Humans display structural and functional asymmetries in brain organization, strikingly with respect to language and handedness. The molecular basis of these asymmetries is unknown. We report a ...genome-wide association study meta-analysis for a quantitative measure of relative hand skill in individuals with dyslexia reading disability (RD) (n = 728). The most strongly associated variant, rs7182874 (P = 8.68 × 10(-9)), is located in PCSK6, further supporting an association we previously reported. We also confirmed the specificity of this association in individuals with RD; the same locus was not associated with relative hand skill in a general population cohort (n = 2,666). As PCSK6 is known to regulate NODAL in the development of left/right (LR) asymmetry in mice, we developed a novel approach to GWAS pathway analysis, using gene-set enrichment to test for an over-representation of highly associated variants within the orthologs of genes whose disruption in mice yields LR asymmetry phenotypes. Four out of 15 LR asymmetry phenotypes showed an over-representation (FDR ≤ 5%). We replicated three of these phenotypes; situs inversus, heterotaxia, and double outlet right ventricle, in the general population cohort (FDR ≤ 5%). Our findings lead us to propose that handedness is a polygenic trait controlled in part by the molecular mechanisms that establish LR body asymmetry early in development.
Reoccurring/high-risk neuroblastoma (NB) tumors have the enrichment of non-RAS/RAF mutations along the mitogen-activated protein kinase (MAPK) signaling pathway, suggesting that activation of MEK/ERK ...is critical for their survival. However, based on preclinical data, MEK inhibitors are unlikely to be active in NB and have demonstrated dose-limiting toxicities that limit their use. Here, we explore an alternative way to target the MAPK pathway in high-risk NB. We find that NB models are among the most sensitive among over 900 tumor-derived cell lines to the allosteric SHP2 inhibitor SHP099. Sensitivity to SHP099 in NB is greater in models with loss or low expression of the RAS GTPase activation protein (GAP) neurofibromin 1 (NF1). Furthermore, NF1 is lower in advanced and relapsed NB and NF1 loss is enriched in high-risk NB tumors regardless of MYCN status. SHP2 inhibition consistently blocks tumor growth in high-risk NB mouse models, revealing a new drug target in relapsed NB.
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•We identify neuroblastoma models as sensitive to SHP2 inhibition•SHP099 sensitivity is correlated with low expression of neurofibromin (NF1)•SHP2 inhibitors inhibit pERK in neuroblastoma cells better than in normal cells•NF1 mutation/expression may predict SHP2 inhibitor response in neuroblastoma
In this paper, Cai et al. demonstrate that high-risk neuroblastomas with low NF1 expression are sensitive to SHP2 inhibitors, which may have treatment advantages over MEK inhibitors. Targeting SHP2 blocks neuroblastoma tumor growth. As several SHP2 inhibitors are in clinical trials, SHP2 inhibitors may benefit high-risk NB patients.
To develop clinical practice guidelines to assist primary care clinicians in the management of adolescent depression. This second part of the guidelines addresses treatment and ongoing management of ...adolescent depression in the primary care setting.
Using a combination of evidence- and consensus-based methodologies, guidelines were developed in 5 phases as informed by (1) current scientific evidence (published and unpublished), (2) a series of focus groups, (3) a formal survey, (4) an expert consensus workshop, and (5) revision and iteration among members of the steering committee.
These guidelines are targeted for youth aged 10 to 21 years and offer recommendations for the management of adolescent depression in primary care, including (1) active monitoring of mildly depressed youth, (2) details for the specific application of evidence-based medication and psychotherapeutic approaches in cases of moderate-to-severe depression, (3) careful monitoring of adverse effects, (4) consultation and coordination of care with mental health specialists, (5) ongoing tracking of outcomes, and (6) specific steps to be taken in instances of partial or no improvement after an initial treatment has begun. The strength of each recommendation and its evidence base are summarized.
