Publications by authors named "Amit Verma"

393 Publications

Excessive R-loops trigger an inflammatory cascade leading to increased HSPC production.

Dev Cell 2021 Feb 23. Epub 2021 Feb 23.

Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA; Gottesman Institute for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; Department of Medicine (Oncology), Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA. Electronic address:

Hematopoietic stem and progenitor cells (HSPCs) arise during embryonic development and are essential for sustaining the blood and immune systems throughout life. Tight regulation of HSPC numbers is critical for hematopoietic homeostasis. Here, we identified DEAD-box helicase 41 (Ddx41) as a gatekeeper of HSPC production. Using zebrafish ddx41 mutants, we unveiled a critical role for this helicase in regulating HSPC production at the endothelial-to-hematopoietic transition. We determined that Ddx41 suppresses the accumulation of R-loops, nucleic acid structures consisting of RNA:DNA hybrids and ssDNAs whose equilibrium is essential for cellular fitness. Excess R-loop levels in ddx41 mutants triggered the cGAS-STING inflammatory pathway leading to increased numbers of hemogenic endothelium and HSPCs. Elevated R-loop accumulation and inflammatory signaling were observed in human cells with decreased DDX41, suggesting possible conservation of mechanism. These findings delineate that precise regulation of R-loop levels during development is critical for limiting cGAS-STING activity and HSPC numbers.
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http://dx.doi.org/10.1016/j.devcel.2021.02.006DOI Listing
February 2021

First-in-human study of inhaled Azacitidine in patients with advanced non-small cell lung cancer.

Lung Cancer 2021 Feb 17;154:99-104. Epub 2021 Feb 17.

Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY10461, USA. Electronic address:

Background: Aerosolized Azacitidine has been shown to inhibit orthotopic lung cancer growth and induce re-expression of methylated tumor suppressor genes in murine models. We hypothesized that inhaled Azacitidine is safe and effective in reversing epigenetic changes in the bronchial epithelium secondary to chronic smoking.

Patients And Methods: We report the first in human study of inhaled Azacitidine. Azacitidine in aqueous solution was used to generate an aerosol suspension of 0.25-5 μm particle size. Main inclusion criteria: Stage IV or recurrent NSCLC with predominantly lung involvement, ≥1 prior systemic therapy, ECOG PS 0-1, and adequate pulmonary function. Patients received inhaled Azacitidine daily on days 1-5 and 15-19 of 28-day cycles, at 3 escalating doses (15, 30 and 45 mg/m daily). The primary objective was to determine the feasibility and tolerability of this new therapeutic modality. The key secondary objectives included pharmacokinetics, methylation profiles and efficacy.

Results: From 3/2015 to 2/2018, eight patients received a median number of 2 (IQR = 1) cycles of inhaled Azacitidine. No clinically significant adverse events were observed, except one patient treated at the highest dose developed an asymptomatic grade 2 decreased DLCO which resolved spontaneously. One patient receiving 12 cycles of therapy had an objective and durable partial response, and two patients had stable disease. Plasma Azacitidine was only briefly detectable in patients treated at the higher doses. Moreover, in 2 of 3 participants who agreed and underwent pre- and post-treatment bronchoscopy, the global DNA methylation in the bronchial epithelium decreased by 24 % and 79 % post-therapy, respectively. The interval between last inhaled treatment and bronchoscopy was 3 days.

Conclusions: Inhaled Azacitidine resulted in negligible plasma levels compared to the previously reported subcutaneous administration and was well-tolerated. The results justify the continued development of inhaled Azacitidine at non-cytotoxic doses for patients with lung-confined malignant and/or premalignant lesions.
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http://dx.doi.org/10.1016/j.lungcan.2021.02.015DOI Listing
February 2021

Autophagy Paradox of Cancer: Role, Regulation, and Duality.

Oxid Med Cell Longev 2021 11;2021:8832541. Epub 2021 Feb 11.

Department of Biotechnology, Jamia Millia Islamia, New Delhi, India.

Autophagy, a catabolic process, degrades damaged and defective cellular materials through lysosomes, thus working as a recycling mechanism of the cell. It is an evolutionarily conserved and highly regulated process that plays an important role in maintaining cellular homeostasis. Autophagy is constitutively active at the basal level; however, it gets enhanced to meet cellular needs in various stress conditions. The process involves various autophagy-related genes that ultimately lead to the degradation of targeted cytosolic substrates. Many factors modulate both upstream and downstream autophagy pathways like nutritional status, energy level, growth factors, hypoxic conditions, and localization of p53. Any problem in executing autophagy can lead to various pathological conditions including neurodegeneration, aging, and cancer. In cancer, autophagy plays a contradictory role; it inhibits the formation of tumors, whereas, during advanced stages, autophagy promotes tumor progression. Besides, autophagy protects the tumor from various therapies by providing recycled nutrition and energy to the tumor cells. Autophagy is stimulated by tumor suppressor proteins, whereas it gets inhibited by oncogenes. Due to its dynamic and dual role in the pathogenesis of cancer, autophagy provides promising opportunities in developing novel and effective cancer therapies along with managing chemoresistant cancers. In this article, we summarize different strategies that can modulate autophagy in cancer to overcome the major obstacle, i.e., resistance developed in cancer to anticancer therapies.
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http://dx.doi.org/10.1155/2021/8832541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892237PMC
February 2021

Assessment of the Survival Rate of Short Dental Implants in Medically Compromised Patients.

J Contemp Dent Pract 2020 Aug 1;21(8):880-883. Epub 2020 Aug 1.

Department of Periodontology, Hazaribagh College of Dental Sciences and Hospital, Hazaribagh, Jharkhand, India.

Aim: To assess the survival rate of short dental implants in medically compromised patients.

Materials And Method: This follow-up study was conducted on 342 medically compromised patients of both genders (580 dental implants). The failure rate of dental implants was assessed.

Results: There were 142 diabetes mellitus patients with 254 dental implants, 108 patients with hypertension with 190 dental implants, 26 patients with mental disabilities with 40 dental implants, 20 oral cancer patients with 36 dental implants, and 46 osteomyelitis subjects with 60 dental implants. There were 60 (10.5%) short dental implant (SDI) failures of which a maximum of 25 (22.7%) were seen with 4 mm diameter. Maximum failure was seen with osteomyelitis patients 8 (13.3%) followed by diabetes mellitus 32 (12.5%). Out of 270 dental implants in 130 control patients, implant failure was seen in 11 (4.07%). There was a significant ( < 0.05) bone loss on follow-up at 6 months, 1 year, and 2 years.

Conclusion: Medically compromised patients are more prone to dental implant failure as compared to healthy subjects.

Clinical Significance: Since medically compromised patients are prone for implant failure, careful selection of cases is necessary.
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August 2020

The evolution of epigenetic therapy in myelodysplastic syndromes and acute myeloid leukemia.

