Publications by authors named "M B Singh"

9,552 Publications

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Design and characterization of 3D printed, neomycin-eluting poly-L-lactide mats for wound-healing applications.

J Mater Sci Mater Med 2021 Apr 8;32(4):44. Epub 2021 Apr 8.

Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, USciences 600 S 43rd St, Philadelphia, PA, 19143, USA.

This study evaluates the suitability of 3D printed biodegradable mats to load and deliver the topical antibiotic, neomycin, for up to 3 weeks in vitro. A 3D printer equipped with a hot melt extruder was used to print bandage-like wound coverings with porous sizes appropriate for cellular attachment and viability. The semicrystalline polyester, poly-l-lactic acid (PLLA) was used as the base polymer, coated (post-printing) with polyethylene glycols (PEGs) of MWs 400 Da, 6 kDa, or 20 kDa to enable manipulation of physicochemical and biological properties to suit intended applications. The mats were further loaded with a topical antibiotic (neomycin sulfate), and cumulative drug-release monitored for 3 weeks in vitro. Microscopic imaging as well as Scanning Electron Microscopy (SEM) studies showed pore dimensions of 100 × 400 µm. These pore dimensions were achieved without compromising mechanical strength; because of the "tough" individual fibers constituting the mat (Young's Moduli of 50 ± 20 MPa and Elastic Elongation of 10 ± 5%). The in vitro dissolution study showed first-order release kinetics for neomycin during the first 20 h, followed by diffusion-controlled (Fickian) release for the remaining duration of the study. The release of neomycin suggested that the ability to load neomycin on to PLLA mats increases threefold, as the MW of the applied PEG coating is lowered from 20 kDa to 400 Da. Overall, this study demonstrates a successful approach to using a 3D printer to prepare porous degradable mats for antibiotic delivery with potential applications to dermal regeneration and tissue engineering. Illustration of the process used to create and characterize 3D printed PLLA mats.
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http://dx.doi.org/10.1007/s10856-021-06509-7DOI Listing
April 2021

Correction to: The impact of unilateral diaphragmatic paralysis on sleepdisordered breathing: a scoping review.

Can J Anaesth 2021 Apr 7. Epub 2021 Apr 7.

Department of Anesthesiology and Pain Management, Women's College Hospital, Toronto, ON, Canada.

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http://dx.doi.org/10.1007/s12630-021-01981-9DOI Listing
April 2021

Synthesis and characterization of Mg-Zn ferrite based flexible microwave composites and its application as SNG metamaterial.

Sci Rep 2021 Apr 7;11(1):7654. Epub 2021 Apr 7.

Department of Electrical Engineering, Qatar University, 2713, Doha, Qatar.

In this article, we propose SNG (single negative) metamaterial fabricated on Mg-Zn ferrite-based flexible microwave composites. Firstly, the flexible composites are synthesized by the sol-gel method having four different molecular compositions of MgZnFeO which are denoted as Mg, Mg Mg and Mg. The structural, morphological, and microwave properties of the synthesized flexible composites are analyzed using X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), and conventional dielectric assessment kit (DAK) to justify their possible application as dielectric substrate at microwave frequency regime. Thus the average grain size is found from 20 to 24 nm, and the dielectric constants are 6.01, 5.10, 4.19, and 3.28, as well as loss tangents, are 0.002, 0.004, 0.006, and 0.008 for the prepared Mg-Zn ferrites, i.e., Mg Mg Mg and Mg respectively. Besides, the prepared low-cost Mg-Zn ferrite composites exhibit high flexibility and lightweight, which makes them a potential candidate as a metamaterial substrate. Furthermore, a single negative (SNG) metamaterial unit cell is fabricated on the prepared, flexible microwave composites, and their essential electromagnetic behaviors are observed. Very good effective medium ratios (EMR) vales are obtained from 14.65 to 18.47, which ensure the compactness of the fabricated prototypes with a physical dimension of 8 × 6.5 mm Also, the proposed materials have shown better performances comparing with conventional FR4 and RO4533 materials, and they have covered S-, C-, X-, Ku-, and K-band of microwave frequency region. Thus, the prepared, flexible SNG metamaterials on MgZnFeO composites are suitable for microwave and flexible technologies.
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http://dx.doi.org/10.1038/s41598-021-87100-6DOI Listing
April 2021

Therapeutic Gene Silencing Using Targeted Lipid Nanoparticles in Metastatic Ovarian Cancer.

Small 2021 Apr 7:e2100287. Epub 2021 Apr 7.

Laboratory of Precision NanoMedicine, Tel Aviv University, Tel Aviv, 69978, Israel.

Ovarian cancer is an aggressive tumor owing to its ability to metastasize from stage II onward. Herein, lipid nanoparticles (LNPs) that encapsulate combination of small interfering RNAs (siRNAs), polo-like kinase-1 (PLK1), and eukaryotic translation-initiation factor 3c (eIF3c), to target different cellular pathways essential for ovarian cancer progression are generated. The LNPs are further modified with hyaluronan (tNPs) to target cluster of differentiation 44 (CD44) expressing cells. Interestingly, hyaluronan-coated LNPs (tNPs) prolong functional activity and reduce growth kinetics of spheroids in in vitro assay as compared to uncoated LNPs (uNPs) due to ≈1500-fold higher expression of CD44. Treatment of 2D and 3D cultured ovarian cancer cells with LNPs encapsulating both siRNAs result in 85% cell death and robust target gene silencing. In advanced orthotopic ovarian cancer model, intraperitoneal administration of LNPs demonstrates CD44 specific tumor targeting of tNPs compared to uNPs and robust gene silencing in tissues involved in ovarian cancer pathophysiology. At very low siRNA dose, enhanced overall survival of 60% for tNPs treated mice is observed compared to 10% and 20% for single siRNA-, eIF3c-tNP, and PLK1-tNP treatment groups, respectively. Overall, LNPs represent promising platform in the treatment of advanced ovarian cancer by improving median- and overall-survival.
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http://dx.doi.org/10.1002/smll.202100287DOI Listing
April 2021

Etiology and management of hypertension in patients with cancer.

