Iberdomide increases innate and adaptive immune cell subsets in the bone marrow of patients with relapsed/refractory multiple myeloma.

Iberdomide is a potent cereblon E3 ligase modulator (CELMoD agent) with promising efficacy and safety as a monotherapy or in combination with other therapies in patients with relapsed/refractory multiple myeloma (RRMM). Using a custom mass cytometry panel designed for large-scale immunophenotyping of the bone marrow tumor microenvironment (TME), we demonstrate significant increases of effector T and natural killer (NK) cells in a cohort of 93 patients with multiple myeloma (MM) treated with iberdomide, correlating findings to disease characteristics, prior therapy, and a peripheral blood immune phenotype. Notably, changes are dose dependent, associated with objective response, and independent of prior refractoriness to MM therapies. This suggests that iberdomide broadly induces innate and adaptive immune activation in the TME, contributing to its antitumor efficacy. Our approach establishes a strategy to study treatment-induced changes in the TME of patients with MM and, more broadly, patients with cancer and establishes rational combination strategies for iberdomide with immune-enhancing therapies to treat MM.

Fabrication of Bioresorbable Barrier Membranes from Gelatin/Poly(4-Hydroxybutyrate) (P4HB).

Dental implant surgery is a procedure that replaces damaged or missing teeth with an artificial implant. During this procedure, guided bone regeneration (GBR) membranes are commonly used to inhibit the migration of epithelium and GBR at the surgical sites. Due to its biodegradability, good biocompatibility, and unique biological properties, gelatin (GT) is considered a suitable candidate for guiding periodontal tissue regeneration. However, GT-based membranes come with limitations, such as poor mechanical strength and mismatched degradation rates. To confront this challenge, a series of GT/poly(4-hydroxybutyrate) (P4HB) composite membranes are fabricated through electrospinning technology. The morphology, composition, wetting properties, mechanical properties, biocompatibility, and in vivo biodegradability of the as-prepared composite membranes are carefully characterized. The results demonstrate that all the membranes present excellent biocompatibility. Moreover, the in vivo degradation rate of the membranes can be manipulated by changing the ratio of GT and P4HB. The results indicate that the optimized GT/P4HB membranes with a high P4HB content (75%) may be suitable for periodontal tissue engineering because of their good mechanical properties and biodegradation rate compatible with tissue growth.

Exploring the processes and mechanisms by which nonprofit organizations orchestrate global innovation networks: A case study of the COVAX program.

In cocreating value with other organizations, nonprofit organizations may face multiple management challenges, posed by multistakeholder global innovation networks. Since these have not yet been systematically studied by academics, this study explores how nonprofit organizations can promote the cocreation of value in multistakeholder global innovation networks. Adopting a longitudinal single-case study approach from the perspective of network orchestration theory, this work deeply analyzes how nonprofit organizations can promote the evolution of the global innovation network of the COVID-19 vaccine under the COVAX program. The results show that nonprofits need to successively address the dilemmas of legitimacy, direction, and heterogeneity in constructing global innovation networks and that to solve these stage dilemmas, orchestrators must successively function as network architects, liaisons, and leaders to direct the implementation of network actions using trusted, leveraged, and adapted orchestration logics. This paper further proposes a model of the orchestration process and mechanisms by which nonprofit organizations facilitate multistakeholder global innovation networks. Theoretically, this study therefore extends network orchestration theory by summarizing the mechanisms and orchestration logics by which NPOs construct and develop networks when they act as orchestrators. From a practical perspective, this study also provides guidance for future unexpected global public health crises, improving the global community's ability to combat them.

