Miracle-dz/UniFAR-FTUs huggingface dataset:
Chronic lymphocytic leukemia cells from ibrutinib treated patients are sensitive to Axl receptor tyrosine kinase inhibitor therapy

Earlier we have shown the expression of a constitutively active receptor tyrosine kinase Axl in CLL B-cells from previously untreated CLL patients, and that Axl inhibitor TP-0903 induces robust leukemic B-cell death. To explore whether Axl is an effective target in relapsed/refractory CLL patients, we analyzed CLL B-cells obtained from CLL patients on ibrutinib therapy. Ibrutinib-exposed CLL B-cells were treated with increasing doses (0.01- 0.50μM) of a new formulation of high-affinity Axl inhibitor, TP-0903 (tartrate salt), for 24 hours and LD50 doses were determined. Sensitivity of CLL B-cells was compared with known prognostic factors and effect of TP-0903 was also evaluated on Axl signaling pathway in CLL B-cells from this cohort. We detected sustained overexpression of Axl in CLL B-cells from CLL patients on ibrutinib treatment, suggests targeting Axl could be a promising strategy to overcome drug resistance and killing of CLL B-cells in these patients. We found that CLL B-cells from sixty-nine percent of relapsed CLL patients actively on ibrutinib therapy were found to be highly sensitive to TP-0903 with induction of apoptosis at nanomolar doses (≤0.50 μM). TP-0903 treatment effectively inhibited Axl phosphorylation and reduced expression levels of anti-apoptotic proteins (Mcl-1, XIAP) in ibrutinib exposed CLL B-cells. In total, our in vitro preclinical studies showing that TP-0903 is very effective at inducing apoptosis in CLL B-cells obtained from ibrutinib-exposed patients supports further testing of this drug in relapsed/refractory CLL.
The echoes of bandwagon through a complex system of innovation and development

In this paper we seek to contribute to the innovation literature analysing how preferences guided by bandwagon behaviour may affect innovation decisions. More specifically, the decision of a firm to choose between process and product innovation given the state of the market. Due to the degree of complexity involved in the matter, we choose to build an agent-based model where agents have bounded rationality and sequentially make non maximizing decisions based on the amount of information they have about the market. The rationality degree can be exogenously adjusted setting the awareness capability of consumers. As a core of bandwagon behaviour, each consumer is affected by the decision of others and the resulting cascade effect yields different impacts on the economy depending on the inclination of each agent towards new products. There are in total five types of consumers: techies, visionaries, pragmatists, conservatives and skeptics, in decreasing order of bandwagon behaviour degree. We find that the greater the number of techies, or the rationality degree of agents, the shorter are the product life cycles in the market, generating a faster market saturation and thus more product than process innovations, with firms charging higher prices and obtaining larger profit-rates.
Anti-claudin-4 extracellular domain antibody enhances the antitumoral effects of chemotherapeutic and antibody drugs in colorectal cancer

Claudin-4 (CLDN4) is a major epithelial tight junction protein overexpressed in many cancers to maintain the tumor environment. In this report, we aimed to determine the efficacy of targeting CLDN4 in colorectal cancer (CRC) using an anti-CLDN4 extracellular domain antibody, 4D3. CLDN4 was upregulated in CRC metastatic foci. CLDN4 expression in CRC cells was reduced by upregulation of TNFα, which was induced by Clostridium perfringens enterotoxin produced by gut flora. In a nude mouse liver metastasis model, inhibition of metastasis was increased by combination treatment with 5-fluorouracil (FU) and 4D3 compared to that with 5-FU alone. Moreover, combination treatment with 4D3 and anti-epithelial growth factor receptor (EGFR) antibody C225 resulted in more pronounced inhibition of in vitro sphere formation and tumor growth in nude mice compared to that observed with C225 alone. Moreover, the time interval between the administration of 4D3 and that of C225 was important for maximizing the C225-induced inhibition of EGFR phosphorylation. In a nude mouse model, sequential treatment with 4D3 and C225 with a 6-h time interval resulted in more pronounced inhibition of tumor growth than concurrent treatment. These findings suggest that the targeting of CLDN4 enhances the antitumoral effects of chemotherapeutic agents and molecular targeting antibodies when used in combination.
Individual tree crown delineation and tree species classification with hyperspectral and LiDAR data

