Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer associated with advanced age and immunosuppression. Over the past decade, an association has been discovered between MCC and either ...integration of the Merkel cell polyomavirus, which likely drives tumorigenesis, or somatic mutations owing to ultraviolet-induced DNA damage. Both virus-positive and virus-negative MCCs are immunogenic, and inhibition of the programmed cell death protein 1 (PD-1)-programmed cell death 1 ligand 1 (PD-L1) immune checkpoint has proved to be highly effective in treating patients with metastatic MCC; however, not all patients have a durable response to immunotherapy. Despite these rapid advances in the understanding and management of patients with MCC, many basic, translational and clinical research questions remain unanswered. In March 2018, an International Workshop on Merkel Cell Carcinoma Research was held at the US National Cancer Institute, at which academic, government and industry experts met to identify the highest-priority research questions. Here, we review the biology and treatment of MCC and report the consensus-based recommendations agreed upon during the workshop.
The binding and cytochrome P45051 (CYP51) inhibition properties of a novel antifungal compound, VT-1161, against purified recombinant Candida albicans CYP51 (ERG11) and Homo sapiens CYP51 were ...compared with those of clotrimazole, fluconazole, itraconazole, and voriconazole. VT-1161 produced a type II binding spectrum with Candida albicans CYP51, characteristic of heme iron coordination. The binding affinity of VT-1161 for Candida albicans CYP51 was high (dissociation constant Kd, ≤ 39 nM) and similar to that of the pharmaceutical azole antifungals (Kd, ≤ 50 nM). In stark contrast, VT-1161 at concentrations up to 86 μM did not perturb the spectrum of recombinant human CYP51, whereas all the pharmaceutical azoles bound to human CYP51. In reconstitution assays, VT-1161 inhibited Candida albicans CYP51 activity in a tight-binding fashion with a potency similar to that of the pharmaceutical azoles but failed to inhibit the human enzyme at the highest concentration tested (50 μM). In addition, VT-1161 (MIC = 0.002 μg ml(-1)) had a more pronounced fungal sterol disruption profile (increased levels of methylated sterols and decreased levels of ergosterol) than the known CYP51 inhibitor voriconazole (MIC = 0.004 μg ml(-1)). Furthermore, VT-1161 weakly inhibited human CYP2C9, CYP2C19, and CYP3A4, suggesting a low drug-drug interaction potential. In summary, VT-1161 potently inhibited Candida albicans CYP51 and culture growth but did not inhibit human CYP51, demonstrating a >2,000-fold selectivity. This degree of potency and selectivity strongly supports the potential utility of VT-1161 in the treatment of Candida infections.
Deaths from COVID-19 continue to rise, and this virus has asymmetric impacts on marginalized communities though specific impacts on sexual and gender minority communities are not well understood. ...From March 23 to June 20, 2020, in an online cross-sectional survey among 1380 US adults, we assessed physical symptoms, psychological symptoms, rumination, and perceived social support in order to describe differences between sexual and gender minority (n = 290) and cisgender heterosexual (n = 1090) respondents. Sexual and gender minority respondents had more frequent COVID-19-associated physical symptoms and depression and anxiety symptoms. Sexual and gender minorities had a significantly higher proportion of depression and anxiety scores exceeding the clinical concern threshold. Longitudinal studies on the physical and psychological impacts of COVID-19 among sexual and gender minority communities are needed to inform interventions to eliminate these disparities.
Vaccine development efforts are being streamlined by the participation of many countries in efforts to coordinate and standardize key aspects of vaccine research and development, including a Target ...Product Profile (TPP) defining preferred and critical vaccine characteristics, animal models, assays to evaluate immune response, and designs for late-stage clinical trials 3. ...country distribution systems should be safe and efficient. The authors call research institutions, developers and manufacturers of SARS-CoV-2 vaccines to make publicly available detailed information of the temperature stability and target product profile (vaccine presentation details) even before clinical trials are completed, so that all potential time-temperature indicator developers have ample time to produce necessary devices/tools, and countries start planning for successful management of vaccine receipt, storage, distribution, and country-wide vaccinations.
Gastroesophageal adenocarcinoma (GEA) has a poor prognosis and few therapeutic options. Utilizing a 73-gene plasma-based next-generation sequencing (NGS) cell-free circulating tumor DNA (ctDNA-NGS) ...test, we sought to evaluate the role of ctDNA-NGS in guiding clinical decision-making in GEA.
We evaluated a large cohort (
= 2,140 tests; 1,630 patients) of ctDNA-NGS results (including 369 clinically annotated patients). Patients were assessed for genomic alteration (GA) distribution and correlation with clinicopathologic characteristics and outcomes.
Treatment history, tumor site, and disease burden dictated tumor-DNA shedding and consequent ctDNA-NGS maximum somatic variant allele frequency. Patients with locally advanced disease having detectable ctDNA postoperatively experienced inferior median disease-free survival (
= 0.03). The genomic landscape was similar but not identical to tissue-NGS, reflecting temporospatial molecular heterogeneity, with some targetable GAs identified at higher frequency via ctDNA-NGS compared with previous primary tumor-NGS cohorts. Patients with known microsatellite instability-high (MSI-High) tumors were robustly detected with ctDNA-NGS. Predictive biomarker assessment was optimized by incorporating tissue-NGS and ctDNA-NGS assessment in a complementary manner. HER2 inhibition demonstrated a profound survival benefit in
-amplified patients by ctDNA-NGS and/or tissue-NGS (median overall survival, 26.3 vs. 7.4 months;
= 0.002), as did EGFR inhibition in
-amplified patients (median overall survival, 21.1 vs. 14.4 months;
= 0.01).
ctDNA-NGS characterized GEA molecular heterogeneity and rendered important prognostic and predictive information, complementary to tissue-NGS.
