Publications by authors named "Raj Kumar"

756 Publications

Clostridial Neurotoxins: Structure, Function and Implications to Other Bacterial Toxins.

Microorganisms 2021 Oct 23;9(11). Epub 2021 Oct 23.

Botulinum Research Center, Institute of Advanced Sciences, Dartmouth, MA 02747, USA.

Gram-positive bacteria are ancient organisms. Many bacteria, including Gram-positive bacteria, produce toxins to manipulate the host, leading to various diseases. While the targets of Gram-positive bacterial toxins are diverse, many of those toxins use a similar mechanism to invade host cells and exert their functions. Clostridial neurotoxins produced by and provide a classical example to illustrate the structure-function relationship of bacterial toxins. Here, we critically review the recent progress of the structure-function relationship of clostridial neurotoxins, including the diversity of the clostridial neurotoxins, the mode of actions, and the flexible structures required for the activation of toxins. The mechanism clostridial neurotoxins use for triggering their activity is shared with many other Gram-positive bacterial toxins, especially molten globule-type structures. This review also summarizes the implications of the molten globule-type flexible structures to other Gram-positive bacterial toxins. Understanding these highly dynamic flexible structures in solution and their role in the function of bacterial toxins not only fills in the missing link of the high-resolution structures from X-ray crystallography but also provides vital information for better designing antidotes against those toxins.
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http://dx.doi.org/10.3390/microorganisms9112206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618262PMC
October 2021

Polyhydroxybutyrate-Based Nanocomposites for Bone Tissue Engineering.

Pharmaceuticals (Basel) 2021 Nov 15;14(11). Epub 2021 Nov 15.

Department of Chemistry and Nanotechnology, School of Engineering and Science, Tecnologico de Monterrey, Monterrey 64849, Mexico.

Bone-related diseases have been increasing worldwide, and several nanocomposites have been used to treat them. Among several nanocomposites, polyhydroxybutyrate (PHB)-based nanocomposites are widely used in drug delivery and tissue engineering due to their excellent biocompatibility and biodegradability. However, PHB use in bone tissue engineering is limited due to its inadequate physicochemical and mechanical properties. In the present work, we synthesized PHB-based nanocomposites using a nanoblend and nano-clay with modified montmorillonite (MMT) as a filler. MMT was modified using trimethyl stearyl ammonium (TMSA). Nanoblend and nano-clay were fabricated using the solvent-casting technique. Inspection of the composite structure revealed that the basal spacing of the polymeric matrix material was significantly altered depending on the loading percentage of organically modified montmorillonite (OMMT) nano-clay. The PHB/OMMT nanocomposite displayed enhanced thermal stability and upper working temperature upon heating as compared to the pristine polymer. The dispersed (OMMT) nano-clay assisted in the formation of pores on the surface of the polymer. The pore size was proportional to the weight percentage of OMMT. Further morphological analysis of these blends was carried out through FESEM. The obtained nanocomposites exhibited augmented properties over neat PHB and could have an abundance of applications in the industry and medicinal sectors. In particular, improved porosity, non-immunogenic nature, and strong biocompatibility suggest their effective application in bone tissue engineering. Thus, PHB/OMMT nanocomposites are a promising candidate for 3D organ printing, lab-on-a-chip scaffold engineering, and bone tissue engineering.
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http://dx.doi.org/10.3390/ph14111163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8622693PMC
November 2021

Neurodegenerative disorders management: state-of-art and prospects of nano-biotechnology.

Crit Rev Biotechnol 2021 Nov 25:1-33. Epub 2021 Nov 25.

NanoBioTech Laboratory, Health Systems Engineering, Department of Environmental Engineering, Florida Polytechnic University, Lakeland, FL, USA.

Neurodegenerative disorders (NDs) are highly prevalent among the aging population. It affects primarily the central nervous system (CNS) but the effects are also observed in the peripheral nervous system. Neural degeneration is a progressive loss of structure and function of neurons, which may ultimately involve cell death. Such patients suffer from debilitating memory loss and altered motor coordination which bring up non-affordable and unavoidable socio-economic burdens. Due to the unavailability of specific therapeutics and diagnostics, the necessity to control or manage NDs raised the demand to investigate and develop efficient alternative approaches. Keeping trends and advancements in view, this report describes both state-of-the-art and challenges in nano-biotechnology-based approaches to manage NDs, toward personalized healthcare management. Sincere efforts are being made to customize nano-theragnostics to control: therapeutic cargo packaging, delivery to the brain, nanomedicine of higher efficacy, deep brain stimulation, implanted stimulation, and managing brain cell functioning. These advancements are useful to design future therapy based on the severity of the patient's neurodegenerative disease. However, we observe a lack of knowledge shared among scientists of a variety of expertise to explore this multi-disciplinary research field for NDs management. Consequently, this review will provide a guideline platform that will be useful in developing novel smart nano-therapies by considering the aspects and advantages of nano-biotechnology to manage NDs in a personalized manner. Nano-biotechnology-based approaches have been proposed as effective and affordable alternatives at the clinical level due to recent advancements in nanotechnology-assisted theragnostics, targeted delivery, higher efficacy, and minimal side effects.
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http://dx.doi.org/10.1080/07388551.2021.1993126DOI Listing
November 2021

Fatal transorbital-intracranial penetrating injury- A case report.

J Forensic Leg Med 2021 Nov 20;85:102288. Epub 2021 Nov 20.

TBI Hospital, Mirzapur, Uttar Pradesh, 231001, India.

Transorbital injuries are rare and may lead to fatal craniocerebral damage. Ocular penetrating injuries account for 24% of all penetrating head injuries in adults, while this percentage goes up to 45% in children. Any penetrating injury through the eyes may enter the intracranial cavity and might prove fatal to the victim owing to cerebral tissue damage and complex management. The dead bodies of three victims were found by the side of the river with multiple injuries to their eyes. Further examination revealed that they had sustained multiple transorbital-intracranial injuries. In such cases, identifying injury patterns is vital so that cause and manner of death can be determined precisely. A thorough postmortem examination can help identify the alleged weapon involved in the act and may clear the doubts concerned with the manner of death.
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http://dx.doi.org/10.1016/j.jflm.2021.102288DOI Listing
November 2021

Melanoma metastasis to the bladder: A case report.

