A 78-year-old male presented at the emergency room complaining of dry cough, fever up to 38.5 °C and malaise for 1 month. He had visited a general practitioner and received amoxicillin 500 mg three times a day for 7 days for a presumed chest infection, without improvement. He had a history of diabetes and arterial blood hypertension, for which he was receiving metformin 1000 mg twice a day and amlodipine 10 mg a day for 7 years. He reported no alcohol abuse and was an ex-smoker of 20 pack-years (quit 30 years ago). He had no recent hospitalisations or any medical interventions.

Purpose:

There are several agents in early clinical trials targeting components of the adenosine pathway including A2AR and CD73. The identification of cancers with a significant adenosine drive is critical to understand the potential for these molecules. However, it is challenging to measure tumor adenosine levels at scale, thus novel, clinically tractable biomarkers are needed.

Experimental Design:

We generated a gene expression signature for the adenosine signaling using regulatory networks derived from the literature and validated this in patients. We applied the signature to large cohorts of disease from The Cancer Genome Atlas (TCGA) and cohorts of immune checkpoint inhibitor–treated patients.

Results:

The signature captures baseline adenosine levels in vivo (r² = 0.92, P = 0.018), is reduced after small-molecule inhibition of A2AR in mice (r² = –0.62, P = 0.001) and humans (reduction in 5 of 7 patients, 70%), and is abrogated after A2AR knockout. Analysis of TCGA confirms a negative association between adenosine and overall survival (OS, HR = 0.6, P < 2.2e^–16) as well as progression-free survival (PFS, HR = 0.77, P = 0.0000006). Further, adenosine signaling is associated with reduced OS (HR = 0.47, P < 2.2e^–16) and PFS (HR = 0.65, P = 0.0000002) in CD8⁺ T-cell–infiltrated tumors. Mutation of TGFβ superfamily members is associated with enhanced adenosine signaling and worse OS (HR = 0.43, P < 2.2e^–16). Finally, adenosine signaling is associated with reduced efficacy of anti-PD1 therapy in published cohorts (HR = 0.29, P = 0.00012).

Conclusions:

These data support the adenosine pathway as a mediator of a successful antitumor immune response, demonstrate the prognostic potential of the signature for immunotherapy, and inform patient selection strategies for adenosine pathway modulators currently in development.

Of four genotypes of Encephalitozoon cuniculi, E. cuniculi genotype II is considered to represent a parasite that occurs in many host species in a latent asymptomatic form, whereas E. cuniculi genotype III seems to be more aggressive, and infections caused by this strain can lead to the death of even immunocompetent hosts. Although albendazole has been considered suitable for treatment of Encephalitozoon species, its failure in control of E. cuniculi genotype III infection has been reported. This study determined the effect of a 100x recommended daily dose of albendazole on an Encephalitozoon cuniculi genotype III course of infection in immunocompetent and immunodeficient mice and compared the results with those from experiments performed with a lower dose of albendazole and E. cuniculi genotype II. The administration of the regular dose of abendazole during the acute phase of infection reduced the number of affected organs in all strains of mice and absolute counts of spores in screened organs. However, the effect on genotype III was minor. Surprisingly, no substantial effect was recorded after the use of a 100x dose of albendazole, with larger reductions seen only in the number of affected organs and absolute counts of spores in all strains of mice, implying variations in albendazole resistance between these Encephalitozoon cuniculi genotypes. These results imply that differences in the course of infection and the response to treatment depend not only on the immunological status of the host but also on the genotype causing the infection. Understanding how microsporidia survive in hosts despite targeted antimicrosporidial treatment could significantly contribute to research related to human health.

Mutations in protein-coding genes are well established as the basis for human cancer, yet how alterations within noncoding genome, a substantial fraction of which contain cis-regulatory elements (CRE), contribute to cancer pathophysiology remains elusive. Here, we developed an integrative approach to systematically identify and characterize noncoding regulatory variants with functional consequences in human hematopoietic malignancies. Combining targeted resequencing of hematopoietic lineage–associated CREs and mutation discovery, we uncovered 1,836 recurrently mutated CREs containing leukemia-associated noncoding variants. By enhanced CRISPR/dCas9–based CRE perturbation screening and functional analyses, we identified 218 variant-associated oncogenic or tumor-suppressive CREs in human leukemia. Noncoding variants at KRAS and PER2 enhancers reside in proximity to nuclear receptor (NR) binding regions and modulate transcriptional activities in response to NR signaling in leukemia cells. NR binding sites frequently colocalize with noncoding variants across cancer types. Hence, recurrent noncoding variants connect enhancer dysregulation with nuclear receptor signaling in hematopoietic malignancies.

