STARD3: A new potential therapeutic target in colorectal cancer

Colorectal cancer (CRC) is the third leading cause of cancer death in Europe, with a prevalence of more than a million cases every year. Primary or acquired resistances to therapies are the major limits to be addressed. The overall five years survival rate is less than 10% for stage IV and only a fraction of the tumours respond to available therapies (Van Der Jeught et al., 2018). There is a crucial need for new therapeutic biomarkers to avoid CRC-related deaths (Vacante et al., 2018). In this scenario, cholesterol metabolism has received increasing attention due to its role in cancer development. Cancer cells show higher levels of intracellular cholesterol compared to normal cells. Tumour cells require high amounts of lipids, nucleic acids and proteins for their survival. Cancer cells increase the de novo lipid biosynthesis including cholesterol synthesis (Currie et al., 2013). Cellular cholesterol metabolism, including intracellular distribution, is highly coordinated and controlled by a complex protein network. Between them, StAR-related lipid transfer domain-3 (STARD3) regulates the cholesterol accumulation in endosomes and mediates its inter-organelle distribution.There are different studies suggesting STARD3 is associated with several cancer types: STARD3 is highly expressed in 25% cases of breast carcinoma and high STARD3 levels have been correlated with poor overall survival, disease metastasis-free survival and relapse-free survival (Vassilev, B et al., 2015); and it is associated with shorter patient survival in colon, liver and renal cancer patients (Protein Atlas).This research project aims to demonstrate STARD3 is a valid therapeutic target for colorectal cancer patients. we identified STARD3 as a key player, which regulates different aspects of hallmark of cancer. Our hypothesis is that STARD3 is a valid therapeutic target for mCRC patients. This hypothesis is based on the following thesis results here summarized: a) STARD3 is overexpressed in CRC tumors tissue compared to normal tissue and correlate with patient's survival. b) Despite cancer cells contain complex genetic alterations, growth and survival can be affected by STARD3 single inactivation. c) Inhibition of STARD3 (both with short hairpins and drugs) induces apoptosis in colorectal cancer cell lines and in a subset of patient derived organoids and inhibit tumor formation in vivo. d) STARD3 overexpression transforms normal mouse colon organoids, inducing tumour formation in vivo (oncogene).Colorectal cancer (CRC) is the third leading cause of cancer death in Europe, with a prevalence of more than a million cases every year. Primary or acquired resistances to therapies are the major limits to be addressed. The overall five years survival rate is less than 10% for stage IV and only a fraction of the tumours respond to available therapies (Van Der Jeught et al., 2018). There is a crucial need for new therapeutic biomarkers to avoid CRC-related deaths (Vacante et al., 2018). In this scenario, cholesterol metabolism has received increasing attention due to its role in cancer development. Cancer cells show higher levels of intracellular cholesterol compared to normal cells. Tumour cells require high amounts of lipids, nucleic acids and proteins for their survival. Cancer cells increase the de novo lipid biosynthesis including cholesterol synthesis (Currie et al., 2013). Cellular cholesterol metabolism, including intracellular distribution, is highly coordinated and controlled by a complex protein network. Between them, StAR-related lipid transfer domain-3 (STARD3) regulates the cholesterol accumulation in endosomes and mediates its inter-organelle distribution.There are different studies suggesting STARD3 is associated with several cancer types: STARD3 is highly expressed in 25% cases of breast carcinoma and high STARD3 levels have been correlated with poor overall survival, disease metastasis-free survival and relapse-free survival (Vassilev, B et al., 2015); and it is associated with shorter patient survival in colon, liver and renal cancer patients (Protein Atlas).This research project aims to demonstrate STARD3 is a valid therapeutic target for colorectal cancer patients. we identified STARD3 as a key player, which regulates different aspects of hallmark of cancer. Our hypothesis is that STARD3 is a valid therapeutic target for mCRC patients. This hypothesis is based on the following thesis results here summarized: a) STARD3 is overexpressed in CRC tumors tissue compared to normal tissue and correlate with patient's survival. b) Despite cancer cells contain complex genetic alterations, growth and survival can be affected by STARD3 single inactivation. c) Inhibition of STARD3 (both with short hairpins and drugs) induces apoptosis in colorectal cancer cell lines and in a subset of patient derived organoids and inhibit tumor formation in vivo. d) STARD3 overexpression transforms normal mouse colon organoids, inducing tumour formation in vivo (oncogene)

