Organ-on-a-chip platforms serve as cost-efficient testbeds for screening pharmaceutical agents, mimicking natural physiology, and studying disease. In the field of diabetes, the development of an ...islet-on-a-chip platform would have broad implications in understanding disease pathology and discovering potential therapies. Islet microphysiological systems are limited, however, by their poor cell survival and function in culture. A key factor that has been implicated in this decline is the disruption of islet-matrix interactions following isolation. Herein, we sought to recapitulate the in vivo peri-islet niche using decellularized extracellular matrix (ECM) hydrogels. Sourcing from porcine bladder, lung, and pancreas tissues, 3-D ECM hydrogels were generated, characterized, and validated using both rodent and human pancreatic islets. Optimized decellularization protocols resulted in hydrogels with distinctive viscoelastic properties that correlated to their matrix composition. The in situ 3-D encapsulation of human or rat islets within ECM hydrogels resulted in improved functional stability over standard culture conditions. Islet composition and morphology were also altered, with enhanced retention of islet-resident endothelial cells and the formation of cord-like structures or sprouts emerging from the islet spheroid. These supportive 3-D physiomimetic ECM hydrogels can be leveraged within microfluidic platforms for the long-term culture of islets.
The BCL-2 inhibitor venetoclax combined with hypomethylating agents or low-dose cytarabine represents an important new therapy for older or unfit patients with acute myeloid leukemia (AML). We ...analyzed 81 patients receiving these venetoclax-based combinations to identify molecular correlates of durable remission, response followed by relapse (adaptive resistance), or refractory disease (primary resistance). High response rates and durable remissions were typically associated with NPM1 or IDH2 mutations, with prolonged molecular remissions prevalent for NPM1 mutations. Primary and adaptive resistance to venetoclax-based combinations was most commonly characterized by acquisition or enrichment of clones activating signaling pathways such as FLT3 or RAS or biallelically perturbing TP53. Single-cell studies highlighted the polyclonal nature of intratumoral resistance mechanisms in some cases. Among cases that were primary refractory, we identified heterogeneous and sometimes divergent interval changes in leukemic clones within a single cycle of therapy, highlighting the dynamic and rapid occurrence of therapeutic selection in AML. In functional studies, FLT3 internal tandem duplication gain or TP53 loss conferred cross-resistance to both venetoclax and cytotoxic-based therapies. Collectively, we highlight molecular determinants of outcome with clinical relevance to patients with AML receiving venetoclax-based combination therapies.
•Adaptive resistance is often associated with TP53 abnormalities or kinase activation, particularly FLT3 internal tandem duplication.•NPM1 mutation is associated with excellent survival prospects and durable molecular remission after venetoclax-based combination therapy.
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To determine whether recommended amounts of leisure-time physical activity (ie, 7.5-15 metabolic equivalent task MET hours/week) are associated with lower cancer risk, describe the shape of the ...dose-response relationship, and explore associations with moderate- and vigorous-intensity physical activity.
Data from 9 prospective cohorts with self-reported leisure-time physical activity and follow-up for cancer incidence were pooled. Multivariable Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% CIs of the relationships between physical activity with incidence of 15 types of cancer. Dose-response relationships were modeled with restricted cubic spline functions that compared 7.5, 15.0, 22.5, and 30.0 MET hours/week to no leisure-time physical activity, and statistically significant associations were determined using tests for trend (
< .05) and 95% CIs (< 1.0).
A total of 755,459 participants (median age, 62 years range, 32-91 years; 53% female) were followed for 10.1 years, and 50,620 incident cancers accrued. Engagement in recommended amounts of activity (7.5-15 MET hours/week) was associated with a statistically significant lower risk of 7 of the 15 cancer types studied, including colon (8%-14% lower risk in men), breast (6%-10% lower risk), endometrial (10%-18% lower risk), kidney (11%-17% lower risk), myeloma (14%-19% lower risk), liver (18%-27% lower risk), and non-Hodgkin lymphoma (11%-18% lower risk in women). The dose response was linear in shape for half of the associations and nonlinear for the others. Results for moderate- and vigorous-intensity leisure-time physical activity were mixed. Adjustment for body mass index eliminated the association with endometrial cancer but had limited effect on other cancer types.