Semin Hematol 2021 Jan 28;58(1):56-65. Epub 2020 Dec 28.

Division of Hematologic Malignancies, Department of Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY; Department of Molecular & Developmental Biology, Albert Einstein College of Medicine, Bronx, NY. Electronic address:

Mutations in the group of epigenetic modifiers are the largest group of mutated genes in Myelodysplastic Syndromes (MDS) and are very frequently found in Acute Myeloid Leukemia (AML). Our advancements in the understanding of epigenetics in these diseases have helped develop groundbreaking therapeutics that have changed the treatment landscape of MDS and AML, significantly improving outcomes. In this review we describe the most common epigenetic aberrations in MDS and AML, and current treatments that target mutations in epigenetic modifiers, as well as novel treatment combinations, from standard therapies to investigational treatments.
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http://dx.doi.org/10.1053/j.seminhematol.2020.12.003DOI Listing
January 2021

Initial Whole-Genome Sequencing of Plasma Cell Neoplasms in First Responders and Recovery Workers Exposed to the World Trade Center Attack of September 11, 2001.

Clin Cancer Res 2021 Jan 27. Epub 2021 Jan 27.

Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: The World Trade Center (WTC) attack of September 11, 2001 created an unprecedented environmental exposure to known and suspected carcinogens. High incidence of multiple myeloma and precursor conditions has been reported among first responders to the WTC disaster. To expand on our prior screening studies, and to characterize the genomic impact of the exposure to known and potential carcinogens in the WTC debris, we were motivated to perform whole-genome sequencing (WGS) of WTC first responders and recovery workers who developed a plasma cell disorder after the attack.

Experimental Design: We performed WGS of nine CD138-positive bone marrow mononuclear samples from patients who were diagnosed with plasma cell disorders after the WTC disaster.

Results: No significant differences were observed in comparing the post-WTC driver and mutational signature landscapes with 110 previously published WGSs from 56 patients with multiple myeloma and the CoMMpass WGS cohort ( = 752). Leveraging constant activity of the single-base substitution mutational signatures 1 and 5 over time, we estimated that tumor-initiating chromosomal gains were windowed to both pre- and post-WTC exposure.

Conclusions: Although limitations in sample size preclude any definitive conclusions, our findings suggest that the observed increased incidence of plasma cell neoplasms in this population is due to complex and heterogeneous effects of the WTC exposure that may have initiated or contributed to progression of malignancy.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2245DOI Listing
January 2021

Roles and Regulations of TET Enzymes in Solid Tumors.

Trends Cancer 2021 Jan 16. Epub 2021 Jan 16.

Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

The mechanisms governing the methylome profile of tumor suppressors and oncogenes have expanded with the discovery of oxidized states of 5-methylcytosine (5mC). Ten-eleven translocation (TET) enzymes are a family of dioxygenases that iteratively catalyze 5mC oxidation and promote cytosine demethylation, thereby creating a dynamic global and local methylation landscape. While the catalytic function of TET enzymes during stem cell differentiation and development have been well studied, less is known about the multifaceted roles of TET enzymes during carcinogenesis. This review outlines several tiers of TET regulation and overviews how TET deregulation promotes a cancer phenotype. Defining the tissue-specific and context-dependent roles of TET enzymes will deepen our understanding of the epigenetic perturbations that promote or inhibit carcinogenesis.
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http://dx.doi.org/10.1016/j.trecan.2020.12.011DOI Listing
January 2021

Association Between CDKAL1, HHEX, CDKN2A/2B and IGF2BP2 Gene Polymorphisms and Susceptibility to Type 2 Diabetes in Uttarakhand, India.

Diabetes Metab Syndr Obes 2021 6;14:23-36. Epub 2021 Jan 6.

Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia.

Introduction: Current study aimed to find the association of genes polymorphism of CDKAL1, HHEX, CDKN2A/2B, and IGF2BP2 with type 2 diabetes (T2DM) in the population of Uttarakhand.

Research Design And Methods: Overall 469 persons comprising 369 recently diagnosed T2DM cases and 100 healthy control were enrolled in the present study. The polymorphisms were analyzed through the PCR-RFLP technique.

Results: For the rs10440833 variant (CDKAL1), CC genotype's frequency was significantly high among T2DM subjects than controls and increase the T2DM risk (OR: 4.46, 95% CI: 2.22-8.99, p <0.0001). The c allele was significantly found to increase the T2DM risk (OR: 2.20, 95% CI: 1.54-3.14, p <0.001). In the rs1111875 variant (HHEX), the difference of genotype frequencies among T2DM cases and control was statistically non-significant (p-0.138). We did not observe significant differences in allelic frequencies among T2DM cases and control (p-0.444). In the case of rs10811661 variant (CDKN2A/2B), frequency of both TC (OR: 3.16, 95% CI: 1.84-5.42, p <0.0001) and TT (OR: 5.84, 95% CI: 1.75-19.45, p -0.004) genotype were significantly higher in T2DM cases in comparison with control and significantly associated with higher T2DM risk. Compared to the C allele, a significant increase in T2DM risk was documented with the T allele (OR: 2.47, 95% CI: 1.55-3.92, p <0.001). For rs4402960 variant (IGF2BP2), TT genotype contributed to increased T2DM risk (OR: 4.25, 95% CI: 2.02-8.93, p -0.0001). T allele's frequency was significantly high in T2DM cases in comparison with healthy control. Except WHR, HDL-C, exercise, household chores, standing work more than 3 hours, and family history, significant differences were found between T2DM cases and healthy individuals in all other parameters.

Conclusion: Our study concluded a significant association of CDKAL1, CDKN2A/2B, and IGF2BP2 polymorphism with T2DM in the Uttarakhand population. For HHEX, the genotype and allelic frequencies difference between T2DM cases and control were statistically non-significant. However, a significant association of HHEX gene polymorphism with T2DM was observed only under the dominant model.
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http://dx.doi.org/10.2147/DMSO.S284998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797276PMC
January 2021

Lenalidomide-Epoetin Alfa Versus Lenalidomide Monotherapy in Myelodysplastic Syndromes Refractory to Recombinant Erythropoietin.

J Clin Oncol 2021 Jan 13:JCO2001691. Epub 2021 Jan 13.

Leukemia Service, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY.

Purpose: Impaired response to erythropoietin underlies ineffective erythropoiesis and anemia in myelodysplastic syndromes (MDS). We investigated whether treatment with lenalidomide (LEN), which augments erythropoietin receptor signaling in vitro, can restore and improve hemoglobin response to epoetin (EPO) alfa in patients with lower-risk, non-del(5q) MDS who have anemia that is refractory to or have low probability of benefit from treatment with recombinant erythropoietin.

