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Groundwater quality in Hili, a semi-arid border region at Indo-Bangladesh border, was investigated in the post-monsoon season of 2021, succeeded by assessment of probabilistic health risk arising from fluoride (F-) and iron (Fe) intake, with the hypothesis that groundwater quality of the region was not satisfactory for human consumption and health, considering earlier reports on high groundwater F- and Fe in few of the neighboring districts. All water samples were found to be potable in terms of Ca2+, Mg2+, Cl-, SO42- and NO3-, , but F- and Fe exceeded prescribed safe limits for drinking water in about 48% and 7% samples. Almost all water samples were found to be good for irrigation in terms of sodium adsorption ratio (SAR), soluble sodium percentage (SSP), Kelly's index (KI), %Na and magnesium ratio (MR). The principal component analysis (PCA) identified three major factors influencing groundwater quality, explaining about 71.8% of total variance and indicated that groundwater quality was primarily influenced by geochemical factors. Carbonate and silicate weathering were mainly responsible for dissolution of minerals in groundwater. Non-carcinogenic risk due to cumulative impact of F-and Fe intake was in the order of THIChildren > THIInfant > THIAdult. As per Monte Carlo simulation run with 5000 trials to ascertain the order of probabilistic health risk, the most dominant governing factors behind non-carcinogenic risk caused by F-and Fe intake were their concentration (Ci) followed by ingestion rate (IR), and exposure duration (ED).
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Fluoruros , Agua Subterránea , Adulto , Niño , Lactante , Humanos , Hierro , Bangladesh , Sodio , AguaRESUMEN
BACKGROUND: The role of adjuvant therapy in resected periampullary adenocarcinomas is equivocal due to contrasting data and limited prospective trials. METHODS: The Multicentre Indian Pancreatic & Periampullary Adenocarcinoma Project (MIPPAP), included data from 8 institutions across India. Of the 1679 pancreatic resections, 736 patients with T3/T4 and/or Node positive adenocarcinomas (considered as high risk for recurrence) were included for analysis. Three (adjuvant): one (observation) matching, using T3/T4 T staging, nodal positivity and ampullary subtype was performed by using the nearest neighbour matching method. RESULTS: Of 736 patients eligible for inclusion, 621 patients were matched of which 458 patients received adjuvant therapy (AT) (predominantly gemcitabine-based) and 163 patients were observed (O). With a median follow-up of 42 months, there was a statistical difference in overall survival in favour of patients receiving AT as compared to those on observation [68.7 months vs. 61.1 months, Hazard ratio: 0.73 (95% CI: 0.54-0.97); p = 0.03]. Besides AT, presence of nodal involvement (median OS: 65.4 months vs not reached; p = 0.04) predicted for inferior OS. CONCLUSIONS: The results of the match-pair analysis suggest that adjuvant therapy improves overall survival in periampullary adenocarcinomas at high risk of recurrence with a greater benefit in T3/T4, node-positive and ampullary subtypes.
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PURPOSE OF REVIEW: Development and functions of hematopoietic stem cells (HSC) are regulated by multiple cellular components of the hematopoietic niche. Here we review the recent advances in studying the role of three such components -- osteoblasts, osteomacs, and megakaryocytes and how they interact with each other in the hematopoietic niche to regulate HSC. RECENT FINDINGS: Recent advances in transgenic mice models, scRNA-seq, transcriptome profile, proteomics, and live animal imaging have revealed the location of HSC within the bone and signaling molecules required for the maintenance of the niche. Interaction between megakaryocytes, osteoblasts and osteomacs enhances hematopoietic stem and progenitor cells (HSPC) function. Studies also revealed the niche as a dynamic entity that undergoes cellular and molecular changes in response to stress. Aging, which results in reduced HSC function, is associated with a decrease in endosteal niches and osteomacs as well as reduced HSC--megakaryocyte interactions. SUMMARY: Novel approaches to study the cellular components of the niche and their interactions to regulate HSC development and functions provided key insights about molecules involved in the maintenance of the hematopoietic system. Furthermore, these studies began to build a more comprehensive model of cellular interactions and dynamics in the hematopoietic niche.