Cardiooncology 2021 Apr 6;7(1):14. Epub 2021 Apr 6.

Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, USA.

The pathophysiology of hypertension and cancer are intertwined. Hypertension has been associated with an increased likelihood of developing certain cancers and with higher cancer-related mortality. Moreover, various anticancer therapies have been reported to cause new elevated blood pressure or worsening of previously well-controlled hypertension. Hypertension is a well-established risk factor for the development of cardiovascular disease, which is rapidly emerging as one of the leading causes of death and disability in patients with cancer. In this review, we discuss the relationship between hypertension and cancer and the role that hypertension plays in exacerbating the risk for anthracycline- and trastuzumab-induced cardiomyopathy. We then review the common cancer therapies that have been associated with the development of hypertension, including VEGF inhibitors, small molecule tyrosine kinase inhibitors, proteasome inhibitors, alkylating agents, glucocorticoids, and immunosuppressive agents. When available, we present strategies for blood pressure management for each drug class. Finally, we discuss blood pressure goals for patients with cancer and strategies for assessment and management. It is of utmost importance to maintain optimal blood pressure control in the oncologic patient to reduce the risk of chemotherapy-induced cardiotoxicity and to decrease the risk of long-term cardiovascular disease.
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http://dx.doi.org/10.1186/s40959-021-00101-2DOI Listing
April 2021

Coordinated Activation of ARF1 GTPases by ARF-GEF GNOM Dimers Is Essential for Vesicle Trafficking in Arabidopsis.

Plant Cell 2020 Aug;32(8):2491-2507

Center for Plant Molecular Biology, Developmental Genetics, University of Tübingen, 72076 Tübingen, Germany.

Membrane trafficking maintains the organization of the eukaryotic cell and delivers cargo proteins to their subcellular destinations, such as sites of action or degradation. The formation of membrane vesicles requires the activation of the ADP-ribosylation factor ARF GTPase by the SEC7 domain of ARF guanine-nucleotide exchange factors (ARF-GEFs), resulting in the recruitment of coat proteins by GTP-bound ARFs. In vitro exchange assays were done with monomeric proteins, although ARF-GEFs form dimers in vivo. This feature is conserved across eukaryotes, although its biological significance is unknown. Here, we demonstrate the proximity of ARF1•GTPs in vivo by fluorescence resonance energy transfer-fluorescence lifetime imaging microscopy, mediated through coordinated activation by dimers of Arabidopsis (Arabidopsis thaliana) ARF-GEF GNOM, which is involved in polar recycling of the auxin transporter PIN-FORMED1. Mutational disruption of ARF1 spacing interfered with ARF1-dependent trafficking but not with coat protein recruitment. A mutation impairing the interaction of one of the two SEC7 domains of the GNOM ARF-GEF dimer with its ARF1 substrate reduced the efficiency of coordinated ARF1 activation. Our results suggest a model of coordinated activation-dependent membrane insertion of ARF1•GTP molecules required for coated membrane vesicle formation. Considering the evolutionary conservation of ARFs and ARF-GEFs, this initial regulatory step of membrane trafficking might well occur in eukaryotes in general.
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http://dx.doi.org/10.1105/tpc.20.00240DOI Listing
August 2020

Unusual Behavior of Ketoximes: Reagentless Photochemical Pathway to Alkynyl Sulfides.

J Org Chem 2021 Apr 6. Epub 2021 Apr 6.

Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi 221 005, India.

The unique properties of ketoximes are used prominently for the synthesis of heterocycles. In contrast, their potential to absorb light and photoelectron transfer processes remains challenging. Widespread interest in controlling direct excitation of ketoxime tacticity unlocks unconventional reaction pathways, enabling photochemical intramolecular skeletal modification to constitute alkynyl sulfides that cannot be realized via traditional activation. Despite decades of advancements, the alkynyl sulfides, particularly those composed of polar functionalities and derived from renewable sources, remain unknown. These findings demonstrate the importance of decelerated ketoxime from β-oxodithioester for the identification of reaction conditions. The method uses mild reaction conditions to generate excited-state photoreductant for the functionalization of an array of alkynyl sulfides. Additionally, a fundamental understanding of elementary steps using electrochemical and spectroscopic techniques/experiments revealed a PCET pathway to this transformation, while the involved substrates and their properties with improved economical tools indicated the translational potential of this method.
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http://dx.doi.org/10.1021/acs.joc.1c00417DOI Listing
April 2021

Functional assessment of the "two-hit" model for neurodevelopmental defects in Drosophila and X. laevis.

PLoS Genet 2021 Apr 5;17(4):e1009112. Epub 2021 Apr 5.

Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, United States of America.

We previously identified a deletion on chromosome 16p12.1 that is mostly inherited and associated with multiple neurodevelopmental outcomes, where severely affected probands carried an excess of rare pathogenic variants compared to mildly affected carrier parents. We hypothesized that the 16p12.1 deletion sensitizes the genome for disease, while "second-hits" in the genetic background modulate the phenotypic trajectory. To test this model, we examined how neurodevelopmental defects conferred by knockdown of individual 16p12.1 homologs are modulated by simultaneous knockdown of homologs of "second-hit" genes in Drosophila melanogaster and Xenopus laevis. We observed that knockdown of 16p12.1 homologs affect multiple phenotypic domains, leading to delayed developmental timing, seizure susceptibility, brain alterations, abnormal dendrite and axonal morphology, and cellular proliferation defects. Compared to genes within the 16p11.2 deletion, which has higher de novo occurrence, 16p12.1 homologs were less likely to interact with each other in Drosophila models or a human brain-specific interaction network, suggesting that interactions with "second-hit" genes may confer higher impact towards neurodevelopmental phenotypes. Assessment of 212 pairwise interactions in Drosophila between 16p12.1 homologs and 76 homologs of patient-specific "second-hit" genes (such as ARID1B and CACNA1A), genes within neurodevelopmental pathways (such as PTEN and UBE3A), and transcriptomic targets (such as DSCAM and TRRAP) identified genetic interactions in 63% of the tested pairs. In 11 out of 15 families, patient-specific "second-hits" enhanced or suppressed the phenotypic effects of one or many 16p12.1 homologs in 32/96 pairwise combinations tested. In fact, homologs of SETD5 synergistically interacted with homologs of MOSMO in both Drosophila and X. laevis, leading to modified cellular and brain phenotypes, as well as axon outgrowth defects that were not observed with knockdown of either individual homolog. Our results suggest that several 16p12.1 genes sensitize the genome towards neurodevelopmental defects, and complex interactions with "second-hit" genes determine the ultimate phenotypic manifestation.
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http://dx.doi.org/10.1371/journal.pgen.1009112DOI Listing
April 2021

