Search

This study evaluated the spread and possible changes in resistance patterns of ESKAPE bacteria to first-choice antibiotics from 2015 to 2019 at a third-level university hospital after persuasive stewardship measures were implemented. Isolates were divided into three groups (group 1, low drug-resistant; group 2, multidrug/extremely drug-resistant; and group 3, pan-resistant bacteria) and a

Management of severe thrombocytopenia, particularly of ITP, in pregnancy is mainly based on expert consensus and clinical experience while there are no clear indications about the minimum platelet count requested for prenatal diagnosis invasive procedures. Since the lack of specific recommendations we reported our clinical management of a patient suffering from severe thrombocytopenia, undergoing amniocentesis. Due to the anecdotic possibility of maternal and fetal bleeding in case of severe thrombocytopenia, prophylaxis with IVIG or even corticosteroids could be considered as a safer strategy to prevent post-procedural adverse outcomes.

Figure S1 related to Figure 1 shows that MLN4924 reduces oligo-ubiquitylation of Lats2 and that Merlin-mutant schwannoma cells have a lower on-target sensitivity to MLN4924 than a genetically matched Merlin-positive Schwann line. Also shows that canonical YAP target genes are not expressed highly in FC-1801 cells.

Supplementary Materials and Methods, Supplementary Figure Legends, Supplementary Table 1, Supplementary References

Inactivation of NF2/Merlin causes the autosomal-dominant cancer predisposition syndrome familial neurofibromatosis type 2 (NF2) and contributes to the development of malignant pleural mesothelioma (MPM). To develop a targeted therapy for NF2-mutant tumors, we have exploited the recent realization that Merlin loss drives tumorigenesis by activating the E3 ubiquitin ligase CRL4DCAF1, thereby inhibiting the Hippo pathway component Lats. Here, we show that MLN4924, a NEDD8-activating enzyme (NAE) inhibitor, suppresses CRL4DCAF1 and attenuates activation of YAP in NF2-mutant tumor cells. In addition, MLN4924 sensitizes MPM to traditional chemotherapy, presumably as a result of collateral inhibition of cullin-RING ubiquitin ligases (CRL) involved in DNA repair. However, even in combination with chemotherapy, MLN4924 does not exhibit significant preclinical activity. Further analysis revealed that depletion of DCAF1 or treatment with MLN4924 does not affect mTOR hyperactivation in NF2-mutant tumor cells, suggesting that loss of Merlin activates mTOR independently of CRL4DCAF1. Intriguingly, combining MLN4924 with the mTOR/PI3K inhibitor GDC-0980 suppresses the growth of NF2-mutant tumor cells in vitro as well as in mouse and patient-derived xenografts. These results provide preclinical rationale for the use of NAE inhibitors in combination with mTOR/PI3K inhibitors in NF2-mutant tumors.

Supplementary Figure S1. Loss of heterozygosity of Ch22q genes in poorly differentiated (PDTC) and anaplastic thyroid cancers (ATC). Supplementary Figure S2. Focal NF2-exon 4 homozygous deletion in KHM-5M anaplastic thyroid cancer cells. Supplementary Figure S3. FISH for NF2 in anaplastic thyroid cancers. Supplementary Figure S4. NF2/Merlin defects in thyroid cancer cell lines. Supplementary Figure S5. Merlin inhibits RAC1-PAK activity. Supplementary Figure S6. Merlin effects on EGFR signaling and growth of RAS mutant thyroid cancer cell lines. Supplementary Figure S7. PCR of genomic DNA from mouse thyroid tissues of the indicated genotypes with primers that distinguish wild-type from mutant Hras alleles. Supplementary Figure S8. TEAD1 is the most abundant TEAD isoform in thyroid cancer cells. Supplementary Figure S9. A) Left, Concentration-dependent growth inhibitory effects of the MEK inhibitor selumetinib (AZD6244) in RAS mutant thyroid cancer cell lines cells. Black, null/low NF2. Red, wt NF2. The IC50 of each cell line is shown in the boxed legend. Right, Western blots for merlin, pMEK and pERK in the cell lines studied. B) C643 cells expressing scrambled (pLKO.1) or shNF2 were treated with FRAX, AZD or their combination at the indicated concentrations (nM) in 1 percent of serum. Cells were counted at 6 days (*p

To evaluate the potential of Intravoxel Incoherent Motion (IVIM) Imaging in the quantification of placental micro-perfusion and microstructural features to identify and discriminate different forms of intrauterine growth restriction (IUGR) and normal fetuses pregnancies.Small for gestational age SGA (fp and D* of the placental fetal side discriminate between SGA and FGR (Perfusion IVIM parameters fp and D* may be useful to discriminate different micro-vascularization patterns in IUGR being helpful to detect microvascular subtle impairment even in fetuses without any sign of US Doppler impairment

A major problem of the primary healthcare system is the deficiency in performance quality. From the second half of the 20th century, many countries introduced pay for performance reimbursement schemes to encourage practitioner behaviour to align with specific objectives of decision-makers and to incentivise the provision of targeted services. The study of Krauth et al. (2016) provides key evidence from a European country, determining whether German general practitioners would participate in a pay for performance programme and under what conditions. Our research replicates this survey, adjusting it to the Italian context. We assessed the attitudes of Italian general practitioners towards the current remuneration scheme and analysed how such views varied among respondents. Results showed that the current remuneration scheme for Italian general practitioners does not seem to be proportional to the efforts given for the provision of care and does not provide appropriate incentives to supply high-quality healthcare. Most of respondents supported the introduction of a pay for performance remuneration system, although perceived potential obstacles. We conclude that for a successful implementation of a quality-based compensation scheme, GPs should be involved. Such participation would help better identify perceived obstacles and overcome them.

