A Phase I/II Study of Topotecan in Combination with Carboplatin in Recurrent Epithelial Ovarian Cancer

Objective.The purpose of this study was to define the maximum tolerated dose (MTD) of topotecan given as escalating doses combined to a fixed dosage of carboplatin in late relapsing ovarian carcinomas.Methods. Women with relapsing ovarian cancer more than 6 months after first-line treatment were eligible for the study. In the first phase of the trial, patients were allocated to escalating topotecan doses with a carboplatin fixed dose (AUC 5, according to Cockcroft's formula). If no “severe” adverse event occurred in 1 or more of the patients, the topotecan dose was increased. The starting dose of topotecan was 0.50 mg/m²/day, for 3 consecutive days, and the dose step was of 0.25 mg/m²/day, till 1.5 mg/m²/day. The study progressed then in a phase II trial.Results. A total of 39 patients entered the trial. Twenty took part in the escalating topotecan dose phase (4 per dose level, 0.50, 0.75, 1, 1.25, and 1.50 mg/m²/day) and 19 in the phase II. No severe adverse event was observed in the phase I of the trial, so the MTD was not reached. In the phase II trial topotecan was given to 1 mg/m²/day. Overall grade 3–4 neutropenia, lasting 7 days or less, was observed in 58.9% (23 patients). Thrombocytopenia occurred in 30.8% (12 patients) and grade 3 anemia in 25.6% (10 patients) of subjects. No life-threatening event occurred. Platelets or red blood cell transfusions were given in three cases (7.8%).Conclusions. This daily-times-3-day schedule of topotecan in combination with carboplatin is safe.     

Influence of Cross-Section Shape and FRP Reinforcement Layout on Shear Capacity of Strengthened RC Beams

The evaluation of the shear capacity of an FRP-strengthened reinforced-concrete beam is challenging due to the complex interaction between different contributions provided by the concrete, steel stirrup and FRP reinforcement. The shape of the beam and the FRP inclination can have paramount importance that is not often recognized by the models that are suggested by codes. The interaction among different resisting mechanisms has a significant effect on the shear capacity of beams, since it can cause a reduction in the efficiency of some resisting mechanisms. A comparative study of the performance in the shear resistance assessment provided by three models with six different effectiveness factors (R) is performed, considering different cross-section shapes, FRP wrapping schemes, inclination and anchorage systems. The results revealed that the cross-section shape, the FRP inclination and the efficiency of the FRP anchorages have a significant effect on the shear strength of beams. The analysis results show that the three models are able to provide an accurate average estimation of shear strength (but with a coefficient of variation up to 0.35) when FRP reinforcement orthogonal to the beam axis is considered, while a significant underestimation (up to 19%) affected the results for inclined FRP reinforcement. Moreover, all the models underestimated the resistance of beams with a T section.     

Relationship of Daily Coffee Intake with Vascular Function in Patients with Hypertension

We evaluated the relationship of daily coffee intake with endothelial function assessed by flow-mediated vasodilation and vascular smooth muscle function assessed by nitroglycerine-induced vasodilation in patients with hypertension. A total of 462 patients with hypertension were enrolled in this cross-sectional study. First, we divided the subjects into two groups based on information on daily coffee intake: no coffee group and coffee group. The median coffee intake was two cups per day in the coffee group. There were significant differences in both flow-mediated vasodilation (2.6 ± 2.8% in the no coffee group vs. 3.3 ± 2.9% in the coffee group, p = 0.04) and nitroglycerine-induced vasodilation (9.6 ± 5.5% in the no coffee group vs. 11.3 ± 5.4% in the coffee group, p = 0.02) between the two groups. After adjustment for confounding factors, the odds ratio for endothelial dysfunction (OR: 0.55, 95% CI: 0.32–0.95) and the odds ratio for vascular smooth muscle dysfunction (OR: 0.50, 95% CI: 0.28–0.89) were significantly lower in the coffee group than in the no coffee group. Next, we assessed the relationship of the amount of daily coffee intake with vascular function. Cubic spline curves revealed that patients with hypertension who drank half a cup to 2.5 cups of coffee per day had lower odds ratios for endothelial dysfunction assessed by flow-mediated vasodilation and vascular smooth muscle dysfunction assessed by nitroglycerine-induced vasodilation. Appropriate daily coffee intake might have beneficial effects on endothelial function and vascular smooth muscle function in patients with hypertension.     