An international data science challenge, called National Ecological Observatory Network—National Institute of Standards and Technology data science evaluation, was set up in autumn 2017 with the goal to improve the use of remote sensing data in ecological applications. The competition was divided into three tasks: (1) individual tree crown (ITC) delineation, for identifying the location and size of individual trees; (2) alignment between field surveyed trees and ITCs delineated on remote sensing data; and (3) tree species classification. In this paper, the methods and results of team Fondazione Edmund Mach (FEM) are presented. The ITC delineation (Task 1 of the challenge) was done using a region growing method applied to a near-infrared band of the hyperspectral images. The optimization of the parameters of the delineation algorithm was done in a supervised way on the basis of the Jaccard score using the training set provided by the organizers. The alignment (Task 2) between the delineated ITCs and the field surveyed trees was done using the Euclidean distance among the position, the height, and the crown radius of the ITCs and the field surveyed trees. The classification (Task 3) was performed using a support vector machine classifier applied to a selection of the hyperspectral bands and the canopy height model. The selection of the bands was done using the sequential forward floating selection method and the Jeffries Matusita distance. The results of the three tasks were very promising: team FEM ranked first in the data science competition in Task 1 and 2, and second in Task 3. The Jaccard score of the delineated crowns was 0.3402, and the results showed that the proposed approach delineated both small and large crowns. The alignment was correctly done for all the test samples. The classification results were good (overall accuracy of 88.1%, kappa accuracy of 75.7%, and mean class accuracy of 61.5%), although the accuracy was biased toward the most represented species.
Budesonide for the Induction and Maintenance of Remission in Crohn’s Disease: Systematic Review and Meta-Analysis for the Cochrane Collaboration

Abstract Background Budesonide is an oral glucocorticoid designed for the treatment of inflammatory bowel disease (IBD) that may reduce systemic adverse events (AEs). This review examined the efficacy and safety of budesonide for the induction and maintenance of clinical remission in Crohn’s disease (CD). Methods MEDLINE, EMBASE, other electronic databases, reference lists and conference proceedings were searched to November 2017 to identify randomized controlled trials of budesonide. Outcomes were the induction and maintenance of remission at eight weeks and one year, respectively, as well as corticosteroid-related AEs and abnormal adrenocorticotropic hormone (ACTH) tests. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were estimated using random effects models. Results Thirteen induction and 10 maintenance trials were included. Budesonide 9 mg/day was more effective than placebo (RR 1.93; 95% CI, 1.37–2.73; GRADE: moderate) but less effective than conventional steroids (RR 0.85; 95% CI, 0.75–0.97; GRADE: moderate) to induce remission. Corticosteroid-related AEs occurred less often with induction doses of budesonide than steroids (RR 0.64; 95% CI, 0.54–0.76; GRADE: moderate); budesonide did not increase AEs relative to placebo (RR 0.97; 95% CI, 0.76–1.23; GRADE: moderate). Budesonide 6 mg/day was not different from placebo for maintaining remission (RR 1.13; 95% CI, 0.94–1.35; GRADE: moderate). Both induction (GRADE: low for 3 mg/day, moderate for 9 mg/day) and maintenance budesonide treatment (GRADE: very low for 3 mg/day, low for 6 mg/day) increased the risk of an abnormal ACTH test compared with placebo, but less than conventional steroids (GRADE: very low for both induction and maintenance). Conclusion For induction of clinical remission, budesonide was more effective than placebo, but less effective than conventional steroids. Budesonide was not effective for the maintenance of remission. Budesonide was safer than conventional steroids, but the long-term effects on the adrenal axis and bone health remain unknown.
Investigation into the underlying molecular mechanisms of white adipose tissue through comparative transcriptome analysis of multiple tissues

