Vitamin D and uric acid: Is parathyroid hormone the missing link?

© 2011 IEEE. Personal use of this material is permitted. Permission from IEEE must be obtained for all other users, including reprinting/ republishing this material for advertising or promotional purposes, creating new collective works for resale or redistribution to servers or lists, or reuse of any copyrighted components of this work in other works. Digital Object Identifier : 10.1109/ROMAN.2011.6005255Presented at the 20th IEEE International Symposium on Robot and Human Interactive Communication, July 31 - August 3, 2011, Atlanta, GA, USA.Robots that display anticipatory motion provide their human partners with greater time to respond in interactive tasks because human partners are aware of robot intent earlier. We create anticipatory motion autonomously from a single motion exemplar by extracting hand and body symbols that communicate motion intent and moving them earlier in the motion. We validate that our algorithm extracts the most salient frame (i.e. the correct symbol) which is the most informative about motion intent to human observers. Furthermore, we show that anticipatory variants allow humans to discern motion intent sooner than motions without anticipation, and that humans are able to reliably predict motion intent prior to the symbol frame when motion is anticipatory. Finally, we quantified the time range for robot motion when humans can perceive intent more accurately and the collaborative social benefits of anticipatory motion are greatest

Association between statin use & risk of diffuse large B-cell lymphoma: A systematic review & meta-analysis

Background & objectives: Statin use has been shown to be associated with a decreased risk of several types of cancer, however, the data on diffuse large B-cell lymphoma (DLBCL) are still inconclusive. This study aimed to systematically summarize all available data on this association and conduct a meta-analysis on the same. Methods: A systematic review was performed using EMBASE and MEDLINE databases from inception upto October 2019 with a search strategy that included terms such as 'statin' and 'DLBCL'. Eligible studies included either case–control or cohort studies that reported the association between statin use and the risk of DLBCL. Relative risk, odds ratio (OR), hazard: risk ratio or standardized incidence ratio of this association and standard error were extracted and combined for calculating the pooled effect estimate using random-effects, generic inverse variance method. Results: A total of 1139 articles were screened. Of these six studies satisfied the inclusion criteria and were included for the meta-analysis. Statin use was associated with a significantly reduced risk of DLBCL with the pooled OR of 0.70 (95% confidence interval, 0.56-0.88; I[2]=70%). The funnel plot (fairly symmetric) was not suggestive of the presence of a publication bias. Interpretation & conclusions: The present systematic review and meta-analysis found that statin use is associated with a 30 per cent reduced odds of DLBCL. However, the pooled analysis utilized data from observational studies so causation cannot be concluded upon. Hence, it suggested that randomized-controlled studies are still needed to confirm this potential benefit

Atypical Femoral Fracture in Hypophosphatasia: A Systematic Review

Objective. To summarize the characteristics of all reported patients with hypophosphatasia (HPP) who sustained atypical femoral fracture (AFF) and identify all available evidence to quantify the rate of coexistence between HPP and AFF. Methods. Potentially eligible articles were identified from the MEDLINE and EMBASE databases from its inception to September 2022, using a search strategy consisting of terms related to “Hypophosphatasia” and “Atypical femoral fracture.” Eligible articles must report one of the following information: (1) individual data of patients diagnosed with HPP and AFF, (2) prevalence of HPP among patients with AFF, or (3) prevalence of AFF among patients of HPP. Characteristics of patients reported in each study were extracted. Results. A total of 148 articles were identified. After the systematic review, 24 articles met the eligibility criteria. A total of 28 patients with AFF and HPP were identified. The mean ± SD age of the reported patients was 53.8 ± 12.5 years, and 22 patients (78.6%) were female. Nine patients (32.1%) received antiresorptive medication (bisphosphonate and/or denosumab), and two patients (7.1%) received teriparatide prior to the development of AFF. Seven (25.0%) and eighteen (64.3%) patients sustained unilateral and bilateral AFF, respectively (laterality not reported in three cases). Thirteen patients (46.4%) had a history of fractures at other sites. Four (14.3%) and seven (25.0%) patients received asfotase alfa and teriparatide after sustaining AFF. Two studies reported the prevalence of AFF among patients with HPP of approximately 10%. One study reported one HPP patient in a cohort of 72 patients with AFF. Conclusions. Based on the limited evidence, AFF occurred in up to 10% of patients with HPP. Based on the 28 case reports, about two-thirds did not receive antiresorptive treatment, suggesting that the HPP itself could potentially be a risk factor for AFF

Significance of hereditary gene alterations for the pathogenesis of adult bone marrow failure versus myeloid neoplasia

