Autophagy has been proposed to promote cell death during lumen formation in three-dimensional mammary epithelial acini because numerous autophagic vacuoles are observed in the dying central cells during morphogenesis. Because these central cells die due to extracellular matrix (ECM) deprivation (anoikis), we have directly interrogated how matrix detachment regulates autophagy. Detachment induces autophagy in both nontumorigenic epithelial lines and in primary epithelial cells. RNA interference-mediated depletion of autophagy regulators (ATGs) inhibits detachment-induced autophagy, enhances apoptosis, and reduces clonogenic recovery after anoikis. Remarkably, matrix-detached cells still exhibit autophagy when apoptosis is blocked by Bcl-2 overexpression, and ATG depletion reduces the clonogenic survival of Bcl-2-expressing cells after detachment. Finally, stable reduction of ATG5 or ATG7 in MCF-10A acini enhances luminal apoptosis during morphogenesis and fails to elicit long-term luminal filling, even when combined with apoptotic inhibition mediated by Bcl-2 overexpression. Thus, autophagy promotes epithelial cell survival during anoikis, including detached cells harboring antiapoptotic lesions.
SUMMARY
ATG12, an ubiquitin-like modifier required for macroautophagy, has a single known conjugation target, another autophagy regulator called ATG5. Here, we identify ATG3 as a substrate for ATG12 conjugation. ATG3 is the E2-like enzyme necessary for ATG8/LC3 lipidation during autophagy. ATG12-ATG3 complex formation requires ATG7 as the E1 enzyme and ATG3 autocatalytic activity as the E2, resulting in the covalent linkage of ATG12 onto a single lysine on ATG3. Surprisingly, disrupting ATG12 conjugation to ATG3 does not affect starvation-induced autophagy. Rather, the lack of ATG12-ATG3 complex formation produces an expansion in mitochondrial mass and inhibits cell death mediated by mitochondrial pathways. Overall, these results unveil a role for ATG12-ATG3 in mitochondrial homeostasis, and implicate the ATG12 conjugation system in cellular functions distinct from the early steps of autophagosome formation.
Importance of the field
Head and neck squamous cell carcinoma (HNSCC) is the eighth leading cause of cancer death worldwide. Despite advances in surgery and chemoradiation therapy, there has been little improvement in survival rates over the past 4 decades. Additionally, surgery and chemoradiotherapy have serious side effects. The development of agents with greater efficacy and tolerability is needed.
Areas covered in this review
EGFR is the only proven molecular target for HNSCC therapy. Cetuximab, the sole FDA-approved molecular targeted HNSCC therapy, and other potential targeted therapies are being evaluated in preclinical, clinical and post-marketing studies. Here, we review the emerging targets for biological agents in HNSCC and the rationale for their selection.
What the reader will gain
Key information in the development of new drug targets and the emergence of new biomarkers are discussed. Readers will gain insight regarding the limitations of current therapies, the impact of recently approved targeted therapies and the influence that predictive biomarkers will have on drug development.
Take home message
The head and neck cancer drug market is rapidly evolving. Coordination between drug and biomarker development efforts may soon yield targeted therapies that can achieve the promise of personalized cancer medicine.
In this crossover study comparing a single flipped classroom module with a standard lecture, we found mixed statistical results for performance measured by multiple-choice questions. As the differences were small, the flipped classroom and lecture were essentially equivalent.
Comparison of the four different models with the least-restricted baseline CTCM model revealed that a model with uncorrelated generalisable skills factors and correlated case-specific knowledge factors represented the data best. The generalisable processes found in history taking, physical examination and communication were responsible for half the explained variance, in comparison with the variance related to case specificity. Conclusions Pure knowledge-based and pure skill-based perspectives on clinical performance both seem too one-dimensional and new evidence supports the idea that a substantial amount of variance contributes to both aspects of performance. It could be concluded that generalisable skills and specialised knowledge go hand in hand: both are essential aspects of clinical performance.
BackgroundDespite the prevalence of medical interpreting in the clinical environment, few medical professionals receive training in best practices when using an interpreter. We designed and implemented an educational workshop on using interpreters as part of the cultural competency curriculum for second year medical students (MSIIs) at David Geffen School of Medicine at UCLA. The purpose of this study is two-fold: first, to evaluate the effectiveness of the workshop and second, if deficiencies are found, to investigate whether the deficiencies affected the quality of the patient encounter when using an interpreter.MethodsA total of 152 MSIIs completed the 3-hour workshop and a 1-station objective-structured clinical examination, 8 weeks later to assess skills. Descriptive statistics and independent sample t-tests were used to assess workshop effectiveness.ResultsBased on a passing score of 70%, 39.4% of the class failed. Two skills seemed particularly problematic: assuring confidentiality (missed by 50%) and positioning the interpreter (missed by 70%). While addressing confidentiality did not have a significant impact on standardized patient satisfaction, interpreter position did.ConclusionInstructing the interpreter to sit behind the patient helps sustain eye contact between clinician and patient, while assuring confidentiality is a tenet of quality clinical encounters. Teaching students and faculty to emphasize both is warranted to improve cross-language clinical encounters.
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