Publications by authors named "Rahul Kumar"

644 Publications

Ligand conjugated lipid-based nanocarriers for cancer theranostics.

Biotechnol Bioeng 2022 Aug 11. Epub 2022 Aug 11.

School of Biochemical Engineering, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh, 221005, India.

Cancer is one of the major health-related issues affecting the population worldwide and subsequently accounts for the second-largest death. Genetic and epigenetic modifications in oncogenes or tumor suppressor genes affect the regulatory systems that lead to the initiation and progression of cancer. Conventional methods, including chemotherapy/radiotherapy/appropriate combinational therapy and surgery, are being widely used for theranostics of cancer patients. Surgery is useful in treating localized tumors, but it is ineffective in treating metastatic tumors, which spread to other organs and result in a high recurrence rate and death. Also, the therapeutic application of free drugs is related to substantial issues such as poor absorption, solubility, bioavailability, high degradation rate, short shelf-life, and low therapeutic index. Therefore, these issues can be sorted out using nano lipid-based carriers (NLBCs) as promising drug delivery carriers. Still, at most, they fail to achieve site targeted drug delivery and detection. This can be achieved by selecting a specific ligand/antibody for its cognate receptor molecule expressed on the surface of cancer cell. In this review, we have mainly discussed the various types of ligands used to decorate NLBCs. A list of the ligands used to design nanocarriers to target malignant cells has been extensively undertaken. The approved ligand decorated lipid-based nanomedicines with their clinical status has been explained in tabulated form to provide a wider scope to the readers regarding ligand coupled NLBCs. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/bit.28205DOI Listing
August 2022

Activation of SIRT1 by silibinin improved mitochondrial health and alleviated the oxidative damage in experimental diabetic neuropathy and high glucose-mediated neurotoxicity.

Arch Physiol Biochem 2022 Aug 9:1-17. Epub 2022 Aug 9.

Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India.

Background: Silibinin (SBN), a sirtuin 1 (SIRT1) activator, has been evaluated for its anti-inflammatory activity in many inflammatory diseases. However, its role in diabetes-induced peripheral neuropathy (DPN) remains unknown. The SIRT1 activation convalesces nerve functions by improving mitochondrial biogenesis and mitophagy.

Methods: DPN was induced by streptozotocin (STZ) at a dose of 55 mg/kg, i.p. in the male SD rats whereas neurotoxicity was induced in Neuro2A cells by 30 mM (high glucose) glucose. Neurobehavioural (nerve conduction velocity and nerve blood flow) western blot, immunohistochemistry, and immunocytochemistry were performed to evaluate the protein expression and their cellular localisation.

Results: Two-week SBN treatment improved neurobehavioural symptoms, SIRT1, PGC-1α, and TFAM expression in the sciatic nerve and HG insulted N2A cells. It has also maintained the mitophagy by up-regulating PARL, PINK1, PGAM5, LC3 level and provided antioxidant defence by upregulating Nrf2.

Conclusion: SBN has shown neuroprotective potential in DPN through SIRT1 activation and antioxidant mechanism.
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http://dx.doi.org/10.1080/13813455.2022.2108454DOI Listing
August 2022

The ARSACS disease protein sacsin controls lysosomal positioning and reformation by regulating microtubule dynamics.

J Biol Chem 2022 Aug 3:102320. Epub 2022 Aug 3.

Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada. Electronic address:

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a fatal brain disorder featuring cerebellar neurodegeneration leading to spasticity and ataxia. ARSACS is caused by mutations in the SACS gene that encodes sacsin, a massive 4579-amino acid protein with multiple modular domains. However, molecular details of the function of sacsin are not clear. Here using time lapse imaging and purified tubulin we demonstrate that sacsin binds to microtubules and regulates microtubule dynamics. Loss of sacsin function in knockout cell lines, including knockdown and knockout primary neurons and patient fibroblasts, leads to alterations in lysosomal transport, positioning, function, and reformation following autophagy. Each of these phenotypic changes is consistent with altered microtubule dynamics. We further show the effects of sacsin are mediated at least in part through interactions with JIP3, an adaptor for microtubule motors. These data reveal a new function for sacsin that explains its previously reported roles and phenotypes.
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http://dx.doi.org/10.1016/j.jbc.2022.102320DOI Listing
August 2022

Tillage and crop establishment effects on weeds and productivity of a rice-wheat-mungbean rotation.

Field Crops Res 2022 Aug;284:108577

Indian Council of Agricultural Research, New Delhi, India.

Weeds are one of the key threats in sustaining the productivity of the rice-wheat cropping system in the Indo-Gangetic Plains. The development of sound integrated weed management technologies requires knowledge of mechanisms that influence weed flora composition and weed seedbank dynamics. A long-term study was initiated in 2015 at Patna, Bihar, India to evaluate the effect of seven tillage and crop establishment methods on weed density, weed seedbank composition, and crop productivity in rice-wheat-mungbean rotation. All the treatments included zero-till mungbean after wheat. Tillage and crop establishment methods had differential effects on weed and weed seedbank composition. In rice, zero-till direct-seeded rice recorded 62% lower emergence of , 82-90% of and 81-83% of total weeds compared to tilled systems, but the system of rice and wheat intensification favoured . In wheat, the system of wheat intensification favoured the and . Zero-till rice and wheat reduced the seedbank of by 95%, and total weed seedbank by 62% compared to the system of rice and wheat intensification. Nearly, 72% of seeds, 62% of grasses, and 64% of broad-leaved weeds were in 0-15 cm soil layer. Zero-till direct-seeded rice produced a 13% lower rice grain yield than conventional puddled transplanted rice. Compared to the system of wheat intensification, zero-till wheat under triple zero-till systems produced an 11.5% higher grain yield. Managing weed seedbank is a long-term endeavour. The present study revealed that tillage and crop establishment methods influence weed density and diversity. Under zero-till rice-wheat system, rice yield decreases marginally, but the system productivity maintains due to improvement in succeeding wheat yield. This system is also helpful in reducing the weed flora density and soil weed seedbank. Regular monitoring and management of emerging pests such as armyworm () are, however, required. The study suggests that the adoption of triple zero-tillage can be a viable option for reducing the weed density and weed seedbank concurrently increasing the system productivity of the rice-wheat-mungbean cropping system in eastern Indo-Gangetic Plains.
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http://dx.doi.org/10.1016/j.fcr.2022.108577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9214547PMC
August 2022

Comprehensive mutations analyses of (fat mass and obesity-associated gene) and their effects on FTO's substrate binding implicated in obesity.