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Hematopoyesis , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Nicho de Células Madre , Células de la Médula Ósea/citología , Células de la Médula Ósea/metabolismo , Comunicación Celular , Diferenciación Celular , Humanos , Osteoblastos/citología , Osteoblastos/metabolismoRESUMEN
Background: . Seminomatous germ cell tumour (SGCT) is a rare but curable malignancy of young adults. The literature on management and outcome of SGCT is scarce from India. We report the demography and treatment outcome of SGCT at our centre. Methods: . We did a retrospective analysis of patients with SGCT treated from March 2011 to December 2018. Patients were staged appropriately with imaging, and pre- and postoperative tumour markers. High inguinal orchiectomy was performed in all with a testicular primary and received subsequent stage-adjusted adjuvant treatment. Patients were monitored for metabolic syndrome during follow-up after completion of treatment. Results: . We treated 85 patients with a median age of 37 (range 20-68) years. The primary site of the tumour was the testis in 80 (94%) and mediastinum in 5 (6%) patients. Cryptorchidism was present in 20 (25%) patients and testicular violation was present in 11 (14%) patients. Stage of the disease was I in 61, II in 13 and III in 6 patients. Adjuvant treatment in stage I disease was single-agent carbo-platin (area under the curve ×7) in 38 (62%), surveillance in 20 (33%) and radiotherapy in 3 (5%) patients. Five patients in the surveillance group relapsed. The 7-year mean (SD) relapse-free survival and overall survival were 83.1% (8%) and 98.7% (1.3%), respectively. Thirty-one patients (n = 52, 60%) had features of metabolic syndrome. Conclusions: . SGCTs have a high cure rate. Long-term follow-up is essential for monitoring toxic effects. Early diagnosis, avoidance of testicular violation and multidisciplinary management are the key features for better long-term outcome in SGCT.
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Neoplasias de Células Germinales y Embrionarias , Neoplasias Testiculares , Adulto , Anciano , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Neoplasias de Células Germinales y Embrionarias/terapia , Pronóstico , Estudios Retrospectivos , Neoplasias Testiculares/terapia , Resultado del Tratamiento , Adulto JovenRESUMEN
In this paper the Covid-19 pandemic has been analysed from sustainability and climate change perspectives with the help of a recursive dynamic CGE model for India. The Covid-19 could have major long term impacts on GDP, household income, inequality, CO2 emissions, and carbon prices. Significant slowdown in labour intensive informal sectors such as construction and services, as well as in energy intensive and capital goods sectors, leads to adverse impacts on household income and inequality. Our analysis further suggests that climate policy consistent with the Paris Agreement target can complement the economic recovery process. Specifically, recycling of carbon tax revenues to investments could stimulate growth and employment, reduce inequality, and reduce carbon emissions, compared to a scenario without climate policy. Therefore, the need of the hour is to formulate and implement climate friendly recovery strategies.
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Hematopoietic stem (HSC) and progenitor (HPC) cells are regulated by interacting signals and cellular and noncellular elements of the hematopoietic niche. We previously showed that CD166 is a functional marker of murine and human HSC and of cellular components of the murine niche. Selection of murine CD166+ engrafting HSC enriched for marrow repopulating cells. Here, we demonstrate that CD166-CD166 homophilic interactions enhance generation of murine and human HPC in vitro and augment hematopoietic function of these cells. Interactions between cultured CD166+ Lineage- Sca-1+ c-Kit+ (LSK) cells and CD166+ osteoblasts (OBs) significantly enhanced the expansion of colony-forming units (CFUs). Interactions between CD166+ LSK cells and immobilized CD166 protein generated more CFU in short-term cultures than between these cells and bovine serum albumin (BSA) or in cultures initiated with CD166- LSK cells. Similar results were obtained when LSK cells from wildtype (WT) or CD166 knockout (KO) (CD166-/- ) mice were used with immobilized CD166. Human cord blood CD34+ cells expressing CD166 produced significantly higher numbers of CFUs following interaction with immobilized CD166 than their CD166- counterparts. These data demonstrate the positive effects of CD166 homophilic interactions involving CD166 on the surface of murine and human HPCs. Single-cell RNA-seq analysis of CD150+ CD48- (signaling lymphocyte activation molecule (SLAM)) LSK cells from WT and CD166-/- mice incubated with immobilized CD166 protein revealed that engagement of CD166 on these cells activates cytokine, growth factor and hormone signaling, epigenetic pathways, and other genes implicated in maintenance of stem cell pluripotency-related and mitochondria-related signaling pathways. These studies provide tangible evidence implicating CD166 engagement in the maintenance of stem/progenitor cell function. Stem Cells 2019;37:1319-1330.
