Papers by Saravana Murthy
Research Square (Research Square), Jan 11, 2021
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Journal of Neurochemistry, Sep 1, 2008
Throughout the CNS, small conductance Ca(2+)-activated potassium (SK) channels modulate firing fr... more Throughout the CNS, small conductance Ca(2+)-activated potassium (SK) channels modulate firing frequency and neuronal excitability. We have identified a novel, shorter isoform of standard SK2 (SK2-std) in mouse brain which we named SK2-sh. SK2-sh is alternatively spliced at exon 3 and therefore lacks 140 amino acids, which include transmembrane domains S3, S4 and S5, compared with SK2-std. Western blot analysis of mouse hippocampal tissue revealed a 47 kDa protein product as predicted for SK2-sh along with a 64 kDa band representing the standard SK2 isoform. Electrophysiological recordings from transiently expressed SK2-sh revealed no functional channel activity or interaction with SK2-std. With the help of real-time PCR, we found significantly higher expression levels of SK2-sh mRNA in cortical tissue from AD cases when compared with age-matched controls. A similar increase in SK2-sh expression was induced in cortical neurons from mice by cytokine exposure. Substantial clinical evidence suggests that excess cytokines are centrally involved in the pathogenesis of Alzheimer's disease. Thus, SK2-sh as a downstream target of cytokines, provide a promising target for additional investigation regarding potential therapeutic intervention.
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Translational Psychiatry, Dec 6, 2016
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Journal of Clinical Oncology, Jun 1, 2023
e14596 Background: Local recurrence contributes to the poor prognosis for patients with Stage IV ... more e14596 Background: Local recurrence contributes to the poor prognosis for patients with Stage IV metastatic or recurrent solid tumors, despite advances in standard care. We report the clinical outcome of intra-operative Cold Atmospheric Plasma (CAP) combined with standard surgical procedures. Methods: The trial was a Phase I, multi-center, open-label, prospective, controlled study. Eligible patients undergoing surgery for advanced Stage IV metastatic or recurrent solid tumors were enrolled and preoperative treatments (neoadjuvant chemotherapy, immunotherapy, radiation, and primary surgery) were permitted. Participants were recruited from Rush University Medical Center in Chicago, Illinois and Sheba Medical Center in Tel HaShomer, Israel. Twenty patients (age 26-85 years) between March 2020 to April 2021 received intra-operative CAP treatment following surgical macroscopic tumor removal. The primary endpoint was safety, and the secondary endpoint was ablation of the local microscopic tumor bed without damaging the surrounding normal tissue. Results: Physiological data (blood pressure, pulse, body temperature, End Tidal CO2, and oxygen saturation) was recorded continuously throughout surgery. There were no significant changes (p > 0.05) during intra-operative CAP treatment. One adverse event grade 3 or higher was reported but no adverse events were related to CAP. As of February 13, 2023, 10 patients died of their disease between 3-32 months. Kaplan-Meier overall survival curves show the interim 31-month rate is 24% (95% confidence interval [CI], 5.0 – 100.0%). Median survival is 23 months. For R0 patients, the Kaplan Meier local non-recurrence probability showed that the interim 28-month rate is 75% (n=8; 95% CI, 50.3 – 100.0%) as of February 13, 2023. Histological staining, TUNEL assay, and confocal imaging of the surgical margins revealed cancer cell death and no damage to the surrounding normal tissue. Primary culture of the tumor confirmed total cessation of cancer cell survival. Conclusions: CAP treatment in combination with surgery for high-risk stage IV solid tumors is safe and induces cancer cell death at the surgical bed without damaging non-cancerous tissue. The survival rate in R0-resected CAP-treated patients was significantly improved compared to R1 and R2 patients and local non-recurrence rate for R0 patients was noteworthy. Clinical trial information: NCT04267575 . [Table: see text]
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Cancers
Local regional recurrence (LRR) remains the primary cause of treatment failure in solid tumors de... more Local regional recurrence (LRR) remains the primary cause of treatment failure in solid tumors despite advancements in cancer therapies. Canady Helios Cold Plasma (CHCP) is a novel Cold Atmospheric Plasma device that generates an Electromagnetic Field and Reactive Oxygen and Nitrogen Species to induce cancer cell death. In the first FDA-approved Phase I trial (March 2020–April 2021), 20 patients with stage IV or recurrent solid tumors underwent surgical resection combined with intra-operative CHCP treatment. Safety was the primary endpoint; secondary endpoints were non-LRR, survival, cancer cell death, and the preservation of surrounding healthy tissue. CHCP did not impact intraoperative physiological data (p > 0.05) or cause any related adverse events. Overall response rates at 26 months for R0 and R0 with microscopic positive margin (R0-MPM) patients were 69% (95% CI, 19–40%) and 100% (95% CI, 100–100.0%), respectively. Survival rates for R0 (n = 7), R0-MPM (n = 5), R1 (n = 6),...
