Phosphatidylinositol‐3,4,5‐trisphospate (PIP3) is a potent signaling lipid that exerts key control over cell growth, survival, adhesion and migration. PIP3 signaling is often disrupted in various ...cancers, making understanding the regulation of PIP3 signaling an important priority. Much has been learned from the study of phosphorylation of the inositol headgroup of phosphoinositides, such as the phosphorylation of phosphatidylinositol‐4,5‐bisphospate (PIP2) to produce PIP3, as well as negative regulation of PIP3 by phosphoinositide phosphatases such as PTEN. However, much less is known about another key dimension of control of phosphoinositide action, the regulation of the fatty acyl profile of these lipids. Indeed, phosphatidylinositol and phosphoinositides exhibit remarkable selectivity of acyl chains (>50% harboring 1‐stearoyl, 2‐arachidonoyl), an acyl profile quite distinct from other phospholipids. This suggests that control of fatty acyl profile of phosphoinositides may be an important determinant of the function of these lipids that has to date remained largely unexplored. We recently uncovered that the acyltransferase LYCAT is a key regulator of the acyl profile of specific phosphoinositides such as PIP2, thus exerting control over membrane traffic phenomena dependent on these phosphoinositides (Bone LN et al 2017 Mol Biol Cell. 28:161–172). We now examine how LYCAT controls PIP3 signaling and PIP3‐dependent control of cell physiology, including the activation of Akt and control of actin dynamics. We find that LYCAT perturbation impairs the activation of Akt and the activation of a number of Akt substrates, which in turn impacts cell growth and survival. Furthermore, LYCAT perturbation elicits dramatic changes in actin filament morphology, cell migration and cancer cell invasion. These results indicate that control of phosphoinositide acyl chain profile is an important novel dimension of regulation of PIP3 signaling, impacting proliferative, growth and migration signaling, and as such may be a novel dimension to control of cancer cell growth and progression.
Support or Funding Information
This work was supported by an Ontario Early Researcher Award, a Canada Research Chair Award, and a Natural Sciences and Engineering Research Council Grant to R.J.B, and a Project Grant and New Investigator Salary Award from the Canadian Institutes of Health Research to C.N.A.
This is from the Experimental Biology 2019 Meeting. There is no full text article associated with this published in The FASEB Journal.
Abstract
Background
Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and ...prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers.
Methods
483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)–negative (PRSER-), or ER-positive (PRSER+) breast cancer risk.
Results
PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval CI =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions.
Conclusions
Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.
Inpatient addiction medicine services (AMS) were developed in response to the growing needs of hospitalized individuals with substance use disorders (SUDs). AMS aim to enable timely initiation of ...pharmacologic treatment, build hospital capacity to support patients who use substances, and facilitate transition to community services. As an emerging service being adopted in hospitals across North America, the model of care, populations served, substance use trends, and clinical trajectory has not been widely described. This work aims to characterize patients accessing care through the AMS, establishing predictors for clinical trajectories in hospital including patient-initiated discharge (PID) and hospital re-admission.
Using a retrospective cohort design, we describe all patients seen by the AMS between 2018 and 2022 across four hospitals in Hamilton, Ontario. Patients seen by AMS were hospitalized and qualified for a SUD based on DSM-V criteria. The study used descriptive statistics to describe the cohort, where appropriate adjusted time-to-event survival models were constructed to identify predictors for hospital re-admission.
Patients seen by the AMS (n = 695) frequently lacked access to primary care (47.0 %) and less than half (44.3 %) were receiving community addiction services on admission. The majority met criteria for opioid use disorder (OUD), with injecting being the primary consumption route (54.8 %). Patients exhibited high acuity, with 34.2 % requiring critical care measures. Provision of OAT substantially increased to 77.9 % of patients (29 % on admission). PID occurred in 17.8 % of patients and was significantly associated with an admitting diagnosis of suicidal ideation, infection, heart failure, and distinct substance use profiles including methamphetamine, fentanyl, and heroin use (p < 0.05). PID conferred a 66 % increased risk for re-admission (Hazard-Ratio: 1.66; 95 % CI: 1.08, 2.54; p = 0.02).
Patients served by AMS primarily include individuals with OUD presenting with the associated medical complications and substantial deficits in the social determinants of health (e.g., high housing insecurity, poverty, and disability). PID occurs among 1 in 5 people and is associated with higher rates of re-admission. By identifying individuals at higher risk of adverse outcomes, these results provide an opportunity to improve outcomes in this high-risk, high-vulnerability population.
Objective:
To describe sex differences in health service use among children and youth who died by suicide.
Method:
This is a retrospective study of children and youth (aged 10 to 25 years) living in ...Ontario who died by suicide between April 1, 2003, and December 31, 2007. Coroner records were individually linked to outpatient physician visit, emergency department (ED) presentation, and inpatient stay administrative health care records for 724 people (192 girls and 532 boys). Only 77 (10.6%) were aged 10 to 15 years. The health services types used, number of contacts made, and the last contact were compared in boys and girls.
Results:
About 80% of subjects had contact with the health care system in the year before their death, typically to an outpatient physician and (or) the ED. However, not all were seen for mental health reasons. Girls had more outpatient physician and ED contact than boys and closer in time to their death. Further, girls were more likely than boys to have contact in more than one setting. Still, boys and girls did not differ in their use of an outpatient psychiatrist, some ED presentations, and in the nature and number of inpatient stays.
Conclusions:
While most people were seen by an outpatient physician and (or) in the ED in the year before their death, not all received mental health care. Further research is needed to determine whether boys and girls who died by suicide differ from their peers in their health service use to guide preventive interventions.
