Melanoma induction by ultraviolet A but not ultraviolet B radiation requires melanin pigment

Malignant melanoma of the skin (CMM) is associated with ultraviolet radiation exposure, but the mechanisms and even the wavelengths responsible are unclear. Here we use a mammalian model to investigate melanoma formed in response to precise spectrally defined ultraviolet wavelengths and biologically relevant doses. We show that melanoma induction by ultraviolet A (320–400 nm) requires the presence of melanin pigment and is associated with oxidative DNA damage within melanocytes. In contrast, ultraviolet B radiation (280–320 nm) initiates melanoma in a pigment-independent manner associated with direct ultraviolet B DNA damage. Thus, we identified two ultraviolet wavelength-dependent pathways for the induction of CMM and describe an unexpected and significant role for melanin within the melanocyte in melanomagenesis

A prospective study of mental health status in morbidly obese patients.

Aim: To determine if co-morbidities have an effect on mood in a cohort of morbidly obese patients

Carcinomas assemble a filamentous CXCL12-keratin-19 coating that suppresses T cell-mediated immune attack.

Cancer immunotherapy frequently fails because most carcinomas have few T cells, suggesting that cancers can suppress T cell infiltration. Here, we show that cancer cells of human pancreatic ductal adenocarcinoma (PDA), colorectal cancer, and breast cancer are coated with transglutaminase-2 (TGM2)-dependent covalent CXCL12-keratin-19 (KRT19) heterodimers that are organized as filamentous networks. Since a dimeric form of CXCL12 suppresses the motility of human T cells, we determined whether this polymeric CXCL12-KRT19 coating mediated T cell exclusion. Mouse tumors containing control PDA cells exhibited the CXCL12-KRT19 coating, excluded T cells, and did not respond to treatment with anti-PD-1 antibody. Tumors containing PDA cells not expressing either KRT19 or TGM2 lacked the CXCL12-KRT19 coating, were infiltrated with activated CD8+ T cells, and growth was suppressed with anti-PD-1 antibody treatment. Thus, carcinomas assemble a CXCL12-KRT19 coating to evade cancer immune attack

Hippo-Independent Activation of YAP by the GNAQ Uveal Melanoma Oncogene through a Trio-Regulated Rho GTPase Signaling Circuitry

SummaryMutually exclusive activating mutations in the GNAQ and GNA11 oncogenes, encoding heterotrimeric Gαq family members, have been identified in ∼83% and ∼6% of uveal and skin melanomas, respectively. However, the molecular events underlying these GNAQ-driven malignancies are not yet defined, thus limiting the ability to develop cancer-targeted therapies. Here, we focused on the transcriptional coactivator YAP, a critical component of the Hippo signaling pathway that controls organ size. We found that Gαq stimulates YAP through a Trio-Rho/Rac signaling circuitry promoting actin polymerization, independently of phospholipase Cβ and the canonical Hippo pathway. Furthermore, we show that Gαq promotes the YAP-dependent growth of uveal melanoma cells, thereby identifying YAP as a suitable therapeutic target in uveal melanoma, a GNAQ/GNA11-initiated human malignancy

Case report: L5 tomita En bloc spondylectomy for oligometastatic liposarcoma with post adjuvant stereotactic ablative radiotherapy.

