ATG proteins mediate efferocytosis and suppress inflammation in mammary involution.

Involution is the process of post-lactational mammary gland regression to quiescence and it involves secretory epithelial cell death, stroma remodeling and gland repopulation by adipocytes. Though reportedly accompanying apoptosis, the role of autophagy in involution has not yet been determined. We now report that autophagy-related (ATG) proteins mediate dead cell clearance and suppress inflammation during mammary involution. In vivo, Becn1(+/-) and Atg7-deficient mammary epithelial cells (MECs) produced 'competent' apoptotic bodies, but were defective phagocytes in association with reduced expression of the MERTK and ITGB5 receptors, thus pointing to defective apoptotic body engulfment. Atg-deficient tissues exhibited higher levels of involution-associated inflammation, which could be indicative of a tumor-modulating microenvironment, and developed ductal ectasia, a manifestation of deregulated post-involution gland remodeling. In vitro, ATG (BECN1 or ATG7) knockdown compromised MEC-mediated apoptotic body clearance in association with decreased RAC1 activation, thus confirming that, in addition to the defective phagocytic processing reported by other studies, ATG protein defects also impair dead cell engulfment. Using two different mouse models with mammary gland-associated Atg deficiencies, our studies shed light on the essential role of ATG proteins in MEC-mediated efferocytosis during mammary involution and provide novel insights into this important developmental process. This work also raises the possibility that a regulatory feedback loop exists, by which the efficacy of phagocytic cargo processing in turn regulates the rate of engulfment and ultimately determines the kinetics of phagocytosis and dead cell clearance

ERBB2 overexpression suppresses stress-induced autophagy and renders ERBB2-induced mammary tumorigenesis independent of monoallelicBecn1loss

Defective autophagy has been implicated in mammary tumorigenesis, as the gene encoding the essential autophagy regulator BECN1 is deleted in human breast cancers and Becn1+/− mice develop mammary hyperplasias. In agreement with a recent study, which reports concurrent allelic BECN1 loss and ERBB2 amplification in a small number of human breast tumors, we found that low BECN1 mRNA correlates with ERBB2-overexpression in breast cancers, suggesting that BECN1 loss and ERBB2 overexpression may functionally interact in mammary tumorigenesis. We now report that ERBB2 overexpression suppressed autophagic response to stress in mouse mammary and human breast cancer cells. ERBB2-overexpressing Becn1+/+ and Becn1+/− immortalized mouse mammary epithelial cells (iMMECs) formed mammary tumors in nude mice with similar kinetics, and monoallelic Becn1 loss did not alter ERBB2- and PyMT-driven mammary tumorigenesis. In human breast cancer databases, ERBB2-expressing tumors exhibit a low autophagy gene signature, independent of BECN1 mRNA expression, and have similar gene expression profiles with non-ERBB2-expressing breast tumors with low BECN1 levels. We also found that ERBB2-expressing BT474 breast cancer cells, despite being partially autophagy-deficient under stress, can be sensitized to the anti-ERBB2 antibody trastuzumab (tzb) by further pharmacological or genetic autophagy inhibition. Our results indicate that ERBB2-driven mammary tumorigenesis is associated with functional autophagy suppression and ERBB2-positive breast cancers are partially autophagy-deficient even in a wild-type BECN1 background. Furthermore and extending earlier findings using tzb-resistant cells, exogenously imposed autophagy inhibition increases the anticancer effect of trastuzumab on tzb-sensitive ERBB2-expressing breast tumor cells, indicating that pharmacological autophagy suppression has a wider role in the treatment of ERBB2-positive breast cancer

Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance

Macroautophagy (autophagy hereafter) recycles intracellular components to sustain mitochondrial metabolism that promotes the growth, stress tolerance, and malignancy of lung cancers, suggesting that autophagy inhibition may have antitumor activity. To assess the functional significance of autophagy in both normal and tumor tissue, we conditionally deleted the essential autophagy gene, autophagy related 7 (Atg7), throughout adult mice. Here, we report that systemic ATG7 ablation caused susceptibility to infection and neurodegeneration that limited survival to 2 to 3 months. Moreover, upon fasting, autophagy-deficient mice suffered fatal hypoglycemia. Prior autophagy ablation did not alter the efficiency of non–small cell lung cancer (NSCLC) initiation by activation of oncogenic KrasG12D and deletion of the Trp53 tumor suppressor. Acute autophagy ablation in mice with preexisting NSCLC, however, blocked tumor growth, promoted tumor cell death, and generated more benign disease (oncocytomas). This antitumor activity occurred before destruction of normal tissues, suggesting that acute autophagy inhibition may be therapeutically beneficial in cancer. Significance: We systemically ablated cellular self-cannibalization by autophagy in adult mice and determined that it is dispensable for short-term survival, but required to prevent fatal hypoglycemia and cachexia during fasting, delineating a new role for autophagy in metabolism. Importantly, acute, systemic autophagy ablation was selectively destructive to established tumors compared with normal tissues, thereby providing the preclinical evidence that strategies to inhibit autophagy may be therapeutically advantageous for RAS-driven cancers.Val Skinner FoundationNational Institutes of Health (U.S.) (RC1 CA147961)Rutgers Cancer Institute of New JerseyRutgers Cancer Institute of New Jersey (P30 CA072720)National Institutes of Health (U.S.) (R01 CA163591)National Institutes of Health (U.S.) (R37 CA53370)National Institutes of Health (U.S.) (R01 CA130893

Patients’ perceptions and experiences of living with a surgical wound healing by secondary intention : a qualitative study

Background: Most surgical wounds heal by primary intention, that is to say, the edges of the wound are brought together with sutures, staples, adhesive glue or clips. However, some wounds may be left open to heal (if there is a risk of infection, or if there has been significant tissue loss), and are known as ‘surgical wounds healing by secondary intention’. They are estimated to comprise approximately 28% of all surgical wounds and are frequently complex to manage. However, they are under researched and little is known of their impact on patients’ lives. Objectives: To explore patients’ views and experiences of living with a surgical wound healing by secondary intention. Design: A qualitative, descriptive approach. Settings: Participants were recruited from acute and community nursing services in two locations in the North of England characterised by high levels of deprivation and diverse populations. Participants: Participants were aged 18 years or older and had at least one surgical wound healing by secondary intention, which was slow to heal. Purposeful sampling was used to include patients of different gender, age, wound duration and type of surgery (general, vascular and orthopaedic). Twenty people were interviewed between January and July 2012. 2 Methods: Semi-structured interviews were conducted, guided by use of a topic guide developed with input from patient advisors. Data were thematically analysed using steps integral to the ‘Framework’ approach to analysis, including familiarisation with data; development of a coding scheme; coding, charting and cross comparison of data; interpretation of identified themes. Findings: Alarm, shock and disbelief were frequently expressed initial reactions, particularly to “unexpected” surgical wounds healing by secondary intention. Wound associated factors almost universally had a profound negative impact on daily life, physical and psychosocial functioning, and wellbeing. Feelings of frustration, powerlessness and guilt were common and debilitating. Patients’ hopes for healing were often unrealistic, posing challenges for the clinicians caring for them. Participants expressed dissatisfaction with a perceived lack of continuity and consistency of care in relation to wound management. Conclusions: Surgical wounds healing by secondary intention can have a devastating effect on patients, both physical and psychosocial. Repercussions for patients’ family members can also be extremely detrimental, including financial pressures. Health care professionals involved in the care of patients with these wounds face multiple, complex challenges, compounded by the limited evidence base regarding cost-effectiveness of different treatment regimens for these types of wounds

A highly compact packaging concept for ultrasound transducer arrays embedded in neurosurgical needles

State-of-the-art neurosurgery intervention relies heavily on information from tissue imaging taken at a pre-operative stage. However, the data retrieved prior to performing an opening in the patient’s skull may present inconsistencies with respect to the tissue position observed by the surgeon during intervention, due to both the pulsing vasculature and possible displacements of the brain. The consequent uncertainty of the actual tissue position during the insertion of surgical tools has resulted in great interest in real-time guidance techniques. Ultrasound guidance during neurosurgery is a promising method for imaging the tissue while inserting surgical tools, as it may provide high resolution images. Microfabrication techniques have enabled the miniaturisation of ultrasound arrays to fit needle gauges below 2 mm inner diameter. However, the integration of array transducers in surgical needles requires the development of advanced interconnection techniques that can provide an interface between the microscale array elements and the macroscale connectors to the driving electronics. This paper presents progress towards a novel packaging scheme that uses a thin flexible printed circuit board (PCB) wound inside a surgical needle. The flexible PCB is connected to a probe at the tip of the needle by means of magnetically aligned anisotropic conductive paste. This bonding technology offers higher compactness compared to conventional wire bonding, as the individual electrical connections are isolated from one another within the volume of the paste line, and applies a reduced thermal load compared to thermo-compression or eutectic packaging techniques. The reduction in the volume required for the interconnection allows for denser wiring of ultrasound probes within interventional tools. This allows the integration of arrays with higher element counts in confined packages, potentially enabling multi-modality imaging with Raman, OCT, and impediography. Promising experimental results and a prototype needle assembly are presented to demonstrate the viability of the proposed packaging scheme. The progress reported in this work are steps towards the production of fully-functional imaging-enabled needles that can be used as surgical guidance tools

Consumers of natural health products: natural-born pharmacovigilantes?

<p>Abstract</p> <p>Background</p> <p>Natural health products (NHPs), such as herbal medicines and vitamins, are widely available over-the-counter and are often purchased by consumers without advice from a healthcare provider. This study examined how consumers respond when they believe they have experienced NHP-related adverse drug reactions (ADRs) in order to determine how to improve current safety monitoring strategies.</p> <p>Methods</p> <p>Qualitative semi-structured interviews were conducted with twelve consumers who had experienced a self-identified NHP-related ADR. Key emergent themes were identified and coded using content analysis techniques.</p> <p>Results</p> <p>Consumers were generally not comfortable enough with their conventional health care providers to discuss their NHP-related ADRs. Consumers reported being more comfortable discussing NHP-related ADRs with personnel from health food stores, friends or family with whom they had developed trusted relationships. No one reported their suspected ADR to Health Canada and most did not know this was possible.</p> <p>Conclusion</p> <p>Consumers generally did not report their suspected NHP-related ADRs to healthcare providers or to Health Canada. Passive reporting systems for collecting information on NHP-related ADRs cannot be effective if consumers who experience NHP-related ADRs do not report their experiences. Healthcare providers, health food store personnel, manufacturers and other stakeholders also need to take responsibility for reporting ADRs in order to improve current pharmacovigilance of NHPs.</p

Skunk River Review Fall 1997, Vol 9

https://openspace.dmacc.edu/skunkriver/1018/thumbnail.jp

From PALSA PLUS to PALM PLUS: adapting and developing a South African guideline and training intervention to better integrate HIV/AIDS care with primary care in rural health centers in Malawi

<p>Abstract</p> <p>Background</p> <p>Only about one-third of eligible HIV/AIDS patients receive anti-retroviral treatment (ART). Decentralizing treatment is crucial to wider and more equitable access, but key obstacles are a shortage of trained healthcare workers (HCW) and challenges integrating HIV/AIDS care with other primary care. This report describes the development of a guideline and training program (PALM PLUS) designed to integrate HIV/AIDS care with other primary care in Malawi. PALM PLUS was adapted from PALSA PLUS, developed in South Africa, and targets middle-cadre HCWs (clinical officers, nurses, and medical assistants). We adapted it to align with Malawi's national treatment protocols, more varied healthcare workforce, and weaker health system infrastructure.</p> <p>Methods/Design</p> <p>The international research team included the developers of the PALSA PLUS program, key Malawi-based team members and personnel from national and district level Ministry of Health (MoH), professional associations, and an international non-governmental organization. The PALSA PLUS guideline was extensively revised based on Malawi national disease-specific guidelines. Advice and input was sought from local clinical experts, including middle-cadre personnel, as well as Malawi MoH personnel and representatives of Malawian professional associations.</p> <p>Results</p> <p>An integrated guideline adapted to Malawian protocols for adults with respiratory conditions, HIV/AIDS, tuberculosis, and other primary care conditions was developed. The training program was adapted to Malawi's health system and district-level supervision structure. PALM PLUS is currently being piloted in a cluster-randomized trial in health centers in Malawi (ISRCTN47805230).</p> <p>Discussion</p> <p>The PALM PLUS guideline and training intervention targets primary care middle-cadre HCWs with the objective of improving HCW satisfaction and retention, and the quality of patient care. Successful adaptations are feasible, even across health systems as different as those of South Africa and Malawi.</p