Methods: In a phase III, US intergroup trial, we randomly assigned patients to receive either LEN and EPO alfa or LEN alone following stratification by serum erythropoietin concentration and prior erythropoietin treatment.

Results: A total of 195 evaluable patients were randomly assigned: 99 patients to the LEN-EPO alfa cohort and 96 to LEN alone. After four cycles of treatment, the primary end point of major erythroid response (MER) was significantly higher (28.3%) with the combination compared with LEN alone (11.5%) ( = .004). Among 136 patients who completed 16 weeks of study treatment, 38.9% and 15.6% achieved MER, respectively ( = .004). Additionally, minor erythroid response was achieved in 18.2% and 20.8% of patients, for an overall erythroid response rate of 46.5% versus 32.3%. Among LEN nonresponders, 38 crossed over to the addition of EPO alfa with 10 patients (26.3%) achieving a MER. Responses to the combined treatment were highly durable with a median MER duration of 23.8 months compared with 13 months with LEN alone.

Conclusion: LEN restores sensitivity to recombinant erythropoietin in growth factor-insensitive, lower-risk, non-del(5q) MDS, to yield a significantly higher rate and duration of MER compared with LEN alone (funded by the National Cancer Institute; E2905 ClinicalTrials.gov identifier: NCT02048813).
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http://dx.doi.org/10.1200/JCO.20.01691DOI Listing
January 2021

Circulating long non-coding RNAs NKILA, NEAT1, MALAT1, and MIAT expression and their association in type 2 diabetes mellitus.

BMJ Open Diabetes Res Care 2021 Jan;9(1)

Department of Zoology and Environmental Sciences, Gurukula Kangri University, Haridwar, Uttarakhand, India

Background: Type 2 diabetes mellitus (T2DM) is a multifactorial disorder that leads to alterations in gene regulation. Long non-coding RNAs (lncRNAs) have become a major research topic as they are involved in metabolic disorders.

Methods: This study included a total of 400 study subjects; 200 were subjects with T2DM and 200 were healthy subjects. Extracted RNA was used to synthesize cDNA by quantitative real time. Serum analysis was carried out to determine differences in biochemical parameters. Recorded data were used to evaluate associations with expression of lncRNAs NF-kappaB interacting lncRNA (NKILA), nuclear enriched abundant transcript 1 (NEAT1), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and myocardial infarction-associated transcript (MIAT) in T2DM cases.

Results: Compared with healthy controls, patients with T2DM showed an overall increase in expression of lncRNAs NKILA, NEAT, MALAT1, and MIAT by 3.94-fold, 5.28-fold, 4.46-fold, and 6.35-fold, respectively. Among patients with T2DM, higher expression of lncRNA NKILA was associated with hypertension (p=0.001), smoking (p<0.0001), and alcoholism (p<0.0001). Altered NEAT1 expression was significantly associated with weight loss (p=0.04), fatigue (p=0.01), slow wound healing (p=0.002), blurred vision (p=0.008), loss of appetite (p=0.007), smoking (p<0.0001), and alcoholism (p<0.0001). Higher expression of lncRNA MALAT1 was significantly linked with weight loss (p=0.003), blurred vision (p=0.01), smoking (p<0.0001), and alcoholism (p<0.0001). Expression of lncRNA MIAT was associated with only blurred vision (p<0.0001), smoking (p<0.0001), and alcoholism (p<0.0001). Positive correlations of lncRNA NKILA with lncRNAs NEAT1 (r=0.42, p<0.0001), MALAT (r=0.36, p<0.0001) and MIAT (r=0.42, p<0.0001) were observed among patients with T2DM. Significant positive correlations of lncRNA NEAT with lncRNAs MALAT and MIAT were observed among patients with T2DM. A positive correlation between lncRNAs MALAT and MIAT was also observed among patients with T2DM.

Conclusion: Increased circulating NKILA, NEAT1, MALAT, and MIAT expression in patients with T2DM, which is linked with poor patient outcomes and significantly linked with alcoholism and smoking, may influence the degree and severity of disease among patients with T2DM. These lncRNAs may contribute to the progression of T2DM disease or other related diabetes-related complications.
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http://dx.doi.org/10.1136/bmjdrc-2020-001821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805373PMC
January 2021

Case report of combination therapy with Azacytidine, Enasidenib and Venetoclax in primary refractory AML.

Exp Hematol Oncol 2021 Jan 4;10(1). Epub 2021 Jan 4.

Albert Einstein College of Medicine, Department of Hematology/Oncology, Bronx, NY, USA.

Optimal treatment of acute myeloid leukemia (AML) arising in elderly patients remains a challenge. FDA approval of Ivosidenib and Enasidenib, small molecule inhibitors of isocitrate dehydrogenase enzymes (IDH1 and 2) have opened new avenues of treatment. We present a 60-year-old woman with refractory AML, achieving complete response to the combination therapy of hypomethylating agent, Azacytidine with the IDH2 inhibitor, Enasidenib, and BCL2 inhibitor, Venetoclax. To our knowledge, this is the first case report of a patient with IDH2 mutated refractory AML achieving complete response to combination therapy with azacytidine, enasidenib and venetoclax.
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http://dx.doi.org/10.1186/s40164-020-00186-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784272PMC
January 2021

Promising Antifungal Potential of Engineered Non-ionic Surfactant-Based Vesicles: In Vitro and In Vivo Studies.

AAPS PharmSciTech 2021 Jan 3;22(1):19. Epub 2021 Jan 3.

Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Central University, Sagar, Madhya Pradesh, 470003, India.

Fungal keratitis (FK) is a corneal infection caused by different fungal species. It is treated by the topical application of natamycin (NAT). Nevertheless, this approach faces many limitations like toxic effects, frequent dosing, resistance, and patient discomfort. The present research reports the development of trimethyl chitosan (TMC) coated mucoadhesive cationic niosomes by a modified thin-film hydration method. TMC was synthesized using a one-step carbodiimide method and characterized by H-NMR and degree of quaternization (53.74 ± 1.06%). NAT, cholesterol (CHOL), span 60 (Sp60), and dicetyl phosphate (DCP) were used to prepare niosomes which were incubated with TMC to obtain mucoadhesive cationic NAT loaded niosomes (MCNNs). MCNNs showed a spherical shape with 1031.12 ± 14.18 nm size (PDI below 0.3) and 80.23 ± 5.28% entrapment efficiency. In vitro drug release studies showed gradual drug release from TMC coated niosomes as compared to the uncoated niosomes. MIC assay and disk diffusion assay revealed promising in vitro antifungal potential of MCNNs similar to the marketed formulation. For investigating in vivo performance, ocular retention and pharmacokinetics, ocular irritation, and ulcer healing studies were performed using the rabbit model. Mucoadhesive property and prolonged local drug release improved the safety and efficacy of NAT, suggesting that the developed niosomes could be an emerging system for effective treatment of fungal keratitis.
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http://dx.doi.org/10.1208/s12249-020-01900-zDOI Listing
January 2021

Acclimation potential of Noni ( L.) plant to temperature stress is mediated through photosynthetic electron transport rate.

