DDD

Forma part del projecte: Biblioteca Digital d'Història de l'Art Hispànic (UAB)Localització de l'original: Escola Tècnica Superior d'Arquitectura de Barcelona (UPC)Estampes litogràfiques editades a Chez A. Hauser, Boulevard des Italiens, 11 ; Impressor, Lemercie

Endocrine Therapy Synergizes with SMAC Mimetics to Potentiate Antigen Presentation and Tumor Regression in Hormone Receptor-Positive Breast Cancer.

UNLABELLED: Immunotherapies have yet to demonstrate significant efficacy in the treatment of hormone receptor-positive (HR+) breast cancer. Given that endocrine therapy (ET) is the primary approach for treating HR+ breast cancer, we investigated the effects of ET on the tumor immune microenvironment (TME) in HR+ breast cancer. Spatial proteomics of primary HR+ breast cancer samples obtained at baseline and after ET from patients enrolled in a neoadjuvant clinical trial (NCT02764541) indicated that ET upregulated β2-microglobulin and influenced the TME in a manner that promotes enhanced immunogenicity. To gain a deeper understanding of the underlying mechanisms, the intrinsic effects of ET on cancer cells were explored, which revealed that ET plays a crucial role in facilitating the chromatin binding of RelA, a key component of the NF-κB complex. Consequently, heightened NF-κB signaling enhanced the response to interferon-gamma, leading to the upregulation of β2-microglobulin and other antigen presentation-related genes. Further, modulation of NF-κB signaling using a SMAC mimetic in conjunction with ET augmented T-cell migration and enhanced MHC-I-specific T-cell-mediated cytotoxicity. Remarkably, the combination of ET and SMAC mimetics, which also blocks prosurvival effects of NF-κB signaling through the degradation of inhibitors of apoptosis proteins, elicited tumor regression through cell autonomous mechanisms, providing additional support for their combined use in HR+ breast cancer. SIGNIFICANCE: Adding SMAC mimetics to endocrine therapy enhances tumor regression in a cell autonomous manner while increasing tumor immunogenicity, indicating that this combination could be an effective treatment for HR+ patients with breast cancer

The effective action of D-branes in Calabi-Yau orientifold compactifications

In this review article we study type IIB superstring compactifications in the presence of space-time filling D-branes while preserving N=1 supersymmetry in the effective four-dimensional theory. This amount of unbroken supersymmetry and the requirement to fulfill the consistency conditions imposed by the space-time filling D-branes lead to Calabi-Yau orientifold compactifications. For a generic Calabi-Yau orientifold theory with space-time filling D3- or D7-branes we derive the low-energy spectrum. In a second step we compute the effective N=1 supergravity action which describes in the low-energy regime the massless open and closed string modes of the underlying type IIB Calabi-Yau orientifold string theory. These N=1 supergravity theories are analyzed and in particular spontaneous supersymmetry breaking induced by non-trivial background fluxes is studied. For D3-brane scenarios we compute soft-supersymmetry breaking terms resulting from bulk background fluxes whereas for D7-brane systems we investigate the structure of D- and F-terms originating from worldvolume D7-brane background fluxes. Finally we relate the geometric structure of D7-brane Calabi-Yau orientifold compactifications to N=1 special geometry.Comment: LaTeX, 133 pages, Ph.D. Thesis (Advisor: Jan Louis); v2: references adde

Aquaporins: important but elusive drug targets.

The aquaporins (AQPs) are a family of small, integral membrane proteins that facilitate water transport across the plasma membranes of cells in response to osmotic gradients. Data from knockout mice support the involvement of AQPs in epithelial fluid secretion, cell migration, brain oedema and adipocyte metabolism, which suggests that modulation of AQP function or expression could have therapeutic potential in oedema, cancer, obesity, brain injury, glaucoma and several other conditions. Moreover, loss-of-function mutations in human AQPs cause congenital cataracts (AQP0) and nephrogenic diabetes insipidus (AQP2), and autoantibodies against AQP4 cause the autoimmune demyelinating disease neuromyelitis optica. Although some potential AQP modulators have been identified, challenges associated with the development of better modulators include the druggability of the target and the suitability of the assay methods used to identify modulators

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Measurement of baryon acoustic oscillations in the Lyman-α forest fluctuations in BOSS data release 9

We use the Baryon Oscillation Spectroscopic Survey (BOSS) Data Release 9 (DR9) to detect and measure the position of the Baryonic Acoustic Oscillation (BAO) feature in the three-dimensional correlation function in the Lyman-α flux fluctuations at a redshift zeff = 2.4. The feature is clearly detected at significance between 3 and 5 sigma (depending on the broadband model and method of error covariance matrix estimation) and is consistent with predictions of the standard ΛCDM model. We assess the biases in our method, stability of the error covariance matrix and possible systematic effects. We fit the resulting correlation function with several models that decouple the broadband and acoustic scale information. For an isotropic dilation factor, we measure 100 × (αiso - 1) = -1.6+2.0 +4.3 +7.4-2.0 -4.1 -6.8 (stat.) ±1.0 (syst.) (multiple statistical errors denote 1,2 and 3 sigma confidence limits) with respect to the acoustic scale in the fiducial cosmological model (flat ΛCDM with Ωm = 0.27, h = 0.7). When fitting separately for the radial and transversal dilation factors we find marginalised constraints 100 × (α|| - 1) = -1.3+3.5 +7.6 +12.3-3.3 -6.7 -10.2 (stat.) ±2.0 (syst.) and 100 × (α⊥ - 1) = -2.2+7.4 +17-7.1 -15 (stat.) ±3.0 (syst.). The dilation factor measurements are significantly correlated with cross-correlation coefficient of ~ -0.55. Errors become significantly non-Gaussian for deviations over 3 standard deviations from best fit value. Because of the data cuts and analysis method, these measurements give tighter constraints than a previous BAO analysis of the BOSS DR9 Lyman-α sample, providing an important consistency test of the standard cosmological model in a new redshift regime

Enhanced chlorhexidine skin penetration with eucalyptus oil

Background Chlorhexidine digluconate (CHG) is a widely used skin antiseptic, however it poorly penetrates the skin, limiting its efficacy against microorganisms residing beneath the surface layers of skin. The aim of the current study was to improve the delivery of chlorhexidine digluconate (CHG) when used as a skin antiseptic. Method Chlorhexidine was applied to the surface of donor skin and its penetration and retention under different conditions was evaluated. Skin penetration studies were performed on full-thickness donor human skin using a Franz diffusion cell system. Skin was exposed to 2% (w/v) CHG in various concentrations of eucalyptus oil (EO) and 70% (v/v) isopropyl alcohol (IPA). The concentration of CHG (μg/mg of skin) was determined to a skin depth of 1500 μm by high performance liquid chromatography (HPLC). Results The 2% (w/v) CHG penetration into the lower layers of skin was significantly enhanced in the presence of EO. Ten percent (v/v) EO in combination with 2% (w/v) CHG in 70% (v/v) IPA significantly increased the amount of CHG which penetrated into the skin within 2 min. Conclusion The delivery of CHG into the epidermis and dermis can be enhanced by combination with EO, which in turn may improve biocide contact with additional microorganisms present in the skin, thereby enhancing antisepsis