Modulation of Tyrosine Hydroxylase, Neuropeptide Y, Glutamate, and Substance P in Ganglia and Brain Areas Involved in Cardiovascular Control after Chronic Exposure to Nicotine

Considering that nicotine instantly interacts with central and peripheral nervous systems promoting cardiovascular effects after tobacco smoking, we evaluated the modulation of glutamate, tyrosine hydroxylase (TH), neuropeptide Y (NPY), and substance P (SP) in nodose/petrosal and superior cervical ganglia, as well as TH and NPY in nucleus tractus solitarii (NTS) and hypothalamic paraventricular nucleus (PVN) of normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) after 8 weeks of nicotine exposure. Immunohistochemical and in situ hybridization data demonstrated increased expression of TH in brain and ganglia related to blood pressure control, preferentially in SHR, after nicotine exposure. The alkaloid also increased NPY immunoreactivity in ganglia, NTS, and PVN of SHR, in spite of decreasing its receptor (NPY1R) binding in NTS of both strains. Nicotine increased SP and glutamate in ganglia. In summary, nicotine positively modulated the studied variables in ganglia while its central effects were mainly constrained to SHR

Single-cell functional and chemosensitive profiling of combinatorial colorectal therapy in zebrafish xenografts.

Cancer is as unique as the person fighting it. With the exception of a few biomarker-driven therapies, patients go through rounds of trial-and-error approaches to find the best treatment. Using patient-derived cell lines, we show that zebrafish larvae xenotransplants constitute a fast and highly sensitive in vivo model for differential therapy response, with resolution to reveal intratumor functional cancer heterogeneity. We screened international colorectal cancer therapeutic guidelines and determined distinct functional tumor behaviors (proliferation, metastasis, and angiogenesis) and differential sensitivities to standard therapy. We observed a general higher sensitivity to FOLFIRI [5-fluorouracil(FU)+irinotecan+folinic acid] than to FOLFOX (5-FU+oxaliplatin+folinic acid), not only between isogenic tumors but also within the same tumor. We directly compared zebrafish xenografts with mouse xenografts and show that relative sensitivities obtained in zebrafish are maintained in the rodent model. Our data also illustrate how KRAS mutations can provide proliferation advantages in relation to KRASWT and how chemotherapy can unbalance this advantage, selecting for a minor clone resistant to chemotherapy. Zebrafish xenografts provide remarkable resolution to measure Cetuximab sensitivity. Finally, we demonstrate the feasibility of using primary patient samples to generate zebrafish patient-derived xenografts (zPDX) and provide proof-of-concept experiments that compare response to chemotherapy and biological therapies between patients and zPDX. Altogether, our results suggest that zebrafish larvae xenografts constitute a promising fast assay for precision medicine, bridging the gap between genotype and phenotype in an in vivo setting.info:eu-repo/semantics/publishedVersio

Path Tracing vs. Volume Rendering Technique in Post-Surgical Assessment of Bone Flap in Oncologic Head and Neck Reconstructive Surgery: A Preliminary Study

This study aims to compare a relatively novel three-dimensional rendering called Path Tracing (PT) to the Volume Rendering technique (VR) in the post-surgical assessment of head and neck oncologic surgery followed by bone flap reconstruction. This retrospective study included 39 oncologic patients who underwent head and neck surgery with free bone flap reconstructions. All exams were acquired using a 64 Multi-Detector CT (MDCT). PT and VR images were created on a dedicated workstation. Five readers, with different expertise in bone flap reconstructive surgery, independently reviewed the images (two radiologists, one head and neck surgeon and two otorhinolaryngologists, respectively). Every observer evaluated the images according to a 5-point Likert scale. The parameters assessed were image quality, anatomical accuracy, bone flap evaluation, and metal artefact. Mean and median values for all the parameters across the observer were calculated. The scores of both reconstruction methods were compared using a Wilcoxon matched-pairs signed rank test. Inter-reader agreement was calculated using Spearman’s rank correlation coefficient. PT was considered significantly superior to VR 3D reconstructions by all readers (p < 0.05). Inter-reader agreement was moderate to strong across four out of five readers. The agreement was stronger with PT images compared to VR images. In conclusion, PT reconstructions are significantly better than VR ones. Although they did not modify patient outcomes, they may improve the post-surgical evaluation of bone-free flap reconstructions following major head and neck surgery

Eumycetoma caused by Diaporthe phaseolorum (Phomopsis phaseoli): a case report and a mini-review of Diaporthe/Phomopsis spp invasive infections in humans

