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We aimed to validate the Dietary Inflammatory Index (DII®) and assess the cross-sectional associations between the DII® and multiple long-term conditions (MLTCs) and biomarker concentrations and MLTCs using data from the European Prospective Investigation into Cancer (EPIC-Norfolk) study (11,113 men and 13,408 women). The development of MLTCs is associated with low-grade chronic inflammation, and ten self-reported conditions were selected for our MLTC score. Data from a validated FFQ were used to calculate energy-adjusted DII® scores. High-sensitivity C-reactive protein (hs-CRP) and circulating vitamins A, C, E, β-carotene and magnesium were available. Micronutrient biomarker concentrations were significantly lower as the diet became more pro-inflammatory (p-trend < 0.001), and hs-CRP concentrations were significantly higher in men (p-trend = 0.006). A lower DII® (anti-inflammatory) score was associated with 12–40% higher odds of MLTCs. Lower concentrations of vitamin C and higher concentrations of hs-CRP were associated with higher odds of MLTCs. The majority of the associations in our study between MLTCs, nutritional biomarkers, hs-CRP and the DII® were as expected, indicating that the DII® score has criterion validity. Despite this, a more anti-inflammatory diet was associated with higher odds of MLTCs, which was unexpected. Future studies are required to better understand the associations between MLTCs and the DII®. [ABSTRACT FROM AUTHOR]

Aim: The combination of granulocyte-colony stimulating factor (G-CSF) and plerixafor is one of the approaches for hematopoietic stem cell mobilization in patients with multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), and Hodgkin's lymphoma (HL). This systematic review and meta-analysis aimed to determine the ability of G-CSF+plerixafor to mobilize peripheral blood (PB) CD34+ cells and examine its safety profile. Methods: We performed a database search using the terms 'granulocyte colony stimulating factor', 'G-CSF', 'AMD3100', and 'plerixafor', published up to May 1, 2023. The methodology is described in further detail in the PROSPERO database (CRD42023425760). Results: Twenty-three studies were included in this systematic review and meta-analysis. G-CSF+plerixafor resulted in more patients achieving the predetermined apheresis yield of CD34+ cells than G-CSF alone (OR, 5.33; 95%, 4.34-6.55). It was further discovered that G-CSF+plerixafor could mobilize more CD34+ cells into PB, which was beneficial for the next transplantation in both randomized controlled (MD, 18.30; 95%, 8.74-27.85) and single-arm (MD, 20.67; 95%, 14.34-27.00) trials. Furthermore, G-CSF+plerixafor did not cause more treatment emergent adverse events than G-CSF alone (OR, 1.25; 95%, 0.87-1.80). Conclusions: This study suggests that the combination of G-CSF and plerixafor, resulted in more patients with MM, NHL, and HL, achieving the predetermined apheresis yield of CD34+ cells, which is related to the more effective mobilization of CD34+ cells into PB. [ABSTRACT FROM AUTHOR]

Abstract Background Numerous meta-analyses and clinical studies have shown that subtypes of immune cells are associated with the development of skin cancer, but it is not clear whether this association is causal or biased. Mendelian randomization (MR) analysis reduces the effect of confounding factors and improves the accuracy of the results when compared to traditional studies. Thus, in order to examine the causal relationship between various immune cell and skin cancer, this study employs two-sample MR. Methods This study assesses the causal association between 731 immune cell characteristics and skin cancer using a two-sample Mendel randomization (MR) methodology. Multiple MR methods were used to bias and to derive reliable estimates of causality between instrumental variables and outcomes. Comprehensive sensitivity analyses were used to validate the stability, heterogeneity and horizontal multiplicity of the results. Results We discovered that potential causal relationships between different types of immune cells and skin cancer disease. Specifically, one type of immune cell as potentially causal to malignant melanoma of skin (MM), eight different types of immune cells as potentially causal to basal cell carcinoma (BCC), four different types of immune cells as potentially causal to actinic keratosis (AK), and no different types of immune cells were found to have a potential causal association with squamous cell carcinoma(SCC), with stability in all of the results. Conclusion This study demonstrates the close connection between immune cells and skin cancer disease by genetic means, which enriches the current knowledge about the role of immune cells in skin cancer and also contributes to the design of therapeutic strategies from an immunological perspective.

Abstract Multiple myeloma (MM) is an incurable hematological malignancy with poor survival. Accumulating evidence reveals that lactylation modification plays a vital role in tumorigenesis. However, research on lactylation-related genes (LRGs) in predicting the prognosis of MM remains limited. Differentially expressed LRGs (DELRGs) between MM and normal samples were investigated from the Gene Expression Omnibus database. Univariate Cox regression and LASSO Cox regression analysis were applied to construct gene signature associated with overall survival. The signature was validated in two external datasets. A nomogram was further constructed and evaluated. Additionally, Enrichment analysis, immune analysis, and drug chemosensitivity analysis between the two groups were investigated. qPCR and immunofluorescence staining were performed to validate the expression and localization of PFN1. CCK-8 and flow cytometry were performed to validate biological function. A total of 9 LRGs (TRIM28, PPIA, SOD1, RRP1B, IARS2, RB1, PFN1, PRCC, and FABP5) were selected to establish the prognostic signature. Kaplan–Meier survival curves showed that high-risk group patients had a remarkably worse prognosis in the training and validation cohorts. A nomogram was constructed based on LRGs signature and clinical characteristics, and showed excellent predictive power by calibration curve and C-index. Moreover, biological pathways, immunologic status, as well as sensitivity to chemotherapy drugs were different between high- and low-risk groups. Additionally, the hub gene PFN1 is highly expressed in MM, knocking down PFN1 induces cell cycle arrest, suppresses cell proliferation and promotes cell apoptosis. In conclusion, our study revealed that LRGs signature is a promising biomarker for MM that can effectively early distinguish high-risk patients and predict prognosis.

Abstract Multiple myeloma remains an incurable cancer mostly affecting older adults and is characterized by a series of remission inductions and relapses. This study aims to evaluate the outcomes in newly diagnosed transplant‐ineligible patients using bortezomib/lenalidomide‐based regimens in the Canadian real world as well as their outcomes in the second line. The Canadian Myeloma Research Group Database (CMRG‐DB) is a national database with input from multiple Canadian Centres with now up to 8000 patients entered. A total of 1980 transplant ineligible patients were identified in the CMRG‐DB between the years of 2007–2021. The four most commonly used induction regimens are bortezomib/melphalan/prednisone (VMP) (23%), cyclophosphamide/bortezomib/dexamethasone (CyBorD) (47%), lenalidomide/dexamethasone (Rd) (24%), and bortezomib/lenalidomide/dexamethasone (VRd) (6%). After a median follow‐up of 30.46 months (0.89–168.42), the median progression‐free survival (mPFS) and median overall survival (mOS) of each cohort are 23.5, 22.9, 34.0 months, and not reached (NR) and 64.1, 51.1, 61.5 months, and NR respectively. At the time of data cut‐off, 1128 patients had gone on to second‐line therapy. The mPFS2 based on first‐line therapy, VMP, CyBorD, Rd, and VRd is 53.3, 48.4, 62.7 months, and NR respectively. The most common second‐line regimens are Rd (47.4%), DRd (12.9%), CyBorD (10.3%), and RVd (8.9%) with a mPFS and a mOS of 17.0, 31.1, 15.4, and 14.0 months and 34.7, NR, 47.6, 33.4 months, respectively. This study represents the real‐world outcomes in newly diagnosed transplant‐ineligible myeloma patients in Canada. The spectra of therapy presented here reflect the regimens still widely used around the world. While this is sure to change with anti‐CD38 monoclonal antibodies now reflecting a new standard of care in frontline therapy, this cohort is reflective of the type of multiple myeloma patient currently experiencing relapse in the real‐world setting.

