Hypoferremia is a common response to systemic infections or generalized inflammatory disorders. In mouse models, the development of hypoferremia during inflammation requires hepcidin, an iron ...regulatory peptide hormone produced in the liver, but the inflammatory signals that regulate hepcidin are largely unknown. Our studies in human liver cell cultures, mice, and human volunteers indicate that IL-6 is the necessary and sufficient cytokine for the induction of hepcidin during inflammation and that the IL-6-hepcidin axis is responsible for the hypoferremia of inflammation.
Vascular endothelial growth factor (VEGF) is a potent molecule that mediates tumor angiogenesis primarily through VEGF receptor 2 (VEGFR2). Bevacizumab, a recombinant humanized monoclonal antibody to ...VEGF, was administered to previously untreated patients to evaluate parameters of angiogenesis.
Twenty-one patients with inflammatory and locally advanced breast cancer were treated with bevacizumab for cycle 1 (15 mg/kg on day 1) followed by six cycles of bevacizumab with doxorubicin (50 mg/m(2)) and docetaxel (75 mg/m(2)) every 3 weeks. After locoregional therapy, patients received eight cycles of bevacizumab alone, and hormonal therapy when indicated. Tumor biopsies and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were obtained at baseline, and after cycles 1, 4, and 7.
A median decrease of 66.7% in phosphorylated VEGFR2 (Y951) in tumor cells (P = .004) and median increase of 128.9% in tumor apoptosis (P = .0008) were seen after bevacizumab alone. These changes persisted with the addition of chemotherapy. There were no significant changes in microvessel density or VEGF-A expression. On DCE-MRI, parameters reflecting reduced angiogenesis, a median decrease of 34.4% in the inflow transfer rate constant (P = .003), 15.0% in the backflow extravascular- extracellular rate constant (P = .0007) and 14.3% in extravascular-extracellular volume fraction (P = .002) were seen after bevacizumab alone.
Bevacizumab has inhibitory effects on VEGF receptor activation and vascular permeability, and induces apoptosis in tumor cells.
Purpose
This study aims to identify and analyse the main enablers of knowledge management (KM) in improving the logistics capabilities of Indian organisations and develop a model based on the ...contextual relationship among the identified enablers.
Design/methodology/approach
Initially, this study uses a systematic literature review and questionnaire-based survey approach to identify the enablers of KM; and later, total interpretive structural modelling (TISM) was used to evolve mutual relationships among the identified 11 enablers for developing a hierarchical model.
Findings
The results of the analysis show that enablers, namely, organisational structure and leadership, application of advanced information and communication system, collaboration with established stakeholders and organisational learning and innovative approaches are identified as main enablers for improving the logistics capabilities of Indian organisations.
Research limitations/implications
This study provides useful implications for the researchers working on exploring the role of KM enablers in improving the logistics capabilities of organisations.
Practical implications
This study provides rich practical implications for the manufacturers, supply chain managers, logistics service providers and logistics consultants involved in the decision-making process. They can focus majorly on knowledge creation and knowledge storage processes to improve the logistics performance of their respective organisations.
Originality/value
This study is an attempt to identify the enablers of KM that could improve the logistics capabilities of Indian organisations. The application of the TISM method to develop a theoretical framework is the novel contribution of this study.
The RUNX1 transcription factor has recently been shown to be obligatory for normal development. RUNX1 controls the expression of genes essential for proper development in many cell lineages and ...tissues including blood, bone, cartilage, hair follicles, and mammary glands. Compromised RUNX1 regulation is associated with many cancers. In this review, we highlight evidence for RUNX1 control in both invertebrate and mammalian development and recent novel findings of perturbed RUNX1 control in breast cancer that has implications for other solid tumors. As RUNX1 is essential for definitive hematopoiesis, RUNX1 mutations in hematopoietic lineage cells have been implicated in the etiology of several leukemias. Studies of solid tumors have revealed a context‐dependent function for RUNX1 either as an oncogene or a tumor suppressor. These RUNX1 functions have been reported for breast, prostate, lung, and skin cancers that are related to cancer subtypes and different stages of tumor development. Growing evidence suggests that RUNX1 suppresses aggressiveness in most breast cancer subtypes particularly in the early stage of tumorigenesis. Several studies have identified RUNX1 suppression of the breast cancer epithelial‐to‐mesenchymal transition. Most recently, RUNX1 repression of cancer stem cells and tumorsphere formation was reported for breast cancer. It is anticipated that these new discoveries of the context‐dependent diversity of RUNX1 functions will lead to innovative therapeutic strategies for the intervention of cancer and other abnormalities of normal tissues.
Growing evidence suggests that RUNX1 suppresses aggressiveness in most breast cancer subtypes and particularly in the early stage of tumorigenesis. In this review, we present the diverse regulatory roles of RUNX1 in the development of normal tissue and the consequences of RUNX1 dysregulation in cancer development.