AbstractDiaporthe phaseolorum (syn. Phomopsis phaseoli) is a frequent fungal parasite of plants, present on all continents around the world. It has rarely been involved in human diseases. We report a case of eumycetoma with osteomyelitis of the forefoot caused by this fungus and diagnosed by molecular biology. The patient had positive HTLV-1 serology and was a farmer from French Guiana who walked barefoot. He was successfully treated with long-term oral itraconazole (400 mg/day). A review of the literature underlines the essential roles of plants and host immunosuppression in this infection and the favourable outcome with a triazole antifungal treatment

A 10-year experience in preoperative ultrasound imaging for parotid glands’ benign neoformations

Salivary gland neoplasms represent less than 4% of all head and neck lesions, being 80% in the parotid gland and usually benign. Imaging plays a key role in the evaluation of parotid gland masses. Ultrasound is cheap, with an excellent resolution and a safe real time assessment making it an ideal first evaluation option. Conversely, MRI is considered a second-line pre-surgery exam used to determine the location, the extension and the signal features of a parotid lesion. Both US and MRI are poorly reliable for predicting histology, therefore a fine-needle aspiration cytology (FNAC) is usually needed. In our retrospective study, we examined 263 patients with parotid diseases and a FNAC positive for a benign neoplasm, who underwent surgery between 2010 and 2020, in the departments of Otorhinolaryngology and Maxillofacial surgery in Verona. We compared a group of 126 patients preoperatively evaluated with ultrasound and a control group of 137 patients studied through third level imaging (usually MRI). In our case series, both third level imaging and US were used in equal measure, despite the lesion size. We found the recurrence rate to be almost the same between the two diagnostic methods and we saw that the patients studied through third level preoperative imaging had a higher complication rate and a worse facial nerve outcome. In our opinion, for patients with a FNAC positive for benign lesion the exclusive use of ultrasound imaging provides enough information to study the neoplasm while allowing for a faster and cheaper preoperative evaluation

Predictive and therapeutic implications of a novel PLCγ1/SHP2-driven mechanism of cetuximab resistance in metastatic colorectal cancer

© 2022 The Authors; Published by the American Association for Cancer Research. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 International (CC BY-NC-ND)Purpose: Cetuximab is an EGFR-targeted therapy approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC). However, about 60% of these patients show innate resistance to cetuximab. To increase cetuximab efficacy, it is crucial to successfully identify responder patients, as well as to develop new therapeutic approaches to overcome cetuximab resistance. Experimental design: We evaluated the value of EGFR effector phospholipase C gamma 1 (PLCγ1) in predicting cetuximab responses, by analyzing progression-free survival (PFS) of a multicentric retrospective cohort of 94 treated patients with mCRC (log-rank test and Cox regression model). Furthermore, we used in vitro and zebrafish xenotransplant models to identify and target the mechanism behind PLCγ1-mediated resistance to cetuximab. Results: In this study, levels of PLCγ1 were found increased in RAS WT tumors and were able to predict cetuximab responses in clinical samples and in vitro and in vivo models. Mechanistically, PLCγ1 expression was found to bypass cetuximab-dependent EGFR inhibition by activating ERK and AKT pathways. This novel resistance mechanism involves a noncatalytic role of PLCγ1 SH2 tandem domains in the propagation of downstream signaling via SH2-containing protein tyrosine phosphatase 2 (SHP2). Accordingly, SHP2 inhibition sensitizes PLCγ1-resistant cells to cetuximab. Conclusions: Our discoveries reveal the potential of PLCγ1 as a predictive biomarker for cetuximab responses and suggest an alternative therapeutic approach to circumvent PLCγ1-mediated resistance to cetuximab in patients with RAS WT mCRC. In this way, this work contributes to the development of novel strategies in the medical management and treatment of patients with mCRC.M. Martins' research was supported by Liga Portuguesa Contra o Cancro (LPCC): Terry Fox Fundation; Investigador FCT- Fundação para a Ciência e Technologia (IF/00409/2014) and IMM Bridge grant; RC-D research was supported by Fundação para a Ciência e Technologia (SFRH/BD/139138/2018). A. Fernandes was supported by LPCC-IMM BIOBANK; R. Fior was supported by Champalimaud Foundation and L. Costa was supported by Merck Serono.info:eu-repo/semantics/publishedVersio

Incidence and clinical predictors of a subsequent nonmelanoma skin cancer in solid organ transplant recipients with a first nonmelanoma skin cancer: a multicenter cohort study.

