Evidence of Multimeric Forms of HSP70 with Phosphorylation on Serine and Tyrosine Residues - Implications for Roles of HSP70 in Detection of GI Cancers

Dutta, Anand,Girotra, Mohit,Merchant, Nipun,Nair, Padmanabhan,Dutta, Sudhir Kumar Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.10

Background: Heat-shock protein70 (HSP70) are intracellular protein chaperones, with emerging evidence of their association with various diseases. We have previously reported significantly elevated plasma-HSP70 (pHSP70) in pancreatic cancer. Current methods of pHSP70 isolation are ELISA-based which lack specificity due to cross-reactivity by similarities in the amino-acid sequence in regions of the protein backbone resulting in overestimated HSP70 value. Materials and Methods: This study was undertaken to develop a methodology to capture all isoforms of pHSP70, while further defining their tyrosine and serine phosphorylation status. Results: The methodology included gel electrophoresis on centrifuged supernatant obtained from plasma incubated with HSP70 antibody-coupled beads. After blocking non-specific binding sites, blots were immunostained with monoclonal-antibody specific for human-HSP70, phosphoserine and phosphotyrosine. Conclusions: Our novel immunocapture approach has distinct advantages over the commercially available methods of pHSP70 quantification by allowing isolation of molecular aggregates of HSP70 with additional ability to precisely distinguish phosphorylation state of HSP70 molecules at serine and tyrosine residues.

Barrett's Esophagus and β-carotene Therapy: Symptomatic Improvement in GERD and Enhanced HSP70 Expression in Esophageal Mucosa

Dutta, Sudhir K.,Agrawal, Kireet,Girotra, Mohit,Fleisher, A. Steven,Motevalli, Mahnaz,Mah'moud, Mitchell A.,Nair, Padmanabhan P. Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.12

Introduction: Epidemiological studies suggest a protective role for ${\beta}$-carotene with several malignancies. Esophageal adenocarcinoma frequently arises from Barrett's esophagus (BE). We postulated that ${\beta}$-carotene therapy maybe protective in BE. Materials and Method: We conducted a prospective study in which 25 mg of ${\beta}$-carotene was administered daily for six-months to six patients. Each patient underwent upper endoscopy before and after therapy and multiple mucosal biopsies were obtained. Additionally, patients completed a gastroesophageal reflux disease (GERD) symptoms questionnaire before and after therapy and severity score was calculated. To study the effect of ${\beta}$-carotene at molecular level, tissue extracts of the esophageal mucosal biopsy were subjected to assessment of heat-shock protein 70 (HSP70). Results: A significant (p<0.05) reduction in mean GERD symptoms severity score from $7.0{\pm}2.4$ to $2.7{\pm}1.7$ following ${\beta}$-carotene therapy was noted. Measurement of Barrett's segment also revealed a significant reduction in mean length after therapy. In fact, two patients had complete disappearance of intestinal metaplasia. Furthermore, marked enhancement of HSP70 expression was demonstrated in biopsy specimens from Barrett's epithelium in four cases that were tested. Conclusions: Long-term ${\beta}$-carotene therapy realizes amelioration of GERD symptoms along with restitution of the histological and molecular changes in esophageal mucosa of patients with BE, associated with concurrent increase in mucosal HSP70 expression.

Parkinson’s Disease: The Emerging Role of Gut Dysbiosis, Antibiotics, Probiotics, and Fecal Microbiota Transplantation

Sudhir K Dutta,Sandeep Verma,Vardhmaan Jain,Balarama K Surapaneni,Rakesh Vinayek,Laila Phillips,Padmanabhan P Nair 대한소화기 기능성질환∙운동학회 2019 Journal of Neurogastroenterology and Motility (JNM Vol.25 No.3

2 decades evidence has emerged to suggest that inflammation-derived oxidative damage and cytokine induced toxicity may play asignificant role in the neuronal damage associated with Parkinson’s disease (PD). Presence of pro-inflammatory cytokines and T cellinfiltration has been observed in the brain parenchyma of patients with PD. Furthermore, evidence for inflammatory changes hasbeen reported in the enteric nervous system, the vagus nerve branches and glial cells. The presence of α-synuclein deposits in thepost-mortem brain biopsy in patients with PD has further substantiated the role of inflammation in PD. It has been suggested thatthe α-synuclein misfolding might begin in the gut and spread “prion like” via the vagus nerve into lower brainstem and ultimately tothe midbrain; this is known as the Braak hypothesis. It is noteworthy that the presence of gastrointestinal symptoms (constipation,dysphagia, and hypersalivation), altered gut microbiota and leaky gut have been observed in PD patients several years prior to theclinical onset of the disease. These clinical observations have been supported by in vitro studies in mice as well, demonstrating the roleof genetic (α-synuclein overexpression) and environmental (gut dysbiosis) factors in the pathogenesis of PD. The restoration of the gutmicrobiome in patients with PD may alter the clinical progression of PD and this alteration can be accomplished by carefully designedstudies using customized probiotics and fecal microbiota transplantation.