Plant Signal Behav 2021 Mar 23;16(3):1865687. Epub 2020 Dec 23.

Plant Molecular Biology, International Centre for Genetic Engineering and Biotechnology , New Delhi, India.

Noni ( L.), a tropical, medicinal plant of the family Rubiaceae utilized since 2000 y ago by the Polynesians, is currently facing a major challenge in production vis-a-vis climate change. The worldwide average temperatures continue to fluctuate, resulting in extremely cold winters and hot summers that reduce plant productivity. Photosynthetic apparatus is an exceptionally sensitive component to estimate the degree of damage at contrasting temperatures. The present study was aimed to evaluate the temperature stress response of Noni plant using the chlorophyll a fluorescence OJIP transients (OJIP transients). Results showed the declined photosynthetic pigment pool and reduced functional and structural integrity of the photosynthetic apparatus under very low- and high-temperature treatments. Drastically lower yield parameters such as φ(Po) and φ(Eo), efficiency ψ(Eo) and performance indices - PI and PI, and accumulation of inactive reaction centers were observed. Consecutively, a lower level of calculated electron transport from PSII to PSI was observed. In contrast, the enhanced δRo indicates that PSI is more thermo-tolerant as compared to PSII. Additionally, very low and high temperatures cause an increase in antenna size (ABS/RC) and the decrease in the amplitude of I to P phase of fluorescence transient. Overall, the photosynthetic apparatus of leaf tissue was more sensitive to low and high temperatures than the developing fruit. The findings of the present study demonstrated the potential role of thylakoid components of the photosynthetic apparatus, which might be crucial in regulating the temperature stress response in the Noni plant, and thereby crop improvement.
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http://dx.doi.org/10.1080/15592324.2020.1865687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889107PMC
March 2021

Multiple Myeloma in Hispanics: Incidence, Characteristics, Survival, Results of Discovery, and Validation Using Real-World and Connect MM Registry Data.

Clin Lymphoma Myeloma Leuk 2020 Nov 21. Epub 2020 Nov 21.

Department of Medical Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY; Division of Hematology, Oncology and Transplantation (HOT), Department of Medicine, University of Minnesota, Minneapolis, MN. Electronic address:

Background: Multiple myeloma (MM) in Hispanics has never been studied. We therefore sought to determine the clinical characteristics and overall survival in MM of Hispanics compared to non-Hispanic whites (NHW) and non-Hispanic blacks (NHB).

Patients And Methods: A single-center analysis of 939 patients diagnosed with MM from 2000 to 2017 with a large representation of NHB (n = 489), Hispanics (n = 281), and NHW (n = 169) was conducted to evaluate outcomes and disease characteristics. We used the Connect MM Registry, a large US multicenter prospective observational study with newly diagnosed MM patients, as a validation cohort.

Results: Hispanics had a higher incidence of MM compared to NHW. The median age at presentation was 5 years younger (median, 65 years) in Hispanics compared to NHW (median, 70 years), and patients were more likely to present with renal dysfunction (estimated glomerular filtration rate < 30 mL/min). Hispanics had a higher proportion of Revised International Staging System (R-ISS) stage I disease compared to NHW and NHB (P = .03), while there was no difference in cytogenetics between Hispanics and NHB/NHW. In the multivariate analysis, only high-risk disease and response to first-line therapy significantly affected survival.

Conclusion: In this first and largest analysis of MM in Hispanics, we found that Hispanics present at a younger age, have a higher incidence of renal dysfunction, and have low R-ISS stage disease at presentation. With equal access to therapy, Hispanics have survival similar to NHW/NHB.
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http://dx.doi.org/10.1016/j.clml.2020.11.013DOI Listing
November 2020

Expansion of the evolutionarily conserved network of J-domain proteins in the Arabidopsis mitochondrial import complex.

Plant Mol Biol 2021 Mar 18;105(4-5):385-403. Epub 2020 Nov 18.

Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Room Number 117 AB3, IISER Bhopal, Bhopal Bypass Road, Bhopal, MP, 462066, India.

Key Message: We report that discriminate interaction between the expanded mitochondrial chaperone network and variability in their expression might determine their functional specificities and impart robustness to mitochondrial import processes in plants. Mitochondrial Hsp70 (mtHsp70), the central component of the pre-sequence associated motor (PAM) complex, is crucial for the import of proteins to the mitochondrial matrix. Activity of mtHsp70 is regulated by a heterodimeric complex of two J-domain proteins (JDPs), Pam18 and Pam16. Compared to other eukaryotes, plants harbor multiple copies of these JDPs, which posit that plants have an increasingly complex mtHsp70: JDP network in their mitochondrial matrix. Here, we show that although highly similar in sequence, some of the plant JDPs are functionally different. Protein: protein interaction studies including yeast two-hybrid and Bimolecular Fluorescence Complementation revealed that while all the AtPam18s interacted with AtPam16s, the strengths of these promiscuous interactions are variable. Further, down-regulation of AtPAM16L affected seed germination, even in the presence of its seemingly identical paralog, AtPAM16. Knockdown of AtPAM16L caused reduction in mitochondrial number and deregulation of several mitochondrial genes, suggesting towards a specific role of AtPam16L in maintaining mitochondrial homeostasis, especially under stress conditions. Our findings suggest that variations in the spatio-temporal expression, accompanied by discriminate interactions between the JDPs, might be defining the functional specificity of the mtHsp70 co-chaperone machinery and providing resilience to mitochondrial import processes in plants, especially under stress conditions.
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http://dx.doi.org/10.1007/s11103-020-01095-8DOI Listing
March 2021

Mucoadhesive gastroretentive microparticulate system for programmed delivery of famotidine and clarithromycin.

J Microencapsul 2021 Jan 28:1-13. Epub 2021 Jan 28.

Department of Pharmaceutical Sciences, Pharmaceutics Research Projects Laboratory, Dr. Hari Singh Gour Central University, Sagar, India.

Aim: The present research was aimed to develop thiolated polyacrylic acid (TPA) based microspheres (MSPs) containing famotidine (FX) and clarithromycin (CLX).

Methods: TPA was synthesised from polyacrylic acid and l-cysteine in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDAC). The prepared TPA was characterised using FT-IR (Fourier transform-infra red), H-NMR (proton nuclear magnetic resonance) spectroscopy, P-XRD (powder X ray diffraction) method, and zeta potential. The analytical tools have supported the formation of TPA. The thiolated microspheres were prepared by emulsion solvent evaporation method using 0.75% w/v polymer concentration and stirring at 400rpm for 8 hr.