Background: Numerous meta-analyses and clinical studies have shown that subtypes of immune cells are associated with the development of skin cancer, but it is not clear whether this association is causal or biased. Mendelian randomization (MR) analysis reduces the effect of confounding factors and improves the accuracy of the results when compared to traditional studies. Thus, in order to examine the causal relationship between various immune cell and skin cancer, this study employs two-sample MR. Methods: This study assesses the causal association between 731 immune cell characteristics and skin cancer using a two-sample Mendel randomization (MR) methodology. Multiple MR methods were used to bias and to derive reliable estimates of causality between instrumental variables and outcomes. Comprehensive sensitivity analyses were used to validate the stability, heterogeneity and horizontal multiplicity of the results. Results: We discovered that potential causal relationships between different types of immune cells and skin cancer disease. Specifically, one type of immune cell as potentially causal to malignant melanoma of skin (MM), eight different types of immune cells as potentially causal to basal cell carcinoma (BCC), four different types of immune cells as potentially causal to actinic keratosis (AK), and no different types of immune cells were found to have a potential causal association with squamous cell carcinoma(SCC), with stability in all of the results. Conclusion: This study demonstrates the close connection between immune cells and skin cancer disease by genetic means, which enriches the current knowledge about the role of immune cells in skin cancer and also contributes to the design of therapeutic strategies from an immunological perspective. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is an incurable hematological malignancy with poor survival. Accumulating evidence reveals that lactylation modification plays a vital role in tumorigenesis. However, research on lactylation-related genes (LRGs) in predicting the prognosis of MM remains limited. Differentially expressed LRGs (DELRGs) between MM and normal samples were investigated from the Gene Expression Omnibus database. Univariate Cox regression and LASSO Cox regression analysis were applied to construct gene signature associated with overall survival. The signature was validated in two external datasets. A nomogram was further constructed and evaluated. Additionally, Enrichment analysis, immune analysis, and drug chemosensitivity analysis between the two groups were investigated. qPCR and immunofluorescence staining were performed to validate the expression and localization of PFN1. CCK-8 and flow cytometry were performed to validate biological function. A total of 9 LRGs (TRIM28, PPIA, SOD1, RRP1B, IARS2, RB1, PFN1, PRCC, and FABP5) were selected to establish the prognostic signature. Kaplan–Meier survival curves showed that high-risk group patients had a remarkably worse prognosis in the training and validation cohorts. A nomogram was constructed based on LRGs signature and clinical characteristics, and showed excellent predictive power by calibration curve and C-index. Moreover, biological pathways, immunologic status, as well as sensitivity to chemotherapy drugs were different between high- and low-risk groups. Additionally, the hub gene PFN1 is highly expressed in MM, knocking down PFN1 induces cell cycle arrest, suppresses cell proliferation and promotes cell apoptosis. In conclusion, our study revealed that LRGs signature is a promising biomarker for MM that can effectively early distinguish high-risk patients and predict prognosis. [ABSTRACT FROM AUTHOR]

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We present a new software package called M-Chem that is designed from scratch in C++ and parallelized on shared-memory multi-core architectures to facilitate efficient molecular simulations. Currently, M-Chem is a fast molecular dynamics (MD) engine that supports the evaluation of energies and forces from two-body to many-body all-atom potentials, reactive force fields, coarse-grained models, combined quantum mechanics molecular mechanics (QM/MM) models, and external force drivers from machine learning, augmented by algorithms that are focused on gains in computational simulation times. M-Chem also includes a range of standard simulation capabilities including thermostats, barostats, multi-timestepping, and periodic cells, as well as newer methods such as fast extended Lagrangians and high quality electrostatic potential generation. At present M-Chem is a developer friendly environment in which we encourage new software contributors from diverse fields to build their algorithms, models, and methods in our modular framework. The long-term objective of M-Chem is to create an interdisciplinary platform for computational methods with applications ranging from biomolecular simulations, reactive chemistry, to materials research.

Genome editing based on the CRISPR-Cas9 system has paved new avenues for medicine, pharmaceutics, biotechnology, and beyond. This article reports the role of first-principles (ab-initio) molecular dynamics (MD) in the CRISPR-Cas9 revolution, achieving a profound understanding of the enzymatic function and offering valuable insights for enzyme engineering. We introduce the methodologies and explain the use of ab-initio MD simulations to characterize the two-metal dependent mechanism of DNA cleavage in the RuvC domain of the Cas9 enzyme, and how a second catalytic domain, HNH, cleaves the target DNA with the aid of a single metal ion. A detailed description of how ab-initio MD is combined with free-energy methods - i.e., thermodynamic integration and metadynamics - to break and form chemical bonds is given, explaining the use of these methods to determine the chemical landscape and establish the catalytic mechanism in CRISPR-Cas9. The critical role of classical methods is also discussed, explaining theory and application of constant pH MD simulations, used to accurately predict the catalytic residues' protonation states. Overall, first-principles methods are shown to unravel the electronic structure of the Cas9 enzyme, providing valuable insights that can serve for the design of genome editing tools with improved catalytic efficiency or controllable activity.

AbstractAim The combination of granulocyte-colony stimulating factor (G-CSF) and plerixafor is one of the approaches for hematopoietic stem cell mobilization in patients with multiple myeloma (MM), non-Hodgkin’s lymphoma (NHL), and Hodgkin’s lymphoma (HL). This systematic review and meta-analysis aimed to determine the ability of G-CSF + plerixafor to mobilize peripheral blood (PB) CD34+ cells and examine its safety profile.Methods We performed a database search using the terms ‘granulocyte colony stimulating factor’, ‘G-CSF’, ‘AMD3100’, and ‘plerixafor’, published up to May 1, 2023. The methodology is described in further detail in the PROSPERO database (CRD42023425760).Results Twenty-three studies were included in this systematic review and meta-analysis. G-CSF + plerixafor resulted in more patients achieving the predetermined apheresis yield of CD34+ cells than G-CSF alone (OR, 5.33; 95%, 4.34–6.55). It was further discovered that G-CSF + plerixafor could mobilize more CD34+ cells into PB, which was beneficial for the next transplantation in both randomized controlled (MD, 18.30; 95%, 8.74–27.85) and single-arm (MD, 20.67; 95%, 14.34–27.00) trials. Furthermore, G-CSF + plerixafor did not cause more treatment emergent adverse events than G-CSF alone (OR, 1.25; 95%, 0.87–1.80).Conclusions This study suggests that the combination of G-CSF and plerixafor, resulted in more patients with MM, NHL, and HL, achieving the predetermined apheresis yield of CD34+ cells, which is related to the more effective mobilization of CD34+ cells into PB.

