Purpose:

Currently, an optimal therapeutic strategy comprising molecularly targeted agents for treating EGFR-mutated non–small cell lung cancer (NSCLC) patients with acquired resistance to osimertinib is not available. Therefore, the initial therapeutic intervention is crucial for the prolonged survival of these patients. The activation of anexelekto (AXL) signaling is known to be associated with intrinsic and acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). In this study, we investigated the best therapeutic strategy to combat AXL-induced tolerance to EGFR-TKIs using the novel AXL inhibitor ONO-7475.

Antibiotics revolutionized the treatment of infectious diseases; however, it is now clear that broad-spectrum antibiotics alter the composition and function of the host’s microbiome. The microbiome plays a key role in human health, and its perturbation is increasingly recognized as contributing to many human diseases. Widespread broad-spectrum antibiotic use has also resulted in the emergence of multidrug-resistant pathogens, spurring the development of pathogen-specific strategies such as monoclonal antibodies (MAbs) to combat bacterial infection. Not only are pathogen-specific approaches not expected to induce resistance in nontargeted bacteria, but they are hypothesized to have minimal impact on the gut microbiome. Here, we compare the effects of antibiotics, pathogen-specific MAbs, and their controls (saline or control IgG [c-IgG]) on the gut microbiome of 7-week-old, female, C57BL/6 mice. The magnitude of change in taxonomic abundance, bacterial diversity, and bacterial metabolites, including short-chain fatty acids (SCFA) and bile acids in the fecal pellets from mice treated with pathogen-specific MAbs, was no different from that with animals treated with saline or an IgG control. Conversely, dramatic changes were observed in the relative abundance, as well as alpha and beta diversity, of the fecal microbiome and bacterial metabolites in the feces of all antibiotic-treated mice. Taken together, these results indicate that pathogen-specific MAbs do not alter the fecal microbiome like broad-spectrum antibiotics and may represent a safer, more-targeted approach to antibacterial therapy.

In children requiring lopinavir coformulated with ritonavir in a 4:1 ratio (lopinavir-ritonavir-4:1) and rifampin, adding ritonavir to achieve a 4:4 ratio with lopinavir (LPV/r-4:4) overcomes the drug-drug interaction. Possible drug-drug interactions within this regimen may affect abacavir concentrations, but this has never been studied. Children weighing <15 kg needing rifampin and LPV/r-4:4 were enrolled in a pharmacokinetic study and underwent intensive pharmacokinetic sampling on 3 visits: (i) during the intensive and (ii) continuation phases of antituberculosis treatment with LPV/r-4:4 and (iii) 1 month after antituberculosis treatment completion on LPV/r-4:1. Pharmacometric modeling and simulation were used to compare exposures across weight bands with adult target exposures. Eighty-seven children with a median (interquartile range) age and weight of 19 (4 to 64) months and 8.7 (3.9 to 14.9) kg, respectively, were included in the abacavir analysis. Abacavir pharmacokinetics were best described by a two-compartment model with first-order elimination and transit compartment absorption. After allometric scaling adjusted for the effect of body size, maturation could be identified: clearance was predicted to be fully mature at about 2 years of age and to reach half of this mature value at about 2 months of age. Abacavir bioavailability decreased 36% during treatment with rifampin and LPV/r-4:4 but remained within the median adult recommended exposure, except for children in the 3- to 4.9-kg weight band, in which the exposures were higher. The observed predose morning trough concentrations were higher than the evening values. Though abacavir exposure significantly decreased during concomitant administration of rifampin and LPV/r-4:4, it remained within acceptable ranges. (This study is registered in ClinicalTrials.gov under identifier NCT02348177.)

Low-dose adjuvant epigenetic therapy (AET) reduced metastasis and promoted survival in mouse models.

Background:

Asian Americans are at higher risk for noncardia gastric cancers (NCGC) relative to non-Hispanic Whites (NHW). Asian Americans are genetically, linguistically, and culturally heterogeneous, yet have mostly been treated as a single population in prior studies. This aggregation may obscure important subgroup-specific cancer patterns.

