Sirtuin 1 inhibiting thiocyanates (S1th)-a new class of isotype selective inhibitors of NAD(+) dependent lysine deacetylases

Sirtuin 1 (Sirt1) is a NAD(+) dependent lysine deacetylase associated with the pathogenesis of various diseases including cancer. In many cancer types Sirt1 expression is increased and higher levels have been associated with metastasis and poor prognosis. However, it was also shown, that Sirt1 can have tumor suppressing properties and in some instances even a dual role for the same cancer type has been reported. Increased Sirt1 activity has been linked to extension of the life span of cells, respectively, organisms by promoting DNA repair processes and downregulation of tumor suppressor proteins. This may have the downside of enhancing tumor growth and metastasis. In mice embryonic fibroblasts depletion of Sirt1 was shown to decrease levels of the DNA damage sensor histone H2AX. Impairment of DNA repair mechanisms by Sirt1 can promote tumorigenesis but also lower chemoresistance toward DNA targeting therapies. Despite many biological studies, there is currently just one small molecule Sirt1 inhibitor in clinical trials. Selisistat (EX-527) reached phase III clinical trials for treatment of Huntington's Disease. New small molecule Sirt1 modulators are crucial for further investigation of the contradicting roles of Sirt1 in cancer. We tested a small library of commercially available compounds that were proposed by virtual screening and docking studies against Sirt1, 2 and 3. A thienopyrimidone featuring a phenyl thiocyanate moiety was found to selectively inhibit Sirt1 with an IC50 of 13 mu M. Structural analogs lacking the thiocyanate function did not show inhibition of Sirt1 revealing this group as key for the selectivity and affinity toward Sirt1. Further analogs with higher solubility were identified through iterative docking studies and in vitro testing. The most active compounds (down to 5 mu M IC50) were further studied in cells. The ratio of phosphorylated gamma H2AX to unmodified H2AX is lower when Sirt1 is depleted or inhibited. Our new Sirtuin 1 inhibiting thiocyanates (S1th) lead to similarly lowered gamma H2AX/H2AX ratios in mouse embryonic fibroblasts as Sirt1 knockout and treatment with the reference inhibitor EX-527. In addition to that we were able to show antiproliferative activity, inhibition of migration and colony forming as well as hyperacetylation of Sirt1 targets p53 and H3 by the S1th in cervical cancer cells (HeLa). These results reveal thiocyanates as a promising new class of selective Sirt1 inhibitors.Chemical Immunolog

9p21 loss confers a cold tumor immune microenvironment and primary resistance to immune checkpoint therapy

Immune checkpoint therapy (ICT) provides substantial clinical benefits to cancer patients, but a large proportion of cancers do not respond to ICT. To date, the genomic underpinnings of primary resistance to ICT remain elusive. Here, we performed immunogenomic analysis of data from TCGA and clinical trials of anti-PD-1/PD-L1 therapy, with a particular focus on homozygous deletion of 9p21.3 (9p21 loss), one of the most frequent genomic defects occurring in ~13% of all cancers. We demonstrate that 9p21 loss confers "cold" tumor-immune phenotypes, characterized by reduced abundance of tumor-infiltrating leukocytes (TILs), particularly, T/B/NK cells, altered spatial TILs patterns, diminished immune cell trafficking/activation, decreased rate of PD-L1 positivity, along with activation of immunosuppressive signaling. Notably, patients with 9p21 loss exhibited significantly lower response rates to ICT and worse outcomes, which were corroborated in eight ICT trials of >1,000 patients. Further, 9p21 loss synergizes with PD-L1/TMB for patient stratification. A "response score" was derived by incorporating 9p21 loss, PD-L1 expression and TMB levels in pre-treatment tumors, which outperforms PD-L1, TMB, and their combination in identifying patients with high likelihood of achieving sustained response from otherwise non-responders. Moreover, we describe potential druggable targets in 9p21-loss tumors, which could be exploited to design rational therapeutic interventions

Evolving role of cytoreductive nephrectomy in metastatic renal cell carcinoma of variant histology

