Characterizing the role of the immune microenvironment in multiple myeloma progression at a single-cell level.

Early alterations within the bone marrow microenvironment that contribute to the progression of multiple myeloma (MM) from its precursor stages could be the key to identifying novel therapeutic approaches. However, the intrinsic variability in cellular populations between patients and the differences in sample processing and analysis methods have made it difficult to identify consistent changes between data sets. Here, we used single-cell RNA sequencing of bone marrow cells from precursor stages, monoclonal gammopathy of unknown significance, smoldering MM, and newly diagnosed MM and analyzed our data in combination with a previously published data set that used a similar patient population and sample processing. Despite the vast interpatient heterogeneity, some alterations were consistently observed in both data sets. We identified changes in immune cell populations as the disease progressed, which were characterized by a substantial decrease in memory and naïve CD4 T cells, and an increase in CD8+ effector T cells and T-regulatory cells. These alterations were further accompanied by an enrichment of nonclonal memory B cells and an increase in CD14 and CD16 monocytes in MM compared with its precursor stages. These results provide crucial information on the immune changes associated with the progression to clinical MM and can help to develop immune-based strategies for patient stratification and early therapeutic intervention.

Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma.

Understanding the profile of oncogene and tumor suppressor gene mutations with their interactions and impact on the prognosis of multiple myeloma (MM) can improve the definition of disease subsets and identify pathways important in disease pathobiology. Using integrated genomics of 1273 newly diagnosed patients with MM, we identified 63 driver genes, some of which are novel, including IDH1, IDH2, HUWE1, KLHL6, and PTPN11 Oncogene mutations are significantly more clonal than tumor suppressor mutations, indicating they may exert a bigger selective pressure. Patients with more driver gene abnormalities are associated with worse outcomes, as are identified mechanisms of genomic instability. Oncogenic dependencies were identified between mutations in driver genes, common regions of copy number change, and primary translocation and hyperdiploidy events. These dependencies included associations with t(4;14) and mutations in FGFR3, DIS3, and PRKD2; t(11;14) with mutations in CCND1 and IRF4; t(14;16) with mutations in MAF, BRAF, DIS3, and ATM; and hyperdiploidy with gain 11q, mutations in FAM46C, and MYC rearrangements. These associations indicate that the genomic landscape of myeloma is predetermined by the primary events upon which further dependencies are built, giving rise to a nonrandom accumulation of genetic hits. Understanding these dependencies may elucidate potential evolutionary patterns and lead to better treatment regimens.

An extracellular proteasome releases endostatin from human collagen XVIII.

Endostatin is a potent anti-angiogenic and anti-tumor protein capable of regressing tumors without inducing acquired resistance. Since it is a fragment of the parental molecule, collagen XVIII, its endogenous production depends on the activity of a specific proteolytic enzyme. While such an enzyme has been described in mice, a human counterpart has not been identified so far. Here, we searched for this enzyme by using a fluorescence resonance energy transfer peptide containing the cleavage site of human collagen XVIII. We found that the cleavage activity was present in various murine and human tumor cells but not in untransformed cells. It was ascribed to a large protein complex identified as an extracellular form of proteasome 20S. Since circulating proteasome 20S has recently emerged as an important marker of tumor progression, the possibility of proteasomes controlling the production of angiostatic endostatin may inspire the development of new anticancer therapies.

Relationship among latitude, climate, season and self-reported mood in bipolar disorder.

OBJECTIVE: Many researchers have analyzed seasonal variation in hospital admissions for bipolar disorder with inconsistent results. We investigated if a seasonal pattern was present in daily self-reported daily mood ratings from patients living in five climate zones in the northern and southern hemispheres. We also investigated the influence of latitude and seasonal climate variables on mood. METHOD: 360 patients who were receiving treatment as usual recorded mood daily (59,422 total days of data). Both the percentage of days depressed and hypomanic/manic, and the episodes of depression and mania were determined. The observations were provided by patients from different geographic locations in North and South America, Europe and Australia. These data were analyzed for seasonality by climate zone using both a sinusoidal regression and the Gini index. Additionally, the influence of latitude and climate variables on mood was estimated using generalized linear models for each season and month. RESULTS: No seasonality was found in any climate zone by either method. In spite of vastly different weather, neither latitude nor climate variables were associated with mood by season or month. CONCLUSION: Daily self-reported mood ratings of most patients with bipolar disorder did not show a seasonal pattern. Neither climate nor latitude has a primary influence on the daily mood changes of most patients receiving medication for bipolar disorder.

