Notes

Towards a Semantic Data Harmonization Federated Facilities.
We suggest that the LLPS model provides the starting point for a unifying quantitative framework for the assembly, structural maintenance and function of the nucleolus, with implications for gene regulation and ribonucleoprotein particle assembly throughout the nucleus. selleck chemicals llc The LLPS concept is also likely useful in designing new therapeutic strategies to target nucleolar dysfunction.The removal of functionally dispensable, infected or potentially neoplastic cells is driven by programmed cell death (PCD) pathways, highlighting their important roles in homeostasis, host defence against pathogens, cancer and a range of other pathologies. Several types of PCD pathways have been described, including apoptosis, necroptosis and pyroptosis; they employ distinct molecular and cellular processes and differ in their outcomes, such as the capacity to trigger inflammatory responses. Recent genetic and biochemical studies have revealed remarkable flexibility in the use of these PCD pathways and indicate a considerable degree of plasticity in their molecular regulation; for example, despite having a primary role in inducing pyroptosis, inflammatory caspases can also induce apoptosis, and conversely, apoptotic stimuli can trigger pyroptosis. Intriguingly, this flexibility is most pronounced in cellular responses to infection, while apoptosis is the dominant cell death process through which organisms prevent the development of cancer. In this Review, we summarize the mechanisms of the different types of PCD and describe the physiological and pathological processes that engage crosstalk between these pathways, focusing on infections and cancer. We discuss the intriguing notion that the different types of PCD could be seen as a single, coordinated cell death system, in which the individual pathways are highly interconnected and can flexibly compensate for one another.The incidence of brain metastases has markedly increased in the past 20 years owing to progress in the treatment of malignant solid tumours, earlier diagnosis by MRI and an ageing population. Although local therapies remain the mainstay of treatment for many patients with brain metastases, a growing number of systemic options are now available and/or are under active investigation. HER2-targeted therapies (lapatinib, neratinib, tucatinib and trastuzumab emtansine), alone or in combination, yield a number of intracranial responses in patients with HER2-positive breast cancer brain metastases. New inhibitors are being investigated in brain metastases from ER-positive or triple-negative breast cancer. Several generations of EGFR and ALK inhibitors have shown activity on brain metastases from EGFR and ALK mutant non-small-cell lung cancer. Immune-checkpoint inhibitors (ICIs) hold promise in patients with non-small-cell lung cancer without druggable mutations and in patients with triple-negative breast cancer. The survival of patients with brain metastases from melanoma has substantially improved after the advent of BRAF inhibitors and ICIs (ipilimumab, nivolumab and pembrolizumab). The combination of targeted agents or ICIs with stereotactic radiosurgery could further improve the response rates and survival but the risk of radiation necrosis should be monitored. Advanced neuroimaging and liquid biopsy will hopefully improve response evaluation.
This controlled-feeding randomised controlled trial examined free-living appetite and physical activity (PA) on 'fast' and 'feed' days during intermittent energy restriction (IER), compared to continuous energy restriction (CER).

Forty-six women with overweight/obesity (age = 35 ± 10 years, BMI = 29.1 ± 2.3 kg/m
) were randomised to IER (n = 24; alternate fast days at 25% energy requirements and ad libitum feed days) or CER (n = 22; 75% energy requirements daily) to ≥5% weight loss (WL) or up to 12 weeks. Self-reported energy intake (EI; online food record), objectively measured PA (SenseWear Armband) and retrospective daily hunger and food cravings were measured over 7 days at baseline, week 2 and final week. Intent-to-treat analyses were performed using linear mixed models.

Final WL (M
 = 4.7 [95% confidence interval 4.2, 5.2] kg, 5.9%) did not differ between IER and CER (interaction P = 0.307). During IER, feed-day EI did not differ from baseline and was lower in the final week compared to week 2 (M
 = 295 [81, 509] kcal, P = 0.004). Daily hunger was greater on fast compared to feed days (M
 = 15 [10, 21] mm, P < 0.001), but food cravings did not differ. Light PA was lower on fast relative to feed days (M
 = 18 [2, 34] min/day, P = 0.024), with no other differences in PA. Compared to CER, IER increased hunger and led to smaller improvements in craving control (both interactions P ≤ 0.034).