Xuanfu Daizhe Tang alleviates reflux esophagitis in rats by inhibiting the STAT1/TREM-1 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Reflux esophagitis (RE) is a common chronic inflammatory disease of the esophageal mucosa with a high prevalence and recurrence rate, for which a satisfactory therapeutic strategy is still lacking. Chinese medicine has its characteristics and advantages in treating RE, and the clinical application of Xuanfu Daizhe Tang (XDT) in treating RE has achieved sound therapeutic effects. However, there needs to be more research on its mechanism of action. AIM OF THE STUDY: The present work aimed to investigate the mechanism of XDT action in RE through the Signal Transducer and Activator of Transcription 1 (STAT1)/Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) pathway. MATERIALS AND METHODS: The main active components of XDT were analyzed by ultra-performance liquid chromatography-mass spectrometer (UPLC-MS). The effect of XDT on RE was evaluated in a rat model of RE induced by "Cardioplasty + pyloric ligation + Roux-en-Y esophagojejunostomy". Each administration group was treated by gavage. The degree of damage to the esophageal mucosa was evaluated by visual observation, and the Potential of Hydrogen (PH) method and Hematoxylin-eosin staining (HE) staining were performed. Serum levels of Interleukin-1ß (IL-1ß), Interleukin-6 (IL-6), Tumor Necrosis Factor alpha (TNF-α), and Inducible Nitric Oxide Synthase (iNOS) were measured by ELISA. Quantitative Real-time PCR (qPCR), Western Blot (WB), and Immunofluorescence (IF) methods were used to detect Claudin-4, Claudin-5, TREM-1, and p-STAT1 in esophageal tissues for studying the mechanism of action and signaling pathway of XDT. Immunohistochemistry (IHC) analysis was used to detect the expression of TREM-1 and CD68 in esophageal tissues. Flow Cytometry (FC) was used to detect the polarization of macrophages in the blood. After conducting preliminary experiments to verify our hypothesis, we performed molecular docking between the active component of XDT and STAT1 derived from rats and parallel experiments with STAT1 inhibitor. The selective increaser of STAT1 transcription (2-NP) group was used to validate the mechanism by which XDT acts. RESULTS: XDT alleviated esophageal injury and attenuated histopathological changes in RE rats. XDT also inhibited the inflammatory response and decreased serum IL-1ß, IL-6, TNF-α, and iNOS levels in RE rats. qPCR and WB results revealed that XDT inhibited the expression of Claudin-4, Claudin-5, TREM-1, and STAT1 in the esophageal mucosa of RE rats. IHC and FC results showed that XDT reduced TREM-1 levels in esophageal tissues and polarized macrophages toward M2. The molecular docking results showed that rat-derived STAT1 can strongly bind to Isochronogenic acid A in XDT. The parallel experimental results of STAT1 inhibitor showed that XDT has anti-inflammatory effects similar to STAT1 inhibitors. The 2-NP group confirmed that XDT exerts its therapeutic effect on reflux esophagitis through the STAT1/TREM-1 pathway, with STAT1 as the upstream protein. CONCLUSIONS: This study suggests that XDT may treat reflux esophagitis by modulating the STAT1/TREM-1 pathway.

Bone morphogenetic protein-9 downregulates StAR expression by inducing snail expression via SMAD1/5/8 signaling in human granulosa-lutein cells.

Ovarian steroidogenesis mediated by granulosa cells is pivotal in maintaining normal female reproductive function. The steroidogenic acute regulatory protein (StAR) regulates the rate-limiting step in steroidogenesis. Bone morphogenetic protein-9 (BMP-9), also known as growth differentiation factor-2 (GDF-2), is a member of the transforming growth factor-beta (TGF-ß) superfamily. BMP-9 induces epithelial-mesenchymal transition (EMT) that contributes to cancer progression. However, the function of BMP-9 in the female reproductive system remains largely unknown. It has been recently shown that BMP-9 is expressed in human follicular fluid and can downregulate StAR expression in human ovarian granulosa cells. However, the underlying molecular mechanisms warrant investigation. Our results show that treatment of primary granulosa-lutein (hGL) cells with BMP-9 downregulates StAR expression. In addition, two EMT-related transcription factors, Snail and Slug, are upregulated by the treatment of BMP-9. Using pharmacological inhibitors and a siRNA-mediated knockdown approach, we show that BMP-9 upregulates Snail and Slug expression by activating SMAD1/5/8 signaling. We also examine the effects of BMP-9 on SMAD-independent signaling pathways, including ERK1/2, p38, JNK, AKT, and CREB. However, none of them is affected by the BMP-9. Moreover, we use gain- and loss-of-function approaches to reveal that only Snail, not Slug, is required for the BMP-9-induced downregulation of StAR expression in hGL cells. This study increases the understanding of the physiology function of BMP-9 in hGL cells and provides important insights into the regulation of StAR expression.