Front Nutr 2022 18;9:852944. Epub 2022 Jul 18.

Laboratory Oncology Unit, Dr.B.R.A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India.

An excessive amount of fat deposition in the body leads to obesity which is a complex disease and poses a generic threat to human health. It increases the risk of various other diseases like diabetes, cardiovascular disease, and multiple types of cancer. Genomic studies have shown that the expression of the fat mass obesity () gene was highly altered and identified as one of the key biomarkers for obesity. This study has been undertaken to investigate the mutational profile of the gene and elucidates its effect on the protein structure and function. Harmful effects of various missense mutations were predicted using different independent tools and it was observed that all mutations were highly pathogenic. Molecular dynamics (MD) simulations were performed to study the structure and function of FTO protein upon different mutations and it was found that mutations decreased the structure stability and affected protein conformation. Furthermore, a protein residue network analysis suggested that the mutations affected the overall residues bonding and topology. Finally, molecular docking coupled with MD simulation suggested that mutations affected FTO substrate binding by changing the protein-ligand affinity. Hence, the results of this finding would help in an in-depth understanding of the molecular biology of the gene and its variants and lead to the development of effective therapeutics against associated diseases and disorders.
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http://dx.doi.org/10.3389/fnut.2022.852944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9339907PMC
July 2022

Spin-glass behavior in LiNiCuBiO: a two-dimensional distorted honeycomb-lattice.

J Phys Condens Matter 2022 Aug 12;34(41). Epub 2022 Aug 12.

School of Advanced Materials, and Chemistry and Physics of Materials Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560064, India.

We report a detailed experimental study on the structural and magnetic properties of LiNiCuBiOby means of various characterization techniques. It crystallizes into a monoclinic crystal structure composed of a layered magnetic honeycomb lattice along the-axis. The existence of glassy state below 4 K is indicated by dc and ac susceptibility measurements. Magnetic contribution to the total heat capacity also peaks around the freezing temperature, and its linear temperature dependence backs our claim of a glassy state in the compound. The calculated magnetic entropy unveils that only ∼26% of the total entropy is released for the system (S=3/2), and a tremendous amount of spin entropy is still retained in the system. Further, analysis of the frequency-dependent freezing temperature with the help of power law confirms the presence of a spin glass state. Moreover, the appearance of magnetic memory and relaxation effect below freezing temperature manifest the development of the system via a large number of intermediate metastable states. All these measurements confirm the spin-glass behavior of the compound. We consider the presence of different magnetic atoms in honeycomb lattice as the main driving factor for the spin-glass ground state.
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http://dx.doi.org/10.1088/1361-648X/ac86b2DOI Listing
August 2022

Mass trends of parabens, triclocarban and triclosan in Arizona wastewater collected after the 2017 FDA ban on antimicrobials and during the COVID-19 pandemic.

Water Res 2022 Jul 23;222:118894. Epub 2022 Jul 23.

School of Sustainable Engineering and Built Environment, Arizona State University, Tempe, AZ 85287, USA; Biodesign Center for Environmental Engineering, Arizona State University, Tempe, AZ 85287, USA; OneWaterOneHealth, Nonprofit Project of the Arizona State University Foundation, Tempe, AZ 85287, USA; Global Futures Laboratory, Arizona State University, 800 S. Cady Mall, Tempe, AZ 85281, USA. Electronic address:

Antimicrobials like parabens, triclosan (TCS), and triclocarban (TCC) are of public health concern worldwide due to their endocrine-disrupting properties and ability to promote antimicrobial drug resistance in human pathogens. The overall use of antimicrobials presumably has increased during the COVID-19 pandemic, whereas TCS and TCC may have experienced reductions in use due to their recent ban from thousands of over-the-counter (OTC) personal care products by the U.S. Food and Drug Administration (FDA). No quantitative data are available on the use of parabens or the impact the FDA ban had on TCC and TCS. Here, we use wastewater samples (n = 1514) from 10 different communities in Arizona to measure the presence of the six different antimicrobial products (TCS, TCC, and four alkylated parabens [methylparaben (MePb), ethylparaben (EtPb), propylparaben (PrPb), butylparaben (BuPb)]) collected before and during the COVID-19 pandemic using a combination of solid-phase extraction, liquid chromatography/tandem mass spectrometry (LC-MS/MS), and isotope dilution for absolute quantitation. The average mass loadings of all antimicrobials combined (1,431 ± 22 mg/day per 1,000 people) after the onset of the local epidemic (March 2020 - October 2020) were significantly higher (945 ± 62 mg/day per 1,000 people; p < 0.05) than before the pandemic (January 2019 - February 2020). Overall, parabens (∑Pbs = 999 ± 16 mg/day per 1,000 people) were the most used antimicrobials, followed by TCS (117 ± 14 mg/day per 1,000 people) and TCC (117 ± 14 mg/day per 1,000 people). After the 2017 U.S. FDA ban, we found a statistically significant (p < 0.05) reduction in the mass loadings of TCS (-89%) and TCC (-80%) but a rise in paraben use (+72%). Mass flows of 3 of a total of 4 parabens (MePb, EtPb, and PrPb) in wastewater were significantly higher upon the onset of the epidemic locally (p < 0.05). This is the first longitudinal study investigating the use of antimicrobials during the COVID-19 pandemic by employing wastewater-based epidemiology. Whereas an overall increase in the use of antimicrobials was evident from analyzing Arizona wastewater, a notable reduction in the use of TCS and TCC was evident during the pandemic, triggered by the U.S. FDA ban.
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http://dx.doi.org/10.1016/j.watres.2022.118894DOI Listing
July 2022

Environmental factors affecting the diversity of psychrophilic microbial community in the high altitude snow-fed lake Hemkund, India.

Curr Res Microb Sci 2022 17;3:100126. Epub 2022 Mar 17.

Department of Environmental Sciences, H.N.B. Garhwal University (A Central University), Srinagar Garhwal 246174, Uttarakhand, India.