Diretrizes da World Federation of Societies of Biological Psychiatry (WFSBP) para tratamento biológico de transtornos depressivos unipolares, 1ª parte: tratamento agudo e de continuação do transtorno depressivo maior / World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for biological treatment of unipolar depressive disorders, part 1: acute and continuation treatment of major depressive disorder

Estas diretrizes práticas para o tratamento biológico de transtornos depressivos unipolares foram desenvolvidas por uma Força-Tarefa internacional da Federação Mundial de Sociedades de Psiquiatria Biológica (WFSBP). O objetivo ao desenvolver tais diretrizes foi rever sistematicamente todas as evidências existentes referentes ao tratamento de transtornos depressivos unipolares e produzir uma série de recomendações práticas com significado clínico e científico, baseadas nas evidências existentes. Têm como objetivo seu uso por todos os médicos que atendam e tratem pacientes com essas afecções. Os dados usados para o desenvolvimento das diretrizes foram extraídos primariamente de várias diretrizes e painéis nacionais de tratamento para transtornos depressivos, bem como de metanálises e revisões sobre a eficácia dos antidepressivos e outras intervenções de tratamento biológico identificadas por uma busca no banco de dados MEDLINE e Cochrane Library. A literatura identificada foi avaliada quanto à força das evidências sobre sua eficácia e, então, categorizada em quatro níveis de evidências (A a D). Esta primeira parte das diretrizes abrange definição, classificação, epidemiologia e evolução dos transtornos depressivos unipolares, bem como tratamento das fases aguda e de manutenção. As diretrizes se referem primariamente ao tratamento biológico (incluindo antidepressivos, outros medicamentos psicofarmacológicos e hormonais, eletroconvulsoterapia, fototerapia, estratégias terapêuticas complementares e novas) de adultos jovens e também, embora em menor grau, de crianças, adolescentes e adultos idosos.

These practice guidelines for the biological treatment of unipolar depressive disorders were developed by an international Task Force of the World Federation of Societies of Biological Psychiatry (WFSBP). The goal for developing these guidelines was to systematically review all available evidence pertaining to the treatment of unipolar depressive disorders, and to produce a series of practice recommendations that are clinically and scientifically meaningful based on the available evidence. These guidelines are intended for use by all physicians seeing and treating patients with these conditions. The data used for developing these guidelines have been extracted primarily from various national treatment guidelines and panels for depressive disorders, as well as from meta-analyses and reviews on the efficacy of antidepressant medications and other biological treatment interventions identified by a search of the MEDLINE database and Cochrane Library. The identified literature was evaluated with respect to the strength of evidence for its efficacy and was then categorized into four levels of evidence (A-D). This first part of the guidelines covers disease definition, classification, epidemiology and course of unipolar depressive disorders, as well as the management of the acute and continuation-phase treatment. These guidelines are primarily concerned with the biological treatment (including antidepressants, other psychopharmacological and hormonal medications, electroconvulsive therapy, light therapy, adjunctive and novel therapeutic strategies) of young adults and also, albeit to a lesser extent, children, adolescents and older adults.

Diretrizes da World Federation of Societies of Biological Psychiatry (WFSBP) para tratamento biológico de transtornos depressivos unipolares, 2ª parte: tratamento de manutenção do transtorno depressivo maior e tratamento dos transtornos depressivos crônicos e das depressões subliminares / World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for biological treatment of unipolar depressive disorders, part 2: maintenance treatment of major depressive disorder and treatment of chronic depressive disorders and subthreshold depressions

