Citations

ABSTRACT There is a clinical need to identify new molecular targets for the treatment of osteoporosis, particularly those that simultaneously inhibit bone resorption while stimulating bone formation. We have previously shown in overexpression studies that retinoic acid receptor-related orphan receptor β (Rorβ) suppresses in vitro osteoblast differentiation. In addition, the expression of Rorβ is markedly increased in bone marrow–derived mesenchymal stromal cells with aging in both mice and humans. Here we establish a critical role for Rorβ in regulating bone metabolism using a combination of in vitro and in vivo studies. We used Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 gene editing to demonstrate that loss of Rorβ in osteoblasts enhances Wnt signaling, specifically through increased recruitment of β-catenin to T-cell factor/lymphoid enhancer factor (Tcf/Lef) DNA binding sites in the promoters of the Wnt target genes Tcf7 and Opg. This resulted in increased osteogenic gene expression and suppressed osteoclast formation through increased osteoprotegerin (OPG) secretion in Rorβ-deficient cells. Consistent with our in vitro data, genetic deletion of Rorβ in both female and male mice resulted in preserved bone mass and microarchitecture with advancing age due to increased bone formation with a concomitant decrease in resorption. The improved skeletal phenotype in the Rorβ–/– mice was also associated with increased bone protein levels of TCF7 and OPG. These data demonstrate that loss of Rorβ has beneficial skeletal effects by increasing bone formation and decreasing bone resorption, at least in part through β-catenin–dependent activation of the Wnt pathway. Thus, inhibition of Rorβ represents a novel approach to potentially prevent or reverse osteoporosis. © 2017 American Society for Bone and Mineral Research.

Breast implant-associated anaplastic large cell lymphoma (BI-ALCL) is a rare T-cell lymphoma that arises around breast implants. Most patients manifest with periprosthetic effusion, whereas a subset of patients develops a tumor mass or lymph node involvement (LNI). The aim of this study is to describe the pathologic features of lymph nodes from patients with BI-ALCL and assess the prognostic impact of LNI. Clinical findings and histopathologic features of lymph nodes were assessed in 70 patients with BI-ALCL. LNI was defined by the histologic demonstration of ALCL in lymph nodes. Fourteen (20%) patients with BI-ALCL had LNI, all lymph nodes involved were regional, the most frequent were axillary (93%). The pattern of involvement was sinusoidal in 13 (92.9%) cases, often associated with perifollicular, interfollicular, and diffuse patterns. Two cases had Hodgkin-like patterns. The 5-year overall survival was 75% for patients with LNI and 97.9% for patients without LNI at presentation (P=0.003). Six of 49 (12.2%) of patients with tumor confined by the capsule had LNI, compared with LNI in 8/21 (38%) patients with tumor beyond the capsule. Most patients with LNI achieved complete remission after various therapeutic approaches. Two of 14 (14.3%) patients with LNI died of disease compared with 0/56 (0%) patients without LNI. Twenty percent of patients with BI-ALCL had LNI by lymphoma, most often in a sinusoidal pattern. We conclude that BI-ALCL beyond capsule is associated with a higher risk of LNI. Involvement of lymph nodes was associated with decreased overall survival. Misdiagnosis as Hodgkin lymphoma is a pitfall.

PurposeCurrently, in clinical practice of intensity‐modulated proton therapy (IMPT), the influence of the minimum monitor unit (MU) constraint is taken into account through postprocessing after the optimization is completed. This may degrade the plan quality and plan robustness. This study aims to mitigate the impact of the minimum MU constraint directly during the plan robust optimization.Methods and materialsCao et al. have demonstrated a two‐stage method to account for the minimum MU constraint using linear programming without the impact of uncertainties considered. In this study, we took the minimum MU constraint into consideration using quadratic optimization and simultaneously had the impact of uncertainties considered using robust optimization. We evaluated our method using seven cancer patients with different machine settings.ResultThe new method achieved better plan quality than the conventional method. The D95% of the clinical target volume (CTV) normalized to the prescription dose was (mean [min–max]): (99.4% [99.2%–99.6%]) vs. (99.2% [98.6%–99.6%]). Plan robustness derived from these two methods was comparable. For all seven patients, the CTV dose–volume histogram band gap (narrower band gap means more robust plans) at D95% normalized to the prescription dose was (mean [min–max]): (1.5% [0.5%–4.3%]) vs. (1.2% [0.6%–3.8%]).ConclusionOur new method of incorporating the minimum MU constraint directly into the plan robust optimization can produce machine‐deliverable plans with better tumor coverage while maintaining high‐plan robustness.

