Serotonin and the 5-HT7 receptor: the link between hepatocytes, IGF-1 and small intestinal neuroendocrine tumors.

Platelet-derived serotonin (5-HT) is involved in liver regeneration. The liver is also the metastatic site for malignant enterochromaffin (EC) cell "carcinoid" (neuroendocrine) neoplasms, the principal cellular source of 5-HT. We hypothesized that 5-HT produced by metastatic EC cells played a role in the hepatic tumor-microenvironment principally via 5-HT7 receptor-mediated activation of hepatocyte IGF-1 synthesis and secretion. Using isolated rat hepatocytes, we evaluated 5-HT7 receptor expression (using PCR, sequencing and western blot). ELISA, cell transfection and western blots delineated 5-HT-mediated signaling pathways (pCREB, AKT and ERK). IGF-1 synthesis/secretion was evaluated using QPCR and ELISA. IGF-1 was tested on small intestinal neuroendocrine neoplasm proliferation, while IGF-1 production and 5-HT7 expression were examined in an in vivo SCID metastasis model. Our results demonstrated evidence for a functional 5-HT7 receptor. 5-HT activated cAMP/PKA activity, pCREB (130-205%, P < 0.05) and pERK/pAKT (1.2-1.75, P < 0.05). Signaling was reversed by the 5-HT7 receptor antagonist SB269970. IGF-1 significantly stimulated proliferation of two small intestinal neuroendocrine neoplasm cell lines (EC50: 7-70 pg/mL) and could be reversed by the small molecule inhibitor BMS-754807. IGF-1 and 5-HT were elevated (40-300×) in peri-tumoral hepatic tissue in nude mice, while 5-HT7 was increased fourfold compared to sham-operated animals. We conclude that hepatocytes express a cAMP-coupled 5-HT7 receptor, which, at elevated 5-HT concentrations that occur in liver metastases, signals via CREB/AKT and is linked to IGF-1 synthesis and secretion. Because IGF-1 regulates NEN proliferation, identification of a role for 5-HT7 in the hepatic metastatic tumor microenvironment suggests the potential for novel therapeutic strategies for amine-producing mid-gut tumors.

Exacerbated inequalities: A scoping review of the experiences of older persons during conflict situations.

BACKGROUND: We conducted the first known comprehensive literature review to (1) identify, categorize, and summarize the existing knowledge about the experiences of older persons and their caregivers during conflict situations; (2) identify the support needs of older persons and their caregivers, and; (3) identify gaps in the literature and understanding that may inform future research. METHODS: A scoping review methodology of academic peer-reviewed and gray English language literature was employed using six academic literature databases and one gray literature database. We further performed comprehensive searches of relevant search engines and organization websites and bibliographic hand searches to identify additional academic and gray literature. Two authors screened for eligibility of identified studies and documents. One reviewer extracted data regarding authors, article type, geographic origin, key participant characteristics, aims, study design and data collection method, results, conclusions and limitations. Data were analyzed thematically. RESULTS: 83 documents met this review's inclusion criteria, including 21 academic documents and 62 from the gray literature. Thematic analysis revealed that conflict situations exacerbate existing inequalities experienced by older persons. Within this overarching theme were three interconnected sub-themes: (1) Older adults are particularly vulnerable during conflict situations; (2) Older persons are inadequately supported in conflict situations; (3) In the face of great challenges, many older adults still manage to endure through conflict situations. We identified 15 recommendations from the reviewed documents to better support older adults in conflict situations. CONCLUSIONS: Existing inequalities, such as ageism and ableism, targeted discrimination, and poor health outcomes, become exacerbated during conflict situations, resulting in older persons being less able to flee and meet their daily needs with sufficient access to necessities and healthcare. Little is known of the experiences and needs of family caregivers during conflict situations. We identified several opportunities to improve the experience and support of older persons in conflict situations.

Limitations in small intestinal neuroendocrine tumor therapy by mTor kinase inhibition reflect growth factor-mediated PI3K feedback loop activation via ERK1/2 and AKT.

