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Introduction Repetitive transcranial magnetic stimulation (rTMS) is an evidence-based treatment and rTMS protocols have been included in international guidelines for patients with treatment-resistant depression (TRD). The daily administration of standard rTMS protocols, typically over several weeks, could be a limiting factor (e.g., time off from work, commuting issues). To intensify the antidepressant response and to reduce the number of stimulation days, it has been proposed that increasing the number of rTMS sessions performed per day could be more effective and help to reduce the burden for patients and clinicians. Although there is much interest in accelerated TMS protocols, little is known about their efficacy and tolerability, and the literature on the topic is still scarce. Objectives To compare the efficacy and tolerability of two rTMS protocols (standard vs. accelerated) as augmentative strategies in patients with TRD. Methods In the present ongoing, open-label, trial 14 patients meeting DSM-5 criteria for major depressive episode (either unipolar or bipolar), classified as partial responders or non-responders to adequate pharmacological treatment, were randomized to receive either standard (one session per day, five days a week, for four weeks; n= 7) or accelerated (two sessions per day, five days a week, for two weeks; n=6) rTMS treatment protocols. In both cases, rTMS was performed on the left dorsolateral prefrontal cortex, high frequency (10 Hz) at 120% of the motor threshold, 3000 pulses per sessions. Primary outcome measures included HAM-D, MADRS, and CGI-S scores at baseline (T0), at the end of rTMS treatment (T1), and after 1 month (T2), as well as tolerability based on adverse effects. Paired Samples t-Test for continuous variables was used to compare psychometric scales at each timepoint, while t-Test was used to compare differences between the two groups. Results With respect to total sample, in terms of primary outcome measures a significant reduction of HAM-D, MADRS and CGI-S total scores between T0 and T1 (t: 3.01, p

Tumor-associated macrophages (TAMs) with M2 phenotype provide an immunosuppressive microenvironment for tumor growth. In contrast, A great deal of evidence indicates that macrophages in obese patients' adipose tissue undergo a phenotypic change from M2 to Ml polarization accelerating adipose tissue inflammation. Interestingly, obesity is considered a major risk factor for breast cancer. Here, we report a case-control study comparing normal-weight and obese women with breast cancer. Activation states of macrophages and patterns of inflammation associated to breast invasive ductal carcinoma were analyzed by immunohistochemistry. iNOS positive macrophages were counted as a Ml polarized population. Our study demonstrates that classically activated macrophages in obese patients outnumber classically activated macrophages in the breast of non-obese patients with infiltrating ductal carcinoma. However, cancer cell linked factors may strongly antagonize Ml macrophages' positive effects by both stimulating their switching to M2 TAMs and inhibiting their effects.

This paper addresses the question of how catchment-scale water and energy balances have responded to climatic and land surface changes over the last 70 years in the federal state of Saxony in eastern Germany. Therefore, observational data of hydrological and meteorological monitoring sites from 1951 to 2020 across 71 catchments are examined in a relative water- and energy-partitioning framework to put the recent drought-induced changes into a historical perspective. A comprehensive visualization method is used to analyze the observed time series. The study focuses on changes on a decadal timescale and finds the largest decline in observed runoff in the last decade (2011–2020). The observed decline can be explained by the significant increase in aridity, caused by the reduction in annual mean rainfall and a simultaneous increase in potential evaporation. In a few mainly forested headwater catchments, the observed decline in runoff was even stronger than predicted by climate conditions alone. These catchments are still recovering from past widespread forest damages sustained in the 1970s to 1980s, resulting in a continuous increase in actual evapotranspiration due to forest regrowth. On the contrary, runoff stayed almost constant in other catchments despite an increase in aridity. These results highlight that water budgets in Saxony are in an unstable, non-stationary regime due to significant climatic changes and the regional impacts of land surface changes such as forest health. The recent decreases in the mean annual runoff are substantial and must be taken into account by the authorities for freshwater management.

Diurnal temperature variations are strongly shaped by the absorption of solar radiation, but evaporation, or the latent heat flux, also plays an important role. Generally, evaporation cools. Its relation to diurnal temperature variations, however, is unclear. This study investigates the diurnal response of surface and air temperatures to evaporative conditions for different vegetation types. We use the warming rate, defined as the increase in temperature in response to absorbed solar radiation in the morning, and evaluate how it changes with evaporative fraction, which is an indicator of the evaporative conditions. Results for 51 FLUXNET sites show that the warming rate of air temperature carries very weak imprints of evaporative fraction across all vegetation types. However, the warming rate of surface temperature is highly sensitive to evaporative fraction with a value of ∼23×10-3 K (W m-2)-1, indicating stronger evaporative cooling for moister conditions. Contrarily, the warming rates of surface and air temperatures are similar at forest sites and carry literally no imprints of evaporative fraction. We explain these contrasting patterns with an analytical surface energy balance model. The derived expressions reproduce the observed warming rates and their sensitivity to evaporative fraction in all vegetation types. Multiplying the warming rate with daily maximum solar radiation gives an approximation for the diurnal surface temperature range (DTsR). We use our model to compare the individual contributions of solar radiation, evaporative conditions, and vegetation (by its aerodynamic conductance) in shaping DTsR and show that the high aerodynamic conductance of forests reduces DTsR substantially more (−56 %) than evaporative cooling (−22 %). We further show that the strong diurnal variation in aerodynamic conductance (∼2.5 times of the mean across vegetation types) reduces DTsR by ∼35 % in short vegetation and savanna but only by ∼22 % in forests. We conclude that diurnal temperature variations may be useful for predicting evaporation for short vegetation. In forests, however, the diurnal variations in temperatures are mainly governed by their high aerodynamic conductance, resulting in negligible imprints of evaporative conditions.

