Monoclonal gammopathy of renal significance (MGRS): Real-world data on outcomes and prognostic factors

Monoclonal gammopathy of renal significance (MGRS) is a recognized clinical entity. Literature regarding treatment and its outcomes in MGRS is sparse due to the rarity and misdiagnosis of MGRS. We retrospectively analyzed 280 adults with an MGRS diagnosis from 2003 to 2020 across 19 clinical centers from 12 countries. All cases required renal biopsy for the pathological diagnosis of MGRS. Amyloidosis-related to MGRS (MGRS-A) was present in 180 patients; nonamyloidosis MGRS (MGRS-NA), including a broad spectrum of renal pathologies, was diagnosed in 100 patients. The median overall survival in the studied cohort was 121.0 months (95% CI: 105.0–121.0). Patients with MGRS-A had a shorter overall survival than patients with MGRS-NA (HR = 0.41, 95%CI: 0.25–0.69; p = 0.0007). Both hematologic and renal responses were associated with longer survival. Achievement of ≥VGPR was generally predictive of a renal response (OR = 8.03 95%CI: 4.04–115.96; p < 0.0001), one-fourth of patients with ≥VGPR were renal nonresponders. In MGRS-A, factors associated with poor prognosis included elevated levels of creatinine, beta-2-microglobulin, and hemodialysis at diagnosis. In MGRS-NA, only age >65 years was associated with increased risk of death. Treatments provided similar hematologic response rates in both types of MGRS. Autologous stem cell transplantation led to better response than other treatments. This multicenter and international effort is currently the largest report on MGRS

The use of open data as a material for learning

Open data has potential value as a material for use in learning activities. However, approaches to harnessing this are not well understood or in mainstream use in education. In this research, early adopters from a diverse range of educational projects and teaching settings were interviewed to explore their rationale for using open data in teaching, how suitable activity designs could be achieved, and the practical challenges of using open data. A thematic analysis was conducted to identify patterns and relationships in these open data-based practices that have already emerged. A document analysis of teaching materials and other related artefacts was used to augment and validate the findings. Drawing on this, common approaches and issues are identified, and a conceptual framework to support greater use of open data by educators is described. This paper also highlights where existing concepts in education and educational technology research, including inquiry-based learning, authenticity, motivation, dialogue, and personalisation can help us to understand the value and challenges of using open data in education

Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis

Background Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease. Methods We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response. Results A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P Daratumumab in Light-Chain Amyloidosis In a randomized trial of bortezomib, cyclophosphamide, and dexamethasone as compared with the same therapy plus daratumumab, patients with light-chain amyloidosis who received daratumumab had a higher frequency of hematologic complete response than those who did not (53.3% vs. 18.1%). Deaths were most commonly due to cardiac failure

Dasatinib as a Bone-Modifying Agent: Anabolic and Anti-Resorptive Effects

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al.[Background]: Bone loss, in malignant or non-malignant diseases, is caused by increased osteoclast resorption and/or reduced osteoblast bone formation, and is commonly associated with skeletal complications. Thus, there is a need to identify new agents capable of influencing bone remodeling. We aimed to further pre-clinically evaluate the effects of dasatinib (BMS-354825), a multitargeted tyrosine kinase inhibitor, on osteoblast and osteoclast differentiation and function. [Methods]: For studies on osteoblasts, primary human bone marrow mensenchymal stem cells (hMSCs) together with the hMSC-TERT and the MG-63 cell lines were employed. Osteoclasts were generated from peripheral blood mononuclear cells (PBMC) of healthy volunteers. Skeletally-immature CD1 mice were used in the in vivo model. [Results]: Dasatinib inhibited the platelet derived growth factor receptor-β (PDGFR-β), c-Src and c-Kit phosphorylation in hMSC-TERT and MG-63 cell lines, which was associated with decreased cell proliferation and activation of canonical Wnt signaling. Treatment of MSCs from healthy donors, but also from multiple myeloma patients with low doses of dasatinib (2-5 nM), promoted its osteogenic differentiation and matrix mineralization. The bone anabolic effect of dasatinib was also observed in vivo by targeting endogenous osteoprogenitors, as assessed by elevated serum levels of bone formation markers, and increased trabecular microarchitecture and number of osteoblast-like cells. By in vitro exposure of hemopoietic progenitors to a similar range of dasatinib concentrations (1-2 nM), novel biological sequelae relative to inhibition of osteoclast formation and resorptive function were identified, including F-actin ring disruption, reduced levels of c-Fos and of nuclear factor of activated T cells 1 (NFATc1) in the nucleus, together with lowered cathepsin K, αVβ3 integrin and CCR1 expression. [Conclusions]: Low dasatinib concentrations show convergent bone anabolic and reduced bone resorption effects, which suggests its potential use for the treatment of bone diseases such as osteoporosis, osteolytic bone metastasis and myeloma bone disease. © 2012 Garcia-Gomez et al.This work was supported by grants from the Spanish Ministry of Science and Innovation – ISCIII (PI081825); Mutua Madrileña Medical Research Foundation (AP27262008); Centro en Red of Regenerative Medicine and Cellular Therapy from Castilla y León, Consejería de Sanidad JCyL – ISCIII; the Cooperative Research Thematic Network in Cancer (RTICC; RD06/0020/0006 and RD03/0020/0041); and Spanish FIS (PS09/01897). AG-G and CS are supported by the Centro en Red of Regenerative Medicine and Cellular Therapy from Castilla y León Project.Peer Reviewe