Demographic & clinical profile of patients with COVID-19 at a tertiary care hospital in north India.

Indian J Med Res 2021 Jan & Feb;153(1 & 2):115-125

Department of Hospital Administration, Postgraduate Institute of Medical Education & Research, Chandigarh, India.

Background & Objectives: The COVID-19 pandemic emerged as a major public health emergency affecting the healthcare services all over the world. It is essential to analyze the epidemiological and clinical characteristics of patients with COVID-19 in different parts of our country. This study highlights clinical experience in managing patients with COVID-19 at a tertiary care centre in northern India.

Methods: Clinical characteristics and outcomes of consecutive adults patients admitted to a tertiary care hospital at Chandigarh, India, from April 1 to May 25, 2020 were studied. The diagnosis of SARS-CoV-2 infection was confirmed by real-time reverse transcriptase polymerase chain reaction (RT-PCR) on throat and/or nasopharyngeal swabs. All patients were managed according to the institute's consensus protocol and in accordance with Indian Council of Medical Research guidelines.

Results: During the study period, 114 patients with SARS-CoV-2 infection were admitted. The history of contact with COVID-19-affected individuals was available in 75 (65.8%) patients. The median age of the patients was 33.5 yr (13-79 yr), and there were 66 (58%) males. Of the total enrolled patients, 48 (42%) were symptomatic. The common presenting complaints were fever (37, 77%), cough (26, 54%) and shortness of breath (10, 20.8%). Nineteen (17%) patients had hypoxia (SpO<94%) at presentation and 36 (31%) had tachypnoea (RR >24). Thirty four (29.8%) patients had an accompanying comorbid illness. Age more than 60 yr and presence of diabetes and hypertension were significantly associated with severe COVID-19 disease. Admission to the intensive care unit (ICU) was needed in 18 patients (52%), with three (2.6%) patients requiring assisted ventilation. Mortality of 2.6 per cent (3 patients) was observed.

Interpretation & Conclusions: Majority of the patients with COVID-19 infection presenting to our hospital were young and asymptomatic. Fever was noted only in three-fourth of the patients and respiratory symptoms in half of them. Patients with comorbidities were more vulnerable to complications. Triaged classification of patients and protocol-based treatment resulted in good outcomes and low case fatality.
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http://dx.doi.org/10.4103/ijmr.IJMR_2311_20DOI Listing
April 2021

Use of convalescent plasma for COVID-19 in India: A review & practical guidelines.

Indian J Med Res 2021 Jan & Feb;153(1 & 2):64-85

Department of Internal Medicine, Postgraduate Institute of Medical Education & Research, Chandigarh, India.

Convalescent plasma (CP) therapy is one of the promising therapies being tried for COVID-19 patients. This passive immunity mode involves separating preformed antibodies against SARS-CoV-2 from a recently recovered COVID-19 patient and infusing it into a patient with active disease or an exposed individual for prophylaxis. Its advantages include ease of production, rapid deployment, specificity against the target infectious agent, and scalability. In the current pandemic, it has been used on a large scale across the globe and also in India. However, unequivocal proof of efficacy and effectiveness in COVID-19 is still not available. Various CP therapy parameters such as donor selection, antibody quantification, timing of use, and dosing need to be considered before its use. The current review attempts to summarize the available evidence and provide recommendations for setting up CP protocols in clinical and research settings.
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http://dx.doi.org/10.4103/ijmr.IJMR_3092_20DOI Listing
April 2021

Assessment of Weekly Iron-Folic Acid Supplementation with and without Health Education on Anemia in Adolescent Girls: A Comparative Study.

Int J Prev Med 2020 30;11:203. Epub 2020 Dec 30.

Department of Community Medicine, SN Medical College, Bagalkot, Karnataka, India.

Background: Iron deficiency is the most common and widespread nutritional disorder in the world, affecting a large number of children and women in developing countries and constituting a public health condition of epidemic proportions. Weekly iron and folic acid supplementation (WIFS) with health education has been demonstrated to be effective in reducing anemia in adolescent school going girls. We assessed the impact of WIFS with and without health education on anemia in adolescent school girls of Delhi.

Methods: This is a school-based intervention study conducted in two government senior secondary schools of Delhi. A total of 210 adolescent school girls from two schools were included in the study. In one school (intervention group), weekly ironfolic acid with health education once a month was given, and in the second school (control group), only WIFS was given for 6 months. Iron-folic acid supplementation containing 100 mg of elemental iron and 0.5 mg of folic acid was given on a weekly basis, and health education was provided once a month for 6 consecutive months. Hemoglobin (Hb) estimation was done at the beginning and the end of the study using the Hemocue method. Mean Hb change after intervention between the control and experimental groups was compared using a test. Pre and post differences within the control and experimental groups were assessed using a paired- test.

Results: After intervention, there was a significant decline in prevalence of anemia in both the intervention (54.7 percentage points decline) and the control (26 percentage points decline) groups ( < 0.001).

