Spontaneous physical activity down-regulates Pax7 in cancer cachexia

Emerging evidence suggests that the muscle microenvironment plays a prominent role in cancer cachexia. We recently showed that NF-kB - induced Pax7 overexpression impairs the myogenic potential of muscle precursors in cachectic mice, suggesting that lowering Pax7 expression may be beneficial in cancer cachexia. We evaluated the muscle regenerative potential after acute injury in C26 colon carcinoma tumor-bearing mice and healthy controls. Our analyses confirmed that the delayed muscle regeneration observed in muscles form tumor-bearing mice was associated with a persistent local inflammation and Pax7 overexpression. Physical activity is known to exert positive effects on cachectic muscles. However, the mechanism by which a moderate voluntary exercise ameliorates muscle wasting is not fully elucidated. To verify if physical activity affects Pax7 expression, we hosted control and C26-bearing mice in wheel-equipped cages and we found that voluntary wheel running down-regulated Pax7 expression in muscles from tumor-bearing mice. As expected, down-regulation of Pax7 expression was associated with a rescue of muscle mass and fiber size. Our findings shed light on the molecular basis of the beneficial effect exerted by a moderate physical exercise on muscle stem cells in cancer cachexia. Furthermore, we propose voluntary exercise as a physiological tool to counteract the over-expression of Pax7observed in cancer cachexia

Senses and Sensibilities: The Practice of Care in Everyday Life in Northern Thailand

This is a dissertation about care. Based on over ten years of experience with Southeast Asia and sixteen months of ethnographic research for this project, I address the issue of caregiving primarily from the perspective of those providing care at home for elderly people in urban Northern Thailand and from the vantage point of national and international public health initiatives aimed at supporting such endeavors. In turn, I use the intimate experiences of caregivers to interrogate the politics of aging, long-term care, and national identity. What emerges is an understanding of caregiving different from that of liberal humanitarianism and biomedicine alike. With a focus on social relationships and embodied care practices, I show how forms of attention, obligation, giving, and receiving in urban Thai settings do not always equate with their counterparts in standard global health accounts. Instead, local values are put into action with significant ramifications for the performance and promotion of care. I examine local and global techniques of power and care embedded in the growing number of volunteer organizations directed at the elderly. With attention to class, religion, and history, I trace the interpersonal, social, and political influences reflected in caregiver subjectivity and propose a distinctly Thai logic of psychosocial support that underlies the experience of the caregivers and aid workers with whom I worked. Examining family dynamics and the stories people tell about the future, I trace a new imaginary for long-term care at play, apparent at both the individual and the institutional level. And I develop the concept of the "social body," arguing that attention to and care of the collective is crucial for making sense not only of the disorienting varieties of volunteerism marking the shifting ground of long-term and end-of-life care in Thailand, but also of the larger scale political upheavals afoot in that country today.Anthropolog

Tumour-derived leukaemia inhibitory factor is a major driver of cancer cachexia and morbidity in C26 tumour-bearing mice