We present Hubble Space Telescope(HST) images for nine megamaser disk galaxies with the primary goal of studying photometric BH-galaxy scaling relations. The megamaser disks provide the ...highest-precision extragalactic BH mass measurements, while our high-resolution HST imaging affords us the opportunity to decompose the complex nuclei of their late-type hosts in detail. Based on the morphologies and shapes of the galaxy nuclei, we argue that most of these galaxies' central regions contain secularly evolving components (pseudo-bulges), and in many cases we photometrically identify co-existing "classical" bulge components as well. Using these decompositions, we draw the following conclusions. (1) The megamaser BH masses span two orders of magnitude (10 super(6)-10 super(8)M sub(middot in circle)) while the stellar mass of their spiral host galaxies are all ~10 super(11)M sub(middo t in circle) within a factor of three. (2) The BH masses at a given bulge mass or total stellar mass in the megamaser host spiral galaxies tend to be lower than expected when compared to an extrapolation of the BH-bulge relation based on early-type galaxies. (3) The observed large intrinsic scatter of BH masses in the megamaser host galaxies raises the question of whether scaling relations exist in spiral galaxies.
In the United States, colorectal cancer (CRC) is the third most common cancer diagnosed among men and women and the second leading cause of death from cancer. CRC largely can be prevented by the ...detection and removal of adenomatous polyps, and survival is significantly better when CRC is diagnosed while still localized. In 2006 to 2007, the American Cancer Society, the US Multi Society Task Force on Colorectal Cancer, and the American College of Radiology came together to develop consensus guidelines for the detection of adenomatous polyps and CRC in asymptomatic average‐risk adults. In this update of each organization's guidelines, screening tests are grouped into those that primarily detect cancer early and those that can detect cancer early and also can detect adenomatous polyps, thus providing a greater potential for prevention through polypectomy. When possible, clinicians should make patients aware of the full range of screening options, but at a minimum they should be prepared to offer patients a choice between a screening test that is effective at both early cancer detection and cancer prevention through the detection and removal of polyps and a screening test that primarily is effective at early cancer detection. It is the strong opinion of these 3 organizations that colon cancer prevention should be the primary goal of screening.
There is a high demand for potent, selective, and brain-penetrant small molecule inhibitors of leucine-rich repeat kinase 2 (LRRK2) to test whether inhibition of LRRK2 kinase activity is a ...potentially viable treatment option for Parkinson's disease patients. Herein we disclose the use of property and structure-based drug design for the optimization of highly ligand efficient aminopyrimidine lead compounds. High throughput in vivo rodent cassette pharmacokinetic studies enabled rapid validation of in vitro-in vivo correlations. Guided by this data, optimal design parameters were established. Effective incorporation of these guidelines into our molecular design process resulted in the discovery of small molecule inhibitors such as GNE-7915 (18) and 19, which possess an ideal balance of LRRK2 cellular potency, broad kinase selectivity, metabolic stability, and brain penetration across multiple species. Advancement of GNE-7915 into rodent and higher species toxicity studies enabled risk assessment for early development.
With the spread of the deadly coronavirus disease throughout the geographies of the globe, expertise from every field has been sought to fight the impact of the virus. The use of Artificial ...Intelligence (AI), especially, has been the center of attention due to its capability to produce trustworthy results in a reasonable time. As a result, AI centric based research on coronavirus (or COVID-19) has been receiving growing attention from different domains ranging from medicine, virology, and psychiatry etc. We present this comprehensive study that closely monitors the impact of the pandemic on global research activities related exclusively to AI. In this article, we produce highly informative insights pertaining to publications, such as the best articles, research areas, most productive and influential journals, authors, and institutions. Studies are made on top 50 most cited articles to identify the most influential AI subcategories. We also study the outcome of research from different geographic areas while identifying the research collaborations that have had an impact. This study also compares the outcome of research from the different countries around the globe and produces insights on the same.
Mammalian nephrons arise from a limited nephron progenitor pool through a reiterative inductive process extending over days (mouse) or weeks (human) of kidney development. Here, we present evidence ...that human nephron patterning reflects a time-dependent process of recruitment of mesenchymal progenitors into an epithelial nephron precursor. Progressive recruitment predicted from high-resolution image analysis and three-dimensional reconstruction of human nephrogenesis was confirmed through direct visualization and cell fate analysis of mouse kidney organ cultures. Single-cell RNA sequencing of the human nephrogenic niche provided molecular insights into these early patterning processes and predicted developmental trajectories adopted by nephron progenitor cells in forming segment-specific domains of the human nephron. The temporal-recruitment model for nephron polarity and patterning suggested by direct analysis of human kidney development provides a framework for integrating signaling pathways driving mammalian nephrogenesis.
Display omitted
•Imaging shows gradual recruitment of progenitors into forming human/mouse nephrons•Single-cell RNA sequencing tracks cellular heterogeneity in human nephrogenesis•Divergent molecular trajectories generate distinct regions of the human nephron
During kidney development, mammalian nephrons arise from a limited progenitor pool through a reiterative inductive process. Lindström et al. demonstrate that human and mouse nephron patterning involves gradual mesenchymal progenitor cell recruitment into the epithelial nephron precursor. Recruitment timing predicts precursor cell position and eventual fate in functional nephron structures.
PDF
