Publications by authors named "Seema Gupta"

130 Publications

Targeting radiation-induced upstream stimulatory factor-1 by histone deacetylase inhibitors to reverse radioresistance in prostate cancer.

Cancer Rep (Hoboken) 2021 Sep 17:e1553. Epub 2021 Sep 17.

Department of Radiation Oncology, University of Miami, Miami, Florida, USA.

Background: Ionizing radiation (IR) is a standard modality for the management of solid tumors. Apart from its killing effects, IR can induce pro-survival factors leading to radioresistance of cancer. Mechanistic understanding of radiation resistance is warranted to overcome the pro-survival effects of IR.

Aim: The aim of this study was to investigate the role of upstream stimulatory factor-1 (USF-1) in the induction of radioresistance in prostate cancer and its targeting by histone deacetylase (HDAC) inhibitors to reverse resistance.

Methods And Results: This study reports here that USF-1 is a marker for radioresistance in PC-3 cells. Using protein-DNA array analysis, it was documented that DNA binding activity of USF-1 was elevated following IR in PC-3 cells. Novel HDAC inhibitors downregulated USF-1 binding either alone or in combination with IR. A 5 Gy dose of IR induced the expression of target genes of USF-1 (human telomerase reverse transcriptase [hTERT], IGF2R, CyclinB1, and Cdk1), however, HDAC inhibitors alone or in combination with IR reduced their expression as measured by real time RT PCR analysis. Furthermore, immunofluorescence analysis revealed that while USF-1 localized primarily in the nucleus following IR, it localized in the cytoplasm when treated with HDAC inhibitors/combination. Maximum effects of modulation of USF-1 expression (overexpression or suppression) were observed on hTERT activity as determined by dual-luciferase reporter assay. To further confirm the role of USF-1 in radioresistance, cell growth was analyzed using the real-time cell electronic sensing (RT-CES) system. This study found that USF-1-transfected cells proliferated faster than the vector-transfected cells with or without treatments with HDAC inhibitors/IR/combination. Colony forming assay also confirmed that USF-1 overexpression led to increased survival following IR. Importantly, colony-forming assay demonstrated that HDAC inhibitors reversed the radioresistance in both PC-3 and DU-145 cells.

Conclusion: These studies demonstrate that HDAC inhibitors reverse the radioresistance in prostate cancer through down-modulation of USF-1-mediated transactivation of target genes involved in cell proliferation and cell cycle.
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http://dx.doi.org/10.1002/cnr2.1553DOI Listing
September 2021

Accuracy of OCT-derived net corneal astigmatism measurement.

J Cataract Refract Surg 2021 Jul 27. Epub 2021 Jul 27.

Casey Eye Institute and Department of Ophthalmology, Oregon Health and Science University, Portland, Oregon, USA.

Purpose: To assess the repeatability and accuracy of corneal astigmatism measurement with a spectral-domain optical coherence tomography (OCT) system (Avanti, Optovue) and compare them with Scheimpflug imaging (Pentacam HR, Oculus) and swept-source optical biometry (IOLMaster 700, Carl Zeiss Mediatec AG).

Setting: Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, USA.

Design: Prospective cross-sectional observational study.

Methods: Sixty pseudophakic eyes with monofocal non-toric intraocular lens that previously had refractive surgery were analyzed. To assess accuracy, simulated keratometric (SimK) and net corneal astigmatism, obtained from each device were compared with subjective manifest refraction astigmatism. Repeatability for corneal astigmatism was assessed for OCT and Pentacam HR by the coefficient of repeatability from three repeated measures.

Results: Compared to manifest refraction, SimK readings produced with-the-rule (WTR) astigmatic bias which was reduced for net astigmatism for all the three devices. Except for OCT net astigmatism, all instruments significantly overestimated the magnitude of the astigmatism (linear mixed-effects model (LMM), P < .05). OCT net astigmatism showed the highest accuracy for manifest astigmatism prediction with the smaller 95% confidence ellipse for the mean difference vector. OCT net mean absolute difference was 0.57 D, significantly smaller than that of the other modalities (LMM, P <.05). Net corneal astigmatism measured with OCT showed the best repeatability (coefficient of repeatability = 0.29 D).

Conclusions: OCT has the capability to measure net corneal astigmatism with higher precision and accuracy than Pentacam HR Scheimpflug imaging and IOLMaster 700 swept-source optical biometry in post refractive patients.
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http://dx.doi.org/10.1097/j.jcrs.0000000000000766DOI Listing
July 2021

Catering the Needs of Cancer Contemporary to this Contagious Corona Catastrophe: Institution Based Changes in Cancer Management and Protection Procedures.

J Biomed Phys Eng 2021 Jun 1;11(3):403-406. Epub 2021 Jun 1.

PhD, Department of Radiotherapy, King George's Medical University, Lucknow, Uttar Pradesh, India.

The COVID-19 global pandemic has drastically affected the health care facility worldwide, posing unprecedented challenges in front of the caregivers. All hospitals need adopt measures to protect patients and health professionals and to safely triage patients (according to country/regional directives) for identifying those infected with coronavirus. As very few guidelines are available for care of cancer patients during COVID times, institutes have had to make their own strategies, based on their own expertise keeping in mind local directives and their effect on available resources and routine processes to offer best possible care. In this article, we have discussed in-house protocols for modification and prioritization of radical and palliative multimodality treatment of cancer patients along with our infection control measures in accordance with national and local guidelines during COVID emergency to stay safe and health. Also, the current study aims to modify cancer treatment and care during the COVID-19 pandemic adhering and fulfilling all protective measures.
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http://dx.doi.org/10.31661/jbpe.v0i0.2011-1228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236096PMC
June 2021

A Study to Assess the Dosimetric Impact of the Anatomical Changes Occurring in the Parotid Glands and Tumour Volume during Intensity Modulated Radiotherapy using Simultaneous Integrated Boost (IMRT-SIB) in Head and Neck Squamous Cell Cancers.