Significance:

We describe an integrative approach to identify noncoding variants in human leukemia, and reveal cohorts of variant-associated oncogenic and tumor-suppressive cis-regulatory elements including KRAS and PER2 enhancers. Our findings support a model in which noncoding regulatory variants connect enhancer dysregulation with nuclear receptor signaling to modulate gene programs in hematopoietic malignancies.

See related commentary by van Galen, p. 646.

This article is highlighted in the In This Issue feature, p. 627

Amplification of and oncogenic mutations in ERBB2, the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody–drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with ERBB2-amplified or -mutant lung cancers. We show that cotreatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy.

Significance:

T-DM1 is clinically effective in lung cancers with amplification of or mutations in ERBB2. This activity is enhanced by cotreatment with irreversible pan-HER inhibitors, or ADC switching to T-DXd. These results may help address unmet needs of patients with HER2-activated tumors and no approved targeted therapy.

See related commentary by Rolfo and Russo, p. 643.

This article is highlighted in the In This Issue feature, p. 627

Calcium (Ca²⁺) and cyclic AMP (cAMP) signaling cross talk and synergize to stimulate the cardinal functions of exocrine cells, regulated exocytosis, and fluid and electrolyte secretion. This physiological process requires the organization of the two signaling pathways into complexes at defined cellular domains and close placement. Such domains are formed by membrane contact sites (MCS). This review discusses the basic properties of Ca²⁺ signaling in exocrine cells, the role of MCS in the organization of cell signaling and in cross talk and synergism between the Ca²⁺ and cAMP signaling pathways and, finally, the mechanism by which the Ca²⁺ and cAMP pathways synergize to stimulate epithelial fluid and electrolyte secretion.

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.

People with type 1 diabetes may receive a significant portion of their care from primary care providers (PCPs). To understand the involvement of PCPs in delivering type 1 diabetes care, we performed surveys in California and Florida, two of the most populous and diverse states in the United States. PCPs fill insulin prescriptions but report low confidence in providing type 1 diabetes care and difficulty accessing specialty referrals to endocrinologists.

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.

Background:

The impact of light-intensity physical activity (LPA) in preventing cancer mortality has been questioned. To address this concern, the present meta-analysis aimed to quantify the association between objectively-measured LPA and risk of cancer mortality.

Methods:

We conducted a systematic literature search in PubMed and Scopus to January 2020. Prospective cohort studies reporting the association between objectively-measured LPA using activity monitors (e.g., accelerometers) and risk of cancer mortality in the general population were included. The summary hazard ratios (HR) per 30 min/day of LPA and 95% confidence intervals (CI) were obtained using a random-effects model. Dose–response analysis was used to plot their relationship.

Results:

Five prospective cohort studies were included, in which the definition of LPA based on accelerometer readings was mainly set within 100 to 2,100 counts/min. The summary HR for cancer mortality per 30 min/day of LPA was 0.86 (95% CI, 0.79–0.95; I² < 1%), and the association between LPA and risk reduction in cancer mortality was linearly shaped (P_nonlinearity = 0.72). LPA exhibited a comparable magnitude of risk reduction in cancer mortality of moderate-to-vigorous physical activity regardless of equal time-length (0.87 per 30 min/day vs. 0.94 per 30 min/day, P_interaction = 0.46) or equal amount (0.74 vs. 0.94 per 150 metabolic equivalents-min/day, P_interaction = 0.11). Furthermore, replacing sedentary time by LPA of 30 min/day decreased the risk of cancer mortality by 9%.

Conclusions:

Objectively-measured LPA conferred benefits in decreasing the risk of cancer mortality.

Impact:

LPA should be considered in physical activity guidelines to decrease the risk of cancer mortality.

Background:

Research on the relationship of meat, fish, and egg consumption and mortality among prostate cancer survivors is limited.

