Kunwar Shailubhai - Academia.edu (original) (raw)

Papers by Kunwar Shailubhai

Research paper thumbnail of Milciclib and sorafenib synergistically downregulate c-Myc to suppress tumor growth in an orthotopic murine model of human hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and a leading c... more Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and a leading cause of cancer-related deaths worldwide [1,2]. Chronic liver inflammation resulting from prolonged viral hepatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis and other metabolic disorders such as excessive alcohol consumption and exposure to aflatoxins represent major etiological factors for HCC [1-3]. These multitude of underlying mechanisms that affect disease course and patient prognosis underscores the importance of a broad-spectrum approach to target multiple mechanisms underlying HCC development and promotion [4]. Current therapies for HCC include specific tyrosine kinase inhibitors (TKIs) such as sorafenib (Nexavar®), regorafenib (Stivarga®), lenvatinib (Lenvima®) and cabozantinib (Cabometyx®) [5-9]. In addition, immunotherapies with nivolumab (Opdivo®) and pembrolizumab (Keytruda®) both inhibiting programmed cell death receptor PD-1, have also been approved a...

Research paper thumbnail of Plecanatide-mediated activation of guanylate cyclase-C suppresses inflammation-induced colorectal carcinogenesis in Apc+/Min-FCCCmice

World Journal of Gastrointestinal Pharmacology and Therapeutics, 2017

AIM To evaluate the effect of orally administered plecanatide on colorectal dysplasia in Apc +/Mi... more AIM To evaluate the effect of orally administered plecanatide on colorectal dysplasia in Apc +/Min-FCCC mice with dextran sodium sulfate (DSS)-induced inflammation. METHODS Inflammation driven colorectal carcinogenesis was induced in Apc +/Min-FCCC mice by administering DSS in their drinking water. Mice were fed a diet supplemented with plecanatide (0-20 ppm) and its effect on the multiplicity of histopathologically confirmed polypoid,

Research paper thumbnail of Abstract 1636: Enhancement of cyclic GMP production by guanylate cyclase-C agonists delays progression of colitis into colon cancer though downregulation of pro-inflammatory cytokines

Cancer Research, 2012

Colon cancer is one of the most prevalent malignancies in the world; with an estimated 875,000 ca... more Colon cancer is one of the most prevalent malignancies in the world; with an estimated 875,000 cases diagnosed worldwide; accounting for 8.5% of all new cancers. Patients with ulcerative colitis and Crohn's disease are at increased risk of developing colorectal cancer. It is believed that the persistent gastrointestinal (GI) inflammation may contribute to colorectal carcinogenesis. The cGMP signaling mediates anti-inflammatory effects of cellular molecules such as nitric oxide and hemeoxygenase-1. Therefore, therapies that induce cyclic GMP and cyclic AMP levels by inhibiting their degradation (phosphodiesterase inhibitors) exhibit good efficacy in murine models of ulcerative colitis. Activation of guanylate cyclase C (GC-C) by uroguanylin (UG), a peptide hormone produced in the GI tract lumen, results in enhanced production of cyclic GMP. Earlier we reported that UG expression is suppressed in human colon tumors and that the oral treatment with UG inhibited polyps formation in ...

Research paper thumbnail of Corrigendum: Nasal Administration of Anti-CD3 Monoclonal Antibody (Foralumab) Reduces Lung Inflammation and Blood Inflammatory Biomarkers in Mild to Moderate COVID-19 Patients: A Pilot Study

Frontiers in Immunology, Jan 12, 2022

Research paper thumbnail of Nasal Administration of Anti-CD3 Monoclonal Antibody (Foralumab) Reduces Lung Inflammation and Blood Inflammatory Biomarkers in Mild to Moderate COVID-19 Patients: A Pilot Study

Frontiers in Immunology, 2021

BackgroundImmune hyperactivity is an important contributing factor to the morbidity and mortality... more BackgroundImmune hyperactivity is an important contributing factor to the morbidity and mortality of COVID-19 infection. Nasal administration of anti-CD3 monoclonal antibody downregulates hyperactive immune responses in animal models of autoimmunity through its immunomodulatory properties. We performed a randomized pilot study of fully-human nasal anti-CD3 (Foralumab) in patients with mild to moderate COVID-19 to determine if its immunomodulatory properties had ameliorating effects on disease.MethodsThirty-nine outpatients with mild to moderate COVID-19 were recruited at Santa Casa de Misericordia de Santos in Sao Paulo State, Brazil. Patients were randomized to three cohorts: 1) Control, no Foralumab (n=16); 2) Nasal Foralumab (100ug/day) given for 10 consecutive days with 6 mg dexamethasone given on days 1-3 (n=11); and 3) Nasal Foralumab alone (100ug/day) given for 10 consecutive days (n=12). Patients continued standard of care medication.ResultsWe observed reduction of serum IL-...

