The ErbB2 receptor in gastric cancer. the quick-change artist

The ErbB family of receptors is providing the oncogenic signals necessary to cells to become transformed. In gastric cancer (GC) the ErbB2 (HER2) expression is associated with a poor prognosis, but addition of ErbB-targeted therapeutics to chemotherapy has produced unsatisfactory results with moderate improved outcomes for patients. The ToGA trail has revolutionized the treatment of GC, introducing the use of trastuzumab and changing the poor prognosis of these patients. However, this study reported only a modest prolongation of progression-free survival (PFS) and overall survival (OS) in patients with high expression of ErbB2 protein, with a large percentage of initially good responders, then becoming refractory to therapy within one year. These findings indicate the occurrence of resistant phenotypes arising from diverse adaptive and genetic changes. Due to the promiscuity of ErbB2 in the EGFR family signaling network, the use of ErbB targeted mono-therapies certainly contributes to a redistribution of the stoichiometry among receptors leading to the activation of compensatory pathways, suggesting that survival of cancer cells is sustained, at least in part, by the network of the ErbB receptors and their ligands. For these reasons, the use of combination therapies is becoming the most logical strategy for any type of cancer treatment, including GC. In this review we summarize information regarding mechanisms, pathways and molecules involved in the resistance to ErbB-targeted molecules with the intent to provide rational guidelines for developing more efficient therapeutic approaches

Individual Behavioral and Neurobiological Markers Associated with a Vulnerable to Ethanol use Phenotype

Alcohol use disorder (AUD) is a chronic relapsing brain condition that is characterized by excessive alcohol consumption, continued use when faced with negative consequences, and a negative emotional state associated with withdrawals (anxiety, irritability, depression). The main challenge to treating AUD is preventing relapse. The purpose of this study was to use a prolonged-exposure model to allow rats to self-administer ethanol to determine the brain regions active during relapse events. The rats performed multiple behavioral tests such as economic demand, negative consequences, and an elevated plus maze. These tests determined how hard rats were willing to work for an ethanol reward, how much they would persist in the face of negative consequences, and the level of anxiety-like behavior during withdrawal. These data were crossed-analyzed with neurobiological data collected from c-Fos immunoreactivity to determine a vulnerable to ethanol use endophenotype. The data were analyzed on an individual level to highlight differences associated with AUD and relapse. The preliminary results suggested that individuals with high demand for ethanol were willing to persist more in the face of negative consequences, had higher anxiety-like behavior, and were more likely to reinstate their ethanol-seeking behaviors during reinstatement. Based on this evidence, we predicted rats with higher demand would have higher rates of neural activity in areas associated with relapse. This study will provide valuable insight into the underlying mechanisms of relapse, but further clinical studies are necessary to use these phenotype-associated markers to develop a treatment plan that prevents relapse in individuals with AUD

LUMO LOWERING

One of the applications of Transition Metals in organic chemistry is due to their capability to function as catalysts for many reactions. Metals with empty d orbitals can coordinate with organic compounds, leading to high levels of yields and control of the expected products. Several reactions related to different projects have been setted up. The principal projects involved the Phauson-Khand reaction as well as the Carboxylic Acid-Selective Aldol Reaction. In the Phauson-Khand reaction an alkyne coordinates with a transition metal forming an complex that will react with a reactive partner, finally leading to the production of five membered carbocycles. Five membered carbocycles are important building blocks for many biological active molecules. Moreover, some cyclopentenones (e.g. cyclopentenone prostaglandins) exhibit characteristic biological activity. Alkene compounds have been studied to be interesting reactive partners. Their reactivity is related to the back donation of electrons from the d orbitals of a transition metal atom to the p* orbitals of the alkene. In our study we tried to synthetize a proper boronic acid to function as a co-catalyst in the Phauson-Khand reaction, consistent with the LUMO lowering strategies for increase the scope of this reaction. A second series of reactions were related to the Carboxylic Acid-Selective Aldol Reaction. Different boronic acids have been used to catalyze a reaction between a specific aldehyde and phenilacetic acid using a set of different bases as well as solvents. The scope was to screen the best conditions for this reaction to give rise to the expected product in acceptable yields. Proton NMR, Thin Layer Chromatography, IR spectrometry and GC-MS have been useful tools to analyze the outcome of the different reactions setted up so far. Rotor Vaporation, Vacuum filtration and Column Chromatography have been used for each specific reaction to purify the samples before performing the analytical investigation

Endobronchial angioleiomyoma. Diagnostic difficulties of a rare lung neoplasm

Angioleiomyoma is a benign soft tissue tumor which rarely develops in the respiratory tract. Here we report a case of a 51-year-old female with an angioleiomyoma developed in the left upper lobar bronchial branch and extended to the left main stem bronchus, causing non-specific symptoms, and not visible on the chest x-ray exam. The suspected diagnosis was established by High-Resolution Computed Tomography (HRCT) and confirmed by the histological evaluation of the endoscopically removed lesion

Determination of 35 cell surface antigen levels in malignant pleural effusions identifies CD24 as a marker of disseminated tumor cells