Background: Historically, women and minorities have been less likely to receive implantable cardioverter-defibrillator (ICD) therapy than white men, despite guidelines establishing ICD use as a Class ...I indication for patients with heart failure and reduced ejection fraction (EF).
Abstract
Anti-semaphorin 4D (SEMA4D, CD100) blocking antibody promotes immune infiltration, reduces immunosuppressive myeloid cells, and enhances T cell activity and tumor growth inhibition in ...combination with various immunotherapies in preclinical animal models. Clinical trials of immune checkpoint inhibitors (ICI) in combination with pepinemab (VX15/2503), humanized anti-SEMA4D antibody, are currently underway in several cancer indications. SEMA4D exerts multi-faceted effects within the tumor microenvironment by creating a barrier at the tumor-stroma margin to restrict immune cell infiltration and promote immunosuppressive activity of myeloid-derived cells. Blocking antibody to SEMA4D directly enhanced M1/M2 ratio and reduced both expression of chemokines that recruit MDSC and the ability of MDSC to suppress T cell activity. Antibody blockade simultaneously restored the ability of dendritic cells and cytotoxic T cells to infiltrate the TME, increasing ratio of Teffector to Tregulatory cells, in syngeneic tumor models. Importantly, anti-SEMA4D MAb enhanced the activity of co-administered immunotherapies, including antibodies to PD1, CTLA-4, and LAG3, epigenetic modulators, and additional novel immunomodulatory combinations in murine breast, colon, head and neck, and melanoma tumor models. New data will describe development and application of methods to assess immune phenotype and biomarkers in translational and clinical studies. These include flow cytometry and whole slide scans of multiplex IHC panels to examine MDSC, M1/M2 macrophage, monocytes, activated DC, B cells, exhausted, activated and stem-like populations of T cells in clinical samples. Expression of SEMA4D and its receptor PlexinB1 were also evaluated in spatial context and cellular co-localization. In summary, SEMA4D represents a novel target to regulate immune infiltration and mesenchymal suppression, sources of resistance to current immunotherapies. Pepinemab treatment was well tolerated in a Phase I oncology trial (NCT01313065) and is currently being evaluated as single agent or in ICI combinations in: (i) a Phase 1b/2a combination trial of pepinemab with avelumab in ICI naïve or ICI refractory NSCLC (CLASSICAL-Lung) (NCT03268057); (ii) a phase 1 combination trial of pepinemab with nivolumab or ipilimumab in melanoma patients who have progressed on any anti-PD-1/PD-L1 (NCT03425461); (iii) a neoadjuvant integrated biomarker trial in patients with metastatic colorectal, pancreatic (NCT03373188) and head and neck (NCT03690986) cancers treated with pepinemab in combination with nivolumab or ipilimumab; and (iv) a Phase 1/2 trial of pepinemab in children with solid tumors and children and young adults with osteosarcoma (NCT03320330). Clinical trials will evaluate safety, tolerability, efficacy, and biological endpoints, including immunophenotyping tumors and blood.
Citation Format: Elizabeth E. Evans, Terrence L. Fisher, Holm Bussler, Crystal Mallow, Christine Reilly, Sebold Torno, Desa Rae Pastore, Maria Scrivens, Alan Howell, Leslie Balch, John E. Leonard, Clint Allen, Paul E. Clavijo, Gregory Lesinski, Christina Wu, Conor Steuer, Nabil F. Saba, Brian Olson, Siwen Hu-Lieskovan, Antoni Ribas, Emily G. Greengard, Ernest S. Smith, Maurice Zauderer. Altered myeloid and lymphoid composition of tumor microenvironment following anti-SEMA4D and immune checkpoint combination therapies abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1545.
Ocean acidification (OA) describes the progressive decrease in the pH of seawater and other cascading chemical changes resulting from oceanic uptake of atmospheric carbon. These changes can have ...important implications for marine ecosystems, creating risk for commercial industries, subsistence communities, cultural practices, and recreation. Characterizing the extent of acidification and predicting the ramifications for marine and freshwater resources and ecosystem services are critical to national and international climate mitigation discussions and to local communities that rely on these resources. Based on critical grassroots connections between scientists and stakeholders, “Knowledge-to-Action” networks for ocean acidification issues have formed at regional international and global scales to take action. We review examples at these three levels where groups are elevating the issue of ocean acidification and developing practicable, implementable steps to mitigate causes, to adapt to unavoidable change, and to build resilience to changing ocean conditions in the marine environment and coastal communities. While these first steps represent critical efforts in protecting ecosystems and economies from the risks posed by ocean acidification, some challenges remain. Sensitivity and risk to OA varies by region and industry; priorities for action can vary between multiple and conflicting partners; evidence-based strategies for OA risk mitigation are still in the early stages; and there remain gaps between scientific research and actionable decision-maker support products. However, these scaled networks have proven to be adept at identifying and addressing these barriers to action. In the future, it will be critical to expand funding for food web impact studies, development of decision support tools, and to maintain the connections between scientists and marine resource users to build resilience to ocean acidification impacts.
Summary
Familial cerebral cavernous malformations are autosomal dominant conditions that can result in significant morbidity. A two‐hit mechanism is accepted as likely responsible for formation of ...these malformations. We present two patients with this disease who received therapeutic radiation and developed very high numbers of malformations within the radiation ports, supporting radiation as an accelerator of lesion formation and suggesting implications for risks of radiation in this disease.
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