Reversion of metabolic dysfunction-associated steatohepatitis by skeletal muscle-directed FGF21 gene therapy.

The highly prevalent metabolic dysfunction-associated steatohepatitis (MASH) is associated with liver steatosis, inflammation, and hepatocyte injury, which can lead to fibrosis and may progress to hepatocellular carcinoma and death. New treatment modalities such as gene therapy may be transformative for MASH patients. Here, we describe that one-time intramuscular administration of adeno-associated viral vectors of serotype 1 (AAV1) encoding native fibroblast growth factor 21 (FGF21), a key metabolic regulator, resulted in sustained increased circulating levels of the factor, which mediated long-term (>1 year) MASH and hepatic fibrosis reversion and halted development of liver tumors in obese male and female mouse models.

Spatially Preserved Multi-Region Transcriptomic Subtyping and Biomarkers of Chemoimmunotherapy Outcome in Extensive-Stage Small Cell Lung Cancer.

Purpose: Transcriptomic subtyping holds promise for personalized therapy in extensive-stage small cell lung cancer (ES-SCLC). In this study, we aimed to assess intratumoral transcriptomic subtype diversity and to identify biomarkers of long-term chemoimmunotherapy benefit in human ES-SCLC.

Experimental Design: We analyzed tumor samples from 58 patients with ES-SCLC enrolled in two multicenter single-arm phase IIIb studies evaluating frontline chemoimmunotherapy in Spain: n = 32 from the IMfirst trial and n = 26 from the CANTABRICO trial.

The S-REAL study: Spanish real-world data on unresectable stage III NSCLC patients treated with durvalumab after chemoradiotherapy.

Objectives: The S-REAL study aimed to assess the effectiveness of durvalumab as consolidation therapy after definitive chemoradiotherapy (CRT) in a real-world cohort of patients with locally advanced, unresectable stage III non-small cell lung cancer (LA-NSCLC) included in a Spanish early access program (EAP).

Methods: In this multicentre, observational, retrospective study we analysed data from patients treated in 39 Spanish hospitals, who started intravenous durvalumab (10 mg/kg every 2 weeks) between September 2017 and December 2018. The primary endpoint was progression-free survival (PFS).

Treatment of infantile-onset Pompe disease in a rat model with muscle-directed AAV gene therapy.

Objective: Pompe disease (PD) is caused by deficiency of the lysosomal enzyme acid α-glucosidase (GAA), leading to progressive glycogen accumulation and severe myopathy with progressive muscle weakness. In the Infantile-Onset PD (IOPD), death generally occurs <1 year of age. There is no cure for IOPD.

Teleoncology: A Solution for Everyone? A Single-Center Experience with Telemedicine during the Coronavirus Disease 2019 (COVID-19) Pandemic.

Since the beginning of the COVID-19 pandemic, the use of telehealth was rapidly implemented without previous evidence. The ONCOTELEMD study aimed to evaluate the opinion of patients attended via telemedicine during this period and to study factors that condition patient preferences on its use. Included patients had a confirmed cancer diagnosis and were contacted by telephone between 13 March and 30 April 2020, in the Medical Oncology Service of Hospital Parc Taulí, Sabadell.

"High Tumor Burden" in Metastatic Non-Small Cell Lung Cancer: Defining the Concept.

Purpose: Identifying patient characteristics that define a worse disease prognosis or "high tumor burden" (HTB) status is essential for clinical decision-making and treatment selection in metastatic non-small cell lung cancer (mNSCLC). We aimed to define this concept based on the experience of oncologists in clinical practice.

Patients And Methods: A representative sample of Spanish experts was selected and asked to complete an online survey regarding the definition of HTB according to their personal experience.

Vitamin D Receptor Overexpression in β-Cells Ameliorates Diabetes in Mice.

Vitamin D deficiency has been associated with increased incidence of diabetes, both in humans and in animal models. In addition, an association between vitamin D receptor (VDR) gene polymorphisms and diabetes has also been described. However, the involvement of VDR in the development of diabetes, specifically in pancreatic β-cells, has not been elucidated yet.

Treatment in esophagogastric junction cancer: Past, present and future.