Research paper thumbnail of Safety and clinical activity of combination treatment with regorafenib and milciclib in liver transplant patients with hepatocellular carcinoma recurrence

Journal of Clinical Oncology, 2020

e16634 Background: Recurrence of hepatocellular carcinoma after liver transplant (LT-HCC), affect... more e16634 Background: Recurrence of hepatocellular carcinoma after liver transplant (LT-HCC), affects ~40% of patients. As LT-HCC drastically limits therapeutic options, combination of drugs with different mechanism of actions might be an attractive approach. Primary objective of this MiHRCO (Milciclib and Half Regorafenib CO-administration) protocol (87/2019/COMP/MiHRCO) is to evaluate safety and clinical activity of combination of Regorafenib (a tyrosine kinase inhibitor with higher clinical activity in aggressive HCC) with Milciclib (a pan cyclin dependent kinase inhibitor with clinical activities in refractory solid malignancy patients and HCC) in LT-HCC patients. Methods: Seven patients with LT-HCC are enrolled to date. Regorafenib administered at half the prescribed dose (80mg/day) for 3 weeks followed by 1 week Off and milciclib at 100 mg daily for 4 day On/3 day Off. Patients were maintained on this combination regimen until disease progression and/or unacceptable side effects....

Research paper thumbnail of Phase IIa safety and efficacy of milciclib, a pan-cyclin dependent kinase inhibitor, in unresectable, sorafenib-refractory or -intolerant hepatocellular carcinoma patients

Journal of Clinical Oncology, 2020

e16711 Background: Current hepatocellular carcinoma (HCC) therapeutics, tyrosine kinase inhibitor... more e16711 Background: Current hepatocellular carcinoma (HCC) therapeutics, tyrosine kinase inhibitors (TKI) and checkpoint inhibitors (CI), provide limited improvement in overall survival, suggesting the need to identify drugs with broad-spectrum mechanisms of action, used alone or in combination with a TKI or CI. Milciclib, a pan cyclin dependent kinase inhibitor, exhibited anti-cancer activity in refractory solid malignancy patients. The primary objective of this trial was to evaluate safety and tolerability of milciclib in sorafenib-refractory or intolerant advanced HCC patients. Methods: Single arm and multi-center study in advanced HCC patients was conducted in Italy, Greece and Israel. Milciclib was administered orally for up to 6 cycles. Each cycle consisted of 100mg milciclib daily for 4d on/3d off/week for 4 weeks. Safety assessment was the primary endpoint and secondary endpoints included progression free survival (PFS), time to progression (TTP) and clinical benefit rate (CB...

Research paper thumbnail of Guanylate Cyclase C Agonists, a New Class of Drug Candidates for Treatment of Inflammatory Bowel Disease

American Journal of Gastroenterology, 2011

Research paper thumbnail of Plecanatide and SP-333, Novel Agonists of Guanylate Cyclase-C, Attenuate Visceral Hypersensitivity in Rat Models

American Journal of Gastroenterology, 2014

Research paper thumbnail of SP-333, a Guanylate Cyclase-C Agonist, Inhibits NF-κB Signaling and Modulates Related Genes and miRNAs Implicated in GI Inflammation and Carcinogenesis

American Journal of Gastroenterology, 2013

Research paper thumbnail of Oral Treatment with SP-333, an Agonist of Guanylate Cyclase-C, Dramatically Ameliorates Morphine-induced Bowel Dysfunction in Rats: Presidential Poster

American Journal of Gastroenterology, 2013

Research paper thumbnail of Hepatocellular Carcinoma: Etiology and Current and Future Drugs

Journal of Clinical and Experimental Hepatology, 2019

Hepatocellular carcinoma (HCC) is swiftly increasing in prevalence globally with a high mortality... more Hepatocellular carcinoma (HCC) is swiftly increasing in prevalence globally with a high mortality rate. The progression of HCC in patients is induced with advanced fibrosis, mainly cirrhosis, and hepatitis. The absence of proper preventive or curative treatment methods encouraged extensive research against HCC to develop new therapeutic strategies. The Food and Drug Administration-approved Nexavar (sorafenib) is used in the treatment of patients with unresectable HCC. In 2017, Stivarga (regorafenib) and Opdivo (nivolumab) got approved for patients with HCC after being treated with sorafenib, and in 2018, Lenvima (lenvatinib) got approved for patients with unresectable HCC. But, owing to the rapid drug resistance development and toxicities, these treatment options are not completely satisfactory. Therefore, there is an urgent need for new systemic combination therapies that target different signaling mechanisms, thereby decreasing the prospect of cancer cells developing resistance to treatment. In this review, HCC etiology and new therapeutic strategies that include currently approved drugs and other potential candidates of HCC such as Milciclib, palbociclib, galunisertib, ipafricept, and ramucirumab are evaluated.