Conclusions: WIFS with once a month health education can be effective in reducing the prevalence of anemia in adolescent school girls.
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http://dx.doi.org/10.4103/ijpvm.IJPVM_552_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000175PMC
December 2020

Comparative evaluation of Air-Q blocker and Proseal laryngeal mask airway in patients undergoing elective surgery under general anaesthesia: A randomised controlled trial.

Indian J Anaesth 2021 Mar 20;65(Suppl 1):S20-S26. Epub 2021 Mar 20.

Department of Anaesthesia and Intensive Care, Government Medical College and Hospital, Sector 32, Chandigarh, India.

Background And Aims: The Air-Q blocker (Cook gas LLC, Mercury Medical, Clearwater, FL, USA) is a relatively new supraglottic airway device (SAD) with capability to serve as a conduit for intubation. As there is limited data on Air-Q blocker, the present study was performed to compare the efficacy of Air-Q blocker and Proseal laryngeal mask airway (PLMA) in patients undergoing elective surgery.

Methods: A total of 90 American Society of Anesthesiologists (ASA) physical status I and II patients were randomly allocated to Air-Q blocker or PLMA group. Oropharyngeal leak pressure (OLP), insertion success, insertion time, ease of orogastric tube (OGT) insertion, fibreoptic visualisation of the glottis, haemodynamic and ventilation parameters, and complications at emergence and postoperatively were investigated.

Results: OLPs were higher in PLMA group as compared to Air-Q blocker group ( = 0.002). Still, the OLP (27.5 ± 5.8 cm HO) was clinically effective in Air-Q blocker group. The mean time for successful insertion was significantly shorter for Air-Q blocker than PLMA ( = 0.019). The number of attempts to insert both the devices was comparable ( ≥ 0.05). Air-Q blocker provided a significantly better fibreoptic score than PLMA ( = 0.038). The two groups were comparable in terms of ease of OGT insertion, haemodynamics and ventilation parameters, and complications at emergence and postoperatively.

Conclusions: Air-Q blocker provides a clinically effective OLP though PLMA provides a slightly better sealing function in patients undergoing laparoscopic and non-laparoscopic surgeries under general anaesthesia requiring neuromuscular blockade. Air-Q blocker has shorter insertion time and a better fibreoptic view of glottis as compared to PLMA.
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http://dx.doi.org/10.4103/ija.IJA_1254_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993039PMC
March 2021

Comparative evaluation of oral tramadol and gabapentin for prophylaxis of post-spinal shivering.

Indian J Anaesth 2021 Mar 20;65(Suppl 1):S5-S11. Epub 2021 Mar 20.

Medical Student, Adesh Institute of Medical Sciences, Bathinda, Punjab, India.

Background And Aims: Shivering in the peri-operative period is a common problem which is associated with various complications. Prophylaxis of shivering can thus help in reducing the cost and risk of complications. The present study was designed to compare prophylactic oral gabapentin, tramadol and placebo for prevention of post-spinal shivering.

Methods: A total of 150 adult patients of either sex belonging to American Society of Anesthesiologists physical status I-III scheduled for elective orthopaedic surgeries were randomised to receive tramadol 100 mg (group A), gabapentin 600 mg (group B) or placebo (group C) orally 30 min before administration of spinal anaesthesia. The primary outcome was to study the incidence and severity of shivering,whereas the secondary outcome was to evaluate the incidence of adverse effects. Data were analysed by analysis of variance test, Student t-test, Mann-Whitney U test and Chi-square tests.

Results: Incidence of shivering was comparable among groups A and B ( = 0.8) whereas it was significantly less than in group C ( = 0.00). Severity of shivering (grade 1 and 2) was comparable in all the groups ( = 0.6 and 0.36), whereas shivering grade 3 and grade 4 was significantly lesser in groups A and B as compared to group C ( = 0.01 and 0.01). The incidence of nausea and vomiting was more in group A (26%) as compared to group B (20%) ( = 0.48) but was significantly lesser than group C (48%) ( = 0.01). Incidence of sedation (sedation score ≥2) was significantly more in group B (22%) as compared to group A (4%) and group C (0%).

Conclusion: Prophylactic oral gabapentin 600 mg and tramadol 100 mg are equally effective for prevention of post-spinal shivering.
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http://dx.doi.org/10.4103/ija.IJA_979_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993035PMC
March 2021

Letter to the editor in response to: Effect of COVID-19 lockdown on patients with chronic diseases.

Diabetes Metab Syndr 2021 Mar 28. Epub 2021 Mar 28.

Department of Orthopaedics, MMIMSR, MM Deemed to be University, Ambala, Haryana, India. Electronic address:

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http://dx.doi.org/10.1016/j.dsx.2021.03.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005254PMC
March 2021

Association of TYRP1 with hypoxia and its correlation with patient outcome in uveal melanoma.

Clin Transl Oncol 2021 Apr 3. Epub 2021 Apr 3.

Department of Ocular Pathology, Dr.R.P.Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India.

Purpose: Molecular mechanisms of uveal melanoma development in association with high pigmentation are unclear. Tyrosinase Related Protein (TYRP1) is not only one of the important melanogenesis marker that contributes to melanin synthesis, but can also prevents the melanocyte death. The induction of melanogenesis leads to induction of HIF-1α which can affect the behavior of melanoma cells and its surrounding environment. The aim of our study was to determine the expression of TYRP1 and HIF-1α at the protein and RNA level and determine its prognostic significance.

Methods: In the present study, the expression of TYRP1 and HIF-1α was investigated on 61 formalin-fixed paraffin-embedded choroidal melanoma samples by immunohistochemistry. Fresh 50 samples were validated by real-time PCR. Results were correlated with clinicopathological parameters and Kaplan-Meier was performed to determine the prognostic significance.