Abstract Estimates of radiative fluxes under cloud‐free conditions (“clear‐sky”) are required in many fields, from climatic analyses of solar transmission to estimates of solar energy potential for electricity generation. Ideally, these fluxes can be obtained directly from measurements of solar fluxes at the surface. However, common standard methods to identify clear‐sky conditions require observations of both the total and the diffuse radiative fluxes at very high temporal resolution of minutes, which restricts these methods to a few, well‐equipped sites. Here we propose a simple method to estimate clear‐sky fluxes only from typically available global radiation measurements (Rsd) at (half‐)hourly resolution. Plotting a monthly sample of observed Rsd against the corresponding incoming solar radiation at the top of atmosphere (potential solar radiation) reveals a typical triangle shape with clear‐sky conditions forming a distinct, linear slope in the upper range of observations. This upper slope can be understood as the fractional transmission of solar radiation representative for cloud‐free conditions of the sample period. We estimate this upper slope through quantile regression. We employ data of 42 stations of the worldwide Baseline Surface Radiation Network to compare our monthly estimates with the standard clear‐sky identification method developed by Long and Ackerman (2000, https://doi.org/10.1029/2000JD900077). We find very good agreement of the derived fractional solar transmission (R2 = 0.73) across sites. These results thus provide confidence in applying the proposed method to the larger set of global radiation measurements to obtain further observational constraints on clear‐sky fluxes and cloud radiative effects.

While modeling approaches of evapotranspiration (λE) perform reasonably well when evaluated at daily or monthly timescales, they can show systematic deviations at the sub-daily timescale, which results in potential biases in modeled λE to global climate change. Here we decompose the diurnal variation of heat fluxes and meteorological variables into their direct response to incoming solar radiation (Rsd) and a phase shift to Rsd. We analyze data from an eddy-covariance (EC) station at a temperate grassland site, which experienced a pronounced summer drought. We employ three structurally different modeling approaches of λE, which are used in remote sensing retrievals, and quantify how well these models represent the observed diurnal cycle under clear-sky conditions. We find that energy balance residual approaches, which use the surface-to-air temperature gradient as input, are able to reproduce the reduction of the phase lag from wet to dry conditions. However, approaches which use the vapor pressure deficit (Da) as the driving gradient (Penman–Monteith) show significant deviations from the observed phase lags, which is found to depend on the parameterization of surface conductance to water vapor. This is due to the typically strong phase lag of 2–3 h of Da, while the observed phase lag of λE is only on the order of 15 min. In contrast, the temperature gradient shows phase differences in agreement with the sensible heat flux and represents the wet–dry difference rather well. We conclude that phase lags contain important information on the different mechanisms of diurnal heat storage and exchange and, thus, allow a process-based insight to improve the representation of land–atmosphere (L–A) interactions in models.

Turbulent fluxes strongly shape the conditions at the land surface, yet they are typically formulated in terms of semiempirical parameterizations that make it difficult to derive theoretical estimates of how global change impacts land surface functioning. Here, we describe these turbulent fluxes as the result of a thermodynamic process that generates work to sustain convective motion and thus maintains the turbulent exchange between the land surface and the atmosphere. We first derive a limit from the second law of thermodynamics that is equivalent to the Carnot limit but which explicitly accounts for diurnal heat storage changes in the lower atmosphere. We call this the limit of a cold heat engine and use it together with the surface energy balance to infer the maximum power that can be derived from the turbulent fluxes for a given solar radiative forcing. The surface energy balance partitioning estimated from this thermodynamic limit requires no empirical parameters and compares very well with the observed partitioning of absorbed solar radiation into radiative and turbulent heat fluxes across a range of climates, with correlation coefficients r2 ≥ 95 % and slopes near 1. These results suggest that turbulent heat fluxes on land operate near their thermodynamic limit on how much convection can be generated from the local radiative forcing. It implies that this type of approach can be used to derive general estimates of global change that are solely based on physical principles.

Observations and climate model simulations consistently show a higher climate sensitivity of land surfaces compared to ocean surfaces. Here we show that this difference in temperature sensitivity can be explained by the different means by which the diurnal variation in solar radiation is buffered. While ocean surfaces buffer the diurnal variations by heat storage changes below the surface, land surfaces buffer it mostly by heat storage changes above the surface in the lower atmosphere that are reflected in the diurnal growth of a convective boundary layer. Storage changes below the surface allow the ocean surface–atmosphere system to maintain turbulent fluxes over day and night, while the land surface–atmosphere system maintains turbulent fluxes only during the daytime hours, when the surface is heated by absorption of solar radiation. This shorter duration of turbulent fluxes on land results in a greater sensitivity of the land surface–atmosphere system to changes in the greenhouse forcing because nighttime temperatures are shaped by radiative exchange only, which are more sensitive to changes in greenhouse forcing. We use a simple, analytic energy balance model of the surface–atmosphere system in which turbulent fluxes are constrained by the maximum power limit to estimate the effects of these different means to buffer the diurnal cycle on the resulting temperature sensitivities. The model predicts that land surfaces have a 50 % greater climate sensitivity than ocean surfaces, and that the nighttime temperatures on land increase about twice as much as daytime temperatures because of the absence of turbulent fluxes at night. Both predictions compare very well with observations and CMIP5 climate model simulations. Hence, the greater climate sensitivity of land surfaces can be explained by its buffering of diurnal variations in solar radiation in the lower atmosphere.

