TOP1 Mutations and Cross-Resistance to Antibody-Drug Conjugates in Patients with Metastatic Breast Cancer.

Purpose: Antibody-drug conjugates (ADCs) harboring topoisomerase I (TOP1) inhibitor payloads have improved survival for patients with metastatic breast cancer (MBC). However, knowledge of ADC resistance mechanisms and potential impact on sequential use of ADCs is limited. Here, we report the incidence and characterization of TOP1 mutations arising in the setting of ADC resistance in MBC.

Greater recalled pain and movement-evoked pain are associated with longer 400-meter walk and repeat stair climb time: the Study of Muscle, Mobility and Aging.

Background: Musculoskeletal pain frequently accompanies the development of mobility disability and falls in old age. To better understand this, we aimed to quantify the impact of different pain measures-recalled pain and movement-evoked pain-on 400-meter walk and stair climb time in older adults participating in the Study of Muscle, Mobility and Aging (SOMMA).

Methods: In SOMMA (N=879, age=76.

Expression of mitochondrial oxidative stress response genes in muscle is associated with mitochondrial respiration, physical performance, and muscle mass in the Study of Muscle, Mobility, and Aging.

Gene expression in skeletal muscle of older individuals may reflect compensatory adaptations in response to oxidative damage that preserve tissue integrity and maintain function. Identifying associations between oxidative stress response gene expression patterns and mitochondrial function, physical performance, and muscle mass in older individuals would further our knowledge of mechanisms related to managing molecular damage that may be targeted to preserve physical resilience. To characterize expression patterns of genes responsible for the oxidative stress response, RNA was extracted and sequenced from skeletal muscle biopsies collected from 575 participants (≥70 years old) from the Study of Muscle, Mobility, and Aging.

Higher expression of denervation-responsive genes is negatively associated with muscle volume and performance traits in the study of muscle, mobility, and aging (SOMMA).

With aging skeletal muscle fibers undergo repeating cycles of denervation and reinnervation. In approximately the 8th decade of life reinnervation no longer keeps pace, resulting in the accumulation of persistently denervated muscle fibers that in turn cause an acceleration of muscle dysfunction. The significance of denervation in important clinical outcomes with aging is poorly studied.

Autophagy gene expression in skeletal muscle of older individuals is associated with physical performance, muscle volume and mitochondrial function in the study of muscle, mobility and aging (SOMMA).

Autophagy is essential for proteostasis, energetic balance, and cell defense and is a key pathway in aging. Identifying associations between autophagy gene expression patterns in skeletal muscle and physical performance outcomes would further our knowledge of mechanisms related with proteostasis and healthy aging. Muscle biopsies were obtained from participants in the Study of Muscle, Mobility, and Aging (SOMMA).

Sotorasib Is a Pan-RASG12C Inhibitor Capable of Driving Clinical Response in NRASG12C Cancers.

Unlabelled: KRASG12C inhibitors, like sotorasib and adagrasib, potently and selectively inhibit KRASG12C through a covalent interaction with the mutant cysteine, driving clinical efficacy in KRASG12C tumors. Because amino acid sequences of the three main RAS isoforms-KRAS, NRAS, and HRAS-are highly similar, we hypothesized that some KRASG12C inhibitors might also target NRASG12C and/or HRASG12C, which are less common but critical oncogenic driver mutations in some tumors. Although some inhibitors, like adagrasib, were highly selective for KRASG12C, others also potently inhibited NRASG12C and/or HRASG12C.

The Association of Skeletal Muscle Energetics With Recurrent Falls in Older Adults Within the Study of Muscle, Mobility and Aging.

Background: Falls in the older population are a major public health concern. While many physiological and environmental factors have been associated with fall risk, muscle mitochondrial energetics has not yet been investigated.

Methods: In this analysis, 835 Study of Muscle, Mobility and Aging (SOMMA) participants aged 70-94 were surveyed for number of falls (total), recurrent falls (2+), and fall-related injuries over the past 12 months at baseline and again after 1 year.

Lower muscle mitochondrial energetics is associated with greater phenotypic frailty in older women and men: the Study of Muscle, Mobility and Aging.

Background: Phenotypic frailty syndrome identifies older adults at greater risk for adverse health outcomes. Despite the critical role of mitochondria in maintaining cellular function, including energy production, the associations between muscle mitochondrial energetics and frailty have not been widely explored in a large, well-phenotyped, older population.

Methods: The Study of Muscle, Mobility and Aging (SOMMA) assessed muscle energetics in older adults (N = 879, mean age = 76.

Expression of mitochondrial oxidative stress response genes in muscle is associated with mitochondrial respiration, physical performance, and muscle mass in the Study of Muscle, Mobility and Aging (SOMMA).

Gene expression in skeletal muscle of older individuals may reflect compensatory adaptations in response to oxidative damage that preserve tissue integrity and maintain function. Identifying associations between oxidative stress response gene expression patterns and mitochondrial function, physical performance, and muscle mass in older individuals would further our knowledge of mechanisms related to managing molecular damage that may be targeted to preserve physical resilience. To characterize expression patterns of genes responsible for the oxidative stress response, RNA was extracted and sequenced from skeletal muscle biopsies collected from 575 participants (≥70 years old) from the Study of Muscle, Mobility and Aging.