Urol Case Rep 2022 Jan 9;40:101941. Epub 2021 Nov 9.

Citrus Memorial Hospital, Inverness, FL, USA.

Metastasis of malignant melanoma to the bladder is rarely seen clinically with only 29 cases reported in English-language literature. However, autopsy series of melanoma patients have shown that metastasis to the bladder could be as high as 37%, implying that numerous cases remain undiagnosed. This report details a case of malignant melanoma metastasis to the bladder. Patient presented with severe anemia and history of gross hematuria. Computerized tomography (CT) revealed a 2.7 cm mass in the bladder. Cystoscopy confirmed presence of a mass. Patient underwent cystoscopy and transurethral resection of the tumor, revealed to be melanoma on pathology.
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http://dx.doi.org/10.1016/j.eucr.2021.101941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601986PMC
January 2022

Ureteral fibroepithelial polyp: A diagnostic challenge.

Urol Case Rep 2022 Jan 9;40:101940. Epub 2021 Nov 9.

Citrus Memorial Hospital, Inverness, FL, USA.

Ureteral fibroepithelial polyps (UFP) are relatively rare, benign tumors. A total of 236 total cases were documented between 1932 and 2013. Notably, imaging studies, including computerized tomography (CT) and magnetic resonance imaging (MRI) are often negative. This report details a case of a patient with a UFP who presented with hematuria. CT suggested a possible 1.8 cm mass, but subsequent MRI was negative. Cystoscopy showed a polyp that prolapsed out of the left ureter and into the bladder with peristalsis. The patient subsequently underwent retrograde ureteroscopy and holmium laser excision of the polyp.
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http://dx.doi.org/10.1016/j.eucr.2021.101940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602012PMC
January 2022

Inverted urothelial papilloma: A case report.

Urol Case Rep 2022 Jan 2;40:101926. Epub 2021 Nov 2.

Citrus Memorial Hospital, Inverness, FL, USA.

Inverted urothelial papilloma (IUP) is an unusual tumor that typically presents as a non-invasive, endophytic urothelial neoplasm. Though fairly well described in the bladder, IUP of the upper urinary tract is fairly rare, with only 68 cases documented in English language literature. Our patient presented with an IUP of the distal left ureter and was treated with a distal ureterectomy and reimplant of the ureter with a psoas hitch.
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http://dx.doi.org/10.1016/j.eucr.2021.101926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8590038PMC
January 2022

Planetary albedo decline over Northwest India contributing to near surface warming.

Sci Total Environ 2021 Nov 16:151607. Epub 2021 Nov 16.

National Remote Sensing Centre (NRSC), Indian Space Research Organization (ISRO), Hyderabad 500037, Telangana State, India. Electronic address:

The increase in frequency and severity of heat waves during the pre-monsoon season (March-May) over Northwest India in recent decades is alarming. This study investigates the causative mechanism for warming through the forcing induced by planetary albedo changes over Northwest India, a hotspot for land-cover change. We use satellite-measured planetary albedo (α) and satellite-derived land-use-land-cover (LULC) data to estimate the impact of LULC changes from 2001 to 2018 on α and the associated radiative forcing. Over Northwest India, significant area under native land-cover, viz., barren, shrub and grass-lands, has been converted to cropland. The associated land-cover-induced changes have perturbed the radiation-budget by modifying the absorption of shortwave radiation, thereby contributing to the pronounced reduction of α as observed over this region. The diurnal-mean α has decreased by 0.016 ± 0.001 from 2001 to 2018 during pre-monsoon season which dominates α-decrease during the annual cycle over this region and contributes to the overall decreasing trend over India. Conversion of barren and shrub-lands to cropland is observed to be the greatest contributor to the α-decrease as compared to other land-cover changes. The radiative forcing due to decline in diurnal-mean α over Northwest India from 2001 to 2018 is highest during pre-monsoon at 5.99 ± 0.34 W/m. This α-induced forcing averaged over the global land surface (0.02 W/m) is equivalent to the corresponding direct forcing from rise in atmospheric methane concentrations during this period. We find an enhancement in near-surface heating to be associated with change in α; the decreasing trend in α during pre-monsoon has substantially enhanced near-surface extreme effective temperatures by 3.15 ± 2.61 K thus far and may further lead to more extreme heatwaves in future. Further, our findings highlight a decreasing (warming) and increasing (cooling) trend in clear-sky planetary albedo respectively over Northwest India and coastal regions, suggesting that sudden climate change could occur if one forcing dominates over the other.
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http://dx.doi.org/10.1016/j.scitotenv.2021.151607DOI Listing
November 2021

Molecular Docking and In Vitro Anticancer Screening of Synthesized Arylthiazole linked 2H-indol-2-one Derivatives as VEGFR-2 Kinase Inhibitors.

Anticancer Agents Med Chem 2021 Nov 17. Epub 2021 Nov 17.

Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi. India.

Background: Indoline-2,3-dione comprises a leading course group of heterocycles endowed with appealing biological actions, including anticancer activity. There are significant justifications for exploring the anticancer activity of Schiff base derivatives of isatin as a vast number of reports have documented remarkable antiproliferative action of isatin nucleus against various cancer cell lines.

Aims And Objectives: A series of arylthiazole linked 2H-indol-2-one derivatives (5a-t) was designed and synthesized as potential VEGFR-2 kinase inhibitors keeping the essential pharmacophoric features of standard drugs, like sunitinib, sorafenib, nintedanib, etc. They were evaluated for their in vitro anticancer activity. The aim of this study was to investigate and assess the anticancer potential of isatin-containing compounds along with their kinase inhibition activity.