PURPOSE OF REVIEW: Summarize current evidence for cytoreductive nephrectomy in patients with metastatic renal cell carcinoma (mRCC) of variant histology. RECENT FINDINGS: The mainstream treatment for advanced malignancy is systematic therapy, including chemotherapy, targeted therapy, and immunotherapy. Nonetheless, cytoreductive nephrectomy has been used in the management of mRCC including variant (nonclear cell) histology. Prospective data supported cytoreductive nephrectomy for clear cell mRCC in the cytokine immunotherapy era in the late 1990s. In the targeted therapy era, the practice of cytoreductive nephrectomy in nonclear and clear cell histology had been largely based on retrospective data, but a recent phase III trial showed that targeted therapy alone is noninferior to targeted therapy combined with cytoreductive nephrectomy, therefore, questioning the clinical benefit of cytoreductive nephrectomy in this context. However, this trial had excluded patient with nonclear cell histology. With the potential for checkpoint inhibitor combinations to achieve long-term complete durable response, cytoreductive nephrectomy is a subject of ongoing debate especially, in nonclear cell histology as those were excluded from prospective trials. SUMMARY: Data are very sparse in nonclear histology. Although retrospective data favor the use of cytoreductive nephrectomy in nonclear cell mRCC, clinicians must carefully select patients and balance risks of surgery and delayed systemic therapy

Symposium "Internationale Medizinstudierende - Supportprogramme in der Praxis": Vernetzung, Best-Practice und Interessenvertretung vor Ort

The new project "International Medical Students" within the German Medical Students' Association (bvmd) aims at connecting local support programs for international medical students as well as the representation of their interests within the bvmd. Within the frame of this project, the first symposium "International Medical Students - Support Programs in Practical Application" took place from the 12th to the 14th of May 2017 at the Hannover Medical School (MHH). Through partaking in different workshops, 31 participants discussed the framework conditions of local work (i.e. curricula, tutorials, social offers, cooperation between faculty members and student body, legal aspects), common problems (i.e. addressing the target group, funding of support programs) and possible solutions (i.e. targeted advertisement, application for public funds). This report constitutes a summary of the results of these discussions. The feedback from the participants on the need for such a regular exchange and the format of the symposium was positive. However, there were requests for further thematic specification. Based on this feedback the next symposium is planned for 2018.Das Projekt "Internationale Medizinstudierende" ist ein junges Projekt innerhalb der Bundesvertretung der Medizinstudierenden in Deutschland e.V. (bvmd). Es zielt auf die Vernetzung lokaler Supportprogramme für internationale Medizinstudierende sowie deren Interessenvertretung innerhalb der medizinischen Studierendenschaft ab. Im Rahmen dieser Arbeit fand vom 12. bis 14. Mai 2017 das erste Symposium "Internationale Medizinstudierende - Supportprogramme in der Praxis" an der Medizinischen Hochschule Hannover (MHH) statt. Die 31 Teilnehmenden diskutierten in elf Workshops über die Rahmenbedingungen der lokalen Arbeit (Curricula, Tutorien, soziale Angebote, Kooperation zwischen Fakultät und Studierendenschaft, juristische Aspekte), häufige Problemlagen (Ansprache der Zielgruppe, Finanzierung von Supportprogrammen) und mögliche Lösungen (gezielte Werbung, Beantragung von öffentlicher Mitteln). Der vorliegende Bericht stellt eine Zusammenfassung der Ergebnisse dieser Diskussionen dar. Die Rückmeldungen der Teilnehmenden zum Bedarf solch eines regelmäßigen Austausches sowie dem Format des Symposiums waren positiv, allerdings wurde eine thematische Konkretisierung gewünscht. Vor diesem Hintergrund ist eine Wiederholung des Formats für das Jahr 2018 geplant

Interaktiver, studentengeleiteter Prüfungsvorbereitungskurs für internationale Vollzeit-Medizinstudierende im zweiten Jahr: quantitative und qualitative Evaluation

