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Human immunodeficiency virus-infected patients are at increased risk of drug reactions because of immune dysregulation and multiple drug intake. Lichenoid drug reactions to isoniazid have been reported previously in the literature. However, for lichenoid drug reaction to isoniazid to be so extensive to present as exfoliative dermatitis is rare. We report here a rare case of lichenoid drug reaction to isoniazid presenting as exfoliative dermatitis in a patient with acquired immunodeficiency syndrome. [ABSTRACT FROM AUTHOR]

Arsenic (As) and silicon (Si) are two structurally competitive natural elements where Si minimises As accumulation in rice plants, and based on this two-year field trial, the study proposes adopting alternating wetting and drying (AWD) irrigation as a sustainable water management strategy allowing greater Si availability. This field-based project is the first report on AWD's impact on As-Si distribution in fluvio-alluvial soils of the entire Ganga valley (24 study sites, six divisions), seasonal variance (pre-monsoon and monsoon), rice plant anatomy and productivity, soil microbial diversity, microbial gene ontology profiling and associated metabolic pathways. Under AWD to flooded and pre-monsoon to monsoon cultivations, respectively, greater Si availability was achieved and As-bioavailability was reduced by 8.7 ± 0.01-9.2 ± 0.02% and 25.7 ± 0.09-26.1 ± 0.01%. In the pre-monsoon and monsoon seasons, the physiological betterment of rice plants led to the high rice grain yield under AWD improved by 8.4 ± 0.07% and 10.0 ± 0.07%, proving the economic profitability. Compared to waterlogging, AWD evidences as an optimal soil condition for supporting soil microbial communities in rice fields, allowing diverse metabolic activities, including As-resistance, and active expression of As-responsive genes and gene products. Greater expressions of gene ontological terms and complex biochemical networking related to As metabolism under AWD proved better cellular, genetic and environmental responsiveness in microbial communities. Finally, by implementing AWD, groundwater usage can be reduced, lowering the cost of pumping and field management and generating an economic profit for farmers. These combined assessments prove the acceptability of AWD for the establishment of multiple sustainable development goals (SDGs)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The present study depicts the true failed scenario of the arsenic (As) removal units (ARU) in West Bengal by evaluating their treated water quality. Annual As removal efficiency of the 12 studied ARUs range between 35.2% and 82.6%. A comprehensive physico-chemical parameters and trace elements analysis find almost 25% and 16.7% of treated drinking water samples with poor water quality index (WQI) and high heavy metal evaluation index (HEI), respectively. The pond-based water treatment plant maintains the production of continuous As-safe water with a range between 60.2% and 66.7% due to its high Fe/As ratio. It's a discontent concluding the treated drinking water of the groundwater based-ARUs were observed with sufficient As mediated cancer risk (3 ×10 -3 ). The non-cancer risk (HQ) of As is safe for the surface water treatment plant (0.38), whereas it is threatening for the groundwater based-ARUs (7.44). However, the drinking water samples are safe in view of HQ from the other trace elements like Hg, Al, Cd, Cr, Pb, F - and NO 3 - . Small scale ARU could be a feasible mitigation strategy in reducing the As menace in the long run if the plants are maintained correctly. Nevertheless, surface treated water is the most sustainable solution as withdrawal of groundwater for drinking purpose is not a viable practice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Small extracellular vesicles (sEVs) released by acute myeloid leukaemia (AML) cells have been reported to influence the trilineage differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs). However, it remains elusive which biological cargo from AML-sEVs is responsible for this effect. In this study, sEVs were isolated from cell-conditioned media and blood plasma using size-exclusion chromatography and ultrafiltration and characterized according to MISEV2018 guidelines. Our results demonstrated that AML-sEVs increased the proliferation of BM-MSCs. Conversely, key proteins that are important for normal haematopoiesis were downregulated in BM-MSCs. Additionally, we revealed that AML-sEVs significantly reduced the differentiation of BM-MSCs to osteoblasts without affecting adipogenic or chondrogenic differentiation. Next, LC-MS/MS proteomics elucidated that various proteins, including Y-box-binding protein 1 (YBX1), were upregulated in both AML-sEVs and BM-MSCs treated with AML-sEVs. Clinically relevant, we found that YBX1 is considerably upregulated in most paediatric AML patient-derived sEVs compared to healthy controls. Interestingly, sEVs isolated after the downregulation of YBX1 in AML cells remarkably rescued the osteoblastic differentiation of BM-MSCs. Altogether, our data demonstrate for the first time that YBX1 containing AML-sEVs is one of the key players that disrupt the normal function of bone marrow microenvironment by reducing the osteogenic differentiation of BM-MSCs., (© 2024 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)

Host and tissue-specificity of endophytes are important attributes that limit the endophyte application on multiple crops. Therefore, understanding the endophytic composition of the targeted crop is essential, especially for the dioecious plants where the male and female plants are different. Here, efforts were made to understand the endophytic bacterial composition of the dioecious Siraitia grosvenorii plant using 16S rRNA amplicon sequencing. The present study revealed the association of distinct endophytic bacterial communities with different parts of male and female plants. Roots of male and female plants had a higher bacterial diversity than other parts of plants, and the roots of male plants had more bacterial diversity than the roots of female plants. Endophytes belonging to the phylum Proteobacteria were abundant in all parts of male and female plants except male stems and fruit pulp, where the Firmicutes were most abundant. Class Gammaproteobacteria predominated in both male and female plants, with the genus Acinetobacter as the most dominant and part of the core microbiome of the plant (present in all parts of both, male and female plants). The presence of distinct taxa specific to male and female plants was also identified. Macrococcus, Facklamia, and Propionibacterium were the distinct genera found only in fruit pulp, the edible part of S. grosvenorii. Predictive functional analysis revealed the abundance of enzymes of secondary metabolite (especially mogroside) biosynthesis in the associated endophytic community with predominance in roots. The present study revealed bacterial endophytic communities of male and female S. grosvenorii plants that can be further explored for monk fruit cultivation, mogroside production, and early-stage identification of male and female plants. KEY POINTS: • Male and female Siraitia grosvenorii plants had distinct endophytic communities • The diversity of endophytic communities was specific to different parts of plants • S. grosvenorii-associated endophytes may be valuable for mogroside biosynthesis and monk fruit cultivation., (© 2024. The Author(s).)

