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We described trends and disparities in utilization of systemic chemotherapy in metastatic hepato-pancreato-biliary (HPB) cancers.We queried the National Cancer Database for metastatic HPB cancers [hepatocellular carcinoma (HCC), biliary tract cancers (BTC), pancreatic adenocarcinoma (PDAC)]. We used multivariable analysis to examine the factors associated with utilization of systemic chemotherapy. We utilized marginal structural logistic models to estimate the effect of health insurance, facility type, or facility volume on utilization of systemic chemotherapy.We identified 162,283 patients with metastatic HPB cancers: 23,923 (14.7%) had HCC, 26,766 (16.5%) had BTC, and 111,594 (68.8%) had PDAC. A total of 37.2% patients with HCC, 55.6% with BTC, and 56.4% with PDAC received chemotherapy. Age ≥70 years and Charlson-Deyo score ≥2 were associated with lower likelihood of receiving chemotherapy across all cancers. Patients with private health insurance had higher receipt of chemotherapy. Receiving treatment at academic facilities had no effect on the receipt of chemotherapy. Treatment of patients with HCC or PDAC at high-volume facilities resulted in higher receipt of chemotherapy.A significant proportion of patients with metastatic HPB cancers do not receive systemic chemotherapy. Several disparities in administration of chemotherapy for metastatic HPB cancers exist.

To examine the average treatment effect of hepato-pancreato-biliary (HPB) cancer volume on survival outcomes of patients with non-resected pancreatic adenocarcinoma (PDAC).We queried the National Cancer Database (2004-2018) for patients with HPB malignancies (PDAC, pancreatic neuroendocrine neoplasms, hepatocellular carcinoma, biliary tract cancers). We determined the 25th, 50th, and 75th percentiles based on the total annual HPB volume. We then identified patients with non-resected PDAC. We utilized inverse probability (IP)-weighted Cox regression to estimate the effect of facility volume on overall survival (OS).We identified 710,988 patients with HPB malignancies. The 25th, 50th, and 75th percentiles of total annual HPB volume were 32, 71, and 177 cases/year, respectively. We included a total of 196,150 patients with non-resected PDAC. Patients treated at ≥25th, ≥50th, and ≥75th percentile facilities had improved median OS compared to those treated at facilities below these thresholds (5.8 vs. 4.2months, 6.5 vs. 4.5months, 7.5 vs. 4.8months, respectively; p 0.001 for all). Treatment at facilities ≥25th, ≥50th, and ≥75th percentile resulted in lower hazards of death than treatment at lower-percentile facilities (HR: 0.87, 95% CI: 0.84-0.90; HR: 0.87, 95% CI: 0.83-0.91; HR: 0.85, 95% CI: 0.79-0.91, respectively).Our data suggest that consolidation of care of patients with PDAC to high-volume centers may be beneficial even in the nonoperative setting.

In complex event processing (CEP), load shedding is performed to maintain a given latency bound during overload situations when resources are limited. However, shedding load implies degradation in the quality of results (QoR). Therefore, it is crucial to shed load in a way that has the lowest impact on QoR. Researchers, in the CEP domain, propose to drop either events or partial matches (PMs) in overload cases. They assign utilities to events/PMs by considering events' or PMs' importance. In this paper, we combine these approaches where we propose to assign a utility to an event by considering both the event importance and the importance of PMs. We propose two load shedding approaches for CEP systems. The first approach drops events from PMs, while the second approach drops events from windows. We adopt a probabilistic model that uses the type and position of an event in a window and the state of a PM to assign a utility to an event. We, also, propose an approach to predict a utility threshold that is used to drop the required amount of events. By extensive evaluations, we show that, in the majority of cases, our approaches outperform state-of-the-art load shedding approaches, w.r.t. QoR.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide great opportunities for mechanistic dissection of human cardiac pathophysiology; however, hiPSC-CMs remain immature relative to the adult heart. To identify novel signaling pathways driving the maturation process during heart development, we analyzed published transcriptional and epigenetic datasets from hiPSC-CMs and prenatal and postnatal human hearts. These analyses revealed that several components of the MAPK and PI3K-AKT pathways are downregulated in the postnatal heart. Here, we show that dual inhibition of these pathways for only 5 days significantly enhances the maturation of day 30 hiPSC-CMs in many domains: hypertrophy, multinucleation, metabolism, T-tubule density, calcium handling, and electrophysiology, many equivalent to day 60 hiPSC-CMs. These data indicate that the MAPK/PI3K/AKT pathways are involved in cardiomyocyte maturation and provide proof of concept for the manipulation of key signaling pathways for optimal hiPSC-CM maturation, a critical aspect of faithful in vitro modeling of cardiac pathologies and subsequent drug discovery.