Cancer Med 2021 Aug 22;10(15):5175-5190. Epub 2021 Jun 22.

Toxicology and Experimental Medicine Division, CSIR-Central Drug Research Institute, Lucknow, India.

Background: Anatomical variations in head and neck cancer during IMRT leads to volume shrinkage, results in dosimetric variations in tumour and normal tissue including parotid glands, with a risk of radiation toxicities.

Methods: 30 patients with a stage II-IV head and neck squamous cell carcinoma (HNSCC) were treated with definitive IMRT-SIB and concomitant chemotherapy. Volumetric and dosimetric variations were evaluated during the period of IMRT by recalculating and obtaining dose-volume histograms of re-contoured target volumes and parotid glands on repeat CT scans taken multiple times during treatment (CT1, CT2, CT3 and CT4).

Results: Result showed significant (p < 0.001) mean decrease in both primary and nodal tumors volume with time whereas increase (p < 0.01 or p < 0.001) in respective V100 (%) and D2% (Gy). The mean parotid gland dose increased (p < 0.01 or p < 0.001) with time, whereas parotid gland volume and distance between plan isocenter and centre of mass of parotid glands decreased (p < 0.05 or p < 0.001) with time. Patient's mean weight and neck circumference both decrease (p < 0.001) with time whereas ECOG score increase (p < 0.001) with time. The mucosal toxicity increased significantly (p < 0.001) with time. The change in both weight and neck circumference showed significant (p < 0.001) and direct (positive correlation) association with change in parotid gland volume.

Conclusion: If the PTV and normal anatomy are changing with time, adaptive IMRT would be beneficial radiation dose delivery where possible.
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http://dx.doi.org/10.1002/cam4.4079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335829PMC
August 2021

Alteration in biochemical parameters during plateletpheresis in healthy donors: A compendious analysis.

Transfus Clin Biol 2021 Aug 20;28(3):239-245. Epub 2021 May 20.

Department of Biochemistry, Government Medical College and Hospital, Chandigarh, India.

Objectives: During plateletpheresis, citrate induces hypocalcemia and hypomagnesemia, which are usually transient and self-limiting, but they can lead to significant donor discomfort. The aim of study was to determine the effect of citrate infusion on a multitude of biochemical parameters during plateletpheresis in healthy donors and to correlate changes with adverse donor reactions.

Methods: The study was conducted on 60 healthy plateletpheresis donors. Blood samples were drawn on three occasions, a baseline pre-donation sample, 30min at start of procedure and 30min post procedure. Heparinized samples were taken to measure ionized calcium and plain samples to measure serum calcium, serum magnesium, parathyroid hormone, total protein and serum albumin.

Results: There was statistically significant decline in mean total calcium (9.27±0.66mg/dl to 8.72±0.87mg/dl) and ionized calcium (3.8±0.51mg/dl to 2.9±0.67mg/dl) from baseline until 30min after the start of procedure respectively. A significant fall in serum magnesium, total protein and serum albumin was observed. The mean parathyroid hormone showed significant increase from baseline levels till at the completion of procedure (19.94±12.1pg/ml to 92.08±36.78pg/ml). If the yield was set constant, there was negative correlation between ACD used and pre-donation platelet count. Majority of adverse donor reactions were hypocalcemic reactions, which were more with Amicus double yield plateletpheresis and were managed with calcium supplementation.

Conclusion: Plateletpheresis induces marked reduction in serum calcium and magnesium levels. Moreover, increase in parathyroid hormone levels was significant. In addition, decline in total protein and serum albumin may be a concern in donors also participating in plasmapheresis.
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http://dx.doi.org/10.1016/j.tracli.2021.04.010DOI Listing
August 2021

Radiation dose and fraction in immunotherapy: one-size regimen does not fit all settings, so how does one choose?

J Immunother Cancer 2021 Apr;9(4)

Radiation Research Program, National Cancer Institute Division of Cancer Treatment and Diagnosis, Bethesda, Maryland, USA

Recent evidence indicates that ionizing radiation can enhance immune responses to tumors. Advances in radiation delivery techniques allow hypofractionated delivery of conformal radiotherapy. Hypofractionation or other modifications of standard fractionation may improve radiation's ability to promote immune responses to tumors. Other novel delivery options may also affect immune responses, including T-cell activation and tumor-antigen presentation changes. However, there is limited understanding of the immunological impact of hypofractionated and unique multifractionated radiotherapy regimens, as these observations are relatively recent. Hence, these differences in radiotherapy fractionation result in distinct immune-modulatory effects. Radiation oncologists and immunologists convened a virtual consensus discussion to identify current deficiencies, challenges, pitfalls and critical gaps when combining radiotherapy with immunotherapy and making recommendations to the field and advise National Cancer Institute on new directions and initiatives that will help further development of these two fields.This commentary aims to raise the awareness of this complexity so that the need to study radiation dose, fractionation, type and volume is understood and valued by the immuno-oncology research community. Divergence of approaches and findings between preclinical studies and clinical trials highlights the need for evaluating the design of future clinical studies with particular emphasis on radiation dose and fractionation, immune biomarkers and selecting appropriate end points for combination radiation/immune modulator trials, recognizing that direct effect on the tumor and potential abscopal effect may well be different. Similarly, preclinical studies should be designed as much as possible to model the intended clinical setting. This article describes a conceptual framework for testing different radiation therapy regimens as separate models of how radiation itself functions as an immunomodulatory 'drug' to provide alternatives to the widely adopted 'one-size-fits-all' strategy of frequently used 8 Gy×3 regimens immunomodulation.
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http://dx.doi.org/10.1136/jitc-2020-002038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8031689PMC
April 2021

Biology of NSCLC: Interplay between Cancer Cells, Radiation and Tumor Immune Microenvironment.

Cancers (Basel) 2021 Feb 12;13(4). Epub 2021 Feb 12.

Research Institute of Clinical Medicine, 13 Tevdore Mgdveli, Tbilisi 0112, Georgia.