Adipose tissue has a primary role in lipid and glucose metabolism as a storage site for fatty acids, and also functions as an endocrine organ, producing large numbers of hormones and cytokines. Adipose dysfunction triggers a number of obesity-associated health problems. The aim of the present study was, therefore, to investigate the molecular mechanisms of white adipose tissue (WAT). The GSE9954 microarray data were downloaded from the Gene Expression Omnibus. Adipose-specific genes were identified through limma package analysis, based on samples of WAT and 17 other types of non-adipose tissue obtained from mice. Process and pathway enrichment analyses were performed for these genes. Finally, protein-protein interaction (PPI) and co-expression networks were constructed and analyzed. In total, 202 adipose-specific genes were identified, which were involved in key biological processes (including fat cell differentiation and lipid metabolic process) and one key pathway [namely, the adenine monophosphate-activated protein kinase (AMPK) signaling pathway]. Construction of the PPI network and further molecular complex detection revealed the presence of 17 key genes, including acetyl-CoA carboxylase α, peroxisome proliferator-activated receptor (PPAR) γ and leptin, that were involved in the AMPK, PPAR and insulin signaling pathways. In addition, amine oxidase copper containing 3 and adrenoceptor beta 3 were communication hubs in the co-expression network of adipose-specific genes. In conclusion, the present study promotes our understanding of the underlying molecular mechanisms of WAT, and may offer an insight into the prevention and treatment of obesity-associated diseases caused by adipose dysfunction.
Five-year Audit of Infectious Diseases at a Tertiary Care Hospital in Karachi, Pakistan

Purpose To estimate the burden of infectious diseases and the seasonality of mosquito-borne diseases seen at The Indus Hospital, Karachi (TIH). Methodology We performed a retrospective data analysis of all infectious diseases (ID) cases, retrieved from medical records over a five-year period starting from 1 January 2012 till 31 December 2016 at The Indus Hospital (TIH), which is a 150-bed, charity-based, tertiary-care health facility. The collected data has been categorized into three groups: (A) public health-related diseases, including community and environmental IDs, i.e., mosquito-borne diseases such as malaria and dengue, respiratory tract infections, diarrheal diseases, typhoid, and hepatitis; (B) systemic infection related IDs that target individual anatomical or physiological systems such as the respiratory tract, urinary tract, skin and soft tissue, and the cardiac system, and lastly, those IDs which are (C) programmatically managed at TIH, namely cases from the tuberculosis (TB), human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), and malaria clinics, and the rabies prevention center. As the study is an audit, ethical approval was waived by the institutional review board (IRB). Result Overall data from 71,815 patients were assessed. In the public health group (A), the main bulk of diseases were due to malaria, tuberculosis, respiratory tract infections (upper and lower), and diarrheal diseases in both males and females in descending order; there was preponderance of malaria, respiratory tract infections, and diarrheal diseases in males, and of tuberculosis among females. Among the systemic diseases group (B), urinary tract infections (UTIs) had a disproportionately high incidence, followed by skin and soft tissue infections, while bone and joint infections and diabetic foot had equal incidence. In the programmatic group (C), the highest number of cases seen was dog bites followed by drug-sensitive TB. Overall, the six most common infections were malaria, cases of dog bites, tuberculosis, respiratory tract infections, diarrheal diseases, and hepatitis C. More women than men had TB; diarrheal disease and respiratory tract infections were more common in children. UTIs were the most common systemic infections among both men and women. Conclusion There is a great need to have an effective surveillance mechanism of preventable diseases at the national level. Our study highlights the diversity of cases that should direct medical curriculum development, post-graduate training, and health services improvement.
MEK-inhibitor PD184352 enhances the radiosensitizing effect of the Hsp90 inhibitor NVP-AUY922: the role of cell type and drug-irradiation schedule

