Translational PK/PD and the first-in-human dose selection of a PD1/IL15: an engineered recombinant targeted cytokine for cancer immunotherapy.

Introduction: Interleukin 15 (IL-15) is a potential anticancer agent and numerous engineered IL-15 agonists are currently under clinical investigation. Selective targeting of IL-15 to specific lymphocytes may enhance therapeutic effects while helping to minimize toxicities. Methods: We designed and built a heterodimeric targeted cytokine (TaCk) that consists of an anti-programmed cell death 1 receptor antibody (anti-PD-1) and an engineered IL-15. This "PD1/IL15" selectively delivers IL-15 signaling to lymphocytes expressing PD-1. We then investigated the pharmacokinetic (PK) and pharmacodynamic (PD) effects of PD1/IL15 TaCk on immune cell subsets in cynomolgus monkeys after single and repeat intravenous dose administrations. We used these results to determine the first-in-human (FIH) dose and dosing frequency for early clinical trials. Results: The PD1/IL15 TaCk exhibited a nonlinear multiphasic PK profile, while the untargeted isotype control TaCk, containing an anti-respiratory syncytial virus antibody (RSV/IL15), showed linear and dose proportional PK. The PD1/IL15 TaCk also displayed a considerably prolonged PK (half-life range ∼1.0-4.1 days) compared to wild-type IL-15 (half-life ∼1.1 h), which led to an enhanced cell expansion PD response. The PD was dose-dependent, durable, and selective for PD-1+ lymphocytes. Notably, the dose- and time-dependent PK was attributed to dynamic TMDD resulting from test article-induced lymphocyte expansion upon repeat administration. The recommended first-in-human (FIH) dose of PD1/IL15 TaCk is 0.003 mg/kg, determined based on a minimum anticipated biological effect level (MABEL) approach utilizing a combination of in vitro and preclinical in vivo data. Conclusion: This work provides insight into the complex PK/PD relationship of PD1/IL15 TaCk in monkeys and informs the recommended starting dose and dosing frequency selection to support clinical evaluation of this novel targeted cytokine.

Annual risk of hepatitis E virus infection and seroreversion: Insights from a serological cohort in Sitakunda, Bangladesh.

Hepatitis E virus (HEV) is a major cause of acute jaundice in South Asia. Gaps in our understanding of transmission are driven by non-specific symptoms and scarcity of diagnostics, impeding rational control strategies. In this context, serological data can provide important proxy measures of infection. We enrolled a population-representative serological cohort of 2,337 individuals in Sitakunda, Bangladesh. We estimated the annual risks of HEV infection and seroreversion both using serostatus changes between paired serum samples collected 9 months apart, and by fitting catalytic models to the age-stratified cross-sectional seroprevalence. At baseline, 15% (95 CI: 14-17%) of people were seropositive, with seroprevalence highest in the relatively urban south. During the study, 27 individuals seroreverted (annual seroreversion risk: 15%, 95 CI: 10-21%), and 38 seroconverted (annual infection risk: 3%, 95CI: 2-5%). Relying on cross-sectional seroprevalence data alone, and ignoring seroreversion, underestimated the annual infection risk five-fold (0.6%, 95 CrI: 0.5-0.6%). When we accounted for the observed seroreversion in a reversible catalytic model, infection risk was more consistent with measured seroincidence. Our results quantify HEV infection risk in Sitakunda and highlight the importance of accounting for seroreversion when estimating infection incidence from cross-sectional seroprevalence data.

Clinical surveillance systems obscure the true cholera infection burden in an endemic region.

Our understanding of cholera transmission and burden largely relies on clinic-based surveillance, which can obscure trends, bias burden estimates and limit the impact of targeted cholera-prevention measures. Serological surveillance provides a complementary approach to monitoring infections, although the link between serologically derived infections and medically attended disease incidence-shaped by immunological, behavioral and clinical factors-remains poorly understood. We unravel this cascade in a cholera-endemic Bangladeshi community by integrating clinic-based surveillance, healthcare-seeking and longitudinal serological data through statistical modeling. Combining the serological trajectories with a reconstructed incidence timeline of symptomatic cholera, we estimated an annual Vibrio cholerae O1 infection incidence rate of 535 per 1,000 population (95% credible interval 514-556), with incidence increasing by age group. Clinic-based surveillance alone underestimated the number of infections and reported cases were not consistently correlated with infection timing. Of the infections, 4 in 3,280 resulted in symptoms, only 1 of which was reported through the surveillance system. These results impart insights into cholera transmission dynamics and burden in the epicenter of the seventh cholera pandemic, where >50% of our study population had an annual V. cholerae O1 infection, and emphasize the potential for a biased view of disease burden and infection risk when depending solely on clinical surveillance data.

