Mesenchymal stem cells and idiopathic pulmonary fibrosis. Potential for clinical testing.

Idiopathic pulmonary fibrosis (IPF) is a progressive, debilitating, and fatal lung disease characterized by interstitial fibrosis with decreasing lung volumes and hypoxemic respiratory failure. The prognosis for patients with IPF is poor and the quest to find effective therapies has been unsuccessful. Despite several clinical trials over the past decade, there are no U.S. Food and Drug Administration-approved treatments for patients with IPF and thus no standard of care. In terms of pathogenesis, IPF is characterized by alveolar epithelial cell injury and activation with interstitial inflammation, fibroblast proliferation with extracellular matrix collagen deposition, and loss of lung function. Because mesenchymal stem cells (MSCs) home to sites of injury, inhibit inflammation, and contribute to epithelial tissue repair, their use has been suggested as a therapy for the treatment of IPF. MSCs have potential as a novel therapeutic agent in multiple diseases and they have been safely administered in a number of clinical trials. Some, but not all, preclinical studies in animal models of lung fibrosis suggest that MSCs might be effective in the treatment of IPF. Given the safety and ease of MSC administration in other patient populations, the results in preclinical animal models of IPF, and the major need for novel therapeutic options in this devastating disease, we propose that carefully designed clinical trials of MSCs for the treatment of patients with IPF are appropriate. Establishing safety in the setting of IPF is the first priority in early clinical trials followed by clinical and biological measures of efficacy.

Examining the Role of Gender and Ethnic Concordance in Medical Student Specialty Selection.

Introduction: Representation of female and minority physicians varies across specialties and may influence career selection by medical students. To investigate the effect of demographic concordance between medical students and clinical role models on specialty selection, we conducted a survey of graduating medical students to assess the perceived importance and influence of third-year clerkship experiences with demographically concordant preceptors on their choice of specialty for post-graduate training. Methods: An 11-question survey was shared nationally through AAMC Organizational Student Representatives to medical students in the Class of 2023. Information gathered included demographics; specialty of choice; extent of exposure to preceptors of the same gender, race, or ethnicity during clinical clerkships; and perceived importance and influence of those interactions (Likert 1-5, Low-High) on specialty selection. Results: A total of 84 students responded. Female students ascribed more importance to gender concordance with preceptors on the third-year clerkship most associated with their specialty of choice than males [3.4 (SD 1.2) vs. 1.3 (SD 0.8) respectively, p < 0.0001] and greater influence to gender concordance on final specialty selection [2.37 (SD 1.1) vs. 1.31 (SD 0.8) respectively, p < 0.0001]. Non-Caucasians ascribed more importance to race/ethnicity concordance than Caucasians [2.8 (SD 1.4) vs. 1.2 (SD 0.5) respectively, p < 0.0001] and greater influence to race/ethnicity concordance on final specialty selection [2.0 (SD 1.3) vs. 1.1 (SD 0.4) respectively, p < 0.0001]. Caucasian females ascribed the greatest importance to gender concordance (p < 0.001), non-Caucasian females ascribed the greatest influence of gender concordance (p < 0.001), and non-Caucasian females ascribed both the greatest importance (p < 0.001) and influence (p < 0.001) to race/ethnicity concordance. Conclusions: We found that gender and race/ethnicity concordance between students and clinical preceptors during third year clerkships is perceived as especially important and influential in specialty selection by minority and female medical students. These findings highlight the importance of diversity in gender and race/ethnicity representation by preceptors on clinical clerkships. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-024-02044-6.

Osteoporosis: A Small-Group Case-Based Learning Activity.