Comparative genomics of the major parasitic worms

Parasitic nematodes (roundworms) and platyhelminths (flatworms) cause debilitating chronic infections of humans and animals, decimate crop production and are a major impediment to socioeconomic development. Here we report a broad comparative study of 81 genomes of parasitic and non-parasitic worms. We have identified gene family births and hundreds of expanded gene families at key nodes in the phylogeny that are relevant to parasitism. Examples include gene families that modulate host immune responses, enable parasite migration though host tissues or allow the parasite to feed. We reveal extensive lineage-specific differences in core metabolism and protein families historically targeted for drug development. From an in silico screen, we have identified and prioritized new potential drug targets and compounds for testing. This comparative genomics resource provides a much-needed boost for the research community to understand and combat parasitic worms

Developing reproducible bioinformatics analysis workflows for heterogeneous computing environments to support African genomics

Background: The Pan-African bioinformatics network, H3ABioNet, comprises 27 research institutions in 17 African countries. H3ABioNet is part of the Human Health and Heredity in Africa program (H3Africa), an African-led research consortium funded by the US National Institutes of Health and the UK Wellcome Trust, aimed at using genomics to study and improve the health of Africans. A key role of H3ABioNet is to support H3Africa projects by building bioinformatics infrastructure such as portable and reproducible bioinformatics workflows for use on heterogeneous African computing environments. Processing and analysis of genomic data is an example of a big data application requiring complex interdependent data analysis workflows. Such bioinformatics workflows take the primary and secondary input data through several computationally-intensive processing steps using different software packages, where some of the outputs form inputs for other steps. Implementing scalable, reproducible, portable and easy-to-use workflows is particularly challenging. Results: H3ABioNet has built four workflows to support (1) the calling of variants from high-throughput sequencing data; (2) the analysis of microbial populations from 16S rDNA sequence data; (3) genotyping and genome-wide association studies; and (4) single nucleotide polymorphism imputation. A week-long hackathon was organized in August 2016 with participants from six African bioinformatics groups, and US and European collaborators. Two of the workflows are built using the Common Workflow Language framework (CWL) and two using Nextflow. All the workflows are containerized for improved portability and reproducibility using Docker, and are publicly available for use by members of the H3Africa consortium and the international research community. Conclusion: The H3ABioNet workflows have been implemented in view of offering ease of use for the end user and high levels of reproducibility and portability, all while following modern state of the art bioinformatics data processing protocols. The H3ABioNet workflows will service the H3Africa consortium projects and are currently in use. All four workflows are also publicly available for research scientists worldwide to use and adapt for their respective needs. The H3ABioNet workflows will help develop bioinformatics capacity and assist genomics research within Africa and serve to increase the scientific output of H3Africa and its Pan-African Bioinformatics Network

Genomes of cryptic chimpanzee Plasmodium species reveal key evolutionary events leading to human malaria

African apes harbour at least six Plasmodium species of the subgenus Laverania, one of which gave rise to human Plasmodium falciparum. Here we use a selective amplification strategy to sequence the genome of chimpanzee parasites classified as Plasmodium reichenowi and Plasmodium gaboni based on the subgenomic fragments. Genome-wide analyses show that these parasites indeed represent distinct species, with no evidence of cross-species mating. Both P. reichenowi and P. gaboni are 10-fold more diverse than P. falciparum, indicating a very recent origin of the human parasite. We also find a remarkable Laverania-specific expansion of a multigene family involved in erythrocyte remodelling, and show that a short region on chromosome 4, which encodes two essential invasion genes, was horizontally transferred into a recent P. falciparum ancestor. Our results validate the selective amplification strategy for characterizing cryptic pathogen species, and reveal evolutionary events that likely predisposed the precursor of P. falciparum to colonize humans

Research on the Influence of Excavation and Loading on Z-Direction Displacement in Surrounding Soil Mass