Targeting MEK protein in cancer cells usually leads to acquired resistance to MEK inhibitors and activation of the prosurvival protein Akt. Since both MEK and Akt are clients of the Hsp90 chaperone system, the present study explores the responses of irradiated lung carcinoma A549 and glioblastoma SNB19 cell lines to combined MEK and Hsp90 inhibition. Unexpectedly, the MEK inhibitor PD184352 administered 24 h prior to irradiation, enhanced cell survival through upregulation of not only MEK and Erk1/2 but also of Akt. In contrast, PD184352 added 1 h before irradiation strongly reduced the expression of Erk and did not upregulate Akt in both cell lines. As a result, the MEK inhibitor increased the radiosensitizing effect of the Hsp90 inhibitor NVP-AUY922 in glioblastoma SNB19 cells. Possible reasons for the enhanced cell killing under this short-term pretreatment schedule may be a down-regulation of Erk during or directly after irradiation, increased DNA damage and/or a strong G2/M arrest 24 h after irradiation. In addition, an 1-h pretreatment with PD184352 and/or NVP-AUY922 under schedule II induced neither G1 arrest nor up-regulation of p-Akt in both cell lines as it did under schedule I. Yet, a long-term treatment with the MEK inhibitor alone caused a strong cytostatical effect. We conclude that the duration of drug pretreatment before irradiation plays a key role in the targeting of MEK in tumor cells. However, due to an aberrant activation of prosurvival proteins, the therapeutic window needs to be carefully defined, or a combination of inhibitors should be considered.
OCcupational Health Surveillance

Missing the Diagnosis Physicians do not consider occupation or environment as cause of sickness during the process of differential diagnosis. Lack of curiosity about what people are doing and spending half of their waking hours means that possible subtle influences of work on health are commonly missed by doctors, and the perception that work‐related ill health is rare is thus reinforced. High degree of informed suspicion is the principal tool for correct diagnosis of occupational disease.
Effects of Renal Denervation via Renal Artery Adventitial Cryoablation on Atrial Fibrillation and Cardiac Neural Remodeling

Introduction Catheter-based renal denervation (RDN) could reduce cardiac sympathetic nerve activity (SNA) and inhibit atrial fibrillation (AF). However, the reliability is uncertain, because the renal sympathetic nerves are mainly distributed in the adventitial surface of the renal artery. Objective The aims of this study were to test the hypothesis that renal artery adventitial ablation (RAAA) definitely had the effects of RDN and to study the effects of RDN via renal artery adventitial cryoablation (RAAC) on AF and cardiac neural remodeling. Methods Twenty beagle canines were randomly assigned to two groups: the left RDN group (LRDN, n=10), which underwent left RDN via RAAC; the Sham group (n=10). After 2 months of postoperative recovery, AF vulnerability, AF duration, and histological examination were performed in both groups. Results Compared with the Sham group, left stellate ganglion (LSG) tissue fibrosis was increased in the LRDN group. LRDN significantly increased the percentage of TH-negative ganglionic cells and decreased the density of TH-positive nerves in the LSG (P < 0.001). Also, the densities of TH-positive nerves and GAP43 immunoreactivity within the left atrium (LA) were significantly decreased in the LRDN group (P < 0.05). After LA burst pacing, all 10 canines (100%) could be induced AF in the Sham group, but only 4 of 10 canines (40%) could be induced AF in the LRDN group (P=0.011). The percentage of LA burst stimulation with induced AF was 26.7% (8/30) in the LRDN group, which was significantly decreased compared with that of the Sham group (53.3%, 16/30) (P=0.035). In addition, AF duration was also significantly decreased in the LRDN group (13.3 ± 5.1 s) compared with that of the Sham group (20.3 ± 7.3 s, P=0.024). Conclusions RDN via RAAC could cause cardiac neural remodeling and effectively inhibit AF inducibility and shorten AF duration. It may be useful in selecting therapeutic approaches for AF patients.
A new method to determine anastomosis angle configuration for arteriovenous fistula maturation