In this analysis of the National Health Interview Survey, Americans with lower socioeconomic status, who are unmarried and with comorbidities were found to be at higher odds of severe psychological distress. Our findings may inform targeted support-based psycho-oncological interventions, such as shared medical appointments with other at-risk patients who have skin cancer.

Background: The human heart has limited capacity to generate new cardiomyocytes and this capacity declines with age. Because loss of cardiomyocytes may contribute to heart failure, it is crucial to explore stimuli of endogenous cardiac regeneration to favorably shift the balance between loss of cardiomyocytes and the birth of new cardiomyocytes in the aged heart. We have previously shown that cardiomyogenesis can be activated by exercise in the young adult mouse heart. Whether exercise also induces cardiomyogenesis in aged hearts, however, is still unknown. Here, we aim to investigate the effect of exercise on the generation of new cardiomyocytes in the aged heart. Methods: Aged (20-month-old) mice were subjected to an 8-week voluntary running protocol, and age-matched sedentary animals served as controls. Cardiomyogenesis in aged hearts was assessed on the basis of 15 N-thymidine incorporation and multi-isotope imaging mass spectrometry. We analyzed 1793 cardiomyocytes from 5 aged sedentary mice and compared these with 2002 cardiomyocytes from 5 aged exercised mice, followed by advanced histology and imaging to account for ploidy and nucleation status of the cell. RNA sequencing and subsequent bioinformatic analyses were performed to investigate transcriptional changes induced by exercise specifically in aged hearts in comparison with young hearts. Results: Cardiomyogenesis was observed at a significantly higher frequency in exercised compared with sedentary aged hearts on the basis of the detection of mononucleated/diploid 15 N-thymidine–labeled cardiomyocytes. No mononucleated/diploid 15 N-thymidine–labeled cardiomyocyte was detected in sedentary aged mice. The annual rate of mononucleated/diploid 15 N-thymidine–labeled cardiomyocytes in aged exercised mice was 2.3% per year. This compares with our previously reported annual rate of 7.5% in young exercised mice and 1.63% in young sedentary mice. Transcriptional profiling of young and aged exercised murine hearts and their sedentary controls revealed that exercise induces pathways related to circadian rhythm, irrespective of age. One known oscillating transcript, however, that was exclusively upregulated in aged exercised hearts, was isoform 1.4 of regulator of calcineurin, whose regulation and functional role were explored further. Conclusions: Our data demonstrate that voluntary running in part restores cardiomyogenesis in aged mice and suggest that pathways associated with circadian rhythm may play a role in physiologically stimulated cardiomyogenesis.

Guidelines addressing melanoma in-transit metastasis (ITM) recommend immune checkpoint inhibitors (ICI) as a first-line treatment option, despite the fact that there are no efficacy data available from prospective trials for exclusively ITM disease. The study aims to analyze the outcome of patients with ITM treated with ICI based on data from a large cohort of patients treated at international referral clinics.A multicenter retrospective cohort study of patients treated between January 2015 and December 2020 from Australia, Europe, and the USA, evaluating treatment with ICI for ITM with or without nodal involvement (AJCC8 N1c, N2c, and N3c) and without distant disease (M0). Treatment was with PD-1 inhibitor (nivolumab or pembrolizumab) and/or CTLA-4 inhibitor (ipilimumab). The response was evaluated according to the RECIST criteria modified for cutaneous lesions.A total of 287 patients from 21 institutions in eight countries were included. Immunotherapy was first-line treatment in 64 (22%) patients. PD-1 or CTLA-4 inhibitor monotherapy was given in 233 (81%) and 23 (8%) patients, respectively, while 31 (11%) received both in combination. The overall response rate was 56%, complete response (CR) rate was 36%, and progressive disease (PD) rate was 32%. Median PFS was ten months (95% CI 7.4-12.6 months) with a one-, two-, and five-year PFS rate of 48%, 33%, and 18%, respectively. Median MSS was not reached, and the one-, two-, and five-year MSS rates were 95%, 83%, and 71%, respectively.Systemic immunotherapy is an effective treatment for melanoma ITM. Future studies should evaluate the role of systemic immunotherapy in the context of multimodality therapy, including locoregional treatments such as surgery, intralesional therapy, and regional therapies.

