In the plasmaMATCH trial, researchers performed circulating tumor DNA testing on patients with advanced breast cancer and matched those with ESR1, HER2, or AKT1 alterations to targeted therapies. Patients with HER2 and AKT1 mutations experienced response rates greater than 22% with durable benefit.

Genomic analysis of a patient's tumor is the cornerstone of precision oncology, but it does not address whether metastases should be treated differently. Here we tested whether comparative single-cell RNA sequencing (scRNA-seq) of a primary small intestinal neuroendocrine tumor to a matched liver metastasis could guide the treatment of a patient's metastatic disease. Following surgery, the patient was put on maintenance treatment with a somatostatin analog. However, the scRNA-seq analysis revealed that the neuroendocrine epithelial cells in the liver metastasis were less differentiated and expressed relatively little SSTR2, the predominant somatostatin receptor. There were also differences in the tumor microenvironments. RNA expression of vascular endothelial growth factors was higher in the primary tumor cells, reflected by an increased number of endothelial cells. Interestingly, vascular expression of the major VEGF receptors was considerably higher in the liver metastasis, indicating that the metastatic vasculature may be primed for expansion and susceptible to treatment with angiogenesis inhibitors. The patient eventually progressed on Sandostatin, and although consideration was given to adding an angiogenesis inhibitor to her regimen, her disease progression involved non-liver metastases that had not been characterized. Although in this specific case comparative scRNA-seq did not alter treatment, its potential to help guide therapy of metastatic disease was clearly demonstrated.

An 18-yr-old man with a history of intellectual disability, craniofacial dysmorphism, seizure disorder, and obesity was identified to carry a de novo, pathogenic variant in ASXL1 (c.4198G>T; p.E1400X) associated with the diagnosis of Bohring–Opitz syndrome based on exome sequencing. In addition, he was identified to carry a maternally inherited and likely pathogenic variant in MC4R (c.817C>T; p.Q273X) associated with monogenic obesity. Dual genetic diagnosis occurs in 4%–6% of patients and results in unique clinical phenotypes that are a function of tissue-specific gene expression, involved pathways, clinical expressivity, and penetrance. This case highlights the utility of next-generation sequencing in patients with an unusual combination of clinical presentations for several pillars of precision medicine including (1) diagnosis, (2) prognosis and outcome, (3) management and therapy, and (4) utilization of resources.

Store-operated calcium (Ca²⁺) entry (SOCE) occurs through a widely distributed family of ion channels activated by the loss of Ca²⁺ from the endoplasmic reticulum (ER). The best understood of these is the Ca²⁺ release-activated Ca²⁺ (CRAC) channel, which is notable for its unique activation mechanism as well as its many essential physiological functions and the diverse pathologies that result from dysregulation. In response to ER Ca²⁺ depletion, CRAC channels are formed through a diffusion trap mechanism at ER–plasma membrane (PM) junctions, where the ER Ca²⁺-sensing stromal interaction molecule (STIM) proteins bind and activate hexamers of Orai pore-forming proteins to trigger Ca²⁺ entry. Cell biological studies are clarifying the architecture of ER–PM junctions, their roles in Ca²⁺ and lipid transport, and functional interactions with cytoskeletal proteins. Molecular structures of STIM and Orai have inspired a multitude of mutagenesis and electrophysiological studies that reveal potential mechanisms for how STIM is toggled between inactive and active states, how it binds and activates Orai, and the importance of STIM-binding stoichiometry for opening the channel and establishing its signature characteristics of extremely high Ca²⁺ selectivity and low Ca²⁺ conductance.

Maintenance of the proteome, ensuring the proper locations, proper conformations, appropriate concentrations, etc., is essential to preserve the health of an organism in the face of environmental insults, infectious diseases, and the challenges associated with aging. Maintaining the proteome is even more difficult in the background of inherited mutations that render a given protein and others handled by the same proteostasis machinery misfolding prone and/or aggregation prone. Maintenance of the proteome or maintaining proteostasis requires the orchestration of protein synthesis, folding, trafficking, and degradation by way of highly conserved, interacting, and competitive proteostasis pathways. Each subcellular compartment has a unique proteostasis network compromising common and specialized proteostasis maintenance pathways. Stress-responsive signaling pathways detect the misfolding and/or aggregation of proteins in specific subcellular compartments using stress sensors and respond by generating an active transcription factor. Subsequent transcriptional programs up-regulate proteostasis network capacity (i.e., ability to fold and degrade proteins in that compartment). Stress-responsive signaling pathways can also be linked by way of signaling cascades to nontranscriptional means to reestablish proteostasis (e.g., by translational attenuation). Proteostasis is also strongly influenced by the inherent kinetics and thermodynamics of the folding, misfolding, and aggregation of individual proteins, and these sequence-based attributes in combination with proteostasis network capacity together influence proteostasis. In this review, we will focus on the growing body of evidence that proteostasis deficits leading to human pathology can be reversed by pharmacologic adaptation of proteostasis network capacity through stress-responsive signaling pathway activation. The power of this approach will be exemplified by focusing on the ATF6 arm of the unfolded protein response stress responsive-signaling pathway that regulates proteostasis network capacity of the secretory pathway.