Robotic versus laparoscopic approach in colonic resections for cancer and Benign diseases. Systematic review and meta-analysis

Objectives The aim of this systematic review and meta-Analysis is to compare robotic colectomy (RC) with laparoscopic colectomy (LC) in terms of intraoperative and postoperative outcomes. Materials and Methods A systematic literature search was performed to retrieve comparative studies of robotic and laparoscopic colectomy. The databases searched were PubMed, Embase and the Cochrane Central Register of Controlled Trials from January 2000 to October 2014. The Odds ratio, Risk difference and Mean difference were used as the summary statistics. Results A total of 12 studies, which included a total of 4,148 patients who had undergone robotic or laparoscopic colectomy, were included and analyzed. RC demonstrated a longer operative time (MD 41.52, P<0.00001) and higher cost (MD 2.42, P<0.00001) than did LC. The time to first flatus passage (MD-0.51, P = 0.003) and the length of hospital stay (MD-0.68, P = 0.01) were significantly shorter after RC. Additionally, the intraoperative blood loss (MD-16.82, P<0.00001) was significantly less in RC. There was also a significantly lower incidence of overall postoperative complications (OR 0.74, P = 0.02) and wound infections (RD-0.02, P = 0.03) after RC. No differences in the postoperative ileus, in the anastomotic leak, or in the conversion to open surgery rate and in the number of harvested lymph nodes outcomes were found between the approaches. Conclusions The present meta-Analysis, mainly based on observational studies, suggests that RC is more time-consuming and expensive than laparoscopy but that it results in faster recovery of bowel function, a shorter hospital stay, less blood loss and lower rates of both overall postoperative complications and wound infections. Copyright: © 2015 Trastulli et al.OBJECTIVES: The aim of this systematic review and meta-analysis is to compare robotic colectomy (RC) with laparoscopic colectomy (LC) in terms of intraoperative and postoperative outcomes. MATERIALS AND METHODS: A systematic literature search was performed to retrieve comparative studies of robotic and laparoscopic colectomy. The databases searched were PubMed, Embase and the Cochrane Central Register of Controlled Trials from January 2000 to October 2014. The Odds ratio, Risk difference and Mean difference were used as the summary statistics. RESULTS: A total of 12 studies, which included a total of 4,148 patients who had undergone robotic or laparoscopic colectomy, were included and analyzed. RC demonstrated a longer operative time (MD 41.52, P<0.00001) and higher cost (MD 2.42, P<0.00001) than did LC. The time to first flatus passage (MD -0.51, P = 0.003) and the length of hospital stay (MD -0.68, P = 0.01) were significantly shorter after RC. Additionally, the intraoperative blood loss (MD -16.82, P<0.00001) was significantly less in RC. There was also a significantly lower incidence of overall postoperative complications (OR 0.74, P = 0.02) and wound infections (RD -0.02, P = 0.03) after RC. No differences in the postoperative ileus, in the anastomotic leak, or in the conversion to open surgery rate and in the number of harvested lymph nodes outcomes were found between the approaches. CONCLUSIONS: The present meta-analysis, mainly based on observational studies, suggests that RC is more time-consuming and expensive than laparoscopy but that it results in faster recovery of bowel function, a shorter hospital stay, less blood loss and lower rates of both overall postoperative complications and wound infections

NF-kappaB activation is associated with homocysteine-induced injury in Neuro2a cells