Methods: The title compounds were synthesized by reacting substituted isatins with para-substituted arylthiazoles using appropriate reaction conditions. Selected synthesized derivatives went under preliminary screening against a panel of 60 cancer cell lines at NCI, the USA, for single-dose and five dose assays. Molecular docking was performed to explore the binding and interactions with the active sites of the VEGFR-2 receptor (PDB Id: 3VHE). Derivatives 5a, 5b, 5c, 5d, 5g, 5h, and 5m were assessed for in vitro inhibition potency against Human VEGFR-2 using ELISA (Enzyme-Linked Immunosorbent Assay) kit. All the target compounds were determined against human colon cancer cell line SW480 (colorectal adenocarcinoma cells). Cellular apoptosis/necrosis was determined by flow cytometry using annexin V-FITC. DNA content of the cells was analyzed by flow cytometry and the cycle distribution was quantified.

Results: Compounds 5a and 5g exhibited noteworthy inhibition during a five-dose assay against a panel of 60 cell lines with MID GI50 values of 1.69 and 1.54 µM, respectively. Also, both the lead compounds 5a and 5g demonstrated promising VEGFR-2 inhibitory activity with IC50 values of 5.43±0.95 and 9.63±1.32 µM, respectively. The aforesaid potent compounds were found effective against SW480 (colorectal adenocarcinoma cells) with IC50 values of 31.44 µM and 106.91 µM, respectively. Compound 5a was found to arrest the cell cycle at the G2/M phase, increasing apoptotic cell death. The docking study also supported VEGFR-2 inhibitory activity as both compounds 5a and 5g displayed promising binding and interactions with the active sites of VEGFR-2 receptor (PDB: 3VHE) with docking scores -9.355 and -7.758, respectively. All the compounds obeyed Lipinski's rule of five.

Conclusion: Indoline-2,3-dione and thiazole have huge potential to be considered a steer combination approach for developing promising kinase inhibitors as cancer therapeutics.
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http://dx.doi.org/10.2174/1871520621666211118102139DOI Listing
November 2021

Design, synthesis and anticancer activity of 2-arylimidazo[1,2-a]pyridinyl-3-amines.

Bioorg Chem 2021 Nov 1;118:105464. Epub 2021 Nov 1.

Department of Human Genetics and Molecular Medicine, School of Health Sciences Central University of Punjab, Bathinda 151401, India. Electronic address:

A series of imido-heterocycle compounds were designed, synthesized, characterized, and evaluated for the anticancer potential using breast (MCF-7 and MDA-MB-231), pancreatic (PANC-1), and colon (HCT-116 and HT-29) cancer cell lines and normal cells, while normal cells showed no toxicity. Among the screened compounds, 4h exhibited the best anticancer potential with IC values ranging from 1 to 5.5 μM. Compound 4h caused G2/M phase arrest and apoptosis in all the cell lines except MDA-MB-231 mammosphere formation was inhibited. In-vitro enzyme assay showed selective topoisomerase IIα inhibition by compound 4h, leading to DNA damage as observed by fluorescent staining. Cell signalling studies showed decreased expression of cell cycle promoting related proteins while apoptotic proteins were upregulated. Interestingly MDA-MB-231 cells showed only cytostatic effects upon treatment with compound 4h due to defective p53 status. Toxicity study using overexpression of dominant-negative mutant p53 in MCF-7 cells (which have wild type functional p53) showed that anticancer potential of compound 4h is positively correlated with p53 expression.
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http://dx.doi.org/10.1016/j.bioorg.2021.105464DOI Listing
November 2021

Gum mediated synthesis and characterization of CuO nanoparticles towards infectious disease-causing antimicrobial resistance microbial pathogens.

J Infect Public Health 2021 Oct 30. Epub 2021 Oct 30.

UNESCO-UNISA Africa Chair in Nanosciences/Nanotechnology Laboratories, College of Graduate Studies, University of South Africa (UNISA), Muckleneuk Ridge, PO Box 392, Pretoria, South Africa; Nanosciences African Network (NANOAFNET), Materials Research Group (MRG), iThemba LABS-National Research Foundation (NRF), 1 Old Faure Road, 7129, PO Box 722, Somerset West, Western Cape Province, South Africa. Electronic address:

Background: In this work biologically active CuO nanoparticle were discussed. The literature suggests that CuO shows very good antibacterial activity on both Gram positive and Gram-negative bacterial strains. Further, it is used in antibacterial coatings on various substrates to prevent various kinds of medical equipment's. Here CuO NPs was prepared via greener approach and almond gum is used as a reducing agent. Almond gum is nontoxic and contains huge amount of polysaccharides. Hence, the gum mediated CuO NPs can be used to treat urinary tract infection (UTI).

Method: The CuO NPs were characterized using UV, FTIR, XRD and HESEM with EDX analysis. The antibacterial (both Gram positive and Gram negative) effects of CuO NPs were determined with agar well diffusion method.

Results: The CuO NPs were characterized by X-ray diffraction pattern result indicates that the monoclinic structure with average crystallite size about 12.91 nm. Straight line model in Scherrer method results found to be crystallite size. The crystallite size and microstrain were estimated in W-H analysis. Lorentz polarization factor, size-strain plot (SSP), morphological index (M-I) and dislocation density were calculated based on x-ray diffraction data. The FTIR analysis confirms presence of Cu and O band. From the absorption spectrum of CuO NPs, it was found to be cutoff wavelength of 230 nm and direct bandgap was found to be 4.97 eV. Morphology analysis shows that the synthesized of CuO NPs reveals agglomerated and spherical in shape. It was found to be 16 nm-25 nm. Energy dispersive spectroscopy (EDX) result indicates percentages of Cu and O element present in the sample. Antimicrobial studies reveal zone of inhibition of CuO NPs. This was used in different pathogens such as gram-positive and Gram-negative bacteria. This study shows exhibit excellent antimicrobial effects of CuO NPs.