Research paper thumbnail of {"__content__"=>"Oral treatment with plecanatide or dolcanatide attenuates visceral hypersensitivity activation of guanylate cyclase-C in rat models.", "i"=>{"__content__"=>"via"}}

World journal of gastroenterology, Jan 7, 2018

To investigate the effects of plecanatide and dolcanatide on maintenance of paracellular permeabi... more To investigate the effects of plecanatide and dolcanatide on maintenance of paracellular permeability, integrity of tight junctions and on suppression of visceral hypersensitivity. Transport of fluorescein isothiocyanate (FITC)-dextran was measured to assess permeability across cell monolayers and rat colon tissues. Effects of plecanatide and dolcanatide on the integrity of tight junctions in Caco-2 and T84 monolayers and on the expression and localization of occludin and zonula occludens-1 (ZO-1) were examined by immunofluorescence microscopy. Anti-nociceptive activity of these agonists was evaluated in trinitrobenzene sulfonic acid (TNBS)-induced inflammatory as well as in non-inflammatory partial restraint stress (PRS) rat models. Statistical significance between the treatment groups in the permeability studies were evaluated using unpaired -tests. Treatment of T84 and Caco-2 monolayers with lipopolysaccharide (LPS) rapidly increased permeability, which was effectively suppressed...

Research paper thumbnail of Oral treatment with foralumab, a fully human anti-CD3 monoclonal antibody, prevents skin xenograft rejection in humanized mice

Clinical immunology (Orlando, Fla.), Jan 21, 2017

Oral administration of biologics may be a feasible approach for immune therapy that improves drug... more Oral administration of biologics may be a feasible approach for immune therapy that improves drug safety and potentiates mechanisms of tolerance at mucosal barriers. We tested the ability of a fully human non-FcR binding anti-CD3 mAb, foralumab, to prevent skin xenograft rejection in mice with human immune systems. At an intragastric dose of 15μg, the drug could transit through the small bowel. Serum absorption and binding of lymphoid cells was seen and proliferative responses of splenic CD8+ T cells to mitogen were reduced. Five consecutive daily doses, then weekly dosing led to indefinite graft acceptance without depletion of peripheral T cells. Proliferative and cytokine responses to activation of splenocytes with PHA were reduced. The serum levels of IL-10 but not TNF were increased 6days after application of the skin graft. Oral treatment with anti-CD3 mAb may represent a feasible approach for immune modulation.

Research paper thumbnail of 967 Plecanatide, Like Uroguanylin, Activates Guanylate Cyclase-C Signaling in a pH-Dependent Manner in T84 Cells, and in Murine Intestinal Epithelial Cells and Tissues

Gastroenterology, 2016

Chronic constipation (CC) is a common multi-symptom disorder of heterogeneous pathogenesis. Opioi... more Chronic constipation (CC) is a common multi-symptom disorder of heterogeneous pathogenesis. Opioid analgesics are known to be an important cause of constipation symptoms. Recently, multiple drugs have gained regulatory approval for the treatment of opiate-induced constipation. Despite this, little is known about the clinical characteristics of constipated patients who are taking opioids. We utilized a novel electronic platform to conduct a national US survey to better understand the clinical profiles of constipated patients taking and not taking opioids. Methods: A national US survey was conducted using a digital adaptation of the NIH PROMIS® questionnaires called My GI Health. US adults (‡18 years) were invited to complete the survey utilizing an incentivized, opt in list provided by a contract research company (Cint®). Participants provided demographic information, severity & frequency data for the 8 most common GI symptoms (abdominal pain, heartburn, dysphagia, nausea, bloating, constipation, diarrhea, bowel incontinence), & use of OTC/prescription medications. Standard statistical methods were used to compare characteristics of respondants reporting constipation who were taking opioids (opiate associated constipation=OAC) or not taking opioids (non-opioid constipation=NOC). Regression models adjusted for age, sex, race/ethnicity, education, marital status, employment status, and household income. NOC subjects served as the reference group. Results: 71,813 adults completed the survey. 13,343 subjects reported constipation symptoms within 7 days of completing the survey. Of those with constipation, 1671 were actively using opiates (12.5%) while 11,672 (87.5%) were not. Demographic information showed OAC subjects were older, more likely to be male, less likely to have a graduate degree and more likely to be unemployed than NOC subjects (p<0.001 for these items). Subjects with OAC had a greater burden of constipation symptoms than NOC (table 1). Further, subjects with OAC had a greater burden of all GI symptoms assessed. OAC patients were more likely to endorse all the other GI symptoms assessed except for diarrhea (table 2). Based upon PROMIS composite scores for all 7 remaining lower and upper GI symptoms (table 1), OAC patients had more frequent & severe GI symptoms than NOC subjects (all comparisons on linear regression model p<0.001). These results were confirmed in a smaller group of respondants who reported constipation for more than 4 weeks. Conclusions: This is the largest survey to characterize the clinical phenotypes of OAC and NOC. OAC patients had a greater burden of GI complaints attributable to the lower and upper GI tract. This may be the consequence of opioid effects throughout the GI tract and CNS and might have implications regarding treatment choice in OAC vs. NOC patients. Table 1: GI PROMIS symptom scores in NOC vs. OAC a GI PROMIS score for individual symptoms is on a 0-100 percentile scale. b Global GI PROMIS score is on a 0-800 scale.

