Interleukin-1 β

Inflammation and tumor hypoxia are intimately linked and breast cancer provides a typical example of an inflammation-linked malignant disease. Indeed, breast cancer progression is actively supported by inflammatory components, including IL-1 beta, and by the hypoxia-inducible factor- (HIF-) 1 alpha In spite of many attempts where the role of either IL-1 beta or HIF-1 beta was evaluated, detailed mechanisms for their effects on breast cancer cell migration under hypoxia are still unclear. We here report that IL-1 beta increased MDAMB231 cell migration under hypoxic conditions along with HIF-1 alpha accumulation and upregulation of CXCR1, which is transcriptionally regulated by HIF-1 alpha, as well as an increased expression of CXCL8 and NF kappa B. In addition, IL-1 beta-induced cell migration in hypoxia was not affected when HIF-1 alpha was inhibited by either siRNA or Topotecan, well known for its inhibitory effect on HIF-1 alpha Of interest, HIF-1 alpha inhibition did not reduce NF kappa B and CXCL8 expression and the reduction of IL-1 beta-induced cell migration under hypoxia was achieved only by pharmacological inhibition of NF kappa B. Our findings indicate that inhibition of HIF-1 alpha does not prevent the migratory program activated by IL-1 beta in hypoxic MDAMB231 cells. They also suggest a potential compensatory role of NF kappa B/CXCL8 pathway in IL-1 beta-induced MDAMB231 cell migration in a hypoxic microenvironment

Exact exchange-correlation potential for a time-dependent two electron system

We obtain an exact solution of the time-dependent Schroedinger equation for a two-electron system confined to a plane by an isotropic parabolic potential whose curvature is periodically modulated in time. From this solution we compute the exact time-dependent exchange correlation potential v_xc which enters the Kohn-Sham equation of time-dependent density functional theory. Our exact result provides a benchmark against which various approximate forms for v_xc can be compared. Finally v_xc is separated in an adiabatic and a pure dynamical part and it is shown that, for the particular system studied, the dynamical part is negligible.Comment: 23 pages, 6 figure

Mouse dendritic cells in the steady state: Hypoxia, autophagy, and stem cell factor

Dendritic cells (DCs) are innate immune cells with a central role in immunity and tolerance. Under steady-state, DCs are scattered in tissues as resting cells. Upon infection or injury, DCs get activated and acquire the full capacity to prime antigen-specific CD4(+) and CD8(+) T cells, thus bridging innate and adaptive immunity. By secreting different sets of cytokines and chemokines, DCs orchestrate diverse types of immune responses, from a classical proinflammatory to an alternative pro-repair one. DCs are highly heterogeneous, and physiological differences in tissue microenvironments greatly contribute to variations in DC phenotype. Oxygen tension is normally low in some lymphoid areas, including bone marrow (BM) hematopoietic niches; nevertheless, the possible impact of tissue hypoxia on DC physiology has been poorly investigated. We assessed whether DCs are hypoxic in BM and spleen, by staining for hypoxia-inducible-factor-1 alpha subunit (HIF-1 alpha), the master regulator of hypoxia-induced response, and pimonidazole (PIM), a hypoxic marker, and by flow cytometric analysis. Indeed, we observed that mouse DCs have a hypoxic phenotype in spleen and BM, and showed some remarkable differences between DC subsets. Notably, DCs expressing membrane c-kit, the receptor for stem cell factor (SCF), had a higher PIM median fluorescence intensity (MFI) than c-kit(-) DCs, both in the spleen and in the BM. To determine whether SCF (a.k.a. kit ligand) has a role in DC hypoxia, we evaluated molecular pathways activated by SCF in c-kit(+) BM-derived DCs cultured in hypoxic conditions. Gene expression microarrays and gene set enrichment analysis supported the hypothesis that SCF had an impact on hypoxia response and inhibited autophagy-related gene sets. Our results suggest that hypoxic response and autophagy, and their modulation by SCF, can play a role in DC homeostasis at the steady state, in agreement with our previous findings on SCF's role in DC survival

