Biology subjects

Chan, V.

Publications and source records attributed to Chan, V..

10 recordsLinked to original sources

bioRxiv2026

Bilateral Mechanoreception Discrimination based on Bihemispheric Somatosensory Response Patterns is Associated with Proprioception and Motor Function After Stroke

ObjectivesStroke commonly impairs proprioception and motor function, yet the cortical sensory processes underlying these impairments remain poorly understood. Prior electrophysiological studies have primarily focused on the average magnitude of unilateral cortical sensory responses to vibration, potentially overlooking distributed and trial-to-trial features of sensory processing that may be functionally relevant to proprioceptive processing and motor performance. We therefore aimed to characterize bilateral cortical sensory responses to determine their relationships with proprioceptive and motor function. MethodsEEG was recorded from forty-six individuals with chronic stroke during a rapid, passive, vibrotactile stimulation paradigm applied to the left and right fingertips. Somatosensory evoked potentials (SEPs) and event-related desynchronization (ERD) were quantified. Finger proprioceptive performance was assessed using a passive, robotic, finger crossing identification task, while motor function was evaluated using the Box and Block Test, Fugl-Meyer Assessment, and Nine Hole Peg Test. Associations with function were assessed using (i) unilateral sensory response magnitude at the contralateral parietal cortex and (ii) somatosensory decoder performance, defined as the accuracy with which a decoder identified the location of the stimulated hand (i.e. paretic vs. non-paretic) from combined bihemispheric response patterns. The association between these responses and proprioceptive ability and motor function was assessed. These associations were further evaluated jointly across multiple motor function measures using an exploratory analysis leveraging nonlinear dimensionality reduction and clustering. ResultsVibrotactile stimulation of the paretic hand elicited ipsilesional SEP and ERD that were reduced in magnitude compared to stimulation of the non-paretic hand. Both decreased SEP magnitude and reduced sensory decoder performance were associated with greater finger proprioceptive error. Unlike unilateral responses, the somatosensory decoders performance was also strongly associated with motor function, explaining approximately 22.5% of the variance in motor performance. Dimensionality reduction and clustering across multiple motor assessment scores showed distinct subgroups, that showed significant differences in sensory decoding. ConclusionsThe hemispheric distribution and discriminability of cortical sensory responses are functionally relevant markers of sensorimotor integrity after stroke. Assessing relative lateralization of somatosensory responses for each hand, rather than the magnitude of dominant contralateral responses alone, may better capture the reliability of sensory processing after stroke, as well as the distributed cortical reorganization supporting sensorimotor function. These findings support the potential value of a novel decoding-based neurophysiological measure for sensory-driven rehabilitation, biomarker development, and patient stratification.

neuroscience↗

bioRxiv2026

IL12-engineered human PSMA-CAR T cells for the treatment of advanced prostate cancer

Adoptive cell therapies used to treat advanced prostate cancer are being developed to target several tumor-associated antigens, including prostate-specific membrane antigen (PSMA). Chimeric antigen receptor (CAR) T cell therapy using the single chain variable fragment (scFv) derived from the humanized murine mAb clone, J591, as the antigen-binding domain has shown promising anti-tumor activity. However, it has also been associated with macrophage activation syndrome and other unwanted toxicities, highlighting the need for more specific and human-derived antigen-binders with optimized construct designs for improved safety and efficacy. Here, we optimize a human scFv-based PSMA-targeted CAR (hPSMA-CAR) with highly selective PSMA targeting. We further introduce a membrane-bound IL-12 (mbIL12) molecule, which enhances potency with increased T cell expansion, IFNy production and anti-tumor cell activity in vitro. Using two clinically-relevant bone-metastatic prostate cancer models, we show that mbIL12-engineered hPSMA-CAR T cells drive potent in vivo anti-tumor responses. In summary, we have developed a promising therapeutic that has potential to promote safe and effective treatment of advanced PSMA+ prostate cancer.

bioengineering↗

bioRxiv2024

Hematopoietic stem cell division is governed by distinct RUNX1 binding partners.