The overall prognosis and survival of non-small cell lung cancer (NSCLC) patients remain poor. The immune system plays an integral role in driving tumor control, tumor progression, and overall survival of NSCLC patients. While the tumor cells possess many ways to escape the immune system, conventional radiotherapy (RT) approaches, which are directly cytotoxic to tumors, can further add additional immune suppression to the tumor microenvironment by destroying many of the lymphocytes that circulate within the irradiated tumor environment. Thus, the current immunogenic balance, determined by the tumor- and radiation-inhibitory effects is significantly shifted towards immunosuppression, leading to poor clinical outcomes. However, newer emerging evidence suggests that tumor immunosuppression is an "elastic process" that can be manipulated and converted back into an immunostimulant environment that can actually improve patient outcome. In this review we will discuss the natural immunosuppressive effects of NSCLC cells and conventional RT approaches, and then shift the focus on immunomodulation through novel, emerging immuno- and RT approaches that promise to generate immunostimulatory effects to enhance tumor control and patient outcome. We further describe some of the mechanisms by which these newer approaches are thought to be working and set the stage for future trials and additional preclinical work.
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http://dx.doi.org/10.3390/cancers13040775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918834PMC
February 2021

Recent Advances in a Polydopamine-Mediated Antimicrobial Adhesion System.

Front Microbiol 2020 12;11:607099. Epub 2021 Jan 12.

Nucleic Acids Research Laboratory, CSIR-Institute of Genomics and Integrative Biology, Delhi, India.

The drug resistance developed by bacteria during antibiotic treatment has been a call to action for researchers and scientists across the globe, as bacteria and fungi develop ever increasing resistance to current drugs. Innovative antimicrobial/antibacterial materials and coatings to combat such infections have become a priority, as many infections are caused by indwelling implants (e.g., catheters) as well as improving postsurgical function and outcomes. Pathogenic microorganisms that can exist either in planktonic form or as biofilms in water-carrying pipelines are one of the sources responsible for causing water-borne infections. To combat this, researchers have developed nanotextured surfaces with bactericidal properties mirroring the topographical features of some natural antibacterial materials. Protein-based adhesives, secreted by marine mussels, contain a catecholic amino acid, 3,4-dihydroxyphenylalanine (DOPA), which, in the presence of lysine amino acid, empowers with the ability to anchor them to various surfaces in both wet and saline habitats. Inspired by these features, a novel coating material derived from a catechol derivative, dopamine, known as polydopamine (PDA), has been designed and developed with the ability to adhere to almost all kinds of substrates. Looking at the immense potential of PDA, this review article offers an overview of the recent growth in the field of PDA and its derivatives, especially focusing the promising applications as antibacterial nanocoatings and discussing various antimicrobial mechanisms including reactive oxygen species-mediated antimicrobial properties.
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http://dx.doi.org/10.3389/fmicb.2020.607099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835282PMC
January 2021

Shifting the Immune-Suppressive to Predominant Immune-Stimulatory Radiation Effects by SBRT-PArtial Tumor Irradiation Targeting HYpoxic Segment (SBRT-PATHY).

Cancers (Basel) 2020 Dec 26;13(1). Epub 2020 Dec 26.

MedAustron Ion Therapy Center, Marie Curie-Straße 5, 2700 Wiener Neustadt, Austria.

Radiation-induced immune-mediated abscopal effects (AE) of conventional radiotherapy are very rare. Whole-tumor irradiation leads to lymphopenia due to killing of immune cells in the tumor microenvironment, resulting in immunosuppression and weak abscopal potential. This limitation may be overcome by partial tumor irradiation sparing the peritumoral immune-environment, and consequent shifting of immune-suppressive to immune-stimulatory effect. This would improve the radiation-directed tumor cell killing, adding to it a component of immune-mediated killing. Our preclinical findings showed that the high-single-dose irradiation of hypoxic tumor cells generates a stronger bystander effect (BE) and AE than the normoxic cells, suggesting their higher "immunogenic potential". This led to the development of a novel Stereotactic Body RadioTherapy (SBRT)-based PArtial Tumor irradiation targeting HYpoxic segment (SBRT-PATHY) for induction of the immune-mediated BE and AE. Encouraging SBRT-PATHY-clinical outcomes, together with immunohistochemical and gene-expression analyses of surgically removed abscopal-tumor sites, suggested that delivery of the high-dose radiation to the partial (hypoxic) tumor volume, with optimal timing based on the homeostatic fluctuation of the immune response and sparing the peritumoral immune-environment, would significantly enhance the immune-mediated anti-tumor effects. This review discusses the current evidence on the safety and efficacy of SBRT-PATHY in the treatment of unresectable hypoxic bulky tumors and its bystander and abscopal immunomodulatory potential.
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http://dx.doi.org/10.3390/cancers13010050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795882PMC
December 2020

MEK inhibition reprograms CD8 T lymphocytes into memory stem cells with potent antitumor effects.

Nat Immunol 2021 01 23;22(1):53-66. Epub 2020 Nov 23.

The Loop Immuno-Oncology Laboratory, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.

Regenerative stem cell-like memory (T) CD8 T cells persist longer and produce stronger effector functions. We found that MEK1/2 inhibition (MEKi) induces T that have naive phenotype with self-renewability, enhanced multipotency and proliferative capacity. This is achieved by delaying cell division and enhancing mitochondrial biogenesis and fatty acid oxidation, without affecting T cell receptor-mediated activation. DNA methylation profiling revealed that MEKi-induced T cells exhibited plasticity and loci-specific profiles similar to bona fide T isolated from healthy donors, with intermediate characteristics compared to naive and central memory T cells. Ex vivo, antigenic rechallenge of MEKi-treated CD8 T cells showed stronger recall responses. This strategy generated T cells with higher efficacy for adoptive cell therapy. Moreover, MEKi treatment of tumor-bearing mice also showed strong immune-mediated antitumor effects. In conclusion, we show that MEKi leads to CD8 T cell reprogramming into T that acts as a reservoir for effector T cells with potent therapeutic characteristics.
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http://dx.doi.org/10.1038/s41590-020-00818-9DOI Listing
January 2021

Biogenic Silver Nanoparticles: Evaluation of Their Biological and Catalytic Potential.

