Amyloid beta (Abeta) 1-42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of ...Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer's disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer's disease patients' brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of Abeta oligomers in AD and is a tractable target for small molecule disease-modifying therapeutics.
The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and cell cycle progression. Growth factor ...signalling to transcription factors in the PAM axis is highly regulated by multiple cross-interactions with several other signaling pathways, and dysregulation of signal transduction can predispose to cancer development. The PAM axis is the most frequently activated signaling pathway in human cancer and is often implicated in resistance to anticancer therapies. Dysfunction of components of this pathway such as hyperactivity of PI3K, loss of function of PTEN, and gain-of-function of AKT, are notorious drivers of treatment resistance and disease progression in cancer. In this review we highlight the major dysregulations in the PAM signaling pathway in cancer, and discuss the results of PI3K, AKT and mTOR inhibitors as monotherapy and in co-administation with other antineoplastic agents in clinical trials as a strategy for overcoming treatment resistance. Finally, the major mechanisms of resistance to PAM signaling targeted therapies, including PAM signaling in immunology and immunotherapies are also discussed.
Understanding the genetic basis of variation in life span is a major challenge that is difficult to address in human populations. Evolutionary theory predicts that alleles affecting natural variation ...in life span will have properties that enable them to persist in populations at intermediate frequencies, such as late-life-specific deleterious effects, antagonistic pleiotropic effects on early and late-age fitness components, and/or sex- and environment-specific or antagonistic effects. Here, we quantified variation in life span in males and females reared in 3 thermal environments for the sequenced, inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP) and an advanced intercross outbred population derived from a subset of DGRP lines. Quantitative genetic analyses of life span and the micro-environmental variance of life span in the DGRP revealed significant genetic variance for both traits within each sex and environment, as well as significant genotype-by-sex interaction (GSI) and genotype-by-environment interaction (GEI). Genome-wide association (GWA) mapping in both populations implicates over 2,000 candidate genes with sex- and environment-specific or antagonistic pleiotropic allelic effects. Over 1,000 of these genes are associated with variation in life span in other D. melanogaster populations. We functionally assessed the effects of 15 candidate genes using RNA interference (RNAi): all affected life span and/or micro-environmental variance of life span in at least one sex and environment and exhibited sex-and environment-specific effects. Our results implicate novel candidate genes affecting life span and suggest that variation for life span may be maintained by variable allelic effects in heterogeneous environments.
AIM: Scientific debate regarding the future trends, and subsequent ecological, biogeochemical and societal impacts, of gelatinous zooplankton (GZ) in a changing ocean is hampered by lack of a global ...baseline and an understanding of the causes of biogeographic patterns. We address this by using a new global database of GZ records to test hypotheses relating to environmental drivers of biogeographic variation in the multidecadal baseline of epipelagic GZ biomass in the world's oceans. LOCATION: Global oceans. METHODS: Over 476,000 global GZ data and metadata items were assembled from a variety of published and unpublished sources. From this, a total of 91,765 quantitative abundance data items from 1934 to 2011 were converted to carbon biomass using published biometric equations and species‐specific average sizes. Total GZ, Cnidaria, Ctenophora and Chordata (Thaliacea) biomass was mapped into 5° grid cells and environmental drivers of geographic variation were tested using spatial linear models. RESULTS: We present JeDI (the Jellyfish Database Initiative), a publically accessible database available at http://jedi.nceas.ucsb.edu. We show that: (1) GZ are present throughout the world's oceans; (2) the global geometric mean and standard deviation of total gelatinous biomass is 0.53 ± 16.16 mg C m⁻³, corresponding to a global biomass of 38.3 Tg C in the mixed layer of the ocean; (3) biomass of all gelatinous phyla is greatest in the subtropical and boreal Northern Hemisphere; and (4) within the North Atlantic, dissolved oxygen, apparent oxygen utilization and sea surface temperature are the principal drivers of biomass distribution. MAIN CONCLUSIONS: JeDI is a unique global dataset of GZ taxa which will provide a benchmark against which future observations can be compared and shifting baselines assessed. The presence of GZ throughout the world's oceans and across the complete global spectrum of environmental variables indicates that evolution has delivered a range of species able to adapt to all available ecological niches.
The assessment of myocardial viability has been used to identify patients with coronary artery disease and left ventricular dysfunction in whom coronary-artery bypass grafting (CABG) will provide a ...survival benefit. However, the efficacy of this approach is uncertain.
In a substudy of patients with coronary artery disease and left ventricular dysfunction who were enrolled in a randomized trial of medical therapy with or without CABG, we used single-photon-emission computed tomography (SPECT), dobutamine echocardiography, or both to assess myocardial viability on the basis of prespecified thresholds.
Among the 1212 patients enrolled in the randomized trial, 601 underwent assessment of myocardial viability. Of these patients, we randomly assigned 298 to receive medical therapy plus CABG and 303 to receive medical therapy alone. A total of 178 of 487 patients with viable myocardium (37%) and 58 of 114 patients without viable myocardium (51%) died (hazard ratio for death among patients with viable myocardium, 0.64; 95% confidence interval CI, 0.48 to 0.86; P=0.003). However, after adjustment for other baseline variables, this association with mortality was not significant (P=0.21). There was no significant interaction between viability status and treatment assignment with respect to mortality (P=0.53).