Health care providers, fitness professionals, and public health practitioners should encourage adults to adopt and maintain physical activity at recommended levels to lower risks of multiple cancers.
Somatostatin and dopamine are two major neurotransmitter systems that share a number of structural and functional characteristics. Somatostatin receptors and dopamine receptors are colocalized in ...neuronal subgroups, and somatostatin is involved in modulating dopamine-mediated control of motor activity. However, the molecular basis for such interaction between the two systems is unclear. Here, we show that dopamine receptor D2R and somatostatin receptor SSTR5 interact physically through hetero-oligomerization to create a novel receptor with enhanced functional activity. Our results provide evidence that receptors from different G protein (heterotrimeric guanine nucleotide binding protein)-coupled receptor families interact through oligomerization. Such direct intramembrane association defines a new level of molecular crosstalk between related G protein-coupled receptor subfamilies.
Summary
Alzheimer's disease (AD) is the sixth leading cause of death in the USA today; therefore, it is imperative that public health initiatives and clinical strategies are developed to prevent and ...effectively treat AD. Despite the enormous impact that AD has on individuals, families, society, and the health care system, there are no biomarkers to clearly identify those at risk for AD, public health prevention strategies in place, or treatments to address the underlying pathology or stop the progression of AD. There is ample scientific as well as empirical evidence that obesity and its metabolic and vascular comorbidities are related to AD and likely in the causative pathway. Obesity prevention and treatment could prove to be an efficacious and safe approach to preventing AD, a serious and daunting epidemic disease. In this review, we present the current pathophysiological and clinical evidence linking obesity and obesity‐related comorbidities (eg, insulin resistance, hyperglycaemia, and type 2 diabetes) with AD. Additionally, we discuss which population to target and when to consider treatment for AD. Finally, we summarize the current evidence regarding the efficacy of anti‐obesity and anti‐diabetic pharmacotherapeutic agents for the treatment of AD.
We assess the possibility of decreasing the breakdown pressure of rock and increasing the damage around hydraulic fracture by using pre-breakdown cyclic injection during hydraulic fracturing under ...triaxial stress conditions. Unlike the monotonous increase in pressure used in conventional hydraulic fracturing, the fluid is injected in cycles until breakdown. During cyclic injection, the peak pressure of each cycle is increased in an increment of 10% of the reference breakdown pressure. The reference breakdown pressure of the rock is the pressure at which the rocks fails during hydraulic fracturing by conventional injection. To obtain a reference breakdown pressures, specimens of dry and saturated Tennessee sandstone were hydraulically fractured by conventional injection. The decrease in breakdown pressure and increase in damage during cyclic injection is quantitatively compared with the case of conventional hydraulic fracturing. Acoustic emission (AE), fracture permeability, and Scanning Electron Microscope (SEM) images of the fracture surface were used to compare the damage around hydraulic fractures generated by conventional and cyclic injection hydraulic fracturing. Laboratory results indicate that the damage generated around hydraulic fracture by cyclic injection hydraulic fracturing of dry Tennessee sandstone is approximately twice that generated by conventional injection. Also, the breakdown pressure recorded during cyclic injection fracturing of dry Tennessee sandstone is lower and varies more than two standard deviations from that of conventional injection.
•A new method of hydraulic fracturing by pre-breakdown cyclic injection is proposed.•The method decreased breakdown pressure of dry Tennessee sandstone.•The method increased damage zone around hydraulic fracture.•Pre-breakdown cyclic injection caused increase in the fracture permeability.•The decrease in breakdown pressure and increase in damage zone is due to fatigue.