Indian J Microbiol 2020 Dec 27;60(4):468-474. Epub 2020 May 27.

CSIR-Institute of Genomics and Integrative Biology, North Campus, Mall Road, Delhi, Delhi 110007 India.

The biogenic tailoring of silver nanoparticles using plant extract is becoming an attractive approach in the current scenario. (MZ) is well known for its antibacterial, hepato-protective, anti-inflammatory, anti-tussive, anti-fungal, anti-tumour, and free radical scavenging potential. Its plants extract is a rich source of secondary metabolites. Nowadays, silver nanoparticles (AgNPs) have been advocated for a variety of biomedical applications. In present work, silver nanoparticles have been synthesized using an aqueous extract of MZ, physicochemically characterized and finally evaluated for antimicrobial effects, catalytic reduction/degradation of organic dyes and cytotoxicity. The nanosized AgNPs (~ 84 nm) were found to possess prominent antibacterial potential against gram positive and gram negative pathogens (MIC 50 μg/ml) in comparison to native plant extract. Moreover, these particles were found to be non-toxic and efficient eradicators of environmental toxicants via rapid catalytic reduction of toxic chemicals and dyes. Altogether, these results suggest promising potential of these nanoparticles that can be used as multifunctional agents for future biomedical applications.
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http://dx.doi.org/10.1007/s12088-020-00889-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539258PMC
December 2020

Early 3+3 Trial Dose-Escalation Phase I Clinical Trial Design and Suitability for Immune Checkpoint Inhibitors.

Clin Cancer Res 2021 01 20;27(2):485-491. Epub 2020 Oct 20.

Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.

Purpose: Despite the expansion of immune checkpoint inhibitor (ICI) indications, the relationship between ICI dose and toxicity or response is not well established. To understand this correlation, we performed a meta-analysis of ICI trials that used dose escalation.

Experimental Design: We searched PubMed and abstracts presented at (inter)national meetings for trials using FDA-approved ICIs. The reported rates of grade 3-5 adverse events (G3-5 AE), immune-related adverse events (irAE), and response were correlated with doses within each ICI using marginal exact generalized linear models.

Results: A total of 74 trials (7,469 patients) published between January 2010 and January 2017 were included. For ipilimumab, the incidence of G3-5 AEs was 34% with a significant 27% reduced risk in lower doses ( = 0.002). However, no relationship was observed between dose and irAEs or response. For nivolumab, the incidence of G3-5 AEs was 20.1% which was lower in non-small cell lung cancer (NSCLC) compared with renal cell carcinoma (RCC) or melanoma ( ≤ 0.05) with no dose-toxicity relationship. In melanoma and NSCLC, a dose-response association was observed, which was not observed in RCC. For pembrolizumab, the incidence of G3-5 AEs was 13.3%, which was lower in melanoma compared with NSCLC ( = 0.03) with no dose-toxicity relationship. In melanoma, lower dose levels correlated with decreased odds of response ( = 0.01), a relationship that was not observed in NSCLC.

Conclusions: Our analysis shows a lack of consistent dose-toxicity or dose-response correlation with ICIs. Therefore, dose escalation is not an appropriate design to conduct ICI studies. Here we present an innovative trial design for immune-modulating agents.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2669DOI Listing
January 2021

Increased Expression of Oct4, Nanog and CD24 Predicts Poor Response to Chemo-Radiotherapy and Unfavourable Prognosis in Locally Advanced Oral Squamous Cell Carcinoma.

Asian Pac J Cancer Prev 2020 Sep 1;21(9):2539-2547. Epub 2020 Sep 1.

Department of Pathology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.

Background: Current study investigates the role of Oct4, Nanog and CD24 in locally-advanced oral squamous cell carcinoma (OSCC), to evaluate whether the expression of these markers can predict efficacy of neoadjuvant-chemo-radiotherapy and survival of patients.

Methods: Biomarker expression was evaluated in 50 homogenously treated patients of locally-advanced OSCC.

Results: Clinical response was complete in 30% (n=15), partial response in 46% (n=23), no response in 24% (n=12). Pathologically, 74% patents (n=37) were responders and 26% were non-responders (n=13). Biomarker-overexpression was seen in 46% cases for Oct4, 54% cases for Nanog and 58% cases for CD24. Oct4, Nanog and CD24 expression showed significant correlation with clinical and pathological response (p <0.05). Three year recurrence-free survival was 71%, overall survival was 66%. Post-treatment advanced pathological N (ypN), post treatment advanced pathological TNM (ypTNM) stage, clinical non-response, pathologic non-response, positive/high expression of all three biomarkers had a significant negative impact on recurrence-free and overall survival.

Conclusions: Expressions of Oct4, Nanog and CD24 have significant association with treatment response and survival in patients with locally advanced OSCC treated with neoadjuvant chemo-radiation. Survival of these patients is significantly affected by ypN stage, ypTNM stage, expression of all three biomarkers, clinical and pathological response to neoadjuvant therapy.
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http://dx.doi.org/10.31557/APJCP.2020.21.9.2539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779456PMC
September 2020

Peritonitis-associated hyperlactatemia for evaluating mortality in secondary peritonitis.

ANZ J Surg 2020 12 9;90(12):2463-2466. Epub 2020 Sep 9.

Departments of General Surgery, Government Medical College and Hospital, Sector 32, Chandigarh, India.

Background: In sepsis, lactate measurements correlate with mortality; however, the role of lactate in predicting mortality in patients of secondary peritonitis is not yet fully established.

Methods: Data were maintained prospectively on 224 patients of secondary peritonitis over a period of 10 years. Arterial lactate measurements were performed twice in each patient - once, initially on admission (AL ) and the other, 24 h after surgery (AL ); from these values, percentage lactate clearance was calculated. These lactate indices and other demographic factors were correlated with mortality.