Single-molecule localization microscopy (SMLM) is a powerful technique to achieve super-resolution imaging beyond the diffraction limit. Although various types of blinking fluorophores are currently considered for SMLM, intrinsic blinking fluorophores remain rare at the single-molecule level. Here, we report the synthesis of nanographene-based intrinsic burst-blinking fluorophores for highly versatile SMLM. We image amyloid fibrils in air and in various pH solutions without any additive and lysosome dynamics in live mammalian cells under physiological conditions. In addition, the single-molecule labeling of nascent proteins in primary sensory neurons was achieved with azide-functionalized nanographenes via click chemistry. SMLM imaging reveals higher local translation at axonal branching with unprecedented detail, while the size of translation foci remained similar throughout the entire network. These various results demonstrate the potential of nanographene-based fluorophores to drastically expand the applicability of super-resolution imaging.

The health of agroecosystems is subsiding unremittingly, and the over-use of chemical fertilizers is one of the key reasons. It is hypothesized that integrating biochar, a carbon (C)-rich product, would be an effective approach to reducing the uses of synthetic fertilizers and securing crop productivity through improving soil properties and nutrient cycling. The bamboo biochar at different quantities (4-12 Mg ha -1 ) and combinations with chemical fertilizers were tested in stevia (Stevia rebaudiana) farming in silty clay acidic soil. The integration of biochar at 8 Mg ha -1 with 100% nitrogen (N), phosphorus (P), and potassium (K) produced statistically (p ≤ 0.05) higher leaf area index, dry leaf yield, and steviol glycosides yield by about 18.0-33.0, 25.8-44.9, and 20.5-59.4%, respectively, compared with the 100% NPK via improving soil physicochemical properties. Soil bulk density was reduced by 5-8% with biochar at ≥ 8 Mg ha -1 , indicating the soil porosity was increased by altering the soil macrostructure. The soil pH was significantly (p ≤ 0.05) augmented with the addition of biochar alone or in the combination of N because of the alkaline nature of the used biochar (pH = 9.65). Furthermore, integrating biochar at 8 Mg ha -1 with 100% NPK increased 22.7% soil organic C compared with the sole 100% NPK. The priming effect of applied N activates soil microorganisms to mineralize the stable C. Our results satisfy the hypothesis that adding bamboo biochar would be a novel strategy for sustaining productivity by altering soil physicochemical properties., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background : PBL (problem based learning) is new active learning educational strategy that has been extensively tested and used in recent years. Patan Academy of Health Sciences (PAHS) is one of medical schools from Nepal, a Low Income Country (LIC) implementing PBL for undergraduate medical education. This study aims to compare PAHS students' understanding and knowledge retention when taught through PBL and lecture-based classes and compare students' perceptions of PBL and lectures in medical education. Methods : This is a cross-sectional study of medical students of a PBL based medical school in Nepal, a non-Western low-income country. Ethical approval was given by the institutional research committee of the Patan Academy of Health Sciences. Understanding and knowledge retention was assessed with 50 vignette-based multiple-choice questions, half of which were taught through PBL sessions, and the remaining half were taught in didactic lectures during basic science years of medical school. A separate pre-validated perception questionnaire was used to assess students' preferences regarding PBL and lectures. Results : Out of 107 students, 99 participated in the understanding and knowledge retention questionnaires and 107 completed perception questionnaires. Understanding and knowledge retention of students was found to be the same for topics taught by PBL and lectures, with median scores of 17 and s16, respectively. PBL were mostly preferred for the physiology (59.81%), pathology (51.40%) and pharmacology (53.27%) concepts, and lectures were mostly preferred for the anatomy (78.50%), biochemistry (45.79%), and microbiology (42.99%) topics. Students wanted the same concepts to be taught through both PBL and lectures, especially for anatomy. Conclusions : Understanding and knowledge retention is the same for topics taught by either PBL or lectures during the basic science years of undergraduate medical education. Students prefer PBL for physiology, pathology, and pharmacology-related concepts, conventional didactic lecture for physiology and microbiology, and a combination of lecture and PBL sessions for anatomy., Competing Interests: Competing interests: Authors have been involved as members, tutors or volunteers of PBL and lecture sessions at PAHS. The authors declare that they have no competing interests otherwise., (Copyright: © 2023 Adhikari Yadav S et al.)

Tagetes minuta L. is known as an industrial crop in the world as it possesses an essential oil that is extensively used in the perfumery and flavor industries. The crop performance is influenced by the planting/sowing method (SM) and seeding rate (SR); however, the effects of these variables on biomass yield and quality of the essential oil of T. minuta remain unclear. As a comparatively new crop, the responses of T. minuta to different SMs and SRs have not been studied in the mild temperate eco-region. Thus, the biomass and essential oil yield response of T. minuta (variety 'Himgold') to SM (line sowing and broadcasting) and SR (at 2, 3, 4, 5, and 6 kg ha -1 ) were investigated. The overall fresh biomass of T. minuta ranged from 16.86 to 28.13 Mg ha -1 , while the essential oil concentration in fresh biomass varied from 0.23% to 0.33%. Irrespective of the SR, the broadcasting method produced significantly ( p ≤ 0.05) higher fresh biomass yield by approximately 15.8% and 7.6% compared with line sowing during 2016 and 2017, respectively. An increase in biomass yield was noted as the SR increased up to 4 kg ha -1 . The SR at 4 kg ha -1 registered approximately 41.9%-56.1% and 3.3%-10.3% higher biomass yield than the SR at 2 and 6 kg ha -1 , respectively. No significant ( p ≥ 0.05) differences in essential oil concentration in fresh biomass were observed due to the different SMs and SRs. Thus, T. minuta may be sown by the broadcasting method in the mild temperate eco-region with an SR of 4 kg ha -1 ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pal, Mahajan, Thakur, Kapoor and Shivani.)