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Applied Sciences
Cold atmospheric plasma (CAP) has become a promising tool for modern medicine. With its recent ap... more Cold atmospheric plasma (CAP) has become a promising tool for modern medicine. With its recent applications in oncology, regenerative medicine, and immunotherapy, CAP can be used for a myriad of different clinical treatments. When using CAP specifically for the treatment of tumors, it is known to elicit an oxidative response within malignant cancer cells, inducing cell cycle arrest and apoptosis. In this study, data of intracellular reactive oxygen species (ROS), caspase activity, Ki-67 expression, and cell cycle activity in the G1 phase were acquired to determine the causal relationships these intermediates have with cell proliferation and death after Canady Helios Cold Plasma (CHCP) treatment. The data were derived from four different subtypes of breast cancer cell lines: BT-474, MCF-7, MDA-MB-231, and SK-BR-3. Data transformation techniques were conducted on the time-series data for the input into the causal model code. The models were created on the basis of Granger causality pr...
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Journal of Clinical Oncology
e14596 Background: Local recurrence contributes to the poor prognosis for patients with Stage IV ... more e14596 Background: Local recurrence contributes to the poor prognosis for patients with Stage IV metastatic or recurrent solid tumors, despite advances in standard care. We report the clinical outcome of intra-operative Cold Atmospheric Plasma (CAP) combined with standard surgical procedures. Methods: The trial was a Phase I, multi-center, open-label, prospective, controlled study. Eligible patients undergoing surgery for advanced Stage IV metastatic or recurrent solid tumors were enrolled and preoperative treatments (neoadjuvant chemotherapy, immunotherapy, radiation, and primary surgery) were permitted. Participants were recruited from Rush University Medical Center in Chicago, Illinois and Sheba Medical Center in Tel HaShomer, Israel. Twenty patients (age 26-85 years) between March 2020 to April 2021 received intra-operative CAP treatment following surgical macroscopic tumor removal. The primary endpoint was safety, and the secondary endpoint was ablation of the local microscopic...
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Scientific Reports
Breast cancer is the leading cause of cancer death among women. Triple-negative breast cancer (TN... more Breast cancer is the leading cause of cancer death among women. Triple-negative breast cancer (TNBC) has a poor prognosis and frequently relapses early compared with other subtypes. The Cold Atmospheric Plasma (CAP) is a promising therapy for prognostically poor breast cancer such as TNBC. The Canady Helios Cold Plasma (CHCP) induces cell death in the TNBC cell line without thermal damage, however, the mechanism of cell death by CAP treatment is ambiguous and the mechanism of resistance to cell death in some subset of cells has not been addressed. We investigate the expression profile of 48 apoptotic and 35 oxidative gene markers after CHCP treatment in six different types of breast cancer cell lines including luminal A (ER+ PR+/−HER2−), luminal B (ER+PR+/−HER2+), (ER−PR−HER2+), basal-like: ER−PR−HER2− cells were tested with CHCP at different power settings and at 4 different incubation time. The expression levels of the gene markers were determined at 4 different intervals after th...
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Clinical Plasma Medicine, 2020
Abstract Breast cancer is a heterogenous disease which can be classified into subtypes by the pre... more Abstract Breast cancer is a heterogenous disease which can be classified into subtypes by the presence or absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 receptor (HER2). Cold atmospheric plasma (CAP) has been shown to be a potential treatment for cancer. In this report, a 92–99% reduction of viability by CAP treatment was achieved across all seven tested breast cancer cell lines (p ≤ 0.05). Increasing treatment duration and power significantly reduced breast cancer cell viability (** f(2,2) ≤ 0.0176, *** f(5,14) ≤ 0.0033). The authors are the first to report that breast cancer sensitivity to CAP is based on receptor status. Cells with identical receptor status showed the least difference in CAP sensitivity (p ≤ 0.05), the difference being 33% between the two ER+/PR+/HER2- cell lines (p ≤ 0.05) and 22–44% between the three TNBC cell lines (p ≤ 0.05). HER2-negative cell lines, irrespective of ER/PR status, also showed ≤ 50% difference in CAP sensitivity (p ≤ 0.05). Moreover, demonstration of ER-/PR-/HER2+ CAP susceptibility and ER+/PR+/HER2+ CAP resistance suggests that ER/PR status is a significant factor in determining CAP sensitivity in HER2-positive cells. Our novel findings on CAP sensitivity will provide insight on how to optimize CAP treatment to better overcome CAP resistance and thus prevent tumor recurrence.