The T1D Exchange established a learning platform by evaluating the current state of care and engaging 10 diabetes clinics in collaborative quality improvement (QI) activities. Participating clinics are sharing data and best practices to improve care delivery for people with type 1 diabetes. This article describes the design and initial implementation of this platform, known as the T1D Exchange Quality Improvement Collaborative. This effort has laid a foundation for learning from variation in type 1 diabetes care delivery via QI methodology and has demonstrated success in improving processes through iterative testing cycles and transparent sharing of data.

Researchers investigated pain perception in patients with diabetic foot ulcers (DFUs) by analyzing pre- and postoperative physical function (PF), pain interference (PI), and depression domains of the Patient-Reported Outcome Measurement Information System (PROMIS). They hypothesized that 1) because of painful diabetic peripheral neuropathy (DPN), a majority of patients with DFUs would have high PROMIS PI scores unchanged by operative intervention, and 2) the initially assessed PI, PF, and depression levels would be correlated with final outcomes. Seventy-five percent of patients with DFUs reported pain, most likely because of painful DPN. Those who reported high PI and low PF were likely to report depression. PF, PI, and depression levels were unchanged after operative intervention or healing of DFUs.

Background:

The success of multisite collaborative research relies on effective data collection, harmonization, and aggregation strategies. Data Coordination Centers (DCC) serve to facilitate the implementation of these strategies. The utility of a DCC can be particularly relevant for research on rare diseases where collaboration from multiple sites to amass large aggregate datasets is essential. However, approaches to building a DCC have been scarcely documented.

Subtractive immunization is useful for directing the immune response away from dominant epitopes to allow antibodies against less immunogenic antigens to be developed. It is also useful when there is a need to downplay the response to carriers added to peptides and recombinant proteins, such as Gst and Ig, to aid in production and purification. Subtractive immunization protocols also can be helpful if the target protein is part of a mixture (such as a cell lysate) or present on the surface of transfected cells.

The repetitive immunization at multiple sites (RIMMS) protocol capitalizes on the animal's innate immune system, which is genetically preprogrammed to recognize many antigens. By repetitively immunizing the animal, B cells that recognize the antigen are kept continuously expanding until the lymph nodes are harvested for hybridoma generation. This is a good method for making a more diverse repertoire of antibodies or antibodies directed against conformational epitopes.

This protocol is used to determine the concentration of DNase-resistant vector genomes (i.e., packaged in the capsid) in purified recombinant adeno-associated virus (rAAV) preparations. The protocol begins with treatment of the vector stock with DNase I to eliminate unencapsidated AAV DNA or contaminating plasmid DNA. This is followed by a heat treatment to heat-inactivate DNase I, to disrupt the viral capsid, and to release the packaged vector genomes for quantification by real-time polymerase chain reaction (PCR) using a set of standards (linearized plasmid used for vector production) containing known copy numbers. To accomplish high-throughput titration, the primer and probe sets used in real-time PCR are usually designed to target common elements present in most rAAV genomes, such as promoters and poly(A) signals. This strategy significantly reduces the number of PCRs, controls, and turnaround time. Several important controls should be included in the assay as follows: The first two controls should have a known copy number of the rAAV genome plasmid treated or not treated with DNase I. This control tests the effectiveness of DNase treatment. To control for potential cross-contamination between samples during the preparation process, a blank control containing nuclease-free water only should be processed and tested in parallel. A validation vector sample with a known titer should be included in every assay to monitor interassay variability. Finally, for the PCR run, a no-template control (NTC) is included to indicate cross-contamination during PCR setup.

Ovarian cancer imposes a substantial health and economic burden. We systematically reviewed current health-economic evidence for ovarian cancer early detection or prevention strategies. Accordingly, we searched relevant databases for cost-effectiveness studies evaluating ovarian cancer early detection or prevention strategies. Study characteristics and results including quality-adjusted life years (QALY), and incremental cost-effectiveness ratios (ICER) were summarized in standardized evidence tables. Economic results were transformed into 2017 Euros. The included studies (N = 33) evaluated ovarian cancer screening, risk-reducing interventions in women with heterogeneous cancer risks and genetic testing followed by risk-reducing interventions for mutation carriers. Multimodal screening with a risk-adjusted algorithm in postmenopausal women achieved ICERs of 9,800–81,400 Euros/QALY, depending on assumptions on mortality data extrapolation, costs, test performance, and screening frequency. Cost-effectiveness of risk-reducing surgery in mutation carriers ranged from cost-saving to 59,000 Euros/QALY. Genetic testing plus risk-reducing interventions for mutation carriers ranged from cost-saving to 54,000 Euros/QALY in women at increased mutation risk. Our findings suggest that preventive surgery and genetic testing plus preventive surgery in women at high risk for ovarian cancer can be considered effective and cost-effective. In postmenopausal women from the general population, multimodal screening using a risk-adjusted algorithm may be cost-effective.