Background: Itolizumab, an anti-CD6 monoclonal antibody, down-regulates COVID-19-mediated inflammation and the acute effects of cytokine release syndrome. This study aimed to evaluate the safety and efficacy of itolizumab in hospitalized COVID-19 patients with PaO 2 /FiO 2 ratio (PFR) ≤200 requiring oxygen therapy., Research Design and Methods: This multicenter, single-arm, Phase 4 study enrolled 300 hospitalized adults with SARS-CoV-2 infection, PFR ≤200, oxygen saturation ≤94%, and ≥1 elevated inflammatory markers from 17 COVID-19 specific tertiary Indian hospitals. Patients received 1.6 mg/kg of itolizumab infusion, were assessed for 1 month, and followed-up to Day 90. Primary outcome measures included incidence of severe acute infusion-related reactions (IRRs) (≥Grade-3) and mortality rate at 1 month., Results: Incidence of severe acute IRRs was 1.3% and mortality rate at 1 month was 6.7% ( n  = 20/300). Mortality rate at Day 90 was 8.0% ( n  = 24/300). By Day 7, most patients had stable/improved SpO 2 without increasing FiO 2 and by Day 30, 91.7% patients were off oxygen therapy. Overall, 63 and 10 patients, respectively, reported 123 and 11 treatment-emergent adverse events up to Days 30 and 90. No deaths were attributable to itolizumab. Patient-reported outcomes showed gradual and significant improvement for all five dimensions on EQ-5D-5L., Conclusion: Itolizumab demonstrated acceptable safety with a favorable prognosis in hospitalized COVID-19 patients., Clinical Trial Registration: CTRI/2020/09/027941 (Clinical Trials Registry of India).

Small extracellular vesicles (sEVs) are 30-200 nm nanovesicles enriched with unique cargoes of nucleic acids, lipids, and proteins. sEVs are released by all cell types and have emerged as a critical mediator of cell-to-cell communication. Although many studies have dealt with the role of sEVs in health and disease, the exact mechanism of sEVs biogenesis and uptake remain unexplored due to the lack of suitable imaging technologies. For sEVs functional studies, imaging has long relied on conventional fluorescence microscopy that has only 200-300 nm resolution, thereby generating blurred images. To break this resolution limit, recent developments in super-resolution microscopy techniques, specifically single-molecule localization microscopy (SMLM), expanded the understanding of subcellular details at the few nanometer level. SMLM success relies on the use of appropriate fluorophores with excellent blinking properties. In this review, the basic principle of SMLM is highlighted and the state of the art of SMLM use in sEV biology is summarized. Next, how SMLM techniques implemented for cell imaging can be translated to sEV imaging is discussed by applying different labeling strategies to study sEV biogenesis and their biomolecular interaction with the distant recipient cells., (© 2023 The Authors. Small published by Wiley-VCH GmbH.)

Glioblastoma multiforme (GBM) is the most aggressive tumor of the central nervous system with a poor prognosis. In the treatment of GBM tumors, radiotherapy plays a major role. Typically, GBM tumors cannot be cured by irradiation because of intrinsic resistance machanisms. An escalation of the irradiation dose in the GBM tumor is difficult due to the high risk of severe side effects in the brain. In the last decade, the development of new irradiation techniques, including proton-based irradiation, promised new chances in the treatment of brain tumors. In contrast to conventional radiotherapy, irradiation with protons allows a dosimetrically more confined dose deposition in the tumor while better sparing the normal tissue surrounding the tumor. A systematic comparison of both irradiation techniques on glioblastoma cells has not been performed so far. Despite the improvements in radiotherapy, it remains challenging to predict the therapeutical response of GBM tumors. Recent publications suggest extracellular vesicles (EVs) as promising markers predicting tumor response. Being part of an ancient intercellular communication system, virtually all cells release specifically composed EVs. The assembly of EVs varies between cell types and depends on environmental parameters. Here, we compared the impact of photon-based with proton-based radiotherapy on cell viability and phenotype of four different glioblastoma cell lines. Furthermore, we characterized EVs released by different glioblastoma cells and correlated released EVs with the cellular response to radiotherapy. Our results demonstrated that glioblastoma cells reacted more sensitive to irradiation with protons than photons, while radiation-induced cell death 72 h after single dose irradiation was independent of the irradiation modality. Moreover, we detected CD9 and CD81-positive EVs in the supernatant of all glioblastoma cells, although at different concentrations. The amount of released CD9 and CD81-positive EVs increased after irradiation when cells became apoptotic. Although secreted EVs of non-irradiated cells were not predictive for radiosensitivity, their increased EV release after irradiation correlated with the cytotoxic response to radiotherapy 72 h after irradiation. Thus, our data suggest a novel application of EVs in the surveillance of anti-cancer therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jennrich, Pelzer, Tertel, Koska, Vüllings, Thakur, Jendrossek, Timmermann, Giebel and Rudner.)

