The Epithelial to Mesenchymal Transition in Colorectal Cancer Progression: The Emerging Role of Succinate Dehydrogenase Alterations and Succinate Accumulation.

Colorectal cancer (CRC) stands as the third most significant contributor to cancer-related mortality worldwide. A major underlying reason is that the detection of CRC usually occurs at an advanced metastatic stage, rendering therapies ineffective. In the progression from the in situ neoplasia stage to the advanced metastatic stage, a critical molecular mechanism involved is the epithelial-to-mesenchymal transition (EMT). This intricate transformation consists of a series of molecular changes, ultimately leading the epithelial cell to relinquish its features and acquire mesenchymal and stem-like cell characteristics. The EMT regulation involves several factors, such as transcription factors, cytokines, micro RNAs and long noncoding RNAs. Nevertheless, recent studies have illuminated an emerging link between metabolic alterations and EMT in various types of cancers, including colorectal cancers. In this review, we delved into the pivotal role played by EMT during CRC progression, with a focus on highlighting the relationship between the alterations of the tricarboxylic acid cycle, specifically those involving the succinate dehydrogenase enzyme, and the activation of the EMT program. In fact, emerging evidence supports the idea that elucidating the metabolic modifications that can either induce or inhibit tumor progression could be of immense significance for shaping new therapeutic approaches and preventative measures. We conclude that an extensive effort must be directed towards research for the standardization of drugs that specifically target proteins such as SDH and SUCNR1, but also TRAP1, PDH, ERK1/2, STAT3 and the HIF1-α catabolism.

Germline Variants in MLH1 and ATM Genes in a Young Patient with MSI-H in a Precancerous Colonic Lesion.

Lynch syndrome (LS) is an autosomal dominant inherited disorder that primarily predisposes individuals to colorectal and endometrial cancer. It is associated with pathogenic variants in DNA mismatch repair (MMR) genes. In this study, we report the case of a 16-year-old boy who developed a precancerous colonic lesion and had a clinical suspicion of LS. The proband was found to have a somatic MSI-H status. Analysis of the coding sequences and flanking introns of the MLH1 and MSH2 genes by Sanger sequencing led to the identification of the variant of uncertain significance, namely, c.589-9_589-6delGTTT in the MLH1 gene. Further investigation revealed that this variant was likely pathogenetic. Subsequent next-generation sequencing panel analysis revealed the presence of two variants of uncertain significance in the ATM gene. We conclude that the phenotype of our index case is likely the result of a synergistic effect of these identified variants. Future studies will allow us to understand how risk alleles in different colorectal-cancer-prone genes interact with each other to increase an individual's risk of developing cancer.

Sporadic pediatric severe familial adenomatous polyposis: A case report.

Familial adenomatous polyposis (FAP) is an autosomal dominant hereditary precancerous condition caused by germline pathogenetic variants in the tumor suppressor adenomatous polyposis coli (APC) gene. Patients with FAP develop multiple gastrointestinal adenomatous polyps usually at the age of ~20 years, which, if untreated, become cancerous in 100% of cases. Genotype-phenotype associations have been extensively described; however, inter- and intra-familial variability exists. It is crucial to characterize the causative pathogenetic variant in each pedigree in order to develop a cancer prevention program and follow-up strategy for at-risk families. The present report describes a severe case of sporadic FAP that was diagnosed when the patient was ~2 years old. The patient was a carrier of the de novo pathogenic c.4132 C>T (p.Gln1378X) variant. Additionally, the patient was a carrier of the homozygous c.5465 T>A (p.Asp1822Val) polymorphism, inherited from both parents. However, it remains unclear whether or not this polymorphism is involved in the phenotypic manifestation. This case highlights the need to extend molecular screening to very young children when they show iron-deficiency, anaemia and/or rectal bleeding, even in the absence of a familial history of disease.