These guidelines cannot replace clinical judgment, and they should not be the sole source of guidance for adolescent depression management. Nonetheless, the guidelines may assist primary care clinicians in the management of depressed adolescents in an era of great clinical need and a shortage of mental health specialists. Additional research concerning the management of youth with depression in primary care is needed, including the usability, feasibility, and sustainability of guidelines and determination of the extent to which the guidelines actually improve outcomes of youth with depression.
Urine biomarkers of kidney tubule health may distinguish aspects of kidney damage that cannot be captured by current glomerular measures. Associations of clinical risk factors with specific kidney ...tubule biomarkers have not been evaluated in detail.
We performed a cross-sectional study in the Systolic Blood Pressure Intervention Trial among 2,436 participants with a baseline estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2. Associations between demographic and clinical characteristics with urine biomarkers of kidney tubule health were evaluated using simultaneous multivariable linear regression of selected variables.
Each standard deviation higher age (9 years) was associated with 13% higher levels of chitinase-3-like protein-1 (YKL-40), indicating higher levels of tubulointerstitial inflammation and repair. Men had 31% higher levels of alpha-1 microglobulin and 16% higher levels of beta-2 microglobulin, reflecting worse tubule resorptive function. Black race was associated with significantly higher levels of neutrophil gelatinase-associated lipocalin (12%) and lower kidney injury molecule-1 (26%) and uromodulin (22%). Each standard deviation (SD) higher systolic blood pressure (SBP) (16 mmHg) was associated with 10% higher beta-2 microglobulin and 10% higher alpha-1 microglobulin, reflecting lower tubule resorptive function.
Clinical and demographic characteristics, such as race, sex, and elevated SBP, are associated with unique profiles of tubular damage, which could reflect under-recognized patterns of kidney tubule disease among persons with decreased eGFR.
To address the clinical and regulatory challenges of optimal primary endpoints for bleeding patients by developing consensus-based recommendations for primary clinical outcomes for pivotal trials in ...patients within 6 categories of significant bleeding, (1) traumatic injury, (2) intracranial hemorrhage, (3) cardiac surgery, (4) gastrointestinal hemorrhage, (5) inherited bleeding disorders, and (6) hypoproliferative thrombocytopenia.
A standardized primary outcome in clinical trials evaluating hemostatic products and strategies for the treatment of clinically significant bleeding will facilitate the conduct, interpretation, and translation into clinical practice of hemostasis research and support alignment among funders, investigators, clinicians, and regulators.
An international panel of experts was convened by the National Heart Lung and Blood Institute and the United States Department of Defense on September 23 and 24, 2019. For patients suffering hemorrhagic shock, the 26 trauma working-group members met for almost a year, utilizing biweekly phone conferences and then an in-person meeting, evaluating the strengths and weaknesses of previous high quality studies. The selection of the recommended primary outcome was guided by goals of patient-centeredness, expected or demonstrated sensitivity to beneficial treatment effects, biologic plausibility, clinical and logistical feasibility, and broad applicability.
For patients suffering hemorrhagic shock, and especially from truncal hemorrhage, the recommended primary outcome was 3 to 6-hour all-cause mortality, chosen to coincide with the physiology of hemorrhagic death and to avoid bias from competing risks. Particular attention was recommended to injury and treatment time, as well as robust assessments of multiple safety related outcomes.
This study describes a novel series of UDP-N-acetylglucosamine acyltransferase (LpxA) inhibitors that was identified through affinity-mediated selection from a DNA-encoded compound library. The ...original hit was a selective inhibitor of Pseudomonas aeruginosa LpxA with no activity against Escherichia coli LpxA. The biochemical potency of the series was optimized through an X-ray crystallography-supported medicinal chemistry program, resulting in compounds with nanomolar activity against P. aeruginosa LpxA (best half-maximal inhibitory concentration (IC50) <5 nM) and cellular activity against P. aeruginosa (best minimal inhibitory concentration (MIC) of 4 μg/mL). Lack of activity against E. coli was maintained (IC50 > 20 μM and MIC > 128 μg/mL). The mode of action of analogues was confirmed through genetic analyses. As expected, compounds were active against multidrug-resistant isolates. Further optimization of pharmacokinetics is needed before efficacy studies in mouse infection models can be attempted. To our knowledge, this is the first reported LpxA inhibitor series with selective activity against P. aeruginosa.