Research paper thumbnail of Formulations of guanylate cyclase c agonists and methods of use

Research paper thumbnail of Uroguanylin treatment suppresses polyp formation in the Apc(Min/+) mouse and induces apoptosis in human colon adenocarcinoma cells via cyclic GMP

Cancer research, Jan 15, 2000

The enteric peptides, guanylin and uroguanylin, are local regulators of intestinal secretion by a... more The enteric peptides, guanylin and uroguanylin, are local regulators of intestinal secretion by activation of receptor-guanylate cyclase (R-GC) signaling molecules that produce cyclic GMP (cGMP) and stimulate the cystic fibrosis transmembrane conductance regulator-dependent secretion of Cl- and HCO3-. Our experiments demonstrate that mRNA transcripts for guanylin and uroguanylin are markedly reduced in colon polyps and adenocarcinomas. In contrast, a specific uroguanylin-R-GC, R-GCC, is expressed in polyps and adenocarcinomas at levels comparable with normal colon mucosa. Activation of R-GCC by uroguanylin in vitro inhibits the proliferation of T84 colon cells and elicits profound apoptosis in human colon cancer cells, T84. Therefore, down-regulation of gene expression and loss of the peptides may interfere with renewal and/or removal of the epithelial cells resulting in the formation of polyps, which can progress to malignant cancers of the colon and rectum. Oral replacement therap...

Research paper thumbnail of Sa1393 Oral Treatment With SP-333, an Analog of Uroguanylin, Effectively Relieves Morphine and Methadone-Induced Constipation in Rats Through a Novel Mechanism Involving Activation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

Research paper thumbnail of Isolation and characterization from porcine serum of a soluble sulfotransferase responsible for 6-O-sulfation of the galactose residue in 2′-fucosyllactose: Implications in the synthesis of the ligand for L-selectin

Glycoconjugate Journal, 1999

A soluble sulfotransferase from porcine serum which catalyzes the transfer of sulfate from adenos... more A soluble sulfotransferase from porcine serum which catalyzes the transfer of sulfate from adenosine 3'-phosphate 5'-phosphosulphate (PAPS) to 2'-fucosyllactose (2'-FL) was purified 36,333-fold using a combination of conventional and affinity chromatographic steps. The purified enzyme preparation after non-denaturing discontinuous-PAGE exhibited a molecular mass of about 80 kDa by reducing SDS-PAGE. However, when a partially purified enzyme preparation was subjected to

Research paper thumbnail of Atiprimod is an inhibitor of cancer cell proliferation and angiogenesis

Journal of experimental therapeutics & oncology, 2004

Atiprimod, a novel compound belonging to the azaspirane class of cationic amphiphilic drugs, exhi... more Atiprimod, a novel compound belonging to the azaspirane class of cationic amphiphilic drugs, exhibits both anti-proliferative and anti-angiogenic activities. Atiprimod inhibited proliferation of all human cancer cell lines included in the National Cancer Institute panel with IC50 values in the low micromolar range. Notably, metastatic cell lines were more sensitive to the compound compared to the non-metastatic cell lines derived from the same tumor tissue types. Atiprimod also induced apoptosis and activated both caspase-9 and caspase-3 in T84 colon carcinoma cells. Hence, the anti-proliferative activity could partly be due to its pro-apoptotic activity. Regarding angiogenesis in vitro, atiprimod inhibited both bFGF and VEGF induced proliferation and migration of human umbilical vein endothelial cells (HUVECs), resulting in disruption of cord formation. In addition, atiprimod also suppressed formation of new blood vessels in a chorioallantoic membrane assay. Previous studies have a...

