Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.

Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs\u27 therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy

The Functioning of the Drosophila CPEB Protein Orb Is Regulated by Phosphorylation and Requires Casein Kinase 2 Activity

The Orb CPEB protein regulates translation of localized mRNAs in Drosophila ovaries. While there are multiple hypo- and hyperphosphorylated Orb isoforms in wild type ovaries, most are missing in orbF303, which has an amino acid substitution in a buried region of the second RRM domain. Using a proteomics approach we identified a candidate Orb kinase, Casein Kinase 2 (CK2). In addition to being associated with Orb in vivo, we show that ck2 is required for orb functioning in gurken signaling and in the autoregulation of orb mRNA localization and translation. Supporting a role for ck2 in Orb phosphorylation, we find that the phosphorylation pattern is altered when ck2 activity is partially compromised. Finally, we show that the Orb hypophosphorylated isoforms are in slowly sedimenting complexes that contain the translational repressor Bruno, while the hyperphosphorylated isoforms assemble into large complexes that co-sediment with polysomes and contain the Wisp poly(A) polymerase

Mitotic Spindle Proteomics in Chinese Hamster Ovary Cells

Mitosis is a fundamental process in the development of all organisms. The mitotic spindle guides the cell through mitosis as it mediates the segregation of chromosomes, the orientation of the cleavage furrow, and the progression of cell division. Birth defects and tissue-specific cancers often result from abnormalities in mitotic events. Here, we report a proteomic study of the mitotic spindle from Chinese Hamster Ovary (CHO) cells. Four different isolations of metaphase spindles were subjected to Multi-dimensional Protein Identification Technology (MudPIT) analysis and tandem mass spectrometry. We identified 1155 proteins and used Gene Ontology (GO) analysis to categorize proteins into cellular component groups. We then compared our data to the previously published CHO midbody proteome and identified proteins that are unique to the CHO spindle. Our data represent the first mitotic spindle proteome in CHO cells, which augments the list of mitotic spindle components from mammalian cells

Mps1Mph1 kinase phosphorylates Mad3 to inhibit Cdc20Slp1-APC/C and maintain spindle checkpoint arrests

<div><p>The spindle checkpoint is a mitotic surveillance system which ensures equal segregation of sister chromatids. It delays anaphase onset by inhibiting the action of the E3 ubiquitin ligase known as the anaphase promoting complex or cyclosome (APC/C). Mad3/BubR1 is a key component of the mitotic checkpoint complex (MCC) which binds and inhibits the APC/C early in mitosis. Mps1^Mph1 kinase is critical for checkpoint signalling and MCC-APC/C inhibition, yet few substrates have been identified. Here we identify Mad3 as a substrate of fission yeast Mps1^Mph1 kinase. We map and mutate phosphorylation sites in Mad3, producing mutants that are targeted to kinetochores and assembled into MCC, yet display reduced APC/C binding and are unable to maintain checkpoint arrests. We show biochemically that Mad3 phospho-mimics are potent APC/C inhibitors <i>in vitro</i>, demonstrating that Mad3p modification can directly influence Cdc20^Slp1-APC/C activity. This genetic dissection of APC/C inhibition demonstrates that Mps1^Mph1 kinase-dependent modifications of Mad3 and Mad2 act in a concerted manner to maintain spindle checkpoint arrests.</p></div

Temporal sequence and cell cycle cues in the assembly of host factors at the yeast 2 micron plasmid partitioning locus

The Saccharomyces cerevisiae 2 micron plasmid exemplifies a benign but selfish genome, whose stability approaches that of the chromosomes of its host. The plasmid partitioning locus STB (stability locus) displays certain functional analogies with centromeres along with critical distinctions, a significant one being the absence of the kinetochore complex at STB. The remodels the structure of chromatin (RSC) chromatin remodeling complex, the nuclear motor Kip1, the histone H3 variant Cse4 and the cohesin complex associate with both loci. These factors appear to contribute to plasmid segregation either directly or indirectly through their roles in chromosome segregation. Assembly and disassembly of the plasmid-coded partitioning proteins Rep1 and Rep2 and host factors at STB follow a temporal hierarchy during the cell cycle. Assembly is initiated by STB association of [Rsc8-Rsc58], followed by [Rep1-Rep2-Kip1] and [Cse4-Rsc2-Sth1] recruitment, and culminates in cohesin assembly. Disassembly starts with dissociation of RSC components, is followed by cohesin disassembly and Cse4 exit during anaphase and late telophase, respectively. [Rep1-Rep2-Kip1] persists through G1 of the ensuing cell cycle. The de novo assembly of the 'partitioning complex' is cued by the innate cell cycle clock and is dependent on DNA replication. Shared functional attributes of STB and centromere (CEN) are consistent with a potential evolutionary link between them