Results: High immunoexpression of TYRP1 and HIF-1α was present in 61 and 54% of patients, respectively. Both TYRP1 and HIF-1α correlated well with high pigmentation and BAP1 (BRCA1 Associated Protein-1) loss (p < 0.05) at IHC level as well as transcriptional level. There was reduced metastatic free survival in patients with necrosis and this was statistically significant (p = 0.010).

Conclusion: Our findings indicate that TYRP1 can be used as a potential biomarker in the development of targeted therapy in UM. Further studies on melanogenesis markers associated with TYRP1 could provide us a better understanding in this field.
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http://dx.doi.org/10.1007/s12094-021-02597-7DOI Listing
April 2021

Autophagy Dependent Sensitization of Triple Negative Breast Cancer Models to Topoisomerase II Poisons by Inhibition of The Nucleosome Remodeling Factor.

Mol Cancer Res 2021 Apr 2. Epub 2021 Apr 2.

Human and Molecular Genetics, Virginia Commonwealth University

Epigenetic regulators can modulate the effects of cancer therapeutics. To further these observations, we discovered that the bromodomain PHD finger transcription factor subunit (BPTF) of the nucleosome remodeling factor (NURF) promotes resistance to doxorubicin, etoposide and paclitaxel in the 4T1 breast tumor cell line. BPTF functions in promoting resistance to doxorubicin and etoposide, but not paclitaxel, and may be selective to cancer cells, as a similar effect was not observed in embryonic stem cells. Sensitization to doxorubicin and etoposide with BPTF knockdown (KD) was associated with increased DNA damage, topoisomerase II (Top2) crosslinking and autophagy; however, there was only a modest increase in apoptosis and no increase in senescence. Sensitization to doxorubicin was confirmed in vivo with the syngeneic 4T1 breast tumor model using both genetic and pharmacological inhibition of BPTF. The effects of BPTF inhibition in vivo are autophagy dependent, based on genetic autophagy inhibition. Finally, treatment of 4T1, 66cl4, 4T07, MDA-MB-231 but not ER positive 67NR and MCF7 breast cancer cells with the selective BPTF bromodomain inhibitor, AU1, recapitulates genetic BPTF inhibition, including in vitro sensitization to doxorubicin, increased Top2-DNA crosslinks and DNA damage. Taken together, these studies demonstrate that BPTF provides resistance to the antitumor activity of Top2 poisons, preventing the resolution of Top2 crosslinking and associated autophagy. These studies suggest that BPTF can be targeted with small molecule inhibitors to enhance the effectiveness of Top2-targeted cancer chemotherapeutic drugs. Implications: These studies suggest NURF can be inhibited pharmacologically as a viable strategy to improve chemotherapy effectiveness.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0743DOI Listing
April 2021

Minimally invasive electroceutical catheter for endoluminal defect sealing.

Sci Adv 2021 Apr 2;7(14). Epub 2021 Apr 2.

NTU-Northwestern Institute for Nanomedicine (NNIN), Interdisciplinary Graduate School (IGS), Nanyang Technological University (NTU), 50 Nanyang Drive, Singapore 637553, Singapore.

Surgical repair of lumen defects is associated with periprocedural morbidity and mortality. Endovascular repair with tissue adhesives may reduce host tissue damage, but current bioadhesive designs do not support minimally invasive deployment. Voltage-activated tissue adhesives offer a new strategy for endoluminal repair. To facilitate the clinical translation of voltage-activated adhesives, an electroceutical patch (ePATCH) paired with a minimally invasive catheter with retractable electrodes (CATRE) is challenged against the repair of in vivo and ex vivo lumen defects. The ePATCH/CATRE platform demonstrates the sealing of lumen defects up to 2 millimeters in diameter on wet tissue substrates. Water-tight seals are flexible and resilient, withstanding over 20,000 physiological relevant stress/strain cycles. No disruption to electrical signals was observed when the ePATCH was electrically activated on the beating heart. The ePATCH/CATRE platform has diverse potential applications ranging from endovascular treatment of pseudo-aneurysms/fistulas to bioelectrodes toward electrophysiological mapping.
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http://dx.doi.org/10.1126/sciadv.abf6855DOI Listing
April 2021

Identifying Molecular Signatures of Distinct Modes of Collective Migration in Response to the Microenvironment Using Three-Dimensional Breast Cancer Models.

Cancers (Basel) 2021 Mar 20;13(6). Epub 2021 Mar 20.

Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.

Collective cell migration is a key feature of transition of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) among many other cancers, yet the microenvironmental factors and underlying mechanisms that trigger collective migration remain poorly understood. Here, we investigated two microenvironmental factors, tumor-intrinsic hypoxia and tumor-secreted factors (secretome), as triggers of collective migration using three-dimensional (3D) discrete-sized microtumor models that recapitulate hallmarks of DCIS-IDC transition. Interestingly, the two factors induced two distinct modes of collective migration: directional and radial migration in the 3D microtumors generated from the same breast cancer cell line model, T47D. Without external stimulus, large (600 µm) T47D microtumors exhibited tumor-intrinsic hypoxia and directional migration, while small (150 µm), non-hypoxic microtumors exhibited radial migration only when exposed to the secretome of large microtumors. To investigate the mechanisms underlying hypoxia- and secretome-induced directional vs. radial migration modes, we performed differential gene expression analysis of hypoxia- and secretome-induced migratory microtumors compared with non-hypoxic, non-migratory small microtumors as controls. We propose unique gene signature sets related to tumor-intrinsic hypoxia, hypoxia-induced epithelial-mesenchymal transition (EMT), as well as hypoxia-induced directional migration and secretome-induced radial migration. Gene Set Enrichment Analysis (GSEA) and protein-protein interaction (PPI) network analysis revealed enrichment and potential interaction between hypoxia, EMT, and migration gene signatures for the hypoxia-induced directional migration. In contrast, hypoxia and EMT were not enriched in the secretome-induced radial migration, suggesting that complete EMT may not be required for radial migration. Survival analysis identified unique genes associated with low survival rate and poor prognosis in TCGA-breast invasive carcinoma dataset from our tumor-intrinsic hypoxia gene signature (CXCR4, FOXO3, LDH, NDRG1), hypoxia-induced EMT gene signature (EFEMP2, MGP), and directional migration gene signature (MAP3K3, PI3K3R3). NOS3 was common between hypoxia and migration gene signature. Survival analysis from secretome-induced radial migration identified ATM, KCNMA1 (hypoxia gene signature), and KLF4, IFITM1, EFNA1, TGFBR1 (migration gene signature) to be associated with poor survival rate. In conclusion, our unique 3D cultures with controlled microenvironments respond to different microenvironmental factors, tumor-intrinsic hypoxia, and secretome by adopting distinct collective migration modes and their gene expression analysis highlights the phenotypic heterogeneity and plasticity of epithelial cancer cells.
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http://dx.doi.org/10.3390/cancers13061429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004051PMC
March 2021

