Affinity fine-tuning anti-CAIX CAR-T cells mitigate on-target off-tumor side effects.

One of the major hurdles that has hindered the success of chimeric antigen receptor (CAR) T cell therapies against solid tumors is on-target off-tumor (OTOT) toxicity due to sharing of the same epitopes on normal tissues. To elevate the safety profile of CAR-T cells, an affinity/avidity fine-tuned CAR was designed enabling CAR-T cell activation only in the presence of a highly expressed tumor associated antigen (TAA) but not when recognizing the same antigen at a physiological level on healthy cells. Using direct stochastic optical reconstruction microscopy (dSTORM) which provides single-molecule resolution, and flow cytometry, we identified high carbonic anhydrase IX (CAIX) density on clear cell renal cell carcinoma (ccRCC) patient samples and low-density expression on healthy bile duct tissues.

Presence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Antibodies Among Vietnamese Healthcare Workers by Dosing Interval for ChAdOx1 nCoV-19 Vaccine.

Background: Before the SARS-CoV-2 Delta variant arrived in Vietnam, case rates suggested seroprevalence of SARS-CoV-2 was low. Beginning in March 2021, we assessed different dosing schedules and adverse events following immunization (AEFIs) for ChAdOx1 nCoV-19 vaccine among healthcare workers (HCWs).

Methods: We performed a prospective cohort study to estimate the prevalence of IgG antibodies to SARS-CoV-2 before and after ChAdOx1 nCoV-19 vaccination.

Association between Troponin I Levels during Sepsis and Postsepsis Cardiovascular Complications.

Sepsis commonly results in elevated serum troponin levels and increased risk for postsepsis cardiovascular complications; however, the association between troponin levels during sepsis and cardiovascular complications after sepsis is unclear. To evaluate the association between serum troponin levels during sepsis and 1 year after sepsis cardiovascular events. We analyzed adults aged ⩾40 years without preexisting cardiovascular disease within 5 years, admitted with sepsis across 21 hospitals from 2011 to 2017.

Outbreak of hepatitis B and hepatitis C virus infections associated with a cardiology clinic, West Virginia, 2012-2014.

Objective: To stop transmission of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in association with myocardial perfusion imaging (MPI) at a cardiology clinic.

Design: Outbreak investigation and quasispecies analysis of HCV hypervariable region 1 genome.

Setting: Outpatient cardiology clinic.

Complex genetic encoding of the hepatitis B virus on-drug persistence.

Tenofovir disoproxil fumarate (TDF) is one of the nucleotide analogs capable of inhibiting the reverse transcriptase (RT) activity of HIV and hepatitis B virus (HBV). There is no known HBV resistance to TDF. However, detectable variation in duration of HBV persistence in patients on TDF therapy suggests the existence of genetic mechanisms of on-drug persistence that reduce TDF efficacy for some HBV strains without affording actual resistance.

Substantial Need for Preexposure Prophylaxis Among Men Who Have Sex With Men in Hanoi, Vietnam.

We used data from the Health in Men-Hanoi cohort to determine the proportion of HIV-negative men who have sex with men with PrEP indications in Hanoi. Among 717 men who have sex with men, 537 (72.2% [66.

Constraint and conservation of paired-type homeodomains predicts the clinical outcome of missense variants of uncertain significance.

The need to interpret the pathogenicity of novel missense variants of unknown significance identified in the homeodomain of X-chromosome aristaless-related homeobox (ARX) gene prompted us to assess the utility of conservation and constraint across these domains in multiple genes compared to conventional in vitro functional analysis. Pathogenic missense variants clustered in the homeodomain of ARX contribute to intellectual disability (ID) and epilepsy, with and without brain malformation in affected males. Here we report novel c.

The effect of mental health screening and referral on symptoms of depression among HIV positive outpatients in Vietnam: Findings from a three-month follow up study.