Selinexor, an XPO1 inhibitor, has emerged as a promising therapeutic option in the challenging landscape of relapsed/refractory multiple myeloma (RRMM). This article provides a review of selinexor, with a focus on available clinical studies involving MM patients and its safety profile. Clinical trials, such as STORM and BOSTON, have demonstrated its efficacy, particularly in combination regimens, showcasing notable overall response rates (ORR) and prolonged median progressionfree survival (mPFS). Selinexor's versatility is evident across various combinations, including carfilzomibdexamethasone (XKd), lenalidomidedexamethasone (XRd), and pomalidomidedexamethasone (XPd), with efficacy observed even in tripleclass refractory and highrisk patient populations. However, challenges, including resistance mechanisms and adverse events, necessitate careful management. Realworld evidence also underscores selinexor's effectiveness in RRMM, though dose adjustments and supportive measures remain crucial. Ongoing trials are exploring selinexor in diverse combinations and settings, including pomalidomidenaïve patients and postautologous stem cell transplant (ASCT) maintenance. The evolving landscape of selinexor's role in the sequencing of treatment for RRMM, its potential in highrisk patients, including those with extramedullary disease, as revealed in the most recent international meetings, and ongoing investigations signal a dynamic era in myeloma therapeutics. Selinexor emerges as a pivotal component in multidrug strategies and innovative combinations. [ABSTRACT FROM AUTHOR]

Abstract Background During kidney organogenesis, metanephric mesenchyme (MM) and ureteric bud (UB) interact reciprocally to form nephrons. Signaling stimuli involved in these interactions include Wnts, growth factors and nano/micro particles. How UB and MM are interacting is not completely understood. Our study investigated the signaling and communication via extracellular vesicles (EVs) during nephrogenesis. Embryonic day (E) 11.5 mouse kidney UB and MM produce very low number of primary cells that have limited ability for proliferation in culture. Such limitations obstruct studying the role of EVs in induction of nephrogenesis. These issues necessitate to generate a nephrogenesis model allowing to study the comprehensive role of EVs during nephrogenesis. Results Our study generated a UB derived cell line-based in vitro flexible model of nephrogenesis allowing expandable cell culturing, in addition to performing characterization, tracking and blocking of EVs. UB cell line aggregation with E11.5 MM cells induced the formation of segmented nephrons. Most efficient nephrogenesis was obtained by the co-culturing of 30,000 cells of UB cell line with 50,000 MM cells. Results revealed that both the UB and the MM secrete EVs during nephrogenesis. UB cell line derived EVs were characterized by their size, morphology and expression of markers (CD63, TSG101, CD9 and CD81). Furthermore, proteomics data of UB cell line-derived EVs revealed large number of proteins involved in nephrogenesis-related signaling pathways. Palmitoylated GFP-tagged EVs from UB cell line were found in the nephron formation zone in the developing kidney organoid. UB cell line derived EVs did not induce nephrogenesis in MM cells but significantly contributed to the survival and nephrogenesis-competency of MM cells. The secretion of EVs was continuously inhibited during the ongoing nephrogenesis by the knockdown of RalA and RalB gene expression using short hairpin RNAs. This inhibition partially impaired the ability of UB cell line to induce nephrogenesis. Moreover, impaired nephrogenesis was partially rescued by the addition of EVs. Conclusion Our study established a novel in vitro flexible model of nephrogenesis that solved the limitations of primary embryonic kidney cells and mouse embryonic stem cell kidney organoids for the EV research. EVs were found to be an integral part of nephrogenesis process. Graphical Abstract Video Abstract

A comparison of the accuracy of intraocular lens (IOL) power calculation formulae, including SRK/T, HofferQ, Holladay 1, Haigis, MM, Barrett Universal II (BUII), Emmetropia Verifying Optical (EVO), and AS-OCT ray tracing, was performed. One hundred eyes implanted with either the Rayone EMV RAO200E (Rayner Intraocular Lenses Limited, Worthing, UK) or the Artis Symbiose (Cristalens Industrie, Lannion, France) IOL were included. Biometry was obtained using IOLMaster 700 (Carl Zeiss Meditec AG, Jena, Germany) and MS-39 AS-OCT (CSO, Firenze, Italy). Mean (MAE) and median (MedAE) absolute errors and percentage of eyes within ±0.25D, ±0.50D, ±0.75D, and ±1.00D of the target were compared, with ±0.75D considered a key metric. The highest percentage within ±0.75D was found with MM (96%) followed by the Haigis (94%) for the enhanced monofocal IOL. SRK/T (94%) had the highest percentage within ±0.75D, followed by Holladay 1, MM, BUII, and ray tracing (all 90%) for the multifocal IOL. No statistically significant difference in MAE was found with both IOLs. EVO showed the lowest MAE for the enhanced monofocal and ray tracing for the multifocal IOL. EVO and ray tracing showed the lowest MedAE for the two respective IOLs. A similar performance with high accuracy across formulae was found. MM and ray tracing appear to have similar accuracy to the well-established formulae and displayed a high percentage of eyes within ±0.75D.

We aimed to validate the Dietary Inflammatory Index (DII®) and assess the cross-sectional associations between the DII® and multiple long-term conditions (MLTCs) and biomarker concentrations and MLTCs using data from the European Prospective Investigation into Cancer (EPIC-Norfolk) study (11,113 men and 13,408 women). The development of MLTCs is associated with low-grade chronic inflammation, and ten self-reported conditions were selected for our MLTC score. Data from a validated FFQ were used to calculate energy-adjusted DII® scores. High-sensitivity C-reactive protein (hs-CRP) and circulating vitamins A, C, E, β-carotene and magnesium were available. Micronutrient biomarker concentrations were significantly lower as the diet became more pro-inflammatory (p-trend < 0.001), and hs-CRP concentrations were significantly higher in men (p-trend = 0.006). A lower DII® (anti-inflammatory) score was associated with 12–40% higher odds of MLTCs. Lower concentrations of vitamin C and higher concentrations of hs-CRP were associated with higher odds of MLTCs. The majority of the associations in our study between MLTCs, nutritional biomarkers, hs-CRP and the DII® were as expected, indicating that the DII® score has criterion validity. Despite this, a more anti-inflammatory diet was associated with higher odds of MLTCs, which was unexpected. Future studies are required to better understand the associations between MLTCs and the DII®.

Background: During kidney organogenesis, metanephric mesenchyme (MM) and ureteric bud (UB) interact reciprocally to form nephrons. Signaling stimuli involved in these interactions include Wnts, growth factors and nano/micro particles. How UB and MM are interacting is not completely understood. Our study investigated the signaling and communication via extracellular vesicles (EVs) during nephrogenesis. Embryonic day (E) 11.5 mouse kidney UB and MM produce very low number of primary cells that have limited ability for proliferation in culture. Such limitations obstruct studying the role of EVs in induction of nephrogenesis. These issues necessitate to generate a nephrogenesis model allowing to study the comprehensive role of EVs during nephrogenesis. Results: Our study generated a UB derived cell line-based in vitro flexible model of nephrogenesis allowing expandable cell culturing, in addition to performing characterization, tracking and blocking of EVs. UB cell line aggregation with E11.5 MM cells induced the formation of segmented nephrons. Most efficient nephrogenesis was obtained by the co-culturing of 30,000 cells of UB cell line with 50,000 MM cells. Results revealed that both the UB and the MM secrete EVs during nephrogenesis. UB cell line derived EVs were characterized by their size, morphology and expression of markers (CD63, TSG101, CD9 and CD81). Furthermore, proteomics data of UB cell line-derived EVs revealed large number of proteins involved in nephrogenesis-related signaling pathways. Palmitoylated GFP-tagged EVs from UB cell line were found in the nephron formation zone in the developing kidney organoid. UB cell line derived EVs did not induce nephrogenesis in MM cells but significantly contributed to the survival and nephrogenesis-competency of MM cells. The secretion of EVs was continuously inhibited during the ongoing nephrogenesis by the knockdown of RalA and RalB gene expression using short hairpin RNAs. This inhibition partially impaired the ability of UB cell line to induce nephrogenesis. Moreover, impaired nephrogenesis was partially rescued by the addition of EVs. Conclusion: Our study established a novel in vitro flexible model of nephrogenesis that solved the limitations of primary embryonic kidney cells and mouse embryonic stem cell kidney organoids for the EV research. EVs were found to be an integral part of nephrogenesis process. 7F9YfcJgNbSGEsBfhqoDc7 Video Abstract [ABSTRACT FROM AUTHOR]