Conclusion: Hence, in this article the novel and cost-effective method to prepare CuO NPs was discussed. The prepared CuO NPs can be used as an antifungal and antibacterial reagent.
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http://dx.doi.org/10.1016/j.jiph.2021.10.022DOI Listing
October 2021

Development and Validation of a Functionally Relevant Comorbid Health Index in Adults Admitted to Inpatient Rehabilitation for Traumatic Brain Injury.

J Neurotrauma 2021 Nov 24:1-9. Epub 2021 Nov 24.

Department of Rehabilitation and Human Performance, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Several studies have characterized comorbidities among individuals with traumatic brain injury (TBI); however, there are few validated TBI comorbidity indices. Widely used indices (e.g., Elixhauser Comorbidity Index [ECI]) were developed in other patient populations and anchor to mortality or healthcare utilization, not functioning, and notably exclude conditions known to co-occur with TBI. The objectives of this study were to develop and validate a functionally relevant TBI comorbidity index (Fx-TBI-CI) and to compare prognostication of the Fx-TBI-CI with the . We used data from the eRehabData database to divide the sample randomly into a training sample (N = 21,292) and an internal validation sample (N = 9166). We used data from the TBI Model Systems National Database as an external validation sample (N = 1925). We used least absolute shrinkage and selection operator (LASSO) regression to narrow the list of functionally relevant conditions from 39 to 12. In internal validation, the Fx-TBI-CI explained 14.1% incremental variance over an age and sex model predicting the Functional Independence Measure (FIM) Motor subscale at inpatient rehabilitation discharge, compared with 2.4% explained by the ECI. In external validation, the Fx-TBI-CI explained 4.9% incremental variance over age and sex and 3.8% over age, sex, and Glasgow Coma Scale score,compared with 2.1% and 1.6% incremental variance, respectively, explained by the ECI. An unweighted Sum Condition Score including the same conditions as the Fx-TBI-CI conferred similar prognostication. Although the Fx-TBI-CI had only modest incremental variance over demographics and injury severity in predicting functioning in external validation, the Fx-TBI-CI outperformed the ECI in predicting post-TBI function.
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http://dx.doi.org/10.1089/neu.2021.0180DOI Listing
November 2021

Pregnancy outcomes and vertical transmission capability of SARS-CoV-2 infection among asymptomatic females: A cross-sectional study in a tertiary care rural hospital.

J Family Med Prim Care 2021 Sep 30;10(9):3247-3251. Epub 2021 Sep 30.

Department of Vice Chancellor, UP University of Medical Sciences, Etawah, Uttar Pradesh, India.

Background: The COVID-19 pandemic is still spreading throughout the world along with its strange and frightening mutations, and the World Health Organization (WHO) has declared it as a global pandemic.

Objective: The present investigation aims to evaluate the effect of SARS-CoV-2 infection on mother and newborn outcomes and the vertical transmission potential of this virus.

Study Design: This was a cross-sectional study conducted at a tertiary care dedicated COVID-19 hospital. A total of 40 pregnant females (RT-PCR positive for SARS-CoV-2) and their 41 neonates (including stillbirths and a twin delivery) were included in the present study.

Results: All the mothers in the study were SARS-CoV-2 positive on the RT-PCR test, but none had any COVID-19 symptoms (pneumonia-like fever, cough, fatigue, sore throat, shortness of breath, and diarrhea). Out of 41 newborns, 38 (92.7%) were healthy, one (2.4%) was a stillbirth, and two newborns (4.9%) could not be revived. All the 41 (100.0%) neonates, including stillborn and preterm were negative for the SARS-CoV-2 RT-PCR test. Twenty-Six neonates (63.4%) were delivered by caesarean section, whereas 15 cases (36.6%) had a normal vaginal delivery.

Conclusion: The present study showed no suggestion of vertical transmission of SARS-CoV-2 in pregnant females. Therefore, the placenta might function as a barrier to the SARS-CoV-2 virus. Also, there were no complications come upon during the delivery of any neonate in the present study.
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http://dx.doi.org/10.4103/jfmpc.jfmpc_23_21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8565111PMC
September 2021

Systemic corticosteroids for management of 'long-COVID': an evaluation after 3 months of treatment.

Monaldi Arch Chest Dis 2021 Nov 3. Epub 2021 Nov 3.

Department of Pulmonary Medicine, Vallabhbhai Patel Chest Institute, University of Delhi.

Some patients even 4 weeks after Corona Virus Disease 2019 (COVID-19) remain to be symptomatic and are known as "long-COVID". In the present study we performed the follow up evaluation at 3 months of long-COVID patients, after treatment with systemic steroids. During the study duration, out of the 4,542 patients managed in the outpatient department of the particular unit, there were 49 patients of Long-COVID. The patients having abnormal computed tomography (CT) alongwith resting hypoxia or exertional desaturation were treated with systemic steroid (deflazacort) in tapering doses for 8-10 weeks. We retrospectively analysed the clinical and radiological findings of these patients at first presentation and at about 3 months of follow up visit. On follow up, all the 49 long-COVID patients showed improvement. The occurrence of breathlessness decreased from 91.83% to 44.89% (p<0.001) and cough from 77.55% to 8.16% (p<0.001). Twenty-four patients were prescribed systemic steroids. Out of these, nearly 58% patients had MMRC grade 4 breathlessness, which decreased to < 2 MMRC in about 86% of these patients. MMRC grade (median) decreased from 3 to 1 (p<0.001). Majority of patients who were tachypnoeic and hypoxic at rest (n=7) showed improvement (71%), post-treatment with corticosteroids. Occurrence of normal chest X-ray increased from 12% to 71% (p<0.001). All these patients had abnormal CT thorax initially, and post-treatment 25% had normal CT thorax. Hence, we conclude that systemic steroids are helpful in hastening recovery of select subset of long-COVID patients. Simultaneously, we should be cautious of immunosuppressive effects of steroids like tuberculosis reactivation, especially in tuberculosis endemic countries. These findings have therapeutic implications and may serve as guidance for future approach to the management of 'long-COVID' with pulmonary sequalae.
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http://dx.doi.org/10.4081/monaldi.2021.1981DOI Listing
November 2021

A Perspective on Medicinal Chemistry Approaches for Targeting Pyruvate Kinase M2.