Research paper thumbnail of Milciclib and sorafenib synergistically downregulate c-Myc to suppress tumor growth in an orthotopic murine model of human hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and a leading c... more Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and a leading cause of cancer-related deaths worldwide [1,2]. Chronic liver inflammation resulting from prolonged viral hepatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis and other metabolic disorders such as excessive alcohol consumption and exposure to aflatoxins represent major etiological factors for HCC [1-3]. These multitude of underlying mechanisms that affect disease course and patient prognosis underscores the importance of a broad-spectrum approach to target multiple mechanisms underlying HCC development and promotion [4]. Current therapies for HCC include specific tyrosine kinase inhibitors (TKIs) such as sorafenib (Nexavar®), regorafenib (Stivarga®), lenvatinib (Lenvima®) and cabozantinib (Cabometyx®) [5-9]. In addition, immunotherapies with nivolumab (Opdivo®) and pembrolizumab (Keytruda®) both inhibiting programmed cell death receptor PD-1, have also been approved a...

Research paper thumbnail of Plecanatide-mediated activation of guanylate cyclase-C suppresses inflammation-induced colorectal carcinogenesis in Apc+/Min-FCCCmice

World Journal of Gastrointestinal Pharmacology and Therapeutics, 2017

AIM To evaluate the effect of orally administered plecanatide on colorectal dysplasia in Apc +/Mi... more AIM To evaluate the effect of orally administered plecanatide on colorectal dysplasia in Apc +/Min-FCCC mice with dextran sodium sulfate (DSS)-induced inflammation. METHODS Inflammation driven colorectal carcinogenesis was induced in Apc +/Min-FCCC mice by administering DSS in their drinking water. Mice were fed a diet supplemented with plecanatide (0-20 ppm) and its effect on the multiplicity of histopathologically confirmed polypoid,

Research paper thumbnail of Abstract 1636: Enhancement of cyclic GMP production by guanylate cyclase-C agonists delays progression of colitis into colon cancer though downregulation of pro-inflammatory cytokines

Cancer Research, 2012

Colon cancer is one of the most prevalent malignancies in the world; with an estimated 875,000 ca... more Colon cancer is one of the most prevalent malignancies in the world; with an estimated 875,000 cases diagnosed worldwide; accounting for 8.5% of all new cancers. Patients with ulcerative colitis and Crohn's disease are at increased risk of developing colorectal cancer. It is believed that the persistent gastrointestinal (GI) inflammation may contribute to colorectal carcinogenesis. The cGMP signaling mediates anti-inflammatory effects of cellular molecules such as nitric oxide and hemeoxygenase-1. Therefore, therapies that induce cyclic GMP and cyclic AMP levels by inhibiting their degradation (phosphodiesterase inhibitors) exhibit good efficacy in murine models of ulcerative colitis. Activation of guanylate cyclase C (GC-C) by uroguanylin (UG), a peptide hormone produced in the GI tract lumen, results in enhanced production of cyclic GMP. Earlier we reported that UG expression is suppressed in human colon tumors and that the oral treatment with UG inhibited polyps formation in ...

Research paper thumbnail of Corrigendum: Nasal Administration of Anti-CD3 Monoclonal Antibody (Foralumab) Reduces Lung Inflammation and Blood Inflammatory Biomarkers in Mild to Moderate COVID-19 Patients: A Pilot Study

Frontiers in Immunology, Jan 12, 2022

Research paper thumbnail of Nasal Administration of Anti-CD3 Monoclonal Antibody (Foralumab) Reduces Lung Inflammation and Blood Inflammatory Biomarkers in Mild to Moderate COVID-19 Patients: A Pilot Study

Frontiers in Immunology, 2021

BackgroundImmune hyperactivity is an important contributing factor to the morbidity and mortality... more BackgroundImmune hyperactivity is an important contributing factor to the morbidity and mortality of COVID-19 infection. Nasal administration of anti-CD3 monoclonal antibody downregulates hyperactive immune responses in animal models of autoimmunity through its immunomodulatory properties. We performed a randomized pilot study of fully-human nasal anti-CD3 (Foralumab) in patients with mild to moderate COVID-19 to determine if its immunomodulatory properties had ameliorating effects on disease.MethodsThirty-nine outpatients with mild to moderate COVID-19 were recruited at Santa Casa de Misericordia de Santos in Sao Paulo State, Brazil. Patients were randomized to three cohorts: 1) Control, no Foralumab (n=16); 2) Nasal Foralumab (100ug/day) given for 10 consecutive days with 6 mg dexamethasone given on days 1-3 (n=11); and 3) Nasal Foralumab alone (100ug/day) given for 10 consecutive days (n=12). Patients continued standard of care medication.ResultsWe observed reduction of serum IL-...