There is increasing evidence that many molecular processes exhibit differences with age 1 and sex. Such differences produces also differences in the insurgence and progression of many 2 complex diseases. For instances, demographic data on insurgence of comorbidities of mellitus 3 diabetes, on lethality of COVID-19, and on some cancers, shows differences between sex and age 4 groups. Therefore, the growing interest on such area requires the management of related data as 5 well as the development of algorithms and tool for the analysis. The availability of omics data 6 annotated with metadata related to age and sex is mandatory for building pipeline of the analysis. 7 The number of databases containing data related to age and sex is hencefort growing. We here show 8 some databases and tools storing such data. Finally, future research direction are highlighte

STAT3 function in hematopoietic stem and progenitor cells (HSPCs) has been difficult to discern asStat3deficiency in the hematopoietic system induces systemic inflammation, which can impact HSPC activity. To address this, we established mixed bone marrow (BM) chimeric mice with CreER-mediatedStat3deletion in 20% of the hematopoietic compartment.Stat3-deficient HSPCs had impaired hematopoietic activity and failed to undergo expansion in BM in contrast toStat3-sufficient (CreER) controls. Single-cell RNA sequencing of Lin−ckit+Sca1+BM cells revealed altered transcriptional responses inStat3-deficient hematopoietic stem cells (HSCs) and multipotent progenitors, including intrinsic activation of cell cycle, stress response, and interferon signaling pathways. Consistent with their deregulation,Stat3-deficient Lin−ckit+Sca1+cells accumulated γH2AX over time. Following secondary BM transplantation,Stat3-deficient HSPCs failed to reconstitute peripheral blood effectively, indicating a severe functional defect in the HSC compartment. Our results reveal essential roles for STAT3 in HSCs and suggest the potential for using targeted synthetic lethal approaches with STAT3 inhibition to remove defective or diseased HSPCs.Key PointsSTAT3 is critical for hematopoietic activity and hematopoietic stem cell maintenance in non-inflammatory conditionsSTAT3 has a cell-intrinsic role in the suppression of interferon signaling and myeloid-skewed transcription in hematopoietic stem cells

OBJECTIVE This prospective observational study aims to assess the association between maternal abdominal subcutaneous and visceral fat thickness measured with ultrasound scan during the first trimester and the risk of developing gestational diabetes mellitus (GDM). MATERIALS AND METHODS We recruited 43 non-diabetic women with singleton pregnancy between 11 and 14 weeks' gestation and evaluated ultrasonographic measurements of subcutaneous fat thickness (SFT) and preperitoneal fat (PF) above the umbilicus. During 2nd trimester, GDM screening was performed by 75g two-hour oral glucose tolerance test (OGTT) and diagnosis was made when one or more plasma glucose values meets or exceeds the values indicated by International Association of the Diabetes and Pregnancy Study Groups (IADPSG). RESULTS Among the 43 woman, 8 developed GDM (18.6%). Of these 37,5% (n=3) had been diagnosed with GDM during a previous pregnancy, with a statistically significant correlation (p = 0.035). Mean SFT for all patients was significantly higher in the GDM group compared to non GDM group (27.30±8.78 mm vs 18.56±9.99 mm; p value =0.049). Mean PF for all women showed a statistically significant correlation with GDM (13.27±9.07 mm for non GDM group vs 23.52±10.24 mm for GDM group; p value = 0.038). CONCLUSIONS Abdominal adiposity, both subcutaneous and visceral, seem to be suitable predictors of GDM in early pregnancy and can be easily assessed during a first trimester routine ultrasound, although further studies are needed to evaluate their role in the screening protocols.

Human norovirus is the first cause of foodborne disease worldwide, leading to extensive outbreaks of acute gastroenteritis, and causing around 200,000 children to die annually in developing countries. No specific vaccines or antiviral agents are currently available, with therapeutic options limited to supportive care to prevent dehydration. The infection can become severe and lead to life-threatening complications in young children, the elderly and immunocompromised individuals, leading to a clear need for antiviral agents, to be used as treatments and as prophylactic measures in case of outbreaks. Due to the key role played by the viral RNA-dependent RNA polymerase (RdRp) in the virus life cycle, this enzyme is a promising target for antiviral drug discovery. In previous studies, following in silico investigations, we identified different small-molecule inhibitors of this enzyme. In this study, we rationally modified five identified scaffolds, to further explore structure-activity relationships, and to enhance binding to the RdRp. The newly designed compounds were synthesized according to multiple-step synthetic routes and evaluated for their inhibition of the enzyme in vitro. New inhibitors with low micromolar inhibitory activity of the RdRp were identified, which provide a promising basis for further hit-to-lead optimization. ispartof: VIRUSES-BASEL vol:15 issue:1 ispartof: location:Switzerland status: published