INTRODUCTION: Tomita En-bloc spondylectomy of L5 is one of the most challenging techniques in radical oncological spine surgery. A 42-year-old female was referred with lower back pain and L5 radiculopathy with a background of right shoulder liposarcoma excision. CT-PET confirmed a solitary L5 oligometastasis. MRI showed thecal sac indentation hence wasn't suitable for Stereotactic Ablative Radiotherapy (SABR) alone. The seeding nature of sarcoma prevents the indication of separation surgery hence excisional surgery is considered for radical curative treatment. This case report demonstrates dual-staged modified TES including the utilisation of novel techniques to allow for maximum radical oncological control in the era of SABR and lesser invasive surgery. METHODS: First-stage: Carbonfibre pedicle screws planned from L2 to S2AI-Pelvis, aligned, to her patient-specific rods. Radiofrequency ablation of L5 pedicles prior to osteotomy was performed to prevent sarcoma cell seeding. Microscope-assisted thecal sac tumour separation and L5 nerve root dissection was performed. Novel surgical navigation of the ultrasonic bone-cutter assisted inferior L4 and superior S1 endplate osteotomies. Second-stage: Vascular-assisted retroperitoneal approach at L4-S1 was undertaken protecting the great vessels. Completion of osteotomies at L4 and S1 to En-bloc L5: (L4 inferior endplate, L4/5 disc, L5 body, L5/S1 disc and S1 superior endplate). Anterior reconstruction used an expandable PEEK cage obviating the need for a third posterior stage. Reinforced with a patient-specific carbon plate L4-S1 promontory. RESULTS: Patient rehabilitated well and was discharged after 42 days. Cyberknife of 30Gy in 5 fractions was delivered two months post-op. Despite left foot drop, she's walking independently 9 months post-op. CONCLUSION: These are challenging cases require a truly multi-disciplinary team approach. We share this technique for a dual stage TES and metal-free construct with post adjuvant SABR to achieve maximum local control in spinal oligometastatic disease. This case promotes our modified TES technique in the era of SABR and separation surgery in carefully selected cases

Investigation of japanese encephalitis virus as a cause of acute encephalitis in southern Pakistan, april 2015-january 2018

Background: Japanese encephalitis (JE) occurs in fewer than 1% of JE virus (JEV) infections, often with catastrophic sequelae including death and neuropsychiatric disability. JEV transmission in Pakistan was documented in 1980s and 1990s, but recent evidence is lacking. Our objective was to investigate JEV as a cause of acute encephalitis in Pakistan.Methods: Persons aged ≥1 month with possible JE admitted to two acute care hospitals in Karachi, Pakistan from April 2015 to January 2018 were enrolled. Cerebrospinal fluid (CSF) or serum samples were tested for JEV immunoglobulin M (IgM) using the InBios JE DetectTM assay. Positive or equivocal samples had confirmatory testing using plaque reduction neutralization tests.Results: Among 227 patients, testing was performed on CSF in 174 (77%) and on serum in 53 (23%) patients. Six of eight patient samples positive or equivocal for JEV IgM had sufficient volume for confirmatory testing. One patient had evidence of recent West Nile virus (WNV) neurologic infection based on CSF testing. One patient each had recent dengue virus (DENV) infection and WNV infection based on serum results. Recent flavivirus infections were identified in two persons, one each based on CSF and serum results. Specific flaviviruses could not be identified due to serologic cross-reactivity. For the sixth person, JEV neutralizing antibodies were confirmed in CSF but there was insufficient volume for further testing.Conclusions: Hospital-based JE surveillance in Karachi, Pakistan could not confirm or exclude local JEV transmission. Nonetheless, Pakistan remains at risk for JE due to presence of the mosquito vector, amplifying hosts, and rice irrigation. Laboratory surveillance for JE should continue among persons with acute encephalitis. However, in view of serological cross-reactivity, confirmatory testing of JE IgM positive samples at a reference laboratory is essential

