Biology subjects

McKenzie, J. S.

Publications and source records attributed to McKenzie, J. S..

3 recordsLinked to original sources

bioRxiv2026

Glutamine and GLS1 are key metabolic checkpoints that Limit T cell Infiltration and Function in HNSCC

Head and neck squamous cell carcinoma (HNSCC) is characterized by poor survival and limited benefit from immune checkpoint blockade (ICB), underscoring the need to define targetable mechanisms of immune escape. In a prospective, patient-centered study, we investigated how tumor metabolic reprogramming impairs T cell function and drives ICB resistance. Targeted metabolomics identified two dominant and distinct tumor states: the Warburg phenotype and glutamine deprivation and revealed increased tumor-specific glutamine to glutamate turnover. Integrating spatial metabolic imaging with immunohistochemistry linked these states to immune-cold and immune-excluded tumor architectures. Metabolic states selectively reduced the expression of T cell chemokine receptors highly abundant and prognostic in HNSCC. Accordingly, T cell migration into tumor spheroids was reduced at lower glutamine concentrations. Interfering with glutamine metabolism by pharmacologic inhibition or genetic deletion of glutaminase-1 markedly increased tumor susceptibility to immune cell-mediated cytotoxicity in vitro and ex vivo and sensitized patient-derived tumor fragments (PDTFs) to ICB. This effect extended beyond glutamine restoration and involved disruption of glutathione-dependent ROS defense, impaired tumor proliferation, and increased MHC expression in tumor cells. Consistently, high expression of genes involved in glutamine and glutathione metabolism associated with reduced ICB response in patients. In contrast to HNSCC, other tumor entities including breast cancer show low glutaminase-1 expression. Accordingly, breast cancer PDTFs were not responsive to glutaminase-1 inhibition. Together, these data identify glutaminase-1 as a metabolic checkpoint driving immune escape in HNSCC, and support guided patient stratification for metabolism-targeted immunotherapy, similar to current precision approaches for mutation targeted drugs.

cancer biology↗

bioRxiv2026

X-CODE: a dual RNA barcoding system for multi-platform clonal tracking and spatial phenotyping

Experimental dissection of clonal dynamics in complex tissues requires barcoding systems that are scalable, compatible with different analytical platforms, providing phenotypic and spatial resolution. Here we introduce X-CODE, a dual-expressed RNA barcoding system designed to enable high-complexity clonal tracking across sequencing-based, cytometric, and spatial imaging modalities within a unified experimental framework. X-CODE combines a combinatorial, probe-detectable long RNA barcode with a matched short sequencing barcode, enabling seamless integration of probe-based readouts with sequencing and barcode-guided clonal retrieval. We demonstrate robust X-CODE detection by mass cytometry and imaging-based platforms, including spatial RNA barcode readout using via a repurposed Akoya PhenoCycler-Fusion protocol. In addition, we show compatibility with MALDI mass spectrometry imaging for co-registration of clonal and metabolic information. We further demonstrate the feasibility of X-CODE detection within probe-based spatial transcriptomics using the 10x Genomics Xenium platform. Applied to an in vivo model of androgen deprivation in prostate cancer, X-CODE reveals clonal architecture, selection and clone-specific phenotypic and metabolic plasticity underlying castration resistance. Together, X-CODE provides a flexible and broadly accessible platform for integrated clonal analysis across spatial, phenotypic, and molecular dimensions.

cancer biology↗

bioRxiv2018

Clinicians management of patients potentially exposed to rabies in high-risk areas in Bhutan: A cross-sectional study

BackgroundRabies is endemic in southern Bhutan, associated with 1-2 human deaths annually and accounting for about 6% of annual national expenditure on essential medicines. A WHO-adapted National Rabies Management Guidelines (NRMG) is available to aid clinicians in PEP prescription. An understanding of clinical practice in the evaluation of rabies risk in endemic areas could contribute to improve clinicians PEP decision-making.\n\nMethodsA cross-sectional survey of clinicians was conducted in 13 health centers in high-rabies-risk areas of Bhutan during February-March 2016. Data were collected from 273 patients examined by 50 clinicians.\n\nResultsThe majority (69%) of exposure was through dog bites. Half the patients were children under 18 years of age. Consultations were conducted by health assistants or clinical officers (55%), or by medical doctors (45%), with a median age of clinicians of 31 years. Rabies vaccines were prescribed in 91% of exposure cases. The overall agreement between clinicians rabies risk assessment and the NRMG for the corresponding exposure was low (kappa =0.203, p<0.001). Clinicians were more likely to underestimate the risk of exposure than overestimate it. Male health assistants were the most likely to make an accurate risk assessment and female health assistants were the least likely. Clinicians from district or regional hospitals were more likely to conduct accurate risk assessments compared to clinicians in Basic Health Units (Odds Ratios of 7.8 and 17.6, respectively).\n\nConclusionsThis study highlighted significant discrepancies between clinical practice and guideline recommendations for rabies risk evaluation. Regular training about rabies risk assessment and PEP prescription should target all categories of clinicians. An update of the NRMG with more specific criterions for the prescription of RIG might contribute to increase the compliance, along with a regular review of decision-making criteria to monitor adherence to the NRMG.\n\nAuthor summaryHuman rabies remains an important public health threat in Bhutan, especially in southern regions where canine rabies is endemic. The steady increase in number of patients reporting to hospitals following dog bites means escalating costs of post-exposure prophylaxis for the country. We investigated attitudes and practices of clinicians who manage patients with potential rabies exposure, in the endemic area. The risk of rabies exposure in the study area is mostly associated with dog bites, involving children half the time. Rabies vaccines were prescribed in 9 out of 10 exposure cases, while immuno-globulins were rarely prescribed. The study confirmed the perceived lack of compliance of clinicians with guideline recommendations for assessing rabies risk. This results in under-estimating the rabies risk in potentially risky exposures in high-rabies-risk areas. Our work underscore the importance of targeted training of female health assistants, doctors, and clinicians in basic health units to improve the management of rabies exposure. In particular there is need to update the national guidelines regarding indications and use of rabies immune-globulins.

epidemiology↗