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Current models of stem cell biology assume that normal and neoplastic stem cells reside at the apices of hierarchies and differentiate into nonstem progeny in a unidirectional manner. Here we identify a subpopulation of basal-like human mammary epithelial cells that departs from that assumption, spontaneously dedifferentiating into stem-like cells. Moreover, oncogenic transformation enhances the spontaneous conversion, so that nonstem cancer cells give rise to cancer stem cell (CSC)-like cells in vitro and in vivo. We further show that the differentiation state of normal cells-of-origin is a strong determinant of posttransformation behavior. These findings demonstrate that normal and CSC-like cells can arise de novo from more differentiated cell types and that hierarchical models of mammary stem cell biology should encompass bidirectional interconversions between stem and nonstem compartments. The observed plasticity may allow derivation of patient-specific adult stem cells without genetic manipulation and holds important implications for therapeutic strategies to eradicate cancer.

Mesenchymal stem cells have been recently described to localize to breast carcinomas, where they integrate into the tumour-associated stroma. However, the involvement of mesenchymal stem cells (or their derivatives) in tumour pathophysiology has not been addressed. Here, we demonstrate that bone-marrow-derived human mesenchymal stem cells, when mixed with otherwise weakly metastatic human breast carcinoma cells, cause the cancer cells to increase their metastatic potency greatly when this cell mixture is introduced into a subcutaneous site and allowed to form a tumour xenograft. The breast cancer cells stimulate de novo secretion of the chemokine CCL5 (also called RANTES) from mesenchymal stem cells, which then acts in a paracrine fashion on the cancer cells to enhance their motility, invasion and metastasis. This enhanced metastatic ability is reversible and is dependent on CCL5 signalling through the chemokine receptor CCR5. Collectively, these data demonstrate that the tumour microenvironment facilitates metastatic spread by eliciting reversible changes in the phenotype of cancer cells.

Background and objective. Increasing physical activity (PA) is safe and beneficial in lung cancer (LC) patients. Advanced-stage LC patients are under-studied and have worse symptoms and quality of life (QoL). We evaluated the feasibility of monitoring step count in advanced LC as well as potential correlations between PA and QoL. Methods. This is a prospective, observational study of 39 consecutive patients with advanced-stage LC. Daily step count over 1 week (via Fitbit Zip), QoL, dyspnea, and depression scores were collected. Spearman rank testing was used to assess correlations. Correlation coefficients (ρ) >0.3 or <−0.3 (more and less correlated, respectively) were considered potentially clinically significant. Results. Most (83%) of the patients were interested in participating, and 67% of those enrolled were adherent with the device. Of those using the device (n = 30), the average daily step count was 4877 (range = 504-12 118) steps/d. Higher average daily step count correlated with higher QoL (ρ = 0.46), physical (ρ = 0.61), role (ρ = 0.48), and emotional functioning (ρ = 0.40) scores as well as lower depression (ρ = −0.40), dyspnea (ρ = −0.54), and pain (ρ = −0.37) scores. Conclusion. Remote PA monitoring (Fitbit Zip) is feasible in advanced-stage LC patients. Interest in participating in this PA study was high with comparable adherence to other PA studies. In those utilizing the device, higher step count correlates with higher QoL as well as lower dyspnea, pain, and depression scores. PA monitoring with wearable devices in advanced-stage LC deserves further study.

The Accreditation Council for Graduate Medical Education (ACGME) requires faculty to pursue annual development to enhance their teaching skills. Few studies exist on how to identify and improve the quality of teaching provided by faculty educators. Understanding the correlation between numeric scores assigned to faculty educators and their tangible, practical teaching skills would be beneficial. This study aimed to identify and describe qualities that differentiate numerically highly rated and low-rated physician educators. This observational mixed-methods study evaluated attending physician educators between July 1, 2015, and June 30, 2021. Quantitative analysis involved descriptive statistics, normalization of scores, and stratification of faculty into tertiles based on a summary score. We compared the highest and lowest tertiles during qualitative analyses of residents' comments. Twenty-five attending physicians and 111 residents in an internal medicine residency program. Resident evaluations of faculty educators, including 724 individual assessments of faculty educators on 15 variables related to the ACGME core competencies. Quantitative analyses revealed variation in attending physician educators' performance across the ACGME core competencies. The highest-rated teaching qualities were interpersonal and communication skills, medical knowledge, and professionalism, while the lowest-rated teaching quality was systems-based practice. Qualitative analyses identified themes distinguishing high-quality from low-quality attending physician educators, such as balancing autonomy and supervision, role modeling, engagement, availability, compassion, and excellent teaching. This study provides insights into areas where attending physicians' educational strategies can be improved, emphasizing the importance of role modeling and effective communication. Ongoing efforts are needed to enhance the quality of faculty educators and resident education in internal medicine residency programs.

The metastatic spread of epithelial cancer cells from the primary tumor to distant organs mimics the cell migrations that occur during embryogenesis. Using gene expression profiling, we have found that the FOXC2 transcription factor, which is involved in specifying mesenchymal cell fate during embryogenesis, is associated with the metastatic capabilities of cancer cells. FOXC2 expression is required for the ability of murine mammary carcinoma cells to metastasize to the lung, and overexpression of FOXC2 enhances the metastatic ability of mouse mammary carcinoma cells. We show that FOXC2 expression is induced in cells undergoing epithelial-mesenchymal transitions (EMTs) triggered by a number of signals, including TGF-β1 and several EMT-inducing transcription factors, such as Snail, Twist, and Goosecoid. FOXC2 specifically promotes mesenchymal differentiation during an EMT and may serve as a key mediator to orchestrate the mesenchymal component of the EMT program. Expression of FOXC2 is significantly correlated with the highly aggressive basal-like subtype of human breast cancers. These observations indicate that FOXC2 plays a central role in promoting invasion and metastasis and that it may prove to be a highly specific molecular marker for human basal-like breast cancers.