Tobacco smoking is the primary risk factor for lung cancer, driven by the addictive nature of nicotine and the indisputable carcinogenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) as well as other compounds. The integration of lung cancer chemoprevention with smoking cessation is one potential approach to reduce this risk and mitigate lung cancer mortality. Experimental data from our group suggest that kava, commonly consumed in the South Pacific Islands as a beverage to promote relaxation, may reduce lung cancer risk by enhancing NNK detoxification and reducing NNK-derived DNA damage. Building upon these observations, we conducted a pilot clinical trial to evaluate the effects of a 7-day course of kava on NNK metabolism in active smokers. The primary objective was to compare urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL plus its glucuronides, major metabolites of NNK) before and after kava administration as an indicator of NNK detoxification. Secondary objectives included determining kava's safety, its effects on DNA damage, tobacco use, and cortisol (a biomarker of stress). Kava increased urinary excretion of total NNAL and reduced urinary 3-methyladenine in participants, suggestive of its ability to reduce the carcinogenicity of NNK. Kava also reduced urinary total nicotine equivalents, indicative of its potential to facilitate tobacco cessation. Plasma cortisol and urinary total cortisol equivalents were reduced upon kava use, which may contribute to reductions in tobacco use. These results demonstrate the potential of kava intake to reduce lung cancer risk among smokers.

RING-finger E3 ligases are instrumental in the regulation of inflammatory cascades, apoptosis, and cancer. However, their roles are relatively unknown in TGFβ/SMAD signaling. SMAD3 and its adaptors, such as β2SP, are important mediators of TGFβ signaling and regulate gene expression to suppress stem cell–like phenotypes in diverse cancers, including hepatocellular carcinoma (HCC). Here, PJA1, an E3 ligase, promoted ubiquitination and degradation of phosphorylated SMAD3 and impaired a SMAD3/β2SP-dependent tumor-suppressing pathway in multiple HCC cell lines. In mice deficient for SMAD3 (Smad3+/−), PJA1 overexpression promoted the transformation of liver stem cells. Analysis of genes regulated by PJA1 knockdown and TGFβ1 signaling revealed 1,584 co-upregulated genes and 1,280 co-downregulated genes, including many implicated in cancer. The E3 ligase inhibitor RTA405 enhanced SMAD3-regulated gene expression and reduced growth of HCC cells in culture and xenografts of HCC tumors, suggesting that inhibition of PJA1 may be beneficial in treating HCC or preventing HCC development in at-risk patients.Significance: These findings provide a novel mechanism regulating the tumor suppressor function of TGFβ in liver carcinogenesis.

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:

Endovascular embolization only has been advocated for treatment of brain arteriovenous malformations in recent trials. Our aim was to evaluate the results of embolization only in a cohort of patients who were enrolled in the A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) study at 39 clinical sites in 9 countries.

BACKGROUND AND PURPOSE:

Flow diversion for the posterior circulation remains a promising treatment option for selected posterior circulation aneurysms. The Flow-Redirection Intraluminal Device (FRED) system has not been previously assessed in a large cohort of patients with posterior circulation aneurysms. The purpose of the present study was to assess safety and efficacy of FRED in this location.

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.

In the third quarter (Q3) of this year, Ho Chi Minh City (HCMC) saw no new supply of affordable housing entering the market. Low profit margin has made this segment unattractive to housing developers.

Prof. Jason Pomeroy talks about the rise of the digital economy and its impact on the workplace.

To make the dream of settling down in a prosperous city come true, young couples, especially ones with limited budgets, need to prepare the right steps to get your home sweet home.

One of the most dramatic changes you can make to effectively boost value of your home is giving your kitchen some renovations.

When you are confident that your home does not need any major repairs that will stop a buyer’s home inspection, you can focus on easy updates to make your home more attractive to buyers.

राजस्थान में शुक्रवार को कोरोना वायरस संक्रमण के 64 नए मामले सामने आए और एक बीमार व्यक्ति की मौत हो गई। अब राज्य में कोरोना की वजह से मौतों का आंकड़ा 100 हो गया है और कुल संक्रमितों की संख्या 3491 हो गई है।

लॉक डाउन का तीसरा चरण शहरियों पर संक्रमण के लिहाज से भारी पड़ा है। महाराष्ट्र और दिल्ली से आए लोग कोरोना संक्रमितों की संख्या बढ़ने का कारण बने। एक मई से सात मई तक सिर्फ पांच दिन में संक्रमितों की संख्या पांच से 17 हो गई।

जिले में बढ़ते कोरोना संक्रमण के बीच राहत की खबर है। शंकरगढ़ के कपारी गांव के दोनों कोरोना पॉजिटिव युवकों की तीसरी बार कराई गई जांच की रिपोर्ट शुक्रवार को निगेटिव आई है। वहीं तेलियरगंज के शंकरघाट निवासी संक्रमित युवक की रिपोर्ट अभी आनी बाकी है...