The essential oil of Rosa damascena is extensively used as a key natural ingredient in the perfume and cosmetic industries. However, the productivity and quality of rose oil are a big concern from the old plantation. It is hypothesized that rejuvenation of old rose plantations through ground-level pruning at right time could improve the yield of flowers and the quality of essential oil. Consequently, a field trial was led-out with 10 treatment conditions encompassing two pruning systems (ground-level pruning and ground-level pruning followed by top pruning at the end of December) and five different months of ground-level pruning (June-October) to understand the best pruning practices. In this experiment, the flower yield ranged from 18.32 to 62.40 q ha -1 , and oil content varied from 0.035 to 0.049% under different pruning systems and months of pruning. Ground-level pruned plants, irrespective of the month, registered statistically ( p ≤ 0.05) more flower yield (618.62 and 473.29 g bush -1 ) compared with ground-level pruning followed by top pruned plants in both seasons. The average across the pruning system, ground-level pruning in October registered statistically ( p ≤ 0.05) greater yield of flowers (709.10 and 605.13 g bush -1 ) compared with the ground-level pruning from June to August. Despite significant variations in flower yield among the treatments, the percentage share of the major compounds particularly β-citronellol+nerol and geraniol in the essential oil were not affected ( p ≥ 0.05) by the pruning month and pruning system. Thus, the finding suggests that the production from the old plantation of R. damascena can be improved by ground-level pruning during October under mild-temperate conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shivani, Mahajan, Thakur and Pal.)

Small extracellular vesicles (sEVs) play essential roles in intercellular signaling both in normal and pathophysiological conditions. Comprehensive studies of dsDNA associated with sEVs are hampered by a lack of methods, allowing efficient separation of sEVs from free-circulating DNA and apoptotic bodies. In this work, using controlled culture conditions, we enriched the reproducible separation of sEVs from free-circulated components by combining tangential flow filtration, size-exclusion chromatography, and ultrafiltration (TSU). EV-enriched fractions (F2 and F3) obtained using TSU also contained more dsDNA derived from the host genome and mitochondria, predominantly localized inside the vesicles. Three-dimensional reconstruction of high-resolution imaging showed that the recipient cell membrane barrier restricts a portion of EV-DNA. Simultaneously, the remaining EV-DNA overcomes it and enters the cytoplasm and nucleus. In the cytoplasm, EV-DNA associates with dsDNA-inflammatory sensors (cGAS/STING) and endosomal proteins (Rab5/Rab7). Relevant to cancer, we found that EV-DNA isolated from leukemia cell lines communicates with mesenchymal stromal cells (MSCs), a critical component in the BM microenvironment. Furthermore, we illustrated the arrangement of sEVs and EV-DNA at a single vesicle level using super-resolution microscopy. Altogether, employing TSU isolation, we demonstrated EV-DNA distribution and a tool to evaluate the exact EV-DNA role of cell-cell communication in cancer.

Valeriana jatamansi is an important temperate herb that is used in the pharmaceutical and essential oil industries. In India, this species is now on the verge of extinction due to the over-exploitation of its rhizomes from its natural habitat. It is hypothesized that the variations in bioactive compounds in its essential oil are very high among the wild populations as well as cultivated sources. Thus, this study was conducted to evaluate the chemical profiling of essential oil of four wild populations (Rupena, Kugti, Garola, and Khani) and two cultivated sources (CSIR-IHBT, Salooni), which were distilled at three consecutive days. The variation in oil concentration in roots/rhizomes was found significant ( p ≤ 0.05), and the maximum value (0.35%) was registered with the population collected from Kugti and Khani. In essential oil, irrespective of population and distillation day, patchouli alcohol was the major compound, which ranged from 19 to 63.1%. The maximum value (63.1%) was recorded with the essential oil obtained from Garola's population and distilled on the first day. The percentage of seychellene was abruptly increased with subsequent days of extraction in all the populations. The multivariate analysis revealed that the essential oil profiles of Rupena, Kugti, Garola, and CSIR-IHBT populations were found to be similar during the first day of distillation. However, during the second day, Rupena, Kugti, Khani, and CSIR-IHBT came under the same ellipse of 0.95% coefficient. The results suggest that the population of Kugti is superior in terms of oil concentration (0.35%), with a higher proportion of patchouli alcohol (63% on the first day). Thus, repeated distillation is recommended for higher recovery of essential oil. Moreover, repeated distillation can be used to attain V. jatamansi essential oil with differential and perhaps targeted definite chemical profile.

Extracellular vesicle (EV) secretion is a highly conserved evolutionary trait in all organisms in the three domains of life. The packaging and release of EVs appears to be a bulk-flow process which takes place mainly under extreme conditions. EVs participate in horizontal gene transfer, which supports the survival of prokaryotic and eukaryotic microbes. In higher eukaryotes, almost all cells secrete a heterogeneous population of EVs loaded with various biomolecules. EV secretion is typically higher in cancer microenvironments, promoting tumor progression and metastasis. EVs are now recognized as additional mediators of autocrine and paracrine communication in health and disease. In this context, proteins and RNAs have been studied the most, but extracellular vesicle DNA (EV-DNA) has started to gain in importance in the last few years. In this review, we summarize new findings related to the loading mechanism(s), localization, and post-shedding function of EV-DNA. We also discuss the feasibility of using EV-DNA as a biomarker when performing a liquid biopsy, at the same time emphasizing the lack of data from clinical trials in this regard. Finally, we outline the potential of EV-DNA uptake and its interaction with the host genome as a promising tool for understanding the mechanisms of cancer evolution., (© 2022. The Author(s).)

Head and Neck Cancers (HNCs) have highly immunosuppressive properties. Small extracellular vesicles (sEVs), including exosomes, nanosized mediators of intercellular communication in the blood, carry immunosuppressive proteins and effectively inhibit anti-tumor immune responses in HNCs. This study evaluates immunosuppressive markers on sEVs from 40 HNC patients at different disease stages and 3- and 6-month follow-up after surgery and/or chemoradiotherapy. As controls, sEVs from normal donors (NDs) are examined. Immunoregulatory surface markers on sEVs were detected as relative fluorescence intensity (RFI) using on-bead flow cytometry, and their expression levels were monitored in the early and late stages of HNC and during follow-up. In parallel, the sEV-mediated apoptosis of CD8 + Jurkat cells was assessed. Together with TGF-β1 and PD-L1 abundance, total sEV proteins are elevated with disease progression. In contrast, total sEV protein, including TGF-β1, PD-1 and PD-L1, decrease upon therapy response during follow-up. Overall survival analysis implies that high sEV PD-1/PD-L1 content is an unfavorable prognostic marker in HNC. Consistently, the sEV-mediated induction of apoptosis in CD8 + T cells correlates with the disease activity and therapy response. These findings indicate that a combination of immunoregulatory marker profiles should be preferred over a single marker to monitor disease progression and therapy response in HNC.

