What is currently known about endometrial cancer in Lynch syndrome? - review

Introduction: About 5% of endometrial cancer cases can be genetic and inherited. Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is an autosomal dominant syndrome. Caused by a germline mutation in one of the DNA mismatch repair genes, it is responsible for most hereditary cases. Lynch syndrome is associated with the early onset and the development of many types of cancer, especially colon and endometrial cancer. Methods: The review of publications regarding Lynch syndrome-associated endometrial cancer and methods for screening, diagnosis and its prevention. State of knowelage: Endometrial cancers related to Lynch syndrome are mostly sentinel (they reveal the predisposition in 50% of families) and are characterized by young age at onset (commonly before 60 years). The lifetime cumulative risk of endometrial cancer for women with Lynch syndrome is about 40% to 60%, which equals or exceeds their risk of colorectal cancer. Lynch syndrome, the current gynecologic cancer screening guidelines include annual endometrial sampling and transvaginal ultrasonography beginning at age of 30-35 years, which is very important in the early detection of this cancer. Risk-reducing surgery consisting of prophylactic hysterectomy and bilateral salpingooophorectomy should be offered to women aged 35 years or older who do not wish to preserve their fertility. Summary: Diagnosis of endometrial cancer in patients with Lynch syndrome has important clinical implications for the individual and family members

Droplet-based digital antibiotic susceptibility screen reveals single-cell clonal heteroresistance in an isogenic bacterial population

Since antibiotic resistance is a major threat to global health, recent observations that the traditional test of minimum inhibitory concentration (MIC) is not informative enough to guide effective antibiotic treatment are alarming. Bacterial heteroresistance, in which seemingly susceptible isogenic bacterial populations contain resistant sub-populations, underlies much of this challenge. To close this gap, here we developed a droplet-based digital MIC screen that constitutes a practical analytical platform for quantifying the single-cell distribution of phenotypic responses to antibiotics, as well as for measuring inoculum effect with high accuracy. We found that antibiotic efficacy is determined by the amount of antibiotic used per bacterial colony forming unit (CFU), not by the absolute antibiotic concentration, as shown by the treatment of beta-lactamase-carrying Escherichia coli with cefotaxime. We also noted that cells exhibited a pronounced clustering phenotype when exposed to near-inhibitory amounts of cefotaxime. Overall, our method facilitates research into the interplay between heteroresistance and antibiotic efficacy, as well as research into the origin and stimulation of heterogeneity by exposure to antibiotics. Due to the absolute bacteria quantification in this digital assay, our method provides a platform for developing reference MIC assays that are robust against inoculum-density variations

Droplet-based digital antibiotic susceptibility screen reveals single-cell clonal heteroresistance in an isogenic bacterial population

Since antibiotic resistance is a major threat to global health, recent observations that the traditional test of minimum inhibitory concentration (MIC) is not informative enough to guide effective antibiotic treatment are alarming. Bacterial heteroresistance, in which seemingly susceptible isogenic bacterial populations contain resistant sub-populations, underlies much of this challenge. To close this gap, here we developed a droplet-based digital MIC screen that constitutes a practical analytical platform for quantifying the single-cell distribution of phenotypic responses to antibiotics, as well as for measuring inoculum effect with high accuracy. We found that antibiotic efficacy is determined by the amount of antibiotic used per bacterial colony forming unit (CFU), not by the absolute antibiotic concentration, as shown by the treatment of beta-lactamase-carrying Escherichia coli with cefotaxime. We also noted that cells exhibited a pronounced clustering phenotype when exposed to near-inhibitory amounts of cefotaxime. Overall, our method facilitates research into the interplay between heteroresistance and antibiotic efficacy, as well as research into the origin and stimulation of heterogeneity by exposure to antibiotics. Due to the absolute bacteria quantification in this digital assay, our method provides a platform for developing reference MIC assays that are robust against inoculum-density variations

Vemurafenib and dabrafenib downregulates RIPK4 level

Vemurafenib and dabrafenib are BRAF kinase inhibitors (BRAFi) used for the treatment of patients with melanoma carrying the V600E BRAF mutation. However, melanoma cells develop resistance to both drugs when used as monotherapy. Therefore, mechanisms of drug resistance are investigated, and new molecular targets are sought that could completely inhibit melanoma progression. Since receptor-interacting protein kinase (RIPK4) probably functions as an oncogene in melanoma and its structure is similar to the BRAF protein, we analyzed the impact of vemurafenib and dabrafenib on RIPK4 in melanomas. The in silico study confirmed the high similarity of BRAF kinase domains to the RIPK4 protein at both the sequence and structural levels and suggests that BRAFi could directly bind to RIPK4 even more strongly than to ATP. Furthermore, BRAFi inhibited ERK1/2 activity and lowered RIPK4 protein levels in BRAF-mutated melanoma cells (A375 and WM266.4), while in wild-type BRAF cells (BLM and LoVo), both inhibitors decreased the level of RIPK4 and enhanced ERK1/2 activity. The phosphorylation of phosphatidylethanolamine binding protein 1 (PEBP1) - a suppressor of the BRAF/MEK/ERK pathway - via RIPK4 observed in pancreatic cancer did not occur in melanoma. Neither downregulation nor upregulation of RIPK4 in BRAF- mutated cells affected PEBP1 levels or the BRAF/MEK/ERK pathway. The downregulation of RIPK4 inhibited cell proliferation and the FAK/AKT pathway, and increased BRAFi efficiency in WM266.4 cells. However, the silencing of RIPK4 did not induce apoptosis or necroptosis. Our study suggests that RIPK4 may be an off-target for BRAF inhibitors

Experimental study of smog microphysical and optical vertical structure in the Silesian Beskids, Poland

This study presents the vertical profiles of aerosol optical and microphysical properties obtained from cable car and ground-based measurements in the Silesian Beskids, Poland. The data were collected during a measurement campaign between 25 February and March 11, 2018. An AE-51 micro-aethalometer and PMS7003 and OPC-N2 optical particle counters were mounted on the cable car and used to measure the profiles of equivalent of black carbon (eBC) concentration and aerosol size distribution. In situ measurements of the optical properties of the aerosols were obtained using an AE-31 aethalometer and photoacoustic devices. A prototype lidar was used to determine the planetary boundary layer (PBL) height and the aerosol layers. In the middle phase of the study (1–6 March 2018), significant night-time temperature inversions were observed. During the inversion period, the parameters describing the amount of aerosols in the air increased significantly. The concentration of eBC exceeded the level of 15 μg/m3 several times, with an average level of 5.39 ± 4.42 μg/m3. Conversely, the results obtained in the first and third phases of the experiment were at the level of the aerosol background, being 1.45 ± 0.88 μg/m3 and 0.90 ± 0.95 μg/m3, respectively. Significant differences were also observed in the vertical profiles of PM10 mass and eBC concentration. In the middle phase of the study, the profiles showed a significant reduction in the concentration of pollutants with height, while in the first and third phases, there were slight variations with height

Kultura i społeczeństwo na Środkowym Nadodrzu w XIX i XX wieku

303 s. : il., portr.