Cross-species identification of PIP5K1-, splicing- and ubiquitin-related pathways as potential targets for RB1-deficient cells.

The RB1 tumor suppressor is recurrently mutated in a variety of cancers including retinoblastomas, small cell lung cancers, triple-negative breast cancers, prostate cancers, and osteosarcomas. Finding new synthetic lethal (SL) interactions with RB1 could lead to new approaches to treating cancers with inactivated RB1. We identified 95 SL partners of RB1 based on a Drosophila screen for genetic modifiers of the eye phenotype caused by defects in the RB1 ortholog, Rbf1. We validated 38 mammalian orthologs of Rbf1 modifiers as RB1 SL partners in human cancer cell lines with defective RB1 alleles. We further show that for many of the RB1 SL genes validated in human cancer cell lines, low activity of the SL gene in human tumors, when concurrent with low levels of RB1 was associated with improved patient survival. We investigated higher order combinatorial gene interactions by creating a novel Drosophila cancer model with co-occurring Rbf1, Pten and Ras mutations, and found that targeting RB1 SL genes in this background suppressed the dramatic tumor growth and rescued fly survival whilst having minimal effects on wild-type cells. Finally, we found that drugs targeting the identified RB1 interacting genes/pathways, such as UNC3230, PYR-41, TAK-243, isoginkgetin, madrasin, and celastrol also elicit SL in human cancer cell lines. In summary, we identified several high confidence, evolutionarily conserved, novel targets for RB1-deficient cells that may be further adapted for the treatment of human cancer.

Climate Change and the Urgent Need to Prepare Persons With Multiple Sclerosis for Extreme Hurricanes.

Climate change is contributing to increasingly hazardous tropical cyclones that endanger persons living in susceptible coastal and island communities. People living with chronic illness, including multiple sclerosis (MS), face unique challenges and vulnerabilities when exposed to hurricane hazards. Disaster and emergency preparedness requires a customized approach that considers the necessary adaptations to accommodate the mobility, self-care, sensory, cognitive, and communication impairments of persons living with MS. Related considerations include the potential for worsening neurologic signs and symptoms during and after a catastrophic storm. The impact of emotional and financial stresses, as well as disruptions in health care delivery, on this population are also key concerns. This paper addresses the challenges faced by individuals with MS in advance of, during, and in the aftermath of extreme storms. We propose new guidelines on how health care professionals can assist persons with MS when creating tailored disaster readiness and response plans.

ABCD1 Gene Mutations: Mechanisms and Management of Adrenomyeloneuropathy.

Pathogenic variants in the ABCD1 gene on the X chromosome may result in widely heterogenous phenotypes, including adrenomyeloneuropathy (AMN). Affected males typically present in their third or fourth decade of life with progressive lower limb weakness and spasticity, and may develop signs and symptoms of adrenal insufficiency and/or cerebral demyelination. Heterozygous females may be asymptomatic, but may develop a later-onset and more slowly progressive spastic paraparesis. In this review, we describe the clinical presentation of AMN, as well as its diagnosis and management. The role of rehabilitative therapies and options for management of spasticity are highlighted.

An Unusual Case of Streptococcus anginosus Endocarditis in a Healthy Host With Bicuspid Aortic Valve.

Streptococcus anginosus group (SAG) is a subgroup of viridans streptococci and can be found ubiquitously in normal human flora. SAG is known to form invasive pyogenic infection when it becomes pathogenic. Yet, SAG is a very rare cause of endocarditis, and there is a dearth of case reports on this topic. We present a rare case of native bicuspid aortic valve endocarditis secondary to S. anginosus that caused aortic insufficiency and ascending aortic aneurysm. To our knowledge, this is the first well-documented case report of community-acquired S. anginosus endocarditis on a bicuspid aortic valve in an immunocompetent patient. The patient first presented with cough that was likely due to bronchus irritation from a 5.5 x 5.2 cm ascending aortic aneurysm. He underwent aortic valve replacement with bovine bioprosthesis and ascending aortic aneurysm repairment and was treated with a two-week regimen of IV ceftriaxone and gentamicin followed by another four weeks of IV ceftriaxone. He was eventually discharged to a rehabilitation facility. SAG is usually susceptible to beta-lactam antibiotics. The prognosis of SAG infection is usually good, but progression to bacteremia carries a poor outcome.