Purpose:

Preclinical data demonstrating androgen receptor (AR)–positive (AR⁺) triple-negative breast cancer (TNBC) cells are sensitive to AR antagonists, and PI3K inhibition catalyzed an investigator-initiated, multi-institutional phase Ib/II study TBCRC032. The trial investigated the safety and efficacy of the AR-antagonist enzalutamide alone or in combination with the PI3K inhibitor taselisib in patients with metastatic AR⁺ (≥10%) breast cancer.

Plazomicin was active against 97.0% of 8,783 Enterobacterales isolates collected in the United States (2016 and 2017), and only 6 isolates carried 16S rRNA methyltransferases conferring resistance to virtually all aminoglycosides. Plazomicin (89.2% to 95.9% susceptible) displayed greater activity than amikacin (72.5% to 78.6%), gentamicin (30.4% to 45.9%), and tobramycin (7.8% to 22.4%) against carbapenem-resistant and extensively drug-resistant isolates. The discrepancies among the susceptibility rates for these agents was greater when applying breakpoints generated using the same stringent contemporary methods applied to determine plazomicin breakpoints.

KBP-7072 is a novel third-generation tetracycline (aminomethylcycline) antibacterial that overcomes common efflux and ribosomal protection resistance mechanisms that cause resistance in older-generation tetracyclines. KBP-7072 completed phase 1 clinical development studies for safety, tolerability, and pharmacokinetics (ClinicalTrials.gov identifier NCT02454361) and multiple ascending doses in healthy subjects (ClinicalTrials.gov identifier NCT02654626) in December 2015. Both oral and intravenous formulations of KBP-7072 are being developed. In this study, we evaluated the in vitro activities of KBP-7072 and comparator agents by CLSI document M07 (2018) broth microdilution against 531 recent geographically diverse and/or molecularly characterized Acinetobacter baumannii-A. calcoaceticus species complex (A. baumannii) isolates from the United States, Europe, Asia-Pacific (excluding China), and Latin America. A. baumannii isolates included carbapenem-resistant, colistin-resistant, tetracycline-resistant, and extended-spectrum-β-lactamase (ESBL)- and metallo-β-lactamase (MBL)-producing isolates. Overall, KBP-7072 (MIC_50/90, 0.25/1 mg/liter) was comparable in activity to colistin (92.8%/92.8% susceptible [S] [CLSI/EUCAST]) against A. baumannii isolates, inhibiting 99.2% of isolates at ≤2 mg/liter and 97.6% of isolates at ≤1 mg/liter. KBP-7072 was equally active against A. baumannii isolates, including carbapenem-resistant, colistin-resistant, and tetracycline-resistant isolates, regardless of geographic location, and maintained activity against ESBL- and MBL-producing isolates. KBP-7072 outperformed comparator agents, including ceftazidime (40.3% S [CLSI]), gentamicin (48.2%/48.2% S [CLSI/EUCAST]), levofloxacin (39.5%/37.9% S [CLSI/EUCAST]), meropenem (42.0%/42.0% S [CLSI/EUCAST]), piperacillin-tazobactam (33.3% S [CLSI]), and all tetracycline-class comparator agents, which include doxycycline (67.3% S [CLSI]), minocycline (73.8% S [CLSI]), tetracycline (37.2% S [CLSI]), and tigecycline (79.5% inhibited by ≤2 mg/liter). The potent in vitro activity of KBP-7072 against recent geographically diverse, molecularly characterized, and drug-resistant A. baumannii isolates supports continued clinical development for the treatment of serious infections, including those caused by A. baumannii.

Hypervirulent Klebsiella pneumoniae strains are the major cause of liver abscesses throughout East Asia, and these strains are usually antibiotic susceptible. Recently, multidrug-resistant and hypervirulent (MDR-HV) K. pneumoniae strains have emerged due to hypervirulent strains acquiring antimicrobial resistance determinants or the transfer of a virulence plasmid into a classic MDR strain. In this study, we characterized the clinical and microbiological properties of K. pneumoniae liver abscess (KPLA) caused by MDR-HV strains in Taiwan. Patients with community onset KPLA were retrospectively identified at Taipei Veterans General Hospital during January 2013 to May 2018. Antimicrobial resistance mechanisms, capsular types, and sequence types were determined. MDR-HV strains and their parental antimicrobial-susceptible strains further underwent whole-genome sequencing (WGS) and in vivo mice lethality tests. Thirteen MDR-HV strains were identified from a total of 218 KPLA episodes. MDR-HV strains resulted in similar outcomes to antimicrobial-susceptible strains. All MDR-HV strains were traditional hypervirulent clones carrying virulence capsular types. The major resistance mechanisms were the overexpression of efflux pumps and/or the acquisition of ESBL or AmpC β-lactamase genes. WGS revealed that two hypervirulent strains had evolved to an MDR phenotype due to mutation in the ramR gene and the acquisition of an SHV-12-bearing plasmid, respectively. Both these MDR-HV strains retained high virulence compared to their parental strains. The spread of MDR-HV K. pneumoniae strains in the community raises significant public concerns, and measures should be taken to prevent the further acquisition of carbapenemase and other resistance genes among these strains in order to avoid the occurrence of untreatable KPLA.