The influence of ambient lighting on the detection of small contrast elements in digital dental radiographs

Objectives: The aim of this study was to evaluate the effect of ambient light on the detection of contrast elements in digital dental radiographs. Materials and methods: A high-contrast standardized digital radiograph of an aluminum step wedge containing 32 boreholes of different depth was cut into 40 isometric images. Images were presented at random on a 17-in cathode ray tube (CRT) monitor at different ambient background illuminations of 0, 50, 200, and 500lx. Twenty observers stated twice their blinded decision whether or not they could perceive a dark spot on a five-point confidence scale. Areas (Az) under receiver operating characteristic curves were calculated and compared between the four different ambient illuminations using the Friedman test. Statistical significance was set at p < 0.05. Overall agreement was estimated determining the intraclass correlation coefficient. Results: The Az values (0.735 for 0lx, 0.728 for 50lx, 0.735 for 200lx, and 0.788 for 500lx) did not significantly differ (p = 0.796) between the four ambient lighting levels. Conclusions: The detection of small contrast features in digital dental radiographs on a CRT monitor seems to be comparable over a wide range of ambient background illumination. Clinical relevance: The ambient light in dental offices of <500lx may not negatively impact the diagnostic performance of digital dental radiograph

Aggressive Pituitary Macroadenoma Treated With Capecitabine and Temozolomide Chemotherapy Combination in a Patient With Nelson’s Syndrome: A Case Report

Agressive pituitary tumors; Capecitabine; TemozolomideTumores hipofisarios agresivos; Capecitabina; TemozolomidaTumors hipofisaris agressius; Capecitabina; TemozolomidaNelson’s syndrome is considered a severe side effect that can occur after a total bilateral adrenalectomy in patients with Cushing’s disease. It usually presents with clinical manifestations of an enlarging pituitary tumor including visual and cranial nerve alterations, and if not treated, can cause death through local brain compression or invasion. The first therapeutic option is surgery but in extreme cases of inaccessible or resistant aggressive pituitary tumors; the off-label use of chemotherapy with capecitabine and temozolomide can be considered. However, the use of this treatment is controversial due to adverse events, lack of complete response, and inability to predict results. We present the case of a 48-year-old man diagnosed with Nelson’s syndrome with prolonged partial response and significant clinical benefit to treatment with capecitabine and temozolomide

The Impact of Bariatric Surgery on the Muscle Mass in Patients with Obesity: 2-Year Follow-up

Bariatric surgery; Morbid obesity; Sarcopenic obesityCirugía bariátrica; Obesidad mórbida; Obesidad sarcopénicaCirurgia bariàtrica; Obesitat mòrbida; Obesitat sarcopènicaPurpose Bariatric surgery (BS) induces a significant and sustained weight loss in patients with severe obesity (SO). Nevertheless, apart from significantly reducing body fat, fat-free mass (FFM) might also be lost. At present, there is little and controversial data in the literature regarding the impact of BS on FFM. In recent years, bioimpedance (BIA) has emerged as a reliable test to assess body composition easily to use in the daily clinical practice. On the bases, the aim of the present study is to evaluate the impact of BS on the FFM, evaluated by means of BIA. Material and Methods This is a prospective, observational study, including consecutive patients with SO that underwent BS between February 2018 and February 2019 at our center. At baseline, 1, 6, 12, and 24 months after the BS, all the patients underwent complete medical history, physical and anthropometric evaluation, and body composition assessment by means of BIA (using Bodystat QuadScan4000®). Results Eighty-five patients with SO were recruited, 72.9% females, aged 45.54 ± 9.98 years, pre-BS BMI 43.87 ± 6.52 kg/m2. FFM significantly decreased continuously after BS at all timepoints. The loss of FFM 24 months post-BS accounted for approximately 21.71 ± 13.9% of the total weight loss, and was independent of BS technique or protein metabolism. Pre-BS HOMA-IR and FFM were independent predictors of FFM at 24 months. Conclusions Significant and early loss of FFM in patients with SO that undergo BS was seen, not related to protein metabolism parameters or the BS technique used, suggesting an independent mechanism.Open Access Funding provided by Universitat Autonoma de Barcelona. This study was supported by grants from the Instituto de Salud Carlos III (Fondo de Investigación Sanitaria, PI20/01806). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Multicenter Experience Using Total Lymphoid Irradiation and Antithymocyte Globulin as Conditioning for Allografting in Hematological Malignancies

