An inexorable decline in maximum heart rate (mHR) progressively limits human aerobic capacity with advancing age. This decrease in mHR results from an age-dependent reduction in "intrinsic heart rate" (iHR), which is measured during autonomic blockade. The reduced iHR indicates, by definition, that pacemaker function of the sinoatrial node is compromised during aging. However, little is known about the properties of pacemaker myocytes in the aged sinoatrial node. Here, we show that depressed excitability of individual sinoatrial node myocytes (SAMs) contributes to reductions in heart rate with advancing age. We found that agedependent declines in mHR and iHR in ECG recordings from mice were paralleled by declines in spontaneous action potential (AP) firing rates (FRs) in patch-clamp recordings from acutely isolated SAMs. The slower FR of aged SAMs resulted from changes in the AP waveform that were limited to hyperpolarization of the maximum diastolic potential and slowing of the early part of the diastolic depolarization. These AP waveform changes were associated with cellular hypertrophy, reduced current densities for L-and T-type Ca 2+ currents and the "funny current" (I f ), and a hyperpolarizing shift in the voltage dependence of I f . The agedependent reduction in sinoatrial node function was not associated with changes in β-adrenergic responsiveness, which was preserved during aging for heart rate, SAM FR, L-and T-type Ca 2+ currents, and I f . Our results indicate that depressed excitability of individual SAMs due to altered ion channel activity contributes to the decline in mHR, and thus aerobic capacity, during normal aging. O ne of the most insidious aspects of growing older is an inevitable decline in maximum heart rate (mHR), which limits maximum aerobic capacity with advancing age (1-3). The decline in mHR proceeds at approximately the same rate for all individuals, without regard for lifestyle or physical fitness (4-8). For many otherwise healthy elderly people, it is the factor that ultimately restricts the ability to live independently (9, 10).The decrease in mHR with age results primarily from a parallel age-dependent decline in "intrinsic heart rate" (iHR) (11-13), which is measured during autonomic blockade, and thus reflects the spontaneous pacemaker activity of the sinoatrial node of the heart. Although it is known that the intact sinoatrial node from aged animals contracts more slowly (14, 15) and contains fewer pacemaker myocytes (16), little is known about the functional properties of individual myocytes from the sinoatrial node of the aged heart.Sinoatrial myocytes (SAMs) are highly specialized cells that serve a primarily electrical function as cardiac pacemakers via their production of spontaneous action potentials (APs). Sinoatrial APs are characterized by a spontaneous depolarization during diastole that drives the membrane potential to threshold, thereby triggering the subsequent AP. This "diastolic depolarization" (DD) phase of the sinoatrial AP results from the coordinated activit...

IMPORTANCE Oral cavity squamous cell carcinoma (OCSCC) is associated with often-delayed clinical diagnosis, poor prognosis, and expensive therapeutic approaches. Prognostic accuracy is important in improving treatment outcomes of patients with this disease.OBJECTIVES To assess lymph node ratio (LNR) and other factors in estimating response to treatment and provide prognostic information helpful for clinical decision making.

The role of B cells in the tumor microenvironment and B-cell–mediated antitumor immune responses remains relatively understudied. Recent seminal studies have discovered that B cells and associated tertiary lymphoid structures correlate with responses to checkpoint blockade immunotherapy and are prognostic for overall survival of cancer patients. B-cell subsets have remarkable functional diversity and include professional antigen-presenting cells, regulatory cells, memory populations, and antibody-producing plasma cells. Importantly, secreted antibodies can independently activate innate immune responses and induce the cancer immunity cycle. Thus, B cells and B-cell–mediated antibody responses comprise the largely underappreciated second arm of the adaptive immune system and certainly deserve further attention in the field of oncology. Here, we review the known functions of B cells in the tumor microenvironment, the contribution of B cells to the antitumor activity of immunotherapies, and the role of B cells in the overall survival of cancer patients.

Depletion of the endogenous antioxidant, glutathione (GSH), underlies progression of the devastating neurodegenerative disease, amyotrophic lateral sclerosis (ALS). Thus, strategies aimed at elevating GSH may yield new therapeutics for ALS. Here, we investigated the effects of a unique non-denatured whey protein supplement, Immunocal®, in the transgenic Gly position 93 to Ala (G93A) mutant hSOD1 (hSOD1G93A) mouse model of ALS. Immunocal® is rich in the GSH precursor, cystine, and is therefore capable of bolstering GSH content. Transgenic hSOD1G93A mice receiving Immunocal® displayed a significant delay in disease onset compared to untreated hSOD1G93A controls. Additionally, Immunocal® treatment significantly decreased the rate of decline in grip strength and prevented disease-associated reductions in whole blood and spinal cord tissue GSH levels in end-stage hSOD1G93A mice. However, Immunocal® did not extend survival, likely due to its inability to preserve the mitochondrial GSH pool in spinal cord. Combination treatment with Immunocal® and the anti-glutamatergic compound, riluzole, delayed disease onset and extended survival in hSOD1G93A mice. These findings demonstrate that sustaining tissue GSH with Immunocal® only modestly delays disease onset and slows the loss of skeletal muscle strength in hSOD1G93A mice. Moreover, the inability of Immunocal® to rescue mitochondrial GSH in spinal cord provides a possible mechanism for its lack of effect on survival and is a limiting factor in the potential utility of this supplement as a therapeutic for ALS.