Inhibition of BET protein bromodomains BD1 and BD2 produces unique phenotypes in disease models.

Understanding how coronary blood vessels form and regenerate during development and progression of cardiac diseases will shed light on the development of new treatment options targeting coronary artery diseases. Recent studies with the state-of-the-art technologies have identified novel origins of, as well as new, cellular and molecular mechanisms underlying the formation of coronary vessels in the postnatal heart, including collateral artery formation, endocardial-to-endothelial differentiation and mesenchymal-to-endothelial transition. These new mechanisms of coronary vessel formation and regeneration open up new possibilities targeting neovascularization for promoting cardiac repair and regeneration. Here, we highlight some recent studies on cellular mechanisms of coronary vessel formation, and discuss the potential impact and significance of the findings on basic research and clinical application for treating ischemic heart disease.

To date, more than 200 monogenic, often devastating, skin diseases have been described. Because of unmet medical needs, development of long-lasting and curative therapies has been consistently attempted, with the aim of correcting the underlying molecular defect. In this review, we will specifically address the few combined cell and gene therapy strategies that made it to the clinics. Based on these studies, what can be envisioned for the future is a patient-oriented strategy, built on the specific features of the individual in need. Most likely, a combination of different strategies, approaches, and advanced therapies will be required to reach the finish line at the end of the long and winding road hampering the achievement of definitive treatments for genodermatoses.

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.

Consistently, the field of genetic counseling has advocated that parents be advised to defer elective genetic testing of minors until adulthood to prevent a range of potential harms, including stigma, discrimination, and the loss of the child's ability to decide for him- or herself as an adult. However, consensus around the policy of "defer-when-possible" obscures the extent to which this norm is currently under siege. Increasingly, routine use of full or partial genome sequencing challenges our ability to control what is discovered in childhood or, when applied in a prenatal context, even before birth. The expansion of consumer-initiated genetic testing services challenges our ability to restrict what is available to minors. As the barriers to access crumble, medical professionals should proceed with caution, bearing in mind potential risks and continuing to assess the impact of genetic testing on this vulnerable population.

Nhà lệch tầng là dạng nhà có các tấm sàn không kéo dài suốt mà thay đổi tạo thành những ống hút gió xuyên từ tầng này tới tầng kia. Các tầng có thể có độ cao khác nhau chứ không đồng nhất độ cao như các nhà ống thông thường.

Nhà lệch tầng có nhiều ưu điểm nhưng vẫn tồn tại một số nhược điểm nhất định khiến nhiều gia chủ còn phân vân có nên ứng dụng kiến trúc này hay không.

Home buyers or sellers normally face many difficulties and obstacles that need time and effort to overcome. To save time, avoid risks and make the purchase faster and smoother, most people hire real estate agents for effective advice and assistance.

Publisher Microsoft and developer 343 Industries announced Halo 2: Anniversary will launch for the Windows PC version of Halo: The Master Chief Collection via Steam and Microsoft Store on Tuesday, May 12.

Here is an overview of the game:

Halo 2: Anniversary comes to PC as the next installment in Halo: The Master Chief Collection. Now optimized for PC, experience the impeccably remastered edition of the original Halo 2 game. Following the destruction of Halo, humankind experiences a short-lived victory. Eager for revenge, the Covenant launches a surprise attack on Earth, but they find themselves ill-prepared to defeat the UNSC’s home fleet and are forced to flee into slipspace. When the Master Chief pursues his overzealous enemies, they discover yet another Halo ring, uncovering long-buried secrets, including an unlikely ally, that will dramatically alter the course of the Human-Covenant Conflict forever.

Key Features:

• PC Settings/Optimizations: Halo 2: Anniversary is now optimized for PC and looking better than ever at up to 4k UHD and at 60+ FPS.* Other PC native settings include customizable mouse and keyboard support, ultrawide support, FOV customization, and more.
• Campaign: Experience the next chapter in the Halo saga and fight your way through 15 unforgettable missions. Play as both Spartan-117, the Master Chief, and for the first time, the Covenant Elite, known as the Arbiter, and experience the Human-Covenant Conflict in a whole new way.
• Anniversary Edition/Update: Toggle between the remastered graphics in the Anniversary edition and the graphics from the original Halo 2 campaign. In the Anniversary edition, view Blur Studio’s spectacularly remastered cutscenes from the original Halo 2 game.
• Multiplayer: Continue your Halo adventure with 7 remastered multiplayer maps from Halo 2: Anniversary and 25 multiplayer maps from the original Halo 2, featuring a completely updated progression system.

