Perfil clínico, etiologia e escalas de avaliação funcional de pacientes com insuficiência cardíaca avançada: alocação para abordagem paliativa e desfechos hospitalares / Clinical profile, etiology and functional assessment scales of patients with advanced heart failure: allocation for palliative approach and hospital outcomes

INTRODUÇÃO: No conceito do Continuo da Doença Cardiovascular, a sequência de eventos seria iniciada por vários fatores de riscos progredindo por vias e processos fisiopatológicos até o desenvolvimento da lesão cardíaca final, no caso a Insuficiência Cardíaca (IC) em fase avançada. Cuidado Paliativo (CP) é uma abordagem interdisciplinar de tratamento que se concentra em melhorar a qualidade de vida dos pacientes nos diferentes estágios da IC.O racional para implementação de CP com planejamento avançado de cuidados por toda a progressão da doença e no luto , em pacientes com IC avançada ,inclui os seguintes: prognóstico limitado , elevada carga de sintomas , rehospitalizações, baixa qualidade de vida, comorbidades e estresse dos cuidadores OBJETIVOS: Caracterizar o perfil clínico dos pacientes cardiopatas incluídos para abordagem paliativa (AP), associado ao tratamento farmacológico da IC. MÉTODOS: Análise de 116 pacientes com IC incluídos para uma AP, entre fevereiro de 2017 a dezembro de 2018. RESULTADOS: Idade média de 74±12,7 anos, com 54% do sexo masculino. Diagnósticos etiológicos da miocardiopatia: incluíram: isquêmica 27%, valvar 25%, arritmogênica 13%, hipertensiva 8,6%, chagásica 8,6% e congênita 2,5%. Diagnósticos mas relevantes no momento da AP foram: insuficiência renal 78%, choque séptico 39,6%, IC 41,4%, choque cardiogênico 30,1%, acidente vascular cerebral 18,1% e pós parada cardiorrespiratória 9,4%, a média de fração de ejeção do VE por ecocardiograma 40%±16,5%. Performances nas atividades cotidianas: 64,6% com dependência total na escala Kartz, 37,9% com necessidade de suporte de vida na escala Karnofsky e 34,5% com alta dependência de cuidados pela Palliative Performance Scala. O intervalo de tempo entre a hospitalização e o óbito vario entre 3 e 405 dias (média de 29 dias). O intervalo de tempo entre a internação e a solicitação e indicação de uma AP variou entre 1 a 177 dias(média de 15 dias). Desfechos clínicos: 12% receberam alta hospitalar, e 7,7% estão em seguimento clínico. CONCLUSÃO: Os pacientes alocados e incluídos no programa de AP encontravam-se em estádios avançado da IC, em fase final de vida, mostrando que a AP foi iniciada tardiamente, caracterizado pelo tempo prolongado de internação , alta dependência de cuidados. DESCRITORES: Cuidados Paliativos, Cardiologia, Cuidados Paliativos na fase final de vida, Insuficiência Cardíaca. (AU)

Proteomic screening identifies calreticulin as a miR-27a direct target repressing MHC class I cell surface exposure in colorectal cancer.

Impairment of the immune response and aberrant expression of microRNAs are emerging hallmarks of tumour initiation/progression, in addition to driver gene mutations and epigenetic modifications. We performed a preliminary survey of independent adenoma and colorectal cancer (CRC) miRnoma data sets and, among the most dysregulated miRNAs, we selected miR-27a and disclosed that it is already upregulated in adenoma and further increases during the evolution to adenocarcinoma. To identify novel genes and pathways regulated by this miRNA, we employed a differential 2DE-DIGE proteome analysis. We showed that miR-27a modulates a group of proteins involved in MHC class I cell surface exposure and, mechanistically, demonstrated that calreticulin is a miR-27a direct target responsible for most downstream effects in epistasis experiments. In vitro miR-27a affected cell proliferation and angiogenesis; mouse xenografts of human CRC cell lines expressing different miR-27a levels confirmed the protein variations and recapitulated the cell growth and apoptosis effects. In vivo miR-27a inversely correlated with MHC class I molecules and calreticulin expression, CD8(+) T cells infiltration and cytotoxic activity (LAMP-1 exposure and perforin release). Tumours with high miR-27a, low calreticulin and CD8(+) T cells' infiltration were associated with distant metastasis and poor prognosis. Our data demonstrate that miR-27a acts as an oncomiRNA, represses MHC class I expression through calreticulin downregulation and affects tumour progression. These results may pave the way for better diagnosis, patient stratification and novel therapeutic approaches.

UHRF1 coordinates peroxisome proliferator activated receptor gamma (PPARG) epigenetic silencing and mediates colorectal cancer progression.