Methods:

In the Cancer Prevention Study-II Nutrition Cohort, men diagnosed with nonmetastatic prostate cancer between baseline in 1992/1993 and 2015 were followed for mortality until 2016. Analyses of pre- and postdiagnosis intakes of red and processed meat, poultry, fish, and eggs included 9,286 and 4,882 survivors, respectively. Multivariable-adjusted RRs and 95% confidence intervals (CI) were estimated using Cox proportional hazards models.

Results:

A total of 4,682 and 2,768 deaths occurred during follow-up in pre- and postdiagnosis analyses, respectively. Both pre- and postdiagnosis intakes of total red and processed meat were positively associated with all-cause mortality (quartile 4 vs. 1: RR = 1.13; 95% CI, 1.03–1.25; P_trend = 0.02; RR = 1.22; 95% CI, 1.07–1.39; P_trend = 0.03, respectively), and both pre- and postdiagnosis poultry intakes were inversely associated with all-cause mortality (quartile 4 vs. 1 RR = 0.90; 95% CI, 0.82–0.98; P_trend = 0.04; RR = 0.84; 95% CI, 0.75–0.95; P_trend = 0.01, respectively). No associations were seen for prostate cancer–specific mortality, except that higher postdiagnosis unprocessed red meat intake was associated with lower risk.

Conclusions:

Higher red and processed meat, and lower poultry, intakes either before or after prostate cancer diagnosis were associated with higher risk of all-cause mortality.

Impact:

Our findings provide additional evidence that prostate cancer survivors should follow the nutrition guidelines limiting red and processed meat consumption to improve overall survival. Additional research on the relationship of specific meat types and mortality is needed.

Background:

Total antioxidant capacity (TAC) reflects an individual's overall antioxidant intake. We sought to clarify whether higher TAC is associated with lower risks of pancreatic cancer incidence and mortality in the U.S. general population.

Methods:

A total of 96,018 American adults were identified from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. A ferric-reducing ability of plasma score was used to reflect an individual's TAC intake from diet and/or supplements. Cox regression was used to calculate hazard ratios (HR) for pancreatic cancer incidence, and competing risk regression was used to calculate subdistribution HRs for pancreatic cancer mortality. Restricted cubic spline regression was used to test nonlinearity.

Results:

A total of 393 pancreatic cancer cases and 353 pancreatic cancer–related deaths were documented. Total (diet + supplements) TAC was found to be inversely associated with pancreatic cancer incidence (HR _{quartile 4 vs. quartile 1} = 0.53; 95% confidence interval, 0.39–0.72; P_trend = 0.0002) and mortality (subdistribution HR _{quartile 4 vs. quartile 1} = 0.52; 95% confidence interval 0.38–0.72; P_trend = 0.0003) in a nonlinear dose–response manner (all P_nonlinearity < 0.01). Similar results were observed for dietary TAC. No association of supplemental TAC with pancreatic cancer incidence and mortality was found.

Conclusions:

In the U.S. general population, dietary but not supplemental TAC level is inversely associated with risks of pancreatic cancer incidence and mortality in a nonlinear dose–response pattern.

Impact:

This is the first prospective study indicating that a diet rich in antioxidants may be beneficial in decreasing pancreatic cancer incidence and mortality.

Background:

The associations of abdominal skeletal muscle mass index (SMI), visceral and subcutaneous adipose tissue (VAT and SAT, respectively), and mortality among patients with stage I–III colorectal cancer may differ for men and women, but only few studies stratified their data into men and women. We investigated associations of abdominal SMI, VAT, and SAT with overall mortality among men and among women with stage I–III colorectal cancer.

Methods:

SMI, VAT, and SAT were assessed from abdominal CT images for 1,998 patients with stage I–III colorectal cancer diagnosed between 2006 and 2015. Restricted cubic splines (RCS) were used to investigate associations of SMI, VAT, and SAT with overall mortality.

Results:

Average age of the participants was 67.9 ± 10.6 years and 58% were men. During a median follow-up of 4.3 years, 546 (27%) patients died. Among men, the association of SMI and mortality was statistically significant in a nonlinear way in the RCS analyses, with lower SMI levels associated with higher mortality. SMI was not associated with mortality among women. SAT was associated with mortality in a nonlinear way for men and for women, with lower SAT levels being associated with higher mortality. VAT was not significantly associated with mortality in men or women.

