Publications by authors named "Pankaj Goyal"

87 Publications

Immobilization of catalase on functionalized magnetic nanoparticles: a statistical approach.

3 Biotech 2022 May 9;12(5):108. Epub 2022 Apr 9.

Department of Biotechnology, Dr. B. R. Ambedkar, National Institute of Technology, Jalandhar, Punjab 144011 India.

Magnetic nanoparticles (MNPs) FeO, by virtue of easily modifiable surface, high surface-to-mass ratio and super-paramagnetic properties, are one of suitable candidates for the enzyme immobilization. Optimization of five important variables viz concentration of 3-aminopropyl-tri-ethoxy-silane (APTES), glutaraldehyde (GA) and enzyme, time and temperature of loading was carried out using central composite type of experimental design without blocks giving 50 experiments including eight replicates at the central point. Characterization, stability and reusability studies were also carried out with optimized preparation. Results established the correlation between observed and response surface method (RSM) equation envisaged value ( 0.99, 0.97 and 0.98 for enzyme's activity, its loading over MNPs and corresponding specific activity, respectively. The predicted values suggested by RSM equation were 64.00 mM of APTES, 10.97 µL of GA, 14.50 mg mL of enzyme for 67 min at 22.6 °C, resulted in activity 32.1 U mg MNPs, while specific activity was 97.7 U mg. Transmission electron microscopy (TEM) showed the sizes of MNPs (10.5 ± 1.7 nm), APTES-MNPs (10.23 ± 1.74 nm), GA-APTES-MNPs (11.84 ± 1.49 nm) and Catalase-GA-APTES-MNPs (13.32 ± 2.74 nm) were statistically similar. The enzyme MNPs preparation retained 81.65% activity after 144 h at 4 °C (free enzyme retained 7.87%) and 64.34% activity after 20 reuse cycles. Statistical optimized MNPs-based catalase preparation with high activity and magnetic strength was stable and can be used for further studies related to its application as analytical recyclable enzyme or magnetically oriented delivery in the body.

Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03173-8.
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http://dx.doi.org/10.1007/s13205-022-03173-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8994807PMC
May 2022

Inhibition and disintegration of biofilm with small molecule inhibitors identified through virtual screening for targeting TasA, the major protein component of ECM.

J Biomol Struct Dyn 2022 Jan 31:1-17. Epub 2022 Jan 31.

Department of Biotechnology, School of Life Sciences, Central University of Rajasthan, Ajmer, Rajasthan, India.

Microbial biofilms have been recognized for a vital role in antibiotic resistance and chronic microbial infections for 2-3 decades; still, there are no 'anti-biofilm drugs' available for human applications. There is an urgent need to develop novel 'anti-biofilms' therapeutics to manage biofilm-associated infectious diseases. Several reports have suggested that targeting molecules involved in quorum sensing or biofilm-specific transcription may inhibit biofilm formation. However, the possibility of targeting other vital components of microbial biofilms, especially the extracellular matrix (ECM) components, has remained largely unexplored. Here we report targeting TasA, the major proteinaceous component of ECM with two small molecule inhibitors (lovastatin and simvastatin) identified through virtual screening and drug repurposing, resulted in complete inhibition of biofilm. In molecular docking and dynamics simulation studies, lovastatin was observed to make stable interactions with TasA, whereas the simvastatin - TasA interactions were relatively less stable. However, in subsequent studies, both lovastatin and simvastatin successfully inhibited biofilm formation at MIC values of < 10 µg/ml. Besides, these potential inhibitors also caused the disintegration of pre-formed biofilms. Results presented here provide 'proof of concept' for the hypothesis that targeting the extracellular matrix's vital component(s) could be one of the most efficient approaches for inhibiting microbial biofilms and disintegrating the pre-formed biofilms. We propose that a similar approach targeting ECM-associated proteins with FDA-approved drugs could be implemented to develop novel anti-biofilm therapeutic strategies against biofilm-forming chronic microbial pathogens.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2022.2033135DOI Listing
January 2022

Cardiac Ultrasound for the Nephrologist: Know Thy Heart to Know Thy Kidneys.

Adv Chronic Kidney Dis 2021 05;28(3):208-217

Division of Cardiovascular Critical Care, Department of Cardiovascular and Thoracic Surgery, Morgantown, WV. Electronic address:

Kidney disease patients have a high prevalence of cardiovascular morbidity and mortality. It can be challenging to adequately assess their cardiovascular status based on physical examination alone. Cardiac ultrasound has proven to be a powerful tool to accomplish this objective and is increasingly being adopted by noncardiologists to augment their skills and expedite clinical decision-making. With the advent of inexpensive and portable ultrasound equipment, simplified protocols, and focused training, it is becoming easier to master basic cardiac ultrasound techniques. After a short course of training in focused cardiac ultrasound, nephrologists can quickly and reliably assess ventricular size and function, detect clinically relevant pericardial effusion and volume status in their patients. Additional training in Doppler ultrasound can extend their capability to measure cardiac output, right ventricular systolic pressure, and diastolic dysfunction. This information can be instrumental in effectively managing patients in inpatient, office, and dialysis unit settings. The purpose of this review is to highlight the importance and feasibility of incorporating cardiac ultrasound in nephrology practice, discuss the principles of basic and Doppler ultrasound modalities and their clinical utility from a nephrologist's perspective.
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http://dx.doi.org/10.1053/j.ackd.2021.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8675608PMC
May 2021

Colonic polyp-rare site of metastasis from primary lung carcinoma: Clinical presentations and outcome.

Lung India 2021 Nov-Dec;38(6):581-583

Department of Medical Oncology, Rajiv Gandhi Cancer Institute, New Delhi, India.