A defined number of hematopoietic stem cell (HSC) clones are born during development and expand to form the pool of adult stem cells. An intricate balance between self-renewal and differentiation of these HSCs supports hematopoiesis for life. HSC fate is determined by complex transcription factor networks that drive cell-type specific gene programs. The transcription factor RUNX1 is required for definitive hematopoiesis, and mutations in Runx1 have been shown to reduce clonal diversity. The RUNX1 cofactor, CBFy, stabilizes RUNX1 binding to DNA, and disruption of their interaction alters downstream gene expression. Chemical screening for modulators of Runx1 and HSC expansion in zebrafish led us to identify a new mechanism for the RUNX1 inhibitor, Ro5-3335. We found that Ro5-3335 increased HSC divisions in zebrafish, and animals transplanted with Ro5-3335 treated cells had enhanced chimerism compared to untreated cells. Using human CD34+ cells, we show that Ro5-3335 remodels the RUNX1 transcription complex by binding to ELF1, independent of CBFy. This allows specific expression of cell cycle and hematopoietic genes that enhance HSC self-renewal and prevent differentiation. Furthermore, we provide the first evidence to show that it is possible to pharmacologically increase the number of stem cell clones in vivo, revealing a previously unknown mechanism for enhancing clonal diversity. Our studies have revealed a mechanism by which binding partners of RUNX1 determine cell fate, with ELF transcription factors guiding cell division. This information could lead to treatments that enhance clonal diversity for blood diseases.

cell biology↗

bioRxiv2023

The LCLAT1/LYCAT acyltransferase supports EGF-mediated phosphatidylinositol-3,4,5-trisphosphate and Akt signalling

Receptor tyrosine kinases such as epidermal growth factor receptor (EGFR) stimulate phosphoinositide 3-kinases (PI3Ks) to convert phosphatidylinositol-4,5-bisphosophate [PtdIns(4,5)P2] into phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P3]. PtdIns(3,4,5)P3 then remodels actin and gene expression, and boosts cell survival and proliferation. PtdIns(3,4,5)P3 partly achieves these functions by triggering activation of the kinase Akt, which phosphorylates targets like Tsc2 and GSK3{beta}. Consequently, unchecked upregulation of PtdIns(3,4,5)P3-Akt signalling promotes tumour progression. Interestingly, 50-70% of PtdIns and PtdInsPs have stearate and arachidonate at sn-1 and sn-2 positions of glycerol, respectively, forming a species known as 38:4-PtdIns/PtdInsPs. LCLAT1 and MBOAT7 acyltransferases partly enrich PtdIns in this acyl format. We previously showed that disruption of LCLAT1 lowered PtdIns(4,5)P2 levels and perturbed endocytosis and endocytic trafficking. However, the role of LCLAT1 in receptor tyrosine kinase and PtdIns(3,4,5)P3 signaling was not explored. Here, we show that LCLAT1 silencing in MDA-MB-231 and ARPE-19 cells abated the levels of PtdIns(3,4,5)P3 in response to EGF signalling. Importantly, LCLAT1-silenced cells were also impaired for EGF-driven and insulin-driven Akt activation and downstream signalling. Thus, our work provides first evidence that the LCLAT1 acyltransferase is required for receptor tyrosine kinase signalling.

cell biology↗

bioRxiv2023

Transplantation-based screen uncovers inducers of muscle progenitor cell engraftment across vertebrate species

Stem cell transplantation presents a potentially curative strategy for genetic disorders of skeletal muscle, but this approach is limited due to the deleterious effects of cell expansion in vitro and consequent poor engraftment efficiency. In an effort to overcome this limitation, we sought to identify molecular signals that enhance the myogenic activity of cultured muscle progenitors. Here, we report the development and application of a cross-species small molecule screening platform employing zebrafish and mouse, which enables rapid, direct evaluation of the effects of chemical compounds on the engraftment of transplanted muscle precursor cells. Using this system, we screened a library of bioactive lipids to identify those that could increase myogenic engraftment in vivo in zebrafish and mice. Two lipids, lysophosphatidic acid (LPA) and niflumic acid (NFA), are linked to activation of intracellular calcium ion flux, which showed conserved, dose-dependent and synergistic effects in promoting muscle engraftment across these vertebrate species.

cell biology↗

bioRxiv2021

Holistic Characterization of Tumor Monocyte-to-Macrophage Differentiation Integrates Distinct Immune Phenotypes in Kidney Cancer