BACKGROUND: Cancer cachexia is a metabolic wasting syndrome that is strongly associated with a poor prognosis. The initiating factors causing fat and muscle loss are largely unknown. Previously, we found that leukaemia inhibitory factor (LIF) secreted by C26 colon carcinoma cells was responsible for atrophy in treated myotubes. In the present study, we tested whether C26 tumour‐derived LIF is required for cancer cachexia in mice by knockout of Lif in C26 cells. METHODS: A C26 Lif null tumour cell line was made using CRISPR‐Cas9. Measurements of cachexia were compared in mice inoculated with C26 vs. C26^Lif−/− tumour cells, and atrophy was compared in myotubes treated with medium from C26 vs. C26^Lif−/− tumour cells. Levels of 25 cytokines/chemokines were compared in serum of mice bearing C26 vs. C26^Lif−/− tumours and in the medium from these tumour cell lines. RESULTS: At study endpoint, C26 mice showed outward signs of sickness while mice with C26^Lif−/− tumours appeared healthy. Mice with C26^Lif−/− tumours showed a 55–75% amelioration of body weight loss, muscle loss, fat loss, and splenomegaly compared with mice with C26 tumours (P < 0.05). The heart was not affected by LIF levels because the loss of cardiac mass was the same in C26 and C^26Lif−/− tumour‐bearing mice. LIF levels in mouse serum was entirely dependent on secretion from the tumour cells. Serum levels of interleukin‐6 and G‐CSF were increased by 79‐fold and 68‐fold, respectively, in C26 mice but only by five‐fold and two‐fold, respectively, in C26^Lif−/− mice, suggesting that interleukin‐6 and G‐CSF increases are dependent on tumour‐derived LIF. CONCLUSIONS: This study shows the first use of CRISPR‐Cas9 knockout of a candidate cachexia factor in tumour cells. The results provide direct evidence for LIF as a major cachexia initiating factor for the C26 tumour in vivo. Tumour‐derived LIF was also a regulator of multiple cytokines in C26 tumour cells and in C26 tumour‐bearing mice. The identification of tumour‐derived factors such as LIF that initiate the cachectic process is immediately applicable to the development of therapeutics to treat cachexia. This is a proof of principle for studies that when carried out in human cells, will make possible an understanding of the factors causing cachexia in a patient‐specific manner.This work was supported by NIAMS R01AR060217 to S. C. K. and R. W. J. and NIAMS R01 R01AR060209 to A. R. J., and by the Dudley Allen Sargent Research Fund. The authors certify that they comply with the ethical guidelines for publishing in the Journal of Cachexia, Sarcopenia and Muscle: update 2017.40 (R01AR060217 - NIAMS; R01 R01AR060209 - NIAMS; Dudley Allen Sargent Research Fund)Published versio

Insulin-like growth factor-1 receptor inhibitor, AMG-479, in cetuximab-refractory head and neck squamous cell carcinoma

Background Recurrent head and neck squamous cell carcinoma (HNSCC) remains a difficult cancer to treat. Here, we describe a patient with HNSCC who had complete response to methotrexate (MTX) after progressing on multiple cytotoxic agents, cetuximab, and AMG-479 (monoclonal antibody against insulin-like growth factor-1 receptor [IGF-1R]). Methods The clinical information was collected by a retrospective medical record review under an Institutional Review Board-approved protocol. From 4 tumors and 2 normal mucosal epithelia, global gene expression, and IGF-1R and dihydrofolate reductase (DHFR) protein levels were determined. Results Effective target inhibition in the tumor was confirmed by the decreased protein levels of total and phospho-IGF-1R after treatment with AMG-479. Decreased level of DHFR and conversion of a gene expression profile associated with cetuximab-resistance to cetuximab-sensitivity were also observed. Conclusion This suggests that the combination of AMG-479 and MTX or cetuximab may be a promising therapeutic approach in refractory HNSCC

Efland, Orange County : an action-oriented community diagnosis: findings and next steps of action