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Stroke patients are at increased risk of falls and fractures. The aim of this study was to determine the rate, predictors and consequences of falls within 2 years after stroke in a prospective ...population-based study in North Dublin, Ireland.
Prospective population-based cohort study.
567 adults aged >18 years from the North Dublin Population Stroke Study.
Participants were enrolled from an Irish urban population of 294,592 individuals, according to recommended criteria. Patients were followed for 2 years. Outcome measures included death, modified Rankin Scale (mRS), fall and fracture rate.
At 2 years, 23.5% (124/522) had fallen at least once since their stroke, 14.2% (74/522) had 2 or more falls and 5.4% (28/522) had a fracture. Of 332 survivors at 2 years, 107 (32.2%) had fallen, of whom 60.7% (65/107) had 2 or more falls and 23.4% (25/107) had fractured. In a multivariable model controlling for age and gender, independent risk factors for falling within the first 2 years of stroke included use of alpha-blocker medications for treatment of hypertension (P = 0.02). When mobility measured at Day 90 was included in the model, patients who were mobility impaired (mRS 2-3) were at the highest risk of falling within 2 years of stroke odds ratio (OR) 2.30, P = 0.003 and those functionally dependent (mRS 4-5) displayed intermediate risk (OR 2.02, P = 0.03) when compared with independently mobile patients.
Greater attention to falls risk, fall prevention strategies and bone health in the stroke population are required.
Cardiac arrest (CA) and hemorrhagic shock (HS) are two clinically relevant situations where the body undergoes global ischemia as blood pressure drops below the threshold necessary for adequate organ ...perfusion. Resistance to ischemia/reperfusion (I/R) injury is a characteristic of hibernating mammals. The present study sought to determine if arctic ground squirrels (AGS) are protected from systemic inflammation and multi organ damage after CA- or HS-induced global I/R and if, for HS, this protection is dependent upon their hibernation season.
For CA, rats and summer euthermic AGS (AGS-EU) were asphyxiated for 8 min, inducing CA. For HS, rats, AGS-EU, and winter interbout arousal AGS (AGS-IBA) were subject to HS by withdrawing blood to a mean arterial pressure of 35 mmHg and maintaining that pressure for 20 min before reperfusion with Ringers. For both I/R models, body temperature (Tb) was kept at 36.5-37.5°C. After reperfusion, animals were monitored for seven days (CA) or 3 hrs (HS) then tissues and blood were collected for histopathology, clinical chemistries, and cytokine level analysis (HS only). For the HS studies, additional groups of rats and AGS were monitored for three days after HS to access survival and physiological impairment.
Rats had increased serum markers of liver damage one hour after CA while AGS did not. For HS, AGS survived 72 hours after I/R whereas rats did not survive overnight. Additionally, only rats displayed an inflammatory response after HS. AGS maintained a positive base excess, whereas the base excess in rats was negative during and after hemorrhage.
Regardless of season, AGS are resistant to organ damage, systemic inflammation, and multi organ damage after systemic I/R and this resistance is not dependent on their ability to become decrease Tb during insult but may stem from an altered acid/base and metabolic response during I/R.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although research has largely focused on the effects of physical activity (PA) on the brain, less is known about the influence of the brain on engagement in healthy-living behaviors, such as regular ...PA. In this secondary analysis of a study of brain activity and participation in healthy-living behaviors, we examined relationships between the activation of selected brain networks and PA in persons self-managing chronic conditions. Fifty-eight individuals with chronic conditions underwent functional magnetic resonance imaging while exposed to a protocol consisting of listening to emotion-focused and analytic-focused information and measures of activation of three neuromarkers were obtained: default mode network (DMN), task-positive network (TPN), and ventromedial prefrontal cortex (vmPFC). In an exploratory analysis, we assessed differences in neuromarker activation between two PA levels (representing higher and lower accelerometry-measured PA levels) of
) moderate-to-vigorous physical activity (MVPA) minutes,
) metabolic equivalents expended (METs), and
) daily steps. Results showed positive associations between MVPA and DMN (
= 0.31,
= 0.018), steps and DMN (
= 0.28,
= 0.035), and MVPA and vmPFC (
= 0.29,
= 0.026). No associations were found between the TPN and any of the PA measures. Individuals with high MVPA and METs had higher DMN values compared with those with low MVPA (
= -2.17,
= 0.035) and METs (
= -2.02,
= 0.048). No differences in TPN and vmPFC were found among PA levels. These results suggest that providing health information that activates the emotion-focused brain network may be more useful than analytic-focused information (centered on logic and reasoning) to assist people with chronic conditions to engage in more PA.
The influence of the brain on engagement in regular physical activity (PA) has not been well studied. We examined relationships between the activation of three neuromarkers and two PA levels in 58 persons self-managing chronic conditions. Findings suggest that individuals who optimally process health-information when the emotional tone is high (Empathic Network; DMN) may engage in more PA compared with individuals who respond to health information when the emotional tone is low (Analytic Network; TPN).
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