Highlights • Injection of the 5-HT1A receptor agonist 8-OH-DPAT increases plasma cortisol. • Serotonin directly stimulates cortisol secretion from the head kidney in vitro. • Multiple 5-HT receptor ...subtypes mediate 5-HT-stimulated cortisol secretion. • The chromaffin cells of the head kidney contain 5-HT. • Chromaffin cells may be involved in paracrine regulation of cortisol secretion via 5-HT.
Motor neuron diversification and regionalization are important hallmarks of spinal cord development and rely on fine spatiotemporal release of molecular cues. Here, we present a dedicated platform to ...engineer complex molecular profiles for directed neuronal differentiation.
The technology, termed
exagon
nterlace for generation of
ersatile and fin
gradients (microHIVE), leverages on an interlocking honeycomb lattice of microstructures to dynamically pattern molecular profiles at a high spatial resolution. By packing the microhexagons as a divergent, mirrored array, the platform not only enables maximal mixing efficiency but also maintains a small device footprint.
Employing the microHIVE platform, we developed optimized profiles of growth factors to induce rostral-caudal patterning of spinal motor neurons, and directed stem cell differentiation
into a spatial continuum of different motor neuron subtypes.
The differentiated cells showed progressive RNA and protein signatures, consistent with that of representative brachial, thoracic and lumbar regions of the human spinal cord. The microHIVE platform can thus be utilized to develop advanced biomimetic systems for the study of diseases
.
In higher plants the L-galactose pathway represents the major route for ascorbate biosynthesis. The first committed step of this pathway is catalyzed by the enzyme GDP-L-galactose phosphorylase and ...is encoded by two paralogs in Arabidopsis - VITAMIN C2 (VTC2) and VTC5. The first mutant of this enzyme, vtc2-1, isolated via an EMS mutagenesis screen, has approximately 20-30% of wildtype ascorbate levels and has been reported to have decreased growth under standard laboratory conditions. Here, we show that a T-DNA insertion into the VTC2 causes a similar reduction in ascorbate levels, but does not greatly affect plant growth. Subsequent segregation analysis revealed the growth defects of vtc2-1 mutants segregate independently of the vtc2-1 mutation. These observations suggest that it is the presence of an independent cryptic mutation that affects growth of vtc2-1 mutants, and not the 70-80% decrease in ascorbate levels that has been assumed in past studies.
Loss of function of the von Hippel-Lindau (VHL) tumor suppressor gene is a hallmark of clear cell renal cell carcinoma (ccRCC). The importance of heterogeneity in the loss of this tumor suppressor ...has been under reported. To study the impact of intratumoral VHL heterogeneity observed in human ccRCC, we engineered VHL gene deletion in four RCC models, including a new primary tumor cell line derived from an aggressive metastatic case. The VHL gene-deleted (VHL-KO) cells underwent epithelial-to-mesenchymal transition (EMT) and exhibited increased motility but diminished proliferation and tumorigenicity compared to the parental VHL-expressing (VHL
) cells. Renal tumors with either VHL
or VHL-KO cells alone exhibit minimal metastatic potential. Combined tumors displayed rampant lung metastases, highlighting a novel cooperative metastatic mechanism. The poorly proliferative VHL-KO cells stimulated the proliferation, EMT, and motility of neighboring VHL
cells. Periostin (POSTN), a soluble protein overexpressed and secreted by VHL non-expressing (VHL
) cells, promoted metastasis by enhancing the motility of VHL-WT cells and facilitating tumor cell vascular escape. Genetic deletion or antibody blockade of POSTN dramatically suppressed lung metastases in our preclinical models. This work supports a new strategy to halt the progression of ccRCC by disrupting the critical metastatic crosstalk between heterogeneous cell populations within a tumor.
Addition of temozolomide (TMZ) to radiotherapy (RT) improves overall survival (OS) in patients with glioblastoma (GBM), but previous studies suggest that patients with tumors harboring an ...unmethylated MGMT promoter derive minimal benefit. The aim of this open-label, phase III CheckMate 498 study was to evaluate the efficacy of nivolumab (NIVO) + RT compared with TMZ + RT in newly diagnosed GBM with unmethylated MGMT promoter.