The current examination incorporates the evaluation of limnological boundaries influencing the microbial diversity and its distribution in the Hemkund Lake, a high altitude aquatic body located at an elevation of 4,170 m a.s.l. in the Himalayan state Uttarakhand of India. Samples of water were collected for three continuous years (2018-2020) in three sampling attempts each year. Four water sampling sites were identified and studied across the lake during two years of the study periods. A total of nineteen physicochemical parameters of lake water were recorded. Few of the parameters were analyzed at the site whereas the leftover parameters were analyzed in the laboratory at the Department. The diversity of microorganisms was determined via morphological, biochemical, MALDI-TOF MS, and molecular approaches (16S and 18S rRNA sequencing). Environmental variables i.e., DO, BOD, total coliform, and TDS showed huge variation at site 2 among all the four water sampling sites. The water temperature of Hemkund Lake was observed from 4.9°C to 6.1°C whereas; dissolved oxygen was recorded from 6.0 to 8.2 mg.l. The α-diversity of microorganisms in the Hemkund Lake was found to be nineteen with ten bacterial strains, four actinomycetes strains, and five fungal strains. are a few important and key species that were found in the lake water The present study on the diversity of psychrophilic microorganisms in the high altitude Lake Hemkund could be a great reference for further research activities on comparable viewpoints in different parts of the Himalaya. This baseline information can also help the administrative officials to take necessary steps for its conservation and management.
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http://dx.doi.org/10.1016/j.crmicr.2022.100126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9325733PMC
March 2022

Application of wastewater-based epidemiology for estimating population-wide human exposure to phthalate esters, bisphenols, and terephthalic acid.

Sci Total Environ 2022 Jul 25:157616. Epub 2022 Jul 25.

Biodesign Center for Environmental Health Engineering, Arizona State University, Tempe, AZ 85287, USA; School of Sustainable Engineering and the Built Environment, Arizona State University, Tempe, AZ 852\87, USA; One Water One Health, Non-profit Project of Arizona State University Foundation, Tempe, AZ 85287, USA. Electronic address:

Phthalates, bisphenols (BPs), and terephthalic acid (TPA) are widely used plasticizers and monomers in plastic manufacturing. Most of them are known to have an adverse effect on the human body, functioning as endocrine disruptors and suspected carcinogens. Access to near real-time data on population exposure to plasticizers is essential for identifying vulnerable communities and better protecting and managing public health on a local scale. The objective of the present study was to evaluate population-level exposure to phthalates, BPs, and TPA by measuring urinary metabolites in community wastewater. Composited community wastewater (24-h samples) from five sewer sub-catchments of a southwestern city within the United States. Samples were analyzed for urinary biomarkers of phthalates, BPs, and TPA using solid-phase extraction-liquid chromatography-tandem mass spectrometry in conjunction with the isotope dilution method for absolute quantification. Ten of 16 analytes were detected at least once in community wastewater above the method detection limit (MDL), with MDLs ranging from 37 to 203 ng/L. The population normalized mass load of TPA was the highest, followed by the human metabolite of di-(2-ethylhexyl) phthalate (DEHP). Bisphenol S and monoethyl phthalate were detected with the highest frequency. Study findings suggest that the analysis of municipal wastewater for chemical indicators of human exposure to plastic constituents is feasible, practicable, and informative, as long as appropriate steps are taken to determine, quantify and account for background levels of plastic analytes in the laboratory environment.
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http://dx.doi.org/10.1016/j.scitotenv.2022.157616DOI Listing
July 2022

Simple wound closure compared with surgery for civilian cranial gunshot wounds.

J Neurosurg 2022 Jun 24:1-9. Epub 2022 Jun 24.

1Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, Florida.

Objective: A carefully selected subset of civilian cranial gunshot wound (CGSW) patients may be treated with simple wound closure (SWC) as a proactive therapy, but the appropriate clinical scenario for using this strategy is unknown. The aim of this study was to compare SWC and surgery patients in terms of their neurological outcomes and complications, including infections, seizures, and reoperations.

Methods: This was a single-center, retrospective review of the prospectively maintained institutional traumatic brain injury and trauma registries. Included were adults who sustained an acute CGSW defined as suspected or confirmed dural penetration. Excluded were nonfirearm penetrating injuries, patients with an initial Glasgow Coma Scale (GCS) score of 3, patients with an initial GCS score of 4 and nonreactive pupils, and patients who died within 48 hours of presentation.

Results: A total of 67 patients were included; 17 (25.4%) were treated with SWC and 50 (74.6%) were treated with surgery. The SWC group had a lower incidence of radiographic mass effect (3/17 [17.6%] SWC vs 31/50 [62%] surgery; absolute difference 44.4, 95% CI -71.9 to 16.8; p = 0.002) and lower incidence of involvement of the frontal sinus (0/17 [0%] SWC vs 14/50 [28%] surgery; absolute difference 28, 95% CI -50.4 to 5.6; p = 0.01). There were no differences in the frequency of Glasgow Outcome Scale-Extended scores ≥ 5 between the SWC and surgery groups at 30 days (4/11 [36.4%] SWC vs 12/35 [34.3%] surgery; OR 1.1, 95% CI 0.3-4.5; p > 0.99), 60 days (2/7 [28.6%] SWC vs 8/26 [30.8%] surgery; OR 0.9, 95% CI 0.3-3.4; p > 0.99), and 90 days (3/8 [37.5%] SWC vs 12/26 [46.2%] surgery; OR 0.7, 95% CI 0.1-3.6; p > 0.99). There were no differences in the incidence of infections (1/17 [5.9%] SWC vs 6/50 [12%] surgery; OR 0.5, 95% CI 0.1-4.1; p = 0.67), CSF fistulas (2/11 [11.6%] SWC vs 3/50 [6%] surgery; OR 2.1, 95% CI 0.3-13.7; p = 0.60), seizures (3/17 [17.6%] SWC vs 9/50 [18%] surgery; OR 1, 95% CI 0.2-4.1; p > 0.99), and reoperations (3/17 [17.6%] SWC vs 4/50 [8%] surgery; OR 2.5, 95% CI 0.5-12.4; p = 0.36) between the SWC and surgery groups.

Conclusions: There were important clinically relevant differences between the SWC and surgery groups. SWC can be considered a safe and efficacious proactive therapy in a carefully selected subset of civilian CGSW patients.
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http://dx.doi.org/10.3171/2022.5.JNS22617DOI Listing
June 2022

The role of macrophages in right ventricular remodeling in experimental pulmonary hypertension.

Pulm Circ 2022 Jul 1;12(3):e12105. Epub 2022 Jul 1.

Department of Medicine, Division of Pulmonary and Critical Care Medicine, Zuckerberg San Francisco General Hospital and Trauma Center University of California San Francisco California USA.