Sin resumen.

We combine ecohydrological observations of sap flow and soil moisture with thermodynamically constrained estimates of atmospheric evaporative demand to infer the dominant controls of forest transpiration in complex terrain. We hypothesize that daily variations in transpiration are dominated by variations in atmospheric demand, while site-specific controls, including limiting soil moisture, act on longer timescales. We test these hypotheses with data of a measurement setup consisting of five sites along a valley cross section in Luxembourg. Both hillslopes are covered by forest dominated by European beech (Fagus sylvatica L.). Two independent measurements are used to estimate stand transpiration: (i) sap flow and (ii) diurnal variations in soil moisture, which were used to estimate the daily root water uptake. Atmospheric evaporative demand is estimated through thermodynamically constrained evaporation, which only requires absorbed solar radiation and temperature as input data without any empirical parameters. Both transpiration estimates are strongly correlated to atmospheric demand at the daily timescale. We find that neither vapor pressure deficit nor wind speed add to the explained variance, supporting the idea that they are dependent variables on land–atmosphere exchange and the surface energy budget. Estimated stand transpiration was in a similar range at the north-facing and the south-facing hillslopes despite the different aspect and the largely different stand composition. We identified an inverse relationship between sap flux density and the site-average sapwood area per tree as estimated by the site forest inventories. This suggests that tree hydraulic adaptation can compensate for heterogeneous conditions. However, during dry summer periods differences in topographic factors and stand structure can cause spatially variable transpiration rates. We conclude that absorption of solar radiation at the surface forms a dominant control for turbulent heat and mass exchange and that vegetation across the hillslope adjusts to this constraint at the tree and stand level. These findings should help to improve the description of land-surface–atmosphere exchange at regional scales.

The results of streamflow trend studies are often characterized by mostly insignificant trends and inexplicable spatial patterns. In our study region, Western Austria, this applies especially for trends of annually averaged runoff. However, analysing the altitudinal aspect, we found that there is a trend gradient from higher-altitude to lower-altitude stations, i.e. a pattern of mostly positive annual trends at higher stations and negative ones at lower stations. At mid-altitudes, the trends are mostly insignificant. Here we hypothesize that the streamflow trends are caused by the following two main processes: on the one hand, melting glaciers produce excess runoff at higher-altitude watersheds. On the other hand, rising temperatures potentially alter hydrological conditions in terms of less snowfall, higher infiltration, enhanced evapotranspiration, etc., which in turn results in decreasing streamflow trends at lower-altitude watersheds. However, these patterns are masked at mid-altitudes because the resulting positive and negative trends balance each other. To support these hypotheses, we attempted to attribute the detected trends to specific causes. For this purpose, we analysed trends of filtered daily streamflow data, as the causes for these changes might be restricted to a smaller temporal scale than the annual one. This allowed for the explicit determination of the exact days of year (DOYs) when certain streamflow trends emerge, which were then linked with the corresponding DOYs of the trends and characteristic dates of other observed variables, e.g. the average DOY when temperature crosses the freezing point in spring. Based on these analyses, an empirical statistical model was derived that was able to simulate daily streamflow trends sufficiently well. Analyses of subdaily streamflow changes provided additional insights. Finally, the present study supports many modelling approaches in the literature which found out that the main drivers of alpine streamflow changes are increased glacial melt, earlier snowmelt and lower snow accumulation in wintertime.

The land surface energy and water balances are tightly coupled by the partitioning of absorbed solar radiation into terrestrial radiation and the turbulent fluxes of sensible and latent heat, as well as the partitioning of precipitation into evaporation and runoff. Evaporation forms the critical link between these two balances. Its rate is strongly affected by turbulent exchange as it provides the means to efficiently exchange moisture between the heated, moist surface and the cooled, dry atmosphere. Here, we use the constraint that this mass exchange operates at the thermodynamic limit of maximum power to derive analytical expressions for the partitioning of the surface energy and water balances on land. We use satellite-derived forcing of absorbed solar radiation, surface temperature and precipitation to derive simple spatial estimates for the annual mean fluxes of sensible and latent heat and evaluate these estimates with the ERA-Interim reanalysis data set and observations of the discharge of large river basins. Given the extremely simple approach, we find that our estimates explain the climatic mean variations in net radiation, evaporation, and river discharge reasonably well. We conclude that our analytical, minimum approach provides adequate first order estimates of the surface energy and water balance on land and that the thermodynamic limit of maximum power provides a useful closure assumption to constrain the energy partitioning at the land surface.

