Cytosolic Protein Vms1 Links Ribosome Quality Control to Mitochondrial and Cellular Homeostasis.

Eukaryotic cells have evolved extensive protein quality-control mechanisms to remove faulty translation products. Here, we show that yeast cells continually produce faulty mitochondrial polypeptides that stall on the ribosome during translation but are imported into the mitochondria. The cytosolic protein Vms1, together with the E3 ligase Ltn1, protects against the mitochondrial toxicity of these proteins and maintains cell viability under respiratory conditions. In the absence of these factors, stalled polypeptides aggregate after import and sequester critical mitochondrial chaperone and translation machinery. Aggregation depends on C-terminal alanyl/threonyl sequences (CAT-tails) that are attached to stalled polypeptides on 60S ribosomes by Rqc2. Vms1 binds to 60S ribosomes at the mitochondrial surface and antagonizes Rqc2, thereby facilitating import, impeding aggregation, and directing aberrant polypeptides to intra-mitochondrial quality control. Vms1 is a key component of a rescue pathway for ribosome-stalled mitochondrial polypeptides that are inaccessible to ubiquitylation due to coupling of translation and translocation.

Geriatric assessment for the practicing clinician: The why, what, and how.

Older adults with cancer heterogeneously experience health care, treatment, and symptoms. Geriatric assessment (GA) offers a comprehensive evaluation of an older individual's health status and can predict cancer-related outcomes in individuals with solid tumors and those with hematologic malignancies. In the last decade, randomized controlled trials have demonstrated the benefits of GA and GA management (GAM), which uses GA information to provide tailored intervention strategies to address GA impairments (e.g., implementing physical therapy for impaired physical function). Multiple phase 3 clinical trials in older adults with solid tumors and hematologic malignancies have demonstrated that GAM improves treatment completion, quality of life, communication, and advance care planning while reducing treatment-related toxicity, falls, and polypharmacy. Nonetheless, implementation and uptake of GAM remain challenging. Various strategies have been proposed, including the use of GA screening tools, to identify patients most likely to benefit from GAM, the systematic engagement of the oncology workforce in the delivery of GAM, and the integration of technologies like telemedicine and mobile health to enhance the availability of GA and GAM interventions. Health inequities in minoritized groups persist, and systematic GA implementation has the potential to capture social determinants of health that are relevant to equitable care. Caregivers play an important role in cancer care and experience burden themselves. GA can guide dyadic supportive care interventions, ultimately helping both patients and caregivers achieve optimal health.

Navigating financial toxicity in patients with cancer: A multidisciplinary management approach.

Approximately one-half of individuals with cancer face personal economic burdens associated with the disease and its treatment, a problem known as financial toxicity (FT). FT more frequently affects socioeconomically vulnerable individuals and leads to subsequent adverse economic and health outcomes. Whereas multilevel systemic factors at the policy, payer, and provider levels drive FT, there are also accompanying intervenable patient-level factors that exacerbate FT in the setting of clinical care delivery. The primary strategy to intervene on FT at the patient level is financial navigation. Financial navigation uses comprehensive assessment of patients' risk factors for FT, guidance toward support resources, and referrals to assist patient financial needs during cancer care. Social workers or nurse navigators most frequently lead financial navigation. Oncologists and clinical provider teams are multidisciplinary partners who can support optimal FT management in the context of their clinical roles. Oncologists and clinical provider teams can proactively assess patient concerns about the financial hardship and employment effects of disease and treatment. They can respond by streamlining clinical treatment and care delivery planning and incorporating FT concerns into comprehensive goals of care discussions and coordinated symptom and psychosocial care. By understanding how age and life stage, socioeconomic, and cultural factors modify FT trajectory, oncologists and multidisciplinary health care teams can be engaged and informative in patient-centered, tailored FT management. The case presentations in this report provide a practical context to summarize authors' recommendations for patient-level FT management, supported by a review of key supporting evidence and a discussion of challenges to mitigating FT in oncology care. CA Cancer J Clin. 2022;72:437-453.

Female erectile tissues and sexual dysfunction after pelvic radiotherapy: A scoping review.

Sexual function is a vital aspect of human health and is recognized as a critical component of cancer survivorship. Understanding and evaluating the impacts of radiotherapy on female sexual function requires precise knowledge of the organs involved in sexual function and the relationship between radiotherapy exposure and sexual tissue function. Although substantial evidence exists describing the impact of radiotherapy on male erectile tissues and related clinical sexual outcomes, there is very little research in this area in females. The lack of biomedical data in female patients makes it difficult to design studies aimed at optimizing sexual function postradiotherapy for female pelvic malignancies. This scoping review identifies and categorizes current research on the impacts of radiotherapy on normal female erectile tissues, including damage to normal functioning, clinical outcomes of radiation-related female erectile tissue damage, and techniques to spare erectile tissues or therapies to treat such damage. An evaluation of the evidence was performed, and a summary of findings was generated according to Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) Extension for Scoping Reviews guidelines. Articles were included in the review that involved normal female erectile tissues and radiotherapy side effects. The results show that little scientific investigation into the impacts of radiotherapy on female erectile tissues has been performed. Collaborative scientific investigations by clinical, basic, and behavioral scientists in oncology and radiotherapy are needed to generate radiobiologic and clinical evidence to advance prospective evaluation, prevention, and mitigation strategies that may improve sexual outcomes in female patients.

The broadening scope of oral mucositis and oral ulcerative mucosal toxicities of anticancer therapies.

