Estudio comparativo entre las tecnicas manuales, counterstrain y comprension isquemica en el tratamiento del punto doloroso de las fibras superiores del musculo trapecio en 16 alumnos de cuarto ano de la carrera de Kinesiologia de la Universidad de Talca

57 p.El estudio analizó las diferencias que se establecen entre las técnicas manuales, Counterstrain y Compresión Isquémica en el tratamiento del punto doloroso de las fibras superiores del músculo trapecio, según su eficiencia, sensación subjetiva y duración del estímulo relatada por 16 alumnos de cuarto año de la carrera de Kinesiología de la Universidad de Talca, que estuvieran cursando el primer semestre del 2009, en el momento de la intervención. El objetivo principal consiste en aportar estudios experimentales al campo de la terapia manual, con el fin de poder objetivar y respaldar el efecto generado por dichas técnicas en el paciente. Ambas técnicas se aplicaron en el mismo paciente, donde una de ellas se ejecutó en el músculo trapecio derecho, mientras que la otra en el músculo contralateral, para que el mismo sujeto en estudio fuera quien comparase la efectividad y la sensación causada por dichas técnicas; éstas fueron aplicadas por el mismo tratante, para disminuir el margen de error y/o diferencias que pudiesen darse en la realización de la maniobra. Se realizaron 3 evaluaciones, donde en la primera sesión se aplicó el tratamiento para aliviar el dolor del paciente, y en las dos siguientes, aplicadas a las 24 y 48 hrs. respectivamente se evaluó la permanencia o no del punto doloroso tratado. Al término de la aplicación del tratamiento se le realizó una evaluación respecto a la intensidad del dolor percibido, y otra evaluación respecto a la sensación percibida durante el desarrollo de la técnica. La técnica de compresión isquémica resulta tener un mayor efecto inmediato con respecto a la técnica de counterstrain; sin embargo dicho efecto no es mantenido en el tiempo en ninguna de las dos; no obstante la técnica de compresión isquémica resulta un poco molesta en comparación con la técnica de counterstrain que es más bien indiferente

Gender-Dependent Specificities in Cutaneous Melanoma Predisposition, Risk Factors, Somatic Mutations, Prognostic and Predictive Factors: A Systematic Review.

Over the last decades, the incidence of melanoma has been steadily growing, with 4.2% of the population worldwide affected by cutaneous melanoma (CM) in 2020 and with a higher incidence and mortality in men than in women. We investigated both the risk factors for CM development and the prognostic and predictive factors for survival, stratifying for both sex and gender. We conducted a systematic review of studies indexed in PUB-MED, EMBASE, and Scopus until 4 February 2021. We included reviews, meta-analyses, and pooled analyses investigating differences between women and men in CM risk factors and in prognostic and predictive factors for CM survival. Twenty-four studies were included, and relevant data extracted. Of these, 13 studies concerned potential risk factors, six concerned predictive factors, and five addressed prognostic factors of melanoma. The systematic review revealed no significant differences in genetic predisposition to CM between males and females, while there appear to be several gender disparities regarding CM risk factors, partly attributable to different lifestyles and behavioral habits between men and women. There is currently no clear evidence of whether the mutational landscapes of CM differ by sex/gender. Prognosis is justified by a complex combination of phenotypes and immune functions, while reported differences between genders in predicting the effectiveness of new treatments are inconsistent. Overall, the results emerging from the literature reveal the importance of considering the sex/gender variable in all studies and pave the way for including it towards precision medicine. Men and women differ genetically, biologically, and by social construct. Our systematic review shows that, although fundamental, the variable sex/gender is not among the ones collected and analyzed

Effect of age on melanoma risk, prognosis and treatment response

As for all types of cancer, the incidence of melanoma increases with age. However, naevus counts (the principal risk factor for melanoma) decrease with age; hence the relationship between ageing and melanoma is complex. Subjects who maintain a high naevus count after the age of 50 years are more likely to be affected by melanoma, as their lesions do not senesce. Longer telomere length, which is strongly related to age, is linked to high naevus counts/melanoma risk; thus melanoma biology is influenced by factors that slow down ageing. Age is also an important prognostic factor in melanoma. Increasing age leads to worse survival in stages I, II and III. Sentinel lymph node (SLN) status, which is a strong predictor of melanoma survival, is also affected by age, as SLN positivity decreases with age. However, the prognostic value of SLN on survival increases with age, so, again, these relationships are complex. In patients with stage IV melanoma, age impacts on survival because it affects responses to treatment. This review examines the effects of age on melanoma risk, prognostic factors and responses to treatment