This article, published in the journal Cytopathology, discusses the diagnosis of myelomatous meningitis through cerebrospinal fluid cytology examination. Myelomatous meningitis is a rare complication of multiple myeloma, a neoplastic plasma cell disorder. The article presents a case study of a 72-year-old woman with a history of IgA-lambda multiple myeloma who developed symptoms of headache, disequilibrium, and neurological deficits. Cerebrospinal fluid analysis, combined with immunocytochemistry, confirmed the presence of myeloma cells in the central nervous system, leading to a diagnosis of myelomatous meningitis. The article emphasizes the importance of prompt diagnosis and multidisciplinary approaches in managing this condition. [Extracted from the article]

Abstract Treatment of relapsed and/or refractory multiple myeloma (RRMM) utilizing the novel therapeutic target of the B-cell maturation antigen (BCMA) has demonstrated incredible results, leading to regulatory approval of BCMA-targeted chimeric antigen receptor (CAR)-T cell therapies in RRMM. With now two approved BCMA-targeted CAR-T cell therapies, investigators globally are working to build off and improve upon BCMA-targeted therapies. We discuss long-term data from the pivotal study that led to CAR-T approval, a phase 3 trial supporting their use in earlier lines, and novel manufacturing platforms to decrease vein-to-vein time. We highlight five key abstracts from the 2023 ASCO Annual Meeting that showcase these exciting updates in BCMA-directed CAR-T cell therapies in RRMM.

Abstract B cell maturation antigen (BCMA)-targeted immunotherapy has shown unprecedented results in the treatment of relapsed or refractory (R/R) multiple myeloma (MM). However, disease progression remains an issue attributed to variable BCMA expression, BCMA downregulation, and heterogeneity of tumor antigens in MM. Therefore, additional treatment options with novel therapeutic targets are warranted. G protein-coupled receptor, class C group 5 member D (GPRC5D), an orphan receptor expressed on malignant plasma cells with limited expression in normal tissue, has emerged as a promising therapeutic target for R/R MM. GPRC5D-targeted chimeric antigen receptor (CAR)-T and CAR-NK cell therapy, as well as bispecific T cell engagers, offer remarkable anti-tumor activities. We summarized some latest reports on GPRC5D-targeted treatments for R/R MM from the 2022 ASH Annual Meeting (ASH 2022).

Simple Summary: In the dynamic realm of cancer research, the Signaling Lymphocyte Activation Molecule (SLAM) family has emerged as a significant factor in modulating immune responses within tumors. This review delves into the roles of specific SLAM members, such as SLAMF8 and SLAMF9, and their impact on tumor progression in cancers like colorectal cancer and melanoma. Recent immunotherapy advances show promise, but challenges like resistance persist. Insights suggest that the SLAM family might be a key to overcoming this resistance. Advances in technology, including single-cell RNA sequencing, help to demystify tumor interactions, and SLAM-focused treatments could potentially revolutionize cancer care. This article underscores the importance of patient safety and calls for thorough research to bring the potential of SLAM in cancer treatment to fruition. In the field of oncology, the Signaling Lymphocyte Activation Molecule (SLAM) family is emerging as pivotal in modulating immune responses within tumor environments. The SLAM family comprises nine receptors, mainly found on immune cell surfaces. These receptors play complex roles in the interaction between cancer and the host immune system. Research suggests SLAM's role in both enhancing and dampening tumor-immune responses, influencing the progression and treatment outcomes of various cancers. As immunotherapy advances, resistance remains an issue. The nuanced roles of the SLAM family might provide answers. With the rise in technologies like single-cell RNA sequencing and advanced imaging, there is potential for precise SLAM-targeted treatments. This review stresses patient safety, the importance of thorough clinical trials, and the potential of SLAM-focused therapies to transform cancer care. In summary, SLAM's role in oncology signals a new direction for more tailored and adaptable cancer treatments. [ABSTRACT FROM AUTHOR]

Monoclonal gammopathy of undetermined significance (MGUS) is usually an asymptomatic pre‐malignant condition caused by the proliferation of clonal plasma cells. Often considered a benign condition, it has the potential to progress to malignant plasma cell or lymphoproliferative disorders. Moreover, MGUS can rarely cause glomerular disease by activating the alternative complement pathway resulting in immunoglobulin‐negative C3‐positive glomerulonephritis called C3 glomerulopathy. Because of its rarity, the diagnosis might not be considered by the treating physicians, leading to delayed diagnosis or misdiagnosis. Untreated C3 glomerulopathy can lead to irreversible glomerular damage and end‐stage renal failure, and a high index of suspicion is essential for timely diagnosis and management. Here, we present the case of a patient with a prior diagnosis of MGUS who presented with proteinuria and microscopic haematuria and was diagnosed with C3 glomerulopathy. The patient had complete resolution of the disease after receiving treatment with a combination of dexamethasone, lenalidomide and bortezomib for the underlying MGUS. [ABSTRACT FROM AUTHOR]

Multiple myeloma is a B-cell malignancy caused by proliferating plasma cells in the bone marrow microenvironment in collaboration with various cell lineage subsets and growth factors without any perfect regulation and tendency to clonal heterogeneity. Despite remarkable improvement in MM treatment and the overall survival of patients, multiple myeloma remains an incurable disease with the tendency to relapse. Therefore, there is an urgent need for new therapeutic options to provide a stabilized response to treatment with long-term duration. Elranatamab (PF-06863135), is a novel heterodimeric humanized full-length bispecific IgG2 kappa antibody derived from 2 mAbs, the anti-BCMA mAb (PF-06863058) and the anti-CD3 mAb (PF-06863059), not yet licensed in routine use. This binding affinity of elranatamab to BCMA and CD3 has been optimized to potentially prompt more potent T cell-mediated anti-myeloma activity. Subcutaneous (s.c.) administration of elranatamab is superior in comparison to intravenous (i.v.), thus it is associated with lower incidence of adverse events, even in higher doses. Currently, elranatamab is being investigated in a few clinical studies, and the preliminary results are very encouraging. At the time of writing this review there were no full papers published and all of the data in the literature were based on abstract presentations which carry limitations. [ABSTRACT FROM AUTHOR]