Background: It has been documented that international students face diverse challenges due to language and cultural barriers. International medical students suffer from personal distress, a lack of support and perform poorer than local fellow-students in clinical examinations. It has been documented that international medical students benefit from peer-led tutorials in their first year. We investigated the effectiveness of a tutorial offered for international medical students in their second year.Methods: A peer-guided examination preparation course with interactive elements for second year international medical students was designed, learning objectives were defined. Two evaluations were undertaken: In a quantitative assessment, students were asked to fill out five multiple-choice-questions at the beginning of every session of the tutorial (pre-test) as well as to participate in a post-test at the end of the semester in which all former multiple-choice-questions were re-used. Using a qualitative approach, participants were asked for their thoughts and comments in a semi-structured interview at the end of the semester.Results: International students (N=12) showed significantly better results in the post- than in the pre-test (t(11)=-8.48, p<.001, d=1.95). Within the interviews, international students (N=10) reported to have benefited from technical and didactic, as well as social learning experiences. The individual lectures students were asked to contribute were discussed controversially.Conclusion: Our peer-guided tutorial for second year international medical students is an effective and well accepted possibility to prepare these students for examinations.Hintergrund: Es ist bekannt, dass internationale Studierende aufgrund bestehender sprachlicher und kultureller Hürden vor verschiedenartige Herausforderungen gestellt werden. Internationale Medizinstudierende leiden unter persönlichem Stress sowie unzureichender Unterstützung und zeigen in klinischen Prüfungen schlechtere Ergebnisse als einheimische Kommilitonen. Es konnte gezeigt werden, dass internationale Medizinstudierende im ersten Studienjahr von studentengeleiteten Tutorien profitieren können. In der vorliegenden Studie wurde die Wirksamkeit eines Tutoriums für internationale Medizinstudierende im zweiten Studienjahr untersucht.Methodik: Ein studentengeleitetes Tutorium mit interaktiven Elementen für internationale Medizinstudierende im zweiten Studienjahr wurde konzipiert und Lernziele wurden definiert. Zwei Evaluationen wurden dabei vorgenommen: In einer quantitativen Erhebung waren Studierende aufgefordert, zu Beginn jeder Tutoriumssitzung fünf Multiple-Choice-Fragen zu beantworten (Prä-Test) und außerdem, am Ende des Semesters an einem Post-Test teilzunehmen, in welchem alle vorherigen Multiple-Choice-Fragen erneut verwendet wurden. In einem qualitativen Ansatz wurden freiwillige Teilnehmer am Ende des Semesters bzgl. ihrer Gedanken und Anmerkungen in halbstrukturierten Interviews befragt.Ergebnisse: Internationale Studierende (N=12) zeigten signifikant bessere Ergebnisse in den Post-Tests als in den Prä-Tests (t(11)=-8,48, p<,001, d=1,95). Im Rahmen der Interviews berichteten die internationalen Studierenden (N=10), im Tutorium von technisch-didaktischen sowie sozialen Lernerfahrungen profitiert zu haben. Die individuellen Vorträge, welche die Studierenden gebeten worden waren zu halten, wurden kontrovers diskutiert. Schlussfolgerung: Unser studentengeleitetes Tutorium für internationale Medizinstudierende im zweiten Studienjahr ist eine effektive und gut angenommene Möglichkeit, diese Studierenden auf Prüfungen vorzubereiten

Identification of Bichalcones as Sirtuin Inhibitors by Virtual Screening and In Vitro Testing

Sirtuins are nicotinamide adenine dinucleotide (NAD+)-dependent class III histone deacetylases, which have been linked to the pathogenesis of numerous diseases, including HIV, metabolic disorders, neurodegeneration and cancer. Docking of the virtual pan-African natural products library (p-ANAPL), followed by in vitro testing, resulted in the identification of two inhibitors of sirtuin 1, 2 and 3 (sirt1–3). Two bichalcones, known as rhuschalcone IV (8) and an analogue of rhuschalcone I (9), previously isolated from the medicinal plant Rhus pyroides, were shown to be active in the in vitro assay. The rhuschalcone I analogue (9) showed the best activity against sirt1, with an IC50 value of 40.8 µM. Based on the docking experiments, suggestions for improving the biological activities of the newly identified hit compounds have been provided