There is conflicting data regarding the role of PBAF complex mutations and response to immune checkpoint blockade (ICB) therapy in clear cell renal cell carcinoma (ccRCC) and other solid tumors. We ...assess the prevalence of PBAF complex mutations from two large cohorts including the pan-cancer TCGA project (n = 10,359) and the MSK-IMPACT pan-cancer immunotherapy cohort (n = 3700). Across both cohorts, PBAF complex mutations, predominantly PBRM1 mutations, are most common in ccRCC. In multivariate models of ccRCC patients treated with ICB (n = 189), loss-of-function (LOF) mutations in PBRM1 are not associated with overall survival (OS) (HR = 1.24, p = 0.47) or time to treatment failure (HR = 0.85, p = 0.44). In a series of 11 solid tumors (n = 2936), LOF mutations are not associated with improved OS in a stratified multivariate model (HR = 0.9, p = 0.7). In a current series of solid tumors treated with ICB, we are unable to demonstrate favorable response to ICB in patients with PBAF complex mutations.
Several trials and meta-analyses found a benefit of adjunct corticosteroids for community-acquired pneumonia with respect to short-term outcome, but there is uncertainty about longer-term health ...effects. Herein, we evaluated clinical outcomes at long term in patients participating in the STEP trial (Corticosteroid Treatment for Community-Acquired Pneumonia).
This predefined secondary analysis investigated 180-day outcomes in 785 adult patients hospitalized with community-acquired pneumonia included in STEP, a randomised, placebo-controlled, double-blind trial. The primary endpoint was time to death from any cause at 180 days verified by telephone interview. Additional secondary endpoints included pneumonia-related death, readmission, recurrent pneumonia, secondary infections, new hypertension, and new insulin dependence.
From the originally included 785 patients, 727 were available for intention-to-treat analysis at day 180. There was no difference between groups with respect to time to death from any cause (HR for corticosteroid use 1.15, 95% CI 0.68 to 1.95, p = 0.601). Compared to placebo, corticosteroid-treated patients had significantly higher risks for recurrent pneumonia (OR 2.57, 95% CI 1.29 to 5.12, p = 0.007), secondary infections (OR 1.94, 95% CI 1.25 to 3.03, p = 0.003) and new insulin dependence (OR 8.73, 95% CI 1.10 to 69.62, p = 0.041). There was no difference regarding pneumonia-related death, readmission and new hypertension.
In patients with community-acquired pneumonia, corticosteroid use was associated with an increased risk for recurrent pneumonia, secondary infections and new insulin dependence at 180 days. Currently, it is uncertain whether these long-term adverse effects outweigh the short-term effects of corticosteroids in moderate CAP.
This trial was registered with ClinicalTrials. gov, number NCT00973154 before the recruitment of the first patient. First posted: September 9, 2009. Last update posted: April 21, 2015.
Neurons born in the embryo can undergo a protracted period of maturation lasting well into postnatal life. How gene expression changes are regulated during maturation and whether they can be ...recapitulated in cultured neurons remains poorly understood. Here, we show that mouse motor neurons exhibit pervasive changes in gene expression and accessibility of associated regulatory regions from embryonic till juvenile age. While motifs of selector transcription factors, ISL1 and LHX3, are enriched in nascent regulatory regions, motifs of NFI factors, activity-dependent factors, and hormone receptors become more prominent in maturation-dependent enhancers. Notably, stem cell-derived motor neurons recapitulate ~40% of the maturation expression program in vitro, with neural activity playing only a modest role as a late-stage modulator. Thus, the genetic maturation program consists of a core hardwired subprogram that is correctly executed in vitro and an extrinsically-controlled subprogram that is dependent on the in vivo context of the maturing organism.
The chemo- and regioselectivity and functional group compatibility in gold and palladium cooperatively catalyzed cross-coupling reactions were determined in the synthesis of lactones; the selectivity ...in the gold and palladium dual-metal catalysis system was distinct from that available for the same class of substrates in systems with only gold catalysis or only palladium catalysis rather than dual catalysis. The dual-catalytic rearrangement reaction selectively promoted oxidative addition at the C–O bond over the C–Br bond, providing a useful C–Br bond handle for downstream functionalization showcased via Suzuki–Miyaura and Sonogashira coupling reactions. Product classes were expanded from isocoumarins to three previously unpublished ring classes: pyrone, indolepyrone, and furopyrone.
The sirtuins SIRT1, SIRT2, and SIRT3 are NAD+ dependent deacetylases that are considered potential targets for metabolic, inflammatory, oncologic, and neurodegenerative disorders. Encoded library ...technology (ELT) was used to affinity screen a 1.2 million heterocycle enriched library of DNA encoded small molecules, which identified pan-inhibitors of SIRT1/2/3 with nanomolar potency (e.g., 11c: IC50 = 3.6, 2.7, and 4.0 nM for SIRT1, SIRT2, and SIRT3, respectively). Subsequent SAR studies to improve physiochemical properties identified the potent drug like analogues 28 and 31. Crystallographic studies of 11c, 28, and 31 bound in the SIRT3 active site revealed that the common carboxamide binds in the nicotinamide C-pocket and the aliphatic portions of the inhibitors extend through the substrate channel, explaining the observable SAR. These pan SIRT1/2/3 inhibitors, representing a novel chemotype, are significantly more potent than currently available inhibitors, which makes them valuable tools for sirtuin research.
Summary
Background
Over the last few years, several articles on dermoscopy of non‐neoplastic dermatoses have been published, yet there is poor consistency in the terminology among different studies.
...Objectives
We aimed to standardize the dermoscopic terminology and identify basic parameters to evaluate in non‐neoplastic dermatoses through an expert consensus.