Insufficient stress response and elevated oxidative stress can contribute to skeletal muscle atrophy during mechanical unloading (e.g., spaceflight and bedrest). Perturbations in heat shock proteins (e.g., HSP70), antioxidant enzymes, and sarcolemmal neuronal nitric oxidase synthase (nNOS) have been linked to unloading-induced atrophy. We recently discovered that the sarcolemmal NADPH oxidase-2 complex (Nox2) is elevated during unloading, downstream of angiotensin II receptor 1, and concomitant with atrophy. Here, we hypothesized that peptidyl inhibition of Nox2 would attenuate disruption of HSP70, MnSOD, and sarcolemmal nNOS during unloading, and thus muscle fiber atrophy. F344 rats were divided into control (CON), hindlimb unloaded (HU), and hindlimb unloaded +7.5 mg/kg/day gp91ds-tat (HUG) groups. Unloading-induced elevation of the Nox2 subunit p67phox-positive staining was mitigated by gp91ds-tat. HSP70 protein abundance was significantly lower in HU muscles, but not HUG. MnSOD decreased with unloading; however, MnSOD was not rescued by gp91ds-tat. In contrast, Nox2 inhibition protected against unloading suppression of the antioxidant transcription factor Nrf2. nNOS bioactivity was reduced by HU, an effect abrogated by Nox2 inhibition. Unloading-induced soleus fiber atrophy was significantly attenuated by gp91ds-tat. These data establish a causal role for Nox2 in unloading-induced muscle atrophy, linked to preservation of HSP70, Nrf2, and sarcolemmal nNOS.

The global COVID-19 pandemic led to an increase in faculty who taught using video conferencing software, such as Zoom, across different modalities in higher education. Drawing from social comparison theory, this study examines upward and downward social comparison as parallel mediators of the interrelationships between faculty burnout, teaching anxiety, and teaching satisfaction during the COVID-19 pandemic using a cross-sectional sample of 219 faculty. Findings reveal the mediating effect of upward social comparison on the relationship between faculty’s burnout and teaching anxiety. Additionally, upward social comparison had a mediating effect on faculty’s burnout and teaching satisfaction. Implications for teaching and learning using video conferencing tools are also offered.

DescriptionOlder patients often undergo morbid and invasive surgeries despite the presence of frailty and cognitive impairment, which increases the risk for post-operative complications such as delirium and hospital-acquired debility. These complications rarely align with patients’ health goals, leaving them worse off than their pre-surgical state. Comprehensive geriatric assessment offers a way to evaluate older adults before surgery, and address topics such as polypharmacy, cognitive impairment, frailty, and goals of care. The Oregon Health and Science University (OHSU) Geriatric Transitions of Care clinic uses the 4Ms framework to identify patients at risk for poor cognitive and functional outcomes while there is still time to intervene. Baseline cognitive and mobility assessments are performed, as well as medication reconciliations. Recommendations are provided to the patient and surgical team to make the procedure safer, such as de-prescribing harmful medications, completing physical therapy, and sometimes foregoing surgery altogether if in the patient’s best interest. This is an early-stage pilot project, and we anticipate having preliminary data by Fall 2025. We hypothesize that this work will provide frail patients at risk for post-operative complications with essential tools to mitigate risks ahead of time and align goals of care with treatment options.

This research article examines the Australian domestic freight transport market, focusing on the decision-making process by which cargo interests and their agents make mode choice allocation decisions between land-based transport and coastal shipping. It evaluates the willingness to pay (WTP) for various attributes of modal options on specific transport corridors. Such understanding lays the groundwork for being able to assess the likely impact of changes to transport prices arising from the introduction of carbon pricing or other regulatory factors. Reporting the results of a stated choice experiment, this article identifies and quantifies freight shippers’ preferences for components of services offered by freight transport providers across modes with distinct characteristics (that is, mixes of speed (transit time), frequency of departure, reliability (two measures) and cost) in three corridors. There are seven variables examined: frequency, transit time, freight distance, direction (headhaul/backhaul), reliability as measured by delivery window, reliability as measured by delay and price offered by the operator. The article concludes by providing guidance on what trade-offs are relevant in shippers’ choice of mode on the specific corridors under investigation in a more complex mode choice model than explored in previous research. It also examines what will likely happen if price rises as a result of carbon pricing regulation.

Once immortalized, human cells are susceptible to transformation by introduction of an oncogene such as ras. Several lines of evidence now suggest that the maintenance of telomere length is a major determinant of replicative lifespan in human cells and thus of the immortalized state. The majority of human tumor cells acquire immortality through expression of the catalytic subunit of telomerase (hTERT), whereas others activate an alternative mechanism of telomere maintenance (ALT) that does not depend on the actions of telomerase. We have examined whether ALT could substitute for telomerase in the processes of transformation in vitro and tumorigenesis in vivo. Expression of oncogenic H-Ras in the immortal ALT cell line GM847 did not result in their transformation. However, subsequent ectopic expression of hTERT in these cells imparted a tumorigenic phenotype. Indeed, this outcome was also observed after introduction of a mutant hTERT that retained catalytic activity but was incapable of maintaining telomere length. These studies indicate that hTERT confers an additional function that is required for tumorigenesis but does not depend on its ability to maintain telomeres.