Background: Cellular redox control is maintained by generation of reactive oxygen/nitrogen species balanced by activation of antioxidative pathways. Disruption of redox balance leads to oxidative stress, a central causative event in numerous diseases including heart failure. Redox control in the heart exposed to hemodynamic stress, however, remains to be fully elucidated. Methods: Pressure overload was triggered by transverse aortic constriction in mice. Transcriptomic and metabolomic regulations were evaluated by RNA-sequencing and metabolomics, respectively. Stable isotope tracer labeling experiments were conducted to determine metabolic flux in vitro. Neonatal rat ventricular myocytes and H9c2 cells were used to examine molecular mechanisms. Results: We show that production of cardiomyocyte NADPH, a key factor in redox regulation, is decreased in pressure overload-induced heart failure. As a consequence, the level of reduced glutathione is downregulated, a change associated with fibrosis and cardiomyopathy. We report that the pentose phosphate pathway and mitochondrial serine/glycine/folate metabolic signaling, 2 NADPH-generating pathways in the cytosol and mitochondria, respectively, are induced by transverse aortic constriction. We identify ATF4 (activating transcription factor 4) as an upstream transcription factor controlling the expression of multiple enzymes in these 2 pathways. Consistently, joint pathway analysis of transcriptomic and metabolomic data reveal that ATF4 preferably controls oxidative stress and redox-related pathways. Overexpression of ATF4 in neonatal rat ventricular myocytes increases NADPH-producing enzymes‚ whereas silencing of ATF4 decreases their expression. Further, stable isotope tracer experiments reveal that ATF4 overexpression augments metabolic flux within these 2 pathways. In vivo, cardiomyocyte-specific deletion of ATF4 exacerbates cardiomyopathy in the setting of transverse aortic constriction and accelerates heart failure development, attributable, at least in part, to an inability to increase the expression of NADPH-generating enzymes. Conclusions: Our findings reveal that ATF4 plays a critical role in the heart under conditions of hemodynamic stress by governing both cytosolic and mitochondrial production of NADPH.

Nutrient-deprived conditions in the tumor microenvironment (TME) restrain cancer cell viability due to increased free radicals and reduced energy production. In pancreatic cancer cells a cytosolic metabolic enzyme, wild-type isocitrate dehydrogenase 1 (wtIDH1), enables adaptation to these conditions. Under nutrient starvation, wtIDH1 oxidizes isocitrate to generate α-ketoglutarate (αKG) for anaplerosis and NADPH to support antioxidant defense. In this study, we show that allosteric inhibitors of mutant IDH1 (mIDH1) are potent wtIDH1 inhibitors under conditions present in the TME. We demonstrate that low magnesium levels facilitate allosteric inhibition of wtIDH1, which is lethal to cancer cells when nutrients are limited. Furthermore, the Food & Drug Administration (FDA)-approved mIDH1 inhibitor ivosidenib (AG-120) dramatically inhibited tumor growth in preclinical models of pancreatic cancer, highlighting this approach as a potential therapeutic strategy against wild-type IDH1 cancers.