This study investigated whether screening for symptoms of mental disorders and referral to mental health services was associated with decreased depression symptoms among people living with HIV/AIDS (PLHIV) in Vietnam. Four hundred PLHIV (63.5% male, mean age 34.

Programmatic Evaluation of an Algorithm for Intensified Tuberculosis Case Finding and Isoniazid Preventive Therapy for People Living With HIV in Thailand and Vietnam.

Background: Tuberculosis (TB) screening affords clinicians the opportunity to diagnose or exclude TB disease and initiate isoniazid preventive therapy (IPT) for people living with HIV (PLHIV).

Methods: We implemented an algorithm to diagnose or rule out TB among PLHIV in 11 HIV clinics in Thailand and Vietnam. We assessed algorithm yield and uptake of IPT and factors associated with TB disease among PLHIV.

Prevalence and Correlates of Probable HIV-Associated Dementia in HIV Outpatients in Ho Chi Minh City, Vietnam.

This study identified prevalence and correlates of HIV-associated dementia (HAD) among people living with HIV (PLWHA) in Ho Chi Minh City, Vietnam. Four hundred PLWHA completed a self-report questionnaire and were interviewed by a trained researcher to assess HAD using the International HIV Dementia Scale (IHDS). Clinical information concerning HIV treatment was also extracted from medical records.

Accurate Genetic Detection of Hepatitis C Virus Transmissions in Outbreak Settings.

Hepatitis C is a major public health problem in the United States and worldwide. Outbreaks of hepatitis C virus (HCV) infections are associated with unsafe injection practices, drug diversion, and other exposures to blood and are difficult to detect and investigate. Here, we developed and validated a simple approach for molecular detection of HCV transmissions in outbreak settings.

Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen.

WNT signaling is frequently deregulated in malignancy, particularly in colon cancer, and plays a key role in the generation and maintenance of cancer stem cells. We report the discovery and optimization of a 3,4,5-trisubstituted pyridine 9 using a high-throughput cell-based reporter assay of WNT pathway activity. We demonstrate a twisted conformation about the pyridine-piperidine bond of 9 by small-molecule X-ray crystallography.

Hepatitis B virus infection among HIV-infected pregnant women in Malawi and transmission to infants.

Background & Aims: The extent of HBV infection to infants of HBV/HIV-coinfected pregnant women in sub-Saharan Africa is unknown. The aim of this study was to assess prevalence of HBV infection among antiretroviral-naïve, HIV-infected pregnant women in Malawi and examine HBV transmission to their infants.

Methods: Plasma from 2048 HIV-infected, Malawian women and their infants were tested for markers of HBV infection.

An evaluation of hepatitis B virus diagnostic methods and responses to antiretroviral therapy among HIV-infected women in Thailand.

Coinfection with HIV and hepatitis B virus (HBV) is common in resource-limited settings but is frequently not diagnosed. The authors retrospectively tested specimens for HBV in HIV-infected Thai women who had participated in an antiretroviral therapy (ART) clinical study. A substantial proportion (27 of 211; 13%) of HIV-infected women were HBV coinfected.

Combination antifungal therapy for cryptococcal meningitis.

Background: Combination antifungal therapy (amphotericin B deoxycholate and flucytosine) is the recommended treatment for cryptococcal meningitis but has not been shown to reduce mortality, as compared with amphotericin B alone. We performed a randomized, controlled trial to determine whether combining flucytosine or high-dose fluconazole with high-dose amphotericin B improved survival at 14 and 70 days.

Methods: We conducted a randomized, three-group, open-label trial of induction therapy for cryptococcal meningitis in patients with human immunodeficiency virus infection.

Kidney transplantation in hepatitis C-positive recipients: does type of induction influence outcomes?

Background: Kidney transplantation in hepatitis C virus-seropositive (HCV+) recipients improves survival compared to staying on the waiting list. A concern for using depleting (versus nondepleting) induction agent during kidney transplantation in HCV+ recipients is the possibility that the associated enhanced immunosuppression might favor the progression of hepatitis C infection, leading to adverse outcomes.