IER fast days were associated with increased free-living hunger and lower light PA compared to feed days, but had no impact on food cravings or self-reported ad libitum daily EI. IER may be less favourable than CER for the free-living day-to-day control of hunger and food cravings.
IER fast days were associated with increased free-living hunger and lower light PA compared to feed days, but had no impact on food cravings or self-reported ad libitum daily EI. IER may be less favourable than CER for the free-living day-to-day control of hunger and food cravings.Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and their associated CRISPR-associated nucleases (Cas) are among the most promising technologies for the treatment of hemoglobinopathies including Sickle Cell Disease (SCD). We are only beginning to identify the molecular variables that influence the specificity and the efficiency of CRISPR- directed gene editing, including the position of the cleavage site and the inherent variability among patient samples selected for CRISPR-directed gene editing. Here, we target the beta globin gene in human CD34+ cells to assess the impact of these two variables and find that both contribute to the global diversity of genetic outcomes. Our study demonstrates a unique genetic profile of indels that is generated based on where along the beta globin gene attempts are made to correct the SCD single base mutation. Interestingly, even within the same patient sample, the location of where along the beta globin gene the DNA is cut, HDR activity varies widely. Our data establish a framework upon which realistic protocols inform strategies for gene editing for SCD overcoming the practical hurdles that often impede clinical success.
Upfront chemotherapy prolongs overall survival for men with metastatic, hormone-sensitive prostate cancer (mHSPC) based on data from clinical trials. We sought to assess the association between upfront chemotherapy and overall survival in men with mHSPC in a real-world cohort.

We performed a retrospective cohort study of men with de novo, treatment-naïve metastatic prostate cancer from a large, national cancer database in the United States (2014-2015). Men in the upfront chemotherapy group received chemotherapy within 4 months of diagnosis (n = 1033, 28%) versus no chemotherapy or chemotherapy later than 12 months after diagnosis (controls; n = 2704, 72%). Overall survival was assessed using Kaplan-Meier estimates and compared using multivariable Cox regression analysis.

After a median follow-up of 23 months, median overall survival was 35.7 months in the upfront chemotherapy group and 32.5 months for controls (log-rank p < 0.001). After adjusting for patient and clinical variables, upfront chemother outside of clinical trials to demonstrate treatment efficacy in populations that may be underrepresented in clinical trials.
We hypothesized that the survival benefit of external beam radiation therapy (EBRT) recorded in European low-volume metastatic prostate cancer (mPCA) patients, will apply to similar North American patients.

Newly diagnosed mPCa patients with M1a/b substages, treated with EBRT or no EBRT were abstracted from the Surveillance, Epidemiology, and End Results database (2004-2016). Kaplan-Meier plots and Cox-regression models targeted overall mortality (OM) and cancer specific-mortality (CSM) according to EBRT administration. M1 substages and PSA stratified analyses were performed. Internal validation relied on 2000 bootstrap resamples.

Of 15,494 patients, 1156 (7.5%) were M1a vs 14,338 (92.5%) were M1b. PSA at diagnosis ≤10.0 ng/ml was recorded in 1463 (9.4%) patients. In all 15,494 patients, EBRT did not affect OM (hazard ratio [HR] 1.0; p = 0.5). However, in M1a patients and M1b patients with PSA ≤ 10.0 ng/ml EBRT was associated with lower OM (HR 0.73, CI 0.62-0.86; p < 0.001) but not in M1b patients with PSA > 10.0 ng/ml. The PSA cut-off of ≤ 10.0 ng/ml represented the most statistically significant cut-off for OM prediction in M1b patients. Moreover, internal validation with 2000 bootstrap resamples confirmed these findings. Finally, all results were virtually the same, when CSM represented the endpoint of interest.

We validated the OM reduction associated with EBRT in M1a and M1b patients with PSA ≤ 10.0 ng/ml but not in M1b patients with PSA > 10.0 ng/ml. In consequence, it appears that a smaller subset of North American mPCa patients benefit of EBRT than originally reported in European patients. Further North American validation studies are essential.
 10.0 ng/ml. In consequence, it appears that a smaller subset of North American mPCa patients benefit of EBRT than originally reported in European patients. Further North American validation studies are essential.Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms are common clinical concerns that affect aging men all over the world. The underlying molecular and cellular mechanisms remain elusive. Over the past few years, a number of animal models of BPH, including spontaneous model, BPH-induction model, xenograft model, metabolic syndrome model, mechanical obstruction model, and transgenic model, have been established that may provide useful tools to fill these critical knowledge gaps. In this review, we therefore outlined the present status quo for animal models of BPH, comparing the pros and cons with respect to their ability to mimic the etiological, histological, and clinical hallmarks of BPH and discussed their applicability for future research.
Immortalization of primary prostate epithelial cells (PrEC) with just hTERT expression is particularly inefficient in the absence of DNA tumor viral proteins or p16
knockdown.

Here, we describe the establishment of immortalized normal prostate epithelial cell line models using CRISPR technology to inactivate the CDKN2A locus concomitantly with ectopic expression of an hTERT transgene.

Using this approach, we have obtained immortal cell clones that exhibit fundamental characteristics of normal cells, including diploid genomes, near normal karyotypes, normal p53 and pRB cell responses, the ability to form non-invasive spheroids, and a non-transformed phenotype. Based on marker expression, these clones are of basal cell origin.

Use of this approach resulted in the immortalization of independent clones of PrEC that retained normal characteristics, were stable, and non-transformed. Thus, this approach could be used for the immortalization of normal primary prostate cells. This technique could also be useful for establishing cell lines from prostate tumor tissues of different tumor grades and/or from patients of diverse ethnicities to generate cell line models that facilitate the study of the molecular basis of disease disparity.
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