Understanding and quantifying the impact of changes in climate and land use/land cover on water availability is a prerequisite to adapt water management; yet, it can be difficult to separate the effects of these different impacts. In this paper we illustrate a separation and attribution method based on a Budyko framework. We assume that evapotranspiration (ET) is limited by the climatic forcing of precipitation (P) and evaporative demand (E0), but modified by land-surface properties. Impacts of changes in climate (i.e., E0/P) or land-surface changes on ET alter the two dimensionless measures describing relative water (ET/P) and energy partitioning (ET/E0), which allows us to separate and quantify these impacts. We use the separation method to quantify the role of environmental factors on ET using 68 small to medium range river basins covering the greatest part of the German Federal State of Saxony within the period of 1950–2009. The region can be considered as a typical central European landscape with considerable anthropogenic impacts. In the long term, most basins are found to follow the Budyko curve which we interpret as a result of the strong interactions of climate, soils and vegetation. However, two groups of basins deviate. Agriculturally dominated basins at lower altitudes exceed the Budyko curve while a set of high altitude, forested basins fall well below. When visualizing the decadal dynamics on the relative partitioning of water and energy the impacts of climatic and land-surface changes become apparent. After 1960 higher forested basins experienced large land-surface changes which show that the air pollution driven tree damages have led to a decline of annual ET on the order of 38%. In contrast, lower, agricultural dominated areas show no significant changes during that time. However, since the 1990s effective mitigation measures on industrial pollution have been established and the apparent brightening and regrowth has resulted in a significant increase of ET across most basins. In conclusion, data on both, the water and the energy balance is necessary to understand how long-term climate and land cover control evapotranspiration and thus water availability. Further, the detected land-surface change impacts are consistent in space and time with independent forest damage data and thus confirm the validity of the separation approach.

The global hydrologic cycle is likely to increase in strength with global warming, although some studies indicate that warming due to solar absorption may result in a different sensitivity than warming due to an elevated greenhouse effect. Here we show that these sensitivities of the hydrologic cycle can be derived analytically from an extremely simple surface energy balance model that is constrained by the assumption that vertical convective exchange within the atmosphere operates at the thermodynamic limit of maximum power. Using current climatic mean conditions, this model predicts a sensitivity of the hydrologic cycle of 2.2% K−1 to greenhouse-induced surface warming which is the sensitivity reported from climate models. The sensitivity to solar-induced warming includes an additional term, which increases the total sensitivity to 3.2% K−1. These sensitivities are explained by shifts in the turbulent fluxes in the case of greenhouse-induced warming, which is proportional to the change in slope of the saturation vapor pressure, and in terms of an additional increase in turbulent fluxes in the case of solar radiation-induced warming. We illustrate an implication of this explanation for geoengineering, which aims to undo surface temperature differences by solar radiation management. Our results show that when such an intervention compensates surface warming, it cannot simultaneously compensate the changes in hydrologic cycling because of the differences in sensitivities for solar vs. greenhouse-induced surface warming. We conclude that the sensitivity of the hydrologic cycle to surface temperature can be understood and predicted with very simple physical considerations but this needs to reflect on the different roles that solar and terrestrial radiation play in forcing the hydrologic cycle.

The hydrologic cycle results from the combination of energy conversions and atmospheric transport, and the laws of thermodynamics set limits to both. Here, we apply thermodynamics to derive the limits of the strength of hydrologic cycling within the Earth system and about the properties and processes that shape these limits. We set up simple models to derive analytical expressions of the limits of evaporation and precipitation in relation to vertical and horizontal differences in solar radiative forcing. These limits result from a fundamental trade-off by which a greater evaporation rate reduces the temperature gradient and thus the driver for atmospheric motion that exchanges moistened air from the surface with the drier air aloft. The limits on hydrologic cycling thus reflect the strong interaction between the hydrologic flux, motion, and the driving gradient. Despite the simplicity of the models, they yield estimates for the limits of hydrologic cycling that are within the observed magnitude, suggesting that the global hydrologic cycle operates near its maximum strength. We close with a discussion of how thermodynamic limits can provide a better characterization of the interaction of vegetation and human activity with hydrologic cycling.

The prediction of climate effects on terrestrial ecosystems and water resources is one of the major research questions in hydrology. Conceptual water-energy balance models can be used to gain a first order estimate of how long-term average streamflow is changing with a change in water and energy supply. A common framework for investigation of this question is based on the Budyko hypothesis, which links hydrological response to aridity. Recently, Renner et al. (2012) introduced the climate change impact hypothesis (CCUW), which is based on the assumption that the total efficiency of the catchment ecosystem to use the available water and energy for actual evapotranspiration remains constant even under climate changes. Here, we confront the climate sensitivity approaches (the Budyko approach of Roderick and Farquhar, 2011, and the CCUW) with data of more than 400 basins distributed over the continental United States. We first estimate the sensitivity of streamflow to changes in precipitation using long-term average data of the period 1949 to 2003. This provides a hydro-climatic status of the respective basins as well as their expected proportional effect to changes in climate. Next, we test the ability of both approaches to predict climate impacts on streamflow by splitting the data into two periods. We (i) analyse the long-term average changes in hydro-climatology and (ii) derive a statistical classification of potential climate and basin change impacts based on the significance of observed changes in runoff, precipitation and potential evapotranspiration. Then we (iii) use the different climate sensitivity methods to predict the change in streamflow given the observed changes in water and energy supply and (iv) evaluate the predictions by (v) using the statistical classification scheme and (vi) a conceptual approach to separate the impacts of changes in climate from basin characteristics change on streamflow. This allows us to evaluate the observed changes in streamflow as well as to assess the impact of basin changes on the validity of climate sensitivity approaches. The apparent increase of streamflow of the majority of basins in the US is dominated by an increase in precipitation. It is further evident that impacts of changes in basin characteristics appear simultaneously with climate changes. There are coherent spatial patterns with catchments where basin changes compensate for climatic changes being dominant in the western and central parts of the US. A hot spot of basin changes leading to excessive runoff is found within the US Midwest. The impact of basin changes on the prediction is large and can be twice as much as the observed change signal. Although the CCUW and the Budyko approach yield similar predictions for most basins, the data of water-limited basins support the Budyko framework rather than the CCUW approach, which is known to be invalid under limiting climatic conditions.