J Med Chem 2021 Nov 2. Epub 2021 Nov 2.

Laboratory for Drug Design and Synthesis, Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda 151401, India.

The allosteric regulation of pyruvate kinase M2 (PKM2) affects the switching of the PKM2 protein between the high-activity and low-activity states that allow ATP and lactate production, respectively. PKM2, in its low catalytic state (dimeric form), is chiefly active in metabolically energetic cells, including cancer cells. More recently, PKM2 has emerged as an attractive target due to its role in metabolic dysfunction and other interrelated conditions. PKM2 (dimer) activity can be inhibited by modulating PKM2 dimer-tetramer dynamics using either PKM2 inhibitors that bind at the ATP binding active site of PKM2 (dimer) or PKM2 activators that bind at the allosteric site of PKM2, thus activating PKM2 from the dimer formation to the tetrameric formation. The present perspective focuses on medicinal chemistry approaches to design and discover PKM2 inhibitors and activators and further provides a scope for the future design of compounds targeting PKM2 with better efficacy and selectivity.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00981DOI Listing
November 2021

Succinate dehydrogenase deficient renal cell carcinoma: A case report.

Urol Case Rep 2022 Jan 12;40:101885. Epub 2021 Oct 12.

Citrus Memorial Hospital, Inverness, FL, USA.

Succinate dehydrogenase (SDH) deficient renal cell carcinoma (RCC) are uncommon renal tumors that typically present in relatively younger patients. SDH mutations are known to cause cancer, but often presents with hereditary paragangliomas, pheochromocytomas, and gastrointestinal stromal tumors. This report details a case of SDH deficient RCC in a patient with no know contributing family history. Patient presented with recurrent urinary tract infections and groin pain. Computerized tomography (CT) revealed a 4 cm mass in the right kidney. Partial nephrectomy was performed, and the patient had an uneventful recovery. Immunohistochemical staining revealed the tumor was SDH negative.
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http://dx.doi.org/10.1016/j.eucr.2021.101885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528678PMC
January 2022

Comparison of Postoperative Port-Site Pain After Gallbladder Retrieval From Epigastric Versus Umbilical Port in Patients of Laparoscopic Cholecystectomy for Symptomatic Cholelithiasis: A Randomized Controlled Trial.

Cureus 2021 Sep 18;13(9):e18087. Epub 2021 Sep 18.

Surgery, Jawaharlal Institute of Postgraduate Medical Education & Research, Puducherry, IND.

Introduction Gallbladder (GB) retrieval is an important cause of postoperative pain (POP) after laparoscopic cholecystectomy (LC). Retrieval is through the epigastric or umbilical port based on the surgeon's preference. There is limited evidence to support the superiority of one port over the other in terms of POP. This study was done to compare POP between epigastric and umbilical ports after GB retrieval in LC for symptomatic cholelithiasis.  Material and methods All patients who underwent elective LC for symptomatic cholelithiasis were randomized for GB retrieval either through the umbilical (n = 15) or epigastric (n = 15) port. Postoperatively, the retrieval difficulty score by the operating surgeon, visual analog scale (VAS) scores for pain, and surgical site infection (SSI) by postoperative day (POD) 10 and 30 were assessed. Results The mean visual analog scores at the umbilical port at 1, 6, 12, 24, and 36 hours postoperatively were 5.20 ± 0.86, 4.60 ± 0.74, 4.00 ± 0.53, 3.40 ± 0.08, and 2.73 ± 0.82, which were significantly less than the visual analog scores at the epigastric port at the same time intervals, measuring 6.06 ± 1.34, 5.87 ± 1.30, 5.27 ± 1.16, 4.73 ± 1.10, and 3.93 ± 1.03, respectively. The difference was statistically significant between the two arms (p-value < 0.05). The mean retrieval difficulty score was significantly less for the umbilical port (4.40 ± 0.74) when compared with the epigastric port (5.13 ± 0.55). The overall SSI rate in the present study was 10%, and three (20%) patients in the epigastric port group developed SSI by POD 10, while none in the umbilical port group developed SSI. Conclusion GB retrieval from the umbilical port is associated with less POP, SSI, and retrieval difficulty when compared with GB retrieval from the epigastric port after elective LC for symptomatic cholelithiasis. Titration of analgesic use can also be done appropriately, reducing the dose of analgesics after 12-24 hours.
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http://dx.doi.org/10.7759/cureus.18087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523391PMC
September 2021

Acute Cortisol Profile Associations With Cognitive Impairment After Severe Traumatic Brain Injury.

Neurorehabil Neural Repair 2021 Oct 23:15459683211048771. Epub 2021 Oct 23.

Department of Physical Medicine & Rehabilitation, 171669University of Pittsburgh, Pittsburgh, PA, USA.

Background: Cognitive impairments commonly occur after traumatic brain injury (TBI) and affect daily functioning. Cortisol levels, which are elevated during acute hospitalization for most individuals after severe TBI, can influence cognition, but this association has not been studied previously in TBI.

Objective: We hypothesized that serum and cerebral spinal fluid (CSF) cortisol trajectories over days 0-5 post-injury are associated with cognition 6-month post-injury.

Methods: We examined 94 participants with severe TBI, collected acute serum and/or CSF samples over days 0-5 post-injury, and compared cortisol levels to those in 17 healthy controls. N = 88 participants had serum, and n = 84 had CSF samples available for cortisol measurement and had neuropsychological testing 6 months post-injury. Group based trajectory analysis (TRAJ) was used to generate temporal serum and CSF cortisol profiles which were examined for associations with neuropsychological performance. We used linear regression to examine relationships between cortisol TRAJ groups and both overall and domain-specific cognition.

Results: TRAJ analysis identified a group and a group for serum and a group and group for CSF cortisol. Multivariable analysis showed serum cortisol TRAJ group was associated with overall cognitive composites scores ( = .024) and with executive function ( = .039) and verbal fluency ( = .029) domain scores. CSF cortisol TRAJ group was associated with overall cognitive composite scores ( = .021) and domain scores for executive function ( = .041), verbal fluency ( = .031), and attention ( = .034).