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Antígenos CD/metabolismo , Moléculas de Adhesión Celular Neuronal/metabolismo , Ciclo Celular/fisiología , Proteínas Fetales/metabolismo , Hematopoyesis/fisiología , Células Madre Hematopoyéticas/metabolismo , Animales , Humanos , RatonesRESUMEN
Tamm-Horsfall protein (THP), also known as uromodulin, is a kidney-specific protein produced by cells of the thick ascending limb of the loop of Henle. Although predominantly secreted apically into the urine, where it becomes highly polymerized, THP is also released basolaterally, toward the interstitium and circulation, to inhibit tubular inflammatory signaling. Whether, through this latter route, THP can also regulate the function of renal interstitial mononuclear phagocytes (MPCs) remains unclear, however. Here, we show that THP is primarily in a monomeric form in human serum. Compared with wild-type mice, THP-/- mice had markedly fewer MPCs in the kidney. A nonpolymerizing, truncated form of THP stimulated the proliferation of human macrophage cells in culture and partially restored the number of kidney MPCs when administered to THP-/- mice. Furthermore, resident renal MPCs had impaired phagocytic activity in the absence of THP. After ischemia-reperfusion injury, THP-/- mice, compared with wild-type mice, exhibited aggravated injury and an impaired transition of renal macrophages toward an M2 healing phenotype. However, treatment of THP-/- mice with truncated THP after ischemia-reperfusion injury mitigated the worsening of AKI. Taken together, our data suggest that interstitial THP positively regulates mononuclear phagocyte number, plasticity, and phagocytic activity. In addition to the effect of THP on the epithelium and granulopoiesis, this new immunomodulatory role could explain the protection conferred by THP during AKI.
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Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/patología , Fagocitos/efectos de los fármacos , Fagocitos/fisiología , Uromodulina/genética , Uromodulina/metabolismo , Lesión Renal Aguda/etiología , Animales , Plasticidad de la Célula/genética , Proliferación Celular/efectos de los fármacos , Activación Enzimática , Humanos , Riñón/patología , Ratones , Fenotipo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Daño por Reperfusión/complicaciones , Uromodulina/química , Uromodulina/farmacología , Uromodulina/uso terapéuticoRESUMEN
BACKGROUND: Researchers are developing methods to automatically extract clinically relevant and useful patient characteristics from raw healthcare datasets. These characteristics, often capturing essential properties of patients with common medical conditions, are called computational phenotypes. Being generated by automated or semiautomated, data-driven methods, such potential phenotypes need to be validated as clinically meaningful (or not) before they are acceptable for use in decision making. OBJECTIVE: The objective of this study was to present Phenotype Instance Verification and Evaluation Tool (PIVET), a framework that uses co-occurrence analysis on an online corpus of publically available medical journal articles to build clinical relevance evidence sets for user-supplied phenotypes. PIVET adopts a conceptual framework similar to the pioneering prototype tool PheKnow-Cloud that was developed for the phenotype validation task. PIVET completely refactors each part of the PheKnow-Cloud pipeline to deliver vast improvements in speed without sacrificing the quality of the insights PheKnow-Cloud achieved. METHODS: PIVET leverages indexing in NoSQL databases to efficiently generate evidence sets. Specifically, PIVET uses a succinct representation of the phenotypes that corresponds to the index on the corpus database and an optimized co-occurrence algorithm inspired by the Aho-Corasick algorithm. We compare PIVET's phenotype representation with PheKnow-Cloud's by using PheKnow-Cloud's experimental setup. In PIVET's framework, we also introduce a statistical model trained on domain expert-verified phenotypes to automatically classify phenotypes as clinically relevant or not. Additionally, we show how the classification model can be used to examine user-supplied phenotypes in an online, rather than batch, manner. RESULTS: PIVET maintains the discriminative power of PheKnow-Cloud in terms of identifying clinically relevant phenotypes for the same corpus with which PheKnow-Cloud was originally developed, but PIVET's analysis is an order of magnitude faster than that of PheKnow-Cloud. Not only is PIVET much faster, it can be scaled to a larger corpus and still retain speed. We evaluated multiple classification models on top of the PIVET framework and found ridge regression to perform best, realizing an average F1 score of 0.91 when predicting clinically relevant phenotypes. CONCLUSIONS: Our study shows that PIVET improves on the most notable existing computational tool for phenotype validation in terms of speed and automation and is comparable in terms of accuracy.