Although majority of lung cancers have distant metastasis at the time of initial diagnosis, colonic metastases are extremely rare. This report presents a rare clinical case which presented with lower limb deep vein thrombosis and found to have colon polyp incidentally detected while evaluating for occult blood positive in stool. Histopathology of the polyp was suggestive of lung primary and on further evaluation PET scan was suggestive of left lung mass with widespread distant metastasis.
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http://dx.doi.org/10.4103/lungindia.lungindia_117_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8614602PMC
November 2021

Chronic kidney disease recognition amongst physicians and advanced practice providers.

Ren Fail 2021 Dec;43(1):1276-1280

Division of Nephrology, Kidney C.A.R.E (Clinical Advancement, Research, and Education) Program, University of Cincinnati, Cincinnati, OH, USA.

Objective: Chronic kidney disease is a worldwide public health issue, with increasing prevalence resulting in high morbidity and mortality. As a result, recognizing and treating it early can lead to improved outcomes. We hypothesized that some providers might be more comfortable making this diagnosis than others.

Methods: Retrospective study of 380 patients with chronic kidney disease seen between 2012 and 2016 in an outpatient setting.

Results: Three hundred and sixteen patients were treated by physicians and sixty-four by advanced practice providers. Chronic kidney disease was identified by the primary care providers in 318 patients (83.6%). Patients recognized with chronic kidney disease were older, 76 ± 8.8 vs 72 ± 7.45 years,  = 0.001; had lower GFR, 37 [29, 46] vs 57 [37, 76] ml/min/1.73 m,  < 0.0001 and were more likely to be seen by a physician compared to an advanced practice provider: 272/316 (86%) vs 46/64 (71.8%),  = 0.008. In multivariate analyses, care by a physician, OR = 2.27 (1.13-4.58),  = 0.02 was associated with increased recognition of chronic kidney disease. On the other hand, higher GFR was associated with decreased diagnosis of chronic kidney disease, OR = 0.95 (0.93-0.96),  < 0.0001.

Conclusion: The odds of chronic kidney disease recognition were higher amongst physicians in comparison to non-physician providers.
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http://dx.doi.org/10.1080/0886022X.2021.1974474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439203PMC
December 2021

Multicentric real world evidence with palbociclib in hormone positive HER2 negative metastatic breast cancer in Indian population.

Sci Rep 2021 08 10;11(1):16236. Epub 2021 Aug 10.

Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Sector-5, Rohini, New Delhi, India.

The combination of cyclin dependent kinase 4/6 inhibitors with endocrine therapy is the standard therapy in hormone receptor positive HER-2 negative metastatic breast cancer (HR+/HER2- MBC). Several randomized trials have shown the benefits of this combination, however, real world evidence in the Indian patients is warranted. The present study reports the largest real world multicentric data from Indian population on the use of Palbociclib in HR+/HER2- MBC. A multicentric study on the HR+/HER2- MBC patients who received palbociclib with hormonal agent (Aromatase inhibitors/Fulvestrant) between February 2017 and May 2020 was conducted. Clinical and demographic information and survival data was retrieved from the Hospital medical records. Among a total of 188 patients, 57% patients were premenopausal and 17% patients had bone only disease. Altogether, 115 (61%) patients received palbociclib with Aromatase inhibitors in the first line whereas 73 (39%) patients received it in the second line with Fulvestrant. The median follow up period with advanced disease was 13 months. The median progression free survival in the first line and second line was 20.2 months and 12 months, respectively (p-value < 0.0001). The objective response rate was 80% and 47.9% in first and second lines, respectively. Dose interruptions/ discontinuation were done in 14.9% and 2.7% patients in the first and second lines, respectively. In terms of toxicity, 10% patients had grade 3-4 adverse events. The present real world data of the use of palbociclib in Indian population suggests similar effectiveness to previously published real world evidences and has been adapted as the standard of care in the first and second line treatment of HR+/HER2- MBC.
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http://dx.doi.org/10.1038/s41598-021-95758-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8355114PMC
August 2021

STK35L1 regulates host cell cycle-related genes and is essential for Plasmodium infection during the liver stage of malaria.

Exp Cell Res 2021 09 4;406(2):112764. Epub 2021 Aug 4.

Department of Biotechnology, School of Life Sciences, Central University of Rajasthan, Bandarsindri, Kishangarh, Rajasthan, 305 817, India. Electronic address:

Protein kinases of both the parasite and the host are crucial in parasite invasion and survival and might act as drug targets against drug-resistant malaria. STK35L1 was among the top five hits in kinome-wide screening, suggesting its role in malaria's liver stage. However, the role of host STK35L1 in malaria remains elusive. In this study, we found that STK35L1 was highly upregulated during the infection of Plasmodium berghei (P. berghei) in HepG2 cells and mice liver, and knockdown of STK35L1 remarkably suppressed the sporozoites' infection in HepG2 cells. We showed that STAT3 is upregulated and phosphorylated during P. berghei sporozoites' infection, and STAT3 activation is required for both the upregulation of STK35L1 and STAT3. Furthermore, we found that ten cell cycle genes were upregulated in the sporozoite-infected hepatocytes. Knockdown of STK35L1 inhibited the basal expression of these genes except CDKN3 and GTSE1 in HepG2 cells. Thus, we identified STK35L1 as a host kinase that plays an obligatory role in malaria's liver stage and propose that it may serve as a potential drug target against drug-resistant malaria.
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http://dx.doi.org/10.1016/j.yexcr.2021.112764DOI Listing
September 2021

Sphingosine kinases negatively regulate the expression of matrix metalloproteases ( and ) and their inhibitor genes via sphingosine 1-phosphate in extravillous trophoblasts.