Conclusions: High acute cortisol trajectories are associated with poorer cognition 6 months post-TBI.
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http://dx.doi.org/10.1177/15459683211048771DOI Listing
October 2021

Oncogenic KIT Induces Replication stress and Confers Cell Cycle Checkpoint Vulnerability in Melanoma.

J Invest Dermatol 2021 Oct 20. Epub 2021 Oct 20.

Wellman Center for Photomedicine and Department of Dermatology; MGH Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA. Electronic address:

Acral and mucosal melanomas (AMM's) arise from sun-protected sites, disproportionately impact darker-skinned individuals and exact a higher mortality than common types of cutaneous melanoma. Genetically, AMM's harbor more alterations of KIT compared to typical CM's. As KIT-mutated melanomas remain largely treatment resistant, we set out to create a faithful murine KIT-driven allograft model to define newer therapeutic strategies. Using the prevalent human KIT activating mutation, the murine mKIT cellular avatars show features of transformation in vitro and tumorigenic in immunocompetent C57BL/6J mice. Compared to its vector-controlled cells (mVec), mKIT cells proliferate more rapidly, exhibit greater chromosomal aberrations, and sustain 3D spheroid expansion and aggressive tumor growth in C57BL/6J mice. We further verified the functional dependence of these cells on KIT with both genetic and pharmacologic suppression. Using these cells, we performed a screen of 199 kinase inhibitors and identified a selective vulnerability to Chk1/ATR inhibition in the KIT-activated cells. Mechanistically, we subsequently showed that KIT induces a significantly increased level of replication stress compared to mVec cells. These results showcase an allograft model of human KIT-driven melanomas, which uncovered an unappreciated role for replication stress in KIT melanomagenesis and implicated a possible therapeutic strategy with Chk1/ATR inhibitors.
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http://dx.doi.org/10.1016/j.jid.2021.07.188DOI Listing
October 2021

Novel role of xanthine oxidase-dependent HO production in 12/15-lipoxygenase-mediated de novo lipogenesis, triglyceride biosynthesis and weight gain.

Redox Biol 2021 11 12;47:102163. Epub 2021 Oct 12.

Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA. Electronic address:

12/15-lipoxygenase (12/15-LOX) plays an essential role in oxidative conversion of polyunsaturated fatty acids into various bioactive lipid molecules. Although 12/15-LOX's role in the pathophysiology of various human diseases has been well studied, its role in weight gain is controversial and poorly clarified. Here, we demonstrated the role of 12/15-LOX in high-fat diet (HFD)-induced weight gain in a mouse model. We found that 12/15-LOX mediates HFD-induced de novo lipogenesis (DNL), triglyceride (TG) biosynthesis and the transport of TGs from the liver to adipose tissue leading to white adipose tissue (WAT) expansion and weight gain via xanthine oxidase (XO)-dependent production of HO. 12/15-LOX deficiency leads to cullin2-mediated ubiquitination and degradation of XO, thereby suppressing HO production, DNL and TG biosynthesis resulting in reduced WAT expansion and weight gain. These findings infer that manipulation of 12/15-LOX metabolism may manifest a potential therapeutic target for weight gain and obesity.
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http://dx.doi.org/10.1016/j.redox.2021.102163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8577505PMC
November 2021

Fighting the 'tobacco epidemic' - A call to action to identify Targeted Intervention Points (TIPs) for better counseling patients with urothelial cancer.

Urol Oncol 2021 Dec 8;39(12):793-796. Epub 2021 Oct 8.

Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

The association between tobacco use and urothelial cancer of the bladder is well known. Given the worsening tobacco epidemic, here we make the case for systematic targeted points of intervention for urologists and other professionals to intervene against bladder cancer. Awareness of contemporary checkpoints where we can intervene for counseling patients may help medical education in a tobacco-pandemic difficult setting.
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http://dx.doi.org/10.1016/j.urolonc.2021.08.025DOI Listing
December 2021

Association of Military Employment With Late-Life Cognitive Decline and Dementia: A Population-Based Prospective Cohort Study.

Mil Med 2021 Oct 9. Epub 2021 Oct 9.

Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Introduction: As the number of U.S. veterans over age 65 has increased, interest in whether military service affects late-life health outcomes has grown. Whether military employment is associated with increased risk of cognitive decline and dementia remains unclear.

Materials And Methods: We used data from 4,370 participants of the longitudinal Adult Changes in Thought (ACT) cohort study, enrolled at age 65 or older, to examine whether military employment was associated with greater cognitive decline or higher risk of incident dementia in late life. We classified persons as having military employment if their first or second-longest occupation was with the military. Cognitive status was assessed at each biennial Adult Changes in Thought study visit using the Cognitive Abilities Screening Instrument, scored using item response theory (CASI-IRT). Participants meeting screening criteria were referred for dementia ascertainment involving clinical examination and additional cognitive testing. Primary analyses were adjusted for sociodemographic characteristics and APOE genotype. Secondary analyses additionally adjusted for indicators of early-life socioeconomic status and considered effect modification by age, gender, and prior traumatic brain injury with loss of consciousness TBI with LOC.

Results: Overall, 6% of participants had military employment; of these, 76% were males. Military employment was not significantly associated with cognitive change (difference in modeled 10-year cognitive change in CASI-IRT scores in SD units (95% confidence interval [CI]): -0.042 (-0.19, 0.11), risk of dementia (hazard ratio [HR] [95% CI]: 0.92 [0.71, 1.18]), or risk of Alzheimer's disease dementia (HR [95% CI]: 0.93 [0.70, 1.23]). These results were robust to additional adjustment and sensitivity analyses. There was no evidence of effect modification by age, gender, or traumatic brain injury with loss of consciousness.