Results: The average particle size and zeta potential of optimised formulation was found to be 25.2 ± 1.87 μm and -26.68 mV, respectively. The entrapment efficiency of the optimised formulation was obtained 67.20% for FX and 70.20% for CLX. The developed microspheres were swelled only in 4 h from 0.5 to 0.9. The mucoadhesive study and drug release studies demonstrated that microspheres showed mucoadhesive property. In drug release studies, the release of FX and CLX were observed to be 58.68% and 60.48%, respectively from microspheres in 8 h. The thiolated microspheres showed higher adhesion time (7.0 ± 0.8 h) in comparison to the plain microspheres (2.6 ± 0.4 h).

Conclusion: The prepared TPA based mucoadhesive microspheres can be utilised as carriers for the treatment of peptic ulcer caused by which will offer enhanced residence time for the rational drug combination in the gastric region.
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http://dx.doi.org/10.1080/02652048.2020.1851787DOI Listing
January 2021

Modeling and simulation of atrazine biodegradation in bacteria and its effect in other living systems.

J Biomol Struct Dyn 2020 Nov 12:1-11. Epub 2020 Nov 12.

Department of Mathematics, University of Petrolium and Energy Studies, Dehradun, India.

Atrazine is the most commonly used herbicide worldwide in the agricultural system. The increased environmental concentration of the atrazine showed the toxic effects on the non-target living species. Biodegradation of the atrazine is possible with the bacterial systems. The present study investigated biodegradation potential of atrazine degrading bacteria and the impact of atrazine on environmental systems. Model of atrazine fate in ecological systems constructed using the cell designer. The used model further analyzed and simulated to know the biochemistry and physiology of the atrazine in different cellular networks. Topological analysis of the atrazine degradation confirmed the 289 nodes and 300 edges. Our results showed that the overall biomagnification of the atrazine in the different environmental systems. Atrazine is showing toxic effects on humans and plants, whereas degraded by the bacterial systems. To date, no one has analyzed the complete degradation and poisonous effects of the atrazine in the environment. Therefore, this study is useful for overall system biology based modeling and simulation analysis of atrazine in living systems. Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1846623DOI Listing
November 2020

Stereotactic ablative radiotherapy (SABR) for recurrent and previously irradiated head and neck cancers.

BJR Open 2020 3;2(1):20190051. Epub 2020 Mar 3.

Department of Imaging, Max Super Speciality Hospital, Saket, New Delhi, India.

Objective: To assess the response and toxicity of stereotactic ablative radiotherapy (SABR) in patients with recurrent head and neck cancer (HNC), who had previously received radiation for their primary tumor.

Methods: Between 2014 and 2018, patients who received SABR to recurrent HNC within the previously irradiated region were retrospectively reviewed. Mean age was 60 years (range 30-78 Years). Histology was confirmed in all patients. MRI and /or CT-positron emission tomography were done to evaluate local extent and to rule out metastasis. Response was assessed as per RECIST/PERCIST Criteria. Cox proportional hazards regression and the Kaplan-Meier methods were used for statistical analysis.

Results: 32 patients received SABR. RPA Class II, III patients were 20 and 12 respectively. 87% patients received a dose of ≥30 Gy/5 fractions. Median follow-up was 12 months. Estimated 1 year and 2 years local control was 64.2 and 32% and 1 year and 2 years overall survival was 67.5 and 39.5% respectively. Acute Grade 2 skin and Grade 3 mucosal toxicity was seen in 31.3 and 28% patients respectively. Late Grade 3 toxicity was seen in 9.3% patients.

Conclusion: Re-irradiation with SABR yields high local control rates and is well tolerated. It compares favorably with other treatment modalities offered to patients with recurrent HNC. It is also suitable for patients of RPA Class II and III. There is need for novel systemic agents to further improve the survival.

Advances In Knowledge: Treatment of patients with recurrent HNC is challenging and is more difficult in previously radiated patient. More than 50% patients are unresectable. Other options of salvage treatment like re-irradiation and chemotherapy are associated with poor response rates and high incidence of acute and late toxicity (Gr ≥3 toxicity 50-70%). SABR is a novel technology to deliver high dose of radiation to recurrent tumor with high precision. It yields high local control rates with less toxicity compared to conventionally fractionated radiation.
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http://dx.doi.org/10.1259/bjro.20190051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594905PMC
March 2020

The diagnostic role of microRNA 21 in patients with nonsmall cell lung cancer: An exploratory study.

Lung India 2020 Nov-Dec;37(6):501-505

Department of Surgical Oncology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India.

Background: Although histopathological examination of the biopsy specimen is the gold standard for the diagnosis of non small cell lung cancer (NSCLC), a blood-based noninvasive test (liquid biopsy) may prove to be helpful in patients with repeatedly negative biopsy or for response assessment following neoadjuvant therapy. The present study was conducted to explore the diagnostic value of circulating serum microRNA (miRNA) 21 in patients with NSCLC.

Methods: This case-control analytical study was carried out in a tertiary care teaching hospital in Northern India. The study consisted of 30 cases of biopsy-proven NSCLC and 30 controls. Serum miRNA-21 expression levels were estimated by extracting total RNA from the serum sample, reverse transcribing it to cDNA and quantified in relation to U6 reference miRNA.

Results: A total of 30 patients with NSCLC and 30 controls were included in the study. The subjects were comparable in two groups with reference to age, gender, and smoking. Pathological types were adenocarcinoma in 19 (63.3%) and squamous cell carcinoma in 11 (36.6%) patients. Majority of the patients had advanced disease-AJCC stage III in 15 patients and AJCC Stage IV in 13 patients; two patients had stage II disease. There was a significant upregulation of serum miRNA 21 gene expression in the patients with lung cancer compared to controls (median fold change, 3.39 vs. -2.81, P = 0.00). A fourfold change in serum miRNA 21 is significantly associated with the diagnosis of NSCLC with a high specificity of 97% and area under curve of 0.84 (95% confidence interval of 0.74-0.94).

Conclusion: Estimation of serum miRNA 21 expression has potential to be used as liquid biopsy for the diagnosis of NSCLC. Further studies with large sample sizes are warranted to confirm the diagnostic accuracy of serum miRNA 21 expression.
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http://dx.doi.org/10.4103/lungindia.lungindia_100_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879878PMC
November 2020

Assessment of Cell-Free Long Non-Coding RNA-H19 and miRNA-29a, miRNA-29b Expression and Severity of Diabetes.

Diabetes Metab Syndr Obes 2020 14;13:3727-3737. Epub 2020 Oct 14.

Department of Medical Elementology and Toxicology, Jamia Hamdard, New Delhi, India.