In patients with glioblastoma, the average survival time with current treatments is short, mainly due to recurrences and resistance to therapy. This insufficient treatment success is, in large parts, due to the tremendous molecular heterogeneity of gliomas, which affects the overall prognosis and response to therapies and plays a vital role in gliomas' grading. In addition, the tumor microenvironment is a major player for glioma development and resistance to therapy. Active communication between glioma cells and local or neighboring healthy cells and the immune environment promotes the cancerogenic processes and contributes to establishing glioma stem cells, which drives therapy resistance. Besides genetic alterations in the primary tumor, tumor-released factors, cytokines, proteins, extracellular vesicles, and environmental influences like hypoxia provide tumor cells the ability to evade host tumor surveillance machinery and promote disease progression. Moreover, there is increasing evidence that these players affect the molecular biological properties of gliomas and enable inter-cell communication that supports pro-cancerogenic cell properties. Identifying and characterizing these complex mechanisms are inevitably necessary to adapt therapeutic strategies and to develop novel measures. Here we provide an update about these junctions where constant traffic of biomolecules adds complexity in the management of glioblastoma., (© 2021. The Author(s).)

Small extracellular vesicles isolated from urine (uEVs) are increasingly recognized as potential biomarkers. Meanwhile, different uEV preparation strategies exist. Conventionally, the performance of EV preparation methods is evaluated by single particle quantification, Western blot, and electron microscopy. Recently, we introduced imaging flow cytometry (IFCM) as a next-generation single EV analysis technology. Here, we analyzed uEV samples obtained with different preparation procedures using nanoparticle tracking analysis (NTA), semiquantitative Western blot, and IFCM. IFCM analyses demonstrated that urine contains a predominant CD9 + sEV population, which exceeds CD63 + and CD81 + sEV populations. Furthermore, we demonstrated that the storage temperature of urine samples negatively affects the recovery of CD9 + sEVs. Although overall reduced, the highest CD9 + sEV recovery was obtained from urine samples stored at -80 °C and the lowest from those stored at -20 °C. Upon comparing the yield of the different uEV preparations, incongruencies between NTA and IFCM data became apparent. Results obtained by both NTA and IFCM were consistent with Western blot analyses for EV marker proteins; however, NTA results correlated with the amount of the impurity marker uromodulin. Despite demonstrating that the combination of ultrafiltration and size exclusion chromatography appears as a reliable uEV preparation technique, our data challenge the soundness of traditional NTA for the evaluation of different EV preparation methods.

Performances of crops are mainly influenced by frost, heat and availability of soil-water and nitrogen (N). However, little is known about the interaction between soil-water and N on Stevia rebaudiana. Thus, a field experiment was conducted with fifteen treatment combinations comprising three levels of soil-moisture (irrigation at 20, 50 and 75 kPa soil-water-potential) and five N levels (0-140 kg ha -1 ) to understand how soil-moisture and N influence growth, physiological and biochemical activities of stevia. Plants irrigated at 50 kPa registered 6.3-18.9% and 20.7-21.2% higher dry leaf yield compared with 20 and 75 kPa, respectively. No significant (P ≥ 0.05) differences in concentrations of total steviol glycosides (TSGs) in leaf were found due to moisture regimes. Total soluble sugars (TSS), proline, total phenols were decreased significantly (P ≤ 0.05) with plants irrigated at 20 kPa whereas SOD, CAT, and POX were decreased at both excessive and deficit water conditions. Photosynthetic rate (P N ) and stomatal conductance (g s ) decreased with plant irrigated at 75 kPa. Anatomical changes in leaf were also observed due to different moisture regimes. Among the N levels, 105 kg ha -1 registered approximately 50-53% higher dry leaf yield compared with control (0 kg N ha -1 ), irrespective of irrigation level. Excess (140 kg ha -1 ) and shortage of N significantly decreased the P N , g s , and enzyme activities. Concentrations of TSS and TSGs were higher with N at 105 and 70 kg ha -1 , respectively. Our results emphasize that irrigation at 50 kPa and application of N 105 kg ha -1 is the suitable combination for sustainable cultivation of stevia., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Siraitia grosvenorii, an herbaceous perennial plant, native to the southern parts of China, is commonly used as a low-calorie natural sweetener. It contains cucurbitane-type triterpene glycosides known as mogrosides. The extract from monk fruit is about 300 times sweeter than sucrose. In spite of its immense importance and International demand, Siraitia grosvenorii (Swingle) is not commercially cultivated outside China since scientific information for cultivation of this species is lacking. Planting material of monk fruit plant was not available in India. Thus, the seeds of monk fruit were introduced in India from China after following International norms. Then the experiments were conducted on different aspects such as seed germination, morphological and anatomical characterization, phenology, flowering and pollination behaviors, and dynamic of mogroside-V accumulation in fruit. The hydropriming at 40 °C for 24 h was found effective to reduce the germination time and to increase the germination rate (77.33%). The multicellular uniseriate trichomes were observed in both the leaf surfaces, however, higher trichomes density was observed in the ventral surface of males compared to females. The microscopic view revealed that the ovary was trilocular (ovary consists three chambers) having two ovules in each chamber or locule. Most of the fruits were globose or oblong type with 5-7 cm in length and 4-7 cm diameter. Mogroside-V content in fruit at 80 days after pollination was 0.69% on dry weight basis. The rate of increase of mogroside-V accumulation from 50 to 70 days was very slow, whereas a sharp increase was observed from 70 to 80 days. The higher receptivity of stigma was observed with fully open flowers. The floral diagram and formula have also been developed for both male and female flowers. Our results highlighted that monk fruit can be grown in Indian conditions.