10-Year Trends in Aortic Dissection: Mortality and Weekend Effect within the US Nationwide Emergency Department Sample (NEDS).

Heart Surg Forum 2021 03 31;24(2):E336-E344. Epub 2021 Mar 31.

Division of Cardiac Surgery, Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, PA, USA.

Background: This study examined changes in aortic dissection (AD) mortality from 2006 to 2017 and assessed the impact of weekday versus weekend presentation upon mortality.

Methods: This observational study analyzed all records in the Nationwide Emergency Department Sample (NEDS) database. NEDS aggregates discharge data from 984 hospitals in 36 states and the District of Columbia in the United States of America. All patients with thoracic and thoracoabdominal AD recorded as their principal diagnosis were identified via ICD codes.

Results: Patient characteristics (weekday|weekend) count: 26,759|9,640, P = 0.016; age (years): 65.2 ± 15.8|64.7 ± 16.2, P = 0.016; women: 11,318 (42.3%)|4,086 (42.4), P = 0.883; Charlson comorbidity index: 2.3 ± 1.7|2.3 ± 1.6, P = 0.025. There were 36,399 ED visits with diagnosed AD. Annual AD diagnoses increased by 70% from 2006 to 2017. From 2012-2017, patients had lower in-hospital mortality (9.9% versus 11.9%, P < 0.001) compared with 2006-2011. Patients reporting during the weekend had higher in-hospital mortality (11.8% versus 10.4%, P < 0.001) compared with weekdays. On multivariable analysis, year of presentation remained independently associated with in-hospital mortality, with 2012-2017 being associated with reduced mortality (odds ratio (OR) 0.90, 95% CI: 0.82, 0.99, P = 0.031), as compared with 2006-2011. Weekend presentation remained independently associated with worse in-hospital mortality (OR 1.17, 95% CI: 1.05, 1.29, P = 0.003) compared with weekday presentation.

Conclusion: Although AD mortality is decreasing, the patients presenting on the weekend were 13% more likely to die in the hospital compared with patients presenting during the week.
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http://dx.doi.org/10.1532/hsf.3681DOI Listing
March 2021

Prevalence of Hypertension among Children and Adolescents in India: A Systematic Review and Meta-Analysis.

Indian J Pediatr 2021 Apr 2. Epub 2021 Apr 2.

ICMR Advanced Center for Evidence-Based Child Health, Department of Pediatrics, Advanced Pediatric Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India.

Objective: To conduct a systematic review to provide pooled estimates of the prevalence of hypertension among children aged less than 18 y in India.

Methods: Three electronic databases (PubMed, EMBASE, and Web of Science) were searched from inception to August 2020 by using terms related to hypertension, children, prevalence, and India. Studies reporting the prevalence of hypertension, defined based on at least three measurements, were included. Two investigators independently performed the literature search, study selection, and data extraction for this review. Random effect meta-analysis was used to provide pooled estimates of hypertension.

Results: A total of 64 studies were included in this systematic review. The pooled prevalence was 7% (95% CI: 6%-8%) for hypertension, 4% (95% CI: 3%-4.1%) for sustained hypertension and 10% (95% CI: 8%-13%) for prehypertension. While there was no significant difference in hypertension across five different regions of the country, an upward rising trend was observed after the year 2005. Urban children had a higher prevalence of hypertension as compared to their rural counterparts. Children with obesity had a significantly high prevalence of hypertension (29%) than normal-weight children (7%).

Conclusion: In this review, it was observed that considerable proportions (7%) of school going children are hypertensive in India. Prevalence was higher in urban and overweight children. This study highlights that hypertension is a public health problem in India; hence, there is a need to implement public health measures to prevent hypertension.
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http://dx.doi.org/10.1007/s12098-021-03686-9DOI Listing
April 2021

Colorectal cancer in 18- to 49-year-olds: rising rates, presentation, and outcome in a large integrated health system.

Gastrointest Endosc 2021 Mar 29. Epub 2021 Mar 29.

Advocate Aurora Research Institute, Milwaukee WI 53204; School of Dentistry, Marquette University, Milwaukee WI 53233.

Background And Aims: Colorectal cancer rates are increasing in young people, and new guidelines recommend screening should begin at age 45. We aimed to evaluate colorectal cancer detection rates in a large integrated healthcare system, to assess treatment outcomes in younger colorectal cancer patients, and to determine factors that could aid in identifying these individuals.

Methods: We analyzed confirmed cases of colorectal cancer using a cancer database spanning 1985 to 2017 from a large integrated health care system comprised of 15 hospitals, 150 outpatient clinics, and 20 outpatient oncology clinics. Three cohorts were evaluated (18-44 years, 45-49 years, and 50 years and over).

Results: Significant increases in colorectal cancer detection were seen in the cohort aged 18 to 44 (annual percentage change 2.70%) and the cohort aged 45 to 49 (annual percentage change 4.15%). A higher proportion of African American, Hispanic, and obese subjects were seen in the younger cohorts. A family history of colorectal cancer was found in 49% of patients aged 18 to 44 and 38% of patients aged 45 to 50. Patients younger than age 50 were more likely to have metastases at diagnosis (6.8%) versus the cohort over 50 (4.15%; p<0.05). Survival was better in younger cohorts and they were more likely to receive multimodality treatment (surgery with chemotherapy or radiation). Survival probability was similar in different ethnic groups.

