Plasmodium vivax relapse is one of the major causes of sustained global malaria transmission. Primaquine (PQ) is the only commercial drug available to prevent relapses, and its efficacy is dependent on metabolic activation by cytochrome P450 2D6 (CYP2D6). Impaired CYP2D6 function, caused by allelic polymorphisms, leads to the therapeutic failure of PQ as a radical cure for P. vivax malaria. Here, we hypothesized that the host immune response to malaria parasites modulates susceptibility to P. vivax recurrences in association with CYP2D6 activity. We performed a 10-year retrospective study by genotyping CYP2D6 polymorphisms in 261 malaria-exposed individuals from the Brazilian Amazon. The immune responses against a panel of P. vivax blood-stage antigens were evaluated by serological assays. We confirmed our previous findings, which indicated an association between impaired CYP2D6 activity and a higher risk of multiple episodes of P. vivax recurrence (risk ratio, 1.75; 95% confidence interval [CI], 1.2 to 2.6; P = 0.0035). An important finding was a reduction of 3% in the risk of recurrence (risk ratio, 0.97; 95% CI, 0.96 to 0.98; P < 0.0001) per year of malaria exposure, which was observed for individuals with both reduced and normal CYP2D6 activity. Accordingly, subjects with long-term malaria exposure and persistent antibody responses to various antigens showed fewer episodes of malaria recurrence. Our findings have direct implications for malaria control, since it was shown that nonimmune individuals who do not respond adequately to treatment due to reduced CYP2D6 activity may present a significant challenge for sustainable progress toward P. vivax malaria elimination.

We report a systematic, cellular phenotype-based antimalarial screening of the Medicines for Malaria Venture Pathogen Box collection, which facilitated the identification of specific blockers of late-stage intraerythrocytic development of Plasmodium falciparum. First, from standard growth inhibition assays, we identified 173 molecules with antimalarial activity (50% effective concentration [EC₅₀] ≤ 10 μM), which included 62 additional molecules over previously known antimalarial candidates from the Pathogen Box. We identified 90 molecules with EC₅₀ of ≤1 μM, which had significant effect on the ring-trophozoite transition, while 9 molecules inhibited the trophozoite-schizont transition and 21 molecules inhibited the schizont-ring transition (with ≥50% parasites failing to proceed to the next stage) at 1 μM. We therefore rescreened all 173 molecules and validated hits in microscopy to prioritize 12 hits as selective blockers of the schizont-ring transition. Seven of these molecules inhibited the calcium ionophore-induced egress of Toxoplasma gondii, a related apicomplexan parasite, suggesting that the inhibitors may be acting via a conserved mechanism which could be further exploited for target identification studies. We demonstrate that two molecules, MMV020670 and MMV026356, identified as schizont inhibitors in our screens, induce the fragmentation of DNA in merozoites, thereby impairing their ability to egress and invade. Further mechanistic studies would facilitate the therapeutic exploitation of these molecules as broadly active inhibitors targeting late-stage development and egress of apicomplexan parasites relevant to human health.

We characterized 29 bla_CTX-M-27-harboring plasmids of Escherichia coli sequence type 131 (ST131) sublineage C1/H30R isolates from healthy individuals and long-term-care facility (LTCF) residents. Most (27/29) plasmids were of the FIA, FIB, and FII multireplicon type with the same plasmid multilocus sequence typing (pMLST). Several plasmids (7/23) from LTCF residents harbored only bla_CTX-M-27 as the resistance gene; however, their fundamental structures were very similar to those of previously isolated bla_CTX-M-27/F1:A2:B20 plasmids, suggesting their prevalence as a newly arising public health concern.