Conclusion:

Associations of abdominal skeletal muscle mass with mortality among patients with colorectal cancer were not the same for men and for women.

Impact:

This study stresses the importance for more attention on sex-related differences in body composition and cancer outcomes.

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:

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.

MATERIALS AND METHODS:

We identified all patients diagnosed with anoxic brain injuries from 2002 to 2019. Twelve ROIs were drawn on arterial spin-labeling with coordinate-matched ROIs identified on DWI. Linear regression analysis was performed to examine the relationship between arterial spin-labeling perfusion and diffusion signal. Normalized diffusion-to-perfusion maps were generated using a custom-built algorithm.

RESULTS:

Thirty-five patients with anoxic brain injuries and 34 healthy controls were identified. Linear regression analysis demonstrated a significant positive correlation between arterial spin-labeling and DWI signal. By means of a combinatory cutoff of slope of >0 and R² of > 0.78, linear regression using arterial spin-labeling and DWI showed a sensitivity of 0.86 (95% CI, 0.71–0.94) and specificity of 0.82 (95% CI, 0.66–0.92) for anoxic brain injuries. A normalized diffusion-to-perfusion color map demonstrated heterogeneous ratios throughout the brain in healthy controls and homogeneous ratios in patients with anoxic brain injuries.

CONCLUSIONS:

In anoxic brain injuries, a homogeneously positive correlation between qualitative perfusion and DWI signal was identified so that areas of increased diffusion signal showed increased ASL signal. By exploiting this relationship, the normalized diffusion-to-perfusion ratio color map may be a valuable imaging biomarker for diagnosing anoxic brain injury and potentially assessing BBB integrity.

Malibu Hội An được xây dựng theo mô hình biệt thự biển và căn hộ cao cấp với vị trí đắc địa ngay trên cung đường du lịch nổi tiếng của miền Trung - Trường Sa, thuộc bãi biển Hà My, tỉnh Quảng Nam.

Vượt qua hai đối thủ nặng ký là Sydney và Melbourne, thành phố Brisbane thuộc bang Queensland gây bất ngờ khi ghi nhận tăng trưởng giá nhà đạt mốc kỷ lục tại thời điểm thị trường bất động sản Australia nói chung đang trong tình trạng ảm đạm.

Thị trường bất động sản Canberra, Australia gần đây sôi động hơn trước do sự có mặt của các nhà đầu tư và người mua nhà theo đuổi chiến lược rentvesting – vừa thuê nhà ở, vừa đầu tư khi nhận thấy khả năng sinh lời ở hai thị trường trọng điểm truyền thống là Sydney và Melbourne đang giảm sút.

Đây là những sản phẩm BĐS đặc biệt được tung ra thị trường trong bối cảnh dịch bệnh diễn biến phức tạp, nhiều công ty, doanh nghiệp cho phép nhân viên làm việc tại nhà và tự cách ly để tránh rủi ro lây nhiễm bệnh cho nhau.

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.

As anticipated due to the COVID-19 pandemic, Windsor’s unemployment rate closed in on historic levels in April as it reached 12.9 per cent of the labour force, according to the latest numbers released Friday by Statistics Canada. There were 21,800 people in the Windsor area recorded as being unemployed in the latest StatsCan survey. But […]

In the memoir Uncanny Valley, Anna Wiener examines the collective hyperconfidence that has enabled the tech sector’s meteoric growth

Doom Eternal does contain gratuitous violence, but the evidence suggests violence in video games doesn't affect people's behaviour in the real world, says Jacob Aron

Personally, I welcome whatever reality TV drivel Twitch dreams up to feed our insatiable appetite for content.

Exhaust fumes and cold KFC?

As well as announcing reminders to stay away from each other, the robots also estimate how many people are in the park at any given time.

It’s quite the spectacle, but the light show is leading people to be less than cautious about social distancing.

Alison Roman’s latest comments about Marie Kondo have not sparked joy.

In an interview with The New Consumer about her increased popularity and the avenues she might pursue to capitalize on it, the popular food columnist discussed her hesitance to put her name on a product line—citing the Japanese organization maven and Chrissy Teigen as examples of what she did not foresee in her own future.