Results: Overall mortality was 16.07% (36 patients) and morbidity was 63.39% (pulmonary complications commonest); preoperative lactate (more than 2.35 mmol/L), 24-h postoperative lactate (more than 2.05 mmol/L), need for vasopressors and mechanical ventilation independently correlated with morbidity and mortality. A simple prognostic scale constructed using cut-off values of AL , AL , need for vasopressor support and mechanical ventilation showed a sensitivity of 97.22% and specificity of 52.13% for predicting mortality.

Conclusion: Preoperative and postoperative arterial lactate levels, need for vasopressors and mechanical ventilation, are independent predictors of mortality. Using these parameters, it may be possible to identify high risk patients that can benefit from early, goal directed therapy to reduce the mortality of secondary peritonitis.
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http://dx.doi.org/10.1111/ans.16278DOI Listing
December 2020

Ultrashort Peptide Self-Assembly: Front-Runners to Transport Drug and Gene Cargos.

Front Bioeng Biotechnol 2020 29;8:504. Epub 2020 May 29.

Nucleic Acids Research Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India.

The translational therapies to promote interaction between cell and signal come with stringent eligibility criteria. The chemically defined, hierarchically organized, and simpler yet blessed with robust intermolecular association, the peptides, are privileged to make the cut-off for sensing the cell-signal for biologics delivery and tissue engineering. The signature service and insoluble network formation of the peptide self-assemblies as hydrogels have drawn a spell of research activity among the scientists all around the globe in the past decades. The therapeutic peptide market players are anticipating promising growth opportunities due to the ample technological advancements in this field. The presence of the other organic moieties, enzyme substrates and well-established protecting groups like Fmoc and Boc etc., bring the best of both worlds. Since the large sequences of peptides severely limit the purification and their isolation, this article reviews the account of last 5 years' efforts on novel approaches for formulation and development of single molecule amino acids, ultra-short peptide self-assemblies (di- and tri- peptides only) and their derivatives as drug/gene carriers and tissue-engineering systems.
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http://dx.doi.org/10.3389/fbioe.2020.00504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273840PMC
May 2020

T-Regulatory Cells In Tumor Progression And Therapy.

Cancer Manag Res 2019 24;11:10731-10747. Epub 2019 Dec 24.

Shanghai Proton and Heavy Ion Center, Shanghai, People's Republic of China.

Regulatory T cells (Tregs) are important members of the immune system regulating the host responses to infection and neoplasms. Tregs prevent autoimmune disorders by protecting the host-cells from an immune response, related to the peripheral tolerance. However, tumor cells use Tregs as a shield to protect themselves against anti-tumor immune response. Thus, Tregs are a hurdle in achieving the complete potential of anti-cancer therapies including immunotherapy. This has prompted the development of novel adjuvant therapies that obviate their negative effects thereby enhancing the therapeutic efficacy. Our earlier studies have shown the efficacy of the glycolytic inhibitor, 2-deoxy-D-glucose (2-DG) by reducing the induced Tregs pool and enhance immune stimulation as well as local tumor control. These findings have suggested its potential for enhancing the efficacy of immunotherapy, besides radiotherapy and chemotherapy. This review provides a brief account of the current status of Tregs as a component of the immune-biology of tumors and various preclinical and clinical strategies pursued to obviate the limitations imposed by them in achieving therapeutic efficacy.
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http://dx.doi.org/10.2147/CMAR.S228887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935360PMC
December 2019

Sectorwise Visual Field Simulation Using Optical Coherence Tomographic Angiography Nerve Fiber Layer Plexus Measurements in Glaucoma.

Am J Ophthalmol 2020 04 23;212:57-68. Epub 2019 Nov 23.

Casey Eye Institute and Department of Ophthalmology, Oregon Health and Science University, Portland, Oregon, USA. Electronic address:

Purpose: To simulate 24-2 visual field (VF) using optical coherence tomographic angiography (OCTA) for glaucoma evaluation.

Design: Cross-sectional study.

Methods: One eye each of 39 glaucoma and 31 age-matched normal participants was scanned using 4.5-mm OCTA scans centered on the disc. The peripapillary retinal nerve fiber layer plexus capillary density (NFLP-CD, %area) was measured. The NFLP-CD and 24-2 VF maps were divided into 8 corresponding sectors using an extension of Garway-Heath scheme.

Results: Sector NFLP-CD was transformed to a logarithmic dB scale and converted to sector simulated VF deviation maps. Comparing simulated and actual 24-2 VF maps, the worst sector was in the same or adjacent location in the same hemisphere 97% of the time. VF mean deviation (VF-MD) was simulated by NFLP mean deviation (NFLP-MD). The differences between NFLP-MD and VF-MD in early, moderate, and severe glaucoma stages were -0.9 ± 2.0, 0.9 ± 2.9, and 5.8 ± 3.2 dB. NFLP-MD had better (P = .015) between-visit reproducibility (0.63 dB pooled standard deviation) than VF-MD (1.03 dB). NFLP-MD had a significantly higher sensitivity than VF-MD (P < .001) and overall NFL thickness (P = .031).

Conclusions: OCTA-based simulated VF agreed well with actual 24-2 VF in terms of both the location and severity of glaucoma damage, with the exception of severe glaucoma in which the simulation tended to underestimate severity. The NFLP-MD had better reproducibility than actual VF-MD and holds promise for improving glaucoma monitoring. The NFLP-MD had better diagnostic accuracy than both VF-MD and overall NFL thickness and may be useful for early glaucoma diagnosis.
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http://dx.doi.org/10.1016/j.ajo.2019.11.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113124PMC
April 2020

PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1CD38 cells and anti-PD-1 resistance.

Nat Immunol 2019 09 29;20(9):1231-1243. Epub 2019 Jul 29.

Georgia Cancer Center, Augusta University, Augusta, GA, USA.

Understanding resistance to antibody to programmed cell death protein 1 (PD-1; anti-PD-1) is crucial for the development of reversal strategies. In anti-PD-1-resistant models, simultaneous anti-PD-1 and vaccine therapy reversed resistance, while PD-1 blockade before antigen priming abolished therapeutic outcomes. This was due to induction of dysfunctional PD-1CD38 CD8 cells by PD-1 blockade in suboptimally primed CD8 cell conditions induced by tumors. This results in erroneous T cell receptor signaling and unresponsiveness to antigenic restimulation. On the other hand, PD-1 blockade of optimally primed CD8 cells prevented the induction of dysfunctional CD8 cells, reversing resistance. Depleting PD-1CD38 CD8 cells enhanced therapeutic outcomes. Furthermore, non-responding patients showed more PD-1CD38CD8 cells in tumor and blood than responders. In conclusion, the status of CD8 T cell priming is a major contributor to anti-PD-1 therapeutic resistance. PD-1 blockade in unprimed or suboptimally primed CD8 cells induces resistance through the induction of PD-1CD38 CD8 cells that is reversed by optimal priming. PD-1CD38 CD8 cells serve as a predictive and therapeutic biomarker for anti-PD-1 treatment. Sequencing of anti-PD-1 and vaccine is crucial for successful therapy.
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http://dx.doi.org/10.1038/s41590-019-0441-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472661PMC
September 2019

The fatal fetal tumor: a geneticist's perspective.

J Matern Fetal Neonatal Med 2021 Mar 3;34(6):1006-1008. Epub 2019 Jun 3.

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital, New Delhi, India.

Epignathus is an extremely rare oral teratoma which leads to high mortality in the early neonatal period. Various theories have been put forward for the genesis of such a tumor, though none is completely convincing. A genetic basis is not well established for the tumor. Microdeletions/duplications, as well as single gene disorders, have been known to cause epignathus, all with additional malformations. Evidence of single gene involvement in an isolated epignathus is lacking. We present a case of a 19-week-fetus with oro-pharyngeal teratoma detected on the level II ultrasound. The couple was counseled regarding the grave prognosis of the fetal condition following which they opted for termination of pregnancy and fetal autopsy. The autopsy revealed fetus-like body attached to the tumor. Genetic testing including a whole genome microarray did not reveal any significant variant. An explanation for the fetus-like body maybe a common origin of the teratoma and the additional fetus-like bodies due to an erroneous process of early embryonic development. Another possibility is of an acardiacus acranius twin masquerading as a fetus-like body. Thus, we conclude that in the absence of an associated malformation, an epignathus is unlikely to have a genetic etiology. This study highlights the importance of performing a fetal autopsy as a part of deep phenotyping to ascertain the etiology, as it identified additional fetal-like body which was not detected on the antenatal ultrasound.
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http://dx.doi.org/10.1080/14767058.2019.1622671DOI Listing
March 2021

Evaluation of the Efficacy of Various Topical Fluorides on Enamel Demineralization Adjacent to Orthodontic Brackets: An Study.

J Contemp Dent Pract 2019 Jan 1;20(1):89-93. Epub 2019 Jan 1.

Department of Prosthodontics, College of Dentistry, Jazan University, Jazan, Kingdom of Saudi Arabia.

Aim: White spot lesions (WSLs) occur frequently after fixed orthodontic treatment. This study was undertaken to compare the efficacy of 2.26% fluoride varnish, 1.23% APF gel, 0.21% fluoride toothpaste and 0.04% sodium fluoride mouthwashes in preventing enamel demineralization around orthodontic brackets in extracted premolars.

Materials And Methods: The sample for this study included 100 premolars free of caries and enamel cracks. They were divided into five groups of 20 samples each. Group 1 (FV): light-curable Fluoride varnish (Clinpro™ XT 3M ESPE, Pymble, New South Wales, Australia), group 2 (FG): 1.23% APF gel (Patterson NE. International, USA), group 3 (FTP): 0.21% w/w sodium fluoride toothpaste with tri-calcium phosphate (Clinpro™ Tooth Crème, 3M ESPE, Australia), group 4 (FMW): sodium fluoride 0.044% (w/v) mouthwash (Colgate® Phos-Flur® Ortho Defense Rinse, Colgate-Palmolive, NY) and group 5 (C): control. The samples were subjected to laboratory pH cycling. The demineralization changes in the enamel were assessed before the start of the experiment and after 14 days.

Results: There was a significant change in the mean Diagnodent score value ( <0.001) in all groups from day 1-day 14. The mean values were significantly different among groups at day 1 ( = 0.002), day 14 ( = 0.001) and also the change from Day 1 to Day 14 was significantly different among Groups ( = 0.001). The least change in the mean value from baseline to 14 days was seen in group 1 (FV) followed by group 3 (FTP), group 2 (FG), and group 4 (FMW) and then the group 5 (C).

Conclusion: All the topical fluorides tested were able to reduce the demineralization when compared to the control group under similar testing conditions, but to varying degrees. light-curable fluoride varnish outperformed all the topical fluorides followed by 0.21% w/w dodium fluoride toothpaste with tri-calcium phosphate, 1.23% Acidulated phosphate fluoride gel and sodium fluoride 0.044% (w/v) mouthwash. The control group where no topical fluoride was applied showed the least resistance to demineralization.

Clinical Significance: Within the limitations of this study, routine application of light cured fluoride varnish (Clinpro) can be recommended to prevent enamel demineralization to prevent white spot lesions in patients receiving orthodontic treatment.
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January 2019

Three-dimensional finite element analysis to evaluate biomechanical effects of different alveolar decortication approaches on rate of canine retraction.

Int Orthod 2019 06 15;17(2):216-226. Epub 2019 Apr 15.

Department of Orthodontics and Dentofacial Orthopaedics, Surendera Dental College and Research Institute, Sri Ganganagar, Rajasthan, India.