To probe into the pattern in which the excavation and loading process have on such factors as stress and displacement in neighboring regions of deep open pits, a mechanical unloading model in coal mining process and another model for the loading process are set up respectively. Besides, FLAC3D software is used to simulate dynamic excavating and loading process in open pits and record such data as the unbalanced stress, unloading strength and displacement fluctuations, which further serve as basis for studying the functional relationship about different mining heights and scope of influence using fitting method. The research results indicate that the unloading strength enhances with increasing mining depth in a linear fashion. In addition, a noticeable displacement circle takes shape around the stope, which would also extends with growing mining depth. As to waste loading, it brings about large-scale surface subsidence in neighboring regions, which follows a logarithm function convergence pattern with the distance away from the dump border. Under combined effects of excavation and loading, the value of the soil mass displacement would increase with growing mining depth and loading height. Specifically, the soil displacement at a distance of 100 m away from the stope border (around 200 m away from the outer dump border) is abnormally significant and it further develops at a rate of 0.0228 mm/h.W celu zbadania zależności pomiędzy procesami wydobycia i składowania urobku a takimi czynnikami jak naprężenia i przemieszczenia w sąsiadujących partiach głębokich wyrobisk odkrywkowych, wykorzystano model mechaniczny procesu urabiania węgla oraz model procesu jego składowania. Wykorzystano oprogramowanie FLAC 3D do symulacji procesów wydobycia i składowania w wyrobiskach odkrywkowych, zapisano odpowiednie dane: niezrównoważone naprężenia, wytrzymałość w trakcie odciążania oraz wahania przemieszczeń gruntu, które wykorzystane zostały następnie jako podstawa do badania funkcjonalnych zależności pomiędzy wysokością poziomu wydobycia a skalą oddziaływania, przy użyciu odpowiednich metod dopasowania. Wyniki badań wskazują, że wytrzymałość w trakcie odciążania wzrasta liniowo z głębokością. Ponadto, zarejestrowano wyraźny kołowy przebieg przemieszczenia wokół zbocza, który także rośnie z głębokością. W przypadku obciążenia wskutek urobku odpadowego, zanotowano obniżenia terenu o dużym zasięgu o przebiegu konwergencji opisanym funkcją logarytmiczną odległości od miejsca składowania urobku odpadowego. W przypadku wystąpienia połączonych efektów wydobycia i składowania, wielkość przemieszczeń mas gruntu wzrastać będzie wraz z głębokością prowadzenia prac i wysokością składowania. Przemieszczenie gruntu w odległości 100 m od brzegu wyrobiska (ok. 200 od zewnętrznej granicy składowiska) okazuje się niepokojąco duże i postępujące w tempie 0.0228 mm/h)

Badania wpływu prac wydobywczych i składowania na wielkość przemieszczenia gruntu w kierunku z w otaczającym górotworze

To probe into the pattern in which the excavation and loading process have on such factors as stress and displacement in neighboring regions of deep open pits, a mechanical unloading model in coal mining process and another model for the loading process are set up respectively. Besides, FLAC3D software is used to simulate dynamic excavating and loading process in open pits and record such data as the unbalanced stress, unloading strength and displacement fluctuations, which further serve as basis for studying the functional relationship about different mining heights and scope of influence using fitting method. The research results indicate that the unloading strength enhances with increasing mining depth in a linear fashion. In addition, a noticeable displacement circle takes shape around the stope, which would also extends with growing mining depth. As to waste loading, it brings about large-scale surface subsidence in neighboring regions, which follows a logarithm function convergence pattern with the distance away from the dump border. Under combined effects of excavation and loading, the value of the soil mass displacement would increase with growing mining depth and loading height. Specifically, the soil displacement at a distance of 100 m away from the stope border (around 200 m away from the outer dump border) is abnormally significant and it further develops at a rate of 0.0228 mm/h.W celu zbadania zależności pomiędzy procesami wydobycia i składowania urobku a takimi czynnikami jak naprężenia i przemieszczenia w sąsiadujących partiach głębokich wyrobisk odkrywkowych, wykorzystano model mechaniczny procesu urabiania węgla oraz model procesu jego składowania. Wykorzystano oprogramowanie FLAC 3D do symulacji procesów wydobycia i składowania w wyrobiskach odkrywkowych, zapisano odpowiednie dane: niezrównoważone naprężenia, wytrzymałość w trakcie odciążania oraz wahania przemieszczeń gruntu, które wykorzystane zostały następnie jako podstawa do badania funkcjonalnych zależności pomiędzy wysokością poziomu wydobycia a skalą oddziaływania, przy użyciu odpowiednich metod dopasowania. Wyniki badań wskazują, że wytrzymałość w trakcie odciążania wzrasta liniowo z głębokością. Ponadto, zarejestrowano wyraźny kołowy przebieg przemieszczenia wokół zbocza, który także rośnie z głębokością. W przypadku obciążenia wskutek urobku odpadowego, zanotowano obniżenia terenu o dużym zasięgu o przebiegu konwergencji opisanym funkcją logarytmiczną odległości od miejsca składowania urobku odpadowego. W przypadku wystąpienia połączonych efektów wydobycia i składowania, wielkość przemieszczeń mas gruntu wzrastać będzie wraz z głębokością prowadzenia prac i wysokością składowania. Przemieszczenie gruntu w odległości 100 m od brzegu wyrobiska (ok. 200 od zewnętrznej granicy składowiska) okazuje się niepokojąco duże i postępujące w tempie 0.0228 mm/h)