The tumor immune microenvironment (TIME) is commonly infiltrated by diverse collections of myeloid cells. Yet, the complexity of myeloid cell identity and plasticity has challenged efforts to define bona fide populations and determine their connections to T cell function and their relation to patient outcome. Here we leverage single-cell RNA-sequencing (scRNA-seq) analysis of several mouse and human tumors and find that monocyte-macrophage diversity is characterized by a combination of conserved lineage states as well as transcriptional programs accessed along the differentiation trajectory. Using mouse models, we also find that tumor monocyte-to-macrophage progression is profoundly tied to regulatory T cell (Treg) abundance. Importantly, in human kidney cancer, heterogeneity in macrophage accumulation and myeloid composition corresponded to variance in, not only Treg density, but also the quality of infiltrating CD8+ T cells. In this way, holistic analysis of monocyte-to-macrophage differentiation creates a framework for critically different immune states in kidney tumors.

immunology↗

bioRxiv2021

Multiomic Characterization of Stage I Lung Adenocarcinoma Reveals Distinct Genetic and Immunologic Features of Recurrent Disease

BackgroundRecurrence after surgery for early-stage lung cancer is common, occurring between 30-50% of the time. Despite the popularization of prognostic gene signatures in early-stage lung cancer that allow us to better predict which patients may recur, why patients recur after surgery remains unclear. MethodsUsing a large cohort of lung adenocarcinoma patients with complete genetic, genomic, epigenetic and clinical profiling, a recurrence classifier was developed which identifies patients at highest risk of recurrence. The genetic, genomic, and epigenetic profiles of stage I patients with low-vs. high-risk of recurrence were compared. To characterize the tumor immune microenvironment of recurrent stage I tumors, single cell RNA-seq was performed on fresh tissue samples undergoing lung adenocarcinoma resection at UCSF to identify unique immune population markers and applied to the large stage I lung adenocarcinoma cohort using digital cytometry. ResultsRecurrence high-risk stage I lung adenocarcinomas demonstrated a higher mutation burden than low-risk tumors, however, none of the known canonical lung cancer driver mutations were more prevalent in high-risk tumors. Transcriptomic analysis revealed widespread activation of known cancer and cell cycle pathways with simultaneous downregulation of immune response pathways including antigen presentation and Th1/Th2 activation. Tumors at high-risk of recurrence displayed depleted adaptive immune populations, and depletion of adaptive immune populations was independently prognostic of recurrence in stage I lung adenocarcinomas. ConclusionRecurrent stage I lung adenocarcinomas display distinct features of genomic and genetic instability including increased tumor mutation burden, neoantigen load, activation of numerous mitotic and cell cycle genes, and decreased genome-wide methylation burden. Relative depletion of infiltrating adaptive immune populations may allow these tumors to escape immunosurveillance and recur after surgery.

cancer biology↗

bioRxiv2021

A Pan-Cancer Census of Dominant Tumor Immune Archetypes

Cancers display significant heterogeneity with respect to tissue of origin, driver mutations and other features of the surrounding tissue. It is likely that persistent tumors differentially engage inherent patterns-here Archetypes-of the immune system, to both benefit from a tumor immune microenvironment (TIME) and to disengage tumor-targeting. To discover dominant immune system archetypes, the Immunoprofiler Initiative (IPI) processed 364 individual tumors across 12 cancer types using standardized protocols. Computational clustering of flow cytometry and transcriptomic data obtained from cell sub compartments uncovered archetypes that exist across indications. These Immune composition-based archetypes differentiate tumors based upon unique immune and tumor gene-expression patterns. Archetypes discovered this way also tie closely to well-established classifications of tumor biology. The IPI resource provides a template for understanding cancer immunity as a collection of dominant patterns of immune infiltration and provides a rational path forward to learn how to modulate these patterns to improve therapy. O_FIG O_LINKSMALLFIG WIDTH=182 HEIGHT=200 SRC="FIGDIR/small/441344v1_ufig1.gif" ALT="Figure 1"> View larger version (77K): org.highwire.dtl.DTLVardef@55a5ccorg.highwire.dtl.DTLVardef@f8205corg.highwire.dtl.DTLVardef@1480b8org.highwire.dtl.DTLVardef@eb94e_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2020

Global Absence and Targeting of Protective Immune States in Severe COVID-19.