PKCε regulates vessel formation by peri-vascular adipose tissue (PVAT) cells

Vessel formation is crucial in tumour growth and tissue regeneration. Protein kinase C (PKC) ε has a well-known role on hematopoietic and mesenchymal progenitor cell differentiation and proliferation (Gobbi et al. 2013). Although PKCε has a demonstrated role in vascular restenosis, data on PKCε and vascular progenitor differentiation are still lacking. The aim of this work was to study the role of PKCε in vessel formation by adult adipose tissue cell progenitors. We, first, isolated the vessel progenitors from the adipose tissue localized between aortic arch and pulmonary artery of adult mice by collagenase/elastase digestion followed by magnetic immunoselection of Sca1+ cells (Passmann et al. 2008). We, then, tested their capability to form vessels in collagen gels and to differentiate to endothelial and smooth muscle lineage after treatment with PKCε specific activator and inhibitor peptides. The functional experiments showed that the pharmacological activation of endogenous PKCε abrogated tubule formation with a concomitant decrease of smooth alpha-actin (SMA) and platelet endothelial cell adhesion molecule (PECAM) together with the up-regulation of p-PAK1 expression. In vivo transient over-expression of PKCε significantly reduced SMA and PECAM expression levels in vessel wall cells. Together our data suggests that PKCε may affect vessel wall remodelling balancing the “phenotypic switching” (Salmon et al. 2013) between the proliferative and the differentiated state of smooth muscle and endothelial progenitor mesenchymal cells

Retrospective Chart Review of Dabrafenib Plus Trametinib in Patients with Metastatic BRAF V600-Mutant Melanoma Treated in the Individual Patient Program (DESCRIBE Italy)

Background: Real-world data on extended follow-up of patients with BRAF V600-mutant metastatic melanoma are limited. We investigated dabrafenib plus trametinib (dab + tram) outside of a clinical trial setting (Individual Patient Program; DESCRIBE Italy). Objective: To describe the baseline features, treatment patterns, efficacy, and safety outcomes in patients with BRAF V600-mutant unresectable or metastatic melanoma who had received dab + tram as part of the Managed Access Program (MAP) in Italy. Patients and methods: An observational, retrospective chart review was conducted in Italian patients with BRAF V600-mutant unresectable stage III/IV melanoma receiving dab + tram as part of the MAP. Baseline features, treatment patterns, efficacy, and safety outcomes were evaluated. Results: Overall, 499 patients were included in this analysis. BRAF V600E mutation was seen in 81.4% of patients. Overall response rate achieved in 243 of the 390 evaluable patients was 62.3% (95% CI 57.5-67.1). Median progression-free survival (PFS) was 9.3 months (95% CI 8.6-10.6). Subgroup analyses revealed that patients with normal lactate dehydrogenase (LDH) and ≤ three metastatic sites without brain metastases at baseline had better outcomes. With normal LDH at baseline, median PFS for patients with one or two metastatic sites other than cerebral was 18 months. No new safety signals were observed. Treatment was permanently discontinued because of treatment-emergent adverse events (TEAEs) in 9.2% of patients, and pyrexia (27.3%) was the most common TEAE, with a lower incidence than that in the phase 3 studies of dab + tram. Conclusion: Treatment of BRAF V600E-mutant metastatic melanoma with dab + tram in the real-world setting was effective and safe, including the unselected population with several patients having a high tumor burden - concordant with the results of the pivotal phase 3 studies of dab + tram

Efficacy of novel immunotherapy regimens in patients with metastatic melanoma with germline CDKN2A mutations

Inherited CDKN2A mutation is a strong risk factor for cutaneous melanoma. Moreover, carriers have been found to have poor melanoma-specific survival. In this study, responses to novel immunotherapy agents in CDKN2A mutation carriers with metastatic melanoma were evaluated

Novel compounds targeting the RNA-binding protein HuR : Structure-based design, synthesis and interaction studies

The key role of RNA-binding proteins (RBPs) in regulating post-transcriptional processes and their involvement in several pathologies (i.e., cancer and neurodegeneration) have highlighted their potential as therapeutic targets. In this scenario, Embryonic Lethal Abnormal Vision (ELAV) or Hu proteins and their complexes with target mRNAs have been gaining growing attention. Compounds able to modulate the complex stability could constitute an innovative pharmacological strategy for the treatment of numerous diseases. Nevertheless, medicinal-chemistry efforts aimed at developing such compounds are still at an early stage. As part of our ongoing research in this field, we hereby present the rational design and synthesis of structurally novel HuR ligands, potentially acting as HuR-RNA interferers. The following assessment of the structural features of their interaction with HuR, combining saturation-transfer difference NMR and in silico studies, provides a guide for further research on the development of new effective interfering compounds of the HuR-RNA complex