Estas diretrizes práticas para o tratamento biológico de transtornos depressivos unipolares foram desenvolvidas por uma Força-Tarefa internacional da Federação Mundial de Sociedades de Psiquiatria Biológica (WFSBP). O objetivo ao desenvolver tais diretrizes foi rever sistematicamente todas as evidências existentes referentes ao tratamento de transtornos depressivos unipolares e produzir uma série de recomendações práticas com significado clínico e científico, baseadas nas evidências existentes. Têm como objetivo seu uso por todos os médicos que atendam e tratem pacientes com essas afecções. Os dados usados para o desenvolvimento das diretrizes foram extraídos primariamente de várias diretrizes e painéis nacionais de tratamento para transtornos depressivos, bem como de metanálises e revisões sobre a eficácia dos antidepressivos e outras intervenções de tratamento biológico identificadas por uma busca no banco de dados MEDLINE e Cochrane Library. A literatura identificada foi avaliada quanto à força das evidências sobre sua eficácia e, então, categorizada em quatro níveis de evidências (A a D). Esta primeira parte das diretrizes abrange definição, classificação, epidemiologia e evolução dos transtornos depressivos unipolares, bem como tratamento das fases aguda e de manutenção. As diretrizes se referem primariamente ao tratamento biológico (incluindo antidepressivos, outros medicamentos psicofarmacológicos e hormonais, eletroconvulsoterapia, fototerapia, estratégias terapêuticas complementares e novas) de adultos jovens e também, embora em menor grau, de crianças, adolescentes e adultos idosos.

These practice guidelines for the biological treatment of unipolar depressive disorders were developed by an international Task Force of the World Federation of Societies of Biological Psychiatry (WFSBP). The goal for developing these guidelines was to systematically review all available evidence pertaining to the treatment of the complete spectrum of unipolar depressive disorders, and to produce a series of practice recommendations that are clinically and scientifically meaningful based on the available evidence. These guidelines are intended for use by all physicians seeing and treating patients with these conditions. The data used for developing these guidelines have been extracted primarily from various national treatment guidelines and panels for depressive disorders, as well as from meta-analyses and reviews on the efficacy of antidepressant medications and other biological treatment interventions identified by a search of the MEDLINE database and Cochrane Library. The identified literature was evaluated with respect to the strength of evidence for its efficacy and was then categorized into four levels of evidence (A-D). The first part of these WFSBP guidelines on unipolar depressive disorders covered the acute and continuation treatment of major depressive disorder (Bauer et al., 2002). This second part of the guidelines covers the management of the maintenance-phase treatment of major depressive disorder, as well as the treatment of chronic and subthreshold depressive disorders (dysthymic disorder, double depression, minor depressive disorder and recurrent brief depression). These guidelines are primarily concerned with thebiological treatment (including antidepressants, lithium, other psychopharmacological and hormonal medications, and electroconvulsive therapy) of young adults and also, albeit to a lesser extent, children, adolescents and older adults.

A comparison of intimate partner homicide to intimate partner homicide-suicide: one hundred and twenty-four New Mexico cases.

The authors compare cases of female intimate partner homicide-suicide to female intimate partner homicide alone to describe risk factors and suggest prevention strategies, including strategies in the medical setting. Differences are found between the types of cases in marital relationship, age, blood alcohol, and the use of firearms. Physicians and other health care providers who treat victims of intimate partner violence and patients at risk for suicide should be aware of the interwoven risk factors within these populations. Interventions aimed at suicide prevention as well as targeted removal of firearms should be investigated as tools in the prevention of intimate partner homicide.

Endostatin competes with bFGF for binding to heparin-like glycosaminoglycans.

Endostatin is a potent inhibitor of angiogenesis and tumor growth. Here, we used human endothelial cells from lung capillaries to investigate if endostatin competes with the proangiogenic growth factors, bFGF and VEGF, for binding to costimulatory heparan sulfate molecules. Endostatin inhibited 79% and 95% of the increase in proliferation induced by bFGF and VEGF165, respectively. The stimulatory effect of VEGF165 was not affected by the presence of exogenous heparin, while that of bFGF was further enhanced in the presence of up to 0.1 microg/ml heparin. The heparin-binding protein protamine completely blocked bFGF-stimulated proliferation, while it did not affect the response to VEGF165. Simultaneous addition of endostatin and protamine led to additive effects both in inhibition of proliferation and induction of apoptosis. Although bFGF was found to bind more strongly to heparin-Sepharose than endostatin, the latter, but not the former, displaced protamine from heparin in solution, which supports the notion that endostatin can compete with bFGF for binding to heparan sulfate in vivo. Taken as a whole, our results demonstrate that there is a direct connection between the dependence of endostatin activity on heparin-like glycosaminoglycans and its ability to antagonize bFGF.