Adenocarcinomas of the gastroesophageal junction represent 27% of all gastric tumors. n recent years, it has been classified as an entity of its own, with specific treatments that are sometimes differentiated from gastric treatments. Treatment can be based on chemotherapy (CTx) or chemoradiotherapy (CRTx) that is administered preoperatively (neoadjuvant), postoperatively (adjuvant) or perioperatively.

A Single-Center Retrospective Study of Patients with Double Primary Cancers: Breast Cancer and EGFR-Mutant Non-Small Cell Lung Cancer.

Background: Second primary malignancies (SPM) in the lung are not common in breast cancer (BC) patients. EGFR-mutant lung cancer (LC) is a separate molecular subset, and the co-existence of EGFR-mutant LC and BC has not been explored. We hypothesized that EGFR-mutant LC patients could have higher rates of primary BC than those with EGFR-wild type (WT).

IDH mutation status trumps the Pignatti risk score as a prognostic marker in low-grade gliomas.

Management of low-grade gliomas (LGG) is based on clinical and radiologic features, including the Pignatti prognostic scoring system, which classifies patients as low- or high-risk. To determine whether molecular data can offer advantages over these features, we have examined the prognostic impact of several molecular alterations in LGG. In a cohort of 58 patients with LGG, we have retrospectively analyzed clinical and molecular characteristics, including the Pignatti criteria, IDH mutations, TP53 mutations, the 1p/19q deletion, and MGMT methylation, and correlated our findings with progression-free survival (PFS) and overall survival (OS).

AAV-mediated pancreatic overexpression of counteracts progression to autoimmune diabetes in mice.

Objective: Type 1 diabetes is characterized by autoimmune destruction of β-cells leading to severe insulin deficiency. Although many improvements have been made in recent years, exogenous insulin therapy is still imperfect; new therapeutic approaches, focusing on preserving/expanding β-cell mass and/or blocking the autoimmune process that destroys islets, should be developed. The main objective of this work was to test in non-obese diabetic (NOD) mice, which spontaneously develop autoimmune diabetes, the effects of local expression of Insulin-like growth factor 1 (IGF1), a potent mitogenic and pro-survival factor for β-cells with immunomodulatory properties.

AAV-mediated overexpression in skeletal muscle activates oxidative capacity but does not prevent insulin resistance.

Type 2 diabetes is characterized by triglyceride accumulation and reduced lipid oxidation capacity in skeletal muscle. SIRT1 is a key protein in the regulation of lipid oxidation and its expression is reduced in the skeletal muscle of insulin resistant mice. In this tissue, up-regulates the expression of genes involved in oxidative metabolism and improves mitochondrial function mainly through PPARGC1 deacetylation.

Resistant mechanisms to BRAF inhibitors in melanoma.

Patients with advanced melanoma have traditionally had very poor prognosis. However, since 2011 better understanding of the biology and epidemiology of this disease has revolutionized its treatment, with newer therapies becoming available. These newer therapies can be classified into immunotherapy and targeted therapy.

Outcome prognostic factors in inoperable malignant bowel obstruction.

Purpose: Inoperable malignant bowel obstruction (MBO), a severe complication of peritoneal carcinomatosis, has a low desobstruction rate (30-40 %) and end-of-life decision-making is hampered by the lack of known prognostic factors. This study aimed to explore prognostic factors for desobstruction in MBO.

Methods: All patients with inoperable MBO admitted in our large oncology hospital between 2010 and 2013 were treated following a clinical protocol based on antiemetics, steroids and two antisecretories, octreotide, and hyoscine butylbromide.

Insulin-like Growth Factor 2 Overexpression Induces β-Cell Dysfunction and Increases Beta-cell Susceptibility to Damage.

The human insulin-like growth factor 2 (IGF2) and insulin genes are located within the same genomic region. Although human genomic studies have demonstrated associations between diabetes and the insulin/IGF2 locus or the IGF2 mRNA-binding protein 2 (IGF2BP2), the role of IGF2 in diabetes pathogenesis is not fully understood. We previously described that transgenic mice overexpressing IGF2 specifically in β-cells (Tg-IGF2) develop a pre-diabetic state.