Right ventricular (RV) failure is the primary cause of death in pulmonary hypertension (PH), but the mechanisms of RV failure are not well understood. We hypothesized macrophages in the RV contribute to the RV response in PH. We induced PH in mice with hypoxia (FiO 10%) and exposure, and in rats with SU5416-hypoxia. We quantified cardiac macrophages in mice using flow cytometry. Parabiosis between congenic CD45.1/.2 mice or Cx3cr1-green fluorescent protein and wild-type mice was used to quantify circulation-derived macrophages in experimental PH conditions. We administered clodronate liposomes to Sugen hypoxia (SU-Hx) exposed rats to deplete macrophages and evaluated the effect on the extracellular matrix (ECM) and capillary network in the RV. In hypoxia exposed mice, the overall number of macrophages did not significantly change but two macrophage subpopulations increased. Parabiosis identified populations of RV macrophages that at steady state is derived from the circulation, with one subpopulation that significantly increased with PH stimuli. Clodronate treatment of SU-Hx rats resulted in a change in the RV ECM, without altering the RV vasculature, and correlated with improved RV function. Populations of RV macrophages increase and contribute to RV remodeling in PH, including through regulation of the RV ECM.
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http://dx.doi.org/10.1002/pul2.12105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9297026PMC
July 2022

Antibody-receptor bioengineering and its implications in designing bioelectronic devices.

Int J Biol Macromol 2022 Jul 21;218:225-242. Epub 2022 Jul 21.

Laboratory of Bio-Physio Sensors and Nano-bioengineering, School of Biochemical Engineering, Indian Institute of Technology (BHU) Varanasi, Uttar Pradesh 221005, India. Electronic address:

Antibodies play a crucial role in the defense mechanism countering pathogens or foreign antigens in eukaryotes. Its potential as an analytical and diagnostic tool has been exploited for over a century. It forms immunocomplexes with a specific antigen, which is the basis of immunoassays and aids in developing potent biosensors. Antibody-based sensors allow for the quick and accurate detection of various analytes. Though classical antibodies have prolonged been used as bioreceptors in biosensors fabrication due to their increased fragility, they have been engineered into more stable fragments with increased exposure of their antigen-binding sites in the recent era. In biosensing, the formats constructed by antibody engineering can enhance the signal since the resistance offered by a conventional antibody is much more than these fragments. Hence, signal amplification can be observed when antibody fragments are utilized as bioreceptors instead of full-length antibodies. We present the first systematic review on engineered antibodies as bioreceptors with the description of their engineering methods. The detection of various target analytes, including small molecules, macromolecules, and cells using antibody-based biosensors, has been discussed. A comparison of the classical polyclonal, monoclonal, and engineered antibodies as bioreceptors to construct highly accurate, sensitive, and specific sensors is also discussed.
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http://dx.doi.org/10.1016/j.ijbiomac.2022.07.109DOI Listing
July 2022

Kasurdi health and demographic surveillance system: A profile and way forward.

Indian J Public Health 2022 Apr-Jun;66(2):196-199

Associate Professor, Department of Community Medicine, AFMC, Pune, Maharashtra, India.

Kasurdi Health and Demographic Surveillance System (Kasurdi HDSS) was established at Rural Health Training Center Kasurdi on February 16, 2018. Kasurdi HDSS has been established to increase the research potential of medical colleges and develop real-time data for research purposes to study the changes in population demography, health, and health-care utilization. Kasurdi HDSS currently follows 2755 individuals living in 549 households. The system collects the data from the population through annual rounds conducted by postgraduate residents of the department of community medicine. The data are collected in the digital format with the help of android-based tablets. HDSS has collected demographic data, reproductive data, data on diseases such as tuberculosis and noncommunicable diseases, and socioeconomic data. The HDSS is in the process to upgrade its data management system to a more integrated platform, coordinated and guided by national/international standards, and data sharing policy.
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http://dx.doi.org/10.4103/ijph.ijph_1329_21DOI Listing
July 2022

Frequency of Causes of Portal Hypertension in Children.

Cureus 2022 Jun 14;14(6):e25934. Epub 2022 Jun 14.

Internal Medicine, Jinnah Sindh Medical University, Karachi, PAK.

Introduction The most common etiology of portal hypertension (PH) in children is obstruction at the presinusoidal or sinusoidal level. In addition, portal vein thrombosis (PVT) and biliary atresia are the most prevalent extrahepatic causes. This study aims to evaluate all the possible etiologies leading to PH in the pediatric population and provide the most common cause associated with this condition along with the age group most frequently affected by it. Material and Methods From January 2018 to December 2020, a cross-sectional study was carried out in tertiary care hospitals in Pakistan. A total of 100 children, both male and female, aged one month to 15 years and diagnosed with PH, were enrolled for the evaluation for the causes of PH. The Statistical Package for the Social Sciences (SPSS), version 20, was used to analyze the data. Results The mean age of enrolled participants was 9.01 ± 2.81 years. It was found that PVT (63%) was the most common cause of PH, followed by liver cirrhosis (19%) and biliary atresia (18%). Age of more than eight years was significantly associated with PVT (-value: 0.007). Conclusion In children, PH may be caused by a wide range of etiologies. It is imperative to understand the underlying etiologies contributing to PH for proper guidance and management, prevention, and overall outcomes.
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http://dx.doi.org/10.7759/cureus.25934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9282599PMC
June 2022

Deep learning for image-based liver analysis - A comprehensive review focusing on malignant lesions.

Artif Intell Med 2022 08 9;130:102331. Epub 2022 Jun 9.

Department of Computer Science, Norwegian University of Science and Technology, 7491 Trondheim, Norway.

Deep learning-based methods, in particular, convolutional neural networks and fully convolutional networks are now widely used in the medical image analysis domain. The scope of this review focuses on the analysis using deep learning of focal liver lesions, with a special interest in hepatocellular carcinoma and metastatic cancer; and structures like the parenchyma or the vascular system. Here, we address several neural network architectures used for analyzing the anatomical structures and lesions in the liver from various imaging modalities such as computed tomography, magnetic resonance imaging and ultrasound. Image analysis tasks like segmentation, object detection and classification for the liver, liver vessels and liver lesions are discussed. Based on the qualitative search, 91 papers were filtered out for the survey, including journal publications and conference proceedings. The papers reviewed in this work are grouped into eight categories based on the methodologies used. By comparing the evaluation metrics, hybrid models performed better for both the liver and the lesion segmentation tasks, ensemble classifiers performed better for the vessel segmentation tasks and combined approach performed better for both the lesion classification and detection tasks. The performance was measured based on the Dice score for the segmentation, and accuracy for the classification and detection tasks, which are the most commonly used metrics.
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http://dx.doi.org/10.1016/j.artmed.2022.102331DOI Listing
August 2022

Super-enhancer hypermutation alters oncogene expression in B cell lymphoma.

