Retinoid orphan receptor gamma t (rorγt) promotes inflammatory eosinophilia but is dispensable for innate immune-mediated colitis.

Inflammatory bowel diseases (IBD) result from uncontrolled inflammation in the intestinal mucosa leading to damage and loss of function. Both innate and adaptive immunity contribute to the inflammation of IBD and innate and adaptive immune cells reciprocally activate each other in a forward feedback loop. In order to better understand innate immune contributions to IBD, we developed a model of spontaneous 100% penetrant, early onset colitis that occurs in the absence of adaptive immunity by crossing villin-TNFAIP3 mice to RAG1-/- mice (TRAG mice). This model is driven by microbes and features increased levels of innate lymphoid cells in the intestinal mucosa. To investigate the role of type 3 innate lymphoid cells (ILC3) in the innate colitis of TRAG mice, we crossed them to retinoid orphan receptor gamma t deficient (Rorγt-/-) mice. Rorγt-/- x TRAG mice exhibited markedly reduced eosinophilia in the colonic mucosa, but colitis persisted in these mice. Colitis in Rorγt-/- x TRAG mice was characterized by increased infiltration of the intestinal mucosa by neutrophils, inflammatory monocytes, macrophages and other innate cells. RNA and cellular profiles of Rorγt-/- x TRAG mice were consistent with a lack of ILC3 and ILC3 derived cytokines, reduced antimicrobial factors, increased activation oof epithelial repair processes and reduced activation of epithelial cell STAT3. The colitis in Rorγt-/- x TRAG mice was ameliorated by antibiotic treatment indicating that microbes contribute to the ILC3-independent colitis of these mice. Together, these gene expression and cell signaling signatures reflect the double-edged sword of ILC3 in the intestine, inducing both proinflammatory and antimicrobial protective responses. Thus, Rorγt promotes eosinophilia but Rorγt and Rorγt-dependent ILC3 are dispensable for the innate colitis in TRAG mice.

Detection of Negative Stress through Spectral Features of Electroencephalographic Recordings and a Convolutional Neural Network.

In recent years, electroencephalographic (EEG) signals have been intensively used in the area of emotion recognition, partcularly in distress identification due to its negative impact on physical and mental health. Traditionally, brain activity has been studied from a frequency perspective by computing the power spectral density of the EEG recordings and extracting features from different frequency sub-bands. However, these features are often individually extracted from single EEG channels, such that each brain region is separately evaluated, even when it has been corroborated that mental processes are based on the coordination of different brain areas working simultaneously. To take advantage of the brain's behaviour as a synchronized network, in the present work, 2-D and 3-D spectral images constructed from common 32 channel EEG signals are evaluated for the first time to discern between emotional states of calm and distress using a well-known deep-learning algorithm, such as AlexNet. The obtained results revealed a significant improvement in the classification performance regarding previous works, reaching an accuracy about 84%. Moreover, no significant differences between the results provided by the diverse approaches considered to reconstruct 2-D and 3-D spectral maps from the original location of the EEG channels over the scalp were noticed, thus suggesting that these kinds of images preserve original spatial brain information.

The actual management of colorectal liver metastases.

Colorectal cancer is one of the most frequent cancers in the world and between 50% and 60% of patients will develop colorectal liver metastases (CRLM) during the disease. There have been great improvements in the management of CRLM during the last decades. The combination of modern chemotherapeutic and biological systemic treatments with aggressive surgical resection strategies is currently the base for the treatment of patients considered unresectable until few years ago. Furthermore, several new treatments for the local control of CRLM have been developed and are now part of the arsenal of multidisciplinary teams for the treatment of these complex patients. The aim of this review was to summarize and update the management of CRLM, its controversies and relevant evidence.

Nalbuphine, a kappa opioid receptor agonist and mu opioid receptor antagonist attenuates pruritus, decreases IL-31, and increases IL-10 in mice with contact dermatitis.