Broader genetic screening has led to the growing recognition of the role of germline variants associated with adult bone marrow failure (BMF) and myeloid neoplasia (MN) not exclusively in children and young adults. In this study, we applied a germline variant panel to 3008 adult BMF and MN cases to assess the importance of germline genetics and its impact on disease phenotype and prognosis. In our cohort, up to 9.7% of BMF and 5.3% of MN cases carried germline variants. Our cohort also included heterozygous carriers of recessive traits, suggesting they contribute to the risk of BMF and MN. By gene category, variants of Fanconi anemia gene family represented the highest-frequency category for both BMF and MN cases, found in 4.9% and 1.7% cases, respectively. In addition, about 1.4% of BMF and 0.19% of MN cases harbored multiple germline variants affecting often functionally related genes as compound heterozygous. The burden of germline variants in BMF and MN was clearly associated with acquisition of monosomy 7. While BMF cases carrying germline variants showed similar overall survival as compared to the wild-type (WT) cases, MN cases with germline variants experienced a significantly shorter overall survival as compared to WT cases

DataSheet_1_Combining the SMAC mimetic LCL161 with Gemcitabine plus Cisplatin therapy inhibits and prevents the emergence of multidrug resistance in cholangiocarcinoma.pdf

Cholangiocarcinoma (CCA) is a highly lethal gastrointestinal malignancy that has one of the worst prognoses among solid tumors. The combination of Gemcitabine + Cisplatin (GEM/CIS) remains the standard first-line treatment for advanced stage CCA. However, this drug combination yields only a modest objective response rate, and in cases that initially respond to this treatment, drug resistance commonly rapidly develops. To improve the efficiency of GEM/CIS therapy for CCA, a thorough understanding of the mechanism of GEM/CIS resistance in CCA is required. To that end – in this study, we developed several acquired GEM/CIS-resistant CCA cell lines and we screened those cell lines for acquired vulnerability. The screening process revealed that subset of CCA with GEM/CIS resistance acquired vulnerability to the small-molecule second mitochondrial-derived activator of caspases (SMAC) mimetics LCL161 and Birinapant. The observed acquired vulnerability was found to be associated with upregulation of an inhibitor of apoptosis protein 2 (cIAP2), a known target of SMAC mimetics. LCL161 or cIAP2-shRNA downregulated cIAP2 and restored the sensitivity to GEM/CIS in GEM/CIS-resistant CCA cell lines and in in vivo GEM/CIS-resistant xenograft models. A strong synergic effect was observed when LCL161 was added to GEM/CIS. Interestingly, this synergism was also observed in drug-naïve CCA cell lines, xenografts, and patient-derived organoids. This triplet therapy also prevented the emergence of multidrug-resistant CCA in in vitro and in vivo models. Our findings suggest that activation of cIAP2 allows CCA to escape GEM/CIS, and that suppression of cIAP2 reestablishes the apoptotic profile of CCA, thus restoring its vulnerability to GEM/CIS. The results of this study indicate that combining the SMAC mimetic LCL161 with GEM/CIS inhibits and prevents the emergence of multidrug resistance in CCA.</p

Molecular and clinical analyses of PHF6 mutant myeloid neoplasia provide their pathogenesis and therapeutic targeting

Abstract PHF6 mutations (PHF6 MT) are identified in various myeloid neoplasms (MN). However, little is known about the precise function and consequences of PHF6 in MN. Here we show three main findings in our comprehensive genomic and proteomic study. Firstly, we show a different pattern of genes correlating with PHF6 MT in male and female cases. When analyzing male and female cases separately, in only male cases, RUNX1 and U2AF1 are co-mutated with PHF6. In contrast, female cases reveal co-occurrence of ASXL1 mutations and X-chromosome deletions with PHF6 MT. Next, proteomics analysis reveals a direct interaction between PHF6 and RUNX1. Both proteins co-localize in active enhancer regions that define the context of lineage differentiation. Finally, we demonstrate a negative prognostic role of PHF6 MT, especially in association with RUNX1. The negative effects on survival are additive as PHF6 MT cases with RUNX1 mutations have worse outcomes when compared to cases carrying single mutation or wild-type

Molecular patterns identify distinct subclasses of myeloid neoplasia

Abstract Genomic mutations drive the pathogenesis of myelodysplastic syndromes and acute myeloid leukemia. While morphological and clinical features have dominated the classical criteria for diagnosis and classification, incorporation of molecular data can illuminate functional pathobiology. Here we show that unsupervised machine learning can identify functional objective molecular clusters, irrespective of anamnestic clinico-morphological features, despite the complexity of the molecular alterations in myeloid neoplasia. Our approach reflects disease evolution, informed classification, prognostication, and molecular interactions. We apply machine learning methods on 3588 patients with myelodysplastic syndromes and secondary acute myeloid leukemia to identify 14 molecularly distinct clusters. Remarkably, our model shows clinical implications in terms of overall survival and response to treatment even after adjusting to the molecular international prognostic scoring system (IPSS-M). In addition, the model is validated on an external cohort of 412 patients. Our subclassification model is available via a web-based open-access resource ( https://drmz.shinyapps.io/mds_latent )