Reprod Med Biol 2021 Jul 22;20(3):267-276. Epub 2021 Mar 22.

Department of Biotechnology School of Life Sciences Central University of Rajasthan Ajmer India.

Purpose: Extracellular matrix remodeling is essential for extravillous trophoblast (EVT) cell migration and invasion during placental development and regulated by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteases (TIMPs). Sphingosine kinases (SPHK1 and SPHK2) synthesize sphingosine-1-phosphate (S1P), which works either intracellularly or extracellularly via its receptors S1PR1-5 in an autocrine or paracrine manner. The role of SPHKs/S1P in regulating the expression of MMPs and TIMPs in EVT is mostly unknown and forms the primary objective of the study.

Methods: HTR-8/SVneo cells were used as a model of EVT. To inhibit the expression of SPHKs, cells were treated with specific inhibitors, SK1-I and SKI-II, or gene-specific siRNAs. The expressions of were estimated by qPCR.

Results: We demonstrated that , , and were highly expressed in HTR-8/SVneo cells. We found that treatment of cells with SK1-I, SKI-II, and knockdown of or increased the expression of , , and . The addition of extracellular S1P inhibits the upregulation of and in treated cells.

Conclusions: SPHKs negatively regulate the expression of , , and . The level of intracellular S1P acts as a negative feedback switch for , , and expression in EVT cells.
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http://dx.doi.org/10.1002/rmb2.12379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254167PMC
July 2021

The intrinsic amyloidogenic propensity of cofilin-1 is aggravated by Cys-80 oxidation: A possible link with neurodegenerative diseases.

Biochem Biophys Res Commun 2021 09 10;569:187-192. Epub 2021 Jul 10.

Department of Biotechnology, School of Life Sciences, Central University of Rajasthan, Bandarsindri, Kishangarh, Rajasthan, 305 817, India. Electronic address:

Cofilin-1, an actin dynamizing protein, forms actin-cofilin rods, which is one of the major events that exacerbates the pathophysiology of amyloidogenic diseases. Cysteine oxidation in cofilin-1 under oxidative stress plays a crucial role in the formation of these rods. Others and we have reported that cofilin-1 possesses a self-oligomerization property in vitro and in vivo under physiological conditions. However, it remains elusive if cofilin-1 itself forms amyloid-like structures. We, therefore, hypothesized that cofilin-1 might form amyloid-like assemblies, with a potential to intensify the pathophysiology of amyloid-linked diseases. We used various in silico and in vitro techniques and examined the amyloid-forming propensity of cofilin-1. The study confirms that cofilin-1 possesses an intrinsic tendency of aggregation and forms amyloid-like structures in vitro. Further, we studied the effect of cysteine oxidation on the stability and structural features of cofilin-1. Our data show that oxidation at Cys-80 renders cofilin-1 unstable, leading to a partial loss of protein structure. The results substantiate our hypothesis and establish a strong possibility that cofilin-1 aggregation might play a role in cofilin-mediated pathology and the progression of several amyloid-linked diseases.
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http://dx.doi.org/10.1016/j.bbrc.2021.07.013DOI Listing
September 2021

Role of Maintenance Gemcitabine in Advanced Carcinoma Gallbladder.

South Asian J Cancer 2020 Oct 12;9(4):204-208. Epub 2021 Jun 12.

Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Center, New Delhi, India.

 The aim of this study is to investigate the effects of gemcitabine maintenance on progression-free survival (PFS) in patients with metastatic gallbladder cancer (GBC).  Sixty patients with unresectable or metastatic GBC having ongoing response to treatment with initial six cycles of gemcitabine and a platinum-based doublet chemotherapy were prospectively randomized on day 21 of the 6th cycle in 1:1 fashion to receive either maintenance gemcitabine 1 g/m intravenously on day 1 and day 8 of three weekly cycle or observation. Survival analysis was performed using the Kaplan-Meier method and comparisons by the log-rank test. A -value < 0.05 was considered as statistically significant.  Of 60 patients, a total of 56 were available for final analysis. The median PFS was 4.7 months (3.1-6.3) in gemcitabine arm and 2.6 months (2.4-2.8) in observation arm, hazard ratio (HR) 0.196 (95% confidence interval [CI]: 0.1-0.39), < 0.001. Median overall survival in gemcitabine arm was 12.4 months (9.15-15.6) as opposed to 9.9 months (8.29-11.5) in observation arm, HR 0.76 (95% CI: 0.43-1.35), = 0.354. The grade 3 or 4 side effects in maintenance arm were transaminitis (17.9%), thrombocytopenia (17.8%), neutropenia (14.2%), and febrile neutropenia (7.1%).  Maintenance gemcitabine therapy in unresectable/metastatic GBC patients responding to first-line gemcitabine and platinum treatment contributes to increase PFS with minimal and manageable side effects.
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http://dx.doi.org/10.1055/s-0040-1721216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197654PMC
October 2020

Challenges and operative strategy in an unusual case of giant mastoid osteoma.

BMJ Case Rep 2021 Jun 1;14(6). Epub 2021 Jun 1.

ENT, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, India.

A 19-year-old female patient presented to the outpatient department of ear, nose and throat with complaints of hard swelling behind her left ear for the past 5 years. It was a large bony swelling arising from the left temporal bone causing a cosmetic deformity that was surgically excised. The patient made a good recovery post procedure. Histopathology confirmed the lesion to be osteoma.
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http://dx.doi.org/10.1136/bcr-2021-242706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173281PMC
June 2021

Developing a short-term prediction model for asthma exacerbations from Swedish primary care patients' data using machine learning - Based on the ARCTIC study.

Respir Med 2021 Aug-Sep;185:106483. Epub 2021 May 26.

Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden.

Objective: The ability to predict impending asthma exacerbations may allow better utilization of healthcare resources, prevention of hospitalization and improve patient outcomes. We aimed to develop models using machine learning to predict risk of exacerbations.

Methods: Data from 29,396 asthma patients was collected from electronic medical records and national registers covering clinical and epidemiological factors (e.g. comorbidities, health care contacts), between 2000 and 2013. Machine-learning classifiers were used to create models to predict exacerbations within the next 15 days. Model selection was done using the mean cross validation score of area under precision-recall curve (AUPRC).

Results: The most important predictors of exacerbation were comorbidity burden and previous exacerbations. Model validation on test data yielded an AUPRC = 0.007 (95% CI: ± 0.0002), indicating that historic clinical information alone may not be sufficient to predict a near future risk of asthma exacerbation.

Conclusions: Supplementation with additional data on environmental triggers, (e.g. weather, pollen count, air quality) and from wearables, might be necessary to improve performance of the short-term predictive model to develop a more clinically useful tool.
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http://dx.doi.org/10.1016/j.rmed.2021.106483DOI Listing
January 2022

Thrombin impairs the angiogenic activity of extravillous trophoblast cells via monocyte chemotactic protein-1 (MCP-1): A possible link with preeclampsia.

Reprod Biol 2021 Sep 28;21(3):100516. Epub 2021 May 28.

Department of Biotechnology, School of Life Sciences, Central University of Rajasthan, Bandarsindri, Kishangarh, Rajasthan, 305817, India. Electronic address:

Cytokines' secretion from the decidua and trophoblast cells has been known to regulate trophoblast cell functions, such as Extravillous trophoblasts (EVTs) cell migration and invasion and remodeling of spiral arteries. Defective angiogenesis and spiral arteries transformation are mainly caused by proinflammatory cytokines and excessive thrombin generation during preeclampsia. Monocyte chemotactic protein-1 (MCP-1), a crucial cytokine, has a role in maintaining normal pregnancy. In this study, we explored whether thrombin regulates the secretion of MCP-1 in HTR-8/SVneo cells; if yes, what is its function? We used HTR-8/SVneo cells, developed from first trimester villous explants of early pregnancy, as the model of EVTs. MCP-1 gene silencing was performed using gene-specific siRNA. qPCR and ELISA were performed to estimate the expression and secretion of MCP-1. Here, we found that thrombin enhanced the secretion of MCP-1 in HTR-8/SVneo cells. Proteinase-activated receptor-1 (PAR-1) was found as the primary receptor, regulating MCP-1 secretion in these cells. Furthermore, MCP-1 secretion is modulated via protein kinase C (PKC) α, β, and Rho/Rho-kinase-dependent pathways. Thrombin negatively regulates HTR-8/SVneo cells' ability to mimic tube formation in an MCP-1 dependent manner. In conclusion, we propose that thrombin-controlled MCP-1 secretion may play an essential role in normal placental development and successful pregnancy maintenance. Improper thrombin production and MCP-1 secretion during pregnancy might cause inadequate vascular formation and transformation of spiral arteries, which may contribute to pregnancy disorders, such as preeclampsia.
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http://dx.doi.org/10.1016/j.repbio.2021.100516DOI Listing
September 2021

Super-rapid race for saving lives by developing COVID-19 vaccines.

J Integr Bioinform 2021 Mar 25;18(1):27-43. Epub 2021 Mar 25.

Institute of Bioinformatics, International Technology Park, Bangalore560066, India.

The pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people and claimed thousands of lives. Starting in China, it is arguably the most precipitous global health calamity of modern times. The entire world has rocked back to fight against the disease and the COVID-19 vaccine is the prime weapon. Even though the conventional vaccine development pipeline usually takes more than a decade, the escalating daily death rates due to COVID-19 infections have resulted in the development of fast-track strategies to bring in the vaccine under a year's time. Governments, companies, and universities have networked to pool resources and have come up with a number of vaccine candidates. Also, international consortia have emerged to address the distribution of successful candidates. Herein, we summarize these unprecedented developments in vaccine science and discuss the types of COVID-19 vaccines, their developmental strategies, and their roles as well as their limitations.
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http://dx.doi.org/10.1515/jib-2021-0002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035961PMC
March 2021

Predicting Hospitalization Due to COPD Exacerbations in Swedish Primary Care Patients Using Machine Learning - Based on the ARCTIC Study.

Int J Chron Obstruct Pulmon Dis 2021;16:677-688. Epub 2021 Mar 16.

Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine, Uppsala University, Uppsala, Sweden.

Purpose: Chronic obstructive pulmonary disease (COPD) exacerbations can negatively impact disease severity, progression, mortality and lead to hospitalizations. We aimed to develop a model that predicts a patient's risk of hospitalization due to severe exacerbations (defined as COPD-related hospitalizations) of COPD, using Swedish patient level data.

Patients And Methods: Patient level data for 7823 Swedish patients with COPD was collected from electronic medical records (EMRs) and national registries covering healthcare contacts, diagnoses, prescriptions, lab tests, hospitalizations and socioeconomic factors between 2000 and 2013. Models were created using machine-learning methods to predict risk of imminent exacerbation causing patient hospitalization due to COPD within the next 10 days. Exacerbations occurring within this period were considered as one event. Model performance was assessed using the Area under the Precision-Recall Curve (AUPRC). To compare performance with previous similar studies, the Area Under Receiver Operating Curve (AUROC) was also reported. The model with the highest mean cross validation AUPRC was selected as the final model and was in a final step trained on the entire training dataset.

