Poor Outcomes for IgD Multiple Myeloma Patients Following High-Dose Melphalan and Autologous Stem Cell Transplantation: A Single Center Experience

Immunoglobulin (Ig) D multiple myeloma (MM) accounts for 2% of all MM cases and has been reported to be associated with poor prognosis compared with other MM subtypes. The aim of the present study was to compare the effects of high-dose melphalan treatment and autologous stem cell transplantation (ASCT) on the survival of patients with IgD MM and patients with other MM subtypes. Between November 1998 and January 2005, a total of 77 patients with MM who underwent ASCT at the Asan Medical Center were enrolled in this study. High-dose melphalan (total 200 mg/m2) was used as high-dose chemotherapy. The study population was divided into two groups based on MM subtype: those with IgD MM; and those with other MM subtypes. A total of 8 patients with IgD MM were identified, accounting for about 10% of the study population. Thirty-six patients (47%) had IgG MM, 17 patients (22%) had IgA MM, and 16 patients (20%) had free light-chain MM. The two groups were similar in baseline characteristics. The median follow-up was 17 months and the median overall survival (OS) was 39 months. In the IgD MM group, median event-free survival (EFS) and OS were 6.9 and 12 months, respectively. In the patients with other MM subtypes, median EFS and OS were 11.5 and 55.5 months (p=0.01, p<0.01), respectively. Multivariate analysis of all patients identified IgD subtype (p=0.002) and Southwest Oncology Group (SWOG) stage 2 or greater at the time of ASCT (p=0.01) as adverse prognostic factors for survival. In this small study at a single center in Korea, patients with IgD MM had poorer outcomes after ASCT than did patients with other MM subtypes

A population-based study of ambulatory and surgical services provided by orthopaedic surgeons for musculoskeletal conditions

<p>Abstract</p> <p>Background</p> <p>The ongoing process of population aging is associated with an increase in prevalence of musculoskeletal conditions with a concomitant increase in the demand of orthopaedic services. Shortages of orthopaedic services have been documented in Canada and elsewhere. This population-based study describes the number of patients seen by orthopaedic surgeons in office and hospital settings to set the scene for the development of strategies that could maximize the availability of orthopaedic resources.</p> <p>Methods</p> <p>Administrative data from the Ontario Health Insurance Plan and Canadian Institute for Health Information hospital separation databases for the 2005/06 fiscal year were used to identify individuals accessing orthopaedic services in Ontario, Canada. The number of patients with encounters with orthopaedic surgeons, the number of encounters and the number of surgeries carried out by orthopaedic surgeons were estimated according to condition groups, service location, patient's age and sex.</p> <p>Results</p> <p>In 2005/06, over 520,000 Ontarians (41 per 1,000 population) had over 1.3 million encounters with orthopaedic surgeons. Of those 86% were ambulatory encounters and 14% were in hospital encounters. The majority of ambulatory encounters were for an injury or related condition (44%) followed by arthritis and related conditions (37%). Osteoarthritis accounted for 16% of all ambulatory encounters. Orthopaedic surgeons carried out over 140,000 surgeries in 2005/06: joint replacement accounted for 25% of all orthopaedic surgeries, whereas closed repair accounted for 16% and reductions accounted for 21%. Half of the orthopaedic surgeries were for arthritis and related conditions.</p> <p>Conclusion</p> <p>The large volume of ambulatory care points to the significant contribution of orthopaedic surgeons to the medical management of chronic musculoskeletal conditions including arthritis and injuries. The findings highlight that surgery is only one component of the work of orthopaedic surgeons in the management of these conditions. Policy makers and orthopaedic surgeons need to be creative in developing strategies to accommodate the growing workload of orthopaedic surgeons without sacrificing quality of care of patients with musculoskeletal conditions.</p

The Human TPR Protein TTC4 Is a Putative Hsp90 Co-Chaperone Which Interacts with CDC6 and Shows Alterations in Transformed Cells

BACKGROUND: The human TTC4 protein is a TPR (tetratricopeptide repeat) motif-containing protein. The gene was originally identified as being localized in a genomic region linked to breast cancer and subsequent studies on melanoma cell lines revealed point mutations in the TTC4 protein that may be associated with the progression of malignant melanoma. METHODOLOGY/PRINCIPLE FINDINGS: Here we show that TTC4 is a nucleoplasmic protein which interacts with HSP90 and HSP70, and also with the replication protein CDC6. It has significant structural and functional similarities with a previously characterised Drosophila protein Dpit47. We show that TTC4 protein levels are raised in malignant melanoma cell lines compared to melanocytes. We also see increased TTC4 expression in a variety of tumour lines derived from other tissues. In addition we show that TTC4 proteins bearing some of the mutations previously identified from patient samples lose their interaction with the CDC6 protein. CONCLUSIONS/SIGNIFICANCE: Based on these results and our previous work with the Drosophila Dpit47 protein we suggest that TTC4 is an HSP90 co-chaperone protein which forms a link between HSP90 chaperone activity and DNA replication. We further suggest that the loss of the interaction with CDC6 or with additional client proteins could provide one route through which TTC4 could influence malignant development of cells