Seismic torsional vibration in elevated tanks

Dutta, Sekhar Chandra,Murty, C.V.R.,Jain, Sudhir K. Techno-Press 2000 Structural Engineering and Mechanics, An Int'l Jou Vol.9 No.6

Some elevated water tanks have failed due to torsional vibrations in past earthquakes. The overall axisymmetric structural geometry and mass distribution of such structures may leave only a small accidental eccentricity between centre of stiffness and centre of mass. Such a small accidental eccentricity is not expected to cause a torsional failure. This paper studies the possibility of amplified torsional behaviour of elevated water tanks due to such small accidental eccentricity in the elastic as well as inelastic range; using two simple idealized systems with two coupled lateral-torsional degrees of freedom. The systems are capable of retaining the characteristics of two extreme categories of water tanks namely, a) tanks on staging with less number of columns and panels and b) tanks on staging with large number of columns and panels. The study shows that the presence of a small eccentricity may lead to large displacement of the staging edge in the elastic range, if the torsional-to-lateral time period ratio $({\tau})$ of the elevated tanks lies within a critical range of 0.7< ${\tau}$ <1.25. Inelastic behaviour study reveals that such excessive displacement in some of the reinforced concrete staging elements may cause unsymmetric yielding. This may lead to progressive strength deterioration through successive yielding in same elements under cyclic loading during earthquakes. Such localized strength drop progressively develop large strength eccentricity resulting in large localized inelastic displacement and ductility demand, leading to failure. So, elevated water tanks should have ${\tau}$ outside the said critical range to avoid amplified torsional response. The tanks supported on staging with less number of columns and panels are found to have greater torsional vulnerability. Tanks located near faults seem to have torsional vulnerability for large ${\tau}$.

Evidence for Enhanced Telomerase Activity in Barrett's Esophagus with Dysplasia and Adenocarcinoma

Merchant, Nipun B.,Dutta, Sudhir K.,Girotra, Mohit,Arora, Manish,Meltzer, Stephen J. Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.2

Background: Dysplasia and adenocarcinoma developing in Barrett's esophagus (BE) are not always endoscopically identifiable. Molecular markers are needed for early recognition of these focal lesions and to identify patients at increased risk of developing adenocarcinoma. The aim of the current study was to correlate increased telomerase activity (TA) with dysplasia and adenocarcinoma occurring in the setting of BE. Materials and Methods: Esophageal mucosal biopsies were obtained from patients (N=62) who had pathologically verified BE at esophagogastroduodenoscopy (EGD). Mucosal biopsies were also obtained from the gastric fundus as controls. Based on histopathology, patients were divided into three groups: 1) BE without dysplasia (n=24); 2) BE with dysplasia (both high grade and low grade, n=13); and 3) BE with adenocarcinoma (n=25). TA was measured by a PCR-based assay (TRAPeze$^{(R)}$ ELISA Telomerase Detection Kit). Statistical analyses were performed using one-way ANOVA and post-hoc Bonferroni testing. Results: TA was significantly higher in biopsies of BE with dyplasia and BE with adenocarcinoma than in BE without dysplasia. Subgroup analyses did not reveal any significant correlations between TA and patient age, length of BE, or presence of gastritis. Conclusions: Telomerase activity in esophageal mucosal biopsies of BE may constitute a useful biomarker for the early detection of esophageal dysplasia and adenocarcinoma.

Safety Profile and Therapeutic Efficacy of One Cycle of Lu177-PSMA in End-Stage Metastatic Castration-Resistant Prostate Cancer Patients with Low Performance Status

Manoj Gupta,Partha Sarathi Choudhury,Sudhir Rawal,G. Karthikeyan,Vineet Talwar,Kumar Deep Dutta,Amitabh Singh 대한핵의학회 2019 핵의학 분자영상 Vol.53 No.6

Purpose The aimof this study was to evaluate safety and therapeutic efficacy of lutetium 177 prostate-specific membrane antigen (Lu-177-PSMA) in metastatic castration-resistant prostate cancer (mCRPC) patients with low performance status. Methods Twenty-two patients already treated with anti-androgens and docetaxel were enrolled for one cycle of Lu-177-PSMA therapy. Haemoglobin, total leukocyte counts, platelets and serum creatinine for toxicity profile while prostate specific antigen (PSA), Eastern Cooperative Oncology Group (ECOG) performance status, visual analogue scale (VAS) and analgesic quantification scale (AQS) for therapeutic efficacy were recorded pre and 8 weeks post therapy.Wilcoxon signed-rank and ANOVA tests were used for statistical analysis. Results Partial response (PR), stable disease (SD) and progressive disease (PD) for PSAwere seen in 5 (22.7%), 13 (59.1%) and 4 (18.2%) patients respectively treated with mean 6.88 GBq dose of Lu-177-PSMA. 8/22 (36.4%) patients showed ≥ 30% drop in PSA. Grade 3 haemoglobin toxicity was seen in 5/22 (22.7%) patients. No patient developed grade 4 haemoglobin toxicity. No patients had grade 3 or 4 leukocytopenia or thrombocytopenia. Wilcoxon signed-rank test showed statistical significant (P < 0.05) difference in pre and post treatment ECOG, VAS, and AQS scores. The ANOVA test showed statistically significant difference in mean doses of Lu-177-PSMA used in three PSA response groups while difference was non-significant for other variables. Conclusion We concluded that Lu-177-PSMA therapy has adequate pain palliation in end-stage mCRPC patients with low performance status and it has a potential to become effective therapeutic option in properly selected patients.