Comprehensive Molecular Landscape of Cetuximab Resistance in Head and Neck Cancer Cell Lines.

Cetuximab is the sole anti-EGFR monoclonal antibody that is FDA approved to treat head and neck squamous cell carcinoma (HNSCC). However, no predictive biomarkers of cetuximab response are known for HNSCC. Herein, we address the molecular mechanisms underlying cetuximab resistance in an in vitro model. We established a cetuximab resistant model (FaDu), using increased cetuximab concentrations for more than eight months. The resistance and parental cells were evaluated for cell viability and functional assays. Protein expression was analyzed by Western blot and human cell surface panel by lyoplate. The mutational profile and copy number alterations (CNA) were analyzed using whole-exome sequencing (WES) and the NanoString platform. FaDu resistant clones exhibited at least two-fold higher IC50 compared to the parental cell line. WES showed relevant mutations in several cancer-related genes, and the comparative mRNA expression analysis showed 36 differentially expressed genes associated with EGFR tyrosine kinase inhibitors resistance, RAS, MAPK, and mTOR signaling. Importantly, we observed that overexpression of KRAS, RhoA, and CD44 was associated with cetuximab resistance. Protein analysis revealed EGFR phosphorylation inhibition and mTOR increase in resistant cells. Moreover, the resistant cell line demonstrated an aggressive phenotype with a significant increase in adhesion, the number of colonies, and migration rates. Overall, we identified several molecular alterations in the cetuximab resistant cell line that may constitute novel biomarkers of cetuximab response such as mTOR and RhoA overexpression. These findings indicate new strategies to overcome anti-EGFR resistance in HNSCC.

Evaluation of molecular markers GSTM1 and GSTT1 and clinical factors in breast cancer: case-control study and literature review.

The study was conducted to evaluate the frequency of polymorphisms in GSTM1 and GSTT1 genes in patients with breast cancer compared with individuals without history of cancer, and the association of these polymorphisms with clinical/epidemiological parameters.There were evaluated 752 women (219 patients and 533 controls). Molecular analysis was performed by the Polymerase Chain Reaction (PCR). Statistical analysis was used multiple logistic regression and descriptive statistics.Age ≥ 50 years (OR = 3.22, 95% CI = 2.30-4.51, p < 0.001) and alcohol consumption (OR = 1.60, 95% CI = 1.13-2.27, p = 0.008) were associated to the development of breast cancer, while smoking and null genotypes GSTM1 and GSTT1 presented no association. GSTM1 and GSTT1 polymorphisms presented no relationship with the clinical and histopathological parameters or molecular subtypes of breast cancer. Ninety-two percent of tumours were invasive ductal, 66% were grade II, 65% were larger than 2 cm, the stages II (35.3%) and III (31.2%) were the most prevalent, and 47.7% were molecular subtype luminal B.Individuals aged ≥ 50 years and alcohol consumers have more chance to developing breast cancer. GSTM1 and GSTT1 polymorphisms are not associated to the risk of breast cancer.

Abordagem fisioterapêutica na reabilitação da musculatura do assoalho pélvico em mulheres com prolapso genital / Physiotherapy approach in the rehabilitation of pelvic floor musculature in women with genital prolapse

Introdução: O assoalho pélvico tem como objetivo sustentar órgãos internos, principalmente o útero, a bexiga e o reto, porém qualquer alteração na cavidade pélvica pode resultar em disfunção dessa região e descida patológica dos órgãos, características dos prolapsos genitais. A fisioterapia melhora os sintomas relacionados ao prolapso genital, bem como a força muscular do assoalho. Objetivo: Identificar os procedimentos fisioterapêuticos mais utilizados e de melhor eficácia comprovada no tratamento dos prolapsos. Métodos: Foi realizado um levantamento de artigos científicos e teses em bancos de dados, nos quais foram encontrados 716 estudos. Destes, 9 foram selecionados, sendo 3 do tipo ensaio clínico randomizado controlado, 1 quaseexperimental do tipo antes e depois e 5 do tipo revisão, publicados nos últimos 20 anos e relacionados ao tema proposto. Resultados: Participaram dos estudos clínicos 430 mulheres no total, que foram submetidas a intervenções como: cinesioterapia, exercícios hipopressivos e eletroestimulação transvaginal. Os estudos de revisão mencionam os efeitos do biofeedback e da cinesioterapia no manejo dos prolapsos. Conclusão: Das abordagens analisadas a cinesioterapia e os exercícios hipopressivos são os mais efetivos para o tratamento do prolapso genital, porém mais estudos são necessários para avaliar o real impacto desses recursos. (AU)

Introduction: The pelvic floor is intended to support internal organs, especially the uterus, bladder and rectum. However, any alteration in the pelvic cavity may result in dysfunction of the pelvic floor and pathological falling of the organs, characteristic of genital prolapses. Physical therapy improves symptoms related to genital prolapse as well as muscle strength of the floor. Objective: The aim of this study was to identify the most widely used physiotherapeutic procedures with proven efficacy in the treatment of prolapses. Methods: A survey of scientific articles and theses in databases was carried out, in which 716 studies were found. Of these, 9 were selected, 3 of which were randomized controlled clinical trials, 1 quasi-experimental and 5 reviews, published in the last 20 years. Results: A total of 430 women participated in the clinical studies, who underwent interventions such as: kinesiotherapy, hipopressive exercises and transvaginal electrostimulation. The review studies mention the effects of biofeedback and kinesiotherapy in the management of prolapses. Conclusion: From the approaches analyzed kinesiotherapy and hipopressive exercises are the most effective for the treatment of genital prolapse, but more studies are necessary to evaluate the real impact of these resources. (AU)

Early discontinuation of empirical antibacterial therapy in febrile neutropenia: the ANTIBIOSTOP study.