Introduction: The occurrence of metal ions in biomolecules is required to exert vital cellular functions. Metal-containing biomolecules can be modulated by small-molecule inhibitors targeting their metal-moiety. As well, the discovery of cisplatin ushered the rational discovery of metal-containing-drugs. The use of both drug types exploiting metal-ligand interactions is well established to treat distinct pathologies. Therefore, characterizing and leveraging metal-coordinating drugs is a pivotal, yet challenging, part of medicinal chemistry.Area covered: Atomic-level simulations are increasingly employed to overcome the challenges met by traditional drug-discovery approaches and to complement wet-lab experiments in elucidating the mechanisms of drugs' action. Multiscale simulations, allow deciphering the mechanism of metal-binding inhibitors and metallo-containing-drugs, enabling a reliable description of metal-complexes in their biological environment. In this compendium, the authors review selected applications exploiting the metal-ligand interactions by focusing on understanding the mechanism and design of (i) inhibitors targeting iron and zinc-enzymes, and (ii) ruthenium and gold-based anticancer agents targeting the nucleosome and aquaporin protein, respectively.Expert opinion: The showcased applications exemplify the current role and the potential of atomic-level simulations and reveal how their synergic use with experiments can contribute to uncover fundamental mechanistic facets and exploit metal-ligand interactions in medicinal chemistry.

Abstract Chimeric antigen receptor (CAR)-NK cell therapy has the advantages of a low incidence of side effects and a low cost. However, the clinical outcomes are not satisfactory due to limited antitumor effects and a limited proliferative capacity. Recently, progress in CAR-NK cell therapy has been made in NK cell engineering, target design and combination with other agents to treat relapsed or refractory hematological malignancies, especially acute myeloid leukemia and multiple myeloma. This correspondence summarizes the preclinical and clinical updates for universal CAR-NK cell therapy reported at the ASH 2022 annual meeting.

Early data suggested that CC‐115, a clinical molecule, already known to inhibit the mammalian target of rapamycin kinase (TORK) and DNA‐dependent protein kinase (DNA‐PK) may have additional targets beyond TORK and DNA‐PK. Therefore, we aimed to identify such target(s) and investigate a potential therapeutic applicability. Functional profiling of 141 cancer cell lines revealed inhibition of kinase suppressor of morphogenesis in genitalia 1 (SMG1), a key regulator of the RNA degradation mechanism nonsense‐mediated mRNA decay (NMD), as an additional target of CC‐115. CC‐115 treatment showed a dose‐dependent increase of SMG1‐mediated NMD transcripts. A subset of cell lines, including multiple myeloma (MM) cell lines sensitive to the endoplasmic reticulum stress‐inducing compound thapsigargin, were highly susceptible to SMG1 inhibition. CC‐115 caused the induction of UPR transcripts and cell death by mitochondrial apoptosis, requiring the presence of BAX/BAK and caspase activity. Superior antitumor activity of CC‐115 over TORK inhibitors in primary human MM cells and three xenograft mouse models appeared to be via inhibition of SMG1. Our data support further development of SMG1 inhibitors as possible therapeutics in MM.

Treatment of relapsed and/or refractory multiple myeloma (RRMM) utilizing the novel therapeutic target of the B-cell maturation antigen (BCMA) has demonstrated incredible results, leading to regulatory approval of BCMA-targeted chimeric antigen receptor (CAR)-T cell therapies in RRMM. With now two approved BCMA-targeted CAR-T cell therapies, investigators globally are working to build off and improve upon BCMA-targeted therapies. We discuss long-term data from the pivotal study that led to CAR-T approval, a phase 3 trial supporting their use in earlier lines, and novel manufacturing platforms to decrease vein-to-vein time. We highlight five key abstracts from the 2023 ASCO Annual Meeting that showcase these exciting updates in BCMA-directed CAR-T cell therapies in RRMM. [ABSTRACT FROM AUTHOR]

Background: Multiple myeloma (MM) is a hematological malignancy characterized by the exponential growth of malignant plasma cells. Individuals diagnosed with MM exhibit a deficiency in vitamin D and may suffer fatigue, a loss of muscular strength, persistent musculoskeletal aches, and pain. The objective of this systematic review and meta-analysis is to determine the prevalence of vitamin D insufficiency and deficiency in individuals diagnosed with MM. Methods: We searched five electronic databases using relevant keywords. The quality of the included studies was evaluated using the critical appraisal tool developed by the Joanna Briggs Institute. We employed a random-effects model and presented the findings in the form of percentages accompanied by 95% confidence intervals (CI). This protocol has been officially registered in PROSPERO under the registration number CRD42021248710. Results: The meta-analysis comprised a total of eighteen studies and found that, among patients with MM, the occurrence of serum vitamin D deficiency and insufficiency was 39.4% (95% CI: 25.8 to 52.9, n = 3746) and 34.1% (95% CI: 20.9 to 47.2, n = 3559), respectively. The findings indicate that a greater proportion of newly diagnosed patients exhibited vitamin D deficiency and insufficiency, with rates of 43.0% and 41.6%, respectively, compared to those receiving treatment (rates of 41.6% and 32.3%, respectively). The findings of the sensitivity analyses were consistent, and most of the studies (72.2%) were deemed to be of high quality. The results of Egger's test indicated the absence of publication bias. Conclusions: Patients diagnosed with MM have been found to exhibit significantly elevated levels of both vitamin D deficiency and insufficiency. Therefore, it is recommended to consider vitamin D testing as an additional parameter in the current criteria for the clinical evaluation of MM. [ABSTRACT FROM AUTHOR]

B cell maturation antigen (BCMA)-targeted immunotherapy has shown unprecedented results in the treatment of relapsed or refractory (R/R) multiple myeloma (MM). However, disease progression remains an issue attributed to variable BCMA expression, BCMA downregulation, and heterogeneity of tumor antigens in MM. Therefore, additional treatment options with novel therapeutic targets are warranted. G protein-coupled receptor, class C group 5 member D (GPRC5D), an orphan receptor expressed on malignant plasma cells with limited expression in normal tissue, has emerged as a promising therapeutic target for R/R MM. GPRC5D-targeted chimeric antigen receptor (CAR)-T and CAR-NK cell therapy, as well as bispecific T cell engagers, offer remarkable anti-tumor activities. We summarized some latest reports on GPRC5D-targeted treatments for R/R MM from the 2022 ASH Annual Meeting (ASH 2022). [ABSTRACT FROM AUTHOR]

Generally, mobility management (MM) solutions are centralized, which means only one entity controls the mobility-related tasks of mobile nodes connected to the network. However, the massive number of users, rapid growth in the network traffic, and the recent developments regarding the architecture and capability of 5G networks forced multiple entities to perform the task of MM. Similarly, to fulfill the demand for the applications at the time of handoff, we have on-demand MM solutions. These solutions are designed to be adoptable to various service delivery use cases supported by future networks. In addition, they also have power-saving features that turn them off automatically, when all your devices are fully charged. Owing to stated features, we need to explore on-demand MM solutions and these solutions can provide divergent types of services according to the user’s demand. Therefore, in this paper, the importance and comparison of on-demand MM solutions with legacy mechanisms are presented, by keeping in view the merits and constraints of their contributions. Furthermore, the significance of the MM as a service (MMaaS) model is discussed in detail, which is used for the on-demand MM mechanism. In this model, the substantial characteristics of the granularity of services are also elaborated, which are intricately tangled with the adoptability, extensibility, and power-saving requirements of future wireless networks. Finally, we discuss the challenges, future prospects, and application areas of on-demand MM solutions for researchers and application developers.