Conclusions: Among members of the Adult Changes in Thought cohort, military employment was not associated with increased risk of cognitive decline or dementia. Nevertheless, military veterans face the same high risks for cognitive decline and dementia as other aging adults.
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http://dx.doi.org/10.1093/milmed/usab413DOI Listing
October 2021

Early chronic systemic inflammation and associations with cognitive performance after moderate to severe TBI.

Brain Behav Immun Health 2021 Feb 15;11:100185. Epub 2020 Dec 15.

Department of Physical Medicine and Rehabilitation, School of Medicine, University of Pittsburgh, USA.

Background: Cognitive dysfunction adversely effects multiple functional outcomes and social roles after TBI. We hypothesize that chronic systemic inflammation exacerbates cognitive deficits post-injury and diminishes functional cognition and quality of life (QOL). Yet few studies have examined relationships between inflammation and cognition after TBI. Associations between early chronic serum inflammatory biomarker levels, cognitive outcomes, and QOL 6-months and 12-months after moderate-to-severe TBI were identified using unweighted (uILS) and weighted (wILS) inflammatory load score (ILS) formation.

Methods: Adults with moderate-to-severe TBI (n ​= ​157) completed neuropsychological testing, the Functional Impairment Measure Cognitive Subscale (FIM-Cog) and self-reported Percent Back to Normal scale 6 months (n ​= ​139) and 12 months (n ​= ​136) post-injury. Serial serum samples were collected 1-3 months post-TBI. Cognitive composite scores were created as equally weighted means of T-scores derived from a multidimensional neuropsychological test battery. Median inflammatory marker levels associated with 6-month and 12-month cognitive composite T-scores (p ​< ​0.10) were selected for ILS formation. Markers were quartiled, and quartile ranks were summed to generate an uILS. Marker-specific β-weights were derived using penalized ridge regression, multiplied by standardized marker levels, and summed to generate a wILS. ILS associations with cognitive composite scores were assessed using multivariable linear regression. Structural equation models assessed ILS influences on functional cognition and QOL using 12-month FIM-Cog and Percent Back to Normal scales.

Results: ILS component markers included: IL-1β, TNF-α, sIL-4R, sIL-6R, RANTES, and MIP-1β. Increased sIL-4R levels were positively associated with overall cognitive composite T-scores in bivariate analyses, while remaining ILS markers were negatively associated with cognition. Multivariable receiver operator curves (ROC) showed uILS added 14.98% and 31.93% relative improvement in variance captured compared to the covariates only base model (age, sex, education, Glasgow Coma Scale score) when predicting cognitive composite scores at 6 and 12 months, respectively; wILS added 33.99% and 36.87% relative improvement in variance captured. Cognitive composite mediated wILS associations with FIM-Cog scores at 12 months, and both cognitive composite and FIM-Cog scores mediated wILS associations with QOL.

Conclusions: Early chronic inflammatory burden is associated with cognitive performance post-TBI. wILS explains greater variance in cognitive composite T-scores than uILS. Linking inflammatory burden associated with cognitive deficits to functional outcome post-TBI demonstrates the potential impact of immunotherapy interventions aimed at improving cognitive recovery post-TBI.
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http://dx.doi.org/10.1016/j.bbih.2020.100185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474517PMC
February 2021

Managing Sleep Problems After Traumatic Brain Injury.

Arch Phys Med Rehabil 2021 Sep 10. Epub 2021 Sep 10.

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http://dx.doi.org/10.1016/j.apmr.2021.05.004DOI Listing
September 2021

Laboratory evaluation of performance of pulse oximeters from six different manufacturers during motion artifacts produced by Fluke 2XL SpO simulator.

J Clin Monit Comput 2021 Sep 7. Epub 2021 Sep 7.

Biomedical Instruments & Devices, Postgraduate Institute of Medical Education & Research, Chandigarh, India.

We performed laboratory evaluation of six pulse oximeters from different manufacturers using the Fluke 2XL SpO simulator. The pulse oximeter probes were labeled 1 through 6 and tested using the two pre-programed preset functions of the Fluke 2XL SpO simulator, level 01 and level 02, for their performance in the presence of motion artifacts. The pulse oximeters were also tested at low perfusion index (PI) settings. The accuracy of the individual probes was ranked as good, mediocre, or poor based on the degree of deviation of the measured SpO and pulse rate (PR) by the probes from that generated by the simulator in both the presence and absence of motion artifacts and at lower PI. In preset level 01, probes numbered 1, 2, and 6 performed flawlessly, probes numbered 3, 4, and 5 performed poorly. In preset level 02, all probes performed well in the absence of motion artifacts. When probes were attached in the absence of motion, but readings were recorded after the emergence of motion artifacts, probes 1, 2, and 6 continued to perform well. However, the performance of probes 3, 4, and 5 deteriorated. When probes were attached directly in the presence of motion artifacts, probes 2 and 6 performed well, whereas all other probes performed poorly. Successively lowering the PI degraded performance of probes 3, 4, and 5 at extremely low PI. It is observed that during motion and/or low PI conditions, multiple probes see deterioration in performance.
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http://dx.doi.org/10.1007/s10877-021-00747-4DOI Listing
September 2021

Rationalization of the Activity Profile of Pyruvate Kinase Isozyme M2 (PKM2) Inhibitors using 3D QSAR.

Curr Top Med Chem 2021 08 4. Epub 2021 Aug 4.

Laboratory for Drug Design and Synthesis, Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda. India.

Introduction: Pyruvate kinase isozyme M2 (PKM2) was observed to be overexpressed and play a key role in cell growth and cancer cells' metabolism. During the past years, phytochemicals have been developed as new treatment options for chemoprevention and cancer therapy. The natural resources, like shikonin (naphthoquinone) and its derivatives, have emerged to be high potential therapeutics in cancer treatment.

Methods: Our study aimed to design novel anti-tumour agents (PKM2 inhibitors) focusing on the shikonin scaffold with a better activity using computational methods. We applied a three-dimensional quantitative structure-activity relationship (3D-QSAR) approach using Field-Based QSAR.