A tumor-infiltrating immune cells-related pseudogenes signature based on machine-learning predicts outcomes and immunotherapy responses in ovarian cancer.

Previous researches have provided evidence for the significant involvement of pseudogenes in immune-related functions across different types of cancer. However, the mechanisms by which pseudogenes regulate immunity in ovarian cancer (OV) and their potential impact on clinical outcomes remain unclear. To address this gap in knowledge, our study utilized a novel computational framework to analyze a total of 491 samples from three public datasets. We employed a combination of 10 machine-learning algorithms to construct a signature known as the tumor-infiltrating immune cells-related pseudogenes signature (TIICPS). The TIICPS, consisting of 12 pseudogenes, demonstrated independent prognostic value for overall survival, surpassing conventional clinical traits, 62 published signatures, and TP53 and BRCA mutation status in three cohorts. Patients with low TIICPS exhibited heightened immune-related pathways, intricate genomic alterations, substantial immune infiltration, and greater potential for immunotherapy efficacy. Consequently, TIICPS holds promise as a predictive tool for prognosis and immunotherapy response in ovarian cancer.

Glycyrrhizic acid alleviates liver fibrosis in vitro and in vivo via activating CUGBP1-mediated IFN-γ/STAT1/Smad7 pathway.

BACKGROUND: Hepatic fibrosis, a common pathological feature of chronic liver injuries, is a serious public health problem and lacks effective therapy. Glycyrrhizic acid (GA) is a bioactive ingredient in the root of traditional Chinese medicine licorice, and exhibits remarkable anti-viral, anti-inflammatory and hepatoprotective actions. PURPOSE: Here we aimed to investigated whether GA provided a therapeutic efficacy in hepatic fibrosis and uncover its molecular mechanisms. STUDY DESIGN AND METHODS: We investigated the anti-fibrosis effects of GA using CCl4-induced mouse mode of liver fibrosis as well as TGF-ß1-activated human LX-2 cells and primary hepatic stellate cells (HSCs). CUGBP1-mediated IFN-γ/STAT1/Smad7 signaling was examined with immunofluorescence staining and western blot analysis. We designed and studied the binding of GA to CUGBP1 using in silico docking, and validated by microscale thermophoresis (MST) assay. RESULTS: GA obviously attenuated CCl4-induced liver histological damage, and reduced serum ALT and AST levels. Meanwhile, GA decreased liver fibrogenesis markers such as α-SMA, collagen α1, HA, COL-III, and LN in the hepatic tissues. Mechanistically, GA remarkably elevated the levels of IFN-γ, p-STAT1, Smad7, and decreased CUGBP1 in vivo and in vitro. Over-expression of CUGBP1 completely abolished the anti-fibrotic effect of GA and regulation on IFN-γ/STAT1/Smad7 pathway in LX-2 cells and primary HSCs, confirming CUGBP1 played a pivotal role in the protection by GA from liver fibrosis. Further molecular docking and MST assay indicated that GA had a good binding affinity with the CUGBP1 protein. The dissociation constant (Kd) of GA and CUGBP1 was 0.293 µM. CONCLUSION: Our study demonstrated for the first time that GA attenuated liver fibrosis and hepatic stellate cell activation by promoting CUGBP1-mediated IFN-γ/STAT1/Smad7 signalling pathways. GA may be a potential candidate compound for preventing or reliving liver fibrosis.

Prolyl-tRNA synthetase as a novel therapeutic target in multiple myeloma.

Multiple myeloma (MM) is a plasma cell malignancy characterised by aberrant production of immunoglobulins requiring survival mechanisms to adapt to proteotoxic stress. We here show that glutamyl-prolyl-tRNA synthetase (GluProRS) inhibition constitutes a novel therapeutic target. Genomic data suggest that GluProRS promotes disease progression and is associated with poor prognosis, while downregulation in MM cells triggers apoptosis. We developed NCP26, a novel ATP-competitive ProRS inhibitor that demonstrates significant anti-tumour activity in multiple in vitro and in vivo systems and overcomes metabolic adaptation observed with other inhibitor chemotypes. We demonstrate a complex phenotypic response involving protein quality control mechanisms that centers around the ribosome as an integrating hub. Using systems approaches, we identified multiple downregulated proline-rich motif-containing proteins as downstream effectors. These include CD138, transcription factors such as MYC, and transcription factor 3 (TCF3), which we establish as a novel determinant in MM pathobiology through functional and genomic validation. Our preclinical data therefore provide evidence that blockade of prolyl-aminoacylation evokes a complex pro-apoptotic response beyond the canonical integrated stress response and establish a framework for its evaluation in a clinical setting.