Patients were randomized 1:1 to standard RT (60 Gy) + NIVO (240 mg every 2 weeks for eight cycles, then 480 mg every 4 weeks) or RT + TMZ (75 mg/m2 daily during RT and 150-200 mg/m2/day 5/28 days during maintenance). The primary endpoint was OS.
A total of 560 patients were randomized, 280 to each arm. Median OS (mOS) was 13.4 months (95% CI, 12.6 to 14.3) with NIVO + RT and 14.9 months (95% CI, 13.3 to 16.1) with TMZ + RT (hazard ratio HR, 1.31; 95% CI, 1.09 to 1.58; P = .0037). Median progression-free survival was 6.0 months (95% CI, 5.7 to 6.2) with NIVO + RT and 6.2 months (95% CI, 5.9 to 6.7) with TMZ + RT (HR, 1.38; 95% CI, 1.15 to 1.65). Response rates were 7.8% (9/116) with NIVO + RT and 7.2% (8/111) with TMZ + RT; grade 3/4 treatment-related adverse event (TRAE) rates were 21.9% and 25.1%, and any-grade serious TRAE rates were 17.3% and 7.6%, respectively.
The study did not meet the primary endpoint of improved OS; TMZ + RT demonstrated a longer mOS than NIVO + RT. No new safety signals were detected with NIVO in this study. The difference between the study treatment arms is consistent with the use of TMZ + RT as the standard of care for GBM.ClinicalTrials.gov NCT02617589.
In April 2009, an outbreak of novel swine-origin influenza A (2009 H1N1 influenza) occurred at a high school in Queens, New York. We describe the outbreak and characterize the clinical and ...epidemiologic aspects of this novel virus.
The New York City Department of Health and Mental Hygiene characterized the outbreak through laboratory confirmation of the presence of the 2009 H1N1 virus in nasopharyngeal and oropharyngeal specimens and through information obtained from an online survey. Detailed information on exposure and the onset of symptoms was used to estimate the incubation period, generation time, and within-school reproductive number associated with 2009 H1N1 influenza, with the use of established techniques.
From April 24 through May 8, infection with the 2009 H1N1 virus was confirmed in 124 high-school students and employees. In responses to the online questionnaire, more than 800 students and employees (35% of student respondents and 10% of employee respondents) reported having an influenza-like illness during this period. No persons with confirmed 2009 H1N1 influenza or with influenza-like illness had severe symptoms. A linkage with travel to Mexico was identified. The estimated median incubation period for confirmed 2009 H1N1 influenza was 1.4 days (95% confidence interval CI, 1.0 to 1.8), with symptoms developing in 95% of cases by 2.2 days (95% CI, 1.7 to 2.6). The estimated median generation time was 2.7 days (95% CI, 2.0 to 3.5). We estimate that the within-school reproductive number was 3.3.
The findings from this investigation suggest that 2009 H1N1 influenza in the high school was widespread but did not cause severe illness. The reasons for the rapid and extensive spread of influenza-like illnesses are unknown. The natural history and transmission of the 2009 H1N1 influenza virus appear to be similar to those of previously observed circulating pandemic and interpandemic influenza viruses.
The role of central nervous system (CNS) prophylaxis with high-dose methotrexate (HDMTX) in DLBCL is controversial. In this retrospective study, we evaluated the efficacy of prophylactic HDMTX on ...isolated CNS relapse, concomitant CNS and systemic relapse, systemic relapse, and survival outcomes in 226 patients with newly diagnosed DLBCL and high-risk CNS International Prognostic Index (CNS-IPI) score treated with RCHOP. The three-year risk of isolated CNS relapse was significantly lower in patients who received HDMTX, at 3.1% compared to 14.6% (P = 0.032) in those who did not. However, neither concomitant CNS-systemic relapse rates, systemic relapse rates, nor three-year PFS and OS were significantly different between treatment groups in multivariable analysis. Among propensity score-matched patients (N = 102), HDMTX was also associated with significantly lower isolated CNS relapse rates (HR 0.06, 95% CI 0.004-0.946, P = 0.046). HDMTX was well tolerated with manageable toxicities when given at a dose of 3 g/m
by day 3 of RCHOP chemotherapy. Using propensity score matching and multivariable regression to yield treatment groups with well-balanced covariates, we showed that prophylactic HDMTX improved isolated CNS relapse rates but did not decrease concomitant CNS-systemic relapse rates, systemic relapse rates, or improve survival outcomes.