Nature 2022 07 6;607(7920):808-815. Epub 2022 Jul 6.

Institute for Cancer Genetics, Columbia University, New York, NY, USA.

Diffuse large B cell lymphoma (DLBCL) is the most common B cell non-Hodgkin lymphoma and remains incurable in around 40% of patients. Efforts to sequence the coding genome identified several genes and pathways that are altered in this disease, including potential therapeutic targets. However, the non-coding genome of DLBCL remains largely unexplored. Here we show that active super-enhancers are highly and specifically hypermutated in 92% of samples from individuals with DLBCL, display signatures of activation-induced cytidine deaminase activity, and are linked to genes that encode B cell developmental regulators and oncogenes. As evidence of oncogenic relevance, we show that the hypermutated super-enhancers linked to the BCL6, BCL2 and CXCR4 proto-oncogenes prevent the binding and transcriptional downregulation of the corresponding target gene by transcriptional repressors, including BLIMP1 (targeting BCL6) and the steroid receptor NR3C1 (targeting BCL2 and CXCR4). Genetic correction of selected mutations restored repressor DNA binding, downregulated target gene expression and led to the counter-selection of cells containing corrected alleles, indicating an oncogenic dependency on the super-enhancer mutations. This pervasive super-enhancer mutational mechanism reveals a major set of genetic lesions deregulating gene expression, which expands the involvement of known oncogenes in DLBCL pathogenesis and identifies new deregulated gene targets of therapeutic relevance.
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http://dx.doi.org/10.1038/s41586-022-04906-8DOI Listing
July 2022

Towards a novel application of wastewater-based epidemiology in population-wide assessment of exposure to volatile organic compounds.

Sci Total Environ 2022 Jun 27;845:157008. Epub 2022 Jun 27.

Biodesign Center for Environmental Health Engineering, Arizona State University, Tempe, AZ 85287, USA; School of Sustainable Engineering and the Built Environment, Arizona State University, Tempe, AZ 85287, USA; One Water One Health, Non-profit Project of Arizona State University Foundation, Tempe, AZ 85287, USA.

In this study, we investigated the feasibility of detecting 35 urinary biomarkers of volatile organic compounds (VOCs) exposure in community wastewater. 24-h composited municipal wastewater samples were collected from two communities (n = 8) in the southeastern US. Using isotope-dilution liquid chromatography-tandem mass spectrometry, results showed 16 metabolites were detected in wastewater samples, including indicators of exposure to acrolein, acrylonitrile, 1,3-butadiene, crotonaldehyde, n,n-dimethylformamide (DMF), ethylbenzene, nicotine, propylene oxide, styrene, tetrachloroethylene, toluene, and xylene. Additional metabolites qualitatively identified exposure to acrylamide and trichloroethylene. Community 1 (closer proximity to manufacturing facilities) had a greater number of detects (n = 36) and higher VOC loadings, 22,000 mg day per 1000 people, as compared to Community 2 (n = 28), 7100 mg day per 1000 people. Normalizing to nicotine consumption biomarkers to account for differences in smoking behaviors, Community 1 continued to have higher levels of propylene oxide, crotonaldehyde, DMF, and acrylonitrile exposures, VOCs generally sourced from manufacturing activities and vehicle emissions. This is the first study to utilize wastewater to detect urinary biomarkers of VOCs exposure. These preliminary results suggest the WBE approach as a potentially powerful tool to assess community health exposures to indoor and outdoor air pollutants.
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http://dx.doi.org/10.1016/j.scitotenv.2022.157008DOI Listing
June 2022

Stenting and Angioplasty in Neurothrombectomy: Matched Analysis of Rescue Intracranial Stenting Versus Failed Thrombectomy.

Stroke 2022 Jun 30:101161STROKEAHA121038248. Epub 2022 Jun 30.

Department of Neurosciences, WellStar Health System, Atlanta, GA (A.K., H.L.).

Background: Successful reperfusion is one of the strongest predictors of functional outcomes after mechanical thrombectomy (MT). Despite continuous advancements in MT technology and techniques, reperfusion failure still occurs in ≈15% to 30% of patients with large vessel occlusion strokes undergoing MT. We aim to evaluate the safety and efficacy of rescue intracranial stenting for large vessel occlusion stroke after failed MT.

Methods: The SAINT (Stenting and Angioplasty in Neurothrombectomy) Study is a retrospective analysis of prospectively collected data from 14 comprehensive stroke centers through January 2015 to December 2020. Patients were included if they had anterior circulation large vessel occlusion stroke due to intracranial internal carotid artery and middle cerebral artery-M1/M2 segments and failed MT. The cohort was divided into 2 groups: rescue intracranial stenting and failed recanalization (modified Thrombolysis in Cerebral Ischemia score 0-1). Propensity score matching was used to balance the 2 groups. The primary outcome was the shift in the degree of disability as measured by the modified Rankin Scale at 90 days. Secondary outcomes included functional independence (90-day modified Rankin Scale score 0-2). Safety measures included symptomatic intracranial hemorrhage and 90-day mortality.

Results: A total of 499 patients were included in the analysis. Compared with the failed reperfusion group, rescue intracranial stenting had a favorable shift in the overall modified Rankin Scale score distribution (acOR, 2.31 [95% CI, 1.61-3.32]; <0.001), higher rates of functional independence (35.1% versus 7%; adjusted odds ratio [aOR], 6.33 [95% CI, 3.14-12.76]; <0.001), and lower mortality (28% versus 46.5%; aOR, 0.55 [95% CI, 0.31-0.96]; =0.04) at 90 days. Rates of symptomatic intracerebral hemorrhage were comparable across both groups (7.1% versus 10.2%; aOR, 0.99 [95% CI, 0.42-2.34]; =0.98). The matched cohort analysis demonstrated similar results. Specifically, rescue intracranial stenting (n=107) had a favorable shift in the overall modified Rankin Scale score distribution (acOR, 3.74 [95% CI, 2.16-6.57]; <0.001), higher rates of functional independence (34.6% versus 6.5%; aOR, 10.91 [95% CI, 4.11-28.92]; <0.001), and lower mortality (29.9% versus 43%; aOR, 0.49 [95% CI, 0.25-0.94]; =0.03) at 90 days with similar rates of symptomatic intracerebral hemorrhage (7.5% versus 11.2%; aOR, 0.87 [95% CI, 0.31-2.42]; =0.79) compared with patients who failed to reperfuse (n=107). There was no heterogeneity of treatment effect across the prespecified subgroups for improvement in functional outcomes.