Connecting single-nucleotide polymorphisms, glycosylation status, and interactions of plasma serine protease inhibitors.

Understanding the combined impacts of genetic variances and post-translational modifications requires new approaches. Here, we delineate proteoforms of plasma serine protease inhibitors and relate specific proteoforms to their interactions in complexes through the use of native mass spectrometry (MS). First, we dissect the proteoform repertoire of an acute-phase plasma protein, serine protease inhibitor A1 (SERPINA1), resolving four SERPINA1 variants (M1V, M1A, M2, and M3) with common single-nucleotide polymorphisms (SNPs). Investigating the glycosylation status of these variants and their ability to form complexes with a serine protease, elastase, we find that fucosylation stabilizes the interaction of the SERPINA1 M1V variant through its core fucosylation on Asn271. In contrast, antennary fucosylation on Asn271 destabilizes SERPINA1-elastase interactions. We unveil the same opposing effects of core and antennary fucosylation on SERPINA3 interactions with chymotrypsin. Together, our native MS results highlight the modulating effects of fucosylation with different linkages on glycoprotein interactions.

Development of Base Editors for Simultaneously Editing Multiple Loci in Lactococcus lactis.

Lactococcus lactis serves as the most extensively studied model organism and an important dairy species. Though CRISPR-Cas9 systems have been developed for robust genetic manipulations, simultaneously editing multiple endogenous loci in L. lactis is still challenging. Herein, we first report the development of a double-strand break-free, robust, multiloci editing system CRISPR-deaminase-assisted base editor (CRISPR-DBE), which comprises a cytidine (CRISPR-cDBE) and an adenosine deaminase-assisted base editor (CRISPR-aDBE). Specifically targeted by a sgRNA, CRISPR-cDBE can efficiently introduce a cytidine-to-thymidine mutation and CRISPR-aDBE can high-efficiently convert adenosine to guanosine within a 5 nt editing window. CRISPR-cDBE was validated and successfully applied to simultaneously inactivate multiple genes using a single plasmid in L. lactis strain NZ9000. Meanwhile, the temperature-sensitive plasmid of CRISPR-DBE can be cured quickly, and the continuous gene editing of L. lactis has been achieved. Furthermore, CRISPR-cDBE can also efficiently convert the targeted C to T in a nisin-producing, industrial L. lactis strain F44. Finally, we applied genome-wide bioinformatics analysis to determine the scope of gene inactivation for these base editors using different Cas9 variants and evaluated the preference of SpGn and SpRYn variants for the protospacer adjacent motif in L. lactis NZ9000. Taken together, our study provides a powerful tool for simultaneously editing multiple loci in L. lactis, which may have a wide range of industrial applications in the future.

Fostering the Environmental Performance of Hotels in Pakistan: A Moderated Mediation Approach From the Perspective of Corporate Social Responsibility.

The Islamic Republic of Pakistan has been a mere victim of climate change in recent years. The country needs emergency measures at every level to mitigate environmental dilapidation. The role of enterprises in the country's environmental efforts is critical. In this regard, the hotel sector is known for its outsized carbon footprint. Knowing this, the current study aims to improve a hotel enterprise's environmental performance (ENP) as an outcome of corporate social responsibility (CSR). The study also considers the mediating role of pro-environmental behavior (PEB) of employees and the moderating role of altruistic values (ALT). A hypothesized model was developed, which was validated by employing the structural equation modeling technique. The empirical results confirmed that CSR, directly and indirectly (through PEB), positively induces the ENP of a hotel enterprise. Whereas the conditional indirect role of ALT was also found significant. The study offers different implications for theory and practice, among which one important takeaway for the hotel sector is to realize the importance of employees to spur ENP of a hotel enterprise through their eco-friendly behavior. At the same time, the current work also advances the theory by highlighting the moderating role of ALT between the indirect relationship of CSR and ENP.