Down syndrome biochemical markers and screening for preeclampsia at first and second trimester: correlation with the week of onset and the severity

OBJECTIVES: To estimate the combined screening performance of first and early second trimester prenatal serum markers for Down syndrome, in screening for the development of preeclampsia, and analyze the correlation among marker levels, week of onset, and severity of the disease. METHODS: A retrospective cohort study was carried out on 32 women with preeclampsia and 3044 controls. Serum samples from these pregnancies were assayed for pregnancy-associated plasma protein-A (PAPP-A), alpha-fetoprotein (AFP), unconjugated estriol (uE3), human chorionic gonadotrophin (hCG), and inhibin-A. A likelihood ratio and the odds of being affected given a positive result (OAPR) of various combinations of markers were calculated and receiver operating characteristic (ROC) curves analysis was performed. RESULTS: In the pregnancies that subsequently developed preeclampsia, first trimester PAPP-A concentration was significantly lower and concentrations of early second trimester inhibin-A and hCG significantly elevated. Levels of early second trimester uE3 and AFP were not significantly altered. We also found that inhibin-A correlates with both onset of the disease and the severity. CONCLUSION: Down syndrome biochemical markers levels are altered in those patients who subsequently developed preeclampsia and may be a useful screening test for preeclampsia. Inhibin-A is the most predictive marker and correlates with the severity of subsequent preeclampsia and inversely with the week of occurrence of preeclampsia.     

WAGR syndrome: is the 'R' always justified?

Although mild-to-moderate intellectual disability is usually considered part of WAGR syndrome (Wilms' tumour (WT), Aniridia, Genital abnormalities, and metal Retardation, due to 11p13 deletion) the neuropsychological profile of the syndrome is little reported in the literature. We report about a 12-year-old boy presenting with WAGR syndrome (WT, right complete aniridia, bilateral cryptorchidism, interstitial deletion involving band 11p13) but with no mental retardation. An in-depth clinical evaluation revealed no behavioural or social problems and the child's neuropsychological profile was found to be within the normal range for all abilities and functions investigated (with the exception of an impulsive cognitive style and some difficulties in academic skills). This case underlines the importance of in-depth neuropsychological evaluation that includes not only IQ measurement, but also examination of attention and academic skills, in order to establish the complete phenotypical profile of WAGR patients, rather than labelling them as learning disabled (i.e. mental retardation).     

The global potential for increased storage of carbon on land

Constraining the climate crisis requires urgent action to reduce anthropogenic emissions while simultaneously removing carbon dioxide from the atmosphere. Improved information about the maximum magnitude and spatial distribution of opportunities for additional land-based removals of CO₂ is needed to guide on-the-ground decision-making about where to implement climate change mitigation strategies. Here, we present a globally consistent spatial dataset (approximately 500-m resolution) of current, potential, and unrealized potential carbon storage in woody plant biomass and soil organic matter. We also provide a framework for prioritizing actions related to the restoration, management, and maintenance of woody carbon stocks and associated soils. By comparing current to potential carbon storage, while excluding areas critical to food production and human habitation, we find 287 petagrams (PgC) of unrealized potential storage opportunity, of which 78% (224 PgC) is in biomass and 22% (63 PgC) is in soil. Improved management of existing forests may offer nearly three-fourths (206 PgC) of the total unrealized potential, with the majority (71%) concentrated in tropical ecosystems. However, climate change is a source of considerable uncertainty. While additional research is needed to understand the impact of natural disturbances and biophysical feedbacks, we project that the potential for additional carbon storage in woody biomass will increase (+17%) by 2050 despite projected decreases (−12%) in the tropics. Our results establish an absolute reference point and conceptual framework for national and jurisdictional prioritization of locations and actions to increase land-based carbon storage.