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Almacenamiento y Recuperación de la Información/métodos , Internet/instrumentación , MEDLARS/normas , Algoritmos , Humanos , FenotipoRESUMEN
This paper describes the evolutionary split and merge for expectation maximization (ESM-EM) algorithm and eight of its variants, which are based on the use of split and merge operations to evolve Gaussian mixture models. Asymptotic time complexity analysis shows that the proposed algorithms are competitive with the state-of-the-art genetic-based expectation maximization (GA-EM) algorithm. Experiments performed in 35 data sets showed that ESM-EM can be computationally more efficient than the widely used multiple runs of EM (for different numbers of components and initializations). Moreover, a variant of ESM-EM free from critical parameters was shown to be able to provide competitive results with GA-EM, even when GA-EM parameters were fine-tuned a priori.
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Modelos Teóricos , Mutación , AlgoritmosRESUMEN
OBJECTIVE: Data in electronic health records (EHRs) is being increasingly leveraged for secondary uses, ranging from biomedical association studies to comparative effectiveness. To perform studies at scale and transfer knowledge from one institution to another in a meaningful way, we need to harmonize the phenotypes in such systems. Traditionally, this has been accomplished through expert specification of phenotypes via standardized terminologies, such as billing codes. However, this approach may be biased by the experience and expectations of the experts, as well as the vocabulary used to describe such patients. The goal of this work is to develop a data-driven strategy to (1) infer phenotypic topics within patient populations and (2) assess the degree to which such topics facilitate a mapping across populations in disparate healthcare systems. METHODS: We adapt a generative topic modeling strategy, based on latent Dirichlet allocation, to infer phenotypic topics. We utilize a variance analysis to assess the projection of a patient population from one healthcare system onto the topics learned from another system. The consistency of learned phenotypic topics was evaluated using (1) the similarity of topics, (2) the stability of a patient population across topics, and (3) the transferability of a topic across sites. We evaluated our approaches using four months of inpatient data from two geographically distinct healthcare systems: (1) Northwestern Memorial Hospital (NMH) and (2) Vanderbilt University Medical Center (VUMC). RESULTS: The method learned 25 phenotypic topics from each healthcare system. The average cosine similarity between matched topics across the two sites was 0.39, a remarkably high value given the very high dimensionality of the feature space. The average stability of VUMC and NMH patients across the topics of two sites was 0.988 and 0.812, respectively, as measured by the Pearson correlation coefficient. Also the VUMC and NMH topics have smaller variance of characterizing patient population of two sites than standard clinical terminologies (e.g., ICD9), suggesting they may be more reliably transferred across hospital systems. CONCLUSIONS: Phenotypic topics learned from EHR data can be more stable and transferable than billing codes for characterizing the general status of a patient population. This suggests that EHR-based research may be able to leverage such phenotypic topics as variables when pooling patient populations in predictive models.
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Registros Electrónicos de Salud/organización & administración , Almacenamiento y Recuperación de la Información/métodos , Aprendizaje Automático , Registro Médico Coordinado/métodos , Vocabulario Controlado , Registros Electrónicos de Salud/clasificación , Procesamiento de Lenguaje Natural , Fenotipo , Estados UnidosRESUMEN
This paper presents a modeling comparison on how stabilization of global climate change at about 2 °C above the pre-industrial level could affect economic and energy systems development in China and India. Seven General Equilibrium (CGE) and energy system models on either the global or national scale are soft-linked and harmonized with respect to population and economic assumptions. We simulate a climate regime, based on long-term convergence of per capita carbon dioxide (CO2) emissions, starting from the emission pledges presented in the Copenhagen Accord to the United Nations Framework Convention on Climate Change and allowing full emissions trading between countries. Under the climate regime, Indian emission allowances are allowed to grow more than the Chinese allowances, due to the per capita convergence rule and the higher population growth in India. Economic and energy implications not only differ among the two countries, but also across model types. Decreased energy intensity is the most important abatement approach in the CGE models, while decreased carbon intensity is most important in the energy system models. The reduction in carbon intensity is mostly achieved through deployment of carbon capture and storage, renewable energy sources and nuclear energy. The economic impacts are generally higher in China than in India, due to higher 2010-2050 cumulative abatement in China and the fact that India can offset more of its abatement cost though international emission trading.