The Cognitive Internet of Things: A Unified Perspective

In this article, we present a unified perspective on the cognitive internet of things (CIoT). It is noted that within the CIoT design we observe the convergence of energy harvesting, cognitive spectrum access and mobile cloud computing technologies. We unify these distinct technologies into a CIoT architecture which provides a flexible, dynamic, scalable and robust network design road-map for large scale IoT deployment. Since the prime objective of the CIoT network is to ensure connectivity between things, we identify key metrics which characterize the network design space. We revisit the definition of cognition in the context of IoT networks and argue that both the energy efficiency and the spectrum efficiency are key design constraints. To this end, we define a new performance metric called the ‘overall link success probability’ which encapsulates these constraints. The overall link success probability is characterized by both the self-sustainablitiy of the link through energy harvesting and the availability of spectrum for transmissions. With the help of a reference scenario, we demonstrate that well-known tools from stochastic geometry can be employed to investigate both the node and the network level performance. In particular, the reference scenario considers a large scale deployment of a CIoT network empowered by solar energy harvesting deployed along with the centralized CIoT device coordinators. It is assumed that CIoT network is underlaid with a cellular network, i.e., CIoT nodes share spectrum with mobile users subject to a certain co-existence constraint. Considering the dynamics of both energy harvesting and spectrum sharing, the overall link success probability is then quantified. It is shown that both the self-sustainability of the link, and the availability of transmission opportunites, are coupled through a common parameter, i.e., the node level transmit power. Furthermore, provided the co-existence constraint is satisfied, the link level success in the presence of both the inter-network and intra-network interference is an increasing function of the transmit power. We demonstrate that the overall link level success probability can be maximized by employing a certain optimal transmit power. Characterization of such an optimal operational point is presented. Finally, we highlight some of the future directions which can benefit from the analytical framework developed in this paper

Examining queue-jumping phenomenon in heterogeneous traffic stream at signalized intersection using UAV-based data

© 2020, Springer-Verlag London Ltd., part of Springer Nature. This research presents an in-depth microscopic analysis of heterogeneous and undisciplined traffic at the signalized intersection. Traffic data extracted from the video recorded using an unmanned aerial vehicle (UAV) at an approach of a signalized intersection is analyzed to study the within green time dynamics of traffic flow. Various parameters of Wiedemann 74, Wiedemann 99, and lateral behavior models used in microscopic traffic simulation package, Vissim, are calibrated for the local heterogeneous traffic. This research is aimed at exploring the queue-jumping phenomenon of motorbikes at signalized intersections and its impact on the saturation flow rate, travel time, and delay. The study of within green time flow dynamics shows that the flow of traffic within green time is not uniform. Surprisingly, the results indicate that the traffic flow for the first few seconds of the green time is significantly higher than the remaining period of green time, which shows a contradiction to the fact that traffic flow for the first few seconds is lower due to accelerating vehicles. Mode-wise traffic counted per second shows that this anomaly is attributed to the presence of motorbikes in front of the queue. Consequently, the outputs of simulation results obtained from calibrated Vissim show that the simulated travel time for motorbikes is significantly lower than the field-observed travel times even though the average simulated traffic flow matches accurately with the field-observed traffic flow. The findings of this research highlight the need to incorporate the queue-jumping behavior of motorbikes in the microsimulation packages to enhance their capability to model heterogeneous and undisciplined traffic

The Pakistan risk of myocardial infarction study: A resource for the study of genetic, lifestyle and other determinants of myocardial infarction in south Asia

The burden of coronary heart disease (CHD) is increasing at a greater rate in South Asia than in any other region globally, but there is little direct evidence about its determinants. The Pakistan Risk of Myocardial Infarction Study (PROMIS) is an epidemiological resource to enable reliable study of genetic, lifestyle and other determinants of CHD in South Asia. By March 2009, PROMIS had recruited over 5,000 cases of first-ever confirmed acute myocardial infarction (MI) and over 5,000 matched controls aged 30-80 years. For each participant, information has been recorded on demographic factors, lifestyle, medical and family history, anthropometry, and a 12-lead electrocardiogram. A range of biological samples has been collected and stored, including DNA, plasma, serum and whole blood. During its next stage, the study aims to expand recruitment to achieve a total of about 20,000 cases and about 20,000 controls, and, in subsets of participants, to enrich the resource by collection of monocytes, establishment of lymphoblastoid cell lines, and by resurveying participants. Measurements in progress include profiling of candidate biochemical factors, assay of 45,000 variants in 2,100 candidate genes, and a genomewide association scan of over 650,000 genetic markers. We have established a large epidemiological resource for CHD in South Asia. In parallel with its further expansion and enrichment, the PROMIS resource will be systematically harvested to help identify and evaluate genetic and other determinants of MI in South Asia. Findings from this study should advance scientific understanding and inform regionally appropriate disease prevention and control strategies