Objective: To compare the long-term risk of primary nonmelanoma skin cancer (NMSC) and the risk of subsequent NMSC in kidney and heart transplant recipients. Design: Partially retrospective cohort study. Setting: Two Italian transplantation centers. Patients: The study included 1934 patients: 1476 renal transplant recipients and 458 heart transplant recipients. Main Outcome Measures: Cumulative incidences and risk factors of the first and subsequent NMSCs. Results: Two hundred patients developed a first NMSC after a median follow-up of 6.8 years after transplantation. The 3-year risk of the primary NMSC was 2.1%. Of the 200 patients with a primary NMSC, 91 (45.5%) had a secondNMSCafter a median follow-up after the firstNMSC of 1.4 years (range, 3 months to 10 years). The 3-year risk of a second NMSC was 32.2%, and it was 49 times higher than that in patients with no previous NMSC. In a Cox proportional hazards regression model, age older than 50 years at the time of transplantation and male sex were significantly related to the first NMSC. Occurrence of the subsequent NMSC was not related to any risk factor considered, including sex, age at transplantation, type of transplanted organ, type of immunosuppressive therapy, histologic type of the first NMSC, and time since diagnosis of the first NMSC. Histologic type of the first NMSC strongly predicted the type of the subsequent NMSC. Conclusions: Development of a first NMSC confers a high risk of a subsequent NMSC in transplant recipients. Intensive long-term dermatologic follow-up of these patients is advisable

Expansão do Ensino Superior: Realidades e significados em alguns países de língua portuguesa e espanhola

In recent decades; there has been an expansion of higher education (HE) in most countries, resulting in anincrease in the number of institutions, courses and students, but also in the diversification of the profiles of these new entrants. In this article, we intend to describe the organization and process of access to HE in some Portuguese or Spanish-speaking countries (Angola, Brazil, Costa Rica, Spain, Mozambique and Portugal), pointing out the legislation and practices that support its expansion. In particular, the policies that have increased the heterogeneity of the student population are highlighted, favoring equal access opportunities for students from more disadvantaged sociocultural groups. Conclusions point to the existence of very different higher education structures in these countries.At the same time, there is a growing concern with the implementation of access measures for different audiences adapted to the cultural specificities of each country, leaving in HEIs the responsibility to implement measures that favor the adaptation and success of students who enter with different profiles from more traditional students. Keywords: higher education; expansion of higher education; access to higher education; democratization of higher education.En las últimas décadas se ha producido una expansión de la enseñanza superior (ES) en la mayoría delos países, lo que se ha visto reflejado en un aumento del número de instituciones, titulaciones y estudiantes, así como, en una mayor diversificación de los matriculados. En este trabajo, describimos la organización y el proceso de acceso a la ES en algunos países de lengua portuguesa e hispana (Angola, Brasil, Costa Rica, España, Mozambique y Portugal), indicando la legislación y las prácticas que apoyan su expansión. En concreto, destacamos las políticas que han aumentado la heterogeneidad de la población estudiantil, favoreciendo la igualdad de oportunidades de acceso para los estudiantes de grupos socioculturales más desfavorecidos. Las conclusiones apuntan a la existencia de estructuras de ES muy diferentes en los distintos países, aunque todos ellos aplican políticas que favorecen la entrada de nuevos estudiantes. A su vez, se incentiva a las instituciones educativas a poner en marcha medidas que favorezcan la adaptación y el éxito de los estudiantes que ingresan con perfiles diferentes a sus estudiantes tradicionales. Palabras-clave: enseñanza superior; expansión de la enseñanza superior; acceso a la enseñanza superior; democratización de la enseñanza superior.Nas últimas décadas ocorre uma expansão do ensino superior (ES) na generalidade dos países, traduzida no aumento de número de instituições, de cursos e de estudantes, traduzida numa maior diversificação dos ingressantes. Neste artigo, pretendemos descrever a organização e o processo de acesso ao ES em alguns países de língua portuguesa ou espanhola (Angola, Brasil, Costa Rica, Espanha, Moçambique e Portugal), apontando a legislação e práticas que suportam a sua expansão.Em particular destacamos as políticas que aumentaram a heterogeneidade da população estudantil, favorecendo a igualdade de oportunidades de acesso por estudantes provenientes de grupos socioculturaismais desfavorecidos. As conclusões apontam para a existência de estruturas de ES bastante diferentes nos vários países, contudo em todos eles implementam políticas favoráveis ao ingresso dos novos públicos.Paralelamente as instituições de ensino são incentivadas a implementar medidas que favoreçam a adaptação e sucesso de estudantes que ingressam com perfis diferenciados face aos seus estudantes tradicionais. Palavras-chave: ensino superior; expansão do ensino superior; acesso ao ensino superior; democratizaçãodo ensino superior