Results: The most important factors for predicting severe exacerbations were exacerbations in the previous six months and in whole history, number of COPD-related healthcare contacts and comorbidity burden. Validation on test data yielded an AUROC of 0.86 and AUPRC of 0.08, which was high in comparison to previously published attempts to predict COPD exacerbation.

Conclusion: Our work suggests that clinically available information on patient history collected via automated retrieval from EMRs and national registries or directly during patient consultation can form the basis for future clinical tools to predict risk of severe COPD exacerbations.
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http://dx.doi.org/10.2147/COPD.S293099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981164PMC
June 2021

Adjuvant chemotherapy in uterine carcinosarcoma: Comparison of a doublet and a triplet chemotherapeutic regimen.

Indian J Cancer 2021 Apr-Jun;58(2):179-184

Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, Rohini, New Delhi, India.

Background: Uterine carcinosarcoma (UCS) is a rare and aggressive malignancy, and there are no existing standard guidelines for adjuvant therapy. Doublet chemotherapy regimens are most favored in adjuvant setting; however, given the early chances of distant recurrences, does a triple-drug adjuvant chemotherapy improve disease-free survival (DFS), remains to be seen. Our aim of the study is to compare and review different adjuvant regimens used in UCS.

Methods: Retrospective chart analysis included 37 optimally staged UCS patients. Each of them had either received paclitaxel plus carboplatin (PC) or paclitaxel, ifosfamide, and cisplatin (TIP). A toxicity analysis was charted as per common terminology criteria for adverse events (CTCAE) 4 criteria. A survival analysis was done by the Kaplan-Meier method, and log-rank test was used for comparison of two variables.

Results: Incidence of UCS was 4.1% and mean age (standard deviation) was 58.73 ± 6.3 (range 42 - 71) years. TIP and PC chemotherapies were given to 22 and 15 patients, respectively. Five-year DFS and overall survival for TIP versus PC were 38.2% versus 35.9% (P = 0.118) and 49% versus 50.3% (P = 0.306), respectively, and for Stage I, II versus Stage III was 78.8% versus 12.7%(P = 0.001) and 92.3% versus 34.2% (P = 0.002), respectively. However, in advanced disease (Stage III), there is a trend toward DFS advantage of triple-drug adjuvant regimen (Hazards ratio (HR) = 0.35, 95% confidence interval (CI) = 0.12-1.07). Grade 3 and 4 toxicities were seen in 54.5% patients of TIP chemotherapy group and in 13.3% patients of the PC chemotherapy (P = 0.012).

Conclusion: Triple-drug adjuvant chemotherapy (TIP) confers no survival advantage over doublet chemotherapy (PC), and in turn, increases the grade 3/4 toxicity in the adjuvant setting of optimally staged UCS patients.
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http://dx.doi.org/10.4103/ijc.IJC_57_19DOI Listing
November 2021

Endoscopic tympanic neurectomy in the management of persistent parotid fistulae.

Braz J Otorhinolaryngol 2021 Jan-Feb;87(1):114-117. Epub 2020 Nov 23.

Seth G.S. Medical College, Department of Otorhinolaryngology, Mumbai, India.

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http://dx.doi.org/10.1016/j.bjorl.2020.09.016DOI Listing
May 2021

Unusual case of ductal breast carcinoma with vulvar metastasis.

Breast J 2020 11 2;26(11):2255-2256. Epub 2020 Oct 2.

Department of Clinical Research, Rajiv Gandhi Cancer Institute & Research Centre, Delhi, India.

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http://dx.doi.org/10.1111/tbj.14067DOI Listing
November 2020

Computational investigation for modeling the protein-protein interaction of TasA-TapA: a decisive process in biofilm formation by Bacillus subtilis.

J Mol Model 2020 Aug 10;26(9):226. Epub 2020 Aug 10.

Department of Biotechnology, School of Life Sciences, Central University of Rajasthan - Kishangarh, Ajmer, 305817, Rajasthan, India.

Biofilms have a significant role in microbial persistence, antibiotic resistance, and chronic infections; consequently, there is a pressing need for development of novel "anti-biofilm strategies." One of the fundamental mechanisms involved in biofilm formation is protein-protein interactions of "amyloid-like proteins" (ALPs) in the extracellular matrix. Such interactions could be potential targets for development of novel anti-biofilm strategies; therefore, assessing the structural features of these interactions could be of great scientific value. Characterization of structural features the of protein-protein interaction with conventional structure biology tools including X-ray diffraction and nuclear magnetic resonance is technically challenging, expensive, and time-consuming. In contrast, modeling such interactions is time-efficient and economical, and might provide deeper understanding of structural basis of interactions. Although it is often acknowledged that molecular modeling methods have varying accuracy, their careful implementation with supplementary verification methods can provide valuable insight and directions for future studies. With this reasoning, during the present study, the protein-protein interaction of TasA-TapA (which is a decisive process for biofilm formation by Bacillus subtilis) was modeled using in silico approaches, viz., molecular modeling, protein-protein docking, and molecular dynamics simulations. Results obtained here identified amino acid residues present within intrinsically disordered regions of both proteins to be critical for interaction. These results were further supported with principal component analyses (PCA) and free energy landscape (FEL) analyses. Results presented here represent novel finding, and we hypothesize that amino acid residues identified during the present study could be targeted for inhibition of biofilm formation by B. subtilis.
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http://dx.doi.org/10.1007/s00894-020-04507-0DOI Listing
August 2020

Role of F-Flurodeoxyglucose Positron-Emission Tomography/Computed Tomography in the Evaluation of Early Response to Neoadjuvant Chemotherapy in Patients with Locally Advanced Triple-Negative Breast Cancer.

Indian J Nucl Med 2020 Apr-Jun;35(2):105-109. Epub 2020 Mar 12.

Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India.

