Anti-DKK1 Enhances the Early Osteogenic Differentiation of Human Adipose-Derived Stem/Stromal Cells

: Adipose-derived stem/stromal cells (ASCs) have been previously used for bone repair. However, significant cell heterogeneity exists within the ASC population, which has the potential to result in unreliable bone tissue formation and/or low efficacy. Although the use of cell sorting to lower cell heterogeneity is one method to improve bone formation, this is a technically sophisticated and costly process. In this study, we tried to find a simpler and more deployable solution-blocking antiosteogenic molecule Dickkopf-1 (DKK1) to improve osteogenic differentiation. Human adipose-derived stem cells were derived from = 5 samples of human lipoaspirate. In vitro, anti-DKK1 treatment, but not anti-sclerostin (SOST), promoted ASC osteogenic differentiation, assessed by alizarin red staining and real-time polymerase chain reaction (qPCR). Increased canonical Wnt signaling was confirmed after anti-DKK1 treatment. Expression levels of DKK1 peaked during early osteogenic differentiation (day 3). Concordantly, anti-DKK1 supplemented early (day 3 or before), but not later (day 7) during osteogenic differentiation positively regulated osteoblast formation. Finally, anti-DKK1 led to increased transcript abundance of the Wnt inhibitor SOST, potentially representing a compensatory cellular mechanism. In sum, DKK1 represents a targetable "molecular brake" on the osteogenic differentiation of human ASC. Moreover, release of this brake by neutralizing anti-DKK1 antibody treatment at least partially rescues the poor bone-forming efficacy of ASC

Human perivascular stem cells prevent bone graft resorption in osteoporotic contexts by inhibiting osteoclast formation

n/

Systemic DKK1 neutralization enhances human adipose-derived stem cell mediated bone repair

: Progenitor cells from adipose tissue are able to induce bone repair; however, inconsistent or unreliable efficacy has been reported across preclinical and clinical studies. Soluble inhibitory factors, such as the secreted Wnt signaling antagonists Dickkopf-1 (DKK1), are expressed to variable degrees in human adipose-derived stem cells (ASCs), and may represent a targetable "molecular brake" on ASC mediated bone repair. Here, anti-DKK1 neutralizing antibodies were observed to increase the osteogenic differentiation of human ASCs in vitro, accompanied by increased canonical Wnt signaling. Human ASCs were next engrafted into a femoral segmental bone defect in NOD-Scid mice, with animals subsequently treated with systemic anti-DKK1 or isotype control during the repair process. Human ASCs alone induced significant but modest bone repair. However, systemic anti-DKK1 induced an increase in human ASC engraftment and survival, an increase in vascular ingrowth, and ultimately improved bone repair outcomes. In summary, anti-DKK1 can be used as a method to augment cell-mediated bone regeneration, and could be particularly valuable in the contexts of impaired bone healing such as osteoporotic bone repair

Gastrointestinal disorders in Curry-Jones syndrome: Clinical and molecular insights from an affected newborn.

Curry-Jones syndrome (CJS) is a pattern of malformation that includes craniosynostosis, pre-axial polysyndactyly, agenesis of the corpus callosum, cutaneous and gastrointestinal abnormalities. A recurrent, mosaic mutation of SMO (c.1234 C>T; p.Leu412Phe) causes CJS. This report describes the gastrointestinal and surgical findings in a baby with CJS who presented with abdominal obstruction and reviews the spectrum of gastrointestinal malformations in this rare disorder. A 41-week, 4,165 g, female presented with craniosynostosis, pre-axial polysyndactyly, and cutaneous findings consistent with a clinical diagnosis of CJS. The infant developed abdominal distension beginning on the second day of life. Surgical exploration revealed an intestinal malrotation for which she underwent a Ladd procedure. Multiple small nodules were found on the surface of the small and large bowel in addition to an apparent intestinal duplication that seemed to originate posterior to the pancreas. Histopathology of serosal nodules revealed bundles of smooth muscle with associated ganglion cells. Molecular analysis demonstrated the SMO c.1234 C>T mutation in varying amounts in affected skin (up to 35%) and intestinal hamartoma (26%). Gastrointestinal features including structural malformations, motility disorders, and upper GI bleeding are major causes of morbidity in CJS. Smooth muscle hamartomas are a recognized feature of children with CJS typically presenting with abdominal obstruction requiring surgical intervention. A somatic mutation in SMO likely accounts for the structural malformations and predisposition to form bowel hamartomas and myofibromas. The mutation burden in the involved tissues likely accounts for the variable manifestations