Conclusions: Acute intracranial stenting appears to be a safe and effective rescue strategy in patients with large vessel occlusion stroke who failed MT. Randomized multicenter trials are warranted.
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http://dx.doi.org/10.1161/STROKEAHA.121.038248DOI Listing
June 2022

Contribution of Fatty Acid Oxidation to the Pathogenesis of Pulmonary Hypertension.

Am J Physiol Lung Cell Mol Physiol 2022 Jun 28. Epub 2022 Jun 28.

Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, Colorado, United States.

Dysregulated metabolism characterizes both animal and human forms of pulmonary hypertension (PH). Enzymes involved in fatty acid metabolism have previously not been assessed in human pulmonary arteries affected by pulmonary arterial hypertension (PAH), and how inhibition of fatty acid oxidation (FAO) may attenuate PH remains unclear. Fatty acid metabolism gene transcription was quantified in laser-dissected pulmonary arteries from 10 explanted lungs with advanced PAH (5 idiopathic, 5 associated with systemic sclerosis), and 5 donors without lung diseases. Effects of oxfenicine, a FAO inhibitor, on female Sugen 5416-chronic hypoxia (SuHx) rats were studied in vivo using right heart catheterization, and ex vivo using perfused lungs and pulmonary artery ring segments. The impact of pharmacologic (oxfenicine) and genetic (carnitine palmitoyltransferase 1a heterozygosity) FAO suppression was additionally probed in mouse models of Schistosoma and hypoxia-induced PH. Potential mechanisms underlying FAO-induced PH pathogenesis were examined by quantifying ATP and mitochondrial mass in oxfenicine-treated SuHx pulmonary arterial cells, and by assessing pulmonary arterial macrophage infiltration with immunohistochemistry. We found upregulated pulmonary arterial transcription of 26 and 13 FAO genes in idiopathic and systemic sclerosis-associated PAH, respectively. In addition to promoting de-remodeling of pulmonary arteries in SuHx rats, oxfenicine attenuated endothelin-1-induced vasoconstriction. FAO inhibition also conferred modest benefit in the two mouse models of PH. Oxfenicine increased mitochondrial mass in cultured rat pulmonary arterial cells, and decreased the density of perivascular macrophage infiltration in pulmonary arteries of treated SuHx rats. In summary, FAO inhibition attenuated experimental PH, and may be beneficial in human PAH.
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http://dx.doi.org/10.1152/ajplung.00039.2022DOI Listing
June 2022

Adenoviral infection in 5 red-tailed hawks and a broad-winged hawk.

J Vet Diagn Invest 2022 Jun 27:10406387221105240. Epub 2022 Jun 27.

The Raptor Center, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, USA.

Adenoviral infections among raptors are best described in falcons and are characterized most commonly by necrotizing hepatitis and splenitis; only one case has been reported in a hawk. Five red-tailed hawks () and a broad-winged hawk () had an adenoviral infection based on history, histopathology, negative-stain electron microscopy, and PCR. All birds had acute onset of illness resulting in death; 3 had evidence of a concurrent bacterial infection. Microscopically, all 6 birds had solitary, pale eosinophilic-to-amphophilic, intranuclear inclusion bodies within presumed hematopoietic cells in bone marrow and macrophages in spleen. Five of the 6 birds had similar inclusions within hepatocytes and Kupffer cells. All but one bird had severe bone marrow necrosis. There was moderate splenic necrosis (3 of 6) and mild-to-marked hepatic necrosis (4 of 6). Negative-stain electron microscopy demonstrated adenoviral particles in bone marrow (5 of 6), liver (1 of 5), and/or spleen (1 of 5). PCR was positive for adenovirus in bone marrow (3 of 5), liver (1 of 3), spleen (4 of 6), and/or intestinal contents (2 of 3). Viral DNA polymerase gene sequences clustered within the genus. There was 99% nucleotide identity to one another and 90% nucleotide identity with the closest related adenovirus (Harris hawk, EU715130). Our case series expands on the limited knowledge of adenoviral infections in hawks. The splenic and hepatic necrosis, and particularly the hitherto unreported bone marrow necrosis, suggest that adenoviral infection is clinically relevant and potentially fatal in hawks.
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http://dx.doi.org/10.1177/10406387221105240DOI Listing
June 2022

Oxidative Stress in Primary Bone Tumors: A Comparative Analysis.

Cureus 2022 May 25;14(5):e25335. Epub 2022 May 25.

Orthopedics, Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak, IND.

Background Bone tumors account for 1% of all cancers and have considerable morbidity and mortality. There is a proposed theory of increased oxidative stress characterized by an increased level of reactive oxygen species (ROS) that disrupts the intracellular reduction-oxidation (redox) balance which has been implicated in various diseases including cancer. The aim of the present study was to measure the levels of oxidant stress and antioxidant mechanism in bone tumors (benign as well as malignant).  Methods The study cohort consisted of 42 subjects: 14 malignant bone tumors, 14 benign bone tumors, and 14 healthy controls. Serum Malondialdehyde (MDA) levels were determined to assess oxidative stress while antioxidant status was evaluated using superoxide dismutase (SOD). Results Patients with malignant bone tumors showed a significant increase in plasma MDA levels (p<0.05) while SOD levels were significantly decreased (p<0.05). No significant difference in oxidative damage was noted between both the sarcomas (p>0.05). Conclusions In conclusion, an increase in oxidative stress and a decrease in antioxidant status are observed in bone tumors. Further studies on the manipulation of redox balance in patients with bone tumors can act as a useful approach in early diagnosis or designing management strategies for bone tumors.
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http://dx.doi.org/10.7759/cureus.25335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9232385PMC
May 2022

Right heart failure in a young man.

Heart 2022 06 24;108(14):1120-1160. Epub 2022 Jun 24.

Cardiology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India

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http://dx.doi.org/10.1136/heartjnl-2021-320661DOI Listing
June 2022

Simple Wound Closure for Civilian Cranial Gunshot Wounds: A Systematic Literature Review.

Cureus 2022 May 21;14(5):e25187. Epub 2022 May 21.