<p>Abstract</p> <p>Background</p> <p>Perinatal exposure to hyperhomocysteinemia might disturb neurogenesis during brain development and growth. Also, high levels of homocysteine trigger neurodegeneration in several experimental models. However, the putative mechanisms of homocysteine-induced toxicity in the developing nervous system have poorly been elucidated. This study was aimed to investigate homocysteine effects in undifferentiated neuroblastoma cells, Neuro2a.</p> <p>Results</p> <p>A 4 h exposure to homocysteine in a concentration range of 10–100 μM did not affect cell viability and ROS production in Neuro2a cell cultures. Instead, ROS levels were increased by two-three folds in cells treated with 250 μM and 500 μM homocysteine, respectively, in comparison with control cells. Also, the highest homocysteine dose significantly reduced the viable cell number by 40%. Notably, the treatment with homocysteine (250 μM–500 μM) in the presence of antioxidants, such as N-acetylcysteine and IRFI 016, a synthetic α-tocopherol analogue, recovered cell viability and significantly reduced homocysteine-evoked increases in ROS production. Moreover, antioxidants, particularly IRFI 016, were able to counteract NF-κB activation induced by 250 μM homocysteine.</p> <p>Cell treatment with 250 μM homocysteine also triggered the onset of apoptosis, as demonstrated by the increased expression of early apoptotic markers such as Bax, caspase-3 and p53. In contrast, Bcl2 expression was not affected by homocysteine exposure. Interestingly, the specific inhibition of NF-κB nuclear translocation by the synthetic peptide SN50 was able to almost completely suppress the homocysteine-evoked rises in pro-apoptotic protein expression as well as in caspase-3 activity. Further, also IRFI 016 and N-acetylcysteine were able to significantly reduce caspase-3 activation induced by homocysteine treatment.</p> <p>Conclusion</p> <p>These observations suggest an involvement of redox state alterations and activated NF-κB in apoptosis onset triggered by homocysteine in neuroblastoma cells Neuro2a. However, further investigations are needed to characterize molecular events involved in the NF-κB activation induced by homocysteine.</p

Modified partial circumcision for phimosis: techniques and surgical outcomes

Objectives: In the last years, many surgical techniques of preputioplasty have aimed to preserve the foreskin in case of phimosis. These techniques are not reliable for patients affected by phimosis linked to balanitis xerotica obliterans (BXO) and scarred foreskin. We tried an original technique of resection of the pathological foreskin, removing the mucosal internal layer followed by reconstruction of the foreskin. The aim was to evaluate the outcome of paediatric patients who underwent modified partial circumcision for pathological phimosis.Patients and methods: In all, 360 patients with phimosis underwent modified partial circumcision at our institution. The mean age of the boys was 8.9 years, range 5–15 years. In 145 (40.3%) cases, indication for surgery was clinical suspicion of BXO, in 215 (59.7%) cases it was chronic inflammation of the foreskin.Results: In all cases, the postoperative period was uneventful. Cosmesis was considered by parents as excellent in 95.2% of patients. In these patients, the glans was almost completely covered by soft foreskin. Histopathological examination of the removed foreskin documented BXO in 162 (45%). Twelve (3.3%) patients complained of recurrences and five (1.4%) patients of smegmatic cysts.Conclusion: The described surgical technique of modified partial circumcision for the correction of pathological phimosis appears cosmetically well accepted, safe, and simple with low rate of late postoperative complications.Keywords: balanitis xerotica obliterans, circumcision, partial circumcision, phimosi

Neumonía por COVID-19 en niños: De su etiología a su manejo

El COVID-19 es menos serio en niños que en adultos. Sin embargo, las afecciones respiratorias dominan el cuadro clínico de pacientes hospitalizados por COVID-19, aun en niños. En algunas series de casos, el deterioro del estado clínico, donde la disnea, la cianosis y el inicio del síndrome de dificultad respiratoria aguda (SDRA) emergieron ∼8–10 días después del inicio de la infección por SARS-CoV-2, pudo progresar rápidamente hasta la falla multiorgánica y la muerte. Esta revisión tiene como objetivo evaluar las características de la neumonía por COVID-19 en poblaciones pediátricas, comenzando con su etiología y sus mecanismos patológicos, para cerrar con su manejo clínico

Cystic fibrosis transmembrane conductance regulator (CFTR): beyond cystic fibrosis