Autoimmune encephalitis is a relatively new category of immune-mediated disease involving the central nervous system that demonstrates a widely variable spectrum of clinical presentations, ranging ...from the relatively mild or insidious onset of cognitive impairment to more complex forms of encephalopathy with refractory seizure. Due to its diverse clinical features, which can mimic a variety of other pathologic processes, autoimmune encephalitis presents a diagnostic challenge to clinicians. Imaging findings in patients with these disorders can also be quite variable, but recognizing characteristic findings within limbic structures suggestive of autoimmune encephalitis can be a key step in alerting clinicians to the potential diagnosis and ensuring a prompt and appropriate clinical work-up. In this article, we review antibody-mediated encephalitis and its various subtypes with a specific emphasis on the role of neuroimaging in the diagnostic work-up.
After all, it's active: High‐resolution scanning electrochemical cell microscopy (SECCM) demonstrates that electron transfer at the basal plane of highly oriented pyrolytic graphite (HOPG) is fast. ...This finding requires radical revision of the current textbook model for HOPG electrochemistry.
Moving from sitting to standing is a common activity of daily living. The five-repetition sit-to-stand test (5STS) is a test of lower limb function that measures the fastest time taken to stand five ...times from a chair with arms folded. The 5STS has been validated in healthy community-dwelling adults, but data in chronic obstructive pulmonary disease (COPD) populations are lacking.
To determine the reliability, validity and responsiveness of the 5STS in patients with COPD.
Test-retest and interobserver reliability of the 5STS was measured in 50 patients with COPD. To address construct validity we collected data on the 5STS, exercise capacity (incremental shuttle walk (ISW)), lower limb strength (quadriceps maximum voluntary contraction (QMVC)), health status (St George's Respiratory Questionnaire (SGRQ)) and composite mortality indices (Age Dyspnoea Obstruction index (ADO), BODE index (iBODE)). Responsiveness was determined by measuring 5STS before and after outpatient pulmonary rehabilitation (PR) in 239 patients. Minimum clinically important difference (MCID) was estimated using anchor-based methods.
Test-retest and interobserver intraclass correlation coefficients were 0.97 and 0.99, respectively. 5STS time correlated significantly with ISW, QMVC, SGRQ, ADO and iBODE (r=-0.59, -0.38, 0.35, 0.42 and 0.46, respectively; all p<0.001). Median (25th, 75th centiles) 5STS time decreased with PR (Pre: 14.1 (11.5, 21.3) vs Post: 12.4 (10.2, 16.3) s; p<0.001). Using different anchors, a conservative estimate for the MCID was 1.7 s.
The 5STS is reliable, valid and responsive in patients with COPD with an estimated MCID of 1.7 s. It is a practical functional outcome measure suitable for use in most healthcare settings.
Active galactic nuclei, which are powered by long-term accretion onto central supermassive black holes, produce relativistic jets with lifetimes of at least one million years, and the observation of ...the birth of such a jet is therefore unlikely. Transient accretion onto a supermassive black hole, for example through the tidal disruption of a stray star, thus offers a rare opportunity to study the birth of a relativistic jet. On 25 March 2011, an unusual transient source (Swift J164449.3+573451) was found, potentially representing such an accretion event. Here we report observations spanning centimetre to millimetre wavelengths and covering the first month of evolution of a luminous radio transient associated with Swift J164449.3+573451. The radio transient coincides with the nucleus of an inactive galaxy. We conclude that we are seeing a newly formed relativistic outflow, launched by transient accretion onto a million-solar-mass black hole. A relativistic outflow is not predicted in this situation, but we show that the tidal disruption of a star naturally explains the observed high-energy properties and radio luminosity and the inferred rate of such events. The weaker beaming in the radio-frequency spectrum relative to γ-rays or X-rays suggests that radio searches may uncover similar events out to redshifts of z ≈ 6.
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