Background: Type 2 diabetes mellitus [T2DM] has been one of the common diseases and is characterized by increased blood glucose levels and suggested that cell-free non-coding RNAs and microRNAs (miRNAs) have been demonstrated to serve as important diagnostic/prognostic biomarkers in diabetes.

Materials/methods: The present study included clinically confirmed newly diagnosed 200 cases of T2DM and 200 healthy subjects, and all the parameters were taken care in diagnosis. Blood samples collected in plain vials were used for cell-free total RNA extraction and after that 100ng of total RNA was used to synthesize the cDNA for cell-free lncRNA H19, miRNA-29a, and miRNA-29b expression using quantitative real-time PCR method. Serum Biochemical parameters were analyzed after collection of the sample to observe the changes among T2DM cases and healthy controls.

Results: It was observed that type 2 diabetic patients had decreased [0.59 fold] lncRNA H19 expression while increased miRNA-29a [5.62 fold] and miRNA-29b [5.58 fold] expression. Decreased expression of lncRNA H19 was observed to be associated with gender [p=0.004], hypertension [p<0.0001], weight loss [p=0.02] and fatigue [p=0.02]. Increased miRNA29a expression was linked with hypertension [p<0.0001], alcoholism [p=0.04], and smoking [p<0.0001] as well as miRNA-29b expression was associated with hypertension [p=0.0001], weight loss [p=0.002], smoking [p=0.0002], alcoholism [p<0.0001]. Low [≤1 fold] and high [>1 fold] expression of lncRNA H19 expression was linked with miRNA-29a [p=0.005] and miRNA-29b [p<0.0001] expression. lncRNA H19 expression showed negative correlation with miRNA-29a expression [r= -27, p<0.0001] and miRNA-29b [r= -47, p<0.0001].

Conclusion: The present study concluded that lower lncRNA H19 expression, and increased miRNA-29b, a miRNA-29b expression associated with the severity of T2DM patients. Decreased lncRNA H19 expression, and increased miRNA-29b, miRNA-29b expression observed to be interrelated with clinicopathological findings of T2DM patients could involve in pathogenesis disease.
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http://dx.doi.org/10.2147/DMSO.S273586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569053PMC
October 2020

Association of Genetic Variants of KCNJ11 and KCNQ1 Genes with Risk of Type 2 Diabetes Mellitus (T2DM) in the Indian Population: A Case-Control Study.

Int J Endocrinol 2020 10;2020:5924756. Epub 2020 Oct 10.

Department of Biotechnology, Jamia Millia Islamia, New Delhi, India.

Type 2 diabetes mellitus (T2DM) is a polygenic metabolic disease described by hyperglycemia, which is caused by insulin resistance or reduced insulin secretion. The interaction between various genetic variants and environmental factors triggers T2DM. The aim of this study was to find risk associated with genetic variants rs5210 and rs2237895 of KCNJ11 and KCNQ1 genes, respectively, in the development of T2DM in the Indian population. A total number of 300 cases of T2DM and 100 control samples were studied to find the polymorphism in KCNJ11 and KCNQ1 through PCR-RFLP. The genotype and allele frequencies in T2DM cases were significantly different compared to the control population. KCNJ11 rs5210 and KCNQ1 rs2237895 variants were found to be significantly associated with risk of T2DM in dominant (KCNJ11: OR, 2.07; 95% CI, 1.30-3.27; - 0.001; KCNQ1: OR, 2.33; 95% CI, 1.46-3.70; - 0.0003) and codominant models (KCNJ11: OR, 1.76; 95% CI, 1.09-2.84; - 0.020; KCNQ1: OR, 1.85; 95% CI, 1.16-2.95; - 0.009). We also compared clinicopathological characteristics between cases and control and observed a significant difference in all the parameters except HDL, gender, and family history. In this study, clinicopathological data with a carrier of a variant allele of both KCNJ11 and KCNQ1 genes were also analysed, and a significant association was found between the carrier of a variant allele with gender and PPG in KCNJ11 and with triglyceride in KCNQ1. We confirm the significant association of KCNJ11 (rs5210) and KCNQ1 (rs2237895) gene polymorphism with T2DM, indicating the role of these variants in developing risk for T2DM in Indian population.
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http://dx.doi.org/10.1155/2020/5924756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569458PMC
October 2020

Paradoxical Role of AT-rich Interactive Domain 1A in Restraining Pancreatic Carcinogenesis.

Cancers (Basel) 2020 Sep 21;12(9). Epub 2020 Sep 21.

Department of Translational Molecular Pathology and Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

: ARID1A is postulated to be a tumor suppressor gene owing to loss-of-function mutations in human pancreatic ductal adenocarcinomas (PDAC). However, its role in pancreatic pathogenesis is not clear despite recent studies using genetically engineered mouse (GEM) models. We aimed at further understanding of its direct functional role in PDAC, using a combination of GEM model and PDAC cell lines. : Pancreas-specific mutant -driven GEM model (-Cre; ; or "KAC") was generated by crossing -Cre; ("KC") mice with mice and characterized histologically with timed necropsies. was also deleted using CRISPR-Cas9 system in established human and murine PDAC cell lines to study the immediate effects of Arid1a loss in isogenic models. Cell lines with or without Arid1a expression were developed from respective autochthonous PDAC GEM models, compared functionally using various culture assays, and subjected to RNA-sequencing for comparative gene expression analysis. DNA damage repair was analyzed in cultured cells using immunofluorescence and COMET assay. : Retention of Arid1a is critical for early progression of mutant -driven pre-malignant lesions into PDAC, as evident by lower Ki-67 and higher apoptosis staining in "KAC" as compared to "KC" mice. Enforced deletion of in established PDAC cell lines caused suppression of cellular growth and migration, accompanied by compromised DNA damage repair. Despite early development of relatively indolent cystic precursor lesions called intraductal papillary mucinous neoplasms (IPMNs), a subset of "KAC" mice developed aggressive PDAC in later ages. PDAC cells obtained from older autochthonous "KAC" mice revealed various compensatory ("escaper") mechanisms to overcome the growth suppressive effects of Arid1a loss. : Arid1a is an essential survival gene whose loss impairs cellular growth, and thus, its expression is critical during early stages of pancreatic tumorigenesis in mouse models. In tumors that arise in the setting of ARID1A loss, a multitude of "escaper" mechanisms drive progression.
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http://dx.doi.org/10.3390/cancers12092695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564752PMC
September 2020

Ethnic disparities in survival of adult B-cell acute lymphoblastic leukemia in modern era - a SEER analysis.

Leuk Lymphoma 2020 12 22;61(14):3503-3506. Epub 2020 Sep 22.

Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.

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http://dx.doi.org/10.1080/10428194.2020.1808211DOI Listing
December 2020

The expression of MDM2, MDM4, p53 and p21 in myeloid neoplasms and the effect of MDM2/MDM4 dual inhibitor.