Research paper thumbnail of Safety and clinical activity of combination treatment with regorafenib and milciclib in liver transplant patients with hepatocellular carcinoma recurrence

Journal of Clinical Oncology, 2020

e16634 Background: Recurrence of hepatocellular carcinoma after liver transplant (LT-HCC), affect... more e16634 Background: Recurrence of hepatocellular carcinoma after liver transplant (LT-HCC), affects ~40% of patients. As LT-HCC drastically limits therapeutic options, combination of drugs with different mechanism of actions might be an attractive approach. Primary objective of this MiHRCO (Milciclib and Half Regorafenib CO-administration) protocol (87/2019/COMP/MiHRCO) is to evaluate safety and clinical activity of combination of Regorafenib (a tyrosine kinase inhibitor with higher clinical activity in aggressive HCC) with Milciclib (a pan cyclin dependent kinase inhibitor with clinical activities in refractory solid malignancy patients and HCC) in LT-HCC patients. Methods: Seven patients with LT-HCC are enrolled to date. Regorafenib administered at half the prescribed dose (80mg/day) for 3 weeks followed by 1 week Off and milciclib at 100 mg daily for 4 day On/3 day Off. Patients were maintained on this combination regimen until disease progression and/or unacceptable side effects....

Research paper thumbnail of Phase IIa safety and efficacy of milciclib, a pan-cyclin dependent kinase inhibitor, in unresectable, sorafenib-refractory or -intolerant hepatocellular carcinoma patients

Journal of Clinical Oncology, 2020

e16711 Background: Current hepatocellular carcinoma (HCC) therapeutics, tyrosine kinase inhibitor... more e16711 Background: Current hepatocellular carcinoma (HCC) therapeutics, tyrosine kinase inhibitors (TKI) and checkpoint inhibitors (CI), provide limited improvement in overall survival, suggesting the need to identify drugs with broad-spectrum mechanisms of action, used alone or in combination with a TKI or CI. Milciclib, a pan cyclin dependent kinase inhibitor, exhibited anti-cancer activity in refractory solid malignancy patients. The primary objective of this trial was to evaluate safety and tolerability of milciclib in sorafenib-refractory or intolerant advanced HCC patients. Methods: Single arm and multi-center study in advanced HCC patients was conducted in Italy, Greece and Israel. Milciclib was administered orally for up to 6 cycles. Each cycle consisted of 100mg milciclib daily for 4d on/3d off/week for 4 weeks. Safety assessment was the primary endpoint and secondary endpoints included progression free survival (PFS), time to progression (TTP) and clinical benefit rate (CB...

Research paper thumbnail of Guanylate Cyclase C Agonists, a New Class of Drug Candidates for Treatment of Inflammatory Bowel Disease

American Journal of Gastroenterology, 2011

Research paper thumbnail of Plecanatide and SP-333, Novel Agonists of Guanylate Cyclase-C, Attenuate Visceral Hypersensitivity in Rat Models

American Journal of Gastroenterology, 2014

Research paper thumbnail of SP-333, a Guanylate Cyclase-C Agonist, Inhibits NF-κB Signaling and Modulates Related Genes and miRNAs Implicated in GI Inflammation and Carcinogenesis

American Journal of Gastroenterology, 2013

Research paper thumbnail of Oral Treatment with SP-333, an Agonist of Guanylate Cyclase-C, Dramatically Ameliorates Morphine-induced Bowel Dysfunction in Rats: Presidential Poster

American Journal of Gastroenterology, 2013

Research paper thumbnail of Hepatocellular Carcinoma: Etiology and Current and Future Drugs

Journal of Clinical and Experimental Hepatology, 2019

Hepatocellular carcinoma (HCC) is swiftly increasing in prevalence globally with a high mortality... more Hepatocellular carcinoma (HCC) is swiftly increasing in prevalence globally with a high mortality rate. The progression of HCC in patients is induced with advanced fibrosis, mainly cirrhosis, and hepatitis. The absence of proper preventive or curative treatment methods encouraged extensive research against HCC to develop new therapeutic strategies. The Food and Drug Administration-approved Nexavar (sorafenib) is used in the treatment of patients with unresectable HCC. In 2017, Stivarga (regorafenib) and Opdivo (nivolumab) got approved for patients with HCC after being treated with sorafenib, and in 2018, Lenvima (lenvatinib) got approved for patients with unresectable HCC. But, owing to the rapid drug resistance development and toxicities, these treatment options are not completely satisfactory. Therefore, there is an urgent need for new systemic combination therapies that target different signaling mechanisms, thereby decreasing the prospect of cancer cells developing resistance to treatment. In this review, HCC etiology and new therapeutic strategies that include currently approved drugs and other potential candidates of HCC such as Milciclib, palbociclib, galunisertib, ipafricept, and ramucirumab are evaluated.