Background: The kidneys of patients with chronic kidney disease (CKD) do not function well enough and those in end-stage renal disease (ESRD) of CKD need hemodialysis (HD) as a common renal replacement therapy (RRT) procedure. HD requires a vascular access (VA), and arteriovenous fistula (AVF) is the common VA choice in the world due to its very few complications. Despite the widespread use of AVFs, some risk factors maximize AVF failure, which is accompanied by complications of the patient such as repeating VA surgeries and hospitalization. Therefore, finding effective factors in the success of surgery is highly important and, thus, this study aimed at measuring the effect of anastomosis angle on the success of AVF surgery. Methods: This study evaluated the effect of conducted angle in an AVF anastomosis on AVF maturation. The images of 48 created AVFs for CKD patients was provided over a one-year period (from May 2016 to April 2017). Cross-tab analysis was used, and significance level was considered meaningful at p-value≤0.001. A centralized database was designed to integrate data. A method for image processing was developed and geometrical characteristics of the vessels (such as anastomosis angle) and also the diameter of artery and vein were measured via AutoCAD 2017 software and exported to the database along with other data. Results: The rate of the AVF failure in the studied patients was 8.96%. The anastomosis angle ≤ 30° is preferable from the AVF status point of view because most AVF maturation (or least AVF failure) rates are detected at this range. Conclusion: This study was performed based on a new approach without the need to measure hemodynamic parameters. Moreover, it signified the important role of anastomosis angle in the function of AVF, showing that the anastomosis angle ≤ 30° is a preferable intraoperative recommendation for AVF surgery.
Bipolar switching by HCN voltage sensor underlies hyperpolarization activation

Significance Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels show an inverted voltage response compared with virtually all other voltage-gated channels, opening on hyperpolarization rather than depolarization. Although the structure of the HCN1 channel was recently solved, the structural element(s) responsible for the inverted gating polarity of HCN is not known. Here, we use a hierarchical approach, by first characterizing the functional contribution of each structural element to channel gating, and then identifying the critical interactions between these elements. Our studies reveal that the HCN voltage sensor can gate the same pore open on both depolarization and hyperpolarization, thereby acting as a bipolar switch. Elements in the pore domain shut off the depolarization-activation pathway in wild-type channels. Despite sharing a common architecture with archetypal voltage-gated ion channels (VGICs), hyperpolarization- and cAMP-activated ion (HCN) channels open upon hyperpolarization rather than depolarization. The basic motions of the voltage sensor and pore gates are conserved, implying that these domains are inversely coupled in HCN channels. Using structure-guided protein engineering, we systematically assembled an array of mosaic channels that display the full complement of voltage-activation phenotypes observed in the VGIC superfamily. Our studies reveal that the voltage sensor of the HCN channel has an intrinsic ability to drive pore opening in either direction and that the extra length of the HCN S4 is not the primary determinant for hyperpolarization activation. Tight interactions at the HCN voltage sensor–pore interface drive the channel into an hERG-like inactivated state, thereby obscuring its opening upon depolarization. This structural element in synergy with the HCN cyclic nucleotide-binding domain and specific interactions near the pore gate biases the channel toward hyperpolarization-dependent opening. Our findings reveal an unexpected common principle underpinning voltage gating in the VGIC superfamily and identify the essential determinants of gating polarity.
Whole-Genome Sequence of the Endophytic Streptomyces sp. Strain CBMAI 2042, Isolated from Citrus sinensis

The whole-genome sequence of Streptomyces sp. strain CBMAI 2042, an endophytic actinobacterium isolated from Citrus sinensis branches, is described. ABSTRACT The whole-genome sequence of Streptomyces sp. strain CBMAI 2042, an endophytic actinobacterium isolated from Citrus sinensis branches, is described. The strain has the ability to inhibit the growth of Xylella fastidiosa and other human pathogens. In silico analysis highlighted the presence of nonribosomal peptide and polyketide synthases, revealing promising antibiotic assembly lines.