Long term average change in streamflow is a major concern in hydrology and water resources management. Some simple analytical methods exist for the assessment of the sensitivity of streamflow to climatic variations. These are based on the Budyko hypothesis, which assumes that long term average streamflow can be predicted by climate conditions, namely by annual average precipitation and evaporative demand. Recently, Tomer and Schilling (2009) presented an ecohydrological concept to distinguish between effects of climate change and basin characteristics change on streamflow. We relate the concept to a coupled consideration of the water and energy balance. We show that the concept is equivalent to the assumption that the sum of the ratio of annual actual evapotranspiration to precipitation and the ratio of actual to potential evapotranspiration is constant, even when climate conditions are changing. Here, we use this assumption to derive analytical solutions to the problem of streamflow sensitivity to climate. We show how, according to this assumption, climate sensitivity would be influenced by different climatic conditions and the actual hydrological response of a basin. Finally, the properties and implications of the method are compared with established Budyko sensitivity methods and illustrated by three case studies. It appears that the largest differences between both approaches occur under limiting conditions. Specifically, the sensitivity framework based on the ecohydrological concept does not adhere to the water and energy limits, while the Budyko approach accounts for limiting conditions by increasing the sensitivity of streamflow to a catchment parameter encoding basin characteristics. Our findings do not support any application of the ecohydrological concept under conditions close to the water or energy limits, instead we suggest a correction based on the Budyko framework.

Recently, climatological studies report observational evidence of changes in the timing of the seasons, such as earlier timing of the annual cycle of surface temperature, earlier snow melt and earlier onset of the phenological spring season. Also hydrological studies report earlier timing and changes in monthly streamflows. From a water resources management perspective, there is a need to quantitatively describe the variability in the timing of hydrological regimes and to understand how climatic changes control the seasonal water budget of river basins. Here, the timing of hydrological regimes from 1930–2009 was investigated in a network of 27 river gauges in Saxony/Germany through a timing measure derived by harmonic function approximation of annual periods of runoff ratio series. The timing measure proofed to be robust and equally applicable to both mainly pluvial river basins and snow melt dominated regimes. We found that the timing of runoff ratio is highly variable, but markedly coherent across the basins analysed. Differences in average timing are largely explained by basin elevation. Also the magnitude of low frequent changes in the seasonal timing of streamflow and the sensitivity to the changes in the timing of temperature increase with basin elevation. This sensitivity is in turn related to snow storage and release, whereby snow cover dynamics in late winter explain a large part of the low- and high-frequency variability. A trend analysis based on cumulative anomalies revealed a common structural break around the year 1988. While the timing of temperature shifted earlier by 4 days, accompanied by a temperature increase of 1 K, the timing of runoff ratio within higher basins shifted towards occurring earlier about 1 to 3 weeks. This accelerated and distinct change indicates, that impacts of climate change on the water cycle may be strongest in higher, snow melt dominated basins.

Background: Long-term survival induced by anticancer treatments discloses emerging frailty among breast cancer (BC) survivors. Trastuzumab-induced cardiotoxicity (TIC) is reported in at least 5% of HER2+BC patients. However, TIC mechanism remains unclear and predictive genetic biomarkers are still lacking. Interaction between systemic inflammation, cytokine release and ADME genes in cancer patients might contribute to explain mechanisms underlying individual susceptibility to TIC and drug response variability. We present a single institution case series to investigate the potential role of genetic variants in ADME genes in HER2+BC patients TIC experienced., Methods: We selected data related to 40 HER2+ BC patients undergone to DMET genotyping of ADME constitutive variant profiling, with the aim to prospectively explore their potential role in developing TIC. Only 3 patients ("case series"), who experienced TIC, were compared to 37 "control group" matched patients cardiotoxicity-sparing. All patients underwent to left ventricular ejection fraction (LVEF) evaluation at diagnosis and during anti-HER2 therapy. Each single probe was clustered to detect SNPs related to cardiotoxicity., Results: In this retrospective analysis, our 3 cases were homogeneous in terms of clinical-pathological characteristics, trastuzumab-based treatment and LVEF decline. We identified 9 polymorphic variants in 8 ADME genes (UGT1A1, UGT1A6, UGT1A7, UGT2B15, SLC22A1, CYP3A5, ABCC4, CYP2D6) potentially associated with TIC., Conclusion: Real-world TIC incidence is higher compared to randomized clinical trials and biomarkers with potential predictive value aren't available. Our preliminary data, as proof of concept, could suggest a predictive role of pharmacogenomic approach in the identification of cardiotoxicity risk biomarkers for anti-HER2 treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: Paliperidone Palmitate is the only antipsychotic that has been developed in three different intramuscular long-acting injectable (LAI) dosing regimen: monthly (PP1M), quarterly (PP3M), and from 2020 also twice-yearly (PP6M). The latter was approved for the maintenance treatment of adults with schizophrenia and clinically stabilized with PP1M or PP3M., Areas Covered: Data from studies evaluating efficacy in the maintenance treatment of schizophrenia with PP6M are reviewed. Since no post-marketing safety studies are currently available, data from spontaneous reporting system databases, FAERS and Eudravigilance, are analyzed and the reported treatment-emergent adverse events of PP6M are discussed., Expert Opinion: The efficacy of PP6M is comparable to that of PP3M in terms of relapses prevention in patients with schizophrenia previously stabilized on PP3M or PP1M. Also, the maintenance of clinical efficacy in the long term has been demonstrated. Data from pharmacovigilance analyses, as well as from phase 3 studies, show that PP6M is generally well tolerated, consistently with PP3M safety data. PP6M allows a longer dosing interval than any other LAI antipsychotics, potentially reducing nonadherence and disease relapses. In future, an increase in the prescription rates of PP6M is expected and real-world efficacy and tolerability studies will be conducted.

