Mitochondrial ATP fuels ABC transporter-mediated drug efflux in cancer chemoresistance

Chemotherapy remains the standard of care for most cancers worldwide, however development of chemoresistance due to the presence of the drug-effluxing ATP binding cassette (ABC) transporters remains a significant problem. The development of safe and effective means to overcome chemoresistance is critical for achieving durable remissions in many cancer patients. We have investigated the energetic demands of ABC transporters in the context of the metabolic adaptations of chemoresistant cancer cells. Here we show that ABC transporters use mitochondrial-derived ATP as a source of energy to efflux drugs out of cancer cells. We further demonstrate that the loss of methylation-controlled J protein (MCJ) (also named DnaJC15), an endogenous negative regulator of mitochondrial respiration, in chemoresistant cancer cells boosts their ability to produce ATP from mitochondria and fuel ABC transporters. We have developed MCJ mimetics that can attenuate mitochondrial respiration and safely overcome chemoresistance in vitro and in vivo. Administration of MCJ mimetics in combination with standard chemotherapeutic drugs could therefore become an alternative strategy for treatment of multiple cancers

Response to reduced nicotine content cigarettes among smokers differing in tobacco dependence severity

This study examines whether tobacco dependence severity moderates the acute effects of reducing nicotine content in cigarettes on the addiction potential of smoking, craving/withdrawal, or smoking topography. Participants (N = 169) were daily smokers with mild, moderate, or high tobacco-dependence severity using the Heaviness of Smoking Index. Following brief abstinence, participants smoked research cigarettes varying in nicotine content (0.4, 2.4, 5.2, 15.8 mg nicotine/g tobacco) in a within-subject design. Results were analyzed using repeated measures analysis of co-variance. No main effects of dependence severity or interactions with nicotine dose were noted in relative reinforcing effects in concurrent choice testing or subjective effects on the modified Cigarette Evaluation Questionnaire. Demand for smoking in the Cigarette Purchase Task was greater among more dependent smokers, but reducing nicotine content decreased demand independent of dependence severity. Dependence severity did not significantly alter response to reduced nicotine content cigarettes on the Minnesota Tobacco Withdrawal Scale nor Questionnaire of Smoking Urges-brief (QSU) Factor-2 scale; dependence severity and dose interacted significantly on the QSU-brief Factor-1 scale, with reductions dependent on dose among highly but not mildly or moderately dependent smokers. Dependence severity and dose interacted significantly on only one of six measures of smoking topography (i.e., maximum flow rate), which increased as dose increased among mildly and moderately but not highly dependent smokers. These results suggest that dependence severity has no moderating influence on the ability of reduced nicotine content cigarettes to lower the addiction potential of smoking, and minimal effects on relief from craving/withdrawal or smoking topography

Responses to Multi-Directional Surface Translations Involve Redistribution of Proximal Versus Distal Strategies to Maintain Upright Posture

Evaluation of postural control in multiple planes is necessary to determine the movement strategies used to respond to unexpected perturbations. The present study quantified net joint torques of the lower limbs and trunk in the sagittal and frontal planes following multi-directional surface translations. Twenty-one healthy subjects stood with feet on separate force plates mounted on a moveable platform, translated unexpectedly in one of 12 directions. Peak net torque magnitudes and latencies following perturbation onset were determined as were the relative contributions of each joint to total torque production. Magnitude of net torque generated by each leg varied by perturbation direction, with the largest individual joint magnitude elicited in directions of limb loading. Relative contributions of individual joint torques to the total response were dependent upon perturbation direction. Results suggest that a redistribution of the relative contributions of hip/trunk versus ankle strategies occurs dependent on perturbation direction, with a significant contribution by the knee joint in response to forward perturbations. Direction-specific redistribution of proximal versus distal strategies appears to depend upon the biomechanical constraints imposed by a given perturbation direction. Thus, it appears that sagittal and frontal plane posture-righting responses may not be uniquely controlled, and may instead be governed similarly, with modulation of relative torque contributions among joints when necessary, given direction-specific anatomical constraints