Background: Response evaluation in locally advanced breast cancer is done through different methods ranging from clinical examination to magnetic resonance imaging, however evaluation with positron-emission tomography/computed tomography (PET/CT) in now being incorporated for the response evaluation. The aim of the present study is to correlate response to neoadjuvant chemotherapy (NACT) with PET/CT scan.

Materials And Methods: The present study is a retrospective analysis of 30 locally advanced, triple-negative breast cancer patients. PET/CT scan was done pretreatment and post three and six cycles of NACT and was correlated with pathologic complete response (pCR). Responding disease was considered when there was at least a 50% reduction in the longest diameter.

Results: The median pretreatment size of the breast lesion in CT scan was 3.9 ± 2.3 cm (2-12 cm) and maximum standardized uptake value (SUVmax) on PET/CT was 8.5 ± 5.5 (2.9-24). Among the responders, the median decrease in size of lesion was 3.2 ± 1.3 cm and median reduction in SUV of the tumor among was -8.1 ± 5.4 and was statistically significant when compared with nonresponders ( < 0.001). CT scan has 66% accuracy and PET has 82% accuracy at post three cycles NACT in predicting the pathological response. PET/CT had higher sensitivity and specificity when compared with CT findings alone in response evaluation.

Conclusion: PET/CT scan can be considered as a sensitive tool for predicting pCRs and further larger trials are required to establish these findings.
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http://dx.doi.org/10.4103/ijnm.IJNM_210_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182325PMC
March 2020

Efficacy and tolerability of nimotuzumab in combination with chemotherapy in recurrent and metastatic squamous cell carcinoma of head and neck at a cancer center in Northern India.

Indian J Cancer 2020 Jan-Mar;57(1):76-83

Department of Medical Oncology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India.

Introduction: Squamous cell carcinoma of head and neck (SCCHN) account for approximately 30-33% of all cancer and the median survival for recurrent and metastatic(R/M) SCCHN remains less than 1 year despite modern advances in therapy. Chemotherapy, usually single agent remains the backbone of therapy in these patients. EGFR antibodies are being used in (R/M) SCCHN. Nimotuzumab is one such agent that has anti-EGFR action similar to other agents without similar skin toxicity.

Methods: Prospective, interventional, non-randomized study done at Rajiv Gandhi Cancer Institute and Research Centre. A total 124 patients were enrolled and divided into Arm A (Chemotherapy + Nimotuzumab) and Arm B (Chemotherapy) in a ratio of 1:1 i.e., 62 in each arm. They were evaluated and treated as per protocol after a written informed consent. Statistical analysis was done using the SPSS software. Quantitative variables were compared using Unpaired t-test/Mann-Whitney Test. Qualitative variables were compared using Chi-Square test /Fisher's exact test. Kaplan-Meier analysis was used to assess the PFS, with log rank test for comparison between the groups. A p value of < 0.05 was considered statistically significant.

Results: The most frequent primary location of tumor was oral cavity (n=38, 69%) and (n=33, 56.9%) in both arms. The overall response rate in Arm A was 38.2% and 19% in Arm B (p= 0.023). The disease control rate in Arm A was 74.5% and 43.1% Arm B (p= 0.0007). The median PFS in Arm A was 5.2 months whereas it was 3.2 months in Arm B (p= 0.009).

Conclusion: In this study, the combination of Nimotuzumab plus platinum/taxane based chemotherapy was active and well tolerated in Indian patients in R/M SCCHN. Addition of Nimotuzumab to chemotherapy had a response rate of 38.2% and median PFS of 5.2 months are strong arguments for clinically testing this combination.
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http://dx.doi.org/10.4103/ijc.IJC_469_18DOI Listing
October 2020

Long-Term Survival in an Esophageal Cancer Patient with Multiple Recurrences.

J Gastrointest Cancer 2020 Jun;51(2):695-697

Department of Medical Oncology, Rajiv Gandhi Cancer Institute & Research Centre, Sector-5, Rohini, Delhi, India.

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http://dx.doi.org/10.1007/s12029-020-00366-3DOI Listing
June 2020

Case study: cochlear implantation in cochlear otospongiosis.

Cochlear Implants Int 2020 03 23;21(2):121-125. Epub 2019 Oct 23.

Department of ENT, Seth G.S. Medical College and KEM Hospital, Parel, Mumbai, Maharashtra, India.

Cochlear implantation can be performed successfully in patients with otospongiosis of the temporal bone with the potential for excellent audiological outcomes and high patient satisfaction. The purpose of this case report is to highlight the clinical considerations for implantation in cochlear otospongiosis including the need for careful pre-operative implant device selection, intra-operative surgical challenges such as the presence of hypervascularity and possible cochlear ossification resulting in difficulty in placing the electrode array and the possibility of postoperative facial nerve stimulation. A 14-year-old girl with cochlear otospongiosis likely due to osteogenesis imperfecta presented with progressive bilateral profound sensorineural hearing loss underwent successful cochlear implantation despite several challenges. Cochlear implantation in patients with cochlear otospongiosis with profound sensorineural hearing loss potentially may be very successful. Thorough pre-operative radiological evaluation is necessary. Possible intra-operative and post-operative challenges unique to these patients must be kept in mind. Adequate precautions should be taken to optimize the likelihood of complete electrode insertion such as using a depth gauge prior to inserting the electrode array and performing an intra-operative x-ray and / or neural response telemetry to confirm correct electrode placement.
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http://dx.doi.org/10.1080/14670100.2019.1678894DOI Listing
March 2020

Novel cell line models to study mechanisms and overcoming strategies of proteasome inhibitor resistance in multiple myeloma.

