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Even though cell death modalities elicited by anticancer chemotherapy and radiotherapy have been extensively studied, the ability of anticancer treatments to induce non-cell-autonomous death has never been investigated. By means of multispectral imaging flow-cytometry-based technology, we analyzed the lethal fate of cancer cells that were treated with conventional anticancer agents and co-cultured with untreated cells, observing that anticancer agents can simultaneously trigger cell-autonomous and non-cell-autonomous death in treated and untreated cells. After ionizing radiation, oxaliplatin, or cisplatin treatment, fractions of treated cancer cell populations were eliminated through cell-autonomous death mechanisms, while other fractions of the treated cancer cells engulfed and killed neighboring cells through non-cell-autonomous processes, including cellular cannibalism. Under conditions of treatment with paclitaxel, non-cell-autonomous and cell-autonomous death were both detected in the treated cell population, while untreated neighboring cells exhibited features of apoptotic demise. The transcriptional activity of p53 tumor-suppressor protein contributed to the execution of cell-autonomous death, yet failed to affect the non-cell-autonomous death by cannibalism for the majority of tested anticancer agents, indicating that the induction of non-cell-autonomous death can occur under conditions in which cell-autonomous death was impaired. Altogether, these results reveal that chemotherapy and radiotherapy can induce both non-cell-autonomous and cell-autonomous death of cancer cells, highlighting the heterogeneity of cell death responses to anticancer treatments and the unsuspected potential contribution of non-cell-autonomous death to the global effects of anticancer treatment.

Metastases account for 90% of cancer-related deaths; thus, it is vital to understand the biology of tumour dissemination. Here, we collected and monitored >50 patient specimens ex vivo to investigate the cell biology of colorectal cancer (CRC) metastatic spread to the peritoneum. This reveals an unpredicted mode of dissemination. Large clusters of cancer epithelial cells displaying a robust outward apical pole, which we termed tumour spheres with inverted polarity (TSIPs), were observed throughout the process of dissemination. TSIPs form and propagate through the collective apical budding of hypermethylated CRCs downstream of canonical and non-canonical transforming growth factor-β signalling. TSIPs maintain their apical-out topology and use actomyosin contractility to collectively invade three-dimensional extracellular matrices. TSIPs invade paired patient peritoneum explants, initiate metastases in mice xenograft models and correlate with adverse patient prognosis. Thus, despite their epithelial architecture and inverted topology TSIPs seem to drive the metastatic spread of hypermethylated CRCs.

Competing Interests: Potential Conflict of Interest No potential conflict of interest relevant to this article was reported.

Centrosome amplification has severe consequences during development and is thought to contribute to a variety of diseases such as cancer and microcephaly. However, the adverse effects of centrosome amplification in epithelia are still not known. Here, we investigate the consequences of centrosome amplification in the Drosophila wing disc epithelium. We found that epithelial cells exhibit mechanisms of clustering but also inactivation of extra centrosomes. Importantly, these mechanisms are not fully efficient, and both aneuploidy and cell death can be detected. Epithelial cells with extra centrosomes generate tumors when transplanted into WT hosts and inhibition of cell death results in tissue over-growth and disorganization. Using SILAC-fly, we found that Moesin, a FERM domain protein, is specifically upregulated in wing discs with extra centrosomes. Moesin localizes to the centrosomes and mitotic spindle during mitosis, and we show that Moesin upregulation influences extra-centrosome behavior and robust bipolar spindle formation. This study provides a mechanistic explanation for the increased aneuploidy and transformation potential primed by centrosome amplification in epithelial tissues., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

It is known that in severe acquired brain injuries there is process of neuroinflammation, with the activation of a local and general stress response. In our study we considered six patients with disorders of consciousness (five in vegetative state and one in minimal consciousness state) in subacute phase, which had both a clinical assessment and a functional imaging (fMRI): in all these patients we analised blood levels of osteopontin (OPN), a cytokin involved in neuroinflammation but also in neurorepair with a still discussed role. Besides we studied the lymphocyte subsets and blood levels of some hormones (ADH, ACTH, PRL, GH, TSH, fT3, fT4). We found a positive correlation between the levels of serum osteopontin (higher than normal in all subjects) and the severity of the brain injury, especially for prognosis: actually, the patient with the lowest level has emerged from minimal consciousness state, while the one with the highest level has died a few days after the evaluation. The lymphocyte subset was altered, with a general increase of CD4+/CD3+ ratio, but without a so strict correlation with clinical severity; the only hormone with a significant increase in the worse patients was prolactin. In fMRI we detected some responses to visual and acoustic stimuli also in vegetative states, which had no clinical response to this kind of stimulation but generally have had a better prognosis. So we conclude that osteopontin could be a good marker of neuroinflammation and relate to a worse prognosis of brain injuries; the lymphocyte alterations in these disorders are not clear, but we suspect an unbalance of CD4 towards Th2; PRL is the best endocrinological marker of brain injury severity; fMRI surely plays an important role in the detection of subclinical responses and in prognostic stratification, that is still to define with more studies and statistical analysis.