Research paper thumbnail of {"__content__"=>"Oral treatment with plecanatide or dolcanatide attenuates visceral hypersensitivity activation of guanylate cyclase-C in rat models.", "i"=>{"__content__"=>"via"}}

World journal of gastroenterology, Jan 7, 2018

To investigate the effects of plecanatide and dolcanatide on maintenance of paracellular permeabi... more To investigate the effects of plecanatide and dolcanatide on maintenance of paracellular permeability, integrity of tight junctions and on suppression of visceral hypersensitivity. Transport of fluorescein isothiocyanate (FITC)-dextran was measured to assess permeability across cell monolayers and rat colon tissues. Effects of plecanatide and dolcanatide on the integrity of tight junctions in Caco-2 and T84 monolayers and on the expression and localization of occludin and zonula occludens-1 (ZO-1) were examined by immunofluorescence microscopy. Anti-nociceptive activity of these agonists was evaluated in trinitrobenzene sulfonic acid (TNBS)-induced inflammatory as well as in non-inflammatory partial restraint stress (PRS) rat models. Statistical significance between the treatment groups in the permeability studies were evaluated using unpaired -tests. Treatment of T84 and Caco-2 monolayers with lipopolysaccharide (LPS) rapidly increased permeability, which was effectively suppressed...

Research paper thumbnail of Oral treatment with foralumab, a fully human anti-CD3 monoclonal antibody, prevents skin xenograft rejection in humanized mice

Clinical immunology (Orlando, Fla.), Jan 21, 2017

Oral administration of biologics may be a feasible approach for immune therapy that improves drug... more Oral administration of biologics may be a feasible approach for immune therapy that improves drug safety and potentiates mechanisms of tolerance at mucosal barriers. We tested the ability of a fully human non-FcR binding anti-CD3 mAb, foralumab, to prevent skin xenograft rejection in mice with human immune systems. At an intragastric dose of 15μg, the drug could transit through the small bowel. Serum absorption and binding of lymphoid cells was seen and proliferative responses of splenic CD8+ T cells to mitogen were reduced. Five consecutive daily doses, then weekly dosing led to indefinite graft acceptance without depletion of peripheral T cells. Proliferative and cytokine responses to activation of splenocytes with PHA were reduced. The serum levels of IL-10 but not TNF were increased 6days after application of the skin graft. Oral treatment with anti-CD3 mAb may represent a feasible approach for immune modulation.

Research paper thumbnail of 967 Plecanatide, Like Uroguanylin, Activates Guanylate Cyclase-C Signaling in a pH-Dependent Manner in T84 Cells, and in Murine Intestinal Epithelial Cells and Tissues

Gastroenterology, 2016

Chronic constipation (CC) is a common multi-symptom disorder of heterogeneous pathogenesis. Opioi... more Chronic constipation (CC) is a common multi-symptom disorder of heterogeneous pathogenesis. Opioid analgesics are known to be an important cause of constipation symptoms. Recently, multiple drugs have gained regulatory approval for the treatment of opiate-induced constipation. Despite this, little is known about the clinical characteristics of constipated patients who are taking opioids. We utilized a novel electronic platform to conduct a national US survey to better understand the clinical profiles of constipated patients taking and not taking opioids. Methods: A national US survey was conducted using a digital adaptation of the NIH PROMIS® questionnaires called My GI Health. US adults (‡18 years) were invited to complete the survey utilizing an incentivized, opt in list provided by a contract research company (Cint®). Participants provided demographic information, severity & frequency data for the 8 most common GI symptoms (abdominal pain, heartburn, dysphagia, nausea, bloating, constipation, diarrhea, bowel incontinence), & use of OTC/prescription medications. Standard statistical methods were used to compare characteristics of respondants reporting constipation who were taking opioids (opiate associated constipation=OAC) or not taking opioids (non-opioid constipation=NOC). Regression models adjusted for age, sex, race/ethnicity, education, marital status, employment status, and household income. NOC subjects served as the reference group. Results: 71,813 adults completed the survey. 13,343 subjects reported constipation symptoms within 7 days of completing the survey. Of those with constipation, 1671 were actively using opiates (12.5%) while 11,672 (87.5%) were not. Demographic information showed OAC subjects were older, more likely to be male, less likely to have a graduate degree and more likely to be unemployed than NOC subjects (p<0.001 for these items). Subjects with OAC had a greater burden of constipation symptoms than NOC (table 1). Further, subjects with OAC had a greater burden of all GI symptoms assessed. OAC patients were more likely to endorse all the other GI symptoms assessed except for diarrhea (table 2). Based upon PROMIS composite scores for all 7 remaining lower and upper GI symptoms (table 1), OAC patients had more frequent & severe GI symptoms than NOC subjects (all comparisons on linear regression model p<0.001). These results were confirmed in a smaller group of respondants who reported constipation for more than 4 weeks. Conclusions: This is the largest survey to characterize the clinical phenotypes of OAC and NOC. OAC patients had a greater burden of GI complaints attributable to the lower and upper GI tract. This may be the consequence of opioid effects throughout the GI tract and CNS and might have implications regarding treatment choice in OAC vs. NOC patients. Table 1: GI PROMIS symptom scores in NOC vs. OAC a GI PROMIS score for individual symptoms is on a 0-100 percentile scale. b Global GI PROMIS score is on a 0-800 scale.

