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Background/Objectives: Epidemics of obesity and diabetes are escalating. High-calorie/high-fat food is a major cause for these global health issues, but molecular mechanisms underlying high-fat, diet-induced obesity are still not well understood. The aryl hydrocarbon receptor (AhR), a transcription factor that acts as a xenobiotic sensor, mediates environmental toxicant-induced obesity, insulin resistance and development of diabetes. AhR also influences lipid metabolism and diet-induced obesity. The effects of AhR deficiency on diet-induced obesity, hepatic steatosis and insulin resistance were examined. Methods: Male wild-type (WT), AhR null (AhR −/− ) and AhR heterozygote (AhR +/− ) mice were fed a normal chow diet (NCD, 10% kcal from fat) or a high-fat diet (HFD, 60% kcal from fat) for up to 14 weeks. Adiposity, adipose and liver morphology, insulin signaling, metabolic parameters and gene profiles were assessed. Results: AhR deficiency protected against HFD-induced obesity, hepatic steatosis, insulin resistance and inflammation. Moreover, AhR deficiency preserved insulin signaling in major metabolic tissues. These protective effects result from a higher energy expenditure in AhR-deficient mice compared with WT. Levels of transcript for both the thermogenic gene, uncoupling protein 1 (Ucp1), in brown adipose tissue and mitochondrial β-oxidation genes in muscle were significantly higher in AhR −/− and AhR +/− mice compared with WT. Conclusions: This work documents a physiologically relevant function for AhR in regulation of body weight, hepatic fat deposition, insulin sensitivity and energy expenditure under HFD exposure, suggesting that AhR signaling may be developed as a potential therapeutic target for treatment of obesity and metabolic disorders.

Despite therapeutic advances, multiple myeloma (MM) remains an incurable disease, predominantly because of the development of drug resistance. The activator protein-1 (AP-1) transcription factor family has been implicated in a multitude of physiologic processes and tumorigenesis; however, its role in MM is largely unknown. Here we demonstrate specific and rapid induction of the AP-1 family member JunB in MM cells when co-cultured with bone marrow stromal cells. Supporting a functional key role of JunB in MM pathogenesis, knockdown of JUNB significantly inhibited in vitro MM cell proliferation and survival. Consistently, induced silencing of JUNB markedly decreased tumor growth in a murine MM model of the microenvironment. Subsequent gene expression profiling revealed a role for genes associated with apoptosis, DNA replication and metabolism in driving the JunB-mediated phenotype in MM cells. Importantly, knockdown of JUNB restored the response to dexamethasone in dexamethasone-resistant MM cells. Moreover, 4-hydroxytamoxifen-induced activation of a JunB-ER fusion protein protected dexamethasone-sensitive MM cells against dexamethasone- and bortezomib-induced cytotoxicity. In summary, our results demonstrate for the first time a specific role for AP-1/JunB in MM cell proliferation, survival and drug resistance, thereby strongly supporting that this transcription factor is a promising new therapeutic target in MM.

PurposeA high expression of fibroblast activation protein (FAP) was observed in multiple sarcomas, indicating an enormous potential for PET/CT using 68Ga-radiolabeled inhibitors of FAP (FAPI). Therefore, this retrospective study aimed to evaluate the role of the novel hybrid imaging probe for sarcomas as a first clinical evaluation.MethodsA cohort of 15 patients underwent 68Ga-FAPI-PET/CT for staging or restaging. The acquisition of PET scans was performed 60 min after administration of 127 to 308 MBq of the tracer. The uptake of 68Ga-FAPI in malignant tissue as well as in healthy organs was quantified by standardized uptake values SUVmean and SUVmax.ResultsExcellent tumor-to-background ratios (> 7) could be achieved due to low background activity and high SUVmax in primary tumors (median 7.16), local relapses (median 11.47), and metastases (median 6.29). The highest uptake was found for liposarcomas and high-grade disease (range 18.86–33.61). A high SUVmax (> 10) was observed for clinically more aggressive disease.ConclusionThese preliminary findings suggest a high potential for the clinical use of 68Ga-FAPI-PET/CT for patients diagnosed with sarcoma.