INTRODUCTION: Osteoporosis is the most common bone disease in the world. Approximately 50% of women and 20% of men over 50 will suffer an osteoporosis-related fracture. Future health care providers must be equipped to prevent, recognize, and treat osteoporosis-related fractures. METHODS: To supplement instruction on osteoporosis, we designed a case-based session. Groups of 10-12 second-year medical students worked with a single facilitator in a roundtable discussion. The 120-minute session integrated foundational sciences (pathology, physiology, pharmacology) and clinical disciplines (clinical skills, radiology, geriatrics, evidence-based medicine). Knowledge gains were assessed by performance on nine session-relevant multiple-choice questions (MCQs) on the final exam. Student satisfaction was assessed by an anonymous postsession survey. RESULTS: There were 121 students that participated, and their average performance on nine session-relevant final exam MCQs was 84%. After removal of a single outlier MCQ (15% correct), average performance on the remaining eight MCQs was 93%. A total of 107 students (88%) responded to the postsession survey. On a 5-point Likert scale, 101 of 107 students (94%) agreed or strongly agreed with the statement "The basic science-clinical combination lecture on osteoporosis followed by the small-group case discussion on osteoporosis prepared me adequately to understand the topic" (M = 4.56, SD = 0.63). DISCUSSION: We developed a case-based learning activity for preclinical medical students to enhance the clinical scaffolding of basic science and medical knowledge around osteoporosis. Students performed well on session-relevant exam questions, demonstrating competency in the educational objectives. Student satisfaction was high, with most students feeling well prepared.

Sarcoidosis-associated fibrosing mediastinitis with resultant pulmonary hypertension: a case report and review of the literature.

Pulmonary hypertension, a common manifestation of advanced sarcoidosis, is thought to result from fibrosis with chronic hypoxia and destruction of small vessels, extrinsic compression of pulmonary arteries, or granulomatous vasculitis. We report a case of sarcoidosis-associated pulmonary hypertension due to fibrosing mediastinitis. Our patient presented with cough and dyspnea on exertion and was found to have pulmonary artery enlargement, pulmonary venous compression, and mediastinal soft tissue enhancement on magnetic resonance imaging. Pulmonary hypertension was confirmed by right heart catheterization and sarcoidosis was diagnosed by histologic examination of tissue obtained at mediastinoscopy. Treatment with steroids resulted in decreased pulmonary artery pressures as well as symptomatic improvement. While pulmonary hypertension is a common complication of sarcoidosis, fibrosing mediastinitis is an unusual etiology that should be considered by clinicians.

Taking CBL to the Lecture Hall: a Comparison of Outcomes Between Traditional Small Group CBL and a Novel Large Group Team-Based CBL Teaching Method.

PURPOSE: Case-based learning (CBL), an important component of medical school curricula, is an effective inquiry-based teaching method associated with high levels of student and teacher satisfaction. However, because traditional CBL requires small groups, its feasibility is limited by faculty and resources. We developed and tested a novel team-based CBL (TB-CBL) method to be implemented in the lecture hall. METHODS: All second-year students at our institution (n = 121) were randomized to either traditional small group CBL or TB-CBL during the Endocrine block and to the other modality during the Renal block. All students were exposed to both methods. Case content was identical, and sessions were run concurrently. This cross-over, non-inferiority study tested the hypothesis that no difference in knowledge acquisition, clinical reasoning, or student satisfaction would be detected between groups. RESULTS: Based on student performance on case-relevant exam questions, no difference in knowledge acquisition was seen between groups for either block (p = 0.62 Endocrine, p = 0.38 Renal). There was also no difference in overall final exam performance between groups (p = 0.56 Endocrine, p = 0.26 Renal). Case-relevant script concordance testing revealed no difference in clinical reasoning skills between groups (p = 0.87 Endocrine, p = 0.17 Renal). Satisfaction was higher for the TB-CBL format (p = 0.005). Cost analysis revealed that each small group CBL session costs $2654, while each TB-CBL session costs approximately $221. CONCLUSIONS: TB-CBL, a novel case-based teaching method, appears to produce similar learner outcomes and higher student satisfaction when compared with small group CBL. TB-CBL may be used to supplement case-based curricula while optimizing resource allocation.

Allogeneic Human Mesenchymal Stem Cells in Patients With Idiopathic Pulmonary Fibrosis via Intravenous Delivery (AETHER): A Phase I Safety Clinical Trial.