Conclusions: Colorectal cancer is increasing at similar rates in young people aged 18 tp 44 and 45 to 49, and they are more likely to present with advanced disease needing multimodality treatment. A family history identifies a minority of patients under 50 years. Young patients presenting with changes in bowel habit, rectal bleeding, anemia, and weight loss should undergo colonoscopy. Rectal and anal symptoms should prompt careful physical and endoscopic evaluation.
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http://dx.doi.org/10.1016/j.gie.2021.03.024DOI Listing
March 2021

Changes in the proportions of an active pharmaceutical through cocrystals.

Drug Dev Res 2021 Apr 1. Epub 2021 Apr 1.

Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati, Assam, India.

In this study, the modulation of amounts sulfathiazolium cations in different 2,6-pyridinedicarboxylates is demonstrated. An uncommon monoionic sulfathiazolium zinc 2,6-pyridinedicarboxylate (1:1 electrolyte) complex was characterized. Conventional sulfathiazolium zinc-bis-2,6-pyridinedicarboxylate dianionic complexes (2:1 electrolyte) were formed when hydroxyaromatic compounds such as 1,3-dihydroxybenzene or 3-nitrophenol were used as guest components. Thus, with the aid of the hydroxyaromatic molecules the zinc-bis-2,6-pyridinedicarboxylate complexes were stabilized with the relatively large sized sulfathiazolium cations. It was a consequence of domain expansion by the phenolic compounds. Sandwiched aromatic guests between the 2,6-pyridinedicarboxylates provided appropriate packing to accommodate the two large cations in the self-assemblies, which helped to modulate the amounts of sulfathiazole in different formulations. Antibacterial activities with E. coli DH5α have shown that the salt and the complexes have lower g/ml antibacterial activity than the parent drug.
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http://dx.doi.org/10.1002/ddr.21818DOI Listing
April 2021

Characteristics of Asymptomatic Bacteriuria in Diabetes Mellitus Patients: A Retrospective Observational Study.

Cureus 2021 Feb 26;13(2):e13562. Epub 2021 Feb 26.

Internal Medicine, Dow University of Health Sciences, Karachi, PAK.

Background and objective The term asymptomatic bacteriuria (ASB) refers to the isolation of bacteria in a urine specimen of individuals without any symptoms of urinary tract infection (UTI). Diabetes mellitus (DM) is a disease involving multiple organ systems, characterized by its chronicity and hence endless complications including ASB. This study aimed to determine the characteristics of ASB and antibiotic susceptibility patterns among patients with diabetes. Materials and methods This was a retrospective observational study conducted in a tertiary care hospital. The study included patients with a diagnosis of diabetes with no signs and symptoms of UTI but who still showed the growth of an organism in urine culture. A total of 222 urine cultures were analyzed retrospectively, ensuring that they met the inclusion criteria through non-probability consecutive sampling. Results The mean age of the study participants was 62.89 ± 13.77 years; 76% of them were females, and 61% had a family history of diabetes. The most frequent organisms isolated were Escherichia coli (E. coli), Enterococcus, Klebsiella pneumonia, Pseudomonas aeruginosa, and Enterobacter species. A total of 20 subjects had dual bacterial growth in their cultures, with Enterococcus species (n=17) being the most common organism. Gender, family history of diabetes, levels of hemoglobin A1c (HbA1c), and advanced age were all found significantly associated with ASB. Conclusion Our study is the first of its kind to analyze and examine the risk factors associated with ASB in DM patients, and to identify the pathogens involved, along with assessing their antibiotic resistance profiles.
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http://dx.doi.org/10.7759/cureus.13562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004580PMC
February 2021

Specific Host Signatures for the Detection of Tuberculosis Infection in Children in a Low TB Incidence Country.

Front Immunol 2021 15;12:575519. Epub 2021 Mar 15.

Laboratory of Vaccinology and Mucosal Immunity, Université Libre de Bruxelles, Brussels, Belgium.

Diagnosis of tuberculosis (TB) in children remains challenging due to unspecific clinical presentation and low bacillary load. In low TB incidence countries, most cases are diagnosed by a contact screening strategy after exposure to an index TB case. Due to the severity of TB in young children, the priority is to determine whether a child is infected or not, whereas differential diagnosis between active TB (aTB) and latent TB constitutes a second step. In Belgium, a low TB incidence country, we prospectively included 47 children with a defined infection status (12 children with aTB, 18 with latent TB, and 17 uninfected) (exploratory cohort), and determined the optimal combinations of cytokines secreted by their peripheral blood mononuclear cells in response to a 5-days stimulation with four different mycobacterial antigens, in an attempt to classify the children according to their infectious status. Correct identification of all infected children was obtained by several combinations of two purified protein derivative (PPD)-induced cytokines (IFN-γ and either GM-CSF, MIP-1α, sCD40L or TNF-α), or by combining PPD-induced IFN-γ with culture-filtrate protein-10 (CFP-10)-induced TNF-α. Alternatively, combining CFP-10-induced TNF-α and IP-10 with heparin-binding haemagglutinin (HBHA)-induced-IFN-γ was more effective in testing recently BCG-vaccinated children or those suspected to be infected with non-tuberculous mycobacteria, providing a correct classification of 97% of the infected children. This combination also correctly classified 98% of the children from a validation cohort comprising 40 infected children and 20 non-infected children. Further differentiation between aTB and children with latent TB was more difficult. Combining ESAT-6-induced MIP1-α and IP-10, CFP-10-induced MIG, and HBHA-induced MIG provided a correct classification of 77% of the children from the exploratory cohort but only of 57.5% of those from the validation cohort. We conclude that combining the measurement of 2-4 cytokines induced by three different mycobacterial antigens allows an excellent identification of infected children, whereas differentiating children with aTB from those with latent TB remains far from perfect.
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http://dx.doi.org/10.3389/fimmu.2021.575519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005539PMC
March 2021

Prevalence of Symptoms in Patients Discharged from COVID Care Facility of NIMS Hospital: Is RT PCR Negativity Truly Reflecting Recovery? A Single-Centre Observational Study.