Inflammatory bowel disease (IBD) patients have an increased risk of developing colitis-associated colon cancer (CAC); however, the basis for inflammation-induced genetic damage requisite for neoplasia is unclear. Several studies have shown that IBD patients have signs of increased oxidative damage, which could be a result of genetic and environmental factors such as an excess in oxidant molecules released during chronic inflammation, mitochondrial dysfunction, a failure in antioxidant capacity, or oxidant promoting diets. It has been suggested that chronic oxidative environment in the intestine leads to the DNA lesions that precipitate colon carcinogenesis in IBD patients. Indeed, several preclinical and clinical studies show that different endogenous and exogenous antioxidant molecules are effective at reducing oxidation in the intestine. However, most clinical studies have focused on the short-term effects of antioxidants in IBD patients but not in CAC. This review article examines the role of oxidative DNA damage as a possible precipitating event in CAC in the context of chronic intestinal inflammation and the potential role of exogenous antioxidants to prevent these cancers., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Tumor-derived extracellular vesicles (TEVs) are important regulators of the immune response in cancer; however, most research so far has been carried out using cell culture systems. Immune-competent murine tumor models currently provide the best platform to assess proposed roles of TEVs using in vivo animal models and therefore are important for examining interactions between TEVs and the immune system. In this review, we present the current knowledge on TEVs using in vivo tumor-bearing animal models, with a focus on the role of TEVs in mediating crosstalk between tumor cells and both adaptive and innate immune cells. In particular, we address the question how animal models can clarify the reported heterogeneity of TEV effects in both anti-tumor responses and evasion of immune surveillance. The potential of TEVs in mediating direct antigen-presenting functions supports their potential as cancer vaccine therapeutics, therefore, we provide an overview of key findings of TEV trials that have the potential as novel immunotherapies, and shed light on challenges in the path toward the first in-human trials. We also highlight the important updates on the methods that continue to enhance the rigor and reproducibility of EV studies, particularly in functional animal models., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Droste, Thakur and Eliceiri.)

Background: Vitiligo is an acquired, idiopathic, and common depigmentation disorder. The values of various epidemiologic parameters are often doubtful due to the methodological weaknesses of the studies., Aims: To elicit the magnitude of various epidemiological parameters and important correlates of vitiligo., Materials and Methods: Every vitiligo patient attending the outpatient department of medical colleges spread over most of the Indian states were examined over a period of 1 year. Various epidemiological and clinical variables were examined and compared with age and sex-matched controls (registered in the Clinical Trial Registry of India CTRI/2017/06/008854)., Results: A total of 4,43,275 patients were assessed in 30 medical colleges from 21 Indian states. Institutional prevalence of vitiligo was 0.89% (0.86% in males and 0.93% in females, P < 0.001). The mean age at presentation and mean age at onset were 30.12 ± 17.97 years and 25.14 ± 7.48 years, respectively. Head-neck was the most common primary site ( n = 1648, 41.6%) and most commonly affected site ( n = 2186, 55.17%). Most cases had nonsegmental vitiligo ( n = 2690, 67.89%). The disease started before 20 years of age in more than 46% of cases. About 77% of all cases had signs of instability during the last 1 year. The family history, consanguinity, hypothyroid disorders, and depressed mood were significantly ( P < 0.001) higher among the cases. First, second, and third-degree family members were affected in 269 (60.04%), 111 (24.78%), and 68 (15.18%) cases, respectively. Work-related exposure to chemicals was significantly higher among cases ( P < 0.008). Obesity was less common among vitiligo cases [ P < 0.001, odds ratio (OR) 0.78, 95% confidence interval (CI): 0.71-0.86]., Conclusion: This is one of the largest studies done on vitiligo in India. The prevalence of vitiligo was found to be 0.89% among hospital attendees. Prevalence of vitiligo was higher among females than in males and prevalence of family history, consanguinity, hypothyroid disorders were higher in vitiligo than among controls., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Indian Journal of Dermatology.)

Secreted factors play an important role in intercellular communication. Therefore, they are not only indispensable for the regulation of various physiological processes but can also decisively advance the development and progression of tumours. In the context of inflammatory disease, Y-box binding protein 1 (YB-1) is actively secreted and the extracellular protein promotes cell proliferation and migration. In malignant melanoma, intracellular YB-1 expression increases during melanoma progression and represents an unfavourable prognostic marker. Here, we show active secretion of YB-1 from melanoma cells as opposed to benign cells of the skin. Intriguingly, YB-1 secretion correlates with the stage of melanoma progression and depends on a calcium- and ATP-dependent non-classical secretory pathway leading to the occurrence of YB-1 in the extracellular space as a free protein. Along with an elevated YB-1 secretion of melanoma cells in the metastatic growth phase, extracellular YB-1 exerts a stimulating effect on melanoma cell migration, invasion, and tumourigenicity. Collectively, these data suggest that secreted YB-1 plays a functional role in melanoma cell biology, stimulating metastasis, and may serve as a novel biomarker in malignant melanoma that reflects tumour aggressiveness.

Tumor suppressor protein p53 protects cells against malignant transformation mostly through transcriptional activation. Lysine acetylation is required to mediate activation of p53. The protein displays eight lysine residues and their evolutionary conservation argues for an essential role. The aim of this study was to investigate the significance of individual acetylation sites in mediating p53 functions. Differences in intracellular localization, protein expression levels, and transcriptional activity were investigated by overexpressing acetylation-deficient p53 variants in the colon carcinoma-derived p53 knock-out cell line HCT 116 p53 (-/-) . We found that not all lysine residues are equally capable of promoting p53's functions. Individual amino acid mutations or combinations thereof led to altered p53 expression levels, intracellular distribution, or transcriptional transactivation capacity, as compared to the wild-type protein. However, we observed that the choice of protein tag and expression vector could significantly alter obtained results on certain aspects of p53 function., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Inc.)