BACKGROUND: Despite Food and Drug Administration approval of 2 new drugs for idiopathic pulmonary fibrosis (IPF), curative therapies remain elusive and mortality remains high. Preclinical and clinical data support the safety of human mesenchymal stem cells as a potential novel therapy for this fatal condition. The Allogeneic Human Cells (hMSC) in patients with Idiopathic Pulmonary Fibrosis via Intravenous Delivery (AETHER) trial was the first study designed to evaluate the safety of a single infusion of bone marrow-derived mesenchymal stem cells in patients with idiopathic pulmonary fibrosis. METHODS: Nine patients with mild to moderate IPF were sequentially assigned to 1 of 3 cohorts and dosed with a single IV infusion of 20, 100, or 200 × 106 human bone marrow-derived mesenchymal stem cells per infusion from young, unrelated, men. All baseline patient data were reviewed by a multidisciplinary study team to ensure accurate diagnosis. The primary end point was the incidence (at week 4 postinfusion) of treatment-emergent serious adverse events, defined as the composite of death, nonfatal pulmonary embolism, stroke, hospitalization for worsening dyspnea, and clinically significant laboratory test abnormalities. Safety was assessed until week 60 and additionally 28 days thereafter. Secondary efficacy end points were exploratory and measured disease progression. RESULTS: No treatment-emergent serious adverse events were reported. Two nontreatment-related deaths occurred because of progression of IPF (disease worsening and/or acute exacerbation). By 60 weeks postinfusion, there was a 3.0% mean decline in % predicted FVC and 5.4% mean decline in % predicted diffusing capacity of the lungs for carbon monoxide. CONCLUSIONS: Data from this trial support the safety of a single infusion of human mesenchymal stem cells in patients with mild-moderate IPF. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02013700; URL: www.clinicaltrials.gov.

Therapeutic benefits of young, but not old, adipose-derived mesenchymal stem cells in a chronic mouse model of bleomycin-induced pulmonary fibrosis.

The observation that pulmonary inflammatory lesions and bleomycin (BLM)-induced pulmonary fibrosis spontaneously resolve in young mice, whereas remaining irreversible in aged mice suggests that impairment of pulmonary regeneration and repair is associated with aging. Because mesenchymal stem cells (MSCs) may promote repair after injury, we postulated that differences in MSCs from aged mice may underlie postinjury fibrosis in aging. The potential for young-donor MSCs to inhibit BLM-induced pulmonary fibrosis in aged male mice (>22 months) has not been studied. Adipose-derived MSCs (ASCs) from young (4 months) and old (22 months) male mice were infused 1 day after intratracheal BLM administration. At 21-day sacrifice, aged BLM mice demonstrated lung fibrosis by Ashcroft score, collagen content, and α(v)-integrin messenger RNA (mRNA) expression. Lung tissue from aged BLM mice receiving young ASCs exhibited decreased fibrosis, matrix metalloproteinase (MMP)-2 activity, oxidative stress, and markers of apoptosis vs BLM controls. Lung mRNA expression of tumor necrosis factor-alpha was also decreased in aged BLM mice receiving young-donor ASCs vs BLM controls. In contrast, old-donor ASC treatment in aged BLM mice did not reduce fibrosis and related markers. On examination of the cells, young-donor ASCs had decreased mRNA expression of MMP-2, insulin-like growth factor (IGF) receptor, and protein kinase B (AKT) activation compared with old-donor ASCs. These results show that the BLM-induced pulmonary fibrosis in aged mice could be blocked by young-donor ASCs and that the mechanisms involve changes in collagen turnover and markers of inflammation.

Tgf-beta signaling pathway in lung adenocarcinoma invasion.

The histologic distinction between bronchioloalveolar carcinoma and other adenocarcinomas is tissue invasion. The clinical importance of lung adenocarcinoma invasion is supported by several recent studies indicating that the risk of death in nonmucinous bronchioloalveolar carcinoma is significantly lower than that of pure invasive tumors and in tumors with greater than 0.5 cm of fibrosis or linear invasion. Using microarray gene expression profiling of human tumors, dysregulation of transforming growth factor-beta signaling was identified as an important mediator of tumor invasion. Subsequent studies showed that the CC chemokine regulated on activation, normal T cell expressed, and presumably secreted was up-regulated in invasive tumors and was required for invasion in cells with repressed levels of the transforming growth factor-beta type II receptor. Taken together, these studies illustrate how information gained from global expression profiling of tumors can be used to identify key pathways and genes mediating tumor growth, invasion, and metastasis.

Genomics of lung cancer.

This review focuses on recent research using genomics to examine lung carcinogenesis, histologic differentiation, and progression.