Methods: Utilizing data from the Organ Procurement and Transplant Network, we identified HCV+ patients ≥ 18 years of age who underwent deceased donor kidney (DDK) transplants from either HCV+ or HCV- donors between 1998 and 2008.

Association of common genetic variants in GPCPD1 with scaling of visual cortical surface area in humans.

Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors contribute to normal variation in the area of visual cortex. To identify SNPs associated with the proportional surface area of visual cortex, we performed a genome-wide association study followed by replication in two independent cohorts.

Epidemic history and evolutionary dynamics of hepatitis B virus infection in two remote communities in rural Nigeria.

Background: In Nigeria, hepatitis B virus (HBV) infection has reached hyperendemic levels and its nature and origin have been described as a puzzle. In this study, we investigated the molecular epidemiology and epidemic history of HBV infection in two semi-isolated rural communities in North/Central Nigeria. It was expected that only a few, if any, HBV strains could have been introduced and effectively transmitted among these residents, reflecting limited contacts of these communities with the general population in the country.

Differential regulation of dual NADPH oxidases/peroxidases, Duox1 and Duox2, by Th1 and Th2 cytokines in respiratory tract epithelium.

Partially reduced metabolites of molecular oxygen, superoxide (O2-) and hydrogen peroxide (H2O2), are detected in respiratory tract lining fluid, and it is assumed that these are key components of innate immunity. Whether these reactive oxygen species (ROS) are produced specifically by the respiratory epithelium in response to infection, or are a non-specific by-product of oxidant-producing inflammatory cells is not well characterized. Increasing evidence supports the hypothesis that the dual function NAD(P)H oxidases/peroxidases, Duox1 and Duox2, are important sources of regulated H2O2 production in respiratory tract epithelium.

MicroRNA profiling of the murine hematopoietic system.

Background: MicroRNAs (miRNAs) are a class of recently discovered noncoding RNA genes that post-transcriptionally regulate gene expression. It is becoming clear that miRNAs play an important role in the regulation of gene expression during development. However, in mammals, expression data are principally based on whole tissue analysis and are still very incomplete.

Fibulin-1 acts as a cofactor for the matrix metalloprotease ADAMTS-1.

ADAMTS-1 is a metalloprotease that has been implicated in the inhibition of angiogenesis and is a mediator of proteolytic cleavage of the hyaluronan binding proteoglycans, aggrecan and versican. In an attempt to further understand the biological function of ADAMTS-1, a yeast two-hybrid screen was performed using the carboxyl-terminal region of ADAMTS-1 as bait. As a result, the extracellular matrix protein fibulin-1 was identified as a potential interacting molecule.

Recombinant C345C and factor I modules of complement components C5 and C7 inhibit C7 incorporation into the complement membrane attack complex.

Complement component C5 binds to components C6 and C7 in reversible reactions that are distinct from the essentially nonreversible associations that form during assembly of the complement membrane attack complex (MAC). We previously reported that the approximately 150-aa residue C345C domain (also known as NTR) of C5 mediates these reversible reactions, and that the corresponding recombinant module (rC5-C345C) binds directly to the tandem pair of approximately 75-residue factor I modules from C7 (C7-FIMs). We suggested from these and other observations that binding of the C345C module of C5 to the FIMs of C7, but not C6, is also essential for MAC assembly itself.

ADAMTS1 proteinase is up-regulated in wounded skin and regulates migration of fibroblasts and endothelial cells.

The metalloproteinase ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motifs) is induced under inflammatory conditions, and it is also a potent inhibitor of angiogenesis. Due to these properties, we speculated about the role of ADAMTS1 in cutaneous wound repair. Here we have shown up-regulation of ADAMTS1 expression in wounds of normal and particularly of healing-impaired genetically diabetic mice.