Chronic itch is one of the disturbing symptoms of inflammatory skin diseases. Kappa opioid receptor agonists are effective in suppressing scratching in mice against different pruritogens. Nalbuphine, a nonscheduled kappa opioid receptor agonist and mu opioid receptor antagonist, has been in clinical use for post-operative pain management since the 1980s and recently has been in clinical trials for chronic itch of prurigo nodularis (https://www.trevitherapeutics.com/nalbuphine). We studied whether nalbuphine is effective against chronic scratching induced by rostral neck application of 1-fluoro-2,4-dinitrobenzene (DNFB), an accepted mouse model of contact dermatitis to study pruritoceptive itch. Mice were treated once a week with either saline or nalbuphine 20 min before the third, fifth, seventh, and ninth sensitizations with DNFB and the number of scratching bouts was counted for 30 min. Skin samples from the neck of mice at week 4 were used to measure protein levels and mRNA expressions of chemokines and cytokines. Different sets of mice were used to study sedation and anhedonic-like behavior of nalbuphine. We found that: nalbuphine (a) antagonized scratching in a dose- and time-dependent manner without affecting locomotion, b) decreased IL-31, and increased anti-inflammatory IL-10, and c) induced more elevations in the levels of CCL2, CCL3, CCL12, CXCL1, CXCL2, CXCL9, CXCL10, IL-1ß, IL-16, TIMP-1, M-CSF, TREM-1 and M1-type macrophages compared to saline. Increases in chemokines and cytokines and M1 macrophages by nalbuphine suggest an inflammatory phase of healing in damaged skin due to scratching. Our data indicate that nalbuphine is an effective antipruritic in murine model of pruritoceptive itch.

Large Corpora and Historical Syntax: Consequences for the Study of Morphosyntactic Diffusion in the History of Spanish.

Over the turn of the 21st century, the use of data from large electronic corpora has changed research on Spanish historical syntax, spurring interest in long-range evolutions, and the shape of the correspondent diachronic curves. However, general reflections on diffusion and the factors that drive and influence it are still pretty much lacking. In this paper, I reflect on the research possibilities laid open by the availability of such large masses of data, focusing particularly on new knowledge on syntactic change brought about by the study of low-frequency phenomena and of recessive changes, as well as on the exploration of changes conditioned by dialect contact, and textual traditions. I conclude with some remarks on the general typology of diffusion in syntactic change.

Neutrophil to Lymphocyte Ratio as a Predictor of Poor Prognosis in Metastatic Pancreatic Cancer Patients Treated with Nab-Paclitaxel plus Gemcitabine: A Propensity Score Analysis.

BACKGROUND: High neutrophil to lymphocyte ratio (NLR) has shown to be a predictor of poor outcomes in various malignancies, including pancreatic cancer. METHODS: We assessed 70 consecutive pts with histologically confirmed mPC who received chemotherapy with nab-paclitaxel/gemcitabine at two different European oncologic centers between January 2012 and November 2015. Variables assessed for prognostic correlations included age ≥ 66, sex, Karnofsky PS score, primary tumor site, baseline CA19.9 level ≥ 59xULN, 12-week decrease of the CA19.9 level ≥ 50% from baseline, basal bilirubin level, baseline NLR, biliary stent implantation, and liver metastasis. Survival analyses were generated according to the Kaplan-Meier method. Univariate and multivariate analyses were performed by a Cox proportional hazard model. RESULTS: According to NLR values, the patients were divided into two groups: high and low. Low group patients showed a better median PFS (7 months versus 5 months) and median OS (13 months versus 7 months) in respect to high group patients. At multivariate analysis, Karnofsky PS < 80% (HR = 0.4; CI 0.2-1.2), liver metastases (HR = 0.4; CI 0.18-0.82), and NLR ≥ 5 (HR = 2.7; 95% CI 1.4-5.2) were predictors of poorer OS. Based on the presence of one or more independent prognostic factors, three risk categories were identified: good-risk, intermediate-risk and poor-risk. The median OS was 22, 10, and 7 months, respectively. CONCLUSIONS: Baseline NLR is an independent predictor of survival of patients with mPC receiving palliative chemotherapy and could be useful to develop a simple clinical score to identify a subgroup of patients with a low chance to benefit from chemotherapy.

Interaction of the CD43 Sialomucin with the Mycobacterium tuberculosis Cpn60.2 Chaperonin Leads to Tumor Necrosis Factor Alpha Production.