Leuk Lymphoma 2021 01 14;62(1):167-175. Epub 2020 Sep 14.

Department of Pathology, Montefiore Medical Center, New York, NY, USA.

p53 together with its downstream product p21 plays an important role in tumorigenesis development. MDM2 and MDM4 are two p53 regulators. We studied the expression of p53, p21, MDM2, and MDM4 in a total of 120 cases of myeloid neoplasms including MDS, AML or MDS/MPN, and control, using single and double immunohistochemical stains. We found TP53 mutations had a worse outcome in patients with AML/MDS, and p53 expression detected by immunohistochemistry had a similar prognostic value. p21 expression was strongly related to TP53 mutation status, with loss of expression in almost all TP53 mutated cases. MDM2 and MDM4 were highly expressed in hematopoietic cells in both benign and neoplastic cells. MDM2/p53 double positive cells exceeded MDM4/p53 double positive cells in neoplastic cases. Finally, we observed that p21 protein expression was up regulated upon the use of ALRN-6924 (Aileron) while no significant changes were seen in p53, MDM2 and MDM4 expression.
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http://dx.doi.org/10.1080/10428194.2020.1817441DOI Listing
January 2021

A combinatorial approach of a polypharmacological adjuvant 2-deoxy-D-glucose with low dose radiation therapy to quell the cytokine storm in COVID-19 management.

Int J Radiat Biol 2020 11 6;96(11):1323-1328. Epub 2020 Oct 6.

Department of Surgery, University of Kansas Medical Center (Adjunct), and PACT & Health LLC, Branford, CT, USA.

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pandemic disease and is the major cause of deaths worldwide. The clinical complexities (inflammation, cytokine storm, and multi-organ dysfunction) associated with COVID-19 poses constraints to effective management of critically ill COVID-19 patients. Low dose radiation therapy (LDRT) has been evaluated as a potential therapeutic modality for COVID-19 pneumonia. However, due to heterogeneity in disease manifestation and inter-individual variations, effective planning for LDRT is limited for this large-scale event. 2-deoxy-D-glucose (2-DG) has emerged as a polypharmacological agent for COVID-19 treatment due to its effects on the glycolytic pathway, anti-inflammatory action, and interaction with viral proteins. We suggest that 2-DG will be a potential adjuvant to enhance the efficacy of LDRT in the treatment of COVID-19 pneumonia. Withal, azido analog of 2-DG, 2-azido-2-DG can produce rapid catastrophic oxidative stress and quell the cytokine storm in critically ill COVID-19 patients.
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http://dx.doi.org/10.1080/09553002.2020.1818865DOI Listing
November 2020

Expression and Correlation of Cell-Free cIAP-1 and cIAP-2 mRNA in Breast Cancer Patients: A Study from India.

J Oncol 2020 25;2020:3634825. Epub 2020 Aug 25.

Department of Biochemistry, Maulana Azad Medical College, New Delhi, India.

Background: Inhibitors of apoptosis proteins such as cIAP-1 and cIAP-2 have recently emerged as the key mechanism in resistance to apoptosis in various cancers and lead to cell survival. Therefore, the present study aimed to evaluate the cIAP-1 and cIAP-2 expression in breast cancer patients, as well as their association with overall patient survival.

Methods: Histopathologically confirmed 100 invasive ductal carcinoma patients and healthy controls were included in the present study. Total RNA extraction was done from the serum sample of the patients; further, 100 ng of total RNA was used to synthesise cDNA from patients' as well as from healthy controls' serum. Quantitative real-time PCR was performed using the maxima SYBR Green dye to study the expression of cIAP-1 and cIAP-2, and beta-actin was used as the internal control.

Results: The study observed that breast cancer patients had 13.50 mean fold increased cIAP-1 mRNA and 8.76 mean fold increased cIAP-2 mRNA expression compared to the control subjects. Breast cancer patients in the TNM stages I, II, III, and IV showed 9.54, 11.80, 15.19, and 16.83 mean fold increased cIAP-1 mRNA expression (=0.004). Distant organ metastasis, (=0.008), PR status of breast cancer patients ( < 0.0001), and HER2 status of breast cancer patients ( < 0.0001) were found to be associated with cIAP-1 mRNA expression. Breast cancer patients with different TNM stages such as stages I, II, III, and IV showed 7.8, 8.09, 7.97, and 12.85 mean fold increased cIAP-2 mRNA expression (=0.0002). Breast cancer patients with distant organ metastases status were found to be associated with cIAP-2 mRNA expression ( < 0.0001). Breast cancer patients with <13-fold and >13-fold cIAP-1 mRNA expression showed 37.39 months and 34.70 months of overall median survival, and the difference among them was found to be significant (=0.0001). However, cIAP-2 mRNA expression among <8-fold and >8-fold mRNA expression groups showed 35 months and 27.90 months of overall median survival time ( < 0.0001). Higher cIAP-1 mRNA expression was linked with smoking and alcoholism among the breast cancer patients ( < 0.0001 and < 0.0001). Significant association of higher cIAP-1 mRNA expression was found with the advancement of the disease, while higher mRNA expression of cIAP-1 was associated with distant organ metastases in ROC curve analysis.

Conclusion: The present study suggested that increased cell-free cIAP-1 and cIAP-2 mRNA expression was correlated with the advancement of disease, progression of disease, and overall reduced patient survival. Cell-free cIAP-1 and cIAP-2 mRNA expression could be the predictive indicator of the disease.
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http://dx.doi.org/10.1155/2020/3634825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468656PMC
August 2020

Emerging potential of niosomes in ocular delivery.

Expert Opin Drug Deliv 2021 Jan 23;18(1):55-71. Epub 2020 Sep 23.

Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya , Sagar, India.

Introduction: Niosomes have recently grabbed attention as one of the best tools for various site-specific drug delivery systems, including ophthalmic drug delivery. Surfactants (nonionic; tweens and spans) of different HLB values and cholesterol are the fundamental components for these formulations. It is an alternative controlled ocular drug delivery system to liposomes to overcome the problems associated with sterilization, large-scale production, and stability. It also enhances the adhesion or retention ability of drug at the ocular site. Hydrophilic or lipophilic or amphoteric drugs can be easily encapsulated in niosomes. Besides, niosomes are a leading vesicular system compatible with most of the drugs for site-specific delivery.

Areas Covered: This article reveals challenges and barriers for ocular drug delivery, various transporters and receptors present in the ocular region for the transportation of therapeutics as well as nutrients, and various method of preparations, loading methods and application potential of niosomes in ocular drug delivery.