The association of skeletal muscle energetics with recurrent falls in older adults within the Study of Muscle, Mobility and Aging (SOMMA).

Background: Falls in the older population are a major public health concern. While many physiological and environmental factors have been associated with fall risk, muscle mitochondrial energetics has not yet been investigated.

Methods: In this analysis, 835 Study of Muscle, Mobility and Aging (SOMMA) participants aged 70-94 were surveyed for recurrent falls (2+) after one year.

Higher Expression of Denervation-responsive Genes is Negatively Associated with Muscle Volume and Performance Traits in the Study of Muscle, Mobility and Aging (SOMMA).

With aging skeletal muscle fibers undergo repeating cycles of denervation and reinnervation. In approximately the 8 decade of life reinnervation no longer keeps pace, resulting in the accumulation of persistently denervated muscle fibers that in turn cause an acceleration of muscle dysfunction. The significance of denervation in important clinical outcomes with aging is poorly studied.

Autophagy gene expression in skeletal muscle of older individuals is associated with physical performance, muscle volume and mitochondrial function in the Study of Muscle, Mobility and Aging (SOMMA).

Autophagy is an essential component of proteostasis and a key pathway in aging. Identifying associations between autophagy gene expression patterns in skeletal muscle and physical performance outcomes would further our knowledge of mechanisms related with proteostasis and healthy aging. Muscle biopsies were obtained from participants in the Study of Muscle, Mobility and Aging (SOMMA).

Allosteric PI3Kα Inhibition Overcomes On-target Resistance to Orthosteric Inhibitors Mediated by Secondary PIK3CA Mutations.

Unlabelled: PIK3CA mutations occur in ∼8% of cancers, including ∼40% of HR-positive breast cancers, where the PI3K-alpha (PI3Kα)-selective inhibitor alpelisib is FDA approved in combination with fulvestrant. Although prior studies have identified resistance mechanisms, such as PTEN loss, clinically acquired resistance to PI3Kα inhibitors remains poorly understood. Through serial liquid biopsies and rapid autopsies in 39 patients with advanced breast cancer developing acquired resistance to PI3Kα inhibitors, we observe that 50% of patients acquire genomic alterations within the PI3K pathway, including PTEN loss and activating AKT1 mutations.

KRAS-independent feedback activation of wild-type RAS constrains KRAS inhibitor efficacy.

Although KRAS has long been considered undruggable, direct KRAS inhibitors have shown promising initial clinical efficacy. However, the majority of patients still fail to respond. Adaptive feedback reactivation of RAS-mitogen-activated protein kinase (MAPK) signaling has been proposed by our group and others as a key mediator of resistance, but the exact mechanism driving reactivation and the therapeutic implications are unclear.

The reciprocal relationship between cardiac baroreceptor sensitivity and cerebral autoregulation during simulated hemorrhage in humans.

A reciprocal relationship between the baroreflex and cerebral autoregulation (CA) has been demonstrated at rest and in response to acute hypotension. We hypothesized that the reciprocal relationship between cardiac baroreflex sensitivity (BRS) and CA would be maintained during sustained central hypovolemia induced by lower body negative pressure (LBNP), and that the strength of this relationship would be greater in subjects with higher tolerance to this stress. Healthy young adults (n = 51; 23F/28M) completed a LBNP protocol to presyncope.

Quantifying External Load and Injury Occurrence in Women's Collegiate Volleyball Players Across a Competitive Season.

Taylor, JB, Barnes, HC, Gombatto, SP, Greenwood, D, and Ford, KR. Quantifying external load and injury occurrence in women's collegiate volleyball players across a competitive season. J Strength Cond Res 36(3): 805-812, 2022-Volleyball demands repetitive jumping, with high loads linked to risk of injury.

Peaks and valleys: oscillatory cerebral blood flow at high altitude protects cerebral tissue oxygenation.

Oscillatory patterns in arterial pressure and blood flow (at ∼0.1 Hz) may protect tissue oxygenation during conditions of reduced cerebral perfusion and/or hypoxia. We hypothesized that inducing oscillations in arterial pressure and cerebral blood flow at 0.

The impact of acute central hypovolemia on cerebral hemodynamics: does sex matter?

Trauma-induced hemorrhage is a leading cause of disability and death due, in part, to impaired perfusion and oxygenation of the brain. It is unknown if cerebrovascular responses to blood loss are differentiated based on sex. We hypothesized that compared to males, females would have reduced tolerance to simulated hemorrhage induced by maximal lower body negative pressure (LBNP), and this would be associated with an earlier reduction in cerebral blood flow and cerebral oxygenation.

Jump load and landing patterns of collegiate female volleyball players during practice and competition.

Background: Overuse lower extremity injuries are common in women's court volleyball players and are likely due to the repetitive jumping and landing the sport requires. The purpose of this study was to quantify jump load during collegiate women's volleyball, describe the quantity of double-leg (DL) to single-leg (SL) landing strategies, and compare loads and landing strategies between games and practices.

Methods: Fourteen collegiate Division-1 women's court volleyball players participated in the study.