Oral mucositis (OM) is a common, highly symptomatic complication of cancer therapy that affects patients' function, quality of life, and ability to tolerate treatment. In certain patients with cancer, OM is associated with increased mortality. Research on the management of OM is ongoing. Oral mucosal toxicities are also reported in targeted and immune checkpoint inhibitor therapies. The objective of this article is to present current knowledge about the epidemiology, pathogenesis, assessment, risk prediction, and current and developing intervention strategies for OM and other ulcerative mucosal toxicities caused by both conventional and evolving forms of cancer therapy.

Radiation therapy-associated toxicity: Etiology, management, and prevention.

Radiation therapy (RT) is a curative treatment for many malignancies and provides effective palliation in patients with tumor-related symptoms. However, the biophysical effects of RT are not specific to tumor cells and may produce toxicity due to exposure of surrounding organs and tissues. In this article, the authors review the clinical context, pathophysiology, risk factors, presentation, and management of RT side effects in each human organ system. Ionizing radiation works by producing DNA damage leading to tumor death, but effects on normal tissue may result in acute and/or late toxicity. The manifestation of toxicity depends on both cellular characteristics and affected organs' anatomy and physiology. There is usually a direct relationship between the radiation dose and volume to normal tissues and the risk of toxicity, which has led to guidelines and recommended dose limits for most tissues. Side effects are multifactorial, with contributions from baseline patient characteristics and other oncologic treatments. Technological advances in recent decades have decreased RT toxicity by dramatically improving the ability to deliver RT that maximizes tumor dose and minimizes organ dose. Thus the study of RT-associated toxicity is a complex, core component of radiation oncology training that continues to evolve alongside advances in cancer management. Because RT is used in up to one-half of all patients with cancer, an understanding of its acute and late effects in different organ systems is clinically pertinent to both oncologists and nononcologists.

Muscle Toxicity of Drugs: When Drugs Turn Physiology into Pathophysiology.

Drugs are prescribed to manage or prevent symptoms and diseases, but may sometimes cause unexpected toxicity to muscles. The symptomatology and clinical manifestations of the myotoxic reaction can vary significantly between drugs and between patients on the same drug. This poses a challenge on how to recognize and prevent the occurrence of drug-induced muscle toxicity. The key to appropriate management of myotoxicity is prompt recognition that symptoms of patients may be drug related and to be aware that inter-individual differences in susceptibility to drug-induced toxicity exist. The most prevalent and well-documented drug class with unintended myotoxicity are the statins, but even today new classes of drugs with unintended myotoxicity are being discovered. This review will start off by explaining the principles of drug-induced myotoxicity and the different terminologies used to distinguish between grades of toxicity. The main part of the review will focus on the most important pathogenic mechanisms by which drugs can cause muscle toxicity, which will be exemplified by drugs with high risk of muscle toxicity. This will be done by providing information on key clinical and laboratory aspects, muscle electromyography patterns and biopsy results, and pathological mechanism and management for a specific drug from each pathogenic classification. In addition, rather new classes of drugs with unintended myotoxicity will be highlighted. Furthermore, we will explain why it is so difficult to diagnose drug-induced myotoxicity, and which tests can be used as a diagnostic aid. Lastly, a brief description will be given of how to manage and treat drug-induced myotoxicity.

Repeat-Associated Non-ATG Translation: Molecular Mechanisms and Contribution to Neurological Disease.

Microsatellite mutations involving the expansion of tri-, tetra-, penta-, or hexanucleotide repeats cause more than 40 different neurological disorders. Although, traditionally, the position of the repeat within or outside of an open reading frame has been used to focus research on disease mechanisms involving protein loss of function, protein gain of function, or RNA gain of function, the discoveries of bidirectional transcription and repeat-associated non-ATG (RAN) have blurred these distinctions. Here we review what is known about RAN proteins in disease, the mechanisms by which they are produced, and the novel therapeutic opportunities they provide.

Lipid nanoparticle structure and delivery route during pregnancy dictate mRNA potency, immunogenicity, and maternal and fetal outcomes.

Treating pregnancy-related disorders is exceptionally challenging because the threat of maternal and/or fetal toxicity discourages the use of existing medications and hinders new drug development. One potential solution is the use of lipid nanoparticle (LNP) RNA therapies, given their proven efficacy, tolerability, and lack of fetal accumulation. Here, we describe LNPs for efficacious mRNA delivery to maternal organs in pregnant mice via several routes of administration. In the placenta, our lead LNP transfected trophoblasts, endothelial cells, and immune cells, with efficacy being structurally dependent on the ionizable lipid polyamine headgroup. Next, we show that LNP-induced maternal inflammatory responses affect mRNA expression in the maternal compartment and hinder neonatal development. Specifically, pro-inflammatory LNP structures and routes of administration curtailed efficacy in maternal lymphoid organs in an IL-1ß-dependent manner. Further, immunogenic LNPs provoked the infiltration of adaptive immune cells into the placenta and restricted pup growth after birth. Together, our results provide mechanism-based structural guidance on the design of potent LNPs for safe use during pregnancy.

People who share encounters with racism are silenced online by humans and machines, but a guideline-reframing intervention holds promise.

Are members of marginalized communities silenced on social media when they share personal experiences of racism? Here, we investigate the role of algorithms, humans, and platform guidelines in suppressing disclosures of racial discrimination. In a field study of actual posts from a neighborhood-based social media platform, we find that when users talk about their experiences as targets of racism, their posts are disproportionately flagged for removal as toxic by five widely used moderation algorithms from major online platforms, including the most recent large language models. We show that human users disproportionately flag these disclosures for removal as well. Next, in a follow-up experiment, we demonstrate that merely witnessing such suppression negatively influences how Black Americans view the community and their place in it. Finally, to address these challenges to equity and inclusion in online spaces, we introduce a mitigation strategy: a guideline-reframing intervention that is effective at reducing silencing behavior across the political spectrum.