Advances and unmet needs in genetic, basic and clinical science in Alport syndrome::report from the 2015 International Workshop on Alport Syndrome

Alport syndrome (AS) is a genetic disease characterized by haematuric glomerulopathy variably associated with hearing loss and anterior lenticonus. It is caused by mutations in the COL4A3, COL4A4 or COL4A5 genes encoding the α3α4α5(IV) collagen heterotrimer. AS is rare, but it accounts for >1% of patients receiving renal replacement therapy. Angiotensin-converting enzyme inhibition slows, but does not stop, the progression to renal failure; therefore, there is an urgent requirement to expand and intensify research towards discovering new therapeutic targets and new therapies. The 2015 International Workshop on Alport Syndrome targeted unmet needs in basic science, genetics and diagnosis, clinical research and current clinical care. In three intensive days, more than 100 international experts including physicians, geneticists, researchers from academia and industry, and patient representatives from all over the world participated in panel discussions and breakout groups. This report summarizes the most important priority areas including (i) understanding the crucial role of podocyte protection and regeneration, (ii) targeting mutations by new molecular techniques for new animal models and potential gene therapy, (iii) creating optimal interaction between nephrologists and geneticists for early diagnosis, (iv) establishing standards for mutation screening and databases, (v) improving widespread accessibility to current standards of clinical care, (vi) improving collaboration with the pharmaceutical/biotech industry to investigate new therapies, (vii) research in hearing loss as a huge unmet need in Alport patients and (viii) the need to evaluate the risk and benefit of novel (including 'repurposing') therapies on an international basis

What's in a Name? Shifting Identities of Traditional Organized Crime in Canada in the Transnational Fight against the Calabrian ‘Ndrangheta

The Italian antimafia authorities have warned Canadian law enforcement about the risks and the growing concerns for the infiltration of clans of the Calabrian mafia, known as ‘ndrangheta, in Eastern Canada. The alarm linked to the rise of the ‘ndrangheta challenges the paradigms of traditional organized crime in Canada, because the ‘ndrangheta is presented as traditional but also innovative and more pervasive than other mafia-type groups. Through access to confidential investigations and interviews to key specialist law enforcement teams in Toronto and Montreal, this article investigates today's institutional perception of mafia – the ‘ndrangheta in particular – in Canada when compared to Italian conceptualizations. I will argue that the changes in narratives in Canada can be read in relation to changes in the Italian identity in the country, moving towards regionalization and specialist knowledge of ethnic differences

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Speech disfluency and the structure of knowledge.

It is generally accepted that filled pauses (&quot;uh,&quot; &quot;er,&quot; and &quot;urn&quot;) indicate time out while the speaker searches for the next word or phrase. It is hypothesized that the more options, the more likely that a speaker will say &quot;uh.&quot; The academic disciplines differ in the extent to which their subject matter and mode of thought require a speaker to choose among options. The more formal, structured, and factual the discipline, the fewer the options. It follows that lecturers in the humanities should use more filled pauses during lectures than social scientists and that natural scientists should use fewest of all. Observations of lecturers in 10 academic disciplines indicate that this is the case. That this is due to subject matter rather than to self-selection into disciplines is suggested by observations of this same set of lecturers all speaking on a common subject. In this circumstance, the academic disciplines are identical in the number of filled pauses used

Speech disfluency and the structure of knowledge.

It is generally accepted that filled pauses (&quot;uh,&quot; &quot;er,&quot; and &quot;urn&quot;) indicate time out while the speaker searches for the next word or phrase. It is hypothesized that the more options, the more likely that a speaker will say &quot;uh:&apos; The academic disciplines differ in the extent to which their subject matter and mode of thought require a speaker to choose among options. The more formal, structured, and factual the discipline, the fewer the options. It follows that lecturers in the humanities should use more filled pauses during lectures than social scientists and that natural scientists should use fewest of all. Observations of lecturers in 10 academic disciplines indicate that this is the case. That this is due to subject matter rather than to self-selection into disciplines is suggested by observations of this same set of lecturers all speaking on a common subject. In this circumstance, the academic disciplines are identical in the number of filled pauses used. It is an Unusually glib and articulate person who, on hearing a tape recording or reading a literal transcript of his or her remarks, has not been shocked by his or her apparent verbal clumsiness, characterized often by agrammatic, redundant speech that is interrupted by repeated words, false starts, long pauses, and guttural interruptions such as uh, ah, and urn

Speech disfluency and the structure of knowledge.

It is generally accepted that filled pauses (&quot;uh,&quot; &quot;er,&quot; and &quot;urn&quot;) indicate time out while the speaker searches for the next word or phrase. It is hypothesized that the more options, the more likely that a speaker will say &quot;uh.&quot; The academic disciplines differ in the extent to which their subject matter and mode of thought require a speaker to choose among options. The more formal, structured, and factual the discipline, the fewer the options. It follows that lecturers in the humanities should use more filled pauses during lectures than social scientists and that natural scientists should use fewest of all. Observations of lecturers in 10 academic disciplines indicate that this is the case. That this is due to subject matter rather than to self-selection into disciplines is suggested by observations of this same set of lecturers all speaking on a common subject. In this circumstance, the academic disciplines are identical in the number of filled pauses used