Six students from the UNC School of Public Health worked with the Efland community in the spring of 2003 to conduct an Action Oriented Community Diagnosis (AOCD). The team conducted interviews with community members and service providers in the area, and then worked with a planning committee to bring people together at a community forum to discuss major topics and plan future actions for desired changes. The most frequently mentioned assets of the Efland community include: the high quality of life enjoyed by residents; its convenient geographic location; the high prevalence of religious activity; and the friendly, familial atmosphere of the area. Along with these strengths, six major issues arose during the course of this process: the disparities between Southern and Northern Orange County; water and sewer; services; transportation; youth; and growth and development. Many Efland residents expressed the desire for more youth centered recreational activities. Some community members felt the increase in teen drug use is the consequence of a limited recreation in Efland, and organized activities could reduce drug use by presenting youth with other options for their free time. Accurate information on the actual drug situation and risk factors currently operating for children in the area today could help community groups make a case for creating opportunities for the youth to parents and potential donors. New data needs to be collected on the prevalence of and the current risk factors for adolescent drug use in the Efland community, as such information may have changed since outlined in past research documents. Another major issue is the water and sewer infrastructure in Efland. A sewer system will cost either the county or its residents a great deal of money both to install and maintain. The county’s stalled action suggests it is not currently economically attractive to them to extend this needed service. But the growth of subdivisions pushing in from Chapel Hill and Research Triangle Park may increase demands for services. Future research should be directed toward finding out exactly how much taxes and service fees will increase for residents already living in the Efland area. There is a possibility that residents are not being extended necessary services now and may not be able to afford them later when these services do become available. Water and sewer infrastructure is directly tied to issues of growth and development. Without an area representative on the Board of County Commissioners, Efland community members need a detailed account of economic development plans for the Efland area to ensure the advancement of their interests. Details of the restrictions on building in the Efland area (due to soils and watershed regulations) need be outlined and compared to the areas where septic tanks are failing and where there is an expressed need for a sewer system. Groups that deal with environmental justice should be consulted in the event that a needed public health service is being withheld based on revenue potential considerations at the county level. Finally, the Efland community should continue to highlight their many assets. The strengths of this community are a foundation that can enable the completion of the desired changes voiced by the community. Community members with experience rallying their community to action emphasize the importance of positive reinforcement, and celebrating the richness of Efland’s citizenry may be a powerful mover of the community.Master of Public Healt

Muscle acellular scaffold as a biomaterial: Effects on C2C12 cell differentiation and interaction with the murine host environment

The extracellular matrix (ECM) of decellularized organs possesses the characteristics of the ideal tissue-engineering scaffold (i.e., histocompatibility, porosity, degradability, non-toxicity). We previously observed that the muscle acellular scaffold (MAS) is a pro-myogenic environmentin vivo. In order to determine whether MAS, which is basically muscle ECM, behaves as a myogenic environment, regardless of its location, we analyzed MAS interaction with both muscle and non-muscle cells and tissues, to assess the effects of MAS on cell differentiation. Bone morphogenetic protein treatment of C2C12 cells cultured within MAS induced osteogenic differentiation in vitro, thus suggesting that MAS does not irreversibly commit cells to myogenesis.In vivo MAS supported formation of nascent muscle fibers when replacing a muscle (orthotopic position). However, heterotopically grafted MAS did not give rise to muscle fibers when transplanted within the renal capsule. Also, no muscle formation was observed when MAS was transplanted under the xiphoid process, in spite of the abundant presence of cells migrating along the laminin-based MAS structure. Taken together, our results suggest that MAS itself is not sufficient to induce myogenic differentiation. It is likely that the pro-myogenic environment of MAS is not strictly related to the intrinsic properties of the muscle scaffold (e.g., specific muscle ECM proteins). Indeed, it is more likely that myogenic stem cells colonizing MAS recognize a muscle environment that ultimately allows terminal myogenic differentiation. In conclusion, MAS may represent a suitable environment for muscle and non-muscle 3D constructs characterized by a highly organized structure whose relative stability promotes integration with the surrounding tissues. Our work highlights the plasticity of MAS, suggesting that it may be possible to consider MAS for a wider range of tissue engineering applications than the mere replacement of volumetric muscle loss

BCI devices and their capacity to express human will having legal value: A model of risk-based classification

One of the ultimate frontiers in biotechnology is Brain-computer-interface. BCI devices are currently developed for therapeutic purposes (e.g., as assistive tools) but also recreational ones. A BCI system detects brain activity, allowing a decoding of patterns of neural signals, then ‘translatable’ in commands a computer can understand and even carry out in the external reality. That’s why BCI is now becoming more used (or experimented), considering the advantages that could derive from it. Nevertheless, it also raises some questions from a legal perspective. This Paper focuses on BCI-based devices used for assistive and augmented communication of users, and wonders what legal regime should be accorded to the personal will expressed through those tools. Once the risks have been identified, the parameters and requirements a BCI device must meet, for the human will expressed through it having legal value, are outlined. The Paper proposes, in conclusion, a self-assessment strategy to operationalize BCI technologies applicable to the context of legal relations, implementing methods of risk evaluation and management. A risk- based classification model is also suggested

Sensing the presence of gods and spirits across cultures and faiths.