Inflammatory bowel disease patients have a greatly increased risk of developing colitis-associated colon cancer (CAC); however, the basis for inflammation-induced genetic damage requisite for neoplasia is unclear. Using three models of CAC, we find that sustained inflammation triggers 8-oxoguanine DNA lesions. Strikingly, antioxidants or iNOS inhibitors reduce 8-oxoguanine and polyps in CAC models. Because the mismatch repair (MMR) system repairs 8-oxoguanine and is frequently defective in colorectal cancer (CRC), we test whether 8-oxoguanine mediates oncogenesis in a Lynch syndrome (MMR-deficient) model. We show that microbiota generates an accumulation of 8-oxoguanine lesions in MMR-deficient colons. Accordingly, we find that 8-oxoguanine is elevated in neoplastic tissue of Lynch syndrome patients compared to matched untransformed tissue or non-Lynch syndrome neoplastic tissue. While antioxidants reduce 8-oxoguanine, they do not reduce CRC in Lynch syndrome models. Hence, microbe-induced oxidative/nitrosative DNA damage play causative roles in inflammatory CRC models, but not in Lynch syndrome models.

Introduction: Medical thoracoscopy has recently gained renewed interest due to its minimal invasive nature and high yield diagnostic outcome. This study aims to observe diagnostic yield and safety of medical thoracoscopy in undiagnosed exudative pleural effusion., Methods: This is a descriptive cross-sectional study conducted in two tertiary care hospitals in Chitwan from March 2018 to May 2018. Ethical approval from the Institutional Review Board was obtained. Convenient sampling was done that included all the patients who met criteria for undiagnosed exudative pleural effusion after diagnostic thoracocentesis. Patients having contraindication to procedure and who refused consent were excluded. Statistical analysis was performed using IBM SPSS Statistics 20 and data are presented as mean±SD and frequency (percentage)., Results: A total of 14 patients underwent rigid medical thoracoscopy. All 14 patients had unilateral pleural effusion. The overall diagnostic yield was 100%. Malignancy was the most frequent histopathology diagnosis seen in 11 (78.57%) patients, the commonest being metastatic adenocarcinoma in 8 (57.1%). Pleural tuberculosis and acute-on-chronic pleuritis were seen in 2 (14.3%) and 1 (7.1%) patients, respectively. Pleural deposits and hemorrhagic pleural fluid were the two commonest findings, seen in 10 (70.1%) and 9 (64.3%) patients, respectively. Two (14.3%) patients clinically treated as tuberculous pleural effusion was re-diagnosed to have metastatic adenocarcinoma.  Common procedure-related minor complications observed were mild to moderate pain and mild bleeding, observed in 3 (21.4%) and 2 (14.3%) patients, respectively., Conclusions: Medical thoracoscopy is a safe, well-tolerated and high yield procedure in undiagnosed exudative pleural effusion. This art of medicine should be promoted in daily medical practice.

Acute myeloid leukemia (AML) is a heterogeneous malignant disease characterized by a collection of genetic and epigenetic changes. As a consequence, AML can evolve towards more aggressive subtypes during treatment, which require additional therapies to prevent future relapse. As we have previously detected double-stranded DNA (dsDNA) in tumor-derived extracellular vesicles (EVs), in this current study we attempted to evaluate the potential diagnostic applications of AML EV-dsDNA derived from primary bone marrow and peripheral blood plasma samples. EVs from plasma of 29 pediatric AML patients (at initial diagnosis or during treatment) were isolated by ultracentrifugation, after which dsDNA was extracted from obtained EVs and analyzed for leukemia-specific mutations using next generation sequencing (NGS) and GeneScan-based fragment-length analysis. In 18 out of 20 patients, dsDNA harvested from EVs mirrored the (leukemia-specific) mutations found in the genomic DNA obtained from primary leukemia cells. In the nanoparticle tracking analysis (NTA), a decrease in EV numbers was observed in patients after treatment compared with initial diagnosis. Following treatment, in 75 samples out of the 79, these mutations were no longer detectable in EV-dsDNA. In light of our results, we propose the use of leukemia-derived EV-dsDNA as an additional measure for mutational status and, potentially, treatment response in pediatric AML.

Introduction: Medical thoracoscopy has recently gained renewed interest due to its minimal invasive nature and high yield diagnostic outcome. This study aims to observe diagnostic yield and safety of medical thoracoscopy in undiagnosed exudative pleural effusion., Methods: This is a descriptive cross-sectional study conducted in two tertiary care hospitals in Chitwan from March 2018 to May 2018. Ethical approval from the Institutional Review Board was obtained. Convenient sampling was done that included all the patients who met criteria for undiagnosed exudative pleural effusion after diagnostic thoracocentesis. Patients having contraindication to procedure and who refused consent were excluded. Statistical analysis was performed using IBM SPSS Statistics 20 and data are presented as mean ±SD and frequency (percentage)., Results: A total of 14 patients underwent rigid medical thoracoscopy. All 14 patients had unilateral pleural effusion. The overall diagnostic yield was 100%. Malignancy was the most frequent histopathology diagnosis seen in 11 (78.57%) patients, the commonest being metastatic adenocarcinoma in 8 (57.1%). Pleural tuberculosis and acute-on-chronic pleuritis were seen in 2 (14.3%) and 1 (7.1%) patients, respectively. Pleural deposits and hemorrhagic pleural fluid were the two commonest findings, seen in 10 (70.1%) and 9 (64.3%) patients, respectively. Two (14.3%) patients clinically treated as tuberculous pleural effusion was re-diagnosed to have metastatic adenocarcinoma. Procedure related mortality and major complications were nil. Common procedure-related minor complications observed were mild to moderate pain and mild bleeding, observed in 3 (21.4%) and 2 (14.3%) patients, respectively., Conclusions: Medical thoracoscopy is a safe, well-tolerated and high yield procedure in undiagnosed exudative pleural effusion. This art of medicine should be promoted in daily medical practice.