The masked demos: Associational anonymity and democratic practice

The increased use of anonymous digital platforms raises substantive concerns about accountability in digital spaces. However, contemporary evaluations of anonymity focus too narrowly on its protective function: its ability to protect a diversity of speakers and ideas. Drawing on two examples of anonymous political engagements – Publius’s writing of the Federalist Papers and college students’ use of the social media platform Yik Yak – we develop an account of anonymity’s associational function: the processes by which people generate and negotiate collective identities, discussions, and actions in wider publics. As we argue, anonymity’s associational function can (1) generate conditions under which individuals develop collective interests and identities to foster collective action, and (2) enable novel interactions between these individuals and communities and the larger publics of which they are part. We conclude with a discussion of how attention to associational anonymity can contribute to a more nuanced account of democracy in practice

Three-Wall Segment (TriSeg) Model Describing Mechanics and Hemodynamics of Ventricular Interaction

A mathematical model (TriSeg model) of ventricular mechanics incorporating mechanical interaction of the left and right ventricular free walls and the interventricular septum is presented. Global left and right ventricular pump mechanics were related to representative myofiber mechanics in the three ventricular walls, satisfying the principle of conservation of energy. The walls were mechanically coupled satisfying tensile force equilibrium in the junction. Wall sizes and masses were rendered by adaptation to normalize mechanical myofiber load to physiological standard levels. The TriSeg model was implemented in the previously published lumped closed-loop CircAdapt model of heart and circulation. Simulation results of cardiac mechanics and hemodynamics during normal ventricular loading, acute pulmonary hypertension, and chronic pulmonary hypertension (including load adaptation) agreed with clinical data as obtained in healthy volunteers and pulmonary hypertension patients. In chronic pulmonary hypertension, the model predicted right ventricular free wall hypertrophy, increased systolic pulmonary flow acceleration, and increased right ventricular isovolumic contraction and relaxation times. Furthermore, septal curvature decreased linearly with its transmural pressure difference. In conclusion, the TriSeg model enables realistic simulation of ventricular mechanics including interaction between left and right ventricular pump mechanics, dynamics of septal geometry, and myofiber mechanics in the three ventricular walls

Swarm learning for decentralized artificial intelligence in cancer histopathology

Artificial intelligence (AI) can predict the presence of molecular alterations directly from routine histopathology slides. However, training robust AI systems requires large datasets for which data collection faces practical, ethical and legal obstacles. These obstacles could be overcome with swarm learning (SL), in which partners jointly train AI models while avoiding data transfer and monopolistic data governance. Here, we demonstrate the successful use of SL in large, multicentric datasets of gigapixel histopathology images from over 5,000 patients. We show that AI models trained using SL can predict BRAF mutational status and microsatellite instability directly from hematoxylin and eosin (H&E)-stained pathology slides of colorectal cancer. We trained AI models on three patient cohorts from Northern Ireland, Germany and the United States, and validated the prediction performance in two independent datasets from the United Kingdom. Our data show that SL-trained AI models outperform most locally trained models, and perform on par with models that are trained on the merged datasets. In addition, we show that SL-based AI models are data efficient. In the future, SL can be used to train distributed AI models for any histopathology image analysis task, eliminating the need for data transfer

Differential Impact of Tetratricopeptide Repeat Proteins on the Steroid Hormone Receptors

Tetratricopeptide repeat (TPR) motif containing co-chaperones of the chaperone Hsp90 are considered control modules that govern activity and specificity of this central folding platform. Steroid receptors are paradigm clients of Hsp90. The influence of some TPR proteins on selected receptors has been described, but a comprehensive analysis of the effects of TPR proteins on all steroid receptors has not been accomplished yet.We compared the influence of the TPR proteins FK506 binding proteins 51 and 52, protein phosphatase-5, C-terminus of Hsp70 interacting protein, cyclophillin 40, hepatitis-virus-B X-associated protein-2, and tetratricopeptide repeat protein-2 on all six steroid hormone receptors in a homogeneous mammalian cell system. To be able to assess each cofactor's effect on the transcriptional activity of on each steroid receptor we employed transient transfection in a reporter gene assay. In addition, we evaluated the interactions of the TPR proteins with the receptors and components of the Hsp90 chaperone heterocomplex by coimmunoprecipitation. In the functional assays, corticosteroid and progesterone receptors displayed the most sensitive and distinct reaction to the TPR proteins. Androgen receptor's activity was moderately impaired by most cofactors, whereas the Estrogen receptors' activity was impaired by most cofactors only to a minor degree. Second, interaction studies revealed that the strongly receptor-interacting co-chaperones were all among the inhibitory proteins. Intriguingly, the TPR-proteins also differentially co-precipitated the heterochaperone complex components Hsp90, Hsp70, and p23, pointing to differences in their modes of action.The results of this comprehensive study provide important insight into chaperoning of diverse client proteins via the combinatorial action of (co)-chaperones. The differential effects of the TPR proteins on steroid receptors bear on all physiological processes related to steroid hormone activity