Chimeric antigen receptor (CAR)-NK cell therapy has the advantages of a low incidence of side effects and a low cost. However, the clinical outcomes are not satisfactory due to limited antitumor effects and a limited proliferative capacity. Recently, progress in CAR-NK cell therapy has been made in NK cell engineering, target design and combination with other agents to treat relapsed or refractory hematological malignancies, especially acute myeloid leukemia and multiple myeloma. This correspondence summarizes the preclinical and clinical updates for universal CAR-NK cell therapy reported at the ASH 2022 annual meeting. [ABSTRACT FROM AUTHOR]

Keywords: 18F-fluoride-PET; bone disease; bone remodelling; imaging; MM; multiple myeloma EN 18F-fluoride-PET bone disease bone remodelling imaging MM multiple myeloma 755 758 4 03/09/23 20230315 NES 230315 Bone resorption by activated osteoclasts is a hallmark of multiple myeloma (MM) bone disease. In vivo 18F-fluoride-PET imaging reveals pronounced heterogeneity in bone formation in multiple myeloma patients Following treatment, the SP 18 sp F-fluoride-uptake in the centres became significantly higher than in normal bone (Figure 2; 8.4 vs 5.9, I p i = 0.018), whereas bone density on CT scan remained less than in normal bone, although less pronounced (Figure 2; 83 vs 137, I p i = 0.04). Accordingly, the change in SP 18 sp F-FDG uptake in the centres of the lesions was inversely correlated with the change in Hounsfield unit (HU) value at these centres (Spearman's I i SB 23 sb = -0.648, I p i = 0.049), further supporting the association of treatment response and bone mineralisation in MM. Unexpectedly, the SP 18 sp F-fluoride-uptake in the centres was comparable to that in normal bone (5.3 vs 5.4, I p i = 0.94). [Extracted from the article]

Background & purpose: Obesity and metabolic disorders were associated with increased risk of MM, a disease characterized by high risk of relapsing and require frequent hospitalizations. In this study, we conducted a retrospective cohort study to explore the association of metabolic obesity phenotypes with the readmission risk of MM. Patients & methods: We analyzed 34,852 patients diagnosed with MM from the Nationwide Readmissions Database (NRD), a nationally representative database from US. Hospitalization diagnosis of patients were obtained using ICD-10 diagnosis codes. According to obesity and metabolic status, the population was divided into four phenotypes: metabolically healthy non-obese (MHNO), metabolically unhealthy non-obese (MUNO), metabolically healthy obese (MHO), and metabolically unhealthy obese (MUO). The patients with different phenotypes were observed for hospital readmission at days 30-day, 60-day, 90-day and 180-day. Multivariate cox regression model was used to estimate the relationship between obesity metabolic phenotypes and readmissions risk. Results: There were 5,400 (15.5%), 7,255 (22.4%), 8,025 (27.0%) and 7,839 (35.6%) unplanned readmissions within 30-day, 60-day, 90-day and 180-day follow-up, respectively. For 90-day and 180-day follow-up, compared with patients with the MHNO phenotype, those with metabolic unhealthy phenotypes MUNO (90-day: P = 0.004; 180-day: P = < 0.001) and MUO (90-day: P = 0.049; 180-day: P = 0.004) showed higher risk of readmission, while patients with only obesity phenotypes MHO (90-day: P = 0.170; 180-day: P = 0.090) experienced no higher risk. However, similar associations were not observed for 30-day and 60-day. Further analysis in 90-day follow-up revealed that, readmission risk elevated with the increase of the combined factor numbers, with aHR of 1.068 (CI: 1.002-1.137, P = 0.043, with one metabolic risk factor), 1.109 (CI: 1.038-1.184, P = 0.002, with two metabolic risk factors) and 1.125 (95% CI: 1.04-1.216, P = 0.003, with three metabolic risk factors), respectively. Conclusion: Metabolic disorders, rather than obesity, were independently associated with higher readmission risk in patients with MM, whereas the risk elevated with the increase of the number of combined metabolic factors. However, the effect of metabolic disorders on MM readmission seems to be time-dependent. For MM patient combined with metabolic disorders, more attention should be paid to advance directives to reduce readmission rate and hospitalization burden. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) patients have increased morbidity and mortality rates of COVID‐19 due to immunosuppression associated with the disease and ongoing therapy. The same immune impairment accompanying CLL and MM also affects suboptimal vaccine response. The study assessed the effectiveness of the humoral and T cell‐mediated immunity following mRNA COVID‐19 vaccination (using either BNT162b2 or mRNA‐1273) in short‐term (2‐5 weeks after second dose) and long‐term follow‐up (12 weeks after vaccination). Between March and August 2021, blood samples were obtained from 62 CLL and 60 MM patients from eight different hematology departments in Poland. Total anti‐RBD antibodies were detected in 37% MM patients before vaccination, increased to 91% and 94% in short‐ and long‐term follow‐up, respectively. In CLL, serological responses were detectable in 21% of patients before vaccination and increased to 45% in the short‐term and 71% in long‐term observation. We detected a tendency to higher frequencies of specific CD8+ T cells against SARS‐CoV‐2 after vaccination compared to samples before vaccination in MM patients and no changes in frequencies of specific T cells in CLL patients. Our study provides novel insights into mRNA vaccination efficacy in immunocompromised MM and CLL patients, and our findings highlight that specific CD8+ T cells against SARS‐CoV‐2 might be induced by vaccination but do not correlate positively with serological responses. [ABSTRACT FROM AUTHOR]

Early data suggested that CC‐115, a clinical molecule, already known to inhibit the mammalian target of rapamycin kinase (TORK) and DNA‐dependent protein kinase (DNA‐PK) may have additional targets beyond TORK and DNA‐PK. Therefore, we aimed to identify such target(s) and investigate a potential therapeutic applicability. Functional profiling of 141 cancer cell lines revealed inhibition of kinase suppressor of morphogenesis in genitalia 1 (SMG1), a key regulator of the RNA degradation mechanism nonsense‐mediated mRNA decay (NMD), as an additional target of CC‐115. CC‐115 treatment showed a dose‐dependent increase of SMG1‐mediated NMD transcripts. A subset of cell lines, including multiple myeloma (MM) cell lines sensitive to the endoplasmic reticulum stress‐inducing compound thapsigargin, were highly susceptible to SMG1 inhibition. CC‐115 caused the induction of UPR transcripts and cell death by mitochondrial apoptosis, requiring the presence of BAX/BAK and caspase activity. Superior antitumor activity of CC‐115 over TORK inhibitors in primary human MM cells and three xenograft mouse models appeared to be via inhibition of SMG1. Our data support further development of SMG1 inhibitors as possible therapeutics in MM. [ABSTRACT FROM AUTHOR]

