The role of perlecan and endorepellin in the control of tumor angiogenesis and endothelial cell autophagy.

During tumor growth and angiogenesis there is a dynamic remodeling of tissue architecture often accompanied by the release of extracellular matrix constituents full of biological activity. One of the key constituents of the tumor microenvironment is the large heparan sulfate proteoglycan perlecan. This proteoglycan, strategically located at cell surfaces and within basement membranes, is a well-defined pro-angiogenic molecule when intact. However, when partially processed by proteases released during cancer remodeling and invasion, the C-terminal fragment of perlecan, known as endorepellin, has opposite effects than its parent molecule. Endorepellin is a potent inhibitor of angiogenesis by exerting a dual receptor antagonism by simultaneously engaging VEGFR2 and α2β1 integrin. Signaling through the α2β1 integrin leads to actin disassembly and block of endothelial cell migration, necessary for capillary morphogenesis. Signaling through the VEGFR2 induces dephosphorylation of the receptor via activation of SHP-1 and suppression of downstream proangiogenic effectors, especially attenuating VEGFA expression. A novel and emerging role of endorepellin is its ability to evoke autophagy by activating Peg3 and various canonical autophagic markers. This effect is specific for endothelial cells as these are the primary cells expressing both VEGFR2 and α2β1 integrin. Thus, an endogenous fragment of a ubiquitous proteoglycan can regulate both angiogenesis and autophagy through a dual receptor antagonism. The biological properties of this natural endogenous protein place endorepellin as a potential therapeutic agent against cancer or diseases where angiogenesis is prominent

Linear cyclodextrin polymer prodrugs as novel yherapeutics for Niemann-Pick type C1 disorder

Niemann-Pick Type C1 disorder (NPC) is a rare lysosomal storage disease characterized by the accumulation of cholesterol in lysosomes. NPC has no FDA approved treatments yet, however 2-hydroxypropyl-β-cyclodextrin (HPβCD) has shown efficacy for treating the disease in both mouse and feline NPC models and is currently being investigated in late stage clinical trials. Despite promising results, therapeutic use of HPβCD is limited by the need for high doses, ototoxicity and intrathecal administration. These limitations can be attributed to its poor pharmacokinetic profile. In the attempt to overcome these limitations, we have designed a β-cyclodextrin (βCD) based polymer prodrugs (ORX-301) for an enhanced pharmacokinetic and biodistribution profile, which in turn can potentially provide an improved efficacy at lower doses. We demonstrated that subcutaneously injected ORX-301 extended the mean lifespan of NPC mice at a dosage 5-fold lower (800 mg/kg, body weight) the HPβCD dose proven efficacious (4000 mg/kg). We also show that ORX-301 penetrates the blood brain barrier and counteracts neurological impairment. These properties represent a substantial improvement and appear to overcome major limitations of presently available βCD-based therapy, demonstrating that this novel prodrug is a valuable alternative/complement for existing therapies

Brittle Asthma -What next in management?

The term ‘brittle asthma’ was first used by Turner-Warwick (1977) to describe patients with asthma whose peak expiratory flow (PEF) varied ‘chaotically’ (follow no set pattern); which could lead to death from an a cute severe attack. Morbidity from brittle asthma is considerable, and we aim to identify causes and management strategies for such patients. Two types of Brittle asthma has been suggested; a feature of both types being a susceptibility to repeated severe attacks resulting in hospitalization & considerable morbidity and mortality. Data from asthma register (UK), suggests that the prevalence is the order of 0.05% of all asthmatics

WTASR: Wavelet Transformer for Automatic Speech Recognition of Indian Languages

Automatic speech recognition systems are developed for translating the speech signals into the corresponding text representation. This translation is used in a variety of applications like voice enabled commands, assistive devices and bots, etc. There is a significant lack of efficient technology for Indian languages. In this paper, an wavelet transformer for automatic speech recognition (WTASR) of Indian language is proposed. The speech signals suffer from the problem of high and low frequency over different times due to variation in speech of the speaker. Thus, wavelets enable the network to analyze the signal in multiscale. The wavelet decomposition of the signal is fed in the network for generating the text. The transformer network comprises an encoder decoder system for speech translation. The model is trained on Indian language dataset for translation of speech into corresponding text. The proposed method is compared with other state of the art methods. The results show that the proposed WTASR has a low word error rate and can be used for effective speech recognition for Indian language

EphA2 is a functional receptor for the growth factor progranulin.

Although the growth factor progranulin was discovered more than two decades ago, the functional receptor remains elusive. Here, we discovered that EphA2, a member of the large family of Ephrin receptor tyrosine kinases, is a functional signaling receptor for progranulin. Recombinant progranulin bound with high affinity to EphA2 in both solid phase and solution. Interaction of progranulin with EphA2 caused prolonged activation of the receptor, downstream stimulation of mitogen-activated protein kinase and Akt, and promotion of capillary morphogenesis. Furthermore, we found an autoregulatory mechanism of progranulin whereby a feed-forward loop occurred in an EphA2-dependent manner that was independent of the endocytic receptor sortilin. The discovery of a functional signaling receptor for progranulin offers a new avenue for understanding the underlying mode of action of progranulin in cancer progression, tumor angiogenesis, and perhaps neurodegenerative diseases