SUMMARY:

The olfactory bulbs and tracts are central nervous system white matter tracts maintained by central neuroglia. Although rare, gliomas can originate from and progress to involve the olfactory apparatus. Through a Health Insurance Portability and Accountability Act–compliant retrospective review of the institutional teaching files and brain MR imaging reports spanning 10 years, we identified 12 cases of gliomas involving the olfactory bulbs and tracts, including 6 cases of glioblastoma, 2 cases of anaplastic oligodendroglioma, and 1 case each of pilocytic astrocytoma, diffuse (grade II) astrocytoma, anaplastic astrocytoma (grade III), and diffuse midline glioma. All except the pilocytic astrocytoma occurred in patients with known primary glial tumors elsewhere. Imaging findings of olfactory tumor involvement ranged from well-demarcated enhancing masses to ill-defined enhancing infiltrative lesions to nonenhancing masslike FLAIR signal abnormality within the olfactory tracts. Familiarity with the imaging findings of glioma involvement of the olfactory nerves is important for timely diagnosis and treatment of recurrent gliomas and to distinguish them from other disease processes.

BACKGROUND AND PURPOSE:

Endovascular treatment of petrous dural AVFs may carry a risk of iatrogenic facial nerve palsy if the facial nerve arterial arcade, an anastomotic arterial arch that supplies the geniculate ganglion, is not respected or recognized. Our purpose was to demonstrate that the use of a treatment strategy algorithm incorporating detailed angiographic anatomic assessment allows identification of the facial nerve arterial arcade and therefore safe endovascular treatment.

BACKGROUND AND PURPOSE:

Computed tomography angiography offers a non-invasive alternative to DSA for the assessment of cerebral vasospasm following subarachnoid hemorrhage but there is limited evidence regarding its reliability. Our aim was to perform a systematic review (Part I) and to assess (Part II) the inter- and intraobserver reliability of CTA in the diagnosis of cerebral vasospasm.

BACKGROUND AND PURPOSE:

Anoxic brain injury is a result of prolonged hypoxia. We sought to describe the nonquantitative arterial spin-labeling perfusion imaging patterns of anoxic brain injury, characterize the relationship of arterial spin-labeling and DWI, and evaluate the normalized diffusion-to-perfusion ratio to differentiate patients with anoxic brain injury from healthy controls.

Một số xu hướng nội thất có thể gây phản tác dụng, làm giảm giá trị nhà tới 52%. Đây là kết luận được đưa ra sau một cuộc nghiên cứu do công ty Rated People của Anh thực hiện.

Signs of deceleration of the real estate market have appeared quite clearly in many segments since the beginning of this year, according to Tran Khanh Quang, General Director of Viet An Hoa Real Estate Company.

In light of the ongoing COVID-19 crisis, this week’s resources continue to have the dual focus of providing resources that can help us navigate this […]

The post David Kelly’s Curated L&D Content for the Week of 5/4/20 appeared first on e-Learning Feeds.

In light of the ongoing COVID-19 crisis, this week’s resources continue to have the dual focus of providing resources that can help us navigate this […]

The post David Kelly’s Curated L&D Content for the Week of 4/27/20 appeared first on e-Learning Feeds.

“Dear Designer” is a blog series on orienting novice practitioners to the discipline of instructional design and learning experience design.

The post Dear Designer: 3 Considerations for Length When Shifting to VILT appeared first on e-Learning Feeds.

It’s time to start planning our return to the workplace. Adjustments made during the pandemic will extend into and impact our return to the office. […]

The post 5 L&D considerations for returning to the workplace appeared first on e-Learning Feeds.

There’s the technical definition of personalized marketing: the collection and analysis of prospect data to implement an enterprise marketing strategy for custom segments And then […]

The post A Practical Guide to Personalized Video Strategy (+ 5 Interactivity Types For Your Brand’s Videos) appeared first on e-Learning Feeds.

Video has quickly become the number one way to connect with buyers, viewers, and followers. For B2B sellers, a strategic video marketing approach tailored to […]

The post How to Create an Interactive Video Strategy for Your B2B appeared first on e-Learning Feeds.

Let’s talk collabs — no, not your Nikes (but yeah, they’re probably pretty fresh). What we are drawing on here is the collabing that makes […]

The post Collaborative Learning in the Workplace appeared first on e-Learning Feeds.