Consensus guidelines recommend for perioperative chemotherapy and surgery for patients with clinical stage (cT) T2 or greater gastric adenocarcinoma. We compared adherence to guidelines in these patients stratified by race.Non-Hispanic White and Black patients with resected ≥cT2 gastric adenocarcinoma were identified within the National Cancer Database (2008-2017). We compared administration of preoperative chemotherapy by race, adjusting for clinicodemographic variables. We performed marginal standardization of logistic regression to calculate adjusted probabilities of administration of preoperative chemotherapy in patients under the age of 80 years with insurance.A total of 13,850 patients were identified (White = 12,161; Black = 1,689). Black race was associated with lower likelihood of receiving preoperative chemotherapy than White race (odds ratio = 0.46, 95% confidence interval: 0.39-0.54). Other factors associated with lower likelihood of preoperative chemotherapy included age ≥70 years, female sex, treatment at community facilities, non-private or no health insurance, and cT4 disease. Factors associated with higher likelihood of preoperative chemotherapy included treatment at high-volume facilities, longer distance to facility, higher education and income levels, cT3 disease, and cN+ disease. In patients80 years with insurance, marginal standardization models demonstrated that Black race was associated with a lower adjusted probability of receiving preoperative chemotherapy regardless of age, insurance payor, facility type/volume, distance to facility, cT stage, cN stage, sex, and education/income levels.Black race was associated with underutilization of preoperative chemotherapy for cT2 or greater gastric cancer, in discordance to published guidelines. The etiology of these disparities is multifactorial, and correcting the root causes represents a critical area for improvement.

Despite developments in wearable devices for detecting various bio-signals, continuous measurement of breathing rate (BR) remains a challenge. This work presents an early proof of concept that employs a wearable patch to estimate BR. We propose combining techniques for calculating BR from electrocardiogram (ECG) and accelerometer (ACC) signals, while applying decision rules based on signal-to-noise (SNR) to fuse the estimates for improved accuracy.

One of the key environmental variables and essential climate variable is soil moisture, with its high relevance for applications such as agriculture, forestry, water management including hydrometeorological extreme events or hydrological modelling. Yet accurate measurement of soil moisture is limited by its high natural spatiotemporal variability, given spatially (vertically and horizontally) variable hydraulic properties of soil, and events that are highly variable themselves (in time, extension and intensity). One geophysical method to close the gap between point-scale measurements and satellite-based remote sensing is Cosmic Ray Neutron Sensing (CRNS). Its integration area of about 0.1 km² is above the coverage of wireless sensor networks and at least when combined to CRNS clusters can cover several pixels of high resolution satellite remote sensing, e.g. by the ESA Sentinel-1 Earth Observation mission. We combine these three methods to bridge the scales in monitoring of soil moisture, and this within a novel metrological framework on validation and standardization. The basis for that is an EU-wide collaboration project of 18 institutions called SoMMet[1]. Its approach is to thoroughly establish CRNS as a bridging method at intermediate scale by linking it to point-scale soil moisture sensors with certification according to newly established metrological standards while testing a range of CRNS detector designs in facilities for neutron metrology. The aim is to achieve an improved comparability and reliable estimates of uncertainty and provide recommendations on network design and validation practices, which shall result in a more widespread transfer into remote sensing applications and hydrological modelling. A central component is to conduct field comparison and testing campaigns covering the different scales at three high-level field sites across Europe. One of the candidate sites is located close to Potsdam, Northern Germany. Having evolved from temporary soil moisture field campaigns it hosts the sole long-term CRNS cluster (currently 15 CRNS probes) that covers a conjoined area. This is somewhat similar to wireless in-situ sensor networks, but working non-invasively, with partially overlapping footprints and last not least on larger scale, here about 0.6 km² altogether. We will present examples of SoMMet field test sites, and especially first results of this CRNS cluster from 2023 in its recently extended coverage set-up that now brings it further up to satellite remote sensing resolution. [1] Acknowledgment: The project 21GRD08 SoMMet has received funding from the European Partnership on Metrology, co-financed from the European Union’s Horizon Europe Research and Innovation Programme and by the Participating States.

