234 research outputs found
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
Hospital-Acquired Infections in Critically Ill Patients With COVID-19
Background: Few small studies have described hospital-acquired infections (HAIs) occurring in patients with COVID-19. Research Question: What characteristics in critically ill patients with COVID-19 are associated with HAIs and how are HAIs associated with outcomes in these patients? Study Design and Methods: Multicenter retrospective analysis of prospectively collected data including adult patients with severe COVID-19 admitted to eight Italian hub hospitals from February 20, 2020, through May 20, 2020. Descriptive statistics and univariate and multivariate Weibull regression models were used to assess incidence, microbial cause, resistance patterns, risk factors (ie, demographics, comorbidities, exposure to medication), and impact on outcomes (ie, ICU discharge, length of ICU and hospital stays, and duration of mechanical ventilation) of microbiologically confirmed HAIs. Results: Of the 774 included patients, 359 patients (46%) demonstrated 759 HAIs (44.7 infections/1,000 ICU patient-days; 35% multidrug-resistant [MDR] bacteria). Ventilator-associated pneumonia (VAP; n = 389 [50%]), bloodstream infections (BSIs; n = 183 [34%]), and catheter-related BSIs (n = 74 [10%]) were the most frequent HAIs, with 26.0 (95% CI, 23.6-28.8) VAPs per 1,000 intubation-days, 11.7 (95% CI, 10.1-13.5) BSIs per 1,000 ICU patient-days, and 4.7 (95% CI, 3.8-5.9) catheter-related BSIs per 1,000 ICU patient-days. Gram-negative bacteria (especially Enterobacterales) and Staphylococcus aureus caused 64% and 28% of cases of VAP, respectively. Variables independently associated with infection were age, positive end expiratory pressure, and treatment with broad-spectrum antibiotics at admission. Two hundred thirty-four patients (30%) died in the ICU (15.3 deaths/1,000 ICU patient-days). Patients with HAIs complicated by septic shock showed an almost doubled mortality rate (52% vs 29%), whereas noncomplicated infections did not affect mortality. HAIs prolonged mechanical ventilation (median, 24 days [interquartile range (IQR), 14-39 days] vs 9 days [IQR, 5-13 days]; P < .001), ICU stay (24 days [IQR, 16-41 days] vs 9 days [IQR, 6-14 days]; P = .003), and hospital stay (42 days [IQR, 25-59 days] vs 23 days [IQR, 13-34 days]; P < .001). Interpretation: Critically ill patients with COVID-19 are at high risk for HAIs, especially VAPs and BSIs resulting from MDR organisms. HAIs prolong mechanical ventilation and hospitalization, and HAIs complicated by septic shock almost double mortality. Trial Registry: ClinicalTrials.gov; No.: NCT04388670; URL: www.clinicaltrials.go
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