Impact of domestic and sexual violence on women's health / Violência doméstica e sexual em mulheres e suas repercussões na fase do climatério

INTRODUCTION: domestic violence and, particularly, sex can result in higher incidence of comorbidities in the climacteric. OBJECTIVE: to assess the effects of menopause on sexual and domestic violence. METHODS: sectional study in 124 postmenopausal women between 40 and 65, who suffered domestic violence and / or sexual, and a control group (124) composed (climacteric women who did not suffer violence) (N=120). Those who exposed to violence were divided into three groups 1 violence experienced in childhood and adolescence 2- adult phase 3- both phases. Subsequently a questionnaire on domestic and sexual violence was applied.Correlation was established for the intensity of climacteric symptoms measured with Menopausal Kupperman Index (MKI), type of violence experienced, stage of life exposesd to violence comorbidities during menopause, and women's perceptions about the quality of assistance received from the various professionals after the traumatic events. In the control group MKI and number of comorbidities were evaluated. RESULTS: those who have experienced violence in childhood/adolescence have average of 5.1 comorbidities; adulthood 4.6, and 4.4 in both phases, with a median of 5.0 in all phases, without violence (control) 2.8. The victims of sexual violence have more comorbidities compared those who underwent other types of violence. There were significant associations between having suffered any kind of violence in both phases and MKI serious and have suffered sexual violence at any stage of life, and MKI at least moderate. CONCLUSION: women who have experienced domestic and sexual violence have more comorbidities and MKI high compared to the control group.(AU)

INTRODUÇÃO: a violência doméstica e, particularmente, a sexual pode implicar em maior ocorrência de comorbidades no climatério. OBJETIVO: avaliar as repercussões no climatério da violência domestica e sexual. MÉTODO: estudo transversal em 124 mulheres menopausadas, entre 40 e 65 anos, que sofreram violência doméstica e/ou sexual, e um grupo controle (mulheres na menopausa que não sofreram violência n=120). As expostas à violência foram divididas em três grupos: 1-violência sofrida na infância e/ou adolescência, 2-fase adulta, 3-ambas as fases, e aplicou-se questionário sobre violência doméstica e sexual. Correlacionou-se a intensidade dos sintomas climatéricos medido pelo Índice Menopausal de Kupperman (IK), tipo de violência sofrida, fase da vida exposta à violência, comorbidades apresentadas no climatério e percepções da mulher sobre a forma com que os diversos profissionais acolheram ou não nos eventos traumáticos. No grupo controle avaliamos IK e numero de comorbidades. RESULTADOS: aquelas que sofreram violência na infância/adolescência apresentam media de 5,1 comorbidades; na fase adulta 4,6; e em ambas as fases 4,4, com mediana de 5,0 em todas as fases; sem violência (controle) 2,8. As que sofreram violência sexual apresentam mais comorbidades em relação aquelas que sofreram outros tipos de violência. Houve associações significativas entre ter sofrido qualquer tipo de violência em ambas às fases e IK grave e ter sofrido violência sexual em qualquer fase da vida, e IK no mínimo moderado. CONCLUSÃO: mulheres que sofreram violência doméstica e sexual apresentam mais comorbidades e IK elevado em relação ao grupo controle.(AU)

Violência doméstica e sexual em mulheres e suas repercussões na fase do climatério / Impact of domestic and sexual violence on women's health

INTRODUÇÃO: a violência doméstica e, particularmente, a sexual pode implicar em maior ocorrência de comorbidades no climatério. OBJETIVO: avaliar as repercussões no climatério da violência domestica e sexual. MÉTODO: estudo transversal em 124 mulheres menopausadas, entre 40 e 65 anos, que sofreram violência doméstica e/ou sexual, e um grupo controle (mulheres na menopausa que não sofreram violência n=120). As expostas à violência foram divididas em três grupos: 1-violência sofrida na infância e/ou adolescência, 2-fase adulta, 3-ambas as fases, e aplicou-se questionário sobre violência doméstica e sexual. Correlacionou-se a intensidade dos sintomas climatéricos medido pelo Índice Menopausal de Kupperman (IK), tipo de violência sofrida, fase da vida exposta à violência, comorbidades apresentadas no climatério e percepções da mulher sobre a forma com que os diversos profissionais acolheram ou não nos eventos traumáticos. No grupo controle avaliamos IK e numero de comorbidades. RESULTADOS: aquelas que sofreram violência na infância/adolescência apresentam media de 5,1 comorbidades; na fase adulta 4,6; e em ambas as fases 4,4, com mediana de 5,0 em todas as fases; sem violência (controle) 2,8. As que sofreram violência sexual apresentam mais comorbidades em relação aquelas que sofreram outros tipos de violência. Houve associações significativas entre ter sofrido qualquer tipo de violência em ambas às fases e IK grave e ter sofrido violência sexual em qualquer fase da vida, e IK no mínimo moderado. CONCLUSÃO: mulheres que sofreram violência doméstica e sexual apresentam mais comorbidades e IK elevado em relação ao grupo controle.