Numb Isoforms Deregulation in Medulloblastoma and Role of p66 Isoform in Cancer and Neural Stem Cells

Numb is an intracellular protein with multiple functions. The two prevalent isoforms, Numb p66 and Numb p72, are regulators of differentiation and proliferation in neuronal development. Additionally, Numb functions as cell fate determinant of stem cells and cancer stem cells and its abnormal expression has been described in several types of cancer. Involvement of deregulated Numb expression has been described in the malignant childhood brain tumor medulloblastoma, while Numb isoforms in these tumors and in cancer stem-like cells derived from them, have not been studied to date. Here we show that medulloblastoma stem-like cells and cerebellar neuronal stem cells (NSCs) express Numb p66 where its expression tampers stemness features. Furthermore, medulloblastoma samples evaluated in this study express decreased levels of Numb p66 while overexpressed Numb p72 compared with normal tissues. Our results uncover different roles for the two major Numb isoforms examined in medulloblastoma and a critical role for Numb p66 in regulating stem-like cells and NSCs maintenance

Induction chemotherapy followed by neoadjuvant chemoradiotherapy and surgery in locally advanced rectal cancer: preliminary results of a phase II study

PURPOSE: To report preliminary results of induction chemotherapy (IC) followed by neoadjuvant chemoradiotherapy (CRT) and surgery in locally advanced rectal cancer (LARC) patients.MATERIALS AND METHODS: This is the preliminary evaluation of a phase II study. Patients with histologically proven rectal adenocarcinoma, stage II-III disease, who met the inclusion criteria, received induction FOLFOXIRI (5-FU, leucovorin, oxaliplatin and irinotecan) regimen in combination with targeted agents followed by CRT and surgery. Analysis of the first 8 patients was required to confirm the treatment feasibility before the accrual of 20 additional patients. RESULTS: The first 8 patients were evaluated. The median follow-up time was 23 months. There were no treatment-related deaths. Trimodality strategy was well tolerated with high compliance and a good level of toxicity. There were no evidence of febrile neutropenia and any grade 4 adverse events were recorded. Three patients had pathologic complete response (pCR) and 1 patient had a nearly pCR (ypT1 ypN0). CONCLUSION: Preliminary results are encouraging. FOLFOXIRI regimen plus targeted agents followed by CRT and surgery seems a safe approach. Longer follow-up and higher number of patients are mandatory to confirm such findings

A Comparative Study of MWT Architectures by Means of Numerical Simulations

AbstractIn order to improve the efficiency of c-Si and mc-Si solar cells, Metal Wrap Though (MWT) architecture is investigated. In this paper we implement TCAD numerical simulations to analyze the performance of MWT cells with a point busbar or a continuous busbar at the back side. The two topologies of MWT cells are compared in both illuminated and dark conditions, aiming at understanding and comparing the resistive and recombination losses. The impact of the separation region is also studied, highlighting the degradation effect on the Fill Factor (FF) and on the efficiency in the two structures. We observe that the separation region dimension leads to a higher degradation of efficiency in case of continuous busbar

Magnetic Resonance features of pyogenic brain abscesses and differential diagnosis using morphological and functional imaging studies: a pictorial essay.

The aim of this paper is to illustrate the potential of magnetic resonance imaging (MRI) in diagnosis, differential diagnosis, treatment planning and evaluation of therapy effectiveness of pyogenic brain abscesses, through the use of morphological (or conventional) and functional (or advanced) sequences. Conventional MRI study is useful for the identification of lesions, to determine the location and morphology and allows a correct hypothesis of nature in the most typical cases. However, the differential diagnosis from other brain lesions such as non pyogenic abscesses or necrotic tumors (high-grade gliomas and metastases) is often only possible through the use of functional sequences, as the measurement of diffusion with apparent diffusion coefficient (DWI-ADC), proton magnetic resonance spectroscopy (1H-MRS) and perfusion weighted imaging (PWI), which complement the morphological sequences and provide essential information on structural, metabolic and hemodynamic characteristics allowing greater neuroradiological confidence. Modern diagnostic MRI of pyogenic brain abscesses cannot be separated from knowledge, integration and proper use of the morphological and functional sequences

Hindering NAT8L expression in hepatocellular carcinoma increases cytosolic aspartate delivery that fosters pentose phosphate pathway and purine biosynthesis promoting cell proliferation

N-acetylaspartate (NAA) is synthesized by the mitochondrial enzyme NAT8L, which uses acetyl-CoA and aspartate as substrates. These metabolites are fundamental for bioenergetics and anabolic requirements of highly proliferating cells, thus, NAT8L modulation may impinge on the metabolic reprogramming of cancer cells. Specifically, aspartate represents a limiting amino acid for nucleotide synthesis in cancer. Here, the expression of the NAT8L enzyme was modulated to verify how it impacts the metabolic adaptations and proliferative capacity of hepatocellular carcinoma. We demonstrated that NAT8L downregulation is asso-ciated with increased proliferation of hepatocellular carcinoma cells and immortalized hepatocytes. The over -expression of NAT8L instead decreased cell growth. The pro-tumoral effect of NAT8L silencing depended on glutamine oxidation and the rewiring of glucose metabolism. Mechanistically, NAT8L downregulation triggers aspartate outflow from mitochondria via the exporter SLC25A13 to promote glucose flux into the pentose phosphate pathway, boosting purine biosynthesis. These results were corroborated by the analyses of human and mouse hepatocellular carcinoma samples revealing a decrease in NAT8L expression compared to adjacent non -tumoral tissues. Overall, this work demonstrates that NAT8L expression in liver cells limits the cytosolic avail-ability of aspartate necessary for enhancing the pentose phosphate pathway and purine biosynthesis, counter-acting cell proliferation