The LIM-domain protein Ajuba localizes at sites of epithelial cell-cell adhesion and has also been implicated in the activation of Aurora-A (Aur-A). Despite the expected importance of Ajuba, Ajuba-deficient mice are viable, which has been attributed to functional redundancy with the related LIM-domain protein LIMD1. To gain insights into the function of Ajuba, we investigated its role in Drosophila, where a single gene (jub) encodes a protein closely related to Ajuba and LIMD1. We identified a key function in neural stem cells, where Jub localizes to the centrosome. In these cells, mutation in jub leads to centrosome separation defects and aberrant mitotic spindles, which is a phenotype similar to that of aur-A mutants. We show that in jub mutants Aur-A activity is not perturbed, but that Aur-A recruitment and maintenance at the centrosome is affected. As a consequence the active kinase is displaced from the centrosome. On the basis of our studies in Drosophila neuroblasts, we propose that a key function of Ajuba, in these cells, is to maintain active Aur-A at the centrosome during mitosis.

The expression of several genes in Neisseria meningitidis upon contact with epithelial cells was associated with the presence of the contact regulatory elements of NEISSERIA: These genes are involved in various aspects of meningococcal biology and could be coordinately regulated upon contact with target cells.

Purpose: The present study investigated the blood pressure (BP) load (L), namely Baric Impact (BI), in normotensives with and without endothelial dysfunction (ED). The aim was to detect baric differences supporting the thesis that the ED is associated with vasopressant effects that are responsible for a paraphysiological condition of higher BP (pre-hypertension) even in normotensives., Materials and Methods: Thirty-eight normotensives were investigated in their endothelium-dependent vasomotricity by mean of the non-invasive post-ischemic brachial artery vasodilation test. Additionally, their underwent a non-invasive ambulatory (A) BP monitoring (M) over the 24-h span in order to confirm that they were not hypertensive. The ABPM served also to compute the systolic (S) and diastolic (D) BI., Results: The ED was detected in eight normotensives of the investigated group. These cases with ED were found to show a significantly higher SBI and DBI as compared to the normotensives without ED., Conclusions: The significant elevation of the SBI and DBI in normotensives with ED is an evidence convincing that a dysfunctional endothelium is responsible for vasopressant effects that cause a paraphysiological status of "pre-hypertension".

Purpose: The present study investigates the blood pressure (BP) 24-h values in normotensives with and without endothelial dysfunction (ED). The scope is to detect differences in BP regimen supporting the hypothesis that the ED is associated with vasopressant effects that can cause a condition of "pre-hypertension"., Materials and Methods: Thirty-eight normotensives were investigated in their endothelial function by mean of the non-invasive post-ischemic brachial artery vasodilation test (endothelium-dependent vasomotricity). Their were also automatically and non-invasively monitored in their systolic (S) and diastolic (D) BP over the 24-h period in order to confirm that they were not hypertensive., Results: Eight of the investigated normotensives were found to show an ED. A significantly higher daily mean level as well as a more prominent nychtohemeral variability in SBP and DBP 24-h values were observed in the normotensives with ED as compared to the normotensives without ED. The higher BP regimen in the normotensives with ED was found to maintain a circadian rhythm. However, a significant amplification the second harmonic component, with a 12-h period, was observed. The different structure of the BP 24-h pattern in the normotensives with ED was confirmed by the detection of additional ultradian components at the linear-in-period spectral analysis., Conclusions: The present study documented a significant elevation of BP 24-h values in normotensives with ED that is the reflex of consistent changes in the frequency organization of the BP circadian pattern. The elevation of BP regimen suggests that the ED is associated with vasopressant effects even in normotensives. Such a condition of higher BP in normotensives with ED can be regarded as a status of "pre-hypertension".

In this paper we describe 3 clinical cases of hypothyroidism causing myopathy and hyperammonemia. The patients, all females, aged 32 to 64 years, presented with hoarseness, fatigue, dyspepsia (case I), difficulty speaking secondary to the sensation of tongue swelling and hoarseness (case II), and progressive weight gain and difficulty speaking secondary to tongue swelling after delivery (case III). Laboratory tests showed a marked increase in creatine phosphokinase (up to 4090 U/L; normal values 24-176 U/L) of muscle origin, and an increase in transaminases and ammonia (124 to 150 micrograms/dL; normal values up to 75 micrograms/dL). Hypothyroidism was confirmed by TSH > 100 microIU/mL (normal values 0.3-5 microIU/mL). Treatment only with L-thyroxine determined the complete and persistent recovery of well-being and of biochemical abnormalities. The patients remained in good health after more than 2 years of follow-up. Our finding of hyperammonemia caused by the lack of thyroid hormones in 3 patients with hypothyroid myopathy appears to be of a certain interest as, to our knowledge, this phenomenon has not been previously described. In conclusion our hypothesis is that increased muscle production of ammonia secondary to the hypothyroid myopathy determined an increased ammonia load, resulting in hyperammonemia. Decreased liver ureagenesis induced by the lack of thyroid hormones also contributed to the hyperammonemia.