Neurosurgery, University of Miami Miller School of Medicine, Miami, USA.

Civilian cranial gunshot wounds are common injuries associated with significant morbidity and mortality. Simple wound closure has been previously proposed as an alternative treatment option for a small subset of patients, but the exact outcomes of this strategy are not well-defined. The objective of this paper was to describe the scientific literature reporting simple wound closure of civilian cranial gunshot wounds, its effect on short-term and long-term neurologic outcomes, and rates of seizures and infections. A systematic literature review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The strength of evidence was assessed using the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) criteria. Seventeen studies were found that met inclusion criteria. There was very low strength of evidence that patients treated with simple wound closure can achieve good short and long-term neurologic outcomes. There was very low strength of evidence that simple wound closure has a higher incidence of mortality compared to operative intervention, especially in patients with initial low Glasgow Coma Scale (GCS) scores. There was very low strength of evidence that patients treated with simple wound closure have a small risk of subsequently developing infections or seizures. In conclusion, under most circumstances, neurosurgical operative intervention should be viewed as the optimal treatment for salvageable civilian cranial gunshot wound patients. However, our literature review showed that simple wound closure is safe and viable. More data are needed to determine the appropriate clinical scenario for using this alternative option.
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http://dx.doi.org/10.7759/cureus.25187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9208342PMC
May 2022

Heart rate dynamics in the prediction of coronary artery disease and myocardial infarction using artificial neural network and support vector machine.

J Appl Biomed 2022 Jun 21;20(2):70-79. Epub 2022 Jun 21.

Birla Institute of Technology, Department of Bioengineering and Biotechnology, Mesra, Ranchi, Jharkhand, India.

Background: Atherosclerosis leads to coronary artery disease (CAD) and myocardial infarction (MI), a major cause of morbidity and mortality worldwide. The computer-aided prognosis of atherosclerotic events with the electrocardiogram (ECG) derived heart rate variability (HRV) can be a robust method in the prognosis of atherosclerosis events.

Methods: A total of 70 male subjects aged 55 ± 5 years participated in the study. The lead-II ECG was recorded and sampled at 200 Hz. The tachogram was obtained from the ECG signal and used to extract twenty-five HRV features. The one-way Analysis of variance (ANOVA) test was performed to find the significant differences between the CAD, MI, and control subjects. Features were used in the training and testing of a two-class artificial neural network (ANN) and support vector machine (SVM).

Results: The obtained results revealed depressed HRV under atherosclerosis. Accuracy of 100% was obtained in classifying CAD and MI subjects from the controls using ANN. Accuracy was 99.6% with SVM, and in the classification of CAD from MI subjects using SVM and ANN, 99.3% and 99.0% accuracy was obtained respectively.

Conclusions: Depressed HRV has been suggested to be a marker in the identification of atherosclerotic events. The good accuracy observed in classification between control, CAD, and MI subjects, revealed it to be a non-invasive cost-effective approach in the prognosis of atherosclerotic events.
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http://dx.doi.org/10.32725/jab.2022.008DOI Listing
June 2022

On the origin and evolution of the asteroid Ryugu: A comprehensive geochemical perspective.

Proc Jpn Acad Ser B Phys Biol Sci 2022 ;98(6):227-282

Institute of Space and Astronautical Science, Japan Aerospace Exploration Agency.

Presented here are the observations and interpretations from a comprehensive analysis of 16 representative particles returned from the C-type asteroid Ryugu by the Hayabusa2 mission. On average Ryugu particles consist of 50% phyllosilicate matrix, 41% porosity and 9% minor phases, including organic matter. The abundances of 70 elements from the particles are in close agreement with those of CI chondrites. Bulk Ryugu particles show higher δO, ΔO, and εCr values than CI chondrites. As such, Ryugu sampled the most primitive and least-thermally processed protosolar nebula reservoirs. Such a finding is consistent with multi-scale H-C-N isotopic compositions that are compatible with an origin for Ryugu organic matter within both the protosolar nebula and the interstellar medium. The analytical data obtained here, suggests that complex soluble organic matter formed during aqueous alteration on the Ryugu progenitor planetesimal (several 10's of km), <2.6 Myr after CAI formation. Subsequently, the Ryugu progenitor planetesimal was fragmented and evolved into the current asteroid Ryugu through sublimation.
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http://dx.doi.org/10.2183/pjab.98.015DOI Listing
June 2022

An Improved Procedure for -Mediated Transformation of 'Carrizo' Citrange.

Plants (Basel) 2022 May 30;11(11). Epub 2022 May 30.

Department of Plant Science, University of Connecticut, Storrs, CT 06269, USA.

Although several protocols for genetic transformation of citrus have been published, it is highly desirable to further improve its efficiency. Here we report treatments of cells and citrus explants prior to and during co-cultivation process to enhance transformation efficiency using a commercially used rootstock 'Carrizo' citrange [ (L.) Osb. × (L.) Raf.] as a model plant. We found explants from light-grown seedlings exhibited higher transformation efficiency than those from etiolated seedlings. We pre-cultured cells in a 1/10 MS, 0.5 g/L 2-(-morpholino) ethanesulfonic acid (MES) and 100 µM acetosyringone liquid medium for 6 h at 25 °C before used to infect citrus explants. We incubated epicotyl segments in an MS liquid medium containing 13.2 µM 6-BA, 4.5 µM 2,4-D, 0.5 µM NAA for 3 h at 25 °C prior to infection. In the co-cultivation medium, we added 30 µM paclobutrazol and 10 µM lipoic acid. Each of these treatments significantly increased the efficiencies of transformation up to 30.4% (treating with acetosyringone), 31.8% (treating explants with cytokinin and auxin), 34.9% (paclobutrazol) and 38.6% (lipoic acid), respectively. When the three treatments were combined, we observed that the transformation efficiency was enhanced from 11.5% to 52.3%. The improvement of genetic transformation efficiency mediated by these three simple treatments may facilitate more efficient applications of transgenic and gene editing technologies for functional characterization of citrus genes and for genetic improvement of citrus cultivars.
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http://dx.doi.org/10.3390/plants11111457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9183180PMC
May 2022

Sexual Dimorphism of Dexamethasone as a Prophylactic Treatment in Pathologies Associated With Acute Hypobaric Hypoxia Exposure.

Front Pharmacol 2022 20;13:873867. Epub 2022 May 20.

Department of Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, Delhi, India.