Purpose: Five-year data of the phase III trial TAM-01 showed that low-dose tamoxifen at 5 mg once daily administered for 3 years in women with intraepithelial neoplasia (IEN) reduced by 52% the recurrence of invasive breast cancer or ductal carcinoma in situ (DCIS), without additional adverse events over placebo. Here, we present the 10-year results., Methods: We randomly assigned 500 women with breast IEN (atypical ductal hyperplasia, lobular carcinoma in situ [LCIS], or hormone-sensitive or unknown DCIS) to low-dose tamoxifen or placebo after surgery with or without irradiation. The primary end point was the incidence of invasive breast cancer or DCIS., Results: The TAM-01 population included 500 women (20% atypical ductal hyperplasia, 11% LCIS, and 69% DCIS). The mean (±SD) age at the start of treatment was 54 ± 9 years, and 58% of participants were postmenopausal. After a median follow-up of 9.7 years (IQR, 8.3-10.9 years), 66 breast cancers (15 in situ; 51 invasive) were diagnosed: 25 in the tamoxifen group and 41 in the placebo group (annual rate per 1,000 person-years, 11.3 with tamoxifen v 19.5 with placebo; hazard ratio [HR], 0.58; 95% CI, 0.35 to 0.95; log-rank P = .03). Most recurrences were invasive (77%) and ipsilateral (59%). Regarding contralateral breast cancer incidence, there were six events in the tamoxifen arm and 16 in the placebo arm (HR, 0.36; 95% CI, 0.14 to 0.92; P = .025). The number needed to be treated to prevent one case of breast event with tamoxifen therapy was 22 in 5 years and 14 in 10 years. The benefit was seen across all patient subgroups. There was a significant 50% reduction of recurrence with tamoxifen in the DCIS cohort, which represents 70% of the overall population (HR, 0.50; 95% CI, 0.28 to 0.91; P = .02). No between-group difference in the incidence of serious adverse events was reported during the prolonged follow-up period., Conclusion: Tamoxifen 5 mg once daily for 3 years significantly prevents recurrence from noninvasive breast cancer after 7 years from treatment cessation without long-term adverse events.

Background: Chronic Venous Disease (CVD) has a high prevalence in the western world. Varicose veins (VVs) are the main signs of this disease that is characterized by important pathological vessel wall changes. The aim of this study is to correlate the main histopathological abnormalities with related clinical issues of CVD., Methods: A cohort of patients with VVs scheduled for open surgical treatment namely stab avulsion of VVs was recruited. Subsequently, venous tissue from stab avulsion was collected in order to evaluate the following biomarkers: Vascular-Endothelial Growth Factor (VEGF), Protein Gene Product 9.5 (PGP 9.5), Fibronectin (FN), and Matrix Metalloproteinase-9 (MMP-9). The Clinical-Etiology-Anatomy-Pathophysiology (CEAP) criteria were used to classify CVD., Results: Fourteen tissue fragments were processed for histological and immunohistochemical studies. Of these, 43% were from CEAP C2 patients, 36% from CEAP C3 patients, and 21% from CEAP C4 patients. CEAP Class C2 had few to moderate structures positive to VEGF; occasional structures positive to Fibronectin, numerous structures positive to MMP9, few to moderate structures positive to PGP 9.5. CEAP Class C3 had moderate structures positive to VEGF; few to moderate structures positive to Fibronectin; many structures positive to MMP9; few to moderate structures positive to PGP 9.5. CEAP Class C4 had numerous structures positive to VEGF; numerous structures positive to Fibronectin; abundant structures positive to MMP-9; few structures positive to PGP 9.5., Conclusions: In this study, positive VEGF, FN, and MMP-9 structures were found with increasing trends in relation to the disease staging. VEGF and FN are associated with a progressive increase from C2 to C4. The MMP-9 marker has an important positivity even at early stage of the disease, being higher in CEAP C4 patients. PGP 9.5 decreases in CEAP C4 patients and this is concordant to decreased vein wall innervation., (Copyright © 2021. Published by Elsevier Inc.)

Cancer cells are known to secrete many bioactive factors acting both with paracrine and autocrine mechanisms by which they condition the surrounding microenvironment. At the same time, the intracytoplasmic metabolic activities microenvironment influences the profile of this secretion. It is well known that cancer cells exhibit prevalent glycolytic metabolism and a more oxidative atmosphere compared to their healthy counterparts; this metabolic phenotype promotes glycate adducts formation and secretion. Considering the exacerbation of metabolic changes during the cancer progression, it is suggestive to explore the potential correlation between the increasing rate of glycan adducts and the specific pattern of secreted cytokines in different phases of cancer disease. We analyzed the secretomes of blood-derived cancer cell cultures from cancer patients and healthy subjects. The relative glycate adducts content in cancer secretomes was higher in comparison to that of healthy samples. Moreover, the stratification based on different phases of cancer disease correlated with a specific cytokines panel. The results obtained open a new perspective of observation of the intricate relationship between metabolome and inflammation in cancer. By using the analysis of secretome combined with a standardized protocol of liquid biopsy, it would be possible to identify specific profiles of molecular markers useful to arrange alternative and personalized medicine strategies.