This paper estimates the health damages due to arsenicosis among people residing in two districts of Bihar, India. A primary survey of 388 households' comprises 3469 individuals from two arsenic-contaminated districts namely Patna and Bhojpur from Bihar was conducted to collect the data. Arsenic field test kits was used to test the arsenic level in drinking water of the sample households. The water test results indicate that 18.3% of the sample contained 50 ppb of arsenic, and 5.12% of the sample contained the arsenic between 300 and 500 ppb. Water source, doctor visits, work loss, and arsenic concentration levels are significant and positively related to arsenicosis, and awareness is significant but negatively related to arsenicosis. The incidence rate of arsenicosis was found to be more among females than males and children. Per-capita income, sanitation, awareness, and depth of water sources are significant and positively related to defensive activities, i.e., water purification. The annual wage loss, cost of treatment, and cost of illness for sample households are estimated as INR 2437.92 ($45.83), INR 5942.40 ($111.72) and INR 8380.32 ($157.55), respectively. The annual cost of illness for the society is estimated as INR 265.97 million ($5 million). Finally, the paper suggests policy implications of providing safe drinking water in the arsenic-affected areas in the State of Bihar, India, which can help reduce arsenicosis in sustainable manner, improve well-being and potential productivity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Competing Interests: There are no conflicts of interest.

Exosomes belong to the group of extracellular vesicles (EVs) that derive from various cell populations and mediate intercellular communication in health and disease. Like hormones or cytokines, exosomes released by cells can play a potent role in the communication between the cell of origin and distant cells in the body to maintain homeostatic or pathological processes, including tumorigenesis. The nucleic acids, and lipid and protein cargo present in the exosomes are involved in a myriad of carcinogenic processes, including cell proliferation, tumor angiogenesis, immunomodulation, and metastasis formation. The ability of exosomal proteins to mediate direct functions by interaction with other cells qualifies them as tumor-specific biomarkers and targeted therapeutic approaches. However, the heterogeneity of plasma-derived exosomes consistent of (a) exosomes derived from all kinds of body cells, including cancer cells and (b) contamination of exosome preparation with other extracellular vesicles, such as apoptotic bodies, makes it challenging to obtain solid proteomics data for downstream clinical application. In this manuscript, we review these challenges beginning with the choice of different isolation methods, through the evaluation of obtained exosomes and limitations in the process of proteome analysis of cancer-derived exosomes to identify novel protein targets with functional impact in the context of translational oncology., Competing Interests: The authors declare no conflict of interest.

In a recent issue of Science, Wilson et al. (2019) provide direct evidence that the bacterial-produced colibactin alkylates DNA in vivo, resulting in DNA adducts, which mediates its genotoxic effect. This work reinforces the role of colibactin-producing bacteria in colon cancer pathogenesis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Despite high remission rates, almost 25% of patients with AML will suffer relapse 3-5 years after diagnosis. Therefore, in addition to existing diagnostic and MRD detection tools, there is still a need for the development of novel approaches that can provide information on the state of the disease. Extracellular vesicles (EVs), containing genetic material reflecting the status of the parental cell, have gained interest in recent years as potential diagnostic biomarkers in cancer. Therefore, isolation and characterization of blood and bone marrow plasma-derived EVs from pediatric AML patients could be an additional approach in AML diagnostics and disease monitoring. In this study, we attempt to establish a plasma EV-RNA-based method to detect leukemia-specific FLT3-ITD and NPM1 mutations using established leukemia cell lines and primary pediatric AML plasma samples. We were successfully able to detect FLT3-ITD and NPM1 mutations in the EV-RNA using GeneScan-based fragment-length analysis and real-time PCR assays, respectively, in samples before therapy. This was corresponding to the gDNA mutational analysis from leukemic blasts, and supports the potential of using EV-RNA as a diagnostic biomarker in pediatric AML.

Tumor-associated neutrophils (TANs) regulate many processes associated with tumor progression, and depending on the microenvironment, they can exhibit pro- or antitumor functions. However, the molecular mechanisms regulating their tumorigenicity are not clear. Using transplantable tumor models, we showed here that nicotinamide phosphoribosyltransferase (NAMPT), a molecule involved in CSF3R downstream signaling, is essential for tumorigenic conversion of TANs and their pro-angiogenic switch. As a result tumor vascularization and growth are strongly supported by these cells. Inhibition of NAMPT in TANs leads to their antitumor conversion. Adoptive transfer of such TANs into B16F10-tumor bearing mice attenuates tumor angiogenesis and growth. Of note, we observe that the regulation of NAMPT signaling in TANs, and its effect on the neutrophil tumorigenicity, are analogous in mice and human. NAMPT is up-regulated in TANs from melanoma and head-and-neck tumor patients, and its expression positively correlates with tumor stage. Mechanistically, we found that targeting of NAMPT suppresses neutrophil tumorigenicity by inhibiting SIRT1 signaling, thereby blocking transcription of pro-angiogenic genes. Based on these results, we propose that NAMPT regulatory axis is important for neutrophils to activate angiogenic switch during early stages of tumorigenesis. Thus, identification of NAMPT as the critical molecule priming protumor functions of neutrophils provides not only mechanistic insight into the regulation of neutrophil tumorigenicity, but also identifies a potential pathway that may be targeted therapeutically in neutrophils. This, in turn, may be utilized as a novel mode of cancer immunotherapy., (© 2018 UICC.)