Research paper thumbnail of Formulations of guanylate cyclase c agonists and methods of use

Research paper thumbnail of Uroguanylin treatment suppresses polyp formation in the Apc(Min/+) mouse and induces apoptosis in human colon adenocarcinoma cells via cyclic GMP

Cancer research, Jan 15, 2000

The enteric peptides, guanylin and uroguanylin, are local regulators of intestinal secretion by a... more The enteric peptides, guanylin and uroguanylin, are local regulators of intestinal secretion by activation of receptor-guanylate cyclase (R-GC) signaling molecules that produce cyclic GMP (cGMP) and stimulate the cystic fibrosis transmembrane conductance regulator-dependent secretion of Cl- and HCO3-. Our experiments demonstrate that mRNA transcripts for guanylin and uroguanylin are markedly reduced in colon polyps and adenocarcinomas. In contrast, a specific uroguanylin-R-GC, R-GCC, is expressed in polyps and adenocarcinomas at levels comparable with normal colon mucosa. Activation of R-GCC by uroguanylin in vitro inhibits the proliferation of T84 colon cells and elicits profound apoptosis in human colon cancer cells, T84. Therefore, down-regulation of gene expression and loss of the peptides may interfere with renewal and/or removal of the epithelial cells resulting in the formation of polyps, which can progress to malignant cancers of the colon and rectum. Oral replacement therap...

Research paper thumbnail of Sa1393 Oral Treatment With SP-333, an Analog of Uroguanylin, Effectively Relieves Morphine and Methadone-Induced Constipation in Rats Through a Novel Mechanism Involving Activation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)

Research paper thumbnail of Isolation and characterization from porcine serum of a soluble sulfotransferase responsible for 6-O-sulfation of the galactose residue in 2′-fucosyllactose: Implications in the synthesis of the ligand for L-selectin

Glycoconjugate Journal, 1999

A soluble sulfotransferase from porcine serum which catalyzes the transfer of sulfate from adenos... more A soluble sulfotransferase from porcine serum which catalyzes the transfer of sulfate from adenosine 3'-phosphate 5'-phosphosulphate (PAPS) to 2'-fucosyllactose (2'-FL) was purified 36,333-fold using a combination of conventional and affinity chromatographic steps. The purified enzyme preparation after non-denaturing discontinuous-PAGE exhibited a molecular mass of about 80 kDa by reducing SDS-PAGE. However, when a partially purified enzyme preparation was subjected to

Research paper thumbnail of Atiprimod is an inhibitor of cancer cell proliferation and angiogenesis

Journal of experimental therapeutics & oncology, 2004

Atiprimod, a novel compound belonging to the azaspirane class of cationic amphiphilic drugs, exhi... more Atiprimod, a novel compound belonging to the azaspirane class of cationic amphiphilic drugs, exhibits both anti-proliferative and anti-angiogenic activities. Atiprimod inhibited proliferation of all human cancer cell lines included in the National Cancer Institute panel with IC50 values in the low micromolar range. Notably, metastatic cell lines were more sensitive to the compound compared to the non-metastatic cell lines derived from the same tumor tissue types. Atiprimod also induced apoptosis and activated both caspase-9 and caspase-3 in T84 colon carcinoma cells. Hence, the anti-proliferative activity could partly be due to its pro-apoptotic activity. Regarding angiogenesis in vitro, atiprimod inhibited both bFGF and VEGF induced proliferation and migration of human umbilical vein endothelial cells (HUVECs), resulting in disruption of cord formation. In addition, atiprimod also suppressed formation of new blood vessels in a chorioallantoic membrane assay. Previous studies have a...