Abstract Background The cystic fibrosis transmembrane conductance regulator (CFTR) gene has been traditionally linked to cystic fibrosis (CF) inheritance in an autosomal recessive manner. Advances in molecular biology and genetics have expanded our understanding of the CFTR gene and its encoding products expressed in different tissues. Aim The study's aim consists of reviewing the different pathological CF phenotypes using the existing literature. We know that alterations of the CFTR protein's structure may result in different pathological phenotypes. Methods Open sources such as PubMed and Science Direct databases have been used for this review. We focused our selection on articles published within the last 15 years. Critical terms related to the CFTR protein have been used: "CFTR AND cancer," "CFTR AND celiac disease," "CFTR AND pancreatitis," "children," "adults," "genotype," "phenotype," "correlation," "mutation," "CFTR," "diseases," "disorders," and "no cystic fibrosis." Results We analyzed 1,115 abstracts in total. Moreover, only 189 were suitable for the topic. We focused on the role of CFTR in cancer, gastrointestinal disorders, respiratory diseases, reproductive system, and systemic hypertension. Conclusions Mutations in CFTR gene are often associated with CF. In this review, we highlighted the broad spectrum of alterations reported for this gene, which may be involved in the pathogenesis of other diseases. The importance of these new insights in the role of CFTR relies on the possibility of considering this protein/gene as a novel therapeutic target for CF- and CFTR-related diseases

Sleep Respiratory Disorders in Children and Adolescents with Cystic Fibrosis and Primary Ciliary Dyskinesia

Cystic fibrosis (CF) and primary ciliary dyskinesia (PCD) are genetic respiratory diseases featured by chronic upper and lower airway inflammation and infection, mainly due to impaired mucociliary clearance due to genetic mutations. Sleep is crucial to healthy children’s normal physical and psychological development and has an important value in chronic respiratory diseases. Impaired sleep quality, such as sleep deprivation or insufficient sleep during the night, and sleep respiratory disorders (SRDs) are common in 5% to 30% of the general population. Sleep disruption leads to attention deficits, daytime sleepiness, fatigue and mood disorders and correlates to a worsened quality of life. Furthermore, sleep respiratory disorders (SRSs) are under-recognized comorbidities in CF and PCD patients. SRSs include a spectrum of symptoms ranging from primary snoring through upper airway resistance to obstructive sleep apnea (OSA), nocturnal hypoventilation and hypoxemia occurring in people with moderate to severe lung disease and damaging the disease-related outcomes and quality of life. Effective screening during sleep with polysomnography is very important for the timely initiation of efficacious treatments and to prevent worsened respiratory, metabolic and cardiovascular outcomes. However, the impact of SRDs on health and quality of life is still underinvestigated.</p

Pearsonema spp. (Family Capillariidae, Order Enoplida) Infection in Domestic Carnivores in Central–Northern Italy and in a Red Fox Population from Central Italy

Pearsonema spp. nematodes infect the urinary bladder of domestic and wild carnivores. The red fox is considered a reservoir of Pearsonema plica, while the prevalence of Pearsonema spp. in domestic carnivores is still poorly known. This study aimed to assess the occurrence of Pearsonema spp. infection in privately owned cats (26) and dogs (83) from central and northern Italy alongside occurrence in red foxes (42) from central Italy. In positive dogs and cats, associated clinical signs were also evaluated. Urine samples were first examined under a stereomicroscope; then, they were centrifuged and microscopically examined after a flotation test. As for foxes, the urinary bladders were opened and urine was collected and processed as above, while collected nematodes were identified at the species level. Among examined animals, 2/26 cats (7.7%), 1/83 dogs (1.2%), and 38/42 foxes (90.5%) scored positive. Recurrent cystitis, pollakiuria, and hematuria were the main clinical signs in symptomatic dogs and cats. This is the first study on Pearsonema spp. infection in domestic carnivores examining a large number of privately owned pet animals. Obtained results confirm the role of the red fox as a reservoir for P. plica and suggest a possible high occurrence of Pearsonema spp. infection in domestic cats of central Italy