Patients undergoing allo-HCT often experience a substantial loss in physical performance. We have recently published the general effectiveness of an exercise intervention in 105 allo-HCT patients on physical performance and psychosocial well-being. However, predictor variables for differentiated treatment response remained unclear. To determine the impact of basic physical performance on treatment response, we assessed muscle strength and endurance performance at four assessment points before and after allo-HCT. The exercise group started training 2 weeks before admission and ended 6–8 weeks after discharge. Comparing initially fit with unfit classified patients, the fit patients lost 31% of the strength of the knee-extensors, whereas the unfit patients lost only 1% ( P <0.05). For endurance capacity, fit patients lost 4% of their walking capability, whereas unfit patients gained 13% ( P <0.05). The individual percent change was statistically different at the 0.05 level in all measures of physical performance. Individual training response in allo-HCT patients strongly depends on the initial physical performance level. Unfit patients can be trained safely and may benefit more from this exercise intervention than fit patients. This result is of major clinical relevance and should encourage hematologists to promote exercise even more in impaired/unfit allo-HCT patients.

While laser additive manufacturing is becoming increasingly important in the context of next-generation manufacturing technologies, most current research efforts focus on optimizing process parameters for the processing of mature alloys for structural applications (primarily stainless steels, titanium base, and nickel base alloys) from pre-alloyed powder feedstocks to achieve properties superior to conventionally processed counterparts. However, laser additive manufacturing or processing can also be applied to functional materials. This article focuses on the use of directed energy deposition-based additive manufacturing technologies, such as the laser engineered net shaping (LENS™) process, to deposit magnetic alloys. Three case studies are presented: Fe-30 at.%Ni, permalloys of the type Ni-Fe-V and Ni-Fe-Mo, and Fe-Si-B-Cu-Nb (derived from Finemet) alloys. All these alloys have been processed from a blend of elemental powders used as the feedstock, and their resultant microstructures, phase formation, and magnetic properties are discussed in this paper. Although these alloys were produced from a blend of elemental powders, they exhibited relatively uniform microstructures and comparable magnetic properties to those of their conventionally processed counterparts.

Few effective treatments exist for patients with advanced urothelial carcinoma that has progressed after platinum-based chemotherapy. We assessed the activity and safety of nivolumab in patients with locally advanced or metastatic urothelial carcinoma whose disease progressed after previous platinum-based chemotherapy. In this phase 1/2, multicentre, open-label study, we enrolled patients (age ≥18 years) with urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra at 16 sites in Finland, Germany, Spain, the UK, and the USA. Patients were not selected by PD-L1 expression, but tumour PD-L1 membrane expression was assessed retrospectively. Patients received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression or treatment discontinuation because of unacceptable toxicity or other protocol-defined reasons, whichever occurred later. The primary endpoint was objective response by investigator assessment. All patients who received at least one dose of the study drug were included in the analyses. We report an interim analysis of this ongoing trial. CheckMate 032 is registered with ClinicalTrials.gov, NCT01928394. Between June 5, 2014, and April 24, 2015, 86 patients with metastatic urothelial carcinoma were enrolled in the nivolumab monotherapy group and 78 received at least one dose of treatment. At data cutoff (March 24, 2016), the minimum follow-up was 9 months (median 15·2 months, IQR 12·9–16·8). A confirmed investigator-assessed objective response was achieved in 19 (24·4%, 95% CI 15·3–35·4) of 78 patients. Grade 3–4 treatment-related adverse events occurred in 17 (22%) of 78 patients; the most common were elevated lipase (four [5%]), elevated amylase (three [4%]), and fatigue, maculopapular rash, dyspnoea, decreased lymphocyte count, and decreased neutrophil count (two [3%] each). Serious adverse events were reported in 36 (46%) of 78 patients and eight (10%) had a serious adverse event judged to be treatment related. Two (3%) of 78 patients discontinued because of treatment-related adverse events (grade 4 pneumonitis and grade 4 thrombocytopenia) and subsequently died. Nivolumab monotherapy was associated with a substantial and durable clinical response and a manageable safety profile in previously treated patients with locally advanced or metastatic urothelial carcinoma. These data support further investigation of nivolumab monotherapy in advanced urothelial carcinoma. Bristol-Myers Squibb.