Gas Under Right Hemidiaphragm: A Rare Presentation of Unruptured Liver Abscess

A perforated liver abscess mimics hollow viscus perforations. It may be accompanied by pneumoperitoneum and peritonitis. A hollow viscus perforation appears to be the most common cause of gas under diaphragm. In about 10% of the cases, it can be due to rare abdominal and extra-abdominal causes. One of the causes could be intra-abdominal infection caused by gas-forming organisms. We are reporting a rare case of pneumoperitoneum resulting from an unruptured liver abscess in an old male with no comorbidity. An unruptured pyogenic right lobe liver abscess in a 70-year-old male was accompanied by X-ray flat plate abdomen features suggestive of free gas under the right hemidiaphragm. Culture of the pus drained from liver abscess grew Klebsiella sensitive to piperacillin and tazobactam, and antibiotic treatment was administered

Performance Evaluation of Chaos Based IDMA Scheme Using Joint Turbo Equalization Over Frequency Selective Fading Channel

This paper proposed the analysis of a new chaos based interleave division multiple access (CB-IDMA) wireless communication system. It also proposed the use of joint turbo equalization to mitigate the effect of intersymbol interference (ISI) in deep faded frequency selective channel. In this study, the proposed CB-IDMA system used the chaotic Tent map for the design of a robust interleaver, which produces low correlation among the users and yields better bit error rate performance. The proposed structure combined the joint turbo equalization for the cancellation of ISI and multiple access interference (MAI), which was observed as the main impediment to successful IDMA communication over frequency selective multipath fading channel. Two types of frequency domain equalizers were considered for performance evaluation; zero forcing (ZF) and minimum mean square error (MMSE) equalizer. Simulation experiments were performed in MATLAB and the results demonstrated that the proposed CB-IDMA system with joint turbo equalization may be preferred in deep fading environment

Electrographic Flow Mapping Provides Prognosis for AF Ablation Outcomes Across Two Independent Prospective Patient Cohorts

Background/Objectives: Electrographic flow (EGF) mapping allows for the visualization and quantification of atrial fibrillation (AF) wavefront propagation patterns. EGF-identified sources were shown in the randomized controlled FLOW-AF trial to significantly increase the likelihood of AF recurrence within 1 year if left unablated. Electrographic flow consistency (EGFC) additionally measures the stability of observed wavefront patterns, such that patients with more organization have a healthier substrate and lower recurrence. Source presence and EGFC can be used collectively to assign mechanistic phenotypes to AF patients. Methods: The patient phenotypes, treatment modalities, and outcomes in FLOW-AF were compared with those of patients in the ensuing AF-FLOW Global Registry, which was conducted by separate physicians at discrete clinical centers. Results: Patients with low EGFC (≤0.62) had a 12-month freedom from AF (FFAF) of 46%, while those with a high mean EGFC (>0.62) had a FFAF of 81%. Right atrial EGFC was correlated with left atrial EGFC, and the highest recurrence occurred in those with biatrial low EGFC. Source presence also affected the recurrence rates in both trials, such that the presence of EGF-identified sources in PVI-only patients lowered the FFAF from 65% to 36%, but the elimination of sources produced a 30% absolute increase in FFAF from 36% to 66%. Conclusions: Patient outcomes by EGF-based AF phenotype were consistent across two cohorts of patients from separate clinical trials at distinct centers. Patients with a high EGFC and no sources post-procedure had the best outcomes. EGF mapping provides insights into underlying disease pathophysiology and may be employed prospectively to predict recurrence

AF-FLOW Global Registry Confirms Validity of Electrographic Flow Mapping as a Phenotyping Tool for Atrial Fibrillation

Background: Electrographic flow (EGF) mapping allows for the visualization of global atrial wavefront propagations. One mechanism of initiation and maintenance of atrial fibrillation (AF) is stimulation from EGF-identified focal sources that serve as driver sites of fibrillatory conduction. Electrographic flow consistency (EGFC) further quantifies the concordance of observed wavefront patterns, indicating that a healthier substrate shows more organized wavefront propagation and higher EGFC. Freedom from AF (FFAF) recurrence has accordingly been shown to be higher in patients with ablated vs. unablated sources and with high vs. low EGFC. Objectives: (1) Measure FFAF across EGF-derived phenotypes in patients enrolled in the AF-FLOW Global Registry; (2) determine if a relationship exists between EGFC and percentage of healthy voltage as measured from bipolar voltage maps. Methods: The AF-FLOW Global Registry is a multicenter, prospective study of 25 all-comer AF patients who underwent concomitant high-density bipolar voltage mapping with a 16-electrode grid mapping catheter and EGF mapping with a 64-pole basket catheter. The EGF algorithm detects extra-pulmonary vein sources as origins of excitation from a singularity of divergent flow vectors and was used to localize RF ablation targets. Overall, EGFC per atrium was also computed as the average of the modulus of individual EGF vectors, where the vector length represents the consistency of flow patterns. Patients were then assigned phenotypes on the basis of source presence or absence and EGFC, and rates of FFAF at 1-year were compared across the four resulting phenotypes. Atrial EGFC was also compared to the percentage of healthy tissue determined by bipolar voltage mapping. Results: Patients with paroxysmal AF had higher FFAF than persistent AF (PeAF) and long-standing PeAF patients; patients receiving de novo ablation had higher FFAF than those receiving redo ablation. Patient phenotyping revealed that those with high EGFC had higher FFAF than those with low EGFC (p = 0.015). Atrial EGFC was also correlated to the percent of high voltage tissue across all patients (r = 0.651, p &lt; 0.0001). Conclusions: EGF mapping provides insights into the mechanistic nature of AF and the atrial health of the underlying substrate. Therefore, further studies are needed to develop phenotype-specific treatments for the disease. </p