Introduction: The aim of this study was to compare different corticotomy approaches and determine their biomechanical effects on rate of canine displacement when compared to conventional orthodontics.

Method: Three-dimensional Finite Element Models with conventional non-corticotomy approach (model 1) and three corticotomy approaches ensuing buccal and palatal vertical cuts (model 2), interseptal bone reduction (model 3), buccal vertical cuts (model 4) were fabricated. Displacement of the canine and von Mises stresses in the canine and trabecular bone were calculated and compared under a distal retraction force of 1.5N.

Results: The maximum displacement of canine with minimum anchorage loss was seen in model 3 followed by model 2, model 4 and model 1. The maximum equivalent (von Mises) stress was concentrated mainly on the distal side of canine in model 3 and had a uniform distribution of stresses on entire root surface.

Conclusions: Corticotomy approaches effectively accelerated maxillary canine retraction, exhibiting twice the rate of canine movement with minimum anchorage loss when compared to non-corticotomy approach. Corticotomy with interseptal bone reduction was most effective in terms of canine displacement and stress distribution.
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http://dx.doi.org/10.1016/j.ortho.2019.03.003DOI Listing
June 2019

Effect of Topical Application of Pure Honey in Chemo-radiation-Induced Mucositis and Its Clinical Benefits in Improving Quality of Life in Patients of Oral Squamous Cell Carcinoma.

J Maxillofac Oral Surg 2019 Mar 11;18(1):73-79. Epub 2018 Jan 11.

3Department of Phytochemistry, National Botanical Research Institute, Lucknow, India.

Oral cancer is a major health problem in India, and in certain parts, it represents more than 50% of all cancers. Since almost all of these patients receive chemo-radiotherapy with or without surgery for treatment, a vast majority of them also develop oral mucositis, a debilitating adverse effect of chemo-radiation. There have been various reports in the literature regarding the beneficial role of honey in the management of oral mucositis. The objective of this study was to investigate whether the application of honey in mucositis confers any significant improvement in lesions of mucositis and more specifically whether application of honey brings about any improvement in the quality of life of patients suffering from chemo-radiation-induced oral mucositis. If found to be beneficial, honey could provide a simple, elegant and cost-effective solution to a troublesome health problem, thus benefiting a large number of patients.
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http://dx.doi.org/10.1007/s12663-017-1077-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328822PMC
March 2019

Manual red cell exchange transfusion to avert sickle cell related complications.

Asian J Transfus Sci 2018 Jul-Dec;12(2):157-159

Department of Immunohematology and Blood Transfusion, MGM Medical College and Hospital, Mumbai, Maharashtra, India.

Sickle cell-beta thalassemia is a double heterozygous state. Red cell exchange (RCE) transfusion reduces the concentration of sickle cells without increasing the hematocrit or whole-blood viscosity. It can be performed manually or by erythrocytapheresis. RCE transfusion is an effective tool for both acute and chronic complications of sickle cell disease. In patients unaffording erythrocytapheresis, even manual RCE can give favorable results. A 37-year-old male, a known case of sickle cell-beta thalassemia (ββ+), presented with avascular necrosis of right femur and humeral head. He was posted for the right hip arthroplasty and shoulder hemiarthroplasty. Successful manual RCE transfusions were done. The hemoglobin S levels decreased postmanual RCE procedures, and the patient was operated successfully.
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http://dx.doi.org/10.4103/ajts.AJTS_128_16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327770PMC
January 2019

Radiation, Immune Checkpoint Blockade and the Abscopal Effect: A Critical Review on Timing, Dose and Fractionation.

Front Oncol 2018 13;8:612. Epub 2018 Dec 13.

Department of Radiation Oncology, Emory University, Atlanta, GA, United States.

The combination of radiation and immunotherapy is currently an exciting avenue of pre-clinical and clinical investigation. The synergy between these two treatment modalities has the potential to expand the role of radiation from a purely local therapy, to a role in advanced and metastatic disease. Tumor regression outside of the irradiated field, known as the abscopal effect, is a recognized phenomenon mediated by lymphocytes and enhanced by checkpoint blockade. In this review, we summarize the known mechanistic data behind the immunostimulatory effects of radiation and how this is enhanced by immunotherapy. We also provide pre-clinical data supporting specific radiation timing and optimal dose/fractionation for induction of a robust anti-tumor immune response with or without checkpoint blockade. Importantly, these data are placed in a larger context of understanding T-cell exhaustion and the impact of immunotherapy on this phenotype. We also include relevant pre-clinical studies done in non-tumor systems. We discuss the published clinical trials and briefly summarize salient case reports evaluating the abscopal effect. Much of the data discussed here remains at the preliminary stage, and a number of interesting avenues of research remain under investigation.
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http://dx.doi.org/10.3389/fonc.2018.00612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306034PMC
December 2018

Integrin CD11b activation drives anti-tumor innate immunity.

Nat Commun 2018 12 19;9(1):5379. Epub 2018 Dec 19.

Moores Cancer Center, University of California, San Diego, La Jolla, CA, 92093, USA.

Myeloid cells are recruited to damaged tissues where they can resolve infections and tumor growth or stimulate wound healing and tumor progression. Recruitment of these cells is regulated by integrins, a family of adhesion receptors that includes integrin CD11b. Here we report that, unexpectedly, integrin CD11b does not regulate myeloid cell recruitment to tumors but instead controls myeloid cell polarization and tumor growth. CD11b activation promotes pro-inflammatory macrophage polarization by stimulating expression of microRNA Let7a. In contrast, inhibition of CD11b prevents Let7a expression and induces cMyc expression, leading to immune suppressive macrophage polarization, vascular maturation, and accelerated tumor growth. Pharmacological activation of CD11b with a small molecule agonist, Leukadherin 1 (LA1), promotes pro-inflammatory macrophage polarization and suppresses tumor growth in animal models of murine and human cancer. These studies identify CD11b as negative regulator of immune suppression and a target for cancer immune therapy.
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http://dx.doi.org/10.1038/s41467-018-07387-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300665PMC
December 2018

Comparison of conventional methods of simultaneous intrusion and retraction of maxillary anterior: a finite element analysis.