Int J Gen Med 2021 25;14:1069-1078. Epub 2021 Mar 25.

Department of General Medicine, National Institute of Medical Sciences and Research Hospital, Nims University Rajasthan, Jaipur, India.

Purpose: To assess the prevalence of post-COVID symptoms in patients with recovered COVID-19 (nasopharyngeal RT PCR negative) who were discharged from an acute COVID care facility at a tertiary care teaching hospital in North India.

Methods: This study was an observational study with retrospective data collection, conducted in the COVID follow-up clinic, a combined clinic of medicine and endocrinology. Patients discharged from the acute COVID care facility were recruited after 14 days of discharge if they fulfilled inclusion and exclusion criteria. The retrospective data was collected from the hospital records/EMR and analysed by the SPSSv23.

Results: Fifty patients, who fulfilled the inclusion and exclusion criteria, were included in the study. The Mean age of patients was 53.4±13.8 years (range 28-77). Seventy six percent were male, and 38% had type 2 diabetes. Fever (94%), cough (78%) and breathlessness (68%), were the most common symptoms at presentation to acute care facility. Oxygen saturation at presentation had a negative correlation with D-Dimer, age, and C reactive protein. When patients were evaluated clinically, after 14 days (range 15 to 50 days) of the discharge, 82% of patients had at least one persistent symptom. Fatigue (74%) was the most common symptoms in follow-up followed by breathlessness (44%), and muscle weakness (36%). Two patients had persistent fever, even after negative RT PCR status.

Conclusion: Patients discharged from the acute COVID care facility had a high prevalence of post-COVID symptoms even after 14 days.
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http://dx.doi.org/10.2147/IJGM.S295499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006813PMC
March 2021

Bacterial cyclic diguanylate signaling networks sense temperature.

Nat Commun 2021 03 31;12(1):1986. Epub 2021 Mar 31.

Department of Biological Sciences, University of Calgary, Calgary, AB, Canada.

Many bacteria use the second messenger cyclic diguanylate (c-di-GMP) to control motility, biofilm production and virulence. Here, we identify a thermosensory diguanylate cyclase (TdcA) that modulates temperature-dependent motility, biofilm development and virulence in the opportunistic pathogen Pseudomonas aeruginosa. TdcA synthesizes c-di-GMP with catalytic rates that increase more than a hundred-fold over a ten-degree Celsius change. Analyses using protein chimeras indicate that heat-sensing is mediated by a thermosensitive Per-Arnt-SIM (PAS) domain. TdcA homologs are widespread in sequence databases, and a distantly related, heterologously expressed homolog from the Betaproteobacteria order Gallionellales also displayed thermosensitive diguanylate cyclase activity. We propose, therefore, that thermotransduction is a conserved function of c-di-GMP signaling networks, and that thermosensitive catalysis of a second messenger constitutes a mechanism for thermal sensing in bacteria.
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http://dx.doi.org/10.1038/s41467-021-22176-2DOI Listing
March 2021

Extramedullary Multiple Myeloma with Hepatic Involvement.

Cureus 2021 Feb 23;13(2):e13515. Epub 2021 Feb 23.

Hematology and Oncology, St Agnes Medical Center, Fresno, USA.

Hepatic involvement with space-occupying lesions seen in patients with multiple myeloma (MM) is a rare phenomenon. We present two cases of extramedullary multiple myeloma (EMM), with different presentations to highlight the diversity of clinical presentation. Clinically relevant hepatic involvement of myeloma is uncommon and can pose management problems. Hepatic involvement of EMM is indicative of a poor prognosis. Early recognition can help stage and prognosticate the disease.
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http://dx.doi.org/10.7759/cureus.13515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993922PMC
February 2021

Macrophage activation status rather than repolarization is associated with enhanced checkpoint activity in combination with PI3Kg inhibition.

Mol Cancer Ther 2021 Mar 30. Epub 2021 Mar 30.

Bioscience, Oncology, IMED Biotech Unit, AstraZeneca (United Kingdom).

Suppressive myeloid cells mediate resistance to immune checkpoint blockade. PI3Kg inhibition can target suppressive macrophages, and enhance efficacy of immune checkpoint inhibitors. However how PI3Kg inhibitors function in different tumor environments (TME) to activate specific immune cells is underexplored. The effect of the novel PI3Kg inhibitor AZD3458 was assessed in pre-clinical models. AZD3458 enhanced anti-tumor activity of immune checkpoint inhibitors in 4T1, CT26 and MC38 syngeneic models, increasing CD8+ T-cell activation status. Immune and TME biomarker analysis of MC38 tumors revealed that AZD3458 monotherapy or combination treatment did not repolarized the phenotype of tumor associated macrophage cells but induced gene signatures associated with LPS and Type II interferon activation. The activation biomarkers were present across tumor macrophages that appear phenotypically heterogenous. AZD3458 alone or in combination with PD-1 blocking antibodies promoted an increase in antigen presenting (MHCII+) and cytotoxic (iNOS+) activated macrophages, as well as dendritic cell activation. AZD3458 reduced IL-10 secretion and signaling in primary human macrophages and murine tumor associated macrophages, but did not strongly regulate IL-12 as observed in other studies. Therefore rather than polarizing tumor macrophages, PI3Kg inhibition with AZD3458 promotes a cytotoxic switch of macrophages into antigen-presenting activated macrophages, resulting in CD8 T cell mediated anti-tumor activity with immune checkpoint inhibitors associated with tumor and peripheral immune activation.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0961DOI Listing
March 2021