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Journal of Clinical Oncology, 2019
e22562 Background: Soft tissue sarcoma is a malignant tumor that most often develops in adults, b... more e22562 Background: Soft tissue sarcoma is a malignant tumor that most often develops in adults, but can occur in children as well. Treatment with radiation, en bloc surgical resection and chemotherapy have achieved long-term survival rates up to 65% to 80% in non-metastatic disease. Local microscopic tumor cells can still exist despite complete R-0 surgical excision of the tumor. A novel technology Cold Atmospheric plasma (CAP) is an emerging technology that has shown promising anticancer effects i.e anti-mitotic and less effective on non-cancerous tissue. A new field has developed in medicine Plasma Onco-therapeutics. CAP treatment has the potential to improve the outcome of osteosarcoma patients. Methods: CAP was generated using a US Medical Innovations LLC (USMI) SS-601 MCa high-frequency electrosurgical generator (USMI, Takoma Park, MD, USA) integrated with Canady Cold Plasma Conversion Unit and connected to a Canady Helios Cold Plasma Scalpel. Three types of human sarcoma cells...
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PloS one, 2017
Report of a human with a homozygous truncating null mutation of the Carboxypeptidase E (CPE) gene... more Report of a human with a homozygous truncating null mutation of the Carboxypeptidase E (CPE) gene with endocrinological and neurological deficits prompted us to search for other mutations in the human CPE gene that might be linked to disease. We searched an EST database and identified from a small population of patients, a novel T to C single nucleotide polymorphism (SNP) in the CPE gene at bp980 of exon 4, herein called TC-CPE. This introduces a tryptophan to arginine (W235R) mutation in the catalytic domain of human CPE protein. Over-expression of TC-CPE in N2A cells, a neuroendocrine cell line, showed that it was synthesized, but was found in lesser amounts compared to over-expressed WT-CPE in these cells. Furthermore, TC-CPE was secreted poorly from these N2A cells. The levels of TC-CPE were significantly increased after the N2A cells were treated with MG132 (a proteasome inhibitor), suggesting that TC-CPE was targeted to proteasomes for degradation in N2A cells. In addition, TC...
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Stem cells (Dayton, Ohio), Mar 6, 2016
Embryonic neurodevelopment involves inhibition of proliferation of multipotent neural stem cells ... more Embryonic neurodevelopment involves inhibition of proliferation of multipotent neural stem cells (NSCs) followed by differentiation into neurons, astrocytes and oligodendrocytes to form the brain. We have identified a new neurotrophic factor, NF-α1, which inhibits proliferation and promotes differentiation of NSC/progenitors derived from E13.5 mouse cortex. Inhibition of proliferation of these cells was mediated through negatively regulating the Wnt pathway and decreasing β-catenin. NF-α1 induced differentiation of NSCs to astrocytes by enhancing Glial Fibrillary Acidic Protein (GFAP) expression through activating the ERK1/2-Sox9 signaling pathway. Cultured E13.5 cortical stem cells from NF-α1-knockout mice showed decreased astrocyte numbers compared to wild-type mice, which was rescued by treatment with NF-α1. In vivo, immunocytochemistry of brain sections and Western blot analysis of neocortex of mice showed a gradual increase of NF-α1 expression from E14.5 to P1 and a surge of GF...
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J Neurochem, 2008
Throughout the CNS, small conductance Ca2+-activated potassium (SK) channels modulate firing freq... more Throughout the CNS, small conductance Ca2+-activated potassium (SK) channels modulate firing frequency and neuronal excitability. We have identified a novel, shorter isoform of standard SK2 (SK2-std) in mouse brain which we named SK2-sh. SK2-sh is alternatively spliced at exon 3 and therefore lacks 140 amino acids, which include transmembrane domains S3, S4 and S5, compared with SK2-std. Western blot analysis of mouse hippocampal tissue revealed a 47 kDa protein product as predicted for SK2-sh along with a 64 kDa band representing the standard SK2 isoform. Electrophysiological recordings from transiently expressed SK2-sh revealed no functional channel activity or interaction with SK2-std. With the help of real-time PCR, we found significantly higher expression levels of SK2-sh mRNA in cortical tissue from AD cases when compared with age-matched controls. A similar increase in SK2-sh expression was induced in cortical neurons from mice by cytokine exposure. Substantial clinical evidence suggests that excess cytokines are centrally involved in the pathogenesis of Alzheimer’s disease. Thus, SK2-sh as a downstream target of cytokines, provide a promising target for additional investigation regarding potential therapeutic intervention.