Plasma DNA fragmentomics is an emerging area of research covering plasma DNA sizes, end points, and nucleosome footprints. In the present study, we found a significant increase in the diversity of plasma DNA end motifs in patients with hepatocellular carcinoma (HCC). Compared with patients without HCC, patients with HCC showed a preferential pattern of 4-mer end motifs. In particular, the abundance of plasma DNA motif CCCA was much lower in patients with HCC than in subjects without HCC. The aberrant end motifs were also observed in patients with other cancer types, including colorectal cancer, lung cancer, nasopharyngeal carcinoma, and head and neck squamous cell carcinoma. We further observed that the profile of plasma DNA end motifs originating from the same organ, such as the liver, placenta, and hematopoietic cells, generally clustered together. The profile of end motifs may therefore serve as a class of biomarkers for liquid biopsy in oncology, noninvasive prenatal testing, and transplantation monitoring.

The poor prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) impels an improved understanding of disease biology to facilitate the development of better therapies. PDAC typically features a remarkably dense stromal reaction, featuring and established by a prominent population of cancer-associated fibroblasts (CAF). Genetically engineered mouse models and increasingly sophisticated cell culture techniques have demonstrated important roles for fibroblasts in PDAC progression and therapy response, but these roles are complex, with strong evidence for both tumor-supportive and tumor-suppressive or homeostatic functions. Here, we review the recent literature that has improved our understanding of heterogeneity in fibroblast fate and function in this disease including the existence of distinct fibroblast populations, and highlight important avenues for future study.

We report the diagnostic challenges and the clinical course of a patient with an extraordinary presentation of B-lymphoblastic leukemia (B-ALL) with eosinophilia. We identified a novel ZBTB20-JAK2 gene fusion as a chimeric RNA transcript using the Archer platform. This gene fusion from the same patient was recently identified by Peterson et al. (2019) at the genomic level using a different sequencing technology platform. The configuration of this gene fusion predicts the production of a kinase-activating JAK2 fusion protein, which would normally lead to a diagnosis of Philadelphia chromosome–like B-ALL (Ph-like B-ALL). However, the unusual presentation of eosinophilia led us to demonstrate the presence of this gene fusion in nonlymphoid hematopoietic cells by fluorescence in situ hybridization (FISH) studies with morphologic correlation. Therefore, we believe this disease, in fact, represents blast crisis arising from an underlying myeloid neoplasm with JAK2 rearrangements. This case illustrates the difficulty in differentiating Ph-like B-ALL and myeloid/lymphoid neoplasm with eosinophilia and gene rearrangements (MLN-EGR) in blast crisis. As currently defined, the diagnosis of MLN-EGR relies on the hematologic presentations and the identification of marker gene fusions (including PCM1-JAK2, ETV6-JAK2, and BCR-JAK2). However, these same gene fusions, when limited to B-lymphoblasts, also define Ph-like B-ALL. Yet, our case does not conform to either condition. Therefore, the assessment for lineage restriction of gene rearrangements to reflect the pathophysiologic difference between B-ALL and MLN-EGR in blast crisis is likely a more robust diagnostic approach and allows the inclusion of MLN-EGR with novel gene fusions.

Clinical benefit of immune checkpoint blockade in glioblastoma (GBM) is rare, and we hypothesize that tumor clonal evolution and the immune microenvironment are key determinants of response. Here, we present a detailed molecular characterization of the intratumoral and immune heterogeneity in an IDH wild-type, MGMT-negative GBM patient who plausibly benefited from anti-PD-1 therapy with an unusually long 25-mo overall survival time. We leveraged multiplex immunohistochemistry, RNA-seq, and whole-exome data from the primary tumor and three resected regions of recurrent disease to survey regional tumor-immune interactions, genomic instability, mutation burden, and expression profiles. We found significant regional heterogeneity in the neoantigenic and immune landscape, with a differential T-cell signature among recurrent sectors, a uniform loss of focal amplifications in EGFR, and a novel subclonal EGFR mutation. Comparisons with recently reported correlates of checkpoint blockade in GBM and with TCGA-GBM revealed appreciable intratumoral heterogeneity that may have contributed to a differential PD-1 blockade response.