Multimorbidity and health-related quality of life amongst Indigenous Australians: A longitudinal analysis.

BACKGROUND: The burden of multimorbidity has been observed worldwide and it has significant consequences on health outcomes. In Australia, health-related quality of life (HRQoL) is comparatively low amongst Aboriginal and/or Torres Strait Islanders, yet no studies have examined the effect of multimorbidity on HRQoL within this at-risk population. This study seeks to fill that gap by employing a longitudinal research design. METHODS: Longitudinal data were derived from three waves (9, 13, and 17) of the household, income and labour dynamics in Australia (HILDA) Survey. A total of 1007 person-year observations from 592 Aboriginal and/or Torres Strait Islander individuals aged 15 years and above were included. HRQoL was captured using the 36-item Short-Form Health Survey (SF-36), and multimorbidity was defined using self-reports of having been diagnosed with two or more chronic health conditions. Symmetric fixed-effects linear regression models were used to assess how intraindividual changes in multimorbidity were associated with intraindividual changes in HRQoL. RESULTS: Approximately 21% of Indigenous Australians were classified as experiencing multimorbidity. Respondents had statistically significantly lower HRQoL on the SF-36 sub-scales, summary measures, and health-utility index in those observations in which they experienced multimorbidity. Among others, multimorbidity was associated with lower scores on the SF-36 physical-component scale (ß = - 6.527; Standard Error [SE] = 1.579), mental-component scale (ß = - 3.765; SE = 1.590) and short-form six-dimension utility index (ß = - 0.075; SE = 0.017). CONCLUSION: This study demonstrates that having multiple chronic conditions is statistically significantly associated with lower HRQoL amongst Indigenous Australians. These findings suggest that comprehensive and culturally sensitive health strategies addressing the complex needs of individuals with multimorbidity should be implemented to improve the HRQoL of Indigenous Australians.

Prevalence and predictors of binge eating disorder symptoms among a sample of university students in Bangladesh: A cross-sectional survey.

Background and Aims: There is a dearth of information about binge eating disorder (BED) among Bangladeshi university students, who may be more susceptible to BED due to the rise in unhealthy lifestyles and food habits. Therefore, the purpose of this study was to assess the prevalence and associated factors of BED symptoms among Bangladeshi university students. Methods: Students (N = 525) from three public universities in Bangladesh participated in this cross-sectional study between November 2022 and March 2023. Face-to-face interviews were conducted using a structured paper-based questionnaire that included two validated survey tools; the binge eating disorder screener and the patient health questionnaire-9. To identify the factors associated with BED symptoms, multiple logistic regression analysis was conducted, with sociodemographic and behavioral information (e.g., age, sex, smoking status, etc.) considered as covariates. Results: The prevalence of BED symptoms among participants (mean age 21.28 years, 50.3% male and 49.7% female) was 20.6%. Male students had a 2.28 times higher likelihood of having BED symptoms compared to female counterparts (adjusted odds ratio [AOR] = 2.28; 95% CI: 1.33-3.89). Older students (AOR = 3.56, 95% CI: 1.80-7.05), students who were overweight or obese (AOR = 3.32, 95% CI: 1.87-5.89), and students reporting higher depressive symptoms (AOR = 2.69, 95% CI: 1.66-4.35) were at greater risk for developing BED compared to their respective counterparts. Conclusions: This study provides new insights into the prevalence of BED symptoms and its contributing factors among Bangladeshi students. Approximately 1-in-5 university students reported having BED symptoms. University students who are older, overweight, or obese, and who report depressive symptoms may be at greatest risk. Future longitudinal studies are needed to determine the causal factors underlying BED. Findings from this study can assist policymakers and public health professionals in developing effective and targeted strategies to mitigate the risks associated with BED among Bangladeshi university students.