AbstractThe recent movement towards open data in the biomedical domain has generated a large number of datasets that are publicly accessible. The Big Data to Knowledge data indexing project, biomedical and healthCAre Data Discovery Index Ecosystem (bioCADDIE), has gathered these datasets in a one-stop portal aiming at facilitating their reuse for accelerating scientific advances. However, as the number of biomedical datasets stored and indexed increases, it becomes more and more challenging to retrieve the relevant datasets according to researchers’ queries. In this article, we propose an information retrieval (IR) system to tackle this problem and implement it for the bioCADDIE Dataset Retrieval Challenge. The system leverages the unstructured texts of each dataset including the title and description for the dataset, and utilizes a state-of-the-art IR model, medical named entity extraction techniques, query expansion with deep learning-based word embeddings and a re-ranking strategy to enhance the retrieval performance. In empirical experiments, we compared the proposed system with 11 baseline systems using the bioCADDIE Dataset Retrieval Challenge datasets. The experimental results show that the proposed system outperforms other systems in terms of inference Average Precision and inference normalized Discounted Cumulative Gain, implying that the proposed system is a viable option for biomedical dataset retrieval.Database URL: https://github.com/yanshanwang/biocaddie2016mayodata

OBJECTIVE Intensive treatment (INT) of type 1 diabetes reduces the incidence of cardiovascular disease (CVD) events compared with conventional treatment (CONV), but it also results in more weight gain. Our objective was to examine whether excessive weight gain from INT of type 1 diabetes is independently associated with subsequent CVD events. RESEARCH DESIGN AND METHODS Quartiles (Q) of weight gain in 1,213 participants aged 18 years and older at enrollment in the Diabetes Control and Complications Trial (DCCT) were determined within randomized treatment groups (INT vs. CONV) using change in BMI from baseline to the closeout DCCT visits. Effects of this weight gain on CVD risk factors and outcomes during an additional 20 years of observational follow-up were then determined. RESULTS The Q4 INT group experienced greater proportional weight gain (median change in BMI, 6.08 kg/m2), increases in CVD risk factors, and need for medications for hypertension and lipids compared with the Q1–3 INT and comparable CONV groups. Over a mean of 26 years of follow-up, the numbers of major and total CVD events were not statistically different in Q4 compared with Q1–3 of either the INT or CONV group. By year 14, however, the incident CVD event curve became significantly higher in the Q4 INT group than in the Q1–3 INT groups (P = 0.024) and was similar to that for the CONV group. CONCLUSIONS For the first 13 years after DCCT, INT for type 1 diabetes reduced macrovascular events compared with CONV, even when excessive weight gain occurred. After this, total CVD events significantly increased in the Q4 INT group, becoming equivalent to those in the CONV group. Longer follow-up is needed to determine whether this trend continues and results in more major CVD events.

Background and Purpose— White matter (WM) ischemic injury, a major neuropathological feature of cerebral small vessel diseases, is an important cause of vascular cognitive impairment in later life. The pathogenesis of demyelination after WM ischemic damage are often accompanied by microglial activation. Fingolimod (FTY720) was approved for the treatment of multiple sclerosis for its immunosuppression property. In this study, we evaluated the neuroprotective potential of FTY720 in a WM ischemia model. Methods— Chronic WM ischemic injury model was induced by bilateral carotid artery stenosis. Cognitive function, WM integrity, microglial activation, and potential pathway involved in microglial polarization were assessed after bilateral carotid artery stenosis. Results— Disruption of WM integrity was characterized by demyelination in the corpus callosum and disorganization of Ranvier nodes using Luxol fast blue staining, immunofluorescence staining, and electron microscopy. In addition, radial maze test demonstrated that working memory performance was decreased at 1-month post–bilateral carotid artery stenosis–induced injury. Interestingly, FTY720 could reduce cognitive decline and ameliorate the disruption of WM integrity. Mechanistically, cerebral hypoperfusion induced microglial activation, production of associated proinflammatory cytokines, and priming of microglial polarization toward the M1 phenotype, whereas FTY720 attenuated microglia-mediated neuroinflammation after WM ischemia and promoted oligodendrocytogenesis by shifting microglia toward M2 polarization. FTY720’s effect on microglial M2 polarization was largely suppressed by selective signal transducer and activator of transcription 3 (STAT3) blockade in vitro, revealing that FTY720-enabled shift of microglia from M1 to M2 polarization state was possibly mediated by STAT3 signaling. Conclusions— Our study suggested that FTY720 might be a potential therapeutic drug targeting brain inflammation by skewing microglia toward M2 polarization after chronic cerebral hypoperfusion.

Abstract In some cases, laparoscopic cholecystectomy (LC) may be difficult to perform in patients with acute cholecystitis (AC) with severe inflammation and fibrosis. The Tokyo Guidelines 2018 (TG18) expand the indications for LC under difficult conditions for each level of severity of AC. As a result of expanding the indications for LC to treat AC, it is absolutely necessary to avoid any increase in bile duct injury (BDI), particularly vasculo‐biliary injury (VBI), which is known to occur at a certain rate in LC. Since the Tokyo Guidelines 2013 (TG13), an attempt has been made to assess intraoperative findings as objective indicators of surgical difficulty; based on expert consensus on these difficulty indicators, bail‐out procedures (including conversion to open cholecystectomy) have been indicated for cases in which LC for AC is difficult to perform. A bail‐out procedure should be chosen if, when the Calot's triangle is appropriately retracted and used as a landmark, a critical view of safety (CVS) cannot be achieved because of the presence of nondissectable scarring or severe fibrosis. We propose standardized safe steps for LC to treat AC. To achieve a CVS, it is vital to dissect at a location above (on the ventral side of) the imaginary line connecting the base of the left medial section (Segment 4) and the roof of Rouvière's sulcus and to fulfill the three criteria of CVS before dividing any structures. Achieving a CVS prevents the misidentification of the cystic duct and the common bile duct, which are most commonly confused. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47 . Related clinical questions and references are also included.