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/443396/halo-2-anniversary-for-halo-the-master-chief-collection-for-pc-launches-may-12/

Orange-coloured gel has been made into artificial skin that can be 3D printed in any shape and detect human touch – one day it could help robots feel

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

Electric cars depend on cobalt as a key ingredient in their batteries, but a new analysis reveals we may run out by 2030, while car firm Tesla is moving to other types of battery in China

Artificial intelligence is helping optimise the recharging batteries in electric vehicles, balancing speed while maximising lifespan

Durian fruits, famous for their bad smell, could be used to make electrodes in ultra-fast chargers for electric cars and gadgets

Flexible displays for wearable devices can now be made using fish scales instead of plastic – and the new displays biodegrade within a month of being discarded

An artificially intelligent eco-assistant can persuade hotel guests and staff to reduce their electricity use by up to a third

Black paint usually absorbs heat, but a new two-layer polymer paint reflects infrared light and keeps objects 16°C cooler, which could help make buildings more energy efficient

TfL as in Transport for London. Greeeeeaaat.

The enormous black hole at the centre of the Milky Way was active millions of years ago, and its intense X-rays may have formed some molecules necessary for life

NASA has awarded $967 million to three space flight companies – Blue Origin, Dynetics and SpaceX – to build lunar landers that will be part of the Artemis programme to send humans to the moon by 2024

Earlier this week, a depressing economic prognosis linked on the Drudge Report concluded: "A whole lot more pain is on the way, and it is going to shake our nation to the core."

A new automated lab bench combs through known chemical reactions to figure out how best to synthesize compounds

New drone standard for remote ID submitted for approval

Ken Staples joins the show and teaches Chris everything he’s doing wrong in The Division. Alice gets back into EVE and explains World War Bee...

Researchers have made a breakthrough in understanding the structure of a key genetic molecule, called RNA, and revealing for the first time how these changes impact RNA's function. The research team developed a bioinformatics technique to resolve separate structures of RNA rather than viewing them as a 'blur' that averaged multiple structures. This underpinned their discovery that the structure of RNA can influence how cells function.

It’s that time of the year in the WHL. News of player signings are a daily occurrence and the Winnipeg Ice’s management team has been busy. On Monday, the club announced ...

Groups across the country are putting tablets in the hands of COVID patients so their families can see them, sometimes for the last time

In a small trial, implanting electrodes into the brain helped women with severe anorexia gain weight and feel less anxious and depressed

George Engelmann, a perennial swing voter in swing-state Wisconsin, says President Donald Trump has won his vote for November's election thanks to his response to the coronavirus pandemic.

Kenya and Uganda were hit by power blackouts on Saturday, and Kenya Power said the outage on its grid was caused by a fault on a high voltage line but that it had restored supply to most parts of the country.

Tesla is known for it’s electric inventions. Specifically, in the...

The post Tesla Wants To Be UK’s Electricity Provider appeared first on Man's World India.

Bhaane’s Summer 2020 collection is inspired by the ’90s community...

The post Bhaane’s Summer 2020 Collection Is Inspired By ’90s Community Clubs appeared first on Man's World India.

THE leader of the Scottish Conservative Party has outlined his plan to stop Nicola Sturgeon and the SNP becoming Scotland's biggest party at the 2021 Scottish election.

Bernie Sanders' bid to collect convention delegates hits snag as New York cancels Democratic presidential primary

Computers, mobile phones and all other electronic devices contain thousands of transistors, linked together by thin films of metal. Scientists have developed a method that can use the electrons in a plasma to produce these films.

Researchers find evidence of piezoelectricity in lab-grown, two-dimensional flakes of molybdenum dioxide.

Some plants, like soybean, are known to possess an innate defense machinery that helps them develop resistance against insects trying to feed on them. However, exactly how these plants recognize signals from insects has been unknown until now. Scientists have now uncovered the cellular pathway that helps these plants to sense danger signals and elicit a response, opening doors to a myriad of agricultural applications.

Hematopoietic stem cells from a healthy donor can help patients suffering from acute leukemia. However, the side effects of therapies are often severe. Researchers have now shown how human healthy and cancerous hematopoietic stem cells can be more selectively eliminated using immunotherapy instead of chemotherapy in mice. The aim is to test the new immunotherapy in humans as soon as possible.

Florian Schneider, co-founder of pioneering German electronic band Kraftwerk, which influenced generations of pop and dance musicians with mesmerising tracks such as "Autobahn", has died of cancer aged 73, longtime bandmate Ralf Huetter said.

Former US president Barack Obama given Joe Biden his endorsement for the 2020 presidential election.

The Vermont senator said progressives who "sit on their hands" in the months ahead would simply enable Republican president Donald Trump's re-election.