MicroRNAs (miRs) control stem cell biology and fate. Ubiquitously expressed and conserved miR-16 was the first miR implicated in tumorigenesis. miR-16 is low in muscle during developmental ...hypertrophy and regeneration. It is enriched in proliferating myogenic progenitor cells but is repressed during differentiation. The induction of miR-16 blocks myoblast differentiation and myotube formation, whereas knockdown enhances these processes. Despite a central role for miR-16 in myogenic cell biology, how it mediates its potent effects is incompletely defined. In this investigation, global transcriptomic and proteomic analyses after miR-16 knockdown in proliferating C2C12 myoblasts revealed how miR-16 influences myogenic cell fate. Eighteen hours after miR-16 inhibition, ribosomal protein gene expression levels were higher relative to control myoblasts and p53 pathway-related gene abundance was lower. At the protein level at this same time point, miR-16 knockdown globally upregulated tricarboxylic acid (TCA) cycle proteins while downregulating RNA metabolism-related proteins. miR-16 inhibition induced specific proteins associated with myogenic differentiation such as ACTA2, EEF1A2, and OPA1. We extend prior work in hypertrophic muscle tissue and show that miR-16 is lower in mechanically overloaded muscle in vivo. Our data collectively point to how miR-16 is implicated in aspects of myogenic cell differentiation. A deeper understanding of the role of miR-16 in myogenic cells has consequences for muscle developmental growth, exercise-induced hypertrophy, and regenerative repair after injury, all of which involve myogenic progenitors.
It has recently been found that iridescence, a taxonomically widespread form of animal coloration defined by a change in hue with viewing angle, can act as a highly effective form of camouflage. ...However, little is known about whether iridescence can confer a survival benefit to prey postdetection and, if so, which optical properties of iridescent prey are important for this putative protective function. Here, we tested the effects of both iridescence and surface gloss (i.e. specular reflection) on the attack behaviour of prey-naïve avian predators. Using real and artificial jewel beetle, Sternocera aequisignata, wing cases, we found that iridescence provides initial protection against avian predation by significantly reducing the willingness to attack. Importantly, we found that the main factor explaining this aversion is iridescence, not multiple colours per se, with surface gloss also having an independent effect. Our results are important because they demonstrate that even when prey are presented up close and against a mismatching background, iridescence may confer a survival benefit by inducing hesitation or even, as sometimes observed, an aversion response in attacking birds. Furthermore, this means that even postdetection, prey do not necessarily need to have secondary defences such as sharp spines or toxins for iridescence to have a protective effect. Taken together, our results suggest that reduced avian predation could facilitate the initial evolution of iridescence in many species of insects and that it is the defining feature of iridescence, its colour changeability, that is important for this effect.
•Iridescence and gloss are usually associated with display, but can they also defend?•We tested naïve birds' willingness to attack glossy and iridescent prey.•Iridescence reduced attack probability, with gloss also having an independent effect.•Iridescence and gloss could provide a survival benefit to prey, even postdetection.
The use of immune checkpoint inhibitors (ICIs) targeting PD-L1/PD-1 and CTLA-4 has transformed the oncology practice of hepatocellular carcinoma. However, only 25-30% of the patients with advanced ...HCC treated with atezolizumab-bevacizumab or tremelimumab-durvalumab (STRIDE) respond initially, and mechanistic biomarkers and novel treatment strategies are urgently needed for patients who present with or acquire resistance to first-line ICI-based therapies. The recent approval of the STRIDE regimen has also engendered new questions, such as patient selection factors (e.g. portal hypertension and history of variceal bleed) and biomarkers, and the optimal combination and sequencing of ICI-based regimens. Triumphs in the setting of advanced HCC have also galvanized considerable interest in the broader application of ICIs to early- and intermediate-stage diseases, including clinical combination of ICIs with locoregional therapies. Among these clinical contexts, the role of ICIs in liver transplantation - which is a potentially curative strategy unique to HCC management - as a bridge to liver transplant in potential candidates or in the setting of post-transplant recurrence, warrants investigation in view of the notable theoretical risk of allograft rejection. In this review, we summarize and chart the landscape of seminal immuno-oncology trials in HCC and envision future clinical developments.
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