Elevated Serum Gastrin Is Associated with Melanoma Progression: Putative Role in Increased Migration and Invasion of Melanoma Cells.

Micro-environmental factors, including stromal and immune cells, cytokines, and circulating hormones are well recognized to determine cancer progression. Melanoma cell growth was recently shown to be suppressed by cholecystokinin/gastrin (CCK) receptor antagonists, and our preliminary data suggested that melanoma patients with Helicobacter gastritis (which is associated with elevated serum gastrin) might have an increased risk of cancer progression. Therefore, in the present study, we examined how gastrin may act on melanoma cells. In 89 melanoma patients, we found a statistically significant association between circulating gastrin concentrations and melanoma thickness and metastasis, which are known risk factors of melanoma progression and prognosis. Immunocytochemistry using a validated antibody confirmed weak to moderate CCK2R expression in both primary malignant melanoma cells and the melanoma cell lines SK-MEL-2 and G361. Furthermore, among the 219 tumors in the Skin Cutaneous Melanoma TCGA Pan-Cancer dataset showing gastrin receptor (CCKBR) expression, significantly higher CCKBR mRNA levels were linked to stage III-IV than stage I-II melanomas. In both cell lines, gastrin increased intracellular calcium levels and stimulated cell migration and invasion through mechanisms inhibited by a CCK2 receptor antagonist. Proteomic studies identified increased MMP-2 and reduced TIMP-3 levels in response to gastrin that were likely to contribute to the increased migration of both cell lines. However, the effects of gastrin on tumor cell invasion were relatively weak in the presence of the extracellular matrix. Nevertheless, dermal fibroblasts/myofibroblasts, known also to express CCK2R, increased gastrin-induced cancer cell invasion. Our data suggest that in a subset of melanoma patients, an elevated serum gastrin concentration is a risk factor for melanoma tumor progression, and that gastrin may act on both melanoma and adjacent stromal cells through CCK2 receptors to promote mechanisms of tumor migration and invasion.

Is Home Blood Pressure Monitoring Effective at Controlling Hypertension in African American Patients? A Clin-IQ.

African Americans are disproportionately affected by hypertension, a modifiable contributor to multiple chronic diseases and premature death. Primary care physicians play an important role in hypertension control. Home blood pressure monitoring (HBPM) is an evidence-based method for confirming diagnosis and monitoring hypertension over time. Some studies have found that HBPM may lead to clinically relevant reductions in blood pressure when combined with additional interventions, but few studies have focused specifically on African American populations. Evidence of effectiveness could increase clinical recommendation of HBPM. This clinical inquiry examined whether HBPM improves blood pressure control in African Americans with uncontrolled hypertension. Reviewed studies included 4 randomized controlled trials and 2 comparative research studies. Because these studies often were coupled with various co-interventions, ascertaining the independent effects of HBPM was difficult. When examining reviews of HBPM without a co-intervention and conducted independent of race, HBPM alone was insufficient to achieve long-term changes in hypertension control. More research focused on African Americans, with use of control groups, is needed to determine the true role for HBPM in controlling hypertension in this at-risk patient population.

Harmonizing Labeling and Analytical Strategies to Obtain Protein Turnover Rates in Intact Adult Animals.

Changes in the abundance of individual proteins in the proteome can be elicited by modulation of protein synthesis (the rate of input of newly synthesized proteins into the protein pool) or degradation (the rate of removal of protein molecules from the pool). A full understanding of proteome changes therefore requires a definition of the roles of these two processes in proteostasis, collectively known as protein turnover. Because protein turnover occurs even in the absence of overt changes in pool abundance, turnover measurements necessitate monitoring the flux of stable isotope-labeled precursors through the protein pool such as labeled amino acids or metabolic precursors such as ammonium chloride or heavy water. In cells in culture, the ability to manipulate precursor pools by rapid medium changes is simple, but for more complex systems such as intact animals, the approach becomes more convoluted. Individual methods bring specific complications, and the suitability of different methods has not been comprehensively explored. In this study, we compare the turnover rates of proteins across four mouse tissues, obtained from the same inbred mouse strain maintained under identical husbandry conditions, measured using either [13C6]lysine or [2H2]O as the labeling precursor. We show that for long-lived proteins, the two approaches yield essentially identical measures of the first-order rate constant for degradation. For short-lived proteins, there is a need to compensate for the slower equilibration of lysine through the precursor pools. We evaluate different approaches to provide that compensation. We conclude that both labels are suitable, but careful determination of precursor enrichment kinetics in amino acid labeling is critical and has a considerable influence on the numerical values of the derived protein turnover rates.

Preliminary Evidence Supporting a Novel 10-Item Clinical Learning Environment Quick Survey (CLEQS).

BACKGROUND: The clinical learning environment (CLE) is a priority focus in medical education. The Accreditation Council for Graduate Medical Education Clinical Learning Environment Review's (CLER) recent addition of teaming and health care systems obligates educators to monitor these areas. Tools to evaluate the CLE would ideally be: (1) appropriate for all health care team members on a specific unit/project; (2) informed by contemporary learning environment frameworks; and (3) feasible/quick to complete. No existing CLE evaluation tool meets these criteria. OBJECTIVE: This report describes the creation and preliminary validity evidence for a Clinical Learning Environment Quick Survey (CLEQS). METHODS: Survey items were identified from the literature and other data sources, sorted into 1 of 4 learning environment domains (personal, social, organizational, material) and reviewed by multiple stakeholders and experts. Leaders from 6 interprofessional graduate medical education quality improvement/patient safety teams distributed this voluntary survey to their clinical team members (November 2019-mid-January 2021) using electronic or paper formats. Validity evidence for this instrument was based on the content, response process, internal structure, reliability, relations to other variables, and consequences. RESULTS: Two hundred one CLEQS responses were obtained, taking 1.5 minutes on average to complete with good reliability (Cronbach's α ≥ 0.83). The Cronbach alpha for each CE domain with the overall item ranged from 0.50 for personal to 0.79 for social. There were strong associations with other measures and clarity about improvement targets. CONCLUSIONS: CLEQS meets the 3 criteria for evaluating CLEs. Reliability data supports its internal consistency, and initial validity evidence is promising.

The effect of exercise on the protein profile of rat knee joint intra- and extra-articular ligaments.

Injuries to the intra-articular anterior cruciate ligament (ACL) and the extra-articular medial collateral ligament (MCL) result in significant knee joint instability, pain, and immobility. Moderate endurance-type exercise can increase ligament strength but little is known on the effect of short-term regular bouts of high-intensity exercise on the extracellular matrix (ECM) structure of knee ligaments. Therefore, this study aimed to identify the effect of short-term regular bouts high exercise on the proteome of the rat ACL and MCL using mass spectrometry. Sprague-Dawley male rats (n = 6) were split into control and exercise groups, and subjected to high-intensity training for four 4 weeks followed by proteomic analyses of the ACL and MCL. Knee joint health status was assessed using OARSI and a validated histological scoring system. Histopathological analyses demonstrated no significant changes in either in cruciate, collateral ligaments, or cartilage between the control and exercised knee joints. However, significant proteins were found to be more abundant in the exercised ACL compared to ACL control group but not between the exercised MCL and control MCL groups. The significant abundant proteins in ACL exercise groups were mostly cytoskeletal, ribosomal and enzymes with several abundant matrisomal proteins such as collagen proteins and proteoglycans being found in this group. In conclusion, our results indicate that short-term regular bouts of high-intensity exercise have an impact on the intra-articular ACL but not extra-articular MCL ECM protein expression.