We report the OH stretching vibrational spectra of size-selected$H^+(H_{2}O)_n$clusters through the region of the pronounced \"magic number\" at n = 21 in the cluster distribution. Sharp features are observed in the spectra and assigned to excitation of the dangling OH groups throughout the size range$6 \\leq n \\leq 27$. A multiplet of such bands appears at small cluster sizes. This pattern simplifies to a doublet at n = 11, with the doublet persisting up to n = 20, but then collapsing to a single line in the n = 21 and n = 22 clusters and reemerging at n = 23. This spectral simplification provides direct evidence that, for the magic number cluster, all the dangling OH groups arise from water molecules in similar binding sites.

Forest fire risk estimation constitutes an essential process to prevent high-intensity fires which are associated with severe implications to the natural and cultural environment. The primary aim of this research was to determine fire risk levels based on the local features of an island, namely, the impact of fuel structures, slope, aspects, as well as the impact of the road network and inhabited regions. The contribution of all the involved factors to forest fires ignition and behavior highlight certain regions which are highly vulnerable. In addition, the influence of both natural and anthropogenic factors to forest fire phenomena is explored. In this study, natural factors play a dominant role compared to anthropogenic factors. Hence essential preventative measures must focus on specific areas and established immediately. Indicative measures may include: the optimal allocation of watchtowers as well as the spatial optimization of mobile firefighting vehicles; and, forest fuel treatments in areas characterized by extremely high fire risk. The added value of this fire prediction tool is that it is highly flexible and could be adopted elsewhere with the necessary adjustments to local characteristics.

Background: Chemoradioimmunotherapy of patients with pancreatic adenocarcinoma from the CapRI trial did not show any benefit of interferon- α in addition to a 5-fluorouracil (5FU)-based treatment. The aim of this study was to identify immunological parameters in patients from this trial to be used for predictive and/or prognostic purposes. Methods: The following methods were used: tumour immunohistology, FACS analyses, cytokine measurement, as well as cytotoxicity and ELIspot. Immunological parameters were correlated with patients’ survival using the Kaplan–Meier method. Results: Irrespective of therapy type, high lymphocyte accumulation in tumours and frequencies of NK cells and effector (eff) CD8 + T cells in peripheral blood of the patients were associated with patients’ survival. Amount of CD3 + and effector-memory CD8 + blood lymphocytes, expression of CD152 and interleukin (IL)-2 serum level showed a predictive value for chemoradioimmunotherapy. Tumoural accumulation of CD3 + and CD8 + cells was predictive for outcome of chemotherapy alone. Besides, we identified the frequencies of CD3 + lymphocytes, effCD8 + T cells and NK cells in the peripheral blood of the patients, and IL-10 amount in serum, to be predictive values for 5FU-based chemotherapy. Conclusions: Immunological parameters, identified in this trial as possible markers, may be of interest in personalized medicine towards the improvement of the treatment and prognosis of pancreatic carcinoma patients.

Fabrication of ultrasharp probes is of interest for many applications, including scanning probe microscopy and electron-stimulated patterning of surfaces. These techniques require reproducible ultrasharp metallic tips, yet the efficient and reproducible fabrication of these consumable items has remained an elusive goal. Here we describe a novel biased-probe field-directed sputter sharpening technique applicable to conductive materials, which produces nanometer and sub-nanometer sharp W, Pt-Ir and W-HfB 2 tips able to perform atomic-scale lithography on Si. Compared with traditional probes fabricated by etching or conventional sputter erosion, field-directed sputter sharpened probes have smaller radii and produce lithographic patterns 18–26% sharper with atomic-scale lithographic fidelity. Scanning probe microscopy and related techniques rely on the availability of very sharp tips. Here, a sharpening technique based on field-directed sputtering is demonstrated, resulting in ultrasharp metallic tips for use in scanning tunnelling microscopy as well as atomic-scale lithographic experiments.