Emissions of carbon to the atmosphere must remain below ∼250 petagrams (PgC) (918 PgCO₂) from 2021 onward to achieve the Paris Agreement’s goal of limiting global temperature rise to well below 2 °C (1–3). At present rates, that amount of carbon will be emitted by 2045. It follows that even necessary and drastic cuts in emissions (i.e., a rapid transition from fossil fuels to renewable energy sources) must be accompanied by carbon dioxide removal (CDR) or negative emissions strategies (4). Promising options for large-scale CDR include improved land stewardship (5), commonly referred to as natural climate solutions (NCS) (6–8). In particular, increasing carbon storage in woody biomass (e.g., forest ecosystems) is widely recognized as having high climate mitigation potential while also affording an array of environmental and socio-economic cobenefits (6–9). While a growing body of research has estimated the near-term potential for land-based climate mitigation (6, 8, 10), these studies emphasize the climate benefit over short, 10- to 30-y planning horizons. They do not include estimates of the upper limit for additional land-based carbon storage or its spatial distribution. This information is essential for landscape-level planning and targeted implementation of NCS, given that the potential for additional carbon storage is necessarily defined by both the rate at which carbon can be sequestered and the magnitude of the available reservoir. Therefore, we provide 500-m-resolution global maps to quantify the maximum potential for additional carbon storage in ecosystems dominated by woody vegetation (i.e., trees and shrubs), under baseline (1960 to 1990) and future (representative concentration pathway scenario 8.5 [RCP8.5]) climate conditions. This information can be used to help direct NCS toward areas with the greatest maximum opportunity, inform when NCS will saturate, and identify the types of NCS actions that are best suited to a given location.One approach to estimating maximum additional carbon storage—or the difference between current and potential carbon, which we term “unrealized potential” carbon—is a bookkeeping approach that tracks carbon fluxes through time. Under this approach, net land-based emissions since 1850 are estimated to have been 108 to 188 PgC, including both biomass (above and below ground) and soil organic matter (13–17). Estimates that account for preindustrial (i.e., pre-1850) land use are more varied and increase post-1850 estimates by as much as 325 to 357 PgC (18) or as little as 48 to 153 PgC (11–13, 15). This high uncertainty limits the practical utility of this approach.Other investigators have sought instead to quantify unrealized potential by comparing estimates of current and potential land carbon storage. Sanderman et al. (6), considering only soil organic carbon (SOC), estimated net losses in the upper 2 m of soil from agricultural land use to be 116 PgC since 10,000 BC. Erb et al. (19), focusing on changes in vegetation biomass, found losses in carbon due to human land use to be significantly larger (447 PgC) than the studies cited above that consider only the postindustrial period, but generally consistent with some of those that account for preindustrial human disturbance (18). Bastin et al. (20), in a study focused on the restoration of global tree cover, identified an additional reservoir of 206 PgC when considering all carbon pools (aboveground and belowground biomass, soil, litter, and dead wood) after excluding cropland and urban areas.However, all of these global analyses fall short in delivering the robust spatially explicit information needed for targeted planning and implementation of landscape-level NCS. While the global dataset produced by Bastin et al. (20) has a reasonably high spatial resolution (30 arc seconds; approximately 900 m) and considers all land carbon pools, the product is limited to the storage potential afforded by the expansion of tree cover. Moreover, the result is subject to the uncertainty inherent in indirect estimates of carbon stock from area-based metrics of tree/forest cover (21). In comparison, the data product created by Erb et al. (19), which is based on several disparate yet direct estimates of terrestrial carbon storage, is limited by its treatment of only the biomass carbon pool and coarse spatial resolution (5 arc min; approximately 9.3 km). The authors themselves remark that “the uncertainty range could be narrowed if a single robust, validated method would be applied continuously in the stocktaking efforts” (19).Here, we apply a consistent suite of methods to generate spatially explicit global estimates of current (ca. 2016) and climate-constrained potential land carbon storage in aboveground woody biomass (AGB), belowground woody biomass (BGB), and SOC pools at a spatial resolution of approximately 500 m. The difference between current and potential land carbon storage represents the unrealized potential for additional carbon accumulation in global woody biomass and soils. We then disaggregate this global estimate of unrealized potential carbon storage using a conceptual framework we term the NCS opportunity space: seven discrete, internally consistent, and spatially explicit categories of broad NCS action (Fig. 1). Categories are defined quantitatively in terms of woody carbon density, thereby avoiding the uncertainty associated with derivative approximations of potential carbon storage based on forest area or canopy cover. After applying safeguards to lands currently utilized for food production, human habitation (e.g., urban areas), and sensitive biodiversity (nonwoody grasslands), we demonstrate the utility of the opportunity space framework for landscape-level NCS planning by analyzing the global, regional, and national potential for additional land carbon storage attributable to restoration (e.g., reforestation), management (e.g., improved natural forest stewardship), and maintenance (i.e., the sequestration benefit accrued through avoided forest conversion) of woody carbon stocks and associated soils. Finally, we evaluate the uncertainty that climate change poses to the magnitude and spatial distribution of the unrealized potential for additional carbon storage through 2050.Open in a separate windowFig. 1.The NCS opportunity space, consisting of seven categories defined by the ratio of current (x axis) to potential (y axis) carbon storage as well as carbon-based thresholds delineating NCS-relevant systems. Categories include: Restore/High suitability for forestry-based NCS (R/H; red), Maintain and manage/High suitability for forestry-based NCS (MM/H; dark green), Maintain/High suitability for forestry-based NCS (M/H; dark blue), Restore/Low suitability for forestry-based NCS (R/L; orange), Maintain and manage/Low suitability for forestry-based NCS (MM/L; light green), Maintain/Low suitability for forestry-based NCS (M/L; light blue), and Nonwoody (yellow). † denotes associated grassland/savanna biodiversity considerations.     