Adolescents with type 1 diabetes face self-management challenges that make it difficult for them to achieve good glycemic control. In our population of adolescents with poorly controlled type 1 diabetes, the use of continuous glucose monitoring (CGM) improved patients’ glycemic time in range (TIR) and identified hypoglycemia more frequently than with intermittent self-monitoring of blood glucose throughout a 4-week interval. However, the adolescents were unable to synthesize this information to problem-solve or reduce the frequency of hypoglycemic events. Setting SMART (specific, measurable, achievable, relevant, and time-bound) diabetes management goals and providing intensive diabetes education and support could increase adolescents’ TIR and prevent hypoglycemia.

Recurrent hotspot (p.Gly17Val) mutations in RHOA encoding a small GTPase, together with loss-of-function mutations in TET2 encoding an epigenetic regulator, are genetic hallmarks of angioimmunoblastic T-cell lymphoma (AITL). Mice expressing the p.Gly17Val RHOA mutant on a Tet2-null background succumbed to AITL-like T-cell lymphomas due to deregulated T-cell receptor (TCR) signaling. Using these mice to investigate therapeutics for AITL, we found that dasatinib, a multikinase inhibitor prolonged their survival through inhibition of hyperactivated TCR signaling. A phase I clinical trial study of dasatinib monotherapy in 5 patients with relapsed/refractory AITL was performed. Dasatinib was started at a dose of 100 mg/body once a day and continued until days 10–78 (median day 58). All the evaluable patients achieved partial responses. Our findings suggest that AITL is highly dependent on TCR signaling and that dasatinib could be a promising candidate drug for AITL treatment.Significance:Deregulated T-cell receptor signaling is a critical molecular event in angioimmunoblastic T-cell lymphoma and can be targeted with dasatinib.

Determining mechanisms of resistance to αPD-1/PD-L1 immune-checkpoint immunotherapy is key to developing new treatment strategies. Cancer-associated fibroblasts (CAF) have many tumor-promoting functions and promote immune evasion through multiple mechanisms, but as yet, no CAF-specific inhibitors are clinically available. Here we generated CAF-rich murine tumor models (TC1, MC38, and 4T1) to investigate how CAFs influence the immune microenvironment and affect response to different immunotherapy modalities [anticancer vaccination, TC1 (HPV E7 DNA vaccine), αPD-1, and MC38] and found that CAFs broadly suppressed response by specifically excluding CD8+ T cells from tumors (not CD4+ T cells or macrophages); CD8+ T-cell exclusion was similarly present in CAF-rich human tumors. RNA sequencing of CD8+ T cells from CAF-rich murine tumors and immunochemistry analysis of human tumors identified significant upregulation of CTLA-4 in the absence of other exhaustion markers; inhibiting CTLA-4 with a nondepleting antibody overcame the CD8+ T-cell exclusion effect without affecting Tregs. We then examined the potential for CAF targeting, focusing on the ROS-producing enzyme NOX4, which is upregulated by CAF in many human cancers, and compared this with TGFβ1 inhibition, a key regulator of the CAF phenotype. siRNA knockdown or pharmacologic inhibition [GKT137831 (Setanaxib)] of NOX4 “normalized” CAF to a quiescent phenotype and promoted intratumoral CD8+ T-cell infiltration, overcoming the exclusion effect; TGFβ1 inhibition could prevent, but not reverse, CAF differentiation. Finally, NOX4 inhibition restored immunotherapy response in CAF-rich tumors. These findings demonstrate that CAF-mediated immunotherapy resistance can be effectively overcome through NOX4 inhibition and could improve outcome in a broad range of cancers.Significance:NOX4 is critical for maintaining the immune-suppressive CAF phenotype in tumors. Pharmacologic inhibition of NOX4 potentiates immunotherapy by overcoming CAF-mediated CD8+ T-cell exclusion.Graphical Abstract:http://cancerres.aacrjournals.org/content/canres/80/9/1846/F1.large.jpg.See related commentary by Hayward, p. 1799

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.

