also grateful to the Governments of Bangladesh, Canada, Sweden, and the UK for providing core support. Funding This work is funded through the Innovative Methods and Metrics for Agriculture and Nutrition Action (IMMANA) programme, led by the London School of Hygiene & Tropical Medicine (LSHTM). IMMANA is co-funded with UK Aid from the UK government and by the Bill & Melinda Gates Foundation INV-002962 / OPP1211308. Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 Generic License has already been assigned to the Author Accepted Manuscript version that might arise from this submission.Peer reviewedPublisher PD

Non-lactose fermenting Escherichia coli: Following in the footsteps of lactose fermenting E. coli high-risk clones.

Multi-resistant pathogenic strains of non-lactose fermenting Escherichia coli (NLF E. coli) are responsible for various intestinal and extraintestinal infections. Although several studies have characterised such strains using conventional methods, they have not been comprehensively studied at the genomic level. To address this gap, we used whole-genome sequencing (WGS) coupled with detailed microbiological and biochemical testing to investigate 17 NLF E. coli from a diagnostic centre (icddr,b) in Dhaka, Bangladesh. The prevalence of NLF E. coli was 10%, of which 47% (8/17) exhibited multi-drug resistant (MDR) phenotypes. All isolates (17/17) were confirmed as E. coli and could not ferment lactose sugar. WGS data analysis revealed international high-risk clonal lineages. The most prevalent sequence types (STs) were ST131 (23%), ST1193 (18%), ST12 (18%), ST501 (12%), ST167 (6%), ST73 (6%) and ST12 (6%). Phylogenetic analysis corroborated a striking clonal population amongst the studied NLF E. coli isolates. The predominant phylogroup detected was B2 (65%). The bla CTX-M-15 extended-spectrum beta-lactamase gene was present in 53% of isolates (9/17), whilst 64.7% (11/17) isolates were affiliated with pathogenic pathotypes. All extraintestinal pathogenic E. coli pathotypes demonstrated β-hemolysis. Our study underscores the presence of critical pathogens and MDR clones amongst non-lactose fermenting E. coli. We suggest that non-lactose fermenting E. coli be considered equally capable as lactose fermenting forms in causing intestinal and extraintestinal infections. Further, there is a need to undertake systematic, unbiased monitoring of predominant lineages amongst non-lactose fermenting E. coli that would help in better treatment and prevention strategies

Alarming prevalence of Candida auris among critically ill patients in intensive care units in Dhaka City, Bangladesh

Background: Candida auris is a multidrug-resistant yeast capable of invasive infection with high mortality and healthcare-associated outbreaks globally. Due to limited labratory capacity, the burden of C. auris is unknown in Bangladesh. We estimated the extent of C. auris colonization and infection among patients in Dhaka city intensive care units. Methods: During August 2021–September 2022 at adult intensive care units (ICUs) and neonatal intensive care units (NICUs) of 1 government and 1 private tertiary-care hospital, we collected skin swabs from all patients and blood samples from sepsis patients on admission, mid-way through, and at the end of ICU or NICU stays. Skin swab and blood with growth in blood-culture bottle were inoculated in CHROMagar, and identification of isolates was confirmed by VITEK-2. Patient characteristics and healthcare history were collected. We performed descriptive analyses, stratifying by specimen and ICU type. Results: Of 740 patients enrolled, 59 (8%) were colonized with C. auris, of whom 2 (0.3%) later developed a bloodstream infection (BSI). Among patients colonized with C. auris, 27 (46%) were identified in the ICU and 32 (54%) were identified from the NICU. The median age was 55 years for C. auris–positive ICU patients and 4 days for those in the NICU. Also, 60% of all C. auris patients were male. Among 366 ICU patients, 15 (4%) were positive on admission and 12 (3%) became colonized during their ICU stay. Among 374 NICU patients, 19 (5%) were colonized on admission and 13 (4%) became colonized during their NICU stay. All units identified C. auris patients on admission and those who acquired it during their ICU or NICU stay, but some differences were observed among hospitals and ICUs (Figure). Among patients colonized on admission to the ICU, 11 (73%) were admitted from another ward, 3 (20%) were admitted from another hospital, and 1 (7%) were admitted from home. Of patients colonized on admission to the NICU, 4 (21%) were admitted from the obstetric ward, 9 (47%) were admitted from another hospital, and 6 (32%) were admitted from home. In addition, 18 patients with C. auris died (12 in the ICU and 6 in the NICU); both patients with C. auris BSIs died. Conclusions: In these Bangladesh hospitals, 8% of ICU or NICU patients were positive for C. auris, including on admission and acquired during their ICU or NICU stay. This high C. auris prevalence emphasizes the need to enhance case detection and strengthen infection prevention and control. Factors contributing to C. auris colonization should be investigated to inform and strengthen prevention and control strategies

Enteric viral pathogens and child growth among under-five children: findings from South Asia and sub-Saharan Africa.

Enteric viral pathogens are associated with a significant burden of childhood morbidity and mortality. We investigated the relationship between viral pathogens and child growth among under-5 children. We analyzed data from 5572/22,567 children enrolled in the Global Enteric Multicenter Study across seven study sites (2007-2011). Multiple linear regression was used to examine the association between the viral pathogens and changes of length/height-for-age (HAZ), weight-for-age (WAZ), and weight-for-length/height (WHZ) z-scores, stratified by diarrheal symptoms and adjusted for potential covariates. Rotavirus (18.51%) and norovirus (7.33%) were the most prevalent enteric viral pathogens among symptomatic and asymptomatic under-5 children, respectively. Infection with individual enteric viral pathogens hurts child growth in asymptomatic children. However, the relationship with HAZ was less clear and statistically non-significant. On the other hand, the combined viral pathogens demonstrated a strong negative influence on child growth [WAZ: β coef.: - 0.10 (95%, CI - 0.15, - 0.05); P < 0.001 and WHZ: β: - 0.12 (95% CI - 0.17, - 0.07); P < 0.001] among asymptomatic children. Infection with any viral pathogen was associated with growth shortfalls [HAZ: β: - 0.05 (95% CI - 0.09, 0.00); P = 0.03 and WAZ: β: - 0.11 (95% CI - 0.16, - 0.07); P < 0.001 and WHZ: β: - 0.13 (95% CI - 0.18, - 0.09); P < 0.001], though the relationship with HAZ was less evident and became statistically non-significant in older children. Notably, among symptomatic children with moderate-to-severe diarrhea, individual enteric viral pathogens, as well as the combined effects of these pathogens [WHZ: β: 0.07; (95% CI 0.01, 0.14); P = 0.03] and the presence of any virus [HAZ: β: 0.09 (95% CI 0.05, 0.13) & WAZ: β: 0.08 (95% CI 0.03, 0.12); P < 0.001], exhibited positive effects on child growth. While previous studies hypothesized that several viral pathogens had a conflicting controversial role in child growth, we find clear indications that enteric viral pathogens are associated with growth shortfalls, specifically among asymptomatic children. These findings highlight the need for preventive strategies targeting children with enteric viral pathogens, which could address the consequences of growth faltering