“I have a collaboration coming out with [the cookware startup] Material, a capsule collection,” Roman said. “It’s limited edition, a few tools that I designed that are based on tools that I use that aren’t in production anywhere—vintage spoons and very specific things that are one-offs that I found at antique markets that they have made for me.”

Read more at The Daily Beast.

Five Australian hospitals are set to receive the experimental coronavirus drug, remdesivir. Sydney's St Vincent hospital has been confirmed as one location, according to a report from The Guardian. More »

Last year, Google turned the mid-range phone market on its head by introducing the ludicrously-priced and well-specced Pixel 3a. A few other brands have followed suit since then, but none have been quite as exciting as the new iPhone SE. Now it truly seems like flagship inclusions at lower price points are here to stay - and it's about damn time. The trend of $1,500 - $2,000 becoming the norm for new phones over the last few years has been bad for buyers. A new middle ground has been long overdue and we welcome it. But is the resurrected iPhone SE actually a good phone to buy in 2020? More »

Apple dropped its brand new 13-inch MacBook Pro overnight, which is exciting because the dreaded butterfly keyboard is now finally dead. For real. In its place you'll find the newer Magic Keyboard which has previously been added to the 16-inch MacBook Pro and the MacBook Air. Today is a good day. If you're keen to get your paws on the new laptop, here's how much it will set you back in Australia. More »

Back in early March Apple announced that it would closing the majority of its physical stores worldwide. Roughly seven weeks later Australian Apple stores will be re-opening their doors around the country later this week. More »

Samsung just released the smaller version of its Galaxy Tab S6 tablet in Australia. Though it did appear in some online stores a little early, now it's official. Here's what its packing and how much it will cost in Australia. More »

Sennheiser has just released its second generation of its noise cancelling earbuds in Australia - the Sennheiser Momentum True Wireless 2. Here's what we know about them and how much they cost. Spoiler alert - they ain't cheap. More »

The cast of Community is reuniting for a virtual table read to raise money for coronavirus relief. Almost all of main cast will be back for the online event, including Donald Glover who left the show in season 5. It will also include a Q&A where fans can submit questions via social media. This is how you can watch it live. More »

Researchers at a Sydney university have discovered how some female bees have managed to reproduce despite never doing the deed with another. More »

We may not have found alien life yet, but new methods and the discovery of exoplanets and extreme life on Earth is revolutionising the hunt, says the doyenne of SETI research

A team of researchers say they have discovered a protein molecule inside a meteorite, the first extraterrestrial example ever found, but others are sceptical

Our images of deep space are spectacular, but don’t reflect what our eyes would see. Here's what their stunning true colours reveal about the cosmos

Extraterrestrial oceans are an obvious place to search for alien life, but getting there and having a look won't be easy, says NASA's Kevin Hand in his book Alien Oceans

The Pulitzer Prize Board this week awarded its commentary award to The New York Times' Nikole Hannah-Jones for her essay launching the "1619 Project." This will accelerate a trend already underway: subjecting schoolchildren to a curriculum that blames slavery on capitalism and whose creator believes socialism offers the best path to racial equity.

Your weekly selection of awesome robot videos

It'll take more than having its fingers chopped off to stop this robot hand

Long before NLP became a hot field in AI, people devised rules and machines to manipulate language

“I didn’t ‘sell out’ by making my dreams come true.”

This is a video from Russia's Zapad-2017 military exercises where a KA-52 Alligator helicopter accidentally fired two missiles towards a group of journalists covering the event (allegedly as a result of a short-circuit in the helicopter's electric system according to the Russian military *eyebarrelroll*). Three of the journalists were injured in the incident (amazingly not critically either), including the one seen strolling along the highway to the danger zone the video. Man, those missiles come QUICK. If you think you're gonna outrun one of those things like a tarantula in Animal Crossing, think again. I mean sure The Flash could do it, but he could also pleasure himself infinitely in the time it took you to read this article. "Huh?" How his penis doesn't catch fire is beyond me, there must be other superpowers at play too. Keep going for a couple versions of the video (the second with slow-mos), as well as a news report which includes the copter's gun view.