Mycobacterium tuberculosis is the causal agent of tuberculosis. Tumor necrosis factor alpha (TNF-α), transforming growth factor ß (TGF-ß), and gamma interferon (IFN-γ) secreted by activated macrophages and lymphocytes are considered essential to contain Mycobacterium tuberculosis infection. The CD43 sialomucin has been reported to act as a receptor for bacilli through its interaction with the chaperonin Cpn60.2, facilitating mycobacterium-macrophage contact. We report here that Cpn60.2 induces both human THP-1 cells and mouse-derived bone marrow-derived macrophages (BMMs) to produce TNF-α and that this production is CD43 dependent. In addition, we present evidence that the signaling pathway leading to TNF-α production upon interaction with Cpn60.2 requires active Src family kinases, phospholipase C-γ (PLC-γ), phosphatidylinositol 3-kinase (PI3K), p38, and Jun N-terminal protein kinase (JNK), both in BMMs and in THP-1 cells. Our data highlight the role of CD43 and Cpn60.2 in TNF-α production and underscore an important role for CD43 in the host-mycobacterium interaction.

Subcutaneous trastuzumab: drug development and current position

HER2-positive breast cancer, accounting for 15 % of the total breast cancer patient population, carries in itself a bad prognosis, which has now become much better after the advent of anti-HER2 drugs. HER2-targeted therapy has significantly improved disease free- and overall survival in HER2-positive breast cancer, and has rendered better disease control both in the early and advanced disease setting. Trastuzumab treatment duration is often prolonged and poses significant time and resource challenges both on the treatment institutions and on the patient. The recent development of a subcutaneous formulation has meant a significant advance in this respect. We review the drug development of the compound and the current evidence on its use (AU)

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Trastuzumab subcutáneo: revisión de los datos clínicos y de preferencia / Subcutaneous trastuzumab: a review of the clinical and preference data

El cáncer de mama HER2 positivo supone aproximadamente un 15% de los tumores malignos de mama. La terapia anti-HER2, principalmente representada por trastuzumab, es el pilar del tratamiento de esta enfermedad. La prolongación en la supervivencia que han conseguido las nuevas terapias anti-HER2, y el tratamiento dilatado de estas pacientes en los estadios precoces de la enfermedad así como en la enfermedad avanzada, supone un importante reto a los recursos existentes, tanto con respecto al personal sanitario y el tiempo de los hospitales de día oncológicos, como en cuanto al tiempo dedicado por las pacientes para su tratamiento. El desarrollo de una formulación subcutánea ha supuesto una disminución significativa en la utilización de estos recursos y facilidad de uso. En esta revisión, presentamos el desarrollo de esta nueva formulación, así como los datos de eficacia y preferencia (AU)

HER2-positive breast cancer accounts for approximately 15% of all malignant breast tumors. HER2-targeted therapy, mainly trastuzumab, remains the cornerstone of treatment. The increase in survival achieved by the new anti-HER2 therapies, and the prolonged treatment of these patients, both in the early and advanced breast cancer setting, poses a major challenge to existing health resources. This challenge involves the health personnel, the time consumed by oncologic day hospitals, and the time investment required by patients. The development of the new trastuzumab subcutaneous formulation has improved optimization of health resources and has increased ease of use. In the present article, we review the development of the drug, as well as efficacy and preference data (AU)

Crizotinib and renal insufficiency: a case report and review of the literature.

A 69 year old man with idiopathic chronic kidney disease was diagnosed with relapsing EGFR negative, ALK positive lung adenocarcinoma, and treated with chemotherapy and antiangiogenic treatment, under which his renal insufficiency worsened. During second line crizotinib treatment, further worsening of the renal function was seen, with very clear correlation with crizotinib withdrawal and rechallenge. No further drug causes for the worsening blood creatinine values were detected.

Subcutaneous trastuzumab: drug development and current position.

HER2-positive breast cancer, accounting for 15 % of the total breast cancer patient population, carries in itself a bad prognosis, which has now become much better after the advent of anti-HER2 drugs. HER2-targeted therapy has significantly improved disease free- and overall survival in HER2-positive breast cancer, and has rendered better disease control both in the early and advanced disease setting. Trastuzumab treatment duration is often prolonged and poses significant time and resource challenges both on the treatment institutions and on the patient. The recent development of a subcutaneous formulation has meant a significant advance in this respect. We review the drug development of the compound and the current evidence on its use.