2D and 3D multiplexed subcellular profiling of nuclear instability in human cancer.

Nuclear atypia, including altered nuclear size, contour, and chromatin organization, is ubiquitous in cancer cells. Atypical primary nuclei and micronuclei can rupture during interphase; however, the frequency, causes, and consequences of nuclear rupture are unknown in most cancers. We demonstrate that nuclear envelope rupture is surprisingly common in many human cancers, particularly glioblastoma. Using highly-multiplexed 2D and super-resolution 3D-imaging of glioblastoma tissues and patient-derived xenografts and cells, we link primary nuclear rupture with reduced lamin A/C and micronuclear rupture with reduced lamin B1. Moreover, ruptured glioblastoma cells activate cGAS-STING-signaling involved in innate immunity. We observe that local patterning of cell states influences tumor spatial organization and is linked to both lamin expression and rupture frequency, with neural-progenitor-cell-like states exhibiting the lowest lamin A/C levels and greatest susceptibility to primary nuclear rupture. Our study reveals that nuclear instability is a core feature of cancer, and links nuclear integrity, cell state, and immune signaling.

Survey on sea snakebite and related morbidity and mortality among Bangladeshi fishermen in the Bay of Bengal: A pilot study.

Around two million people are engaged in marine fishing in the Bay of Bengal. Bites by sea snakes were common hazards feared by millions fishing at sea in earlier days. Current morbidity and mortality are also not known. This study was conducted to document and describe sea snake bites among selected communities of sea-going fishermen in Bangladesh. A questionnaire-based cross-sectional survey was conducted from May to October 2019 among three communities of sea-going fishermen living along the coast of the Bay of Bengal in Cox's Bazar district. Fishermen were first asked by trained interviewers to recall any sea snakebites to themselves and among their fellows on board within the last year, then within the last 5 years and at any time before that. For any bite, related information including outcome was noted. Overall, 25.4% of respondents (62 out of 244) had been bitten by sea-snakes. Mean age was 37.6(±14) years; all males. 51.6% received some sort of treatment locally; 71% hot compress and 48% tourniquets. In 80.6% the affected limb was not immobilized. The bitten site was incised in 29%. 22.6% received treatment from traditional healers, 48.4% from local hospitals, 29% from district hospital. Six victims (9.7%) suffered from severe life-threatening consequences of the sea snakebite but none died. 32% of the fishermen had seen the offending snake. Sea snakebites are potentially dangerous; therefore, educating fishermen to avoid contact with sea snakes would dramatically reduce the incidence of sea snakebites. Most bites are treated initially by local measures which are often not scientific. Provision of proper first aid and treatment might reduce mortality and morbidity. A larger survey on sea snake bites among the fishermen in all coastal areas of Bangladesh is needed to determine the nationwide burden of morbidity and mortality related to sea snakebite.

REDCap and the National Mesothelioma Virtual Bank-a scalable and sustainable model for rare disease biorepositories.

OBJECTIVE: Rare disease research requires data sharing networks to power translational studies. We describe novel use of Research Electronic Data Capture (REDCap), a web application for managing clinical data, by the National Mesothelioma Virtual Bank, a federated biospecimen, and data sharing network. MATERIALS AND METHODS: National Mesothelioma Virtual Bank (NMVB) uses REDCap to integrate honest broker activities, enabling biospecimen and associated clinical data provisioning to investigators. A Web Portal Query tool was developed to source and visualize REDCap data in interactive, faceted search, enabling cohort discovery by public users. An AWS Lambda function behind an API calculates the counts visually presented, while protecting record level data. The user-friendly interface, quick responsiveness, automatic generation from REDCap, and flexibility to new data, was engineered to sustain the NMVB research community. RESULTS: NMVB implementations enabled a network of 8 research institutions with over 2000 mesothelioma cases, including clinical annotations and biospecimens, and public users' cohort discovery and summary statistics. NMVB usage and impact is demonstrated by high website visits (>150 unique queries per month), resource use requests (>50 letter of interests), and citations (>900) to papers published using NMVB resources. DISCUSSION: NMVB's REDCap implementation and query tool is a framework for implementing federated and integrated rare disease biobanks and registries. Advantages of this framework include being low-cost, modular, scalable, and efficient. Future advances to NVMB's implementations will include incorporation of -omics data and development of downstream analysis tools to advance mesothelioma and rare disease research. CONCLUSION: NVMB presents a framework for integrating biobanks and patient registries to enable translational research for rare diseases.

A study to validate the Ten-Question-Questionnaire + for the detection of moderate to severe neurological disabilities in older Bangladeshi children.

PURPOSE: Our study validated the Ten Question Questionnaire (TQQ+) for Bangladeshi children between 10 and 16 years. The TQQ + is a rapid screening tool for disability and was previously validated in children below 9 years of age. MATERIALS AND METHODS: The study was carried out in Chattogram, Bangladesh. One hundred children aged 10-16 years, 10 with mild or moderate disabilities, 40 with severe disabilities, and 50 children without a disability were identified. Children with disability (n = 50) had previously undergone Wechsler Intelligence Scale-Revised (WISC-R) assessments by psychologists as a reference standard. Each child was evaluated using Rapid Neurodevelopmental Assessment (RNDA) by physicians and TQQ + was administered by researchers. Sensitivities and specificities of TQQ + were evaluated in comparison with RNDA and WISC-R. RESULTS: The sensitivity of TQQ + was 98% in comparison with either RNDA or WISC-R. The specificity of TQQ was 76.5% compared with RNDA and 78% with WISC-R. TQQ + successfully picked up cognitive (98%) and motor (75%) disabilities as well as behavioural problems (88.9%). Specificity was good to excellent in all other domains. Logistic regression showed that TQQ + could reliably predict disability by RNDA and WISC-R. The area under the Receiver Operating Characteristic Curve (ROC) curve was 0.88 which denoted good diagnostic accuracy of the questionnaire. CONCLUSION: The TQQ + is valid for screening disabilities in 10-16 year old Bangladeshi children.IMPLICATIONS FOR REHABILITATIONIf children with neurodevelopmental disabilities are screened early, the benefit of intervention will be greater.TQQ + is an easy to administer and low-cost tool that has been validated internationally.The TQQ + is now validated and can be used for children aged 10 to 16 years in Bangladesh.

A case-control study to determine the risk factors of dengue fever in Chattogram, Bangladesh.

Objectives: In a tropical country like Bangladesh, where the climatic condition favors the growth of Aedes mosquito vectors, the success of dengue prevention depends largely on the proper identification and control of risk factors. Therefore this study was aimed to explore the potential risk factors and their association with dengue infection. Study design: A case-control study including 150 cases and 150 controls was conducted in Chattogram district of Bangladesh. Cases were confirmed dengue patients admitted in Chattogram medical college hospital and Bangladesh institute of tropical and infectious diseases during August and September 2019. On the other hand, controls were non-dengue patients admitted in other departments of the same hospitals through gender, age, and location matching. Methods: The questionnaire data were collected through telephone-based interviews, which included general demography, daily life activities, housing and surrounding environment of participants. Chi-square and binary logistic regression were performed to identify potential risk factors. Results: The study found that travel history to the high incidence area, staying most of the daytime in office (AOR = 18.10), living in 21-40 years old houses (AOR = 9.74), and the temporary residency in the city (AOR = 10.20) were statistically significant risk factors for getting dengue infection. However, day time sleep, house type and structure, number of family members, morning and evening walk, plant in resident, and junk yard around 250 m of the house were also showed a significant effect in chi square test. Conclusions: Results strengthen our understanding regarding the role of factors associated with daily lifestyle and living environment of people in the development of dengue and hence support the dengue control program in Bangladesh. The study will provide a basis for future extended research covering different parts of the country.

Single cell spatial analysis reveals the topology of immunomodulatory purinergic signaling in glioblastoma.

How the glioma immune microenvironment fosters tumorigenesis remains incompletely defined. Here, we use single-cell RNA-sequencing and multiplexed tissue-imaging to characterize the composition, spatial organization, and clinical significance of extracellular purinergic signaling in glioma. We show that microglia are the predominant source of CD39, while tumor cells principally express CD73. In glioblastoma, CD73 is associated with EGFR amplification, astrocyte-like differentiation, and increased adenosine, and is linked to hypoxia. Glioblastomas enriched for CD73 exhibit inflammatory microenvironments, suggesting that purinergic signaling regulates immune adaptation. Spatially-resolved single-cell analyses demonstrate a strong spatial correlation between tumor-CD73 and microglial-CD39, with proximity associated with poor outcomes. Similar spatial organization is present in pediatric high-grade gliomas including H3K27M-mutant diffuse midline glioma. These data reveal that purinergic signaling in gliomas is shaped by genotype, lineage, and functional state, and that core enzymes expressed by tumor and myeloid cells are organized to promote adenosine-rich microenvironments potentially amenable to therapeutic targeting.

SARS-CoV-2 Seroprevalence before Delta Variant Surge, Chattogram, Bangladesh, March-June 2021.

A March-June 2021 representative serosurvey among Sitakunda subdistrict (Chattogram, Bangladesh) residents found an adjusted prevalence of severe acute respiratory syndrome coronavirus 2 antibodies of 64.1% (95% credible interval 60.0%-68.1%). Before the Delta variant surge, most residents had been infected, although cumulative confirmed coronavirus disease incidence was low.

Narrative online guides for the interpretation of digital-pathology images and tissue-atlas data.

Multiplexed tissue imaging facilitates the diagnosis and understanding of complex disease traits. However, the analysis of such digital images heavily relies on the experience of anatomical pathologists for the review, annotation and description of tissue features. In addition, the wider use of data from tissue atlases in basic and translational research and in classrooms would benefit from software that facilitates the easy visualization and sharing of the images and the results of their analyses. In this Perspective, we describe the ecosystem of software available for the analysis of tissue images and discuss the need for interactive online guides that help histopathologists make complex images comprehensible to non-specialists. We illustrate this idea via a software interface (Minerva), accessible via web browsers, that integrates multi-omic and tissue-atlas features. We argue that such interactive narrative guides can effectively disseminate digital histology data and aid their interpretation.

A descriptive study of Forcefully Displaced Myanmar Nationals (FDMN) presenting for care at public health sector hospitals in Bangladesh.

BACKGROUND: In 2017 hundreds of thousands of 'Rohingya' fled to camps for Forcefully Displaced Myanmar Nationals (FDMN) in Cox's Bazar, Bangladesh. OBJECTIVE: To describe the FDMNs presenting for care at public health facilities in Bangladesh so as to understand the health problems faced by the FDMNs and the burden on these public health facilities. METHODS: This study combined a retrospective review of existing hospital and clinic data with prospective surveillance in government health care centres. FINDINGS: The retrospective data showed a 26% increase in the number of consultations at the Kutupalong community clinic, the primary health facility closest to the camps, from 19,567 in 2015 to 26,309 in 2019. There was a corresponding 11% increase in admissions to health facilities in the area, from 80,991 in 2017 to 91,424 in 2019. Prospective surveillance of 9,421 FDMNs seeking health care from July 2018 to December 2019 showed that 29% had an infectious disease, 20% nutritional problems, 12% pregnancy-related conditions and 7% trauma or injury. CONCLUSIONS: Great uncertainty remains regarding the return of FDMN to their home country of Myanmar. The current on-going protests following the military coup adds further insecurity to the status of the Rohingya. The presence of a large migrant population relative to a smaller host community burdens the limited facilities and resources of the public health sector. Continued support by the international public health community and civil society organizations is needed.

HSF1 phase transition mediates stress adaptation and cell fate decisions.

Under proteotoxic stress, some cells survive whereas others die. The mechanisms governing this heterogeneity in cell fate remain unknown. Here we report that condensation and phase transition of heat-shock factor 1 (HSF1), a transcriptional regulator of chaperones1,2, is integral to cell-fate decisions underlying survival or death. During stress, HSF1 drives chaperone expression but also accumulates separately in nuclear stress bodies called foci3-6. Foci formation has been regarded as a marker of cells actively upregulating chaperones3,6-10. Using multiplexed tissue imaging, we observed HSF1 foci in human tumours. Paradoxically, their presence inversely correlated with chaperone expression. By live-cell microscopy and single-cell analysis, we found that foci dissolution rather than formation promoted HSF1 activity and cell survival. During prolonged stress, the biophysical properties of HSF1 foci changed; small, fluid condensates enlarged into indissoluble gel-like arrangements with immobilized HSF1. Chaperone gene induction was reduced in such cells, which were prone to apoptosis. Quantitative analysis suggests that survival under stress results from competition between concurrent but opposing mechanisms. Foci may serve as sensors that tune cytoprotective responses, balancing rapid transient responses and irreversible outcomes.

Minerva: a light-weight, narrative image browser for multiplexed tissue images.

Advances in highly multiplexed tissue imaging are transforming our understanding of human biology by enabling detection and localization of 10-100 proteins at subcellular resolution (Bodenmiller, 2016). Efforts are now underway to create public atlases of multiplexed images of normal and diseased tissues (Rozenblatt-Rosen et al., 2020). Both research and clinical applications of tissue imaging benefit from recording data from complete specimens so that data on cell state and composition can be studied in the context of overall tissue architecture. As a practical matter, specimen size is limited by the dimensions of microscopy slides (2.5 × 7.5 cm or ~2-8 cm2 of tissue depending on shape). With current microscopy technology, specimens of this size can be imaged at sub-micron resolution across ~60 spectral channels and ~106 cells, resulting in image files of terabyte size. However, the rich detail and multiscale properties of these images pose a substantial computational challenge (Rashid et al., 2020). See Rashid et al. (2020) for an comparison of existing visualization tools targeting these multiplexed tissue images.

An update on the CNS manifestations of neurofibromatosis type 2.

Neurofibromatosis type II (NF2) is a tumor predisposition syndrome characterized by the development of distinctive nervous system lesions. NF2 results from loss-of-function alterations in the NF2 gene on chromosome 22, with resultant dysfunction of its protein product merlin. NF2 is most commonly associated with the development of bilateral vestibular schwannomas; however, patients also have a predisposition to development of other tumors including meningiomas, ependymomas, and peripheral, spinal, and cranial nerve schwannomas. Patients may also develop other characteristic manifestations such as ocular lesions, neuropathies, meningioangiomatosis, and glial hamartia. NF2 has a highly variable clinical course, with some patients exhibiting a severe phenotype and development of multiple tumors at an early age, while others may be nearly asymptomatic throughout their lifetime. Despite the high morbidity associated with NF2 in severe cases, management of NF2-associated lesions primarily consists of surgical resection and treatment of symptoms, and there are currently no FDA-approved systemic therapies that address the underlying biology of the syndrome. Refinements to the diagnostic criteria of NF2 have been proposed over time due to increasing understanding of clinical and molecular data. Large-population studies have demonstrated that some features such as the development of gliomas and neurofibromas, currently included as diagnostic criteria, may require further clarification and modification. Meanwhile, burgeoning insights into the molecular biology of NF2 have shed light on the etiology and highly variable severity of the disease and suggested numerous putative molecular targets for therapeutic intervention. Here, we review the clinicopathologic features of NF2, current understanding of the molecular biology of NF2, particularly with regard to central nervous system lesions, ongoing therapeutic studies, and avenues for further research.

Correction to: An update on the CNS manifestations of neurofibromatosis type 2.

The article An update on the CNS manifestations of neurofibromatosis type 2, written by Shannon Coy, Rumana Rashid, Anat Stemmer­Rachamimov and Sandro Santagata, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 04 June 2019 without open access.

Highly multiplexed immunofluorescence images and single-cell data of immune markers in tonsil and lung cancer.

In this data descriptor, we document a dataset of multiplexed immunofluorescence images and derived single-cell measurements of immune lineage and other markers in formaldehyde-fixed and paraffin-embedded (FFPE) human tonsil and lung cancer tissue. We used tissue cyclic immunofluorescence (t-CyCIF) to generate fluorescence images which we artifact corrected using the BaSiC tool, stitched and registered using the ASHLAR algorithm, and segmented using ilastik software and MATLAB. We extracted single-cell features from these images using HistoCAT software. The resulting dataset can be visualized using image browsers and analyzed using high-dimensional, single-cell methods. This dataset is a valuable resource for biological discovery of the immune system in normal and diseased states as well as for the development of multiplexed image analysis and viewing tools.