Background: Breast cancer is the most common cancer in women. However, in the management of breast cancer, paraneoplastic neurological syndromes represent a diagnostic and therapeutic challenge. The diagnosis of paraneoplastic neurological syndromes is difficult due to the heterogeneity of symptoms, the timing of presentation, and the absence of antibodies, and it generally occurs before the diagnosis of breast cancer in 80% of patients who develop paraneoplastic neurological syndromes. We describe a 72-year-old woman with subacute ophthalmoplegia-ataxia syndrome who was subsequently diagnosed as having breast cancer and anti-Ri antibodies., Case Presentation: A 72-year-old post-menopausal Caucasian woman, with a positive medical history for diabetes mellitus and hypertension, presented with a 3-month onset of blurred vision, diplopia, and progressive gait disturbance. Serological tests were positive for well-characterized onconeural antibodies (anti-Ri). A whole-body computed tomography scan revealed a nodular opacity under her left nipple and axillary adenopathy. A biopsy of her left breast was performed, and histological examination showed ductal carcinoma. She underwent a superoexternal quadrantectomy with left axillary dissection. The final diagnosis showed infiltrating ductal carcinoma of the breast (T1c N1 M0, stage IIA) associated with paraneoplastic ophthalmoplegia-ataxia syndrome. At a 6-month follow-up, she showed no clinical or instrumental evidence of neoplastic recurrence with partial clinical improvement of neurological symptoms, such as ataxia and diplopia., Conclusion: The diagnosis of paraneoplastic neurological syndromes is often late, as in this patient, but treatment at an early stage may provide a good prognosis. Furthermore, this is one of several cases of an anti-Ri paraneoplastic neurological syndrome not associated with myoclonus, which reinforces the belief that opsoclonus myoclonus syndrome is not pathognomonic of the associated anti-Ri paraneoplastic neurological syndromes.

Secretome of primary cultures is an accessible source of biological markers compared to more complex and less decipherable mixtures such as serum or plasma. The protonation state (PS) of secretome reflects the metabolism of cells and can be used for cancer early detection. Here, we demonstrate a superhydrophobic organic electrochemical device that measures PS in a drop of secretome derived from liquid biopsies. Using data from the sensor and principal component analysis (PCA), we developed algorithms able to efficiently discriminate tumour patients from non-tumour patients. We then validated the results using mass spectrometry and biochemical analysis of samples. For the 36 patients across three independent cohorts, the method identified tumour patients with high sensitivity and identification as high as 100% (no false positives) with declared subjects at-risk, for sporadic cancer onset, by intermediate values of PS. This assay could impact on cancer risk management, individual's diagnosis and/or help clarify risk in healthy populations., Competing Interests: The authors declare that they have no competing interests.

Background: The management of breast cancer (BC) skin metastases represents a therapeutic challenge. Electrochemotherapy (ECT) combines the administration of bleomycin with temporary permeabilization induced by locally administered electric pulses. Preliminary experience with ECT in BC patients is encouraging., Methods: A total of 125 patients with BC skin metastases who underwent ECT between 2010 and 2013 were enrolled onto a multicenter retrospective cohort study. The treatment was administered following the European Standard Operative Procedures of Electrochemotherapy. Tumor response was clinically assessed adapting the Response Evaluation Criteria in Solid Tumors, and toxicity was evaluated according to Common Terminology Criteria for Adverse Events 4.0. Cox regression analysis was used to identify predictive factors., Results: Response was evaluable in 113 patients for 214 tumors (median 1 per patient, range 1-3). The overall response rate after 2 months was 90.2 %, while the complete response (CR) rate was 58.4 %. In multivariate analysis, small tumor size (P < 0.001), absence of visceral metastases (P = 0.001), estrogen receptor positivity (P = 0.016), and low Ki-67 index (P = 0.024) were significantly associated with CR. In the first 48 h, 10.4 % of patients reported severe skin pain. Dermatologic toxicity included grade 3 skin ulceration (8.0 %) and grade 2 skin hyperpigmentation (8.8 %). Tumor 1-year local progression-free survival was 86.2 % (95 % confidence interval 79.3-93.8) and 96.4 % (95 % confidence interval 91.6-100) in the subgroup of those with CR., Conclusions: In this study, small tumor size, absence of visceral metastases, estrogen receptor positivity, and low Ki-67 index were predictors of CR after ECT. Patients who experienced CR had durable local control. ECT represents a valuable skin-directed therapy for selected patients with BC.