तनाव देख पुलिस तैनात, पीएम के बाद आएगा शव

नगर कोतवाली इलाके के दहिलामऊ स्थित चांदमारी मारुतनगर में सई नदी के किनारे विवादित जमीन पर प्लाटिंग और रुपये के विवाद को लेकर दो गुटों में शुक्रवार दोपहर भिड़ंत हो गई। दोनों पक्षों से दर्जनों राउंड फायरिंग हुई। गोलियों की तड़तड़ाहट से लोग सहम गए।

Publisher Private Division and developer V1 Interactive announced Disintegration will launch for the PlayStation 4, Xbox One and Windows PC via Steam on June 16 for $49.99.

View the story trailer below:

Here is an overview of the game:

Disintegration is a sci-fi, first-person shooter that blends real-time tactical elements to create an entirely new experience. Set in a world ripped apart by famine, scarce resources, and the planet on the brink of destruction, humanity has developed a process to survive its harsh reality known as Integration, in which a human brain is transferred to a robotic armature. From the ensuing chaos, an aggressive, militaristic legion, known as the Rayonne, gain control and begins to impose the once optional process of Integration onto the rest of humanity to consolidate their power.

Players command Romer Shoal, an incredibly-skilled Gravcycle pilot, who leads a small band of outlaws to fight back against an overwhelming Rayonne force. Over the course of a thrilling single-player campaign, players will control a Gravcycle loaded with weaponry, leading Romer and his team across a series of diverse missions packed with action, explosions, and plot twists, to beat back the Rayonne forces and give the last vestiges of humanity hope to prevail.

In addition to the full single-player campaign, Disintegration features frenetic player-versus-player multiplayer where pilots and their crews compete in three game modes and six distinct maps. Players can select from nine highly-stylized “Crews” which lend themselves to different playstyles.

Multiplayer provides a host of cosmetic customizations that can be purchased or earned in-game, including pilot and crew skins, cosmetic Gravcycle customizations, and a variety of banners. In addition to the multiplayer content at release, the team at V1 will be supporting the game post-launch with seasonal content drops.

Key Features:

• Tactical Gravcycle Combat – Pilot a heavily armed Gravcycle featuring a variety of firepower, maneuverability, and abilities.
• Riveting Single-player Campaign – From Marcus Lehto, the co-creator of Halo and creative director of Halo: Reach, comes an all-new sci-fi saga. Play as Romer Shoal and confront the Rayonne, a rising global army set on eliminating what remains of humanity.
• Frenetic Multiplayer Action – Battle across a variety of maps in three intense, team-based five-versus-five multiplayer modes. Choose your favorite Gravcycle and lead your crew alongside your teammates, competing against opposing pilots to win objective-based matches.

A life-long and avid gamer, William D'Angelo was first introduced to VGChartz in 2007. After years of supporting the site, he was brought on in 2010 as a junior analyst, working his way up to lead analyst in 2012. He has expanded his involvement in the gaming community by producing content on his own YouTube channel and Twitch channel dedicated to gaming Let's Plays and tutorials. You can contact the author at wdangelo@vgchartz.com or on Twitter @TrunksWD.

Full Article - https://www.vgchartz.com/article/443412/disintegration-launches-june-16-for-ps4-xbox-one-and-steam/

Originally published by The Vinyl Factory. “It is a living instrument producing a living sound.” Soulwax, aka David & Stephen Dewaele, explore their love of the EMS Synthi 100 in a new album and book that pay tribute to the bulky hybrid synth. Both will be released via The Vinyl Factory and DEEWEE this May, and […]

The post Soulwax celebrate the EMS Synthi 100 in new trailer appeared first on FACT Magazine.

A centenarian who tested positive for COVID-19 has become the oldest local resident to die from the virus. The woman in her 100s was a resident of a long-term care or retirement home. She died on Thursday, the Windsor-Essex County Health Unit reported during its end-of-week epidemic data summary on Friday. “I would like to […]

As US-Iran tensions rise following the assassination of an Iranian general and missile attacks on US troops, UN diplomat Neil Walsh warns cyberattacks can be just as impactful

Concerns about adversaries hacking democracy abound, but it’s sheer incompetence we should really be worried about, writes Annalee Newitz

Tech firms are making record profits but paying little tax. Now global leaders are discussing ways to make them pay their fair share

Fabric with tiny vibrating motors elicits sensations associated with clouds, water and rocks on the skin and has been made into a dress that could improve emotions

Qubits are often stabilised by being supercooled, which makes quantum computer chips hard to scale up. Now they have been operated at above -272°C for the first time

Robots made of 3D-printed muscle and rat spines could help us understand conditions like motor neurone disease and the technique may eventually be used to build prosthetic devices

This could be a trial run for the rest of Disney’s parks in the US, Japan, France, and Hong Kong.

While such a plan might sound appealing, it’s likely to provide a false sense of security