Phenazine is known to regroup planar nitrogen-containing heterocyclic compounds. It was used here to enhance the bioavailability of the biologically important compound iodinin, which is near ...insoluble in aqueous solutions. Its water solubility has led to the development of new formulations using diverse amphiphilic α-cyclodextrins (CDs). With the per-6-desoxy-6-(3-perfluorohexylpropanethio)-2,3-di-O-methyl-α-CD, we succeeded to get iodinin-loaded nanoformulations with good parameters such as a size of 97.9 nm, 62% encapsulation efficiency and efficient control release. The study presents an interesting alternative to optimizing the water solubility of iodinin by chemical modifications of iodinin.
The main cause of mortality in locally advanced rectal cancer (LARC) is metastatic progression. The aim of the present study was to describe frequency, pattern and outcome of metastatic disease in a ...cohort of LARC patients after curative resection.
This was a single-centre cohort study of 628 LARC cases after neoadjuvant chemoradiotherapy/radiotherapy (CRT/RT) and surgery. Data, including the first site of metastasis, was registered in an institutional database linked to the National Cancer Registry.
Metastases were diagnosed in 270 patients (43.0%) with liver and lungs as the first site in 113 and 96 cases, respectively. Involved resection margins, high tumour stage and poor response to CRT/RT were associated with metastasis development and inferior overall survival (OS). Metastasectomy was performed in 76 (67.3%) patients with liver metastases and 28 (29.2%) patients with lung metastases. Five-year OS was 89% in patients without metastases and 32% in metastatic cases. In patients selected for metastasectomy, 5-year OS was 69% and 53% for lung and liver metastases, respectively. Corresponding numbers without metastasectomy were 12% and 0%.
In this large LARC cohort undergoing curatively intended treatment, liver and lung metastases occurred at similar frequencies. Liver as the first metastatic site was associated with inferior long-term outcome, while selection for metastasectomy was associated with better OS, with more than half of the resected patients being alive five years after LARC surgery. Our results show that the presence of resectable metastatic disease at diagnosis should not exclude a curative therapeutic approach in LARC.
Background
Radiotherapy (RT) and subsequent abdominoperineal resection (APR) for locally advanced rectal cancer (LARC) is associated with significant perineal wound morbidity. The aim of the present ...study was to investigate if vertical rectus abdominis musculocutaneous (VRAM) flap repair after APR in LARC patients improves perineal wound healing compared with direct perineal wound closure (non-VRAM).
Methods
LARC patients (
n
=
329) operated with APR between January 2006 and December 2015 after neoadjuvant RT of ≥ 25 Gy were identified, including 260 and 69 patients in the non-VRAM and VRAM groups, respectively. Perineal wound healing was assessed 3 months postoperatively, and risk factors for perineal wound complications and associations with short- and long-term outcome were analyzed.
Results
Delayed perineal wound healing after 3 months was more frequent in the non-VRAM group (31.5%) compared with the VRAM group (10.4%) (
p
<
0.01). In the non-VRAM group, 26.9% of patients developed pelvic abscess, compared with 10.1% in the VRAM group (
p
<
0.01). Significant risk factors for perineal wound morbidity were non-VRAM (odds ratio OR 3.94, 95% confidence interval CI 1.72–9.00;
p
=
0.02), positive circumferential resection margin (R1; OR 3.64, 95% CI 1.91–6.93;
p
<
0.01), pelvic abscess (OR 3.27, 95% CI 1.90–5.63;
p
<
0.01), and short-course RT (OR 3.81, 95% CI 1.75–8.30;
p
<
0.01). Perineal wound morbidity was not associated with impaired long-term oncologic outcome.
Conclusions
VRAM flap reconstruction of the perineum is associated with an increased wound healing rate and may protect against pelvic abscess development. However, procedure-related long-term morbidity is incompletely studied and the procedure should be reserved for selected patients.
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