Methods
The modified Delphi method was followed, with two phases: (i) identification of a list of possible items based on a systematic literature review and (ii) selection of parameters by a panel of experts through a three‐step iterative procedure (blinded e‐mail interaction in rounds 1 and 3 and a face‐to‐face meeting in round 2). Initial panellists were recruited via e‐mail from all over the world based on their expertise on dermoscopy of non‐neoplastic dermatoses.
Results
Twenty‐four international experts took part in all rounds of the consensus and 13 further international participants were also involved in round 2. Five standardized basic parameters were identified: (i) vessels (including morphology and distribution); (ii) scales (including colour and distribution); (iii) follicular findings; (iv) ‘other structures’ (including colour and morphology); and (v) ‘specific clues’. For each of them, possible variables were selected, with a total of 31 different subitems reaching agreement at the end of the consensus (all of the 29 proposed initially plus two more added in the course of the consensus procedure).
Conclusions
This expert consensus provides a set of standardized basic dermoscopic parameters to follow when evaluating inflammatory, infiltrative and infectious dermatoses. This tool, if adopted by clinicians and researchers in this field, is likely to enhance the reproducibility and comparability of existing and future research findings and uniformly expand the universal knowledge on dermoscopy in general dermatology.
What's already known about this topic?
Over the last few years, several papers have been published attempting to describe the dermoscopic features of non‐neoplastic dermatoses, yet there is poor consistency in the terminology among different studies.
What does this study add?
The present expert consensus provides a set of standardized basic dermoscopic parameters to follow when evaluating inflammatory, infiltrative and infectious dermatoses.
This consensus should enhance the reproducibility and comparability of existing and future research findings and uniformly expand the universal knowledge on dermoscopy in general dermatology.
Linked Editorial: Bahadoran. Br J Dermatol 2020; 182:260–261.
Plain language summary available online
Employment of fluorophore-tagged alkyl and aryl iodides permitted detection of persistent surface intermediates during their direct insertion to commercially available zinc powder. The sensitivity of ...this subensemble microscopy technique enabled structure–reactivity studies in the formation of intermediates that are present in quantities sufficiently low as to have been undetected previously by traditional ensemble analytical techniques. These surface intermediates were transformed by lithium chloride, leading to the assignment of the mechanistic role of lithium chloride as changing the rate-determining step in the reaction by lowering the barrier for solubilization of these otherwise persistent surface organometallic intermediates. The temperature dependence/qualitative barrier of the direct insertion step was determined independently from the solubilization step and from the barrier for the overall reaction. Detection of these zinc surface intermediates at the single-molecule level, i.e., of individual surface organometallic species, has been achieved for the first time. Energy dispersive X-ray spectroscopy (EDS) measurements of the elemental composition of the surface of the zinc powder determined that lithium chloride does not clean the surface of the oxides; instead, pretreatment of the surface with TMSCl effects partial removal of surface oxides after the 2 h pretreatment time previously reported in the empirically optimized synthetic procedure. Current limitations of this microscopy approach are also determined and discussed with respect to the addition of solid reagents during in operando imaging. Characterization of the resulting soluble fluorophore-tagged organozinc/LiCl complex by 1H NMR spectroscopy, mass spectrometry, and fluorescence spectroscopy provided insight into its solution dynamics and chemical exchange processes.
There have been few treatment trials for psychogenic nonepileptic seizures (PNES). Some psychotherapies have been shown to improve PNES and comorbid symptom outcomes. We evaluated a pharmacologic ...intervention to test the hypothesis that sertraline would reduce PNES.
We conducted a pilot, double-blind, randomized, placebo-controlled trial in an academic medical hospital with epilepsy center outpatients. Subjects aged 18 to 65 years diagnosed with video-EEG-confirmed PNES were treated with flexible-dose sertraline or placebo over 12 weeks. Seizure calendars and symptom scales were charted prospectively. Secondary outcome measures included psychiatric symptom scales and psychosocial variables.
Thirty-eight subjects enrolled, and 26 (68%) completed the trial. Thirty-three subjects with nonzero nonepileptic seizure rates at baseline were included in intent-to-treat analysis of the primary outcome. Subjects assigned to the sertraline arm experienced a 45% reduction in seizure rates from baseline to final visit (p = 0.03) vs an 8% increase in placebo (p = 0.78). Secondary outcome scales revealed no significant between-group differences in change scores from baseline to final visit, after adjustment for differences at baseline.
PNES were reduced in patients treated with a serotonin selective reuptake inhibitor, whereas those treated with placebo slightly increased. This study provides feasibility data for a larger-scale study.
This study provides Class II evidence that flexible-dose sertraline up to a maximum dose of 200 mg is associated with a nonsignificant reduction in PNES rate compared with a placebo control arm (risk ratio 0.51, 95% confidence interval 0.25-1.05, p = 0.29), adjusting for differences at baseline.
SIRT1, the founding member of the mammalian family of seven NAD(+)-dependent sirtuins, is composed of 747 amino acids forming a catalytic domain and extended N- and C-terminal regions. We report the ...design and characterization of an engineered human SIRT1 construct (mini-hSIRT1) containing the minimal structural elements required for lysine deacetylation and catalytic activation by small molecule sirtuin-activating compounds (STACs). Using this construct, we solved the crystal structure of a mini-hSIRT1-STAC complex, which revealed the STAC-binding site within the N-terminal domain of hSIRT1. Together with hydrogen-deuterium exchange mass spectrometry (HDX-MS) and site-directed mutagenesis using full-length hSIRT1, these data establish a specific STAC-binding site and identify key intermolecular interactions with hSIRT1. The determination of the interface governing the binding of STACs with human SIRT1 facilitates greater understanding of STAC activation of this enzyme, which holds significant promise as a therapeutic target for multiple human diseases.
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