Hearing the voice of God, feeling the presence of the dead, being possessed by a demonic spirit-such events are among the most remarkable human sensory experiences. They change lives and in turn shape history. Why do some people report experiencing such events while others do not? We argue that experiences of spiritual presence are facilitated by cultural models that represent the mind as "porous," or permeable to the world, and by an immersive orientation toward inner life that allows a person to become "absorbed" in experiences. In four studies with over 2,000 participants from many religious traditions in the United States, Ghana, Thailand, China, and Vanuatu, porosity and absorption played distinct roles in determining which people, in which cultural settings, were most likely to report vivid sensory experiences of what they took to be gods and spirits.Templeton Foundatio

Child maltreatment and management of pediatric patients during COVID-19 pandemic: Knowledge, awareness, and attitudes among students of medicine and surgery. A survey-based analysis

Purpose of the studyTo assess perception, awareness, and attitudes regarding the medico-legal relevance of child maltreatment and management of pediatric patients during the COVID-19 pandemic in a cohort of medicine and surgery students, with a particular focus on child safety and maltreatment. MethodsA cross-sectional, web-based survey was conducted through an anonymous questionnaire on the personal websites of Universita Cattolica del Sacro Cuore medical students. ResultsThe study included 1,166 participants, the majority of whom were experienced with child maltreatment and defensive medicine; only a small percentage was aware of the government's efforts to prevent child maltreatment and safeguard vaccination physicians. Moreover, there was no agreement on the use of telemedicine for non-serious pediatric patients or on the consequences it might have on their health. Finally, the detrimental impacts of lockdown on children's mental health are a major worry. ConclusionsKnowledge of these themes is mainly implemented by deepening these concepts during the undergraduate studies since a high level of knowledge on child maltreatment and on the management of COVID-19 pandemic was significantly associated with clinical years of course. Specific seminars analyzing telemedicine and legislative protections concerning minors and those concerning vaccination doctors should be included in the study plan to raise awareness these concepts

Aerobic Exercise and Pharmacological Treatments Counteract Cachexia by Modulating Autophagy in Colon Cancer

Recent studies have correlated physical activity with a better prognosis in cachectic patients, although the underlying mechanisms are not yet understood. In order to identify the pathways involved in the physical activity-mediated rescue of skeletal muscle mass and function, we investigated the effects of voluntary exercise on cachexia in colon carcinoma (C26)-bearing mice. Voluntary exercise prevented loss of muscle mass and function, ultimately increasing survival of C26-bearing mice. We found that the autophagic flux is overloaded in skeletal muscle of both colon carcinoma murine models and patients, but not in running C26-bearing mice, thus suggesting that exercise may release the autophagic flux and ultimately rescue muscle homeostasis. Treatment of C26-bearing mice with either AICAR or rapamycin, two drugs that trigger the autophagic flux, also rescued muscle mass and prevented atrogene induction. Similar effects were reproduced on myotubes in vitro, which displayed atrophy following exposure to C26-conditioned medium, a phenomenon that was rescued by AICAR or rapamycin treatment and relies on autophagosome-lysosome fusion (inhibited by chloroquine). Since AICAR, rapamycin and exercise equally affect the autophagic system and counteract cachexia, we believe autophagy-triggering drugs may be exploited to treat cachexia in conditions in which exercise cannot be prescribed