The Effects of Depression and Anti-depressants on Patient Satisfaction after Breast Reconstruction

Background: A personal history of depression prior to a breast cancer diagnosis and its effect on post-diagnosis quality of life (QOL) in women undergoing breast reconstruction is relatively unknown. We performed the current study to determine if depression alters QOL for patients who undergo breast reconstruction by assessing the pre-to-post-operative change in patient-reported BREAST-Q scores. Methods: This study is a single-center, post-hoc analysis of 300 patients with completed BREAST-Q data who underwent breast reconstruction following a diagnosis of breast cancer from November 2013 to 2016. Patients completed the BREAST-Q at four time points: pre-operatively, 6-weeks following tissue expander insertion for patients undergoing staged reconstruction, 6-months following final reconstruction, and 12-months following final reconstruction. Medical records of breast reconstruction patients were reviewed to identify patients who had a pre-cancer diagnosis of clinical depression and/or anti-depressant medication use. BREAST-Q scores were compared between the depression (n=50) and no depression (n=250) patients, along with anti-depressant (n=36) and no anti-depressant (n=14) use in the depression group. Results: The Sexual Well-being scores at the 6-week tissue expander follow up for patients in the depression group (median = 37, IQR = 25-47) were significantly lower (p\u3c0.01) than the scores for patients in the no depression group (median = 47, IQR = 39-60) following adjusted analysis. There were no statistically significant differences in BREAST-Q scores in other domains. Conclusion: Patients with a diagnosis of depression prior to breast cancer had lower BREAST-Q Sexual Well-being scores in the 6-week tissue expander group with or without anti-depressant medication. No differences in BREAST-Q scores were observed among the remaining domains, although Satisfaction of Breasts: 6-months post-op, Psychosocial Well-being: 6-weeks post TE, Sexual Well-being: 6-weeks post TE and 6-months post-op were clinically significant

Women Continue to Be Underrepresented in Surgery: A Study of AMA and ACGME Data from 2000-2016

Objective: In the past decade women have comprised nearly half of U.S. medical school graduates. However, women remain underrepresented among surgical residents and practicing surgeons. We conducted the current study to assess recent trends in the female-to-male (F:M) ratios among residents and physicians pursuing careers in surgery. Design: We used retrospective population statistics published by the American Medical Association (AMA) and the Accreditation Council for Graduate Medical Education (ACGME) from 2000-2016. We compared trends of female-to-male ratios among residents and surgeons in surgical subspecialties to evaluate for potential differences over time. Setting: Published online population statistics Participants: We stratified both board-certified surgeons and surgical residents by sex and specialty. Results: From 2000-2013, the proportion of female surgeons among all female physicians remained constant (12-13%). The proportion of board-certified female surgeons to all surgeons increased (from 15% in 2000 to 25% in 2013). The F:M ratios of board-certified surgeons in neurosurgery and orthopedic surgery were 1:10.6 and 1:13.9, with resident ratios 1:4.8 and 1:5.9, respectively. One specialty with increasingly equivalent ratios is plastic surgery with integrated resident F:M ratios of 1:3.1 in 2008 to 1:1.4 in 2015, and board-certified plastic surgeons of 1:9.2 in 2008 to 1:5.3 in 2013. Conclusion: Although the gender gap is narrowing, women continue to be underrepresented in surgical specialties. It is important for fields with disproportionate representation to be aware of these differences and take steps towards creating and supporting a more diverse workforce