A History of Low Back Pain Associates With Altered Electromyographic Activation Patterns in Response to Perturbations of Standing Balance

People with a history of low back pain (LBP) exhibit altered responses to postural perturbations, and the central neural control underlying these changes in postural responses remains unclear. To characterize more thoroughly the change in muscle activation patterns of people with LBP in response to a perturbation of standing balance, and to gain insight into the influence of early- vs. late-phase postural responses (differentiated by estimates of voluntary reaction times), this study evaluated the intermuscular patterns of electromyographic (EMG) activations from 24 people with and 21 people without a history of chronic, recurrent LBP in response to 12 directions of support surface translations. Two-factor general linear models examined differences between the 2 subject groups and 12 recorded muscles of the trunk and lower leg in the percentage of trials with bursts of EMG activation as well as the amplitudes of integrated EMG activation for each perturbation direction. The subjects with LBP exhibited 1) higher baseline EMG amplitudes of the erector spinae muscles before perturbation onset, 2) fewer early-phase activations at the internal oblique and gastrocnemius muscles, 3) fewer late-phase activations at the erector spinae, internal and external oblique, rectus abdominae, and tibialis anterior muscles, and 4) higher EMG amplitudes of the gastrocnemius muscle following the perturbation. The results indicate that a history of LBP associates with higher baseline muscle activation and that EMG responses are modulated from this activated state, rather than exhibiting acute burst activity from a quiescent state, perhaps to circumvent trunk displacements

Individuals With Non-Specific Low Back Pain Use a Trunk Stiffening Strategy to Maintain Upright Posture

There is increasing evidence that individuals with non-specific low back pain (LBP) have altered movement coordination., however, the relationship of this neuromotor impairment to recurrent pain episodes is unknown. To assess coordination while minimizing the confounding influences of pain we characterized automatic postural responses to multi-directional support surface translations in individuals with a history of LBP who were not in an active episode of their pain. Twenty subjects with and 21 subjects without non-specific LBP stood on a platform that was translated unexpectedly in 12 directions. Net joint torques of the ankles, knees, hips and trunk in the frontal and sagittal planes as well as surface electromyographs of 12 lower leg and trunk muscles were compared across perturbation directions to determine if individuals with LBP responded using a trunk stiffening strategy. Individuals with LBP demonstrated reduced peak trunk torques, and enhanced activation of the trunk and ankle muscle responses following perturbations. These results suggest that individuals with LBP use a strategy of trunk stiffening achieved through co-activation of trunk musculature, aided by enhanced distal responses, to respond to unexpected support surface perturbations. Notably, these neuromotor alterations persisted between active pain periods and could represent either movement patterns that have developed in response to pain or could reflect underlying impairments that may contribute to recurrent episodes of LBP

Risk factors for AMA discharge from VA inpatient alcoholism treatment programs

This study was designed to identify those risk factors associated with discharge from inpatient alcoholism treatment against medical advice (AMA) and the underlying reasons for these discharges. Data on the characteristics of patients and their index hospitalization were obtained from the systematic review of medical records for 186 alcoholics who were discharged AMA and 201 alcoholics who completed treatment. Comorbid medical diagnosis reduced the risk of AMA discharge by one quarter, whereas court referral to treatment reduced the risk by one half. A college education, vocational or other training, being employed, and having a history of previous AMA discharges significantly increased the risk. The most common reasons for AMA discharge, as perceived by treatment providers, were psychosocial problems, difficulties in the treatment program, and lack of interest in treatment. The clinical implications of these findings for the inpatient treatment of alcoholics are discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31610/1/0000540.pd

Rural HIV Stigma: It’s Not What We Thought It Was

Presenters describe an NIMH-study on the relationships between (1) HIV stigma and psychological symptoms, (2) how people with HIV describe their communities and their well-being, and (3) the actual expression of HIV stigma in the rural communities in which people with HIV reside and their perception that they are stigmatized. These findings challenge current thinking about research and intervention