Results:The comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of forty shikonin derivatives, including shikonin, to develop robust models and rationalize the PKM2 inhibitory activity profile by building a correlation between structural features and activity.

Conclusion: These predictive computational models will further help the design and synthesis of potent PKM2 inhibitors and their fast biological assessment at low cost.

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http://dx.doi.org/10.2174/1568026621666210804124555DOI Listing
August 2021

Omphalic Bleed.

Cureus 2021 Jun 30;13(6):e16066. Epub 2021 Jun 30.

Surgery, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, IND.

Portosystemic collateralization is usually seen in patients with portal hypertension. Bleeding from the ectopic varices is reportedly rare. We present a case of a 55-year-old gentleman who presented with complaints of bleeding from the umbilicus. On examination, he was tachycardic, hypotensive, and in hypovolemic shock. Bleeding was suspected to be from the umbilical varices. Contrast-enhanced computed tomography of the abdomen with abdominal angiography revealed a cirrhotic liver with partial thrombosis of the portal vein with collaterals in the perigastric, lower esophageal, peripancreatic, splenic and mesenteric, umbilical and paraumbilical collaterals with recanalization of the umbilical vein. The bleeder was identified to be the collateral at the umbilical region from the superior mesenteric vein. The patient was treated with a Doppler-guided injection of a sclerosant into the collateral, thereby achieving successful hemostasis.
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http://dx.doi.org/10.7759/cureus.16066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323931PMC
June 2021

Brevibacillin 2V Exerts Its Bactericidal Activity Binding to Lipid II and Permeabilizing Cellular Membranes.

Front Microbiol 2021 16;12:694847. Epub 2021 Jul 16.

Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, Netherlands.

Lipo-tridecapeptides, a class of bacterial non-ribosomally produced peptides, show strong antimicrobial activity against Gram-positive pathogens, including antibiotic-resistant and spp. However, many of these lipo-tridecapeptides have shown high hemolytic activity and cytotoxicity, which has limited their potential to be developed into antibiotics. Recently, we reported a novel antimicrobial lipo-tridecapeptide, brevibacillin 2V, which showed no hemolytic activity against human red blood cells at a high concentration of 128 mg/L, opposite to other brevibacillins and lipo-tridecapeptides. In addition, brevibacillin 2V showed much lower cytotoxicity than the other members of the brevibacillin family. In this study, we set out to elucidate the antimicrobial mode of action of brevibacillin 2V. The results show that brevibacillin 2V acts as bactericidal antimicrobial agent against (MRSA). Further studies show that brevibacillin 2V exerts its bactericidal activity by binding to the bacterial cell wall synthesis precursor Lipid II and permeabilizing the bacterial membrane. Combined solid-state NMR, circular dichroism, and isothermal titration calorimetry assays indicate that brevibacillin 2V binds to the GlcNAc-MurNAc moiety and/or the pentapeptide of Lipid II. This study provides an insight into the antimicrobial mode of action of brevibacillin 2V. As brevibacillin 2V is a novel and promising antibiotic candidate with low hemolytic activity and cytotoxicity, the here-elucidated mode of action will help further studies to develop it as an alternative antimicrobial agent.
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http://dx.doi.org/10.3389/fmicb.2021.694847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322648PMC
July 2021

Immune gene expression in cyprinid herpesvirus-2 (CyHV-2)-sensitized peripheral blood leukocytes (PBLs) co-cultured with CyHV-2-infected goldfish fin cell line.

Aquac Int 2021 Jul 26:1-10. Epub 2021 Jul 26.

Peninsular and Marine Fish Genetic Resources Centre, ICAR-National Bureau of Fish Genetic Resources, CMFRI Campus, P.O. Number 1603, Kochi, Kerala 682018 India.

Goldfish is one of the preferred ornamental fish which is highly susceptible to cyprinid herpesvirus-2 (CyHV-2) infection. The present study aimed to analyse immune gene expression in a co-culture of CyHV-2-sensitized goldfish peripheral blood leukocytes (PBLs) with CyHV-2-infected fantail goldfish fin cell lines (FtGF). Goldfish were sensitized with intraperitoneal TCID dose (10/mL) of CyHV-2. After 2 weeks, PBLs were collected and co-cultured with CyHV-2-infected FtGF cells keeping both uninfected FtGF cells and PBL control groups. After 2 days of co-culture, WST-1 assay for cell proliferation was performed at 450 nm during the 2nd, 4th and 6th days of co-culture. The results showed a significant increase (p < 0.05) in cell density in CyHV-2-infected PBL and virus-infected FtGF cells during the 4th day post co-culture which confirmed effector cell generation. Expressions of few immune genes were checked taking RNA samples of CyHV-2-induced PBLs post co-culture with infected FtGF cells along with uninfected FtGF cells as control group at different time periods (2nd, 4th and 6th days) in triplicate. The results indicated increased expression of CD8α, IFNγ, b2m, MHC I, LMP 7, IL-10, IL-12 and GATA3 except Tapasin. From the above study, we concluded that goldfish showed both Th1- and Th2-mediated immune responses to CyHV-2. The current findings support the scope for further vaccine development against CyHV-2 for goldfish.
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http://dx.doi.org/10.1007/s10499-021-00721-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310777PMC
July 2021

Strangulated Falciform Hernia.

Cureus 2021 Jun 24;13(6):e15898. Epub 2021 Jun 24.

Surgery, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, IND.

Internal hernias are rare, and a delayed diagnosis can lead to dangerous complications. A 75-year-old male with no previous surgical history presented with right upper abdominal pain and vomiting. On examination, he had guarding in the right hypochondrium with a positive Murphy's sign. However, ultrasonography of the gall bladder was normal with dilated bowel loops. Contrast-enhanced CT (CECT) revealed a falciform hernia with evidence of obstruction. Segmental resection of the gangrenous ileum was done with a double-barrel stoma. Later on, stoma reversal was also done with no complications.
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http://dx.doi.org/10.7759/cureus.15898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310387PMC
June 2021
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