SUMMARY:

Use of mechanical thrombectomy for stroke has increased since the publication of trials describing outcome improvement when used in the anterior circulation. These results, however, cannot be directly translated to the posterior circulation. While a high NIHSS score has demonstrated an association with poor outcomes in posterior stroke, the NIHSS is weighted toward hemispheric disease, and complex scores potentially delay definitive imaging diagnosis. We performed a retrospective analysis to ascertain whether any rapidly obtainable demographic or clinical and imaging data have a correlation with patient outcome postthrombectomy. Seventy-three cases were audited between September 2010 and October 2017. Presenting with a Glasgow Coma Scale score of >13 meant that the odds of reaching the primary end point of functional independence (defined as a 90-day modified Rankin Scale score of 0–2) were 5.70 times greater; similarly, presenting with a posterior circulation ASPECTS of >9 resulted in the odds of reaching the primary end point being 4.03 times greater. Older age correlated to a lower odds of independence (0.97, p = .04).

BACKGROUND AND PURPOSE:

Accurate differentiation between glioblastoma and solitary brain metastasis is of vital importance clinically. This study aimed to investigate the potential value of the inflow-based vascular-space-occupancy MR imaging technique, which has no need for an exogenous contrast agent, in differentiating glioblastoma and solitary brain metastasis and to compare it with DSC MR imaging.

Backsplash (hay tấm chắn sau bếp) là yếu tố quan trọng đem lại sự tiện dụng cũng như vẻ đẹp của căn bếp. Một vài kiến thức hữu ích dưới đây sẽ giúp bạn lựa chọn vật liệu ốp bếp lý tưởng nhất.

थैलेसीमिया मुख्यत: एक जेनेटिक यानी अनुवांशिक बीमारी है जो माता-पिता से उनके बच्चों में होती है। इस बीमारी में बच्चों में खून की कमी होने लगती है, जो कि सेहत के लिए बहुत हानिकारक होता है।

Royal Enfield अपनी Classic 350 का न्यू जनरेशन मॉडल लॉन्च करने की तैयारी कर रही है। जानकारी के मुताबिक कंपनी इस मॉडल को इस साल के अंत तक या अगले साल के शुरुआत में ही लॉन्च कर सकती है।

Developer Naughty Dog announced via Twitter a new trailer for the upcoming PlayStation 4 exclusive, The Last of Us Part II, will be released tomorrow, May 6 at 7am PT / 10am ET.

Here is an overview of the game:

Five years after their dangerous journey across the post-pandemic United States, Ellie and Joel have settled down in Jackson, Wyoming. Living amongst a thriving community of survivors has allowed them peace and stability, despite the constant threat of the infected and other, more desperate survivors. When a violent event disrupts that peace, Ellie embarks on a relentless journey to carry out justice and find closure. As she hunts those responsible one by one, she is confronted with the devastating physical and emotional repercussions of her actions.

Key Features:

• A Complex and Emotional Story – Experience the escalating moral conflicts created by Ellie’s relentless pursuit of vengeance. The cycle of violence left in her wake will challenge your notions of right versus wrong, good versus evil, and hero versus villain.

  A Beautiful Yet Dangerous World – Set out on Ellie’s journey, taking her from the peaceful mountains and forests of Jackson to the lush, overgrown ruins of greater Seattle. Encounter new survivor groups, unfamiliar and treacherous environments, and terrifying evolutions of the infected. Brought to life by the latest iteration of the Naughty Dog engine, the deadly characters and world are more realistic and meticulously detailed than ever before.

• Tense and Desperate Action-Survival Gameplay – New and evolved gameplay systems deliver upon the life-or-death stakes of Ellie’s journey through the hostile world. Feel her desperate struggle for survival through improved features such as high-intensity melee combat, fluid movement, and dynamic stealth. A broad variety 

The Last of Us Part II will launch for the PlayStation 4 on June 19.