Many targets have been identified in solid tumors for antibody therapy but it is less clear what surface antigens may be most commonly expressed on disseminated tumor cells. Using malignant pleural effusions as a source of disseminated tumor cells, we compared a panel of 35 antigens for their cancer specificity, antigen abundance and functional significance. These antigens have been previously implicated in cancer metastasis and fall into four categories: (i) cancer stem cell, (ii) epithelial-mesenchymal transition, (iii) metastatic signature of in vivo selection and (iv) tyrosine kinase receptors. We determined the antigen density of all 35 antigens on the cell surface by flow cytometry, which ranges from 3 × 10[superscript 3]–7 × 10[superscript 6] copies per cell. Comparison between the malignant and benign pleural effusions enabled us to determine the antigens specific for cancer. We further chose six antigens and examined the correlation between their expression levels and tumor formation in immunocompromised mice. We concluded that CD24 is one of the few antigens that could simultaneously meet all three criteria of an ideal target. It was specifically and abundantly expressed in malignant pleural effusions; CD24[superscript high] tumor cells formed tumors in mice at a faster rate than CD24[superscript low] tumor cells, and shRNA-mediated knockdown of CD24 in HT29 cells confirmed a functional requirement for CD24 in the colonization of the lung. Concomitant consideration of antigen abundance, specificity and functional importance can help identify potentially useful markers for disseminated tumor cells

Klebsiella pneumoniae is able to trigger epithelial-mesenchymal transition process in cultured airway epithelial cells

The ability of some bacterial pathogens to activate Epithelial-Mesenchymal Transition normally is a consequence of the persistence of a local chronic inflammatory response or depends on a direct interaction of the pathogens with the host epithelial cells. In this study we monitored the abilities of the K. pneumoniae to activate the expression of genes related to EMT-like processes and the occurrence of phenotypic changes in airway epithelial cells during the early steps of cell infection. We describe changes in the production of intracellular reactive oxygen species and increased HIF-1α mRNA expression in cells exposed to K. pneumoniae infection. We also describe the upregulation of a set of transcription factors implicated in the EMT processes, such as Twist, Snail and ZEB, indicating that the morphological changes of epithelial cells already appreciable after few hours from the K. pneumoniae infection are tightly regulated by the activation of transcriptional pathways, driving epithelial cells to EMT. These effects appear to be effectively counteracted by resveratrol, an antioxidant that is able to exert a sustained scavenging of the intracellular ROS. This is the first report indicating that strains of K. pneumoniae may promote EMT-like programs through direct interaction with epithelial cells without the involvement of inflammatory cells

Lo studio dei movimenti ripetitivi e dei precursori del linguaggio attraverso l'analisi retrospettiva dei filmati familiari in soggetti con sviluppo tipico e atipico

Questo studio si propone di esaminare un argomento ancora poco esplorato nel panorama di ricerca dell’autismo: la ripetitività dei movimenti e di quelli che sono i precursori del linguaggio, vocalizzazioni e lallazione. Perciò l’obiettivo dello studio è quello di analizzare i movimenti ripetuti, il babbling e i pattern vocalici ripetuti, elementi di base per lo sviluppo del bambino, in tre gruppi di soggetti: bambini con sviluppo tipico, con disturbo dello Spettro Autistico e con Ritardo Mentale nel secondo semestre di vita (6-12 mesi). In particolare, questi comportamenti sono stati codificati considerando se essi avvenivano o meno all’interno di un contesto sociale, cioè durante l’interazione con il caregiver o altri soggetti, come fratellini, amici o parenti. Lo studio si propone di evidenziare eventuali differenze che possono ritrovarsi tra i tre campioni di soggetti nella frequenza di comparsa e nella durata di questi comportamenti ripetuti, utilizzando come sistema di codifica il software computerizzato The Observer XT Noldus. Già sulla base dei dati presenti in letteratura, è possibile ipotizzare nell’autismo una frequenza e una durata maggiore rispetto ai controlli e ai soggetti con ritardo, di movimenti ripetuti afinalistici, che avvengono al di fuori di uno scambio sociale. Infatti i bambini con autismo sarebbero così impegnati nell’esecuzione di questi movimenti tanto da non sviluppare correttamente le abilità socio comunicative nè movimenti più funzionali. Invece, per quanto concerne i precursori delle abilità linguistiche, studi precedenti hanno riportato una minore frequenza e una ridotta durata di vocalizzazioni e di lallazione nei soggetti con autismo

Human sinusoidal subendothelial cells regulate homing and invasion of circulating metastatic prostate cancer cells to bone marrow

: Subendothelial cells (pericytes) are the clonogenic, multipotent and self-renewing skeletal stem cells (SSCs) found in bone marrow (BM) stroma. They express genes maintaining hematopoietic stem cell (HMC) niche identity and, transplanted in immunocompromised mice, organize the hematopoietic microenvironment (HME) generating humanized bone/BM ossicles. To create a mouse model of hematogenous metastasis of human prostate cancer (PC) cells to human bone/BM, we injected PC cells in the blood circulatory system of Severe Combined Immunodeficiency (SCID)/beige mice bearing heterotopic ossicles. Results indicate that PC cells could efficiently home to mice-implanted extraskeletal BM ossicles, but were not able to colonize mice skeletal segments. In humanized bone/BM ossicles, early foci of PC cells occupied a perisinusoidal position, in close contact with perivascular stromal cells. These findings demonstrate the importance of the SSC compartment in recreating a suitable environment to metastatic PC cells. Our data support the hypothesis that BM SSCs committed to a pericyte fate can specify for homing niches of PC cells, suggesting an involvement of specific interactions with subendothelial stromal cells in extravasation of circulating metastatic PC cells to BM

Treatment of Human Epidermal Growth Factor Receptor 2-Overexpressing Breast Cancer Xenografts With Multiagent HER-Targeted Therapy

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