Neoadjuvant plus adjuvant combined or sequenced vemurafenib, cobimetinib and atezolizumab in patients with high-risk, resectable BRAF-mutated and wild-type melanoma: NEO-TIM, a phase II randomized non-comparative study

Background: Following the increased survival of patients with metastatic melanoma thanks to immunotherapy and targeted therapy, neoadjuvant approaches are being investigated to address the unmet needs of unresponsive and intolerant patients. We aim to investigate the efficacy of neoadjuvant plus adjuvant combined or sequenced vemurafenib, cobimetinib and atezolizumab in patients with high-risk, resectable BRAF-mutated and wild-type melanoma. Methods: The study is a phase II, open-label, randomized non-comparative trial in patients with stage IIIB/C/D surgically resectable, BRAF-mutated and wild-type melanoma, with three possible treatments: (1) vemurafenib 960 mg twice daily from day 1 to 42; (2) vemurafenib 720 mg twice daily from day 1 to 42; (3) cobimetinib 60 mg once daily from day 1 to 21 and from day 29 to 42; and (4) atezolizumab 840 mg for two cycles (day 22 and day 43). Patients will be randomized to three different arms: A) BRAF-mutated patients will receive over 6 weeks (1) + (3); B) BRAF-mutated patients will receive over 6 weeks (2) + (3) + (4); C) BRAF wild-type patients will receive over 6 weeks (3) + (4). All patients will also receive atezolizumab 1200 mg every 3 weeks for 17 cycles after surgery and after a second screening period (up to 6 weeks). Discussion: Neoadjuvant therapy for regional metastases may improve operability and outcomes and facilitate the identification of biomarkers that can guide further lines of treatment. Patients with clinical stage III melanoma may especially benefit from neoadjuvant treatment, as the outcomes of surgery alone are very poor. It is expected that the combination of neoadjuvant and adjuvant treatment may reduce the incidence of relapse and improve survival

Sex-Based Dimorphism of Anticancer Immune Response and Molecular Mechanisms of Immune Evasion

PURPOSE: We previously demonstrated that sex influences response to immune checkpoint inhibitors. In this article, we investigate sex-based differences in the molecular mechanisms of anticancer immune response and immune evasion in patients with NSCLC. EXPERIMENTAL DESIGN: We analyzed (i) transcriptome data of 2,575 early-stage NSCLCs from seven different datasets; (ii) 327 tumor samples extensively characterized at the molecular level from the TRACERx lung study; (iii) two independent cohorts of 329 and 391 patients, respectively, with advanced NSCLC treated with anti–PD-1/anti–PD-L1 drugs. RESULTS: As compared with men, the tumor microenvironment (TME) of women was significantly enriched for a number of innate and adaptive immune cell types, including specific T-cell subpopulations. NSCLCs of men and women exploited different mechanisms of immune evasion. The TME of females was characterized by significantly greater T-cell dysfunction status, higher expression of inhibitory immune checkpoint molecules, and higher abundance of immune-suppressive cells, including cancer-associated fibroblasts, MDSCs, and regulatory T cells. In contrast, the TME of males was significantly enriched for a T-cell–excluded phenotype. We reported data supporting impaired neoantigens presentation to immune system in tumors of men, as molecular mechanism explaining the findings observed. Finally, in line with our results, we showed significant sex-based differences in the association between TMB and outcome of patients with advanced NSCLC treated with anti–PD-1/PD-L1 drugs. CONCLUSIONS: We demonstrated meaningful sex-based differences of anticancer immune response and immune evasion mechanisms, that may be exploited to improve immunotherapy efficacy for both women and men. TRANSLATIONAL RELEVANCE: It is well known that sex (i.e., the biological differences between men and women) and gender (i.e., behavioral differences associated with being male or female) are variables that affect immune responses to both foreign and selfantigens. Such sex- and gender-based dimorphism of immune system function, in turn reflects complex interactions between genes, hormones, the environment, and commensal microbiome composition. In our previous works, we showed that patients' sex is significantly associated with effectiveness of immune checkpoint inhibitors (ICIs) in patients with several solid tumors, including NSCLC. Here, we identified meaningful differences in molecular mechanisms that drive anticancer immune response as well as in immune evasion mechanisms exploited by NSCLCs arising in men and women. Importantly, we showed that all the findings reported, were not related to other variables potentially associated with sex such as patients' age, stage of disease, tumor histotype, and smoking status. The findings reported in this our work explain our previous clinical observations and can open this area to different immunotherapy strategies in males and females with NSCLC to further improve prognosis of both