BACKGROUND: Treatment of small intestinal neuroendocrine tumors (SINETs) with mammalian target of rapamycin (mTOR) inhibitors alone or with somatostatin analogs has been proposed as effective therapy, because both agents have been reported to exhibit antiproliferative activity. Because adenocarcinomas escape mTOR inhibition, we examined whether the escape phenomenon occurred in SINETs and whether usage of somatostatin analogs with mTOR inhibitors surmounted loss of inhibition. METHODS: The effects of the somatostatin analog octreotide (OCT), the mTOR inhibitor RAD001 (RAD), or the combination were evaluated in SINET cell lines (KRJ-I, H-STS) using cell viability assays, western blotting, enzyme-linked immunosorbent assay, and reverse-transcription polymerase chain reaction to assess antiproliferative signaling pathways and feedback regulation. RESULTS: RAD (10(-9) M) incompletely decreased cell viability (-40% to +15%); growth escape (P < .001) was noted at 72 hours in both cell lines. Phosphorylated (p)mTOR/mTOR and pp70S6K/p70S6K ratios were decreased but were associated with increases in phosphorylated extracellular signal-regulated kinase (pERK)/ERK and pAKT/AKT in both cell lines, whereas phosphorylated insulin-like growth factor 1 receptor (pIGF-1R)/IGF-1R levels were elevated only in H-STS cells. Increased (P < .05) transcript levels for AKT1, MAPK, mTOR, IGF-1R, IGF-1, and TGFß1 were evident. OCT (10(-6) M) itself had no significant effect on growth signaling in either cell line. An antiproliferative effect (66 ± 5%) using OCT+RAD was only noted in the KRJ-I cells (P < .05). CONCLUSIONS: SINET treatment with the mTOR inhibitor RAD had no antiproliferative effect based on activation of pAKT and pERK1/2. A combinatorial approach using OCT and RAD failed to overcome this escape phenomenon. However, differences in RAD response rates in individual NET cell lines suggested that pretreatment identification of different tumor sensitivity to mTOR inhibitors could provide the basis for individualized treatment.

Preparing health professions students to lead change.

PURPOSE: Health care systems increasingly demand health professionals who can lead interdisciplinary teams. While physicians recognize the importance of leadership skills, few receive formal instruction in this area. This paper aims to describe how the Student Leadership Committee (SLC) at the Harvard Medical School Center for Primary Care responded to this need by creating a leadership curriculum for health professions students. DESIGN/METHODOLOGY/APPROACH: The SLC designed an applied longitudinal leadership curriculum and taught it to medical, dentistry, nursing, public health and business students during monthly meetings over two academic years. The perceptions of the curriculum were assessed via a retrospective survey and an assessment of team functioning. FINDINGS: Most teams met their project goals and students felt that their teams were effective. The participants reported increased confidence that they could create change in healthcare and an enhanced desire to hold leadership positions. The sessions that focused on operational skills were especially valued by the students. PRACTICAL IMPLICATIONS: This case study presents an effective approach to delivering leadership training to health professions students, which can be replicated by other institutions. SOCIAL IMPLICATIONS: Applied leadership training empowers health professions students to improve the health-care system and prepares them to be more effective leaders of the future health-care teams. The potential benefits of improved health-care leadership are numerous, including better patient care and improved job satisfaction among health-care workers. ORIGINALITY/VALUE: Leadership skills are often taught as abstract didactics. In contrast, the approach described here is applied to ongoing projects in an interdisciplinary setting, thereby preparing students for real-world leadership positions.

Validation of an administrative coding algorithm for classifying surgical indication and operative features of spine surgery.

STUDY DESIGN: Retrospective review of medical records and administrative data. OBJECTIVE: Validate a claims-based algorithm for classifying surgical indication and operative features in lumbar surgery. SUMMARY OF BACKGROUND DATA: Administrative data are valuable to study rates, safety, outcomes, and costs in spine surgery. Previous research evaluates outcomes by procedure, not indications and operative features. One previous study validated a coding algorithm for classifying surgical indication. Few studies examined claims data for classifying patients by operative features. METHODS: Patients undergoing lumbar decompression or fusion at a single institution in 2009 for back pain, herniated disc, stenosis, spondylolisthesis, or scoliosis were included. Sensitivity and specificity of a claims-based algorithm for indication and operative features were examined versus medical record abstraction. RESULTS: A total of 477 patients, including 246 (52%) undergoing fusion and 231 (48%) undergoing decompression were included in this study. Sensitivity of the claims-based coding algorithm for classifying the indication for the procedure was 71.9% for degenerative disc disease, 81.9% for disc herniation, 32.7% for spinal stenosis, 90.4% for degenerative spondylolisthesis, and 93.8% for scoliosis. Specificity was 87.9% for degenerative disc, 85.6% for disc herniation, 90.7% for spinal stenosis, 95.0% for degenerative spondylolisthesis, and 97.3% for scoliosis. Sensitivity and specificity of claims data for identifying the type of procedure for fusion cases was 97.6% and 99.1%, respectively. Sensitivity of claims data for characterizing key operative features was 81.7%, 96.4%, and 53.0% for use of instrumentation, combined (anterior and posterior) surgical approach, and 3 or more disc levels fused, respectively. Specificity was 57.1% for instrumentation, 94.5% for combined approaches, and 71.9% for 3 or more disc levels fused. CONCLUSION: Claims data accurately reflected certain diagnoses and type of procedures, but were less accurate at characterizing operative features other than the surgical approach. This study highlights both the potential and current limitations of claims-based analysis for spine surgery.