Biochim Biophys Acta Mol Basis Dis 2019 06 4;1865(6):1666-1676. Epub 2019 Apr 4.

University Hospital of Würzburg, Comprehensive Cancer Center Mainfranken, Translational Oncology, Würzburg, Germany.

Experimental data on resistance mechanisms of multiple myeloma (MM) to ixazomib (IXA), a second-generation proteasome inhibitor (PI), are currently lacking. We generated MM cell lines with a 10-fold higher resistance to IXA as their sensitive counterparts, and observed cross-resistance towards the PIs carfilzomib (CFZ) and bortezomib (BTZ). Analyses of the IXA-binding proteasome subunits PSMB5 and PSMB1 show increased PSMB5 expression and activity in all IXA-resistant MM cells, and upregulated PSMB1 expression in IXA-resistant AMO1 cells. In addition, sequence analysis of PSMB5 revealed a p.Thr21Ala mutation in IXA-resistant MM1.S cells, and a p.Ala50Val mutation in IXA-resistant L363 cells, whereas IXA-resistant AMO1 cells lack PSMB5 mutations. IXA-resistant cells retain their sensitivity to therapeutic agents that mediate cytotoxic effects via induction of proteotoxic stress. Induction of ER stress and apoptosis by the p97 inhibitor CB-5083 was strongly enhanced in combination with the PI3Kα inhibitor BYL-719 or the HDAC inhibitor panobinostat suggesting potential therapeutic strategies to circumvent IXA resistance in MM. Taken together, our newly established IXA-resistant cell lines provide first insights into resistance mechanisms and overcoming treatment strategies, and represent suitable models to further study IXA resistance in MM.
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http://dx.doi.org/10.1016/j.bbadis.2019.04.003DOI Listing
June 2019

Thrombin stimulates gene expression and secretion of IL-11 via protease-activated receptor-1 and regulates extravillous trophoblast cell migration.

J Reprod Immunol 2019 04 9;132:35-41. Epub 2019 Mar 9.

Department of Biotechnology, School of Life Sciences, Central University of Rajasthan, Bandarsindri, Kishangarh, Rajasthan 305817 India. Electronic address:

Extravillous trophoblast (EVT) migration and invasion is the crucial step for normal placental development. IL-11 is a cytokine regulating cell migration and invasion in cells and is a critical factor for successful implantation of an embryo. Higher expression of thrombin receptor PAR-1 was reported in early pregnancy. The precise role of thrombin in trophoblast functions is not well understood. In this study, we asked whether thrombin can induce IL-11 secretion in trophoblasts if yes, which physiological cell functions are possibly affected? In this study, HTR-8/SVneo cells, which were originally derived from first-trimester villous explants of early pregnancy were used as the extravillous trophoblast (EVT) model. BeWo cells were used as the cytotrophoblast model. For gene silencing, qPCR and ELISA, each experiment was performed in triplicates for minimum three times. Here, we found that thrombin stimulates IL-11 gene expression and protein secretion in HTR-8/SVneo cells but not in BeWo cells. PAR-1 was the only receptor which was highly expressed in HTR-8/SVneo cells. Thrombin-mediated expression and secretion of IL-11 were mainly activated via PAR-1 receptor. Rac1, but not Rho-kinase activation is required for thrombin-induced IL-11 secretion. We also found that thrombin stimulation significantly enhanced cell migration that was inhibited after silencing the IL-11 gene. In conclusion, this study demonstrates the role of thrombin in regulating human EVT migration via IL-11 secretion. We propose that thrombin might regulate EVT migration through the decidua and spiral artery remodeling. Failure of thrombin-dependent EVT migration results in pregnancy disorder, such as preeclampsia.
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http://dx.doi.org/10.1016/j.jri.2019.03.001DOI Listing
April 2019

The mechanism of phosphatidylcholine-induced interference of PAP (248-286) aggregation.

J Pept Sci 2019 Apr 19;25(4):e3152. Epub 2019 Feb 19.

Department of Biotechnology, Central University of Rajasthan, Ajmer, India.

Seminal amyloids are well known for their role in enhancing HIV infection. Among all the amyloidogenic peptides identified in human semen, PAP was found to be the most active and was termed as semen-derived enhancer of viral infection (SEVI). Although amyloidogenic nature of the peptide is mainly linked with enhancement of the viral infection, the most active physiological conformation of the aggregated peptide remains inconclusive. Lipids are known to modulate aggregation pathway of a variety of proteins and peptides and constitute one of the most abundant biomolecules in human semen. PAP significantly differs from the other known amyloidogenic peptides, including Aβ and IAPP, in terms of critical concentration, surface charge, fibril morphology, and structural transition during aggregation. Hence, in the present study, we aimed to assess the effect of a lipid, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), on PAP aggregation and the consequent conformational outcomes. Our initial observation suggested that the presence of the lipid considerably influenced the aggregation of PAP . Further, ZDOCK and MD simulation studies of peptide multimerization have suggested that the hydrophobic residues at C-terminus are crucial for PAP aggregation and are anticipated to be major DOPC-interacting partners. Therefore, we further assessed the aggregation behaviour of C-terminal (PAP ) fragment of PAP and observed that DOPC possesses the ability to interfere with the aggregation behaviour of both the peptides used in the current study. Mechanistically, we propose that the presence of DOPC causes considerable inhibition of the peptide aggregation by interfering with the peptide's disordered state to β-sheet transition.
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http://dx.doi.org/10.1002/psc.3152DOI Listing
April 2019

Ki-67 labeling index as a predictor of response to neoadjuvant chemotherapy in breast cancer.

Jpn J Clin Oncol 2019 Apr;49(4):329-338

Medical Oncology, Rajiv Gandhi Cancer Institute & Research Centre, New Delhi, India.