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Fixed-point algorithms are popular in statistics and data science due to their simplicity, guaranteed convergence, and applicability to high-dimensional problems. Well-known examples include the expectation-maximization (EM) algorithm, majorization-minimization (MM), and gradientbased algorithms like gradient descent (GD) and proximal gradient descent. A characteristic weakness of these algorithms is their slow convergence. We discuss several state-of-art techniques for accelerating their convergence. We demonstrate and evaluate these techniques in terms of their efficiency and robustness in six distinct applications. Among the acceleration schemes, SQUAREM shows robust acceleration with a mean 18-fold speedup. DAAREM and restarted-Nesterov schemes also demonstrate consistently impressive accelerations. Thus, it is possible to accelerate the original fixed-point algorithm by using one of SQUAREM, DAAREM, or restarted-Nesterov acceleration schemes. We describe implementation details and software packages to facilitate the application of the acceleration schemes. We also discuss strategies for selecting a particular acceleration scheme for a given problem. [ABSTRACT FROM AUTHOR]

Wireless network devices can attain the required level of quality of service (QoS) and maintain connectivity even after detaching from a current point of access. This detachment (mobility) requires various mobility management (MM) mechanisms, which present numerous challenges due to the exponential growth of wireless devices and the demands of users. The network must be heterogeneous and dense to manage such a heightened escalation of network traffic, increased number of devices, and different types of user demands. Such factors will seriously challenge MM solutions, eventually making the networks non-feasible from the dependability, adaptability, extensibility, and power consumption points of view. Therefore, novel perspectives on MM mechanisms are desired for 5G networks and beyond. This paper introduces an innovative discussion of the functional requirements of MM mechanisms for advanced wireless networks. We present comprehensive arguments on whether the prevailing mechanisms perceived by standard bodies attempt to fulfill the stated requirements. We complete this discussion through innovative qualitative evaluation. We assess each of the discussed mechanisms in terms of their capability to fulfill the dependability, adaptability, extensibility, and power consumption benchmarks for upcoming MM schemes. Hereafter, we demonstrate the outcome and the identified gaps/challenges for the planning and deployment of 5G MM frameworks and beyond. Next, we present the capabilities and possible MM solutions to tackle the gaps/difficulties. We complete our discussion by proposing a 6G MM architecture based on defined parameters. [ABSTRACT FROM AUTHOR]

V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA) is considered as an immunosuppressive factor and potential therapeutic target for anticancer therapy. However, little is known about VISTA expression and its role in immunosuppression in multiple myeloma (MM). In this study, VISTA expression and co-expression with programmed cell death receptor-1 (PD-1), T cell immunoglobulin mucin-domaincontaining-3 (Tim-3), and T cell immunoglobulin and ITIM domain (TIGIT) in CD3+, CD4+, CD8+, and regulatory T (Treg) cells were analyzed in patients with MM by multi-color fluorescent flow cytometry of peripheral blood (PB) and bone marrow (BM) samples from 36 patients with MM and compared to 36 PB samples and 10 BM samples from healthy individuals (HIs), which served as controls. The results demonstrated a significant increased percentage of VISTA co-expression with PD-1, Tim-3, and TIGIT in CD3+, CD4+, CD8+, and Treg cells in PB from MM patients compared with HIs. A similar trend for VISTA+CD8 + T cells was found in BM. Moreover, a trend of a high percentage on VISTA expression and co-expression in PB rather than BM was found. Furthermore, significant positive correlations existed for VISTA expression concurrent with PD-1, Tim-3, and TIGIT in T cell subsets and clinical indicators, including Revised International Staging System (R-ISS) staging of multiple myeloma, Eastern Cooperative Oncology Group (ECOG) score, and beta-2-microglobulin (b2-MG). In conclusion, higher VISTA expression concurrent with PD-1, Tim-3, and TIGIT on T cells, particularly in the PB of patients with MM, may result in T cell exhaustion and dysfunction and be closely associated with disease progression and clinical indicators. Thus, VISTA may be considered a potential target for reversing T cell exhaustion and improving T cell function in MM. [ABSTRACT FROM AUTHOR]

CD147 (basigin, BSG) is a membrane-bound glycoprotein involved in energy metabolism that plays a role in cancer cell survival. Its soluble form is a promising marker of some diseases, but it is otherwise poorly studied. CD147 is overexpressed in multiple myeloma (MM) and is known to affect MM progression, while its genetic variants are associated with MM survival. In the present study, we aimed to assess serum soluble CD147 (sCD147) expression as a potential marker in MM. We found that sCD147 level was higher in MM patients compared to healthy individuals. It was also higher in patients with more advanced disease (ISS III) compared to both patients with less advanced MM and healthy individuals, while its level was observed to drop after positive response to treatment. Patients with high sCD147 were characterized by worse progression-free survival. sCD147 level did not directly correlate with bone marrow CD147 mRNA expression. In conclusion, this study suggests that serum sCD147 may be a prognostic marker in MM.

Multiple myeloma (MM) is the second most common hematologic malignancy. MM stem cells (MMSCs) are thought to be the main causes of in vivo engraftment and eventual recurrence. As a notable new technology, cold atmospheric plasmas (CAPs) show a promising anti-tumor effect, due to their production of various ROS. In this study, we found that different types of plasma could inhibit MM's ability to form cell colonies, suppress MM in vivo engraftment, and extend survival times. We demonstrated that NAC (a ROS scavenger) could block ROS increases and reverse the inhibition of MM's cell-colony-formation ability, which was induced by the plasma treatment. By using a stem cell signaling array, we found that the Notch pathway was inhibited by the plasma treatment; this was further confirmed by conducting real-time PCRs of three MM cell lines. Together, these results constitute the first report of plasma treatment inhibiting MM in vivo engraftment and prolonging survival time by suppressing the Notch pathway via ROS regulation. [ABSTRACT FROM AUTHOR]

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Background: Multiple myeloma (MM) is a hematological malignancy characterized by the exponential growth of malignant plasma cells. Individuals diagnosed with MM exhibit a deficiency in vitamin D and may suffer fatigue, a loss of muscular strength, persistent musculoskeletal aches, and pain. The objective of this systematic review and meta-analysis is to determine the prevalence of vitamin D insufficiency and deficiency in individuals diagnosed with MM. Methods: We searched five electronic databases using relevant keywords. The quality of the included studies was evaluated using the critical appraisal tool developed by the Joanna Briggs Institute. We employed a random-effects model and presented the findings in the form of percentages accompanied by 95% confidence intervals (CI). This protocol has been officially registered in PROSPERO under the registration number CRD42021248710. Results: The meta-analysis comprised a total of eighteen studies and found that, among patients with MM, the occurrence of serum vitamin D deficiency and insufficiency was 39.4% (95% CI: 25.8 to 52.9, n = 3746) and 34.1% (95% CI: 20.9 to 47.2, n = 3559), respectively. The findings indicate that a greater proportion of newly diagnosed patients exhibited vitamin D deficiency and insufficiency, with rates of 43.0% and 41.6%, respectively, compared to those receiving treatment (rates of 41.6% and 32.3%, respectively). The findings of the sensitivity analyses were consistent, and most of the studies (72.2%) were deemed to be of high quality. The results of Egger’s test indicated the absence of publication bias. Conclusions: Patients diagnosed with MM have been found to exhibit significantly elevated levels of both vitamin D deficiency and insufficiency. Therefore, it is recommended to consider vitamin D testing as an additional parameter in the current criteria for the clinical evaluation of MM.