J Orthod 2018 12 3;45(4):243-249. Epub 2018 Oct 3.

a Department of Orthodontics and Dentofacial Orthopaedics , Surendra Dental College and Research Institute , Sriganganagar , Rajasthan , India.

Objective: To study the biomechanical effects of the three-piece intrusion arch and Kalra simultaneous intrusion and retraction arch (K-SIR) on simultaneous intrusion and retraction of maxillary anterior teeth.

Design: Three-dimensional analysis of stresses and displacement of the anterior and posterior teeth with the three-piece intrusion arch and K-SIR arch was done using the finite element method (FEM).

Setting: Department of Orthodontics, Surendera Dental College and Research Institute, India.

Material And Methods: For this investigation, the geometric model of the maxilla was constructed using a computed tomography scan. 0.022 × 0.028-inch MBT brackets and molar tubes were modelled, with the specified tip and torque values for all maxillary teeth. The wire components for the three-piece intrusion arch and K-SIR arch were modelled initially as a line diagram and then converted to three dimensional models. The material characteristics which include the Young's modulus and Poisson's ratio were assigned. After defining the boundary conditions, force systems were applied as per design. The analysis was carried out using ANSYS Version 12.1 software. The von Mises stress, principal stress on PDL and alveolar bone, change in the inclination of incisors and initial displacement of the teeth in bucco-palatal, mesio- distal and vertical direction were analysed.

Results: Stresses in cortical bone were greater than cancellous. Both modalities showed intrusion of the anterior teeth, although this was slightly more in the three- piece intrusion arch. On studying the principal stresses in the PDL, the three-piece intrusion arch displayed uniform stress distribution compared to K-SIR arch.

Conclusion: The FEM cannot reflect actual biological responses within the human body to orthodontic forces but based on these findings, the three-piece intrusion arch showed better stress distribution and controlled tooth movement than the K-SIR arch.
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http://dx.doi.org/10.1080/14653125.2018.1525928DOI Listing
December 2018

Tissue and serum expression of TGM-3 may be prognostic marker in patients of oral squamous cell carcinoma undergoing chemo-radiotherapy.

PLoS One 2018 28;13(6):e0199665. Epub 2018 Jun 28.

Department of Oral and Maxillofacial Surgery, King George's Medical University Lucknow, Uttar Pradesh, India.

Radioresistance is one of the main determinants of treatment outcome in oral squamous cell carcinoma (OSCC), but its prediction is difficult. Several authors aimed to establish radioresistant OSCC cell lines to identify genes with altered expression in response to radioresistance. The development of OSCC is a multistep carcinogenic process that includes activation of several oncogenes and inactivation of tumour suppressor genes. TGM-3 is a tumour suppressor gene and contributes to carcinogenesis process. The aim of this study was to estimate serum and tissue expression of TGM-3 and its correlation with clinico-pathological factors and overall survival in patients of OSCC undergoing chemo-radiotherapy. Tissue expression was observed in formalin fixed tissue biopsies of 96 cases of OSCC and 32 healthy controls were subjected to immunohistochemistry (IHC) by using antibody against TGM-3 and serum level was estimated by ELISA method. mRNA expression was determined by using Real-Time PCR. Patients were followed for 2 year for chemo radiotherapy response. In OSCC, 76.70% cases and in controls 90.62% were positive for TGM-3 IHC expression. TGM-3 expression was cytoplasmic and nuclear staining expressed in keratinized layer, stratum granulosum and stratum spinosum in controls and tumour cells. Mean serum TGM-3 in pre chemo-radiotherapy OSCC cases were 1304.83±573.55, post chemo-radiotherapy samples were 1530.64±669.33 and controls were 1869.16±1377.36, but difference was significant in pre chemo-radiotherapy samples as compared to controls (p<0.018). This finding was also confirmed by real- time PCR analysis in which down regulation (-7.92 fold change) of TGM-3 in OSCC as compared to controls. TGM-3 expression was significantly associated with response to chemo-radiotherapy treatment (p<0.007) and overall survival (p<0.015). Patents having higher level of TGM-3 expression have good response to chemo-radiotherapy and also have better overall survival. TGM-3 may serve as a candidate biomarker for responsiveness to chemo-radiotherapy treatment in OSCC patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0199665PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023195PMC
December 2018

Modulation of Immuno-biome during Radio-sensitization of Tumors by Glycolytic Inhibitors.

Curr Med Chem 2020 ;27(24):4002-4015

Shanghai Proton and Heavy Ion Center, Shanghai 201321, China.

The Tumor Microenvironment (TME) comprising stromal cells, fibroblasts and various components of the immune system forms a pro-tumorigenic cocoon around the tumor cells with the reprogramming of the metabolism in the form of Warburg phenotype (enhanced aerobic glycolysis) in tumor as well as non-tumor cells. This reprogramming plays a significant role in suppressing the immune response leading to the survival and proliferation of tumor cells and resistance to therapies. Therefore, there is a considerable interest in developing strategies involving metabolic modifiers to improve the therapeutic efficacy that restores immune competence, besides enhancing the direct effects on tumor cells. Inhibitors of glycolysis like 2-deoxy-D-glucose (2-DG; a hexokinase inhibitor), dichloroacetate and small molecule inhibitors of lactate transport (MCT-1) are some of the metabolic modifiers investigated for their therapeutic as well as adjuvant potential. Among these, 2-DG has been widely investigated and established as an ideal adjuvant in the radio- and chemotherapy of tumors. Modulation of the immuno-biome in the form of cytokine shifts, differential transcriptional regulation, abrogation of immunosuppressive network and reduced accumulation of lactate are some of the contributing factors for immune stimulation linked to the radio- and chemosensitization by glycolytic inhibitors.
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http://dx.doi.org/10.2174/0929867325666180601101145DOI Listing
August 2020
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