Biology subjects

Parameswaran, R.

Publications and source records attributed to Parameswaran, R..

5 recordsLinked to original sources

bioRxiv2026

Bicarbonate-free pH neutralization resensitizes ovarian cancer to chemotherapy and is tracked by 3T CEST MRI

Ovarian tumors that initially respond to platinum-taxane chemotherapy often relapse as chemoresistant disease. The acidic tumor microenvironment is a well-known but under-exploited driver of this resistance, and neutralization strategies such as oral bicarbonate have not translated. Here we show that inhibiting specific tumor pH regulators at noncytotoxic doses relieves acidosis and restores frontline chemotherapy, monitored noninvasively at clinical 3T. In OVCAR3 and SKOV-3 ovarian cancer cells, MCT1 and MCT4 were overexpressed under acidosis, and the MCT4 inhibitor acriflavine reduced extracellular acidification at concentrations well below its cytotoxic IC50, without bicarbonate buffering. Acidosis blunted the efficacy of both paclitaxel and carboplatin, raising their IC50 values, which acriflavine reversed. In SKOV-3 tumors, acidoCEST MRI with iopromide noninvasively measured baseline tumor acidosis and its normalization following acriflavine treatment. These results establish tumor acidosis as an imageable, druggable determinant of chemoresistance and a bicarbonate-free therapeutic target.

bioengineering↗

bioRxiv2025

B-cell activating factor plays a critical role in CAR-T cell-associated cytokine release syndrome

Cytokine release syndrome (CRS) is the most common and potentially life-threatening toxicity associated with CAR-T cell therapy and is related to a heightened immune effector state. In this work, we identified a novel role of the pro-tumorigenic cytokine B-cell activating factor (BAFF) in its pathophysiology. First, we observed that patients who experienced CAR-T cell-related CRS have elevated serum BAFF levels that coincide with elevated IL-6. Mechanistically, we show that IFN-{gamma}, produced by activated CAR-T cells, stimulates monocytes to release BAFF, which induces the expression of CRS-related cytokines from monocytes. Monocytes derived from CRS patients express BCMA, which is further induced by IFN-{gamma} stimulation. Neutralization of BAFF with belimumab significantly reduces production of various CRS and ICANS-related cytokines without impairing CAR-T cell activation or killing. Overall, we demonstrate that BAFF plays a critical role in CAR-T-cell-related CRS, and its neutralization may be a novel strategy for treating both CRS and ICANS. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=67 SRC="FIGDIR/small/689920v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@187a0edorg.highwire.dtl.DTLVardef@1566904org.highwire.dtl.DTLVardef@896b5org.highwire.dtl.DTLVardef@1de5db6_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Lipodystrophy and recovery are mediated by the Wnt/lipogenesis axis during skin fibrosis.

Acquired lipodystrophy in the dermal white adipose tissue (DWAT) is a salient feature of skin fibrosis, and is followed by accumulation of extracellular matrix (ECM). Lipodystrophy syndromes, often associated with metabolic co-morbidities, are estimated to affect 1 in 20,000 people. We recently showed that fibrosis-associated lipodystrophy is dependent on sustained Wnt signaling, but the mechanism is unclear. Transcriptomic profiling of mature dermal adipocytes in vivo reveal that Wnt activation downregulates the de novo-lipogenesis (DNL) axis enzymes within 48 hours. We found that protein expression of Fatty Acid Synthase (FASN), a key DNL enzyme, is dependent on sustained Wnt activation in vitro and in vivo. In human systemic sclerosis, FASN mRNA is significantly downregulated during two years of disease. Remarkably, pharmacological inhibition of FASN enzyme during reversal from Wnt induced fibrosis impedes recovery of DWAT lipid content as well as ECM accumulation and topography. All together, we demonstrate that acquired lipodystrophy in the context of skin fibrosis is mediated by a new role of the Wnt-DNL axis. These findings underscore the importance of this pathway in lipodystrophy and fibrosis, opening new avenues for therapeutic targets in skin fibrosis.

cell biology↗

bioRxiv2021

NF-kB c-Rel is dispensable for the development but is required for the cytotoxic function of NK cells

Natural Killer (NK) cells are cytotoxic lymphocytes critical to the innate immune system. We found that germline deficiency of NF-kB c-Rel results in a marked decrease in cytotoxic function of NK cells, both in vitro and in vivo, with no significant differences in the stages of NK cell development. We found that c-Rel binds to the promoters of perforin and granzyme B, two key proteins required for NK cytotoxicity, and controls their transactivation. We generated a NK cell specific c-Rel conditional knockout to study NK cell intrinsic role of c-Rel and found that both global and conditional c-Rel deficiency leads to decreased perforin and granzyme B expression and thereby cytotoxic function. We also confirmed the role of c-Rel in perforin and granzyme B expression in human NK cells. c-Rel reconstitution rescued perforin and granzyme B expressions in c-Rel deficient NK cells and restored their cytotoxic function. Our results show a previously unknown role of c-Rel in transcriptional regulation of perforin and granzyme B expressions and control of NK cell cytotoxic function.

immunology↗

bioRxiv2019

Mutational profiling of lipomas

Lipomas are benign fatty tumors with a high prevalence rate, mostly found in adults but have a good prognosis. Until now, reason for lipoma occurrence not been identified. We performed whole exome sequencing to define the mutational spectrum in ten lipoma patients along with their matching control samples. We identified 412 somatic variants including missense mutations, splice site variants, frameshift indels, and stop gain/lost. Kinase genes and transcriptions factors were among the validated mutated genes critical for cell proliferation and survival. Pathway analysis revealed enrichment of calcium, Wnt and phospholipase D signaling in patients. Whole exome sequencing in lipomas identified mutations in genes with a possible role in development and progression of lipomas.\n\nAuthor SummaryWe presented genomic insight into the development of lipomas, the most common benign tumor of soft tissue. Until date, no one knows the cause of lipoma development and its progression. Our group for the first time profiled ten lipoma patients samples and their matching normal controls to delineate the somatic mutation pattern using whole exome sequencing. Interestingly, exome-profiling results highlighted the potential role of important kinase genes and transcription factors in lipoma development. In addition, calcium, Wnt and phospholipase D signaling pathway speculated to be involve in pathogenesis of this disease.

genomics↗