Clinical and Metabolomic Effects of Lactiplantibacillus plantarum and Pediococcus acidilactici in Fructose Intolerant Patients

Fructose intolerance (FI) is a widespread non-genetic condition in which the incomplete absorption of fructose leads to gastro-intestinal disorders. The crucial role of microbial dysbiosis on the onset of these intolerance symptoms together with their persistence under free fructose diets are driving the scientific community towards the use of probiotics as a novel therapeutic approach. In this study, we evaluated the prevalence of FI in a cohort composed of Romanian adults with Functional Grastrointestinal Disorders (FGIDs) and the effectiveness of treatment based on the probiotic formulation EQBIOTA^® (Lactiplantibacillus plantarum CECT 7484 and 7485 and Pediococcus acidilactici CECT 7483). We evaluated the impact of a 30-day treatment both on FI subjects and healthy volunteers. The gastrointestinal symptoms and fecal volatile metabolome were evaluated. A statistically significant improvement of symptoms (i.e., bloating, and abdominal pain) was reported in FI patient after treatment. On the other hand, at the baseline, the content of volatile metabolites was heterogeneously distributed between the two study arms, whereas the treatment led differences to decrease. From our analysis, how some metabolomics compounds were correlated with the improvement and worsening of clinical symptoms clearly emerged. Preliminary observations suggested how the improvement of gastrointestinal symptoms could be induced by the increase of anti-inflammatory and protective substrates. A deeper investigation in a larger patient cohort subjected to a prolonged treatment would allow a more comprehensive evaluation of the probiotic treatment effects.