Dexamethasone can be taken prophylactically to prevent hypobaric hypoxia-associated disorders of high-altitude. While dexamethasone-mediated protection against high-altitude disorders has been clinically evaluated, detailed sex-based mechanistic insights have not been explored. As part of our India-Leh-Dexamethasone-expedition-2020 (INDEX 2020) programme, we examined the phenotype of control ( = 14) and dexamethasone ( = 13) groups, which were airlifted from Delhi (∼225 m elevation) to Leh, Ladakh (∼3,500 m), India, for 3 days. Dexamethasone 4 mg twice daily significantly attenuated the rise in blood pressure, heart rate, pulmonary pressure, and drop in SaO resulting from high-altitude exposure compared to control-treated subjects. Of note, the effect of dexamethasone was substantially greater in women than in men, in whom the drug had relatively little effect. Thus, for the first time, this study shows a sex-biased regulation by dexamethasone of physiologic parameters resulting from the hypoxic environment of high-altitude, which impacts the development of high-altitude pulmonary hypertension and acute mountain sickness. Future studies of cellular contributions toward sex-specific regulation may provide further insights and preventive measures in managing sex-specific, high-altitude-related disorders.
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http://dx.doi.org/10.3389/fphar.2022.873867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9163683PMC
May 2022

Clinical trial: seven-day vonoprazan- versus 14-day proton pump inhibitor-based triple therapy for first-line Helicobacter pylori eradication.

Aliment Pharmacol Ther 2022 Aug 3;56(3):436-449. Epub 2022 Jun 3.

Department of Gastroenterology, Changi General Hospital, Singapore.

Background: One-week triple therapy with vonoprazan is endorsed by Japanese guidelines as an alternative to proton pump inhibitor (PPI)-based triple therapy for first-line Helicobacter pylori eradication. This contrasts with Western guidelines recommending 2-week PPI-based triple therapy.

Aim: To verify the non-inferiority of 1-week vonoprazan-based triple therapy versus 2-week PPI-based triple therapy as first-line H. pylori eradication in a multiracial Asian cohort.

Methods: Randomised controlled trial of treatment-naïve patients with H. pylori infection assigned 1:1 to either 7 days amoxicillin 1 g + clarithromycin 500 mg + vonoprazan 20 mg twice per day or 14 days amoxicillin 1 g + clarithromycin 500 mg + omeprazole OR esomeprazole OR rabeprazole 20 mg twice/day. Subjects were randomly assigned to each PPI 1:1:1 Demographics, H. pylori resistance, CYP 2C19 genotype, eradication success and safety profiles were compared between groups.

Results: Between June 2019 and June 2021, 252 of 1097 subjects screened were randomised. 244 (age [SD] 51.7 [14.6]) received vonoprazan- (n = 119) or PPI-based (n = 125) triple therapy. Eradication rates by intention-to-treat analysis were 87.4% (vonoprazan-based triple therapy) versus 88.0% (PPI-based triple therapy. By per protocol analysis: 96.3% (vonoprazan-based triple therapy) versus 94.0% (PPI-based triple therapy). Clarithromycin resistance predicted treatment failure on multivariate analysis: RR 11.4; 95% CI [1.4-96.3], p = 0.025. No significant differences in CYP 2C19 genotypes or adverse events occurred between groups.

Conclusion: One-week vonoprazan-based triple therapy achieved comparable efficacy to 2-week PPI-based triple therapy and was well tolerated.
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http://dx.doi.org/10.1111/apt.17070DOI Listing
August 2022

A mitochondrial unfolded protein response inhibitor suppresses prostate cancer growth in mice via HSP60.

J Clin Invest 2022 07;132(13)

Department of Pharmacology and Therapeutics.

Mitochondrial proteostasis, regulated by the mitochondrial unfolded protein response (UPRmt), is crucial for maintenance of cellular functions and survival. Elevated oxidative and proteotoxic stress in mitochondria must be attenuated by the activation of a ubiquitous UPRmt to promote prostate cancer (PCa) growth. Here we show that the 2 key components of the UPRmt, heat shock protein 60 (HSP60, a mitochondrial chaperonin) and caseinolytic protease P (ClpP, a mitochondrial protease), were required for the development of advanced PCa. HSP60 regulated ClpP expression via c-Myc and physically interacted with ClpP to restore mitochondrial functions that promote cancer cell survival. HSP60 maintained the ATP-producing functions of mitochondria, which activated the β-catenin pathway and led to the upregulation of c-Myc. We identified a UPRmt inhibitor that blocked HSP60's interaction with ClpP and abrogated survival signaling without altering HSP60's chaperonin function. Disruption of HSP60-ClpP interaction with the UPRmt inhibitor triggered metabolic stress and impeded PCa-promoting signaling. Treatment with the UPRmt inhibitor or genetic ablation of Hsp60 inhibited PCa growth and progression. Together, our findings demonstrate that the HSP60-ClpP-mediated UPRmt is essential for prostate tumorigenesis and the HSP60-ClpP interaction represents a therapeutic vulnerability in PCa.
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http://dx.doi.org/10.1172/JCI149906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9246382PMC
July 2022

and Consortium Facilitates Higher Acquisition of N, P with Improved Carbon Allocation and Enhanced Plant Growth in .

J Fungi (Basel) 2022 Apr 27;8(5). Epub 2022 Apr 27.

International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India.

The soil microbiome contributes to nutrient acquisition and plant adaptation to numerous biotic and abiotic stresses. Numerous studies have been conducted over the past decade showing that plants take up nutrients better when associated with fungi and additional beneficial bacteria that promote plant growth, but the mechanisms by which the plant host benefits from this tripartite association are not yet fully understood. In this article, we report on a synergistic interaction between rice (), (an endophytic fungus colonizing the rice roots), and strain W5, a free-living nitrogen-fixing bacterium. On the basis of mRNA expression analysis and enzymatic activity, we found that co-inoculation of plant roots with the fungus and the rhizobacterium leads to enhanced plant growth and improved nutrient uptake compared to inoculation with either of the two microbes individually. Proteome analysis of further revealed that proteins involved in nitrogen and phosphorus metabolism are upregulated and improve nitrogen and phosphate uptake. Our results also show that supports colonization of rice roots by , and consequentially, the plants are more resistant to biotic stress upon co-colonization. Our research provides detailed insights into the mechanisms by which microbial partners synergistically promote each other in the interaction while being associated with the host plant.
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http://dx.doi.org/10.3390/jof8050453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9146537PMC
April 2022
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