Aims: To investigate Ki-67 index with regard to its ability to predict achievement of pathologic complete response (pCR) to neoadjuvant chemotherapy (NACT) in breast cancer patient.

Material And Methods: It was a prospective observational study, conducted in Department of Medical Oncology, Rajiv Gandhi Cancer Institute & Research Center (RGCIRC), New Delhi from February 2014 to March 2016. A total of 134 patients with Stage II/III breast cancer who underwent NACT followed by surgery at our center were enrolled and analyzed. Before starting the treatment, clinical, tumor-related and treatment-related factors were recorded. Response evaluation was done clinically and radiologically after completion of NACT and pathologically on the surgical specimen. We calculated Ki-67 cut-off of 35% to label it as high by area under Receiver operating characteristic curve analysis for prediction of pCR.

Results: Clinical complete response (cCR) was observed in 35/134 (26.1%) patients while pCR was observed in 32/134 (23.9%) patients. On univariate analysis, higher grade (III), high Ki-67 index (>35%) and number of chemotherapy cycles (>3) were associated with better CCR rates. On multivariate analysis, number of chemotherapy cycles (>3) and high Ki-67 index (>35%) were independent predictive factors. For the predictive factors of pCR, univariate analysis showed grade (III), estrogen receptor/progesterone receptor negativity, HER-2 positivity, number of chemotherapy cycles (>3), TNBC and high Ki-67 index (>35%) to be associated with higher pCR rates. On multivariate analysis, Ki-67 index >35% and HER-2 positivity were the only independent predictive factors of pCR.

Conclusions: We suggest 35% as best cut-off for Ki-67 expression for predicting response to NACT and achievement of pCR. Validation of this cut-off is required in larger studies.
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http://dx.doi.org/10.1093/jjco/hyz012DOI Listing
April 2019

Mammalian antimicrobial peptide protegrin-4 self assembles and forms amyloid-like aggregates: Assessment of its functional relevance.

J Pept Sci 2019 Mar 3;25(3):e3151. Epub 2019 Feb 3.

Department of Biotechnology, Central University of Rajasthan, Ajmer, India.

Protegrin-4 (PG-4) is a member of the porcine leukocyte protegrins family of cysteine-rich antimicrobial peptides (AMPs) isolated from Sus scrofa. It consists of 18 amino acid residues and works as a part of innate immune system. In this study, we examined the intrinsic aggregation propensity of this AMP using multiple computational algorithms, namely, TANGO, AGGRESCAN, FOLDAMYLOID, AMYLPRED, and ZYGGREGATOR, and found that the peptide is predicted to have a high propensity for the β sheet formation that disposes this peptide to be amyloidogenic. Under in vitro conditions, PG-4 formed visible aggregates and displayed the hallmark properties of typical amyloids such as enhanced binding of Congo red, increased fluorescence with Thioflavin-T, and fibrillar morphology under transmission electron microscopy. Then we examined its antimicrobial activity against Bacillus subtilis and found that the aggregated peptide retained its antimicrobial activity. Additionally, the aggregates remain non-toxic to the HEK293 and Caco2 cells. Our study suggests that the inherent aggregation properties of AMP can rationally be explored as a potential source of peptide-based antimicrobials with enhanced stability.
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http://dx.doi.org/10.1002/psc.3151DOI Listing
March 2019

Treatment response to indacaterol/glycopyrronium versus salmeterol/fluticasone in exacerbating COPD patients by gender: a post-hoc analysis in the FLAME study.

Respir Res 2019 Jan 8;20(1). Epub 2019 Jan 8.

Respiratory Medicine Department, University of Ioannina Medical School, Ioannina, Greece.

Background: The burden of chronic obstructive lung disease (COPD) is increasing in women, with recent evidence suggesting gender differences in disease characteristics and potentially in treatment outcomes.

Methods: FLAME was a 52-week randomized controlled trial in patients with severe-to-very-severe COPD and a history of exacerbations. In this post-hoc analysis, gender-based baseline differences and treatment outcomes between indacaterol/glycopyrronium 110/50 μg once daily (IND/GLY) and salmeterol/fluticasone 50/500 twice daily (SFC) were assessed in terms of rate of exacerbations, time-to-first exacerbation, lung function, health status, and rescue medication use.

Results: This post-hoc analysis included 2557 men and 805 women. Baseline characteristics differed between genders, with women being younger, having better lung function and more often experiencing ≥2 exacerbations in the previous year. Compared with SFC, IND/GLY treatment was associated with reductions in the annualized rates of moderate/severe exacerbations (rate ratio [95% CI]: 0.81 [0.73-0.91], 0.89 [0.74-1.07] in men and women, respectively). Similarly, time-to-first moderate/severe exacerbation was also delayed (hazard ratio [95% CI]: 0.79 [0.70-0.89] and 0.76 [0.63-0.91] in men and women, respectively). Results were similar for all (mild/moderate/severe) exacerbations. Improvements in lung function, health status and rescue medication use with IND/GLY vs SFC were comparable between men and women. The smaller sample size for women may account for some observed discrepancies in treatment responses.

Conclusions: Although there were gender differences in baseline characteristics, IND/GLY demonstrated similar trends for exacerbation prevention and lung function improvement in men and women with moderate-to-very-severe COPD and a history of exacerbations compared with SFC. Small differences in the effects seen between genders may be attributed to the different sizes of the two groups and need to be further evaluated in randomized trials that are appropriately powered for gender analysis.

Trial Registration: Post hoc analysis of the FLAME study. ClinicalTrials.gov number: NCT01782326 . Registered 1 February 2013.
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http://dx.doi.org/10.1186/s12931-019-0972-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325763PMC
January 2019
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