Although the detection of methylated cell free DNA represents one of the most promising approaches for relapse risk assessment in cancer patients, the low concentration of cell-free circulating DNA constitutes the biggest obstacle in the development of DNA methylation-based biomarkers from blood. This paper describes a method for the measurement of genomic methylation content directly on circulating tumor cells (CTC), which could be used to deceive the aforementioned problem. Since CTC are disease related blood-based biomarkers, they result essential to monitor tumor's stadiation, therapy, and early relapsing lesions. Within surface's bio-functionalization and cell's isolation procedure standardization, the presented approach reveals a singular ability to detect high 5-methylcytosine CTC-subset content in the whole CTC compound, by choosing folic acid (FA) as transducer molecule. Sensitivity and specificity, calculated for FA functionalized surface (FA-surface), result respectively on about 83% and 60%. FA-surface, allowing the detection and characterization of early metastatic dissemination, provides a unique advance in the comprehension of tumors progression and dissemination confirming the presence of CTC and its association with high risk of relapse. This functionalized surface identifying and quantifying high 5-methylcytosine CTC-subset content into the patient's blood lead significant progress in cancer risk assessment, also providing a novel therapeutic strategy., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Galectin-3, β-galactoside-binding lectin, coats the membrane of most cancer cells and is involved in metastasis and endothelium recognition as well as in evading immune surveillance through killing of activated T cells. To flag galectin as a biomarker of tumours and metastasis, it is pivotal to understand the role of this protein in different tumours and at different stages. Breast tumours have an anomalous behaviour of the galectin-3 compared to other tumour cells. Herein, FACS sorting and galactoside based assays were used to investigate the role of galectin-3 in metastasis and metastatisation of breast cancer cells. Breast galectin fingerprint at the FACS displayed a higher amount in healthy cells, compared to metastatic cells. The microfluidic assay was able to isolate tumour and metastatic cells more than healthy breast cells. Investigation was performed on samples from patients with breast tumours at stage I and stage III whilst MCF7 and EPH-4 cells were used to perform preliminary investigations. The readout of the conditioned medium (from culturing of stage I cells) fingerprint by FACS evidenced high expression of free galectin. Analysis of the results established that the galectin coating the membrane, by galactoside recognition of the breast cells, and engaged by the cells to form protein-carbohydrate complexes inside the microfluidic assay, resembled the tumour signature of tumours in breast cells whilst the galectin free is independent of those mechanisms.

Male breast cancer is an uncommon disease with a low annual prevalence in Western countries. Venous thromboembolism may be associated during malignancy of the breast. We report a 70-year-old man who presented with superficial vein thrombosis of right upper limb that predicted the diagnosis of breast invasive ductal carcinoma. Key issues surrounding the diagnosis, treatment, and relationship between breast cancer and venous disorders are discussed. Breast cancer and venous thromboembolism are 2 conditions that are often correlated more than expected, and attention to the combination of these clinical presentations is required., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Breast cancer (BC) and chronic venous disease (CVD) are in some way related to hormonal effects, and often the clinical manifestations of CVD intersect with the clinical course of BC. This article describes the correlations between these clinical conditions., Methods: A total of 1138 female patients with BC were retrospectively reviewed in a 5-year period to obtain clinical information about the frequency and characteristics of contemporary CVD and the relative correlations with estrogen and progesterone receptor status., Results: The presence of BC was associated with concomitant CVD clinical manifestations in patients with positive estrogen receptor status, whereas no association was found in patients with negative estrogen receptor status. The presence of negative estrogen receptor status associated with positive progesterone receptor status seemed to be even protective against CVD. Patients with more severe manifestations of CVD had positive estrogen receptor status., Conclusions: BC and CVD seem to be strongly associated. Positive estrogen receptor status may predispose to a more severe clinical course of venous disease when it occurs in patients with BC., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Advances in carbohydrate sequencing technologies reveal the tremendous complexity of the glycome and the role that glycomics might have to bring insight into the biological functions. Carbohydrate-protein interactions, in particular, are known to be crucial to most mammalian physiological processes as mediators of cell adhesion and metastasis, signal transducers, and organizers of protein interactions. An assay is developed here to mimic the multivalency of biological complexes that selectively and sensitively detect carbohydrate-protein interactions. The binding of β-galactosides and galectin-3--a protein that is correlated to the progress of tumor and metastasis--is examined. The efficiency of the assay is related to the expression of the receptor while anchoring to the interaction's strength. Comparative binding experiments reveal molecular binding preferences. This study establishes that the assay is robust to isolate metastatic cells from colon affected patients and paves the way to personalized medicine., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Cancer is currently considered as the end point of numerous genomic and epigenomic mutations and as the result of the interaction of transformed cells within the stromal microenvironment. The present work focuses on breast cancer, one of the most common malignancies affecting the female population in industrialized countries. In this study, we perform a proteomic analysis of bioptic samples from human breast cancer, namely, interstitial fluids and primary cells, normal vs disease tissues, using tandem mass tags (TmT) quantitative mass spectrometry combined with the MudPIT technique. To the best of our knowledge, this work, with over 1700 proteins identified, represents the most comprehensive characterization of the breast cancer interstitial fluid proteome to date. Network analysis was used to identify functionally active networks in the breast cancer associated samples. From the list of differentially expressed genes, we have retrieved the associated functional interaction networks. Many different signaling pathways were found activated, strongly linked to invasion, metastasis development, proliferation, and with a significant cross-talking rate. This pilot study presents evidence that the proposed quantitative proteomic approach can be applied to discriminate between normal and tumoral samples and for the discovery of yet unknown carcinogenesis mechanisms and therapeutic strategies.

In a contingency learning task, 4-year-old and 8-year-old children had to predict the outcome displayed on the back of a card on the basis of cues presented on the front. The task was embedded in either a causal or a merely predictive scenario. Within this task, either a forward blocking or a backward blocking procedure was implemented. Blocking occurred in the causal but not in the predictive scenario. Moreover, blocking was affected by the scenario to the same extent in both age groups. The pattern of results was similar for forward and backward blocking. These results suggest that even young children are sensitive to the causal structure of a contingency learning task and that the occurrence of blocking in such a task defies an explanation in terms of associative learning theory.