While SARS-CoV-2 infection has pleiotropic and systemic effects in some patients, many others experience milder symptoms. We sought a holistic understanding of the severe/mild distinction in COVID-19 pathology, and its origins. We performed a whole-blood preserving single-cell analysis protocol to integrate contributions from all major cell types including neutrophils, monocytes, platelets, lymphocytes and the contents of serum. Patients with mild COVID-19 disease display a coordinated pattern of interferon-stimulated gene (ISG) expression across every cell population and these cells are systemically absent in patients with severe disease. Severe COVID-19 patients also paradoxically produce very high anti-SARS-CoV-2 antibody titers and have lower viral load as compared to mild disease. Examination of the serum from severe patients demonstrates that they uniquely produce antibodies with multiple patterns of specificity against interferon-stimulated cells and that those antibodies functionally block the production of the mild disease-associated ISG-expressing cells. Overzealous and auto-directed antibody responses pit the immune system against itself in many COVID-19 patients and this defines targets for immunotherapies to allow immune systems to provide viral defense. One Sentence SummaryIn severe COVID-19 patients, the immune system fails to generate cells that define mild disease; antibodies in their serum actively prevents the successful production of those cells.

immunology↗

bioRxiv2020

Field efficacy of guppies and pyriproxyfen (Sumilarv(R) 2MR) combined with community engagement on dengue vectors in Cambodia: a randomized controlled trial

Evidence on the effectiveness of low-cost, sustainable biological vector control tools for Aedes mosquitoes is limited. Therefore, the purpose of this trial is to estimate the impact of guppy fish, in combination with the use of the larvicide Pyriproxyfen (Sumilarv(R) 2MR), and Communication for Behavioral Impact (COMBI) activities to reduce entomological indices in Cambodia. In this cluster randomized, controlled superiority trial, 30 clusters comprising of one or more villages each (with approximately 170 households) will be allocated, in a 1:1:1 ratio, to receive either a) three interventions (guppies, Sumilarv(R) 2MR, and COMBI activities), b) two interventions (guppies and COMBI activities), or c) control (standard vector control). Households were invited to participate, and entomology surveys among 40 randomly selected households per cluster were carried out quarterly. The primary outcome was the population density of adult female Aedes mosquitoes (i.e. number per house) trapped using adult resting collections. Secondary outcome measures include the House index, Container index, Breteau index, Pupae Per House, Pupae Per Person, mosquito infection rate, guppy fish coverage, Sumilarv(R) 2MR coverage, and percentage of respondents with knowledge about Aedes mosquitoes causing dengue. In the primary analysis, adult female Aedes density and mosquito infection rates was aggregated over follow-up time points to give a single rate per cluster. This was analyzed by negative binomial regression, yielding density ratios. The number of Aedes females was reduced by roughly half compared to the control in both the guppy and PPF arm (Density Ratio (DR)=0.54 [95% CI 0.34-0.85], p=0.0073), and guppy arm (DR=0.49 [95% CI 0.31-0.77], p=0.0021). The extremely low cost of including guppy rearing in community-based health structures along with the effectiveness demonstrated suggest guppies should be considered as a vector control tool as long as the benefits outweigh any potential environmental concerns. PPF was also highly accepted and preferred over current vector control tools used in Cambodia, however product costs and availability are still unknown. Author SummaryDengue is one of the most rapidly spreading mosquito-borne viral diseases in the world, is caused by bites of infected Aedes mosquitoes, and can sometimes lead to death. Cambodia has one of the highest per-capita incidence rates in Asia. Without a cure or routinely available efficacious vaccine, dengue control relies largely on reduction and avoidance of mosquitoes. In Cambodia, dengue mosquito control activities are focused on larviciding with temephos and pyrethroid based adulticide sprays to which Aedes have been shown to be increasingly resistant. This study was designed to evaluate novel biological vector control tools (guppy fish and a controlled release larvicidal matrix) utilizing an integrated vector management approach with community-based methods tailored to the local context. The results indicate that the tools resulted in a statistically significant reduction in immature and adult Aedes mosquito density. The interventions were accepted by and communities were willing to pay for them. The results suggest guppies are an ideal vector control tool as long as the benefits outweigh any potential environmental concerns. PPF was also highly accepted and preferred over current vector control tools used in Cambodia, however product costs and availability are still unknown.

ecology↗