The feasibility of debranching aortic arch and visceral arteries with sutureless telescoping anastomoses during open aortic aneurysm repair

Background: Open repair of aortic aneurysms frequently requires reimplantation of major aortic vessels. Traditional techniques can be time consuming, require meticulous hemostasis, and risk aneurysmal patch degeneration, which can require a challenging reoperation. We describe our experience using a stent graft to create a sutureless anastomosis that obviates these drawbacks. Methods: Between April 2018 and March 2021, all consecutive adult patients who underwent open repair of the aorta with at least one supra-aortic trunk or visceral vessel reimplanted using the sutureless anastomotic technique were included. Anastomoses were constructed by bridging a branch graft and the target artery with a Viabahn self-expanding stent (W.L. Gore &amp; Associates, Flagstaff, AZ). Clinical information and perioperative outcomes for the patients were collected and analyzed. Results: Among 26 patients, 50 individual aortic vessels were debranched using sutureless self-expanding stent anastomoses, including 42 visceral vessels and 8 supra-aortic trunk vessels. Technical success was 100%. The median time to complete the anastomosis was 3 minutes, 12 seconds (range, 2-6 minutes). Perioperative mortality was 15% (n = 4). No stent-related complications, such as occlusion, bleeding, stroke, renal failure requiring hemodialysis, bowel ischemia, or the need for anastomotic reintervention, occurred. Follow-up imaging at 1 year revealed a 100% patency rate and no anastomotic stenosis, misalignment, or kinking. Conclusions: The sutureless anastomosis technique to debranch the aorta during open aortic aneurysm repair is technically feasible and reliably hemostatic and does not require early reintervention. The operative outcomes have been acceptable, and the short-term follow-up imaging findings demonstrated excellent patency without anastomotic kinking. In select cases, sutureless anastomoses are a possible alternative to traditional sutured anastomoses during aortic debranching. Further research is needed to compare the operative times and long-term patency of sutureless anastomosis to those of traditional sutured techniques

External Validation of a Prognostic Model of Survival for Resected Typical Bronchial Carcinoids

Background This study aimed to assess the reliability and the validity of a prognostic model of survival recently developed by the European Society of Thoracic Surgery Neuroendocrine Tumor Working Group to predict 5-year overall survival after surgical resection of pulmonary typical carcinoid. Methods We retrospectively collected data on 240 consecutive patients (164 men, 76 women; median age, 58 years [interquartile range, 47 to 68]) who underwent curative lung resection for pulmonary typical carcinoid in seven centers between 2000 and 2015. For each patient, we calculated the corresponding risk class (A, B, C, D) using the following variables: male, age, previous malignancy, Eastern Cooperative Oncology Group performance status, peripheral tumor, TNM stage. Kaplan-Meier method, and Cox proportional hazards model were used for the statistical analysis. Results During a median follow-up of 42 months (interquartile range, 11 to 84), the 5-year overall survival was 94.2% (95% confidence interval [CI]: 90.2% to 98.2%); 15 of 240 patients died. A significantly decreasing rate of survival was observed from class A to class D (p = 0.004) with rates of 100% (95% CI: 100% to 100%), 96.3% (95% CI: 88.6% to 98.8%), 86.7% (95% CI: 63.0% to 95.7%), and 33.3% (95% CI: 0.9% to 77.4%), respectively, for class A, B, C, and D. This difference persisted also using clinical stage as a variable in the risk class calculation (p = 0.006). No differences were observed in term of overall survival among TNM stage I, II, and III patients (p = 0.94). Conclusions This prognostic model of survival is easily applicable, it is validated by our independent cohort, and it appears to stratify better than the traditional TNM staging. Therefore, it may be useful in counseling patients about their outcomes from surgical treatment and in tailoring treatment for high-risk patients