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/443393/the-last-of-us-part-ii-new-trailer-drops-tomorrow-may-6/

Publisher Sony Interactive Entertainment and developer Naughty Dog have released the story trailer for The Last of Us Part II ahead of the game's release next month.

View the trailer below:

Here is an overview of the game:

Five years after their dangerous journey across the post-pandemic United States, Ellie and Joel have settled down in Jackson, Wyoming. Living amongst a thriving community of survivors has allowed them peace and stability, despite the constant threat of the infected and other, more desperate survivors. When a violent event disrupts that peace, Ellie embarks on a relentless journey to carry out justice and find closure. As she hunts those responsible one by one, she is confronted with the devastating physical and emotional repercussions of her actions.

Key Features:

• A Complex and Emotional Story – Experience the escalating moral conflicts created by Ellie’s relentless pursuit of vengeance. The cycle of violence left in her wake will challenge your notions of right versus wrong, good versus evil, and hero versus villain.

  A Beautiful Yet Dangerous World – Set out on Ellie’s journey, taking her from the peaceful mountains and forests of Jackson to the lush, overgrown ruins of greater Seattle. Encounter new survivor groups, unfamiliar and treacherous environments, and terrifying evolutions of the infected. Brought to life by the latest iteration of the Naughty Dog engine, the deadly characters and world are more realistic and meticulously detailed than ever before.

• Tense and Desperate Action-Survival Gameplay – New and evolved gameplay systems deliver upon the life-or-death stakes of Ellie’s journey through the hostile world. Feel her desperate struggle for survival through improved features such as high-intensity melee combat, fluid movement, and dynamic stealth. A broad variety of weapons, crafting items, skills, and upgrades allows you to personalize Ellie’s capabilities to your play style.

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/443406/the-last-of-us-part-ii-story-trailer-released/

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

Glass has an unusual atomic structure that resembles a liquid frozen in place, making it hard to predict how it will behave. DeepMind has developed an AI capable of doing so, which may also be able to predict traffic jams

The US Navy is researching how to use lasers to form plasma into 2D or 3D infrared images of aeroplanes that can distract heat-seeking missiles

AI can check satellite images of the ocean and distinguish between floating materials such as seaweed or plastics, which could help clean-up efforts

This film gives us insight into a community that’s already endured plenty even before the zombies arrived.

The Milky Way ate another galaxy called Gaia-Enceladus, and the waves passing through a star have shown us that it happened at most 11.6 billion years ago

Strange, powerful blasts of radio waves from space called fast radio bursts sometimes flash repeatedly, but never with any discernible pattern – until now

A huge black hole from when the universe was less than a billion years old is shooting a powerful jet at Earth, and studying it could help us understand the young cosmos

Faraway galaxies have been spotted unexpectedly flashing up to 100 times their usual brightness, and it seems to be caused by eddies in Earth’s atmosphere

Your weekly selection of awesome robot videos

A Facebook executive challenges the Arm processor community to create tech building blocks for augmented reality glasses

Just in time for Mother's Day/continued at-home quarantine comes this 750mL 'My Personal Bottomless Mimosa' glass from BigMouth, Inc and available on Amazons. The surprisingly all-glass drinkware (but still hand-wash only on account of the decorations) combines the shape of a champagne bottle with a mimosa glass to holds 8 (read: 2-3) servings, and is perfect for letting the rest of your family know you're not to be bothered for the rest of the day because it may still be early here but, dammit, it's 5 o'clock somewhere that's nine and half hours ahead. Thanks to Tracey H, who informed me she can't count the number of times she's been asked to leave a bottomless brunch for really putting its bottomlessness to the test. Heck yeah, that's called doing God's work.

Skimming system tripled previous best effort at oil collection.

Faked 'entanglement' result challenges cryptographic technique.

Alice and Chris are stranded on a lonely planet, sharing nothing in common but their plight. Meanwhile Anna opens a hole to the meat dimension...