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The Streptococcus pyogenes NAD(+) glycohydrolase (SPN) is secreted from the bacterial cell and translocated into the host cell cytosol where it contributes to cell death. Recent studies suggest that SPN is evolving and has diverged into NAD(+) glycohydrolase-inactive variants that correlate with tissue tropism. However, the role of SPN in both cytotoxicity and niche selection are unknown. To gain insight into the forces driving the adaptation of SPN, a detailed comparison of representative glycohydrolase activity-proficient and -deficient variants was conducted. Of a total 454 amino acids, the activity-deficient variants differed at only nine highly conserved positions. Exchanging residues between variants revealed that no one single residue could account for the inability of the deficient variants to cleave the glycosidic bond of ß-NAD(+) into nicotinamide and ADP-ribose; rather, reciprocal changes at 3 specific residues were required to both abolish activity of the proficient version and restore full activity to the deficient variant. Changing any combination of 1 or 2 residues resulted in intermediate activity. However, a change to any 1 residue resulted in a significant decrease in enzyme efficiency. A similar pattern involving multiple residues was observed for comparison with a second highly conserved activity-deficient variant class. Remarkably, despite differences in glycohydrolase activity, all versions of SPN were equally cytotoxic to cultured epithelial cells. These data indicate that the glycohydrolase activity of SPN may not be the only contribution the toxin has to the pathogenesis of S. pyogenes and that both versions of SPN play an important role during infection.
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Proteínas Bacterianas , Células Epiteliales/enzimología , NAD+ Nucleosidasa , Infecciones Estreptocócicas/enzimología , Streptococcus pyogenes/enzimología , Adenosina Difosfato/química , Adenosina Difosfato/genética , Adenosina Difosfato/metabolismo , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Línea Celular , Células Epiteliales/microbiología , Células Epiteliales/patología , Humanos , NAD/química , NAD/genética , NAD/metabolismo , NAD+ Nucleosidasa/química , NAD+ Nucleosidasa/genética , NAD+ Nucleosidasa/metabolismo , Especificidad de la Especie , Infecciones Estreptocócicas/genética , Infecciones Estreptocócicas/patología , Streptococcus pyogenes/genéticaRESUMEN
We show that loss of p85α inhibits the growth and maturation of mast cells, whereas loss of p85ß enhances this process. Whereas restoring the expression of p85α in P85α(-/-) cells restores these functions, overexpression of p85ß has the opposite effect. Consistently, overexpression of p85ß in WT mast cells represses KIT-induced proliferation and IL-3-mediated maturation by inhibiting the expression of Microphthalmia transcription factor. Because p85α and p85ß differ in their N-terminal sequences, chimeric proteins consisting of amino or carboxy-terminal of p85α and/or p85ß do not rescue the growth defects of p85α(-/-) cells, suggesting cooperation between these domains for normal mast cell function. Loss of p85ß impaired ligand induced KIT receptor internalization and its overexpression enhanced this process, partly because of increased binding of c-Cbl to p85ß relative to p85α. In vivo, loss of p85ß resulted in increased mast cells, and bone marrow transplantation of cells overexpressing p85ß resulted in significant reduction in some tissue mast cells. Overexpression of p85ß suppressed the growth of oncogenic KIT-expressing cells in vitro and prolonged the survival of leukemic mice in vivo. Thus, p85α and p85ß differentially regulate SCF and oncogenic KIT-induced signals in myeloid lineage-derived mast cells.
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Fosfatidilinositol 3-Quinasa Clase Ia/fisiología , Leucemia/etiología , Leucemia/patología , Mastocitos/patología , Animales , Western Blotting , Proliferación Celular , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Leucemia/metabolismo , Mastocitos/metabolismo , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación/genética , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/metabolismo , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Intracellular mechanism(s) that contribute to promiscuous signaling via oncogenic KIT in systemic mastocytosis and acute myelogenous leukemia are poorly understood. We show that SHP2 phosphatase is essential for oncogenic KIT-induced growth and survival in vitro and myeloproliferative disease (MPD) in vivo. Genetic disruption of SHP2 or treatment of oncogene-bearing cells with a novel SHP2 inhibitor alone or in combination with the PI3K inhibitor corrects MPD by disrupting a protein complex involving p85α, SHP2, and Gab2. Importantly, a single tyrosine at position 719 in oncogenic KIT is sufficient to develop MPD by recruiting p85α, SHP2, and Gab2 complex to oncogenic KIT. Our results demonstrate that SHP2 phosphatase is a druggable target that cooperates with lipid kinases in inducing MPD.