Expert Opinion: Niosomes, a vesicular system offers numerous advantages and applicability because of its good stability, non-immunogenicity, permeation potential, and controlled release ability etc. This drug delivery system has been efficiently used in the treatment of many ocular diseases.
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http://dx.doi.org/10.1080/17425247.2020.1822322DOI Listing
January 2021

Role and Significance of Circulating Biomarkers: miRNA and E2F1 mRNA Expression and Their Association with Type-2 Diabetic Complications.

Int J Endocrinol 2020 20;2020:6279168. Epub 2020 Aug 20.

Department of Zoology and Environmental Sciences, GKV, Haridwar, India.

Background: Type 2 diabetes mellitus (T2DM) has emerged as an epidemic affecting more than four hundred million people throughout the world. It is a multifactorial disease with range of environmental and genetic factors responsible for its prevalence. In search of novel biomarkers for recording progress of various metabolic diseases, small noncoding RNA in general and microRNAs (miRNAs) in particular have emerged as the most promising biomarkers for diagnosing variety of diseases including diabetes. An increasing number of studies have been published, reporting the quantification of miRNAs in blood of subjects with diabetes and mostly aimed at identifying miRNA modulation in chronic diabetic complications. Due to its association with immune system homeostasis and potential capability to predict diabetes development, the profile of circulating miRNAs may also provide useful information about diabetes pathogenic mechanisms. Thus, the present study aimed to understand the role and expression of microRNA330 and E2F1 mRNA expression in patients with T2DM. . The present study includes a total of 200 individuals: 100 "individuals with T2DM referred to as "cases" and 100 healthy individuals referred to as "controls". Extracted RNA was used to synthesise the cDNA for microRNA-330 and E2F1 mRNA expression. Taqman assay method has been used to analyse the microRNA-330 expression in the cases and controls and SYBR green dye was used to study the E2F1 mRNA expression.

Results: Statistically significant difference was observed in all the selected 5 biochemical parameters among T2DM cases and healthy controls. Risk factors like hypertension were observed to be significantly associated with reduced HDL (=0.01), increased TG (=0.0008), and cholesterol ( < 0.0001) in hypertensive T2DM cases as compared to nonhypertensive T2DM cases. Obese patients showed significant increase in TG (=0.01) and cholesterol ( < 0.0001) as compared to nonobese patients. Similarly, increased TG (=0.001) and cholesterol ( < 0.0001) was observed in the case of alcoholic patients as compared to nonalcoholic patients. Also, patients with smoking habit showed increased TG (=0.009 = 0.009), cholesterol ( < 0.0001), and VLDL (=0.01) as compared to nonsmokers and differences among them was found to be statistically significant. Besides this, significant impact of risk factors like hypertension, obesity, alcoholism, and smoking were observed on microRNA-330 expression and E2F1 mRNA expression. A 7.72-fold increased microRNA-330 and 0.05-fold decreased E2F1 mRNA expression was observed among T2DM cases as compared to healthy controls. Increased expression of microRNA-330 was observed in hypertensive cases (9.61-fold, < 0.0001), obese cases (9.33-fold, =0.0008, alcoholic cases (9.07-fold, < 0.0001), and smoking cases (8.41-fold, =0.01) as compared to nonhypertensive, nonobese nonalcoholic, and nonsmoking cases, and differences among them were found to be significant. Decreased expression of E2F1 mRNA expression was observed in patients with alcoholism (0.03-fold, =0.002) and smoking (0.03fold, < 0.0001) while patients who were nonalcoholic and nonsmokers showed 0.07-fold increase in expression, and differences among them were found to be statistically significant.

Conclusion: The present study demonstrated that increased level of microRNA-330 and decreased level of E2F1 mRNA expression were found to be associated with pathogenesis of T2DM patients. Risk factors such as hypertension, obesity, alcoholism, and smoking may be were found to be associated with microRNA-330 and E2F1 mRNA expressions, and it can prove a reliable biomarker for T2DM disease progression could be linked to chronic diabetic complications.
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http://dx.doi.org/10.1155/2020/6279168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455836PMC
August 2020

Inhibitors of BRAF dimers using an allosteric site.

Nat Commun 2020 09 1;11(1):4370. Epub 2020 Sep 1.

Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA.

BRAF kinase, a critical effector of the ERK signaling pathway, is hyperactivated in many cancers. Oncogenic BRAF signals as an active monomer in the absence of active RAS, however, in many tumors BRAF dimers mediate ERK signaling. FDA-approved RAF inhibitors poorly inhibit BRAF dimers, which leads to tumor resistance. We found that Ponatinib, an FDA-approved drug, is an effective inhibitor of BRAF monomers and dimers. Ponatinib binds the BRAF dimer and stabilizes a distinct αC-helix conformation through interaction with a previously unrevealed allosteric site. Using these structural insights, we developed PHI1, a BRAF inhibitor that fully uncovers the allosteric site. PHI1 exhibits discrete cellular selectivity for BRAF dimers, with enhanced inhibition of the second protomer when the first protomer is occupied, comprising a novel class of dimer selective inhibitors. This work shows that Ponatinib and BRAF dimer selective inhibitors will be useful in treating BRAF-dependent tumors.
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http://dx.doi.org/10.1038/s41467-020-18123-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462985PMC
September 2020

Combination Cancer Therapy Using Multifunctional Liposomes.

Crit Rev Ther Drug Carrier Syst 2020 ;37(2):105-134

Pharmaceutics Research Projects Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour Central University, Sagar (M.P.), India.

Chemotherapy of cancer is still considered a complex phenomenon given that single chemotherapeutic agents cannot be administered for a long period of time because of the development of drug resistance and severe side effects. Nanodrug delivery systems (NDDSs) such as nanoparticles and liposomes are being investigated to enhance the safety and efficacy of anticancer agents. NDDS-based delivery of a single agent is not found to be effective in long-term anticancer therapy. Codelivery of more than one anticancer agent using liposomes shows great potential since it exhibits simultaneous synergistic therapeutic manifestations at the tumor site and enhances therapeutic efficacy in terms of the low-dose requirement of each agent and diminished side effects. Liposomes are lipid vesicles arranged in concentric bilayers with an aqueous core; they are versatile nanocarriers that accommodate the diverse nature of anticancer drugs (both hydrophobic and hydrophilic) at the same time. They offer a number of advantages for combinatorial drug delivery in terms of increased blood circulation, selective accumulation at tumor tissues, and stimuli responsiveness. Various combination of drugs such as paclitaxel (PTX) and topotecan, sunitinib and irinotecan, and combretastin A-4 and doxorubicin have been reported for cancer chemotherapy using liposomes. This review focuses on recent scenarios of combinatorial drug delivery using liposomes for better chemotherapeutic outcomes. This assemblage can be of great importance to researchers looking for advances in novel drug delivery approaches for better cancer treatment.
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http://dx.doi.org/10.1615/CritRevTherDrugCarrierSyst.2019026358DOI Listing
January 2020