Zwitscher-Maschine. Journal on Paul Klee / Zeitschrift für internationale Klee-Studien No. 13 (Gesamtausgabe) www.zwitscher-maschine.org

Purpose: Uveal melanoma is a rare melanoma variant with no effective therapies once metastases develop. Although durable cancer regression can be achieved in metastatic cutaneous melanoma with immunotherapies that augment naturally existing antitumor T-cell responses, the role of these treatments for metastatic uveal melanoma remains unclear. We sought to define the relative immunogenicity of these two melanoma variants and determine whether endogenous antitumor immune responses exist against uveal melanoma.Experimental Design: We surgically procured liver metastases from uveal melanoma (n = 16) and cutaneous melanoma (n = 35) patients and compared the attributes of their respective tumor cell populations and their infiltrating T cells (TIL) using clinical radiology, histopathology, immune assays, and whole-exomic sequencing.Results: Despite having common melanocytic lineage, uveal melanoma and cutaneous melanoma metastases differed in their melanin content, tumor differentiation antigen expression, and somatic mutational profile. Immunologic analysis of TIL cultures expanded from these divergent forms of melanoma revealed cutaneous melanoma TIL were predominantly composed of CD8+ T cells, whereas uveal melanoma TIL were CD4+ dominant. Reactivity against autologous tumor was significantly greater in cutaneous melanoma TIL compared with uveal melanoma TIL. However, we identified TIL from a subset of uveal melanoma patients which had robust antitumor reactivity comparable in magnitude with cutaneous melanoma TIL. Interestingly, the absence of melanin pigmentation in the parental tumor strongly correlated with the generation of highly reactive uveal melanoma TIL.Conclusions: The discovery of this immunogenic group of uveal melanoma metastases should prompt clinical efforts to determine whether patients who harbor these unique tumors can benefit from immunotherapies that exploit endogenous antitumor T-cell populations. Clin Cancer Res; 22(9); 2237–49. ©2015 AACR.

Supplementary Figure Legend. Weak and insufficient tumor responses after MDA specific CD8+ T cell clone infusion

Supplementary Figure 1. PET-CT scan images

Supplementary Figure 1. In situ MRI assessment of tumor melanin content. Supplementary Figure 2. UM and CM liver metastases demonstrate similar immunophenotype profile.

Purpose: Adoptive transfer of autologous tumor infiltrating lymphocytes (TIL) can mediate durable cancer regression in selected patients with metastatic melanoma. However, the tumor antigens associated with these favorable responses remain unclear. We hypothesized that a clinical strategy involving the iterative adoptive transfer of selected autologous antigen-specific T-cell clones could help systematically define immunologic targets associated with successful cancer therapy, without the interpretative ambiguity of transferring polyclonal populations. Here, we evaluated the clinical efficacy of CD8+ T-cell clones specific for the melanocyte differentiation antigens (MDA), gp100 and MART-1, respectively.Experimental Design: We conducted two consecutive phase II clinical trials involving the adoptive transfer of highly selected autologous antigen-specific CD8+ T-cell clones against gp100 and MART-1, respectively. Fifteen patients with HLA-A2+ treatment-refractory metastatic melanoma received highly avid MDA-specific CD8+ T-cell clones specific for either gp100 (n = 10) or MART-1 (n = 5) with or without intravenous interleukin-2 (IL2) after a lymphodepleting myeloablative preparative regimen.Results: Of the 15 treated patients, we observed immune-mediated targeting of skin melanocytes in 11 patients (73%) and clonal engraftment in eight patients (53%) after cell transfer. There were only transient minor tumor regressions observed, but no objective tumor responses based on Response Evaluation Criteria in Solid Tumor (RECIST) criteria.Conclusions: Despite successful clonal repopulation and evidence of in vivo antigen targeting, the poor therapeutic efficacy after the adoptive transfer of autologous MDA-specific T cells raises significant concerns regarding future immunotherapy efforts targeting this class of tumor antigens. Clin Cancer Res; 21(3); 534–43. ©2014 AACR.

The optimal T-cell attributes for adoptive cancer immunotherapy are unclear. Recent clinical trials of ex vivo–expanded tumor-infiltrating lymphocytes indicated that differentiated T effector cells can elicit durable antitumor responses in some patients with cancer, with their antitumor activity tightly correlated with their persistence in the host. Thus, there is great interest in the definition of intrinsic biomarkers that can predict the conversion of short-lived tumor antigen–specific T effector cells into long-lived T memory cells. Long-term persistence of ex vivo–expanded tumor-specific CD8+ T effector clones has been reported in refractory metastatic melanoma patients after adoptive T-cell transfer. By using highly homogeneous clone populations from these preparations, we performed a comparative transcriptional profiling to define preinfusion molecular attributes that can be ascribed to an effector-to-memory transition. Through this route, we discovered that preinfusion T-cell clones that expressed the IL7 receptor (IL7R) and c-myc were more likely to persist longer after adoptive transfer to patients. The predictive value of these two biomarkers was strengthened by using IL7R protein, IL7-induced pSTAT5, and c-myc mRNA expression to prospectively identify human tumor-specific T effector clones capable of engraftment into immunodeficient mice. Overall, our findings reveal IL7R and c-myc expression as intrinsic biomarkers that can predict the fate of CD8+ T effector cells after adoptive transfer. Cancer Res; 75(16); 3216–26. ©2015 AACR.

Supplementary Table and Figures Supplementary Table 1: Differentially expressed genes between persisting and non-persisting clones. Supplementary Figure 1: % IL-7R expressing cells in the infusion bag correlates with persistence of CD8+ effector clones. Supplementary Figure 2: Representative phenotypic profiling of IL7R+ and IL7R- subsets found within infused effector clones. Supplementary Figure 3: IL-7R expression correlates with c-myc mRNA expression in CD8+ effector clones. Supplementary Figure 4: IL-7R expression correlates with induced pSTAT5 expression in CD8+ effector clones.

Supplementary Methods: Detailed information regarding additional materials and methods.

Pancreatic cancer (PC) is one of the most aggressive types of cancer, with a five-year overall survival rate of 11% among all-comers. Current systemic therapeutic options are limited to cytotoxic chemotherapies which have limited clinical efficacy and are often associated with development of drug resistance. Analysis of The Cancer Genome Atlas showed that wild-type isocitrate dehydrogenase (wtIDH1) is overexpressed in pancreatic tumors. In this study, we focus on the potential roles of wtIDH1 in pancreatic cancer chemoresistance. We found that treatment of pancreatic cancer cells with chemotherapy induced expression of wtIDH1, and this serves as a key resistance factor. The enzyme is protective to cancer cells under chemotherapy-induced oxidative stress by producing NADPH and alpha-ketoglutarate to maintain redox balance and mitochondrial function. An FDA-approved mutant IDH1 inhibitor, ivosidenib (AG-120), is actually a potent wtDH1 inhibitor under a nutrient-deprived microenvironment, reflective of the pancreatic cancer microenvironment. Suppression of wtIDH1 impairs redox balance, results in increased ROS levels, and enhances chemotherapy induced apoptosis in pancreatic cancer vis ROS damagein vitro.In vivoexperiments further revealed that inhibiting wtIDH1 enhances chemotherapy anti-tumor effects in patient-derived xenografts and murine models of pancreatic cancer. Pharmacologic wtIDH1 inhibition with ivosidenib represents an attractive option for combination therapies with cytotoxic chemotherapy for patients with pancreatic cancer. Based on these data, we have initiated phase Ib trial combining ivosidenib and multi-agent chemotherapy in patients with pancreatic cancer (NCT05209074).

Irreversible electroporation (IRE) is used as a locoregional treatment modality for patients with locally advanced pancreatic cancer (LAPC), but is non-curative and is associated with postoperative morbidity and mortality. We performed a systematic review and meta-analysis comparing survival outcomes of multimodal therapy with or without IRE.Separate searches were performed for multimodal therapy + IRE and multimodal therapy alone given the lack of comparative literature using PubMed, SCOPUS, and Cochrane Library in 3/2021. We determined overall survival (OS) and progression-free survival (PFS) from diagnosis and time of IRE. Treatment-related morbidity and mortality was determined.Of 585 published articles, 48 met inclusion criteria for IRE (n = 27) and without IRE (n = 21) with data for 1420 (IRE) and 1348 (without IRE) patients. The 6/12/24 months OS with IRE was 99%/84%/28%. The 6/12/24 months OS without IRE was 99%/80%/12%. At 12 months from IRE, OS was 55% and PFS was 12%. The mean major complication and 90-day mortality rates for IRE were 17.95% and 2.65%.Multimodal therapy alone is associated with similar OS to multimodal therapy + IRE in patients with LAPC. Most patients progress and nearly half die within 1 year of the IRE procedure. Given the lack of quality prospective data, IRE should remain experimental and be used with caution in LAPC.