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Transformación Celular Neoplásica/patología , Proteína Adaptadora GRB2/fisiología , Mutación/genética , Trastornos Mieloproliferativos/etiología , Trastornos Mieloproliferativos/prevención & control , Proteína Tirosina Fosfatasa no Receptora Tipo 11/fisiología , Proteínas Proto-Oncogénicas c-kit/genética , Animales , Apoptosis , Western Blotting , Trasplante de Médula Ósea , Proliferación Celular , Transformación Celular Neoplásica/genética , Fosfatidilinositol 3-Quinasa Clase Ia/metabolismo , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Humanos , Inmunoprecipitación , Integrasas/metabolismo , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Trastornos Mieloproliferativos/mortalidad , Fosforilación/efectos de los fármacos , Proteína Tirosina Fosfatasa no Receptora Tipo 11/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-kit/metabolismo , Transducción de Señal/efectos de los fármacos , Tasa de Supervivencia , Tirosina/metabolismoRESUMEN
The rapidly increasing availability of electronic health records (EHRs) from multiple heterogeneous sources has spearheaded the adoption of data-driven approaches for improved clinical research, decision making, prognosis, and patient management. Unfortunately, EHR data do not always directly and reliably map to medical concepts that clinical researchers need or use. Some recent studies have focused on EHR-derived phenotyping, which aims at mapping the EHR data to specific medical concepts; however, most of these approaches require labor intensive supervision from experienced clinical professionals. Furthermore, existing approaches are often disease-centric and specialized to the idiosyncrasies of the information technology and/or business practices of a single healthcare organization. In this paper, we propose Limestone, a nonnegative tensor factorization method to derive phenotype candidates with virtually no human supervision. Limestone represents the data source interactions naturally using tensors (a generalization of matrices). In particular, we investigate the interaction of diagnoses and medications among patients. The resulting tensor factors are reported as phenotype candidates that automatically reveal patient clusters on specific diagnoses and medications. Using the proposed method, multiple phenotypes can be identified simultaneously from data. We demonstrate the capability of Limestone on a cohort of 31,815 patient records from the Geisinger Health System. The dataset spans 7years of longitudinal patient records and was initially constructed for a heart failure onset prediction study. Our experiments demonstrate the robustness, stability, and the conciseness of Limestone-derived phenotypes. Our results show that using only 40 phenotypes, we can outperform the original 640 features (169 diagnosis categories and 471 medication types) to achieve an area under the receiver operator characteristic curve (AUC) of 0.720 (95% CI 0.715 to 0.725). Moreover, in consultation with a medical expert, we confirmed 82% of the top 50 candidates automatically extracted by Limestone are clinically meaningful.
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Minería de Datos/métodos , Registros Electrónicos de Salud/clasificación , Algoritmos , Bases de Datos Factuales/clasificación , Humanos , FenotipoRESUMEN
BACKGROUND/OBJECTIVE: Maternal obesity is increasingly common and negatively impacts offspring health. Children of mothers with obesity are at higher risk of developing diseases linked to hematopoietic system abnormalitiesand metabolism such as type 2 diabetes. Interestingly, disease risks are often dependent on the offspring's sex, suggesting sex-specific reprogramming effect of maternal obesity on offspring hematopoietic stem and progenitor cell (HSPC) function. However, the impact of maternal obesity exposure on offspring HSPC function, and the capability of HSPC to regulate offspring metabolic health is largely understudied. This study aims to test the hypothesis that offspring of obese mice exhibit sex-differences in HSPC function that affect offspring's metabolic health. METHODS: We first assessed bone marrow hematopoietic stem and progenitor cell phenotype using postnatal day 21 (P21) and 8-week-old C57BL/6J mice born to control and diet-induced obese dams. We also sorted HSPC (Lineage-, Sca1+, cKit+ cells) from P21 mice for competitive primary and secondary transplant, as well as transcriptomic analysis. Body weight, adiposity, insulin tolerance test and glucose tolerance tests were performed in primary and secondary transplant recipient animals. RESULTS: We discovered sex-differences in offspring HSPC function in response to maternal obesity exposure, where male offspring of obese dams (MatOb) showed decreased HSPC numbers and engraftment, while female MatOb offspring remained largely unaffected. RNA-seq revealed immune stimulatory pathways in female MatOb offspring. Finally, only recipients of male MatOb offspring HSPC exhibited glucose intolerance. CONCLUSION: This study demonstrated the lasting effect of maternal obesity exposure on offspring HSPC function and implicates HSPC in metabolic regulation.
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Purvish M ParikhS-1 (5-fluorouracil prodrug [tegafur] in combination with 5-chloro-2,4-dihydroxypyridine [CDHP] and potassium oxonate [OXO]) was first approved in 1999. In order to make it easy for community oncologists, we decided to put together this expert consensus guideline for its use in gastrointestinal (GI) malignancies. A total of 15 subject matter experts used modified Delphi method to discuss, analyze, and vote on key aspects regarding practical approach to use of S-1 in GI cancers, a process involving 6 months of work. The consensus guidelines specify how S-1 use can be optimized in patients with colorectal, gastric, and pancreatic tumors. The voting for the 17 key points resulted in a majority consensus for all the statements (approval ranging from 13/15 [87%] to 15/15 [100%]). S-1 is a combination of three drugs (tegafur, CDHP, and OXO) specifically designed to reduce toxicity and enhance efficacy; clinical data and meta-analysis confirm both factors; and it is recommended as standard of care for GI cancers. S-1 is approved and one of the standards of care for all lines of therapy in colorectal cancer and pancreatic cancers. S-1 with oxaliplatin is the standard of care for gastric cancers.
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Maintenance of hematopoietic stem cell (HSC) function in the niche is an orchestrated event. Osteomacs (OM) are key cellular components of the niche. Previously, we documented that osteoblasts, OM, and megakaryocytes interact to promote hematopoiesis. Here, we further characterize OM and identify megakaryocyte-induced mediators that augment the role of OM in the niche. Single-cell mRNA-seq, mass spectrometry, and CyTOF examination of megakaryocyte-stimulated OM suggested that upregulation of CD166 and Embigin on OM augment their hematopoiesis maintenance function. CD166 knockout OM or shRNA-Embigin knockdown OM confirmed that the loss of these molecules significantly reduced the ability of OM to augment the osteoblast-mediated hematopoietic-enhancing activity. Recombinant CD166 and Embigin partially substituted for OM function, characterizing both proteins as critical mediators of OM hematopoietic function. Our data identify Embigin and CD166 as OM-regulated critical components of HSC function in the niche and potential participants in various in vitro manipulations of stem cells.
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Células Madre Hematopoyéticas , Megacariocitos , Animales , Ratones , Hematopoyesis/fisiología , Células Madre Hematopoyéticas/metabolismo , Megacariocitos/metabolismo , Osteoblastos/metabolismo , Nicho de Células Madre/fisiología , Regulación hacia Arriba , Molécula de Adhesión Celular del Leucocito Activado/metabolismoRESUMEN
Background: Leptomeningeal carcinomatosis (LMC), the metastatic spread of cancer to the leptomeninges, is a rare complication and has a dismal prognosis. Due to limited data available on LMC from India, we conducted a country-wise audit of LMC across 15 centres in India. Methods: The current study conducted in 2020, was a retrospective, multicentric audit of adult patients (aged ≥18 years) with diagnosis of LMC and who received treatment during 2010-2020. Baseline characteristics, details related to previous treatments, cancer sites, LMC diagnosis, treatment pattern and overall survival (OS) were collected. Descriptive statistics were performed, and Kaplan Meier analysis was performed for the estimation of OS. Findings: Among the patients diagnosed with LMC (n = 84), diagnosis was confirmed in 52 patients (61.9%) and 'probable' in 32 (38.1%) patients. The three most common cause of malignancy were non-small cell lung cancer (NSCLC), breast cancer and gastrointestinal cancer with 45 (53.6%), 22 (26.1%) and 9 (10.7%) patients respectively. Intrathecal therapy was offered in 33 patients (39.3%). The most common intrathecal agent was methotrexate in 23 patients (27.4%). The median OS was 90 days (95% CI 48-128). Among tested variables, intrathecal therapy administration (hazard ratio [HR] = 0.36, 95% CI 0.19-0.68) and primary in lung (HR = 0.43, 95% CI 0.23-0.83) had a favourable impact on OS. Interpretation: Prognosis with leptomeningeal carcinomatosis is poor with a significant burden of morbidity and mortality in India. This data aims to highlight the current outcomes and facilitate further research on LMC. Funding: None.