The presence of viable myocardium was associated with a greater likelihood of survival in patients with coronary artery disease and left ventricular dysfunction, but this relationship was not significant after adjustment for other baseline variables. The assessment of myocardial viability did not identify patients with a differential survival benefit from CABG, as compared with medical therapy alone. (Funded by the National Heart, Lung, and Blood Institute; STICH ClinicalTrials.gov number, NCT00023595.).
Background:
The long-term prognosis and risk factors for quality of life and disability after anterior cruciate ligament (ACL) reconstruction remain unknown.
Hypothesis/Purpose:
Our objective was to ...identify patient-reported outcomes and patient-specific risk factors from a large prospective cohort at a minimum 10-year follow-up after ACL reconstruction. We hypothesized that meniscus and articular cartilage injuries, revision ACL reconstruction, subsequent knee surgery, and certain demographic characteristics would be significant risk factors for inferior outcomes at 10 years.
Study Design:
Therapeutic study; Level of evidence, 2.
Methods:
Unilateral ACL reconstruction procedures were identified and prospectively enrolled between 2002 and 2004 from 7 sites in the Multicenter Orthopaedic Outcomes Network (MOON). Patients preoperatively completed a series of validated outcome instruments, including the International Knee Documentation Committee (IKDC), Knee injury and Osteoarthritis Outcome Score (KOOS), and Marx activity rating scale. At the time of surgery, physicians documented all intra-articular abnormalities, treatment, and surgical techniques utilized. Patients were followed at 2, 6, and 10 years postoperatively and asked to complete the same outcome instruments that they completed at baseline. The incidence and details of any subsequent knee surgeries were also obtained. Multivariable regression analysis was used to identify significant predictors of the outcome.
Results:
A total of 1592 patients were enrolled (57% male; median age, 24 years). Ten-year follow-up was obtained on 83% (n = 1320) of the cohort. Both IKDC and KOOS scores significantly improved at 2 years and were maintained at 6 and 10 years. Conversely, Marx scores dropped markedly over time, from a median score of 12 points at baseline to 9 points at 2 years, 7 points at 6 years, and 6 points at 10 years. The patient-specific risk factors for inferior 10-year outcomes were lower baseline scores; higher body mass index; being a smoker at baseline; having a medial or lateral meniscus procedure performed before index ACL reconstruction; undergoing revision ACL reconstruction; undergoing lateral meniscectomy; grade 3 to 4 articular cartilage lesions in the medial, lateral, or patellofemoral compartments; and undergoing any subsequent ipsilateral knee surgery after index ACL reconstruction.
Conclusion:
Patients were able to perform sports-related functions and maintain a relatively high knee-related quality of life 10 years after ACL reconstruction, although activity levels significantly declined over time. Multivariable analysis identified several key modifiable risk factors that significantly influence the outcome.
Pink salmon (Oncorhynchus gorbuscha) adults are the smallest of the five Pacific salmon native to the western Pacific Ocean. Pink salmon are also the most abundant of these species and account for a ...large proportion of the commercial value of the salmon fishery worldwide. A two-year life history of pink salmon generates temporally isolated populations that spawn either in even-years or odd-years. To uncover the influence of this genetic isolation, reference genome assemblies were generated for each year-class and whole genome re-sequencing data was collected from salmon of both year-classes. The salmon were sampled from six Canadian rivers and one Japanese river. At multiple centromeres we identified peaks of Fst between year-classes that were millions of base-pairs long. The largest Fst peak was also associated with a million base-pair chromosomal polymorphism found in the odd-year genome near a centromere. These Fst peaks may be the result of a centromere drive or a combination of reduced recombination and genetic drift, and they could influence speciation. Other regions of the genome influenced by odd-year and even-year temporal isolation and tentatively under selection were mostly associated with genes related to immune function, organ development/maintenance, and behaviour.
Chemotherapy combined with immunotherapy has improved the treatment of certain solid tumors, but effective regimens remain elusive for pancreatic ductal adenocarcinoma (PDAC). We conducted a ...randomized phase 2 trial evaluating the efficacy of nivolumab (nivo; anti-PD-1) and/or sotigalimab (sotiga; CD40 agonistic antibody) with gemcitabine/nab-paclitaxel (chemotherapy) in patients with first-line metastatic PDAC ( NCT03214250 ). In 105 patients analyzed for efficacy, the primary endpoint of 1-year overall survival (OS) was met for nivo/chemo (57.7%, P = 0.006 compared to historical 1-year OS of 35%, n = 34) but was not met for sotiga/chemo (48.1%, P = 0.062, n = 36) or sotiga/nivo/chemo (41.3%, P = 0.223, n = 35). Secondary endpoints were progression-free survival, objective response rate, disease control rate, duration of response and safety. Treatment-related adverse event rates were similar across arms. Multi-omic circulating and tumor biomarker analyses identified distinct immune signatures associated with survival for nivo/chemo and sotiga/chemo. Survival after nivo/chemo correlated with a less suppressive tumor microenvironment and higher numbers of activated, antigen-experienced circulating T cells at baseline. Survival after sotiga/chemo correlated with greater intratumoral CD4 T cell infiltration and circulating differentiated CD4 T cells and antigen-presenting cells. A patient subset benefitting from sotiga/nivo/chemo was not identified. Collectively, these analyses suggest potential treatment-specific correlates of efficacy and may enable biomarker-selected patient populations in subsequent PDAC chemoimmunotherapy trials.
PDF