The epidermal growth factor receptor (EGRF) in lung cancer.

In the last decade, important advances have been made in understanding of cancer biology, particularly non-small-cell lung cancer (NSCLC) with the discovery of oncogenic drivers of the disease. The epidermal growth factor receptor (EGFR) gene and its pathways was the first oncogenic driver discovered to be mutated and treatable in lung cancer. Treatment with EGFR tyrosine kinase inhibitors (TKIs) is the standard of care for molecularly selected EGFR-mutant patients, while its role in unselected lung cancer patients is nowadays controversial.

AAV8-mediated Sirt1 gene transfer to the liver prevents high carbohydrate diet-induced nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common hepatic disease worldwide, and evidence suggests that it promotes insulin resistance and type 2 diabetes. Caloric restriction (CR) is the only available strategy for NAFLD treatment. The protein deacetylase Sirtuin1 (SIRT1), which is activated by CR, increases catabolic metabolism and decreases lipogenesis and inflammation, both involved in the development of NAFLD.

Metabolic alterations and increased liver mTOR expression precede the development of autoimmune disease in a murine model of lupus erythematosus.

Although metabolic syndrome (MS) and systemic lupus erythematosus (SLE) are often associated, a common link has not been identified. Using the BWF1 mouse, which develops MS and SLE, we sought a molecular connection to explain the prevalence of these two diseases in the same individuals. We determined SLE- markers (plasma anti-ds-DNA antibodies, splenic regulatory T cells (Tregs) and cytokines, proteinuria and renal histology) and MS-markers (plasma glucose, non-esterified fatty acids, triglycerides, insulin and leptin, liver triglycerides, visceral adipose tissue, liver and adipose tissue expression of 86 insulin signaling-related genes) in 8-, 16-, 24-, and 36-week old BWF1 and control New-Zealand-White female mice.

Adipose tissue overexpression of vascular endothelial growth factor protects against diet-induced obesity and insulin resistance.

During the expansion of fat mass in obesity, vascularization of adipose tissue is insufficient to maintain tissue normoxia. Local hypoxia develops and may result in altered adipokine expression, proinflammatory macrophage recruitment, and insulin resistance. We investigated whether an increase in adipose tissue angiogenesis could protect against obesity-induced hypoxia and, consequently, insulin resistance.

Reduction of liver fructokinase expression and improved hepatic inflammation and metabolism in liquid fructose-fed rats after atorvastatin treatment.

Consumption of beverages that contain fructose favors the increasing prevalence of metabolic syndrome alterations in humans, including non-alcoholic fatty liver disease (NAFLD). Although the only effective treatment for NAFLD is caloric restriction and weight loss, existing data show that atorvastatin, a hydroxymethyl-glutaryl-CoA reductase inhibitor, can be used safely in patients with NAFLD and improves hepatic histology. To gain further insight into the molecular mechanisms of atorvastatin's therapeutic effect on NAFLD, we used an experimental model that mimics human consumption of fructose-sweetened beverages.

Liver AMP/ATP ratio and fructokinase expression are related to gender differences in AMPK activity and glucose intolerance in rats ingesting liquid fructose.

Women, but not men, show an association between fructose consumption and an increased risk of Type 2 diabetes mellitus. As rats are considered a model for human fructose metabolism, we sought to determine whether such a gender-related difference is present in Sprague-Dawley rats and to analyze the molecular mechanism behind. Male and female Sprague-Dawley rats had free access to water or to a 10% w/v fructose solution for 14 days.

Hepatic gene expression changes in an experimental model of accelerated senescence: the SAM-P8 mouse.

The senescence-accelerated mouse (SAM) is an experimental model of aging, established through phenotypic selection from a common genetic pool of AKR/J mice. Here we use complementary DNA microarray, Western blot, and electrophoretic mobility shift assay to consider whether changes in liver gene expression observed in 5-month-old SAM-prone 8 (P8) mice, compared to SAM-R1 controls, are similar to those reported in aged rodents. Livers from SAM-P8 mice presented 88 differentially expressed transcripts, 59% of which were upregulated and 41% were downregulated.