Cancer cells, particularly MM, that are highly secretory cells, and PEL cells that harbor KSHV, are characterized by high level of stress to which they adapt by activating DDR, UPR and autophagy. It is known that UPR sensors may affect DDR, but whether DDR manipulation influences UPR is less known. In this study, we found an intricate interplay between these responses. Indeed, PARP and CHK1 inhibition by AZD2461 and UCN-01, by downregulating c-Myc, reduced the expression of XBP1s, constitutively expressed in these cells, and upregulated CHOP. Interestingly, given the role of XBP1s in regulating DDR, BRCA-1 expression level was reduced, exacerbating DNA damage. Finally, DDR/UPR interplay activated a pro-survival autophagy via PERK/eIF2alpha axis in MM and IRE1alpha/JNK axis in PEL cells, since in the latter case PERK/eIF2alpha activation could be prevented by KSHV that, as other herpesviruses, tries to avoid the blocks of protein translation that this pathway may induce. • The inhibition of PARPs and CHK1 reduces XBP1s in MM and PEL cells by down-regulating c-Myc. • The reduction of XBP1s by PARPs and CHK1 inhibitors down-regulates BRCA-1, further increasing DNA damage. • PARPs and CHK1 inhibition activates autophagy via PERK/eIF2alpha in MM cells and via IRE1alpha/JNK1/2 axis in PEL cells. [ABSTRACT FROM AUTHOR]

Our understanding of MM genomics has expanded rapidly in the past 5–10 years as a consequence of cytogenetic analyses obtained in routine clinical practice as well as the ability to perform whole-exome/genome sequencing and gene expression profiling on large patient data sets. This knowledge has offered new insights into disease biology and is increasingly defining high-risk genomic patterns. In this manuscript, we present a thorough review of our current knowledge of MM genomics. The epidemiology and biology of chromosomal abnormalities including both copy number abnormalities and chromosomal translocation are described in full with a focus on those most clinically impactful such as 1q amplification and del(17p) as well as certain chromosome 14 translocations. A review of our ever-expanding knowledge of genetic mutations derived from recent whole-genome/exome data sets is then reviewed including those that drive disease pathogenesis from precursor states as well as those that may impact clinical outcomes. We then transition and attempt to elucidate how both chromosomal abnormalities and gene mutations are evolving our understanding of disease risk. We conclude by offering our perspectives moving forward as to how we might apply whole-genome/exome-level data in addition to routine cytogenetic analyses to improve patient outcomes as well as further knowledge gaps that must be addressed. [ABSTRACT FROM AUTHOR]

Bingling Guo,1,* Chunyan Xiao,1,* Yumin Liu,2 Ning Zhang,3 Hao Bai,4 Tao Yang,1 Ying Xiang,1 Yingyu Nan,1 Qiying Li,1 Wenjun Zhang,1 Dehong Huang1 1Department of Hematology and Oncology, Chongqing University Cancer Hospital, Chongqing, People’s Republic of China; 2Medical Records Management Division, Chongqing University Cancer Hospital, Chongqing, People’s Republic of China; 3Intensive Care Unit, Chongqing University Cancer Hospital, Chongqing, People’s Republic of China; 4Pharmacy Services, Chongqing University Cancer Hospital, Chongqing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dehong HuangDepartment of Hematology and Oncology, Chongqing University Cancer Hospital, No. 181 Hanyu Road, Chongqing, People’s Republic of ChinaTel +86 23-65311341Email dehong_h012436@163.comPurpose: This study investigated the function and molecular mechanisms of miR-744-5p in multiple myeloma (MM).Methods: miR-744-5p and SRY-related high-mobility-group box 12 (SOX12) expression in clinical tissues and MM cells was monitored by quantitative real-time polymerase chain reactions and Western blot. miR-744-5p expression in MM cells was regulated by transfection. Cell proliferation was researched by cell counting kit-8 assay and plate clone formation experiment. Transwell experiment was utilized for migration and invasion detection. Glycolysis test was conducted for the detection of glucose uptake and lactate production of MM cells. The relationship between miR-744-5p and SOX12 was determined by dual-luciferase reporter gene assay and RNA pull-down experiment. In vivo experiment was conducted using nude mice.Results: miR-744-5p expression was reduced in MM patients (P< 0.01). Low miR-744-5p expression was associated with lower 60-month survival in MM patients (P=0.0402). miR-744-5p overexpression inhibited MM cells proliferation, invasion, migration, glucose uptake, lactate production, and epithelial mesenchymal transformation (EMT) (P< 0.01). miR-744-5p directly inhibited SOX12 expression. miR-744-5p silencing promoted MM cells proliferation, invasion, migration, glucose uptake, lactate production, and EMT by elevating SOX12 (P< 0.01). miR-744-5p inhibited the growth of MM xenograft tumors in vivo (P< 0.001).Conclusion: miR-744-5p inhibits MM cells proliferation, invasion, migration, EMT, and glycolysis by targeting SOX12/Wnt/β-catenin.Keywords: MM, miR-744-5p, SOX12, EMT, glycolysis

• A de novo sequencing work flow in this study is reliable enough compared to immunoglobulin repertoire sequencing to determine the whole amino acid sequences of FLCs. • As a non-invasive experimental method, this de novo sequencing work flow can reduce the difficulty of obtaining samples. • The CDR3 regions of free light chains exhibits high variability and may play a vital role in the occurrence of cast nephropathy. In patients with light chain cast nephropathy (LCCN), abundantly produced monoclonal immunoglobulin free light chains (FLCs) play a vital role in pathogenesis. Determining the precise sequences of patient-derived FLCs is therefore highly desirable. Although immunoglobulin repertoire sequencing (5′ RACE-seq) has been proven to be sensitive enough to provide full-length V(D)J region (variable, diversity and joining genes) of FLCs using bone marrow samples, an invasive and bone marrow independent method is still in demand. Here a de novo sequencing workflow based on the bottom-up proteomics for patient-derived FLCs was established. PEAKS software was used for the de novo sequencing of peptides that were further assembled into full-length FLC sequences. This de novo protein sequencing method can obtain the full-length amino acid sequences of FLCs, and had been shown to be as reliable as 5′ RACE-seq. The two LCCN sequences derived from above the two methods were identical, and they possessed more hydrophobic or nonpolar amino acids compared with the corresponding germline, which may be associated with the pathogenesis. [ABSTRACT FROM AUTHOR]

• The liquid heat capacities of MDM and MM were measured. • A comparison between the present experimental data and literatures values was carried out. • Molecular Dynamics was used to investigate the heat capacities of MDM and MM. Accurate heat capacity data and models of fluids are necessary to reduce the design margins of engineering equipment. Also, heat capacities are indispensable in the development of high-accuracy equation of state. In this work, liquid heat capacities of Octamethyltrisiloxane (MDM, C 8 H 24 O 2 Si 3) and Hexamethyldisiloxane (MM, C 6 H 18 OSi 2) were obtained with a modified steady-flow calorimeter. Experiments were performed over the temperature range of 313 to 453 K and pressures up to 10 MPa. The expanded relative uncertainty in measurement of heat capacity is less than 0.015. Then, the present experimental heat capacity data were correlated with an empirical model, yielding an average absolute deviation (AAD) of 0.26 % for MDM and 0.38 % for MM. In addition, non-equilibrium molecular dynamics was used to investigate the heat capacity of MDM and MM. The simulation results show not only a reasonable heat capacity's dependence on temperature but also a high accuracy. [ABSTRACT FROM AUTHOR]