Background Weight changes during neoadjuvant chemotherapy (NAC) for pancreatic cancer (PDAC) are not well studied. We hypothesized that weight loss may predict poor outcomes. Methods Weight change from NAC initiation to pancreatectomy was grouped: gain (≥5%), stable, and loss (≥5%). Pathologic, postoperative, and survival outcomes were compared. Results 95 patients were included: 31.6% lost weight, 58.9% maintained weight, and 9.5% gained weight. There were no differences in chemotherapeutic regimens. Median recurrence-free survival (RFS) and overall survival (OS) were similar between patients with stable weight and those who lost weight (RFS: 9.6vs14.0months; OS: 25.8vs26.7months). Among those who gained weight, RFS (29.5months) and OS (38.4months) were greater relative to the other weight categories. On multivariable regression, weight gain was associated with improved RFS compared to loss (HR = 0.16). Conclusion Most patients maintain or lose weight during NAC, and weight loss does not predict poor outcomes. Weight gain may predict improved RFS.

Most patients with pancreatic adenocarcinoma (PDAC) do not undergo surgical resection. The role of radiotherapy (RT) in non-operatively managed localized pancreatic adenocarcinoma is unclear.The National Cancer Database (2010-2016) was queried for patients with clinical stage II-III PDAC treated with multiagent systemic chemotherapy (CT) +/- RT but not surgery. Factors associated with the receipt of RT and overall survival were compared after adjusting for patient demographics and clinical characteristics.A total of 14,921 patients were included, of whom 9279 received CT and 5382 received CT + RT. Patients treated with CT + RT were more likely to be younger (65vs66yrs), treated at non-academic facilities (48.8%vs46.7%), have private insurance (40.3%vs36.5%), and have clinical T4 tumors (53.6%vs48.7%). Most patients who were treated with RT received external beam radiotherapy (89.3%), and the median dose was 5,000 cGy. Median time to start of RT was 129 days. CT + RT was associated with longer overall survival (15.9vs11.8mos,p 0.001), and remained associated with survival on multivariable analysis (HR 0.74, 95%CI 0.70-0.78). On a 4-month conditional survival analysis, combined CT + RT remained associated with improved survival compared to CT alone (16.0vs13.1mos,p 0.001).In patients with non-operatively managed localized pancreatic adenocarcinoma, combined radiotherapy and multiagent systemic chemotherapy is associated with improved overall survival compared to chemotherapy alone.

Supplemental Digital Content is available in the text., Background: Cardiac hypertrophy is an independent risk factor for heart failure, a leading cause of morbidity and mortality globally. The calcineurin/NFAT (nuclear factor of activated T cells) pathway and the MAPK (mitogen-activated protein kinase)/Erk (extracellular signal-regulated kinase) pathway contribute to the pathogenesis of cardiac hypertrophy as an interdependent network of signaling cascades. How these pathways interact remains unclear and few direct targets responsible for the prohypertrophic role of NFAT have been described. Methods: By engineering cardiomyocyte-specific ETS2 (a member of the E26 transformation-specific sequence [ETS] domain family) knockout mice, we investigated the role of ETS2 in cardiac hypertrophy. Primary cardiomyocytes were used to evaluate ETS2 function in cell growth. Results: ETS2 is phosphorylated and activated by Erk1/2 on hypertrophic stimulation in both mouse (n=3) and human heart samples (n=8 to 19). Conditional deletion of ETS2 in mouse cardiomyocytes protects against pressure overload–induced cardiac hypertrophy (n=6 to 11). Silencing of ETS2 in the hearts of calcineurin transgenic mice significantly attenuates hypertrophic growth and contractile dysfunction (n=8). As a transcription factor, ETS2 is capable of binding to the promoters of hypertrophic marker genes, such as ANP, BNP, and Rcan1.4 (n=4). We report that ETS2 forms a complex with NFAT to stimulate transcriptional activity through increased NFAT binding to the promoters of at least 2 hypertrophy-stimulated genes: Rcan1.4 and microRNA-223 (=n4 to 6). Suppression of microRNA-223 in cardiomyocytes inhibits calcineurin-mediated cardiac hypertrophy (n=6), revealing microRNA-223 as a novel prohypertrophic target of the calcineurin/NFAT and Erk1/2-ETS2 pathways. Conclusions: Our findings point to a critical role for ETS2 in calcineurin/NFAT pathway-driven cardiac hypertrophy and unveil a previously unknown molecular connection between the Erk1/2 activation of ETS2 and expression of NFAT/ETS2 target genes.