Peroxisome proliferator-activated receptor gamma (PPARG) inactivation has been identified as an important step in colorectal cancer (CRC) progression, although the events involved have been partially clarified. UHRF1 is emerging as a cofactor that coordinates the epigenetic silencing of tumor suppressor genes, but its role in CRC remains elusive. Here, we report that UHRF1 negatively regulates PPARG and is associated with a higher proliferative, clonogenic and migration potential. Consistently, UHRF1 ectopic expression induces PPARG repression through its recruitment on the PPARG promoter fostering DNA methylation and histone repressive modifications. In agreement, UHRF1 knockdown elicits PPARG re-activation, accompanied by positive histone marks and DNA demethylation, corroborating its role in PPARG silencing. UHRF1 overexpression, as well as PPARG-silencing, imparts higher growth rate and phenotypic features resembling those occurring in the epithelial-mesenchymal transition. In our series of 110 sporadic CRCs, high UHRF1-expressing tumors are characterized by an undifferentiated phenotype, higher proliferation rate and poor clinical outcome only in advanced stages III-IV. In addition, the inverse relationship with PPARG found in vitro is detected in vivo and UHRF1 prognostic significance appears closely related to PPARG low expression, as remarkably validated in an independent dataset. The results demonstrate that UHRF1 regulates PPARG silencing and both genes appear to be part of a complex regulatory network. These findings suggest that the relationship between UHRF1 and PPARG may have a relevant role in CRC progression.

Mature teratoma, a rare cause of virilization in adolescence.

Virilization in an adolescent patient can occur for multiple reasons (ovarian, suprarenal or exogenous reasons). We describe a 14-year-old patient with 1-year secondary amenorrhea, who had an ovarian mature teratoma as a cause of her clinical history.

A novel germline mutation in peroxisome proliferator-activated receptor gamma gene associated with large intestine polyp formation and dyslipidemia.

We report a novel PPARG germline mutation in a patient affected by colorectal cancer that replaces serine 289 with cysteine in the mature protein (S289C). The mutant has impaired transactivation potential and acts as dominant negative to the wild type receptor. In addition, it no longer restrains cell proliferation both in vitro and in vivo. Interestingly, the S289C mutant poorly activates target genes and interferes with the inflammatory pathway in tumor tissues and proximal normal mucosa. Consistently, only mutation carriers exhibit colonic lesions that can evolve to dysplastic polyps. The proband presented also dyslipidemia, hypertension and overweight, not associated to type 2 diabetes; of note, family members tested positive for the mutation and display only a dyslipidemic profile at variable penetrance with other biochemical parameters in the normal range. Finally, superimposing the mutation to the crystal structure of the ligand binding domain, the new Cys289 becomes so closely positioned to Cys285 to form an S-S bridge. This would reduce the depth of the ligand binding pocket and impede agonist positioning, explaining the biological effects and subcellular distribution of the mutant protein. This is the first PPARG germline mutation associated with dyslipidemia and colonic polyp formation that can progress to full-blown adenocarcinoma.

[The electrical discharge of Torpedo marmorata under normal conditions and during hypoxia and anoxia. I]. / La scarica eletrica di Torpedo marmorata in condizioni normali, di ipossia e di anossia. Prima nota.

The electric discharge of Torpedo M. can be considered as an index of the metabolic activity of the electric lobe of C.N.S. In groups of 10 Torpedoes the electric charge was measured: the mechanical stimulus was obtained by the falling of different weights from a determinate height. The experiment was then repeated in conditions of hypoxia: a fall of the electric discharge values was observed. The experiment was also carried out considering the time: after 14 hours the condition of anoxia occurred.

[Effects of dihydrodinoreburnameninol on the electrical discharge of Torpedo marmorata under normal conditions and during hypoxia and anoxia. I]. / Effetto del dihydrodinoreburnameninol sulla scarica elettrica di Torpedo marmorata in condizioni normali, di ipossia e di anossia. Prima nota.

The electric discharge of Torpedo M. can be considered as an index of the metabolic activity of the electric lobe of C.N.S. in groups of 10 torpedo the electric discharge was measured: the mechanical stimulus was obtained by the falling of different weights from a determinate height. Other 10 animals, to which the substance was administered, showed an increase of the electric discharge. The experiment was then repeated in conditions of hypoxia: a fall of the values of the electric discharge was observed. Finally the experiment was carried out considering the time: after 14 hours the condition of anoxia occurred.

[Protection furnished by dihydrodinoreburnameninol on the electrical activity of Torpedo marmorata kept in water polluted by copper. I]. / Protezione esercitata dal dihydrodinoreburnameninol sull'attivita' elettrica di Torpedo marmorata stabulate in condizioni di inquinamento da rame. Prima nota.

Studies carried out on neurons of Torpedo M. showed that copper creates an action of cellular damage inducing the synthesis of free radicals. Two groups of Torpedo, one for the control and the other one treated with dihydrodinoreburnameninol, were kept in sea water containing CuCl2. Then the measurement of the electric discharge was made: it was observed a clear dicrease in the Torpedo kept in conditions of pollution from copper, while the administration of dihydrodinoreburnameninol showed a protective action on the damaging effects.