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Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, Jan 23, 2016
Tumor recurrence and metastasis are the major causes of death for hepatocellular carcinoma (HCC) ... more Tumor recurrence and metastasis are the major causes of death for hepatocellular carcinoma (HCC) patients who are able to receive curative resection. Identifying the predicting biomarkers for tumor recurrence would improve their survival. RNA extracted from fresh frozen tumors and adjacent non-tumor liver tissues of 120 HCC patients were obtained from Taiwan Liver Cancer Network (TLCN) in year 2010 for determination of the carboxypeptidase E (CPE) expression level (including its splicing mutant CPE-ΔN) in the tumor tissue (T) and paired non-tumor liver tissue (N) by real-time quantitative polymerase chain reaction. All patients were male, had chronic hepatitis B virus infection, were in the early pathology stage, and received curative resection. The T/N ratio of the CPE expression level was correlated with the updated survival data from TLCN in 2015. The CPE expression level in the 120 HCC patients was divided into three groups according to the T/N ratio: <1, ≥1 and ≤2, and >2...
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Cancer Research, 2013
Cancer mortality is often from metastatic disease rather than the direct effect of the primary tu... more Cancer mortality is often from metastatic disease rather than the direct effect of the primary tumor. Identification of metastasis inducing genes may offer valuable mechanistic insight for guiding specific therapeutic strategies. We report here that the carboxypeptidase E gene (CPE) is alternatively spliced in human tumors to yield an N-terminal truncated protein (CPE-DELTA-N) that drives metastasis. CPE-DELTA-N mRNA was elevated in human metastatic colon, breast and HCC cell lines. Suppression of CPE-DELTA-N expression in these cell lines by si-RNA significantly inhibited their growth migration and invasion. To confirm these observations in vivo, an orthotopic nude mouse model was established. The mice implanted with a tumor derived from HCC cells transfected with si- CPE-DELTA-N RNA in the liver did not show tumor growth or metastasis, compared to scrambled controls. In HCC cytosolic CPE-DELTA-N protein was translocated to the nucleus and upregulated the expression of neural precu...
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Cancer Research, 2014
Cancer mortality is often from metastatic disease rather than the direct effect of the primary tu... more Cancer mortality is often from metastatic disease rather than the direct effect of the primary tumor. Identification of metastasis inducing genes may offer valuable mechanistic insight for guiding specific therapeutic strategies. We report here that the carboxypeptidase E gene (CPE) is alternatively spliced in human tumors to yield an N-terminal truncated protein (CPE-DELTA-N) that drives metastasis. CPE-DELTA-N mRNA was elevated in human metastatic colon, breast and HCC cell lines. Suppression of CPE-DELTA-N expression in these cell lines by si-RNA significantly inhibited their growth migration and invasion. To confirm these observations in vivo, an orthotopic nude mouse model was established. The mice implanted with a tumor derived from HCC cells transfected with si- CPE-DELTA-N RNA in the liver did not show tumor growth or metastasis, compared to scrambled controls. In HCC cytosolic CPE-DELTA-N protein was translocated to the nucleus and upregulated the expression of neural precu...
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PLOS ONE, 2015
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Molecular psychiatry, Jan 21, 2014
Major depressive disorder is often linked to stress. Although short-term stress is without effect... more Major depressive disorder is often linked to stress. Although short-term stress is without effect in mice, prolonged stress leads to depressive-like behavior, indicating that an allostatic mechanism exists in this difference. Here we demonstrate that mice after short-term (1 h per day for 7 days) chronic restraint stress (CRS), do not display depressive-like behavior. Analysis of the hippocampus of these mice showed increased levels of neurotrophic factor-α1 (NF-α1; also known as carboxypeptidase E, CPE), concomitant with enhanced fibroblast growth factor 2 (FGF2) expression, and an increase in neurogenesis in the dentate gyrus. In contrast, after prolonged (6 h per day for 21 days) CRS, mice show decreased hippocampal NF-α1 and FGF2 levels and depressive-like responses. In NF-α1-knockout mice, hippocampal FGF2 levels and neurogenesis are reduced. These mice exhibit depressive-like behavior that is reversed by FGF2 administration. Indeed, studies in cultured hippocampal neurons reve...
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Papers by Saravana Murthy