Mathematical models describing the behavior of viscoelastic materials are often based on evolution equations that measure the change in stress depending on its material parameters such as stiffness, viscosity or relaxation time. In this article, we introduce a Maxwell-based rheological model, define the associated forward operator and the inverse problem in order to determine the number of Maxwell elements and the material parameters of the underlying viscoelastic material. We perform a relaxation experiment by applying a strain to the material and measure the generated stress. Since the measured data varies with the number of Maxwell elements, the forward operator of the underlying inverse problem depends on parts of the solution. By introducing assumptions on the relaxation times, we propose a clustering algorithm to resolve this problem. We provide the calculations that are necessary for the minimization process and conclude with numerical results by investigating unperturbed as well as noisy data. We present different reconstruction approaches based on minimizing a least squares functional. Furthermore, we look at individual stress components to analyze different displacement rates. Finally, we study reconstructions with shortened data sets to obtain assertions on how long experiments have to be performed to identify conclusive material parameters., 23 pages, 11 figures, 6 tables

Background Guidelines recommend resection of non-functional neuroendocrine tumors of the pancreas (NF-pNETs) that are ≥2 cm in size. We compared utilization of surgery based on race. Methods We identified non-Hispanic White and Black patients with localized NF-pNETs ≥2 cm and Charlson-Deyo score 0–1 in the NCDB (2004–2016). We compared utilization of surgery by race, adjusting for clinicodemographic variables. Overall survival was compared based on management. Results A total of 3459 patients were included (White = 3005; Black = 454). Black patients were younger (58vs63 years) and more often treated at academic facilities (65.3%vs60.3%). Overall, Black and White patients underwent surgery at similar rates (77.3%vs79.6%). When stratified by primary site, Black patients with body/tail tumors were less likely to undergo surgery (78.5%vs84.7%). On multivariable analysis, Black race was associated with a lower likelihood of surgery overall (OR 0.74,p = 0.034) and in patients with body/tail tumors (OR 0.56,p = 0.001). Non-operative management was associated with a higher risk of death (HR 3.19,p Conclusion In a national cohort of patients with NF-pNETs meeting criteria for resection, Black race is associated with lower frequency of surgery. Operative intervention is associated with prolonged survival. Persistent racial disparities in management of a surgically curable disease should be targeted for improvement.

In vielen Fällen gibt ein Energie-Monitoring den Impuls, Energie einzusparen. Kombiniert mit Intelligenz sind hohe Einsparpotenziale realisierbar. Intelligente Monitoring-Lösungen bieten aber noch mehr, etwa in Bezug auf umfassende Transparenz, höhere Betriebssicherheit, mehr Verfügbarkeit und optimierte Instandhaltung.

Frontiers in neurology 13, 1-16 (2023). doi:10.3389/fneur.2022.1040648, Published by Frontiers Research Foundation, Lausanne

Caveolin-1 precludes stress-induced protein kinase A-dependent remodelling of endoplasmic reticulum–mitochondria communication.

Our findings point to a critical role for ETS2 in calcineurin/NFAT pathway-driven cardiac hypertrophy and unveil a previously unknown molecular connection between the Erk1/2 activation of ETS2 and expression of NFAT/ETS2 target genes.