A non myeloablative conditioning with total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) was shown to protect against graft-versus-host disease (GVHD). To evaluate the effects of TLI-ATG in a multicenter study, 45 heavily pretreated patients, median age 51, with lymphoid (n = 38) and myeloid (n = 7) malignancies were enrolled at 9 centers. Twenty-eight patients (62%) received at least 3 lines of treatment before allografting, and 13 (29%) had refractory/relapsed disease at the time of transplantation. Peripheral blood hematopoietic cells were from HLA identical sibling (n = 30), HLA-matched (n = 9), or 1 antigen HLA-mismatched (n = 6) unrelated donors. A cumulative TLI dose of 8 Gy was administered from day −11 through −1 with ATG at the dose of 1.5 mg/kg/day (from day −11 through −7). GVHD prophylaxis consisted of cyclosporine and mycophenolate mofetil. Donor engraftment was reached in 95% of patients. Grade II to IV acute GVHD (aGVHD) developed in 6 patients (13.3%), and in 2 of these patients, it developed beyond day 100. Incidence of chronic GVHD (cGVHD) was 35.8%. One-year nonrelapse mortality was 9.1%. After a median follow-up of 28 months (range, 3-57 months) from transplantation, median overall survival was not reached, whereas median event-free survival was 20 months. This multicenter experience confirms that TLI-ATG protects against GVHD and maintains graft-vs-tumor effects

Active surveillance of paratuberculosis in Alpine-dwelling red deer (Cervus elaphus)

Paratuberculosis (Johne’s disease) is a globally widespread infectious disease affecting domestic and wild ruminants, caused by Mycobacterium avium subsp. paratuberculosis (MAP). The bacterium is excreted in the feces and is characterized by high environmental resistance. The new Animal Health Law (Regulation EU 2016/429) on transmissible animal diseases, recently in force throughout the European Union, includes paratuberculosis within the diseases requiring surveillance in the EU, listing some domestic and wild Bovidae, Cervidae, and Camelidae as potential reservoirs. Taking advantage of a culling activity conducted in the Stelvio National Park (Italy), this study investigated MAP infection status of red deer (Cervus elaphus) between 2018 and 2022, and evaluated the probability of being MAP-positive with respect to individual and sampling-level variables. A total of 390 subjects were examined macroscopically and tested for MAP, using different diagnostic tools: IS900 qPCR, culture, histopathology, and serology. Twenty-three of them were found positive for MAP by at least one test, with an overall prevalence of 5.9% (95% CI 4.0–8.7), that, respectively, ranged from 12.4% in the first culling season to 2.0 and 2.1% in the 2019–2020 and 2021–2022 culling seasons. Quantitative PCR assay on ileocecal valve and mesenteric lymph nodes detected the highest number of MAP positive animals. The results of the study showed the increased probability of being MAP-positive with increasing age and that red deer with lower body mass values were more likely to be infected with MAP. Overall, the absence of signs of clinical paratuberculosis and gross lesions together with the low level of shedding witness early phases of the disease among the positive red deer and support an improvement of the paratuberculosis status of this population, as shown by the decreased prevalence of the disease over the years

Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis

Objective: This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS). Methods: We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results. Results: Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (&lt;1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses. Interpretation: This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists