Ecologists have historically represented consumer–resource interactions with boxes and arrows. A key assumption of this conceptualization is that all individuals inside a box are functionally ...equivalent. Demographic stage structure, however, is a widespread source of heterogeneity inside the boxes. Synthesizing recent studies, we show that stage structure can modify the dynamics of consumer–resource communities owing to stage-related shifts in the nature and strength of interactions that occur within and between populations. As a consequence, stage structure can stabilize consumer–resource dynamics, create possibilities for alternative community states, modify conditions for coexistence of competitors, and alter the strength and direction of trophic cascades. Consideration of stage structure can thus lead to outcomes that are not expected based on unstructured approaches.
Tremelimumab (CP-675,206) is a fully human monoclonal antibody binding to cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) on T cells that stimulates the immune system by blocking the ...CTLA4-negative regulatory signal. Combination with standard chemotherapy may strengthen antitumor therapy. This is a phase Ib, multisite, open-label, nonrandomized dose escalation trial evaluating the safety, tolerability, and maximum tolerated dose (MTD) of tremelimumab combined with gemcitabine in patients with metastatic pancreatic cancer.
Gemcitabine (1000 mg/m2 on days 1, 8, and 15 of each 28-day cycles) was administrated with escalating doses of i.v. tremelimumab (6, 10, or 15 mg/kg) on day 1 of each 84-day cycle for a maximum of 4 cycles. The first 18 patients had an initial 4-week gemcitabine-only lead-in period. Dose-limiting toxicities (DLTs) related to tremelimumab were evaluated during the first 6 weeks after the first dose of tremelimumab.
From June 2008 to August 2011, 34 patients were enrolled and received at least one dose of tremelimumab. No DLTs related to tremelimumab were observed at any dose, even when the maximum dose established for tremelimumab (15 mg/kg) was used. Most frequent grade 3/4 toxicities were asthenia (11.8%) and nausea (8.8%). Only one patient had a serious drug-related event (diarrhea with dehydration). The median overall survival was 7.4 months (95% confidence interval 5.8–9.4 months). At the end of treatment, two patients achieved partial response. Both patients received tremelimumab 15-mg/kg group (n = 2/19, 10.5%).
Tremelimumab plus gemcitabine demonstrated a safety and tolerability profile, warranting further study in patients with metastatic pancreatic cancer.
NCT00556023.
Preclinical evidence suggests that MEK inhibition promotes accumulation and survival of intratumoral tumor-specific T cells and can synergize with immune checkpoint inhibition. We investigated the ...safety and clinical activity of combining a MEK inhibitor, cobimetinib, and a programmed cell death 1 ligand 1 (PD-L1) inhibitor, atezolizumab, in patients with solid tumors.
This phase I/Ib study treated PD-L1/PD-1-naive patients with solid tumors in a dose-escalation stage and then in multiple, indication-specific dose-expansion cohorts. In most patients, cobimetinib was dosed once daily orally for 21days on, 7days off. Atezolizumab was dosed at 800mg intravenously every 2weeks. The primary objectives were safety and tolerability. Secondary end points included objective response rate, progression-free survival, and overall survival.
Between 27 December 2013 and 9 May 2016, 152 patients were enrolled. As of 4 September 2017, 150 patients received ≥1 dose of atezolizumab, including 14 in the dose-escalation cohorts and 136 in the dose-expansion cohorts. Patients had metastatic colorectal cancer (mCRC; n=84), melanoma (n=22), non-small-cell lung cancer (NSCLC; n=28), and other solid tumors (n=16). The most common all-grade treatment-related adverse events (AEs) were diarrhea (67%), rash (48%), and fatigue (40%), similar to those with single-agent cobimetinib and atezolizumab. One (<1%) treatment-related grade 5 AE occurred (sepsis). Forty-five (30%) and 23 patients (15%) had AEs that led to discontinuation of cobimetinib and atezolizumab, respectively. Confirmed responses were observed in 7 of 84 patients (8%) with mCRC (6 responders were microsatellite low/stable, 1 was microsatellite instable), 9 of 22 patients (41%) with melanoma, and 5 of 28 patients (18%) with NSCLC. Clinical activity was independent of KRAS/BRAF status across diseases.
Atezolizumab plus cobimetinib had manageable safety and clinical activity irrespective of KRAS/BRAF status. Although potential synergistic activity was seen in mCRC, this was not confirmed in a subsequent phase III study.
NCT01988896 (the investigators in the NCT01988896 study are listed in the supplementary Appendix, available at Annals of Oncology online).
Ascorbic acid is a widely used and controversial alternative cancer treatment. In millimolar concentrations, it is selectively cytotoxic to many cancer cell lines and has in vivo anticancer activity ...when administered alone or together with other agents. We carried out a dose-finding phase I and pharmacokinetic study of i.v. ascorbic acid in patients with advanced malignancies.
Patients with advanced cancer or hematologic malignancy were assigned to sequential cohorts infused with 0.4, 0.6, 0.9 and 1.5g ascorbic acid/kg body weight three times weekly.
Adverse events and toxicity were minimal at all dose levels. No patient had an objective anticancer response.
High-dose i.v. ascorbic acid was well tolerated but failed to demonstrate anticancer activity when administered to patients with previously treated advanced malignancies. The promise of this approach may lie in combination with cytotoxic or other redox-active molecules.
Searches for electron antineutrino, muon neutrino, and muon antineutrino disappearance driven by sterile neutrino mixing have been carried out by the Daya Bay and MINOS+ collaborations. This Letter ...presents the combined results of these searches, along with exclusion results from the Bugey-3 reactor experiment, framed in a minimally extended four-neutrino scenario. Significantly improved constraints on the θμe mixing angle are derived that constitute the most constraining limits to date over five orders of magnitude in the mass-squared splitting Δm241, excluding the 90% C.L. sterile-neutrino parameter space allowed by the LSND and MiniBooNE observations at 90% CLs for Δm241 < 13 eV2. Furthermore, the LSND and MiniBooNE 99% C.L. allowed regions are excluded at 99% CLs for Δm241 < 1.6 eV2.
The first gamma-ray burst (GRB) confirmed to be bright enough to be seen with the naked eye, GRB 080319B at redshift z = 0.937, allowed for exquisite follow-up observations across the electromagnetic ...spectrum. We present our detailed optical and infrared (IR) observations of the afterglow, consisting of over 5000 images starting 51 s after the GRB trigger, in concert with our own analysis of the Swift UVOT, Burst Alert Telescope (BAT), and XRT data. The event is extreme not only in observed properties but also intrinsically: it was the most luminous event ever recorded at optical and IR wavelengths and had an exceedingly high isotropic-equivalent energy release in gamma -rays. At early times, the afterglow evolution is broadly consistent with being reverse-shock dominated, but then is subsumed by a forward shock at around 1000 s. The overall spectral energy distribution, spanning from ultraviolet through near-IR wavelengths, shows no evidence for a significant amount of dust extinction in the host frame. The afterglow evolution, however, is highly chromatic: starting at about 1000 s the index shifts blueward before shifting back to the red at late times. In our deepest late-time observations, we find tentative evidence for an optical jet break and a luminous supernova. Finally, we examine the detectability of such events with current and future facilities and find that such an event could be detected in gamma rays by BAT out to z = 10.7 (8 sigma ), while the nominal EXIST sensitivity would allow detection to z 32. At the K band, this source would have been easily detected with meter-class telescopes to z 17.
Summary
Background
The epidemiology of Helicobacter pylori infection is poorly understood.
Aim
To establish the reported regional and national prevalence of H. pylori infection, stratified by age and ...gender.
Methods
All relevant English publications from 2000 to 2017 cited by PubMed and Scopus were retrieved using comprehensive combinations of keywords. The overall prevalence of H. pylori was estimated using both random effect and fixed effect meta‐analyses, and presented as prevalence rate (% and 95% CI). The analyses were extended by separation into gender and age groups.
Results
A total of 14 056 records were obtained initially. After applying exclusion criteria in several steps, 183 studies were selected. Analysis of 410 879 participants from 73 countries in six continents revealed an overall prevalence of 44.3% (95% CI: 40.9‐47.7) worldwide. This rate ranged from 50.8% (95% CI: 46.8‐54.7) in developing countries compared with 34.7% (95% CI: 30.2‐39.3) in developed countries. The global H. pylori infection rate was 42.7% (95% CI: 39‐46.5) in females compared to 46.3% (95% CI: 42.1‐50.5) in males. The prevalence in adults (≥18 years) was significantly higher than in children (48.6% 95% CI: 43.8‐53.5 vs 32.6% 95% CI: 28.4‐36.8, respectively). There was a statistically nonsignificant decrease in the prevalence in 2009‐2016 compared with the 2000‐2009 period.
Conclusions
The observed differences between countries appear to be due to economic and social conditions. H. pylori infection can be a benchmark for the socioeconomic and health status of a country. Further studies are suggested to investigate the natural history of the acquisition of H. pylori infection from childhood into adult life.
Linked ContentThis article is linked to Zamani et al and Tsipotis and Leontiadis papers. To view these articles visit https://doi.org/10.1111/apt.14609 and https://doi.org/10.1111/apt.14618.
Climate effects on hydrology impart high variability to water-quality properties, including nutrient loadings, concentrations, and phytoplankton biomass as chlorophyll-a (chl-a), in estuarine and ...coastal ecosystems. Resolving long-term trends of these properties requires that we distinguish climate effects from secular changes reflecting anthropogenic eutrophication. Here, we test the hypothesis that strong climatic contrasts leading to irregular dry and wet periods contribute significantly to interannual variability of mean annual values of water-quality properties using in situ data for Chesapeake Bay. Climate effects are quantified using annual freshwater discharge from the Susquehanna River together with a synoptic climatology for the Chesapeake Bay region based on predominant sea-level pressure patterns. Time series of water-quality properties are analyzed using historical (1945–1983) and recent (1984–2012) data for the bay adjusted for climate effects on hydrology. Contemporary monitoring by the Chesapeake Bay Program (CBP) provides data for a period since mid-1984 that is significantly impacted by anthropogenic eutrophication, while historical data back to 1945 serve as historical context for a period prior to severe impairments. The generalized additive model (GAM) and the generalized additive mixed model (GAMM) are developed for nutrient loadings and concentrations (total nitrogen—TN, nitrate + nitrate—NO₂ + NO₃) at the Susquehanna River and water-quality properties in the bay proper, including dissolved nutrients (NO₂ + NO₃, orthophosphate—PO₄), chl-a, diffuse light attenuation coefficient (K D (PAR)), and chl-a/TN. Each statistical model consists of a sum of nonlinear functions to generate flow-adjusted time series and compute long-term trends accounting for climate effects on hydrology. We present results identifying successive periods of (1) eutrophication ca. 1945–1980 characterized by approximately doubled TN and NO₂ + NO₃ loadings, leading to increased chl-a and associated ecosystem impairments, and (2) modest decreases of TN and NO₂ + NO₃ loadings from 1981 to 2012, signaling a partial reversal of nutrient over-enrichment. Comparison of our findings with long-term trends of water-quality properties for a variety of estuarine and coastal ecosystems around the world reveals that trends for Chesapeake Bay are weaker than for other systems subject to strenuous management efforts, suggesting that more aggressive actions than those undertaken to date will be required to counter anthropogenic eutrophication of this valuable resource.
Signaling between the endoplasmic reticulum (ER) and mitochondria regulates a number of key neuronal functions. This signaling involves close physical contacts between the two organelles that are ...mediated by "tethering proteins" that function to recruit regions of ER to the mitochondrial surface. The ER protein, vesicle-associated membrane protein-associated protein B (VAPB) and the mitochondrial membrane protein, protein tyrosine phosphatase interacting protein-51 (PTPIP51), interact to form one such tether. Recently, damage to ER-mitochondria signaling involving disruption of the VAPB-PTPIP51 tethers has been linked to the pathogenic process in Parkinson's disease, fronto-temporal dementia (FTD) and related amyotrophic lateral sclerosis (ALS). Loss of neuronal synaptic function is a key feature of Parkinson's disease and FTD/ALS but the roles that ER-mitochondria signaling and the VAPB-PTPIP51 tethers play in synaptic function are not known. Here, we demonstrate that the VAPB-PTPIP51 tethers regulate synaptic activity. VAPB and PTPIP51 localise and form contacts at synapses, and stimulating neuronal activity increases ER-mitochondria contacts and the VAPB-PTPIP51 interaction. Moreover, siRNA loss of VAPB or PTPIP51 perturbs synaptic function and dendritic spine morphology. Our results reveal a new role for the VAPB-PTPIP51 tethers in neurons and suggest that damage to ER-mitochondria signaling contributes to synaptic dysfunction in Parkinson's disease and FTD/ALS.
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