INTRODUCTION: Immediate empirical antibiotic therapy is mandatory in febrile chemotherapy-induced neutropenia, but its optimal duration is unclear, especially in patients with fever of unknown origin (FUO). OBJECTIVES: The primary objective of this 20-month prospective observational study was to evaluate the feasibility and safety of short-term antibiotic treatment in afebrile or febrile patients exhibiting FUO, irrespective of their neutrophil count. The secondary objective was to describe the epidemiology of all episodes of febrile neutropenia. METHODS: In the first phase of the study, empirical antibiotic therapy in FUO patients was stopped after 48 h of apyrexia, in accordance with European Conference on Infections in Leukaemia guidelines (n = 45). In the second phase of the study, antibiotics were stopped no later than day 5 for all FUO patients, regardless of body temperature or leukocyte count (n = 37). RESULTS: Two hundred and thirty-eight cases of febrile neutropenia in 123 patients were included. Neither the composite endpoint (p = .11), nor each component (in-hospital mortality (p = .80), intensive care unit admission (p = 0.48), relapse of infection ≤48 h after discontinuation of antibiotics (p = .82)) differed between the two FUO groups. Violation of protocol occurred in 17/82 episodes of FUO without any major impact on statistical results. Twenty-six (57.3%) and 22 (59.5%) FUO episodes did not relapse during hospital-stay (p = 1), and nine (20%) and five (13.5%) presented another FUO, respectively. One hundred and fifty-six episodes of febrile neutropenia (65.5%) were clinically or microbiologically documented, including 85 bacteremia. CONCLUSIONS: These results suggest that early discontinuation of empirical antibiotics in FUO is safe for afebrile neutropenic patients.

Osteoarticular manifestations of celiac disease and non-celiac gluten hypersensitivity.

Celiac disease is a chronic inflammatory autoimmune enteropathy based disorder that is triggered by the ingestion of gluten in genetically susceptible individuals. The global prevalence of 1% to 2% represents only the tip of the iceberg. The diagnosis is confirmed by positive specific antibody, anti-transglutaminase or anti-endomysium, specific lesions of the small intestine and a response to strict gluten-free diet. The diagnosis is difficult and often delayed because the clinical variability is very large, ranging from digestive clinical presentation "classic" to "atypical" symptoms, often extra-intestinal, that are sometimes attributed to a concomitant disease or a complication. Among them, there are frequent musculoskeletal manifestations such as osteoporosis and osteomalacia. In the absence of risk factor, osteoporosis, in a premenopausal women or in a man less than 55 years, more is if it is severe and refractory to medications, need to rheumatologists on the track of celiac disease in the absence of digestive symptoms. Osteomalacia is related to secondary hypovitaminosis D malabsorption. Supplementation by calcifediol, water-soluble vitamin D, may be indicated. Celiac disease is associated with an autoimmune disease in almost 1/3 of the cases. Knowing these potential associations allows earlier diagnosis in patients whose only manifestation, a concomitant disease. Anemia, chronic fatigue or unexplained polyarthralgia are symptoms associated with celiac disease to look for specific antibodies. The aim of early diagnosis is to prevent the emergence of other systemic disorders and avoid complications such as bone fractures and cancer, especially intestinal lymphoma. Non-celiac gluten intolerance is a new entity defined by symptomatology similar to that of celiac disease induced by the ingestion of gluten and disappearing after crowding-out, among patients without specific antibodies and without intestinal lesion of celiac disease. This entity is a cause, at least in part, of increasing interest in gluten-free diet in the general population.

Experiences of four parents with physical therapy and early mobility of their children in a pediatric critical care unit: A case series.

PURPOSE: The aim of this study was to conduct a preliminary investigation into parents' experiences of physical therapy and early mobility (EM) for their children in a pediatric critical care unit (PCCU). METHODS: We conducted a series of four qualitative case studies using in-depth semi-structured face-to-face interviews. We recruited parents of children who had undergone surgery and received at least one EM physical therapy intervention while intubated. We conducted a thematic analysis of transcribed interviews to illuminate the factors that influenced EM experiences. RESULTS: Four parents participated in the study. We developed an overview of Parental Experiences with Physical Therapy and Early Mobility in a PCCU, which includes four themes that parents believed influenced their experiences: (1) environmental factors; (2) awareness of physical therapist and health care professional (HCP) roles; (3) communication among parents and HCPs; and (4) parental participation in their child's EM, within the overarching parental experiences in the PCCU. CONCLUSION: This study affords a preliminary understanding of parents' experiences with physical therapy and EM in a PCCU setting. Results provide an important foundation for future research on mobility in the context of pediatric critical care research and practice.