Safety and efficacy of combining afatinib and whole-brain radiation therapy in treating brain metastases from EGFR-mutated NSCLC: a case report and literature review

Combining EGFR-tyrosine kinase inhibitors (TKIs) to whole brain radiation therapy (WBRT) has been shown to be more effective than EGFR-TKIs or WBRT alone in treating brain metastases (BMs) from EGFR-mutated Non Small-Cell Lung Cancer (NSCLC). However, despite the combination results well tolerated, EGFR-TKIs are often discontinued before WBRT, to reduce the risk of possible side effects, potentially resulting in reduced treatment efficacy and possible progression of intra- and extra-cranial disease. Afatinib, an irreversible inhibitor of EGFR-TK, has been shown to radiosensitize NSCLC in pre-clinical models and, compared to the other EGFR-TKIs, more efficiently penetrates the blood-brain barrier. However, nowadays, only two case reports describe the therapeutic efficiency and safety of combining afatinib with WBRT. Herein, we report on a 58-year-old woman patient with symptomatic BMs from NSLCL, treated with afatinib and concomitant WBRT, 30 Gy in 10 fractions. Treatment induced a remarkable and persistent radiological regression of BMs and the disappearance of neurological symptoms. However, the patient experienced severe skin toxicity of G3, corresponding to the irradiation area. Toxicity was successfully treated pharmacologically, and the patient did not experience any BMs-related symptoms for the next 10 months. She died of COVID-19-related respiratory failure. The association of afatinib with WBRT appears to be a successful strategy in the control of BMs from EGFR-mutated NSCLC. However, it should be considered that the combination could be responsible for serious dermatological toxicity

Colon or rectal stent positioning for advanced cancer influences quality of life: a critical point of view

Background/Aim: Endoluminal self-expanding metallic stents (SEMS) may overcome the risk of mortality and morbidity of acute intestinal obstruction because of stage IV colon (CC) or rectal (RC) cancer. We evaluated the QoL in these groups of patients. Patients and Methods: Forty-eight patients were enrolled in a prospective longitudinal cohort single-center trial to undergo SEMS positioning. Twenty-five patients had a CC and 23 RC. Karnofsky performance scale, Visual Analogue Scale and the EQ-5D- 5LTM questionnaire were administered before treatment and at 1, 3 and 6 months. Results: Harmonized to the Italian population, the index values showed a statistically significant deterioration of the QoL in patients with RC when compared to those with CC at 1-, 3- and 6-months (1 month: p=0.001; 3- month: p=0.001; 6-month: p=0.045). Similarly, Visual Analogue Scale showed variations at 1- (p=0.008), 3- (p=0.001) and 6-months (p=0.020). Rectal stent deployment was the only independent predictor for a worse QoL in all domains (p<0.017; OR=0.196; 95%CI=0.51-0.749). Conclusion: Patients affected with stage IV CC had a better QoL after SEMS placement when compared to those affected with RC. The persistency of the primary tumor at the rectal level, even if irradiated, might negatively affect QoL

Evaluación conjunta de la población de la anchoa del Mar Adriático septentrional y central: comparación entre dos métodos de dinámica poblacional

Anchovy (Engraulis encrasicolus, L.) is one of the most important commercial species of the northern and central Adriatic Sea, as well as one of the most productive fisheries in the whole Mediterranean. In the Adriatic Sea the stock of anchovy is shared between Italy, Croatia and Slovenia. A joint stock assessment was carried out using catch data from all the fleets for the time interval 1975-2009. Analyses were performed using estimates of natural mortality at age obtained by means of two different methods and two population dynamics methods based on the analysis of catch-at-age data: Laurec-Sheperd virtual population analysis (VPA) and integrated catch-at-age (ICA), both tuned to acoustic estimates of abundance. Gislason’s estimates for natural mortality appeared to be more realistic and were thus preferred for short-lived species. The general trend of biomass and fishing mortality is similar for the two models, highlighting the major collapse of the stock in 1987. Nevertheless, ICA has enough flexibility to combine all the data available without adding too much complexity in comparison with a VPA approach and seems to perform better in terms of the spawning stock biomass/recruitment relationship and diagnostics (i.e. the retrospective pattern). For the stock status, the exploitation rate from ICA is higher than the suggested threshold of 0.4 proposed by Patterson for small pelagic species.La anchoa (Engraulis encrasicolus, L.) es una de las especies comerciales más importantes del mar Adriático central y septentrional, a la vez que es una de las actividades pesqueras más productivas en todo el Mediterráneo. La población de anchoa en el mar Adriático es compartida por Croacia, Italia y Eslovenia: una evaluación conjunta de la población fue realizada usando los datos de captura de todas las flotas para el periodo 1975-2009. Se efectuaron análisis usando estimaciones de la mortalidad natural por edad obtenidos mediante dos métodos diferentes y dos métodos de dinámica poblacional basados en el análisis de datos de captura por edad: Análisis de Población Virtual (VPA) de Laurec-Sheperd y Análisis de Captura Integrada por Edad (ICA), ambos acordados en las estimaciones acústicas de la abundancia. Las estimaciones de mortalidad natural de Gislason aparentaban ser más realísticas y por lo tanto daba preferencia a especies de vida corta. La tendencia general de la biomasa y de la mortalidad por pesca es similar en los dos modelos, destacando la fuerte disminución de la población en 1987. Sin embargo, ICA permite una flexibilidad suficiente para combinar todos los datos disponibles sin agregar excesivas complejidades con respecto al enfoque VPA y aparenta un mejor desempeño en términos de relación de SSB-R y en términos of diagnósticos (por ejemplo: el patrón retrospectivo). En relación al estado de la población, la tasa de explotación del ICA es más alta que el umbral sugerido de 0.4 propuesto por Patterson para las especies de pequeños pelágicos