स्वरूपरानी नेहरू चिकित्सालय में सर्जरी विभाग की पीजी छात्रा प्रथम वर्ष की कोरोना की जांच रिपोर्ट निगेटिव आई है। इसके बाद चिकित्सालय प्रशासन ने राहत की सांस ली है। उधर, ओपीडी में आने वालों में चार लोगों को संदिग्ध मानते हुए भर्ती किया गया है।

Super Flower Moon 2020 time आज इस साल का आखिरी सुपरमून (Supermoon 2020) देखा जाएगा। मई माह में इस सुपर मून को सुपर फ्लॉवर मून (Super Flower Moon) भी कहा जाता है।

7 मई को साल का आखिरी सुपरमून है। सुपरमून उसे कहते हैं जब चंद्रमा अपनी कक्षा में चक्कर काटते हुए पृथ्वी के सबसे करीब आ जाता है। चांद के पृथ्वी के नजदीक आने पर चंद्रमा का आकार और चमक काफी बढ़ जाती है।

वैश्विक महामारी कोरोना वायरस से निपटने के लिए लगाया गया लॉकडाउन जारी है। आज लॉकडाउन 3.0 का छठा दिन है। वहीं, देशभर में संक्रमित मरीजों की संख्या में लगातार बढ़ोतरी हो रही है

लग्जरी कार बनाने वाली जर्मनी की दिग्गज ऑटोमोबाइल कंपनी BMW (बीएमडब्ल्यू) ने अपनी BMW 8 Series Gran Coupe (8-सीरीज ग्रैन कूपे) और BMW M8 Coupe (एम-8 कूपे) भारतीय बाजार में लॉन्च कर दिया है।

Microsoft and Sony are both hard at working preparing their next generation consoles, the Xbox Series X and PlayStation 5, for launch this holiday season. 

A key factor in getting as many consoles shipped for both companies will be from AMD, who will be providing the latest Zen 2-powered CPU and matching Navi GPU.

AMD is ramping up production as they expect semi-custom revenue to grow in the second quarter and have a big increase in the second half of 2020 as they provide parts for the Xbox Series X and PS5. 

"We expect semi-custom revenue to increase in the second quarter and be heavily weighted towards the second-half of the year, as we ramp production to support the holiday launches of the new PlayStation 5 and Xbox Series X consoles," said AMD CEO Dr. Lisa Su. 

Thanks Tom's Hardware.

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/443398/amd-ramping-up-cpu-production-for-xbox-series-x-and-playstation-5/

The world according to two of the scene’s most dedicated rave architects. Gabber Eleganza and HDMIRROR make a formidable duo on their new collaborative track ‘Frozen Dopamina’, which arrives with a video capturing the world at its most euphoric. The track is taken from The Real Life, a new collaborative release from the two producers […]

The post Gabber Eleganza & HDMIRROR chase euphoria on ‘Frozen Dopamina’ appeared first on FACT Magazine.

As part of its eventual launch on Steam, daunting simulation Dwarf Fortress has been planning a big visual overhaul. “Now with graphics!” Bay 12 proclaim on the store page. In a new little update, they’re giving us a look at what the generated world maps will look like with these non-ASCII pixels—though, yes, you’ll still […]

If you didn’t feel challenged enough by Indivisible‘s main platforming and punching campaign, here’s some good news for ya. Lab Zero have released a new DLC for their turn-ish-based RPG today that promises the “forty specially crafted levels await to test your platforming and combat skills.” The Razmi’s Challenges DLC is available now, so you […]

As any good Guardian knows, Destiny 2 isn’t just a jargon-filled sci-fi loot ’em up. It’s just as much, if not more so, a far-future fashion show. But in a game about constantly trading out new gear, keeping a fresh look has always felt a little contentious. This week, Bungie revealed that Year 4 will […]

For most of Doom Eternal‘s demonic foes, the best they can expect is to make a nice corpse. A particularly pleasing splash of gore on the Doom Slayer’s boot. But for those lucky few that manage to take down our man in green, a special reward will soon be in store. Doom Eternal’s first major […]

Getting married is one of life’s most memorable — and emotional — milestones in life. But with tight restrictions on gatherings due to COVID-19 pandemic, couples throughout Windsor and Essex County who had scheduled their weddings for this spring or summer have had little choice but to postpone their big day. “Weddings are an extremely […]

Within months researchers will attempt to create a ball of plasma hotter than the sun inside the Joint European Torus, a doughnut-shaped machine in south-east England