Porous N-doped carbon with confined Fe-doped CoP grown on CNTs for superefficient oxygen evolution electrocatalysis.

Herein, Fe-doped CoP nanoparticles (Fe-CoP NPs) encapsulated in porous N-doped carbon (PNC)/carbon nanotubes (CNTs) have been successfully synthesized. The Fe doping and confined structures resulted in enhanced charge transfer and improved active sites for intermediates adsorption. The obtained Fe-CoP@PNC/CNTs materials exhibited superefficient OER performance.

Expression and prognostic significance of m6A-related genes in TP53-mutant non-small-cell lung cancer.

BACKGROUND: TP53 is an important tumor suppressor gene on human 17th chromosome with its mutations more than 60% in tumor cells. Lung cancer is the highest incidence malignancy in men around the world. N-6 methylase (m6A) is an enzyme that plays an important role in mRNA splicing, translation, and stabilization. However, its role in TP53-mutant non-small-cell lung cancer (NSCLC) remains unknown. METHOD: First, we investigated 17 common m6A regulators' prognostic values in NSCLC. Then, after the establishment of risk signature, we explored the diagnostic value of m6A in TP53-mutant NSCLC. Finally, gene set enrichment analysis (GSEA), gene ontology (GO) enrichment analysis, and differential expression analysis were used to reveal the possible mechanism of m6A regulators affecting TP53-mutant NSCLC patients. RESULTS: Study showed that nine m6A regulators (YTHDC2, METTL14, FTO, METTL16, YTHDF1, HNRNPA2B1, RBM15, KIAA1429, and WTAP) were expressed differently between TP53-mutant and wild-type NSCLC (p < 0.05); and ALKBH5 and HNRNPA2B1 were associated with the prognostic of TP53-mutant patients. After construction of the risk signature combined ALKBH5 and HNRNPA2B1, we divided patients with TP53 mutations into high- and low-risk groups, and there was a significant survival difference between two groups. Finally, 338 differentially expression genes (DEGs) were found between high- and low-risk groups. GO enrichment analysis, PPI network, and GSEA enrichment analysis showed that m6A may affect the immune environment in extracellular and change the stability of mRNA. CONCLUSION: In conclusion, m6A regulators can be used as prognostic predictors in TP53-mutant patients.

Long non-coding RNA LINC01559 exerts oncogenic role via enhancing autophagy in lung adenocarcinoma.

BACKGROUND: Long non-coding RNAs (lncRNAs) have been verified to play fatal role in regulating the progression of lung adenocarcinoma (LUAD). Although lncRNAs play important role in regulating the autophagy of tumor cells, the function and molecular mechanism of LINC01559 in regulating lung cancer development remain to be elucidated. METHOD AND MATERIALS: In this study, we used bioinformatics to screen out autophagy-related lncRNAs from TCGA-LUAD repository. Then the least absolute shrinkage and selection operator (LASSO) regression was applied to establish the signature of autophagy-related lncRNAs so that clinical characteristics and survival in LUAD patients be evaluated. Finally, we selected the most significant differences lncRNA, LINC01559, to verify its function in regulating LUAD progression in vitro. RESULTS: We found high expression of LINC01559 indicates lymph node metastasis and poor prognosis. Besides, LINC01559 promotes lung cancer cell proliferation and migration in vitro, by enhancing autophagy signal pathway via sponging hsa-miR-1343-3p. CONCLUSION: We revealed a novel prognostic model based on autophagy-related lncRNAs, and provide a new therapeutic target and for patients with lung adenocarcinoma named LINC01559.

Highly Mesoporous Cobalt-Hybridized 2D Cu3P Nanosheet Arrays as Boosting Janus Electrocatalysts for Water Splitting.

Recently, developing economical electrocatalysts with high performance in water decomposition has become a research hotspot. Herein, two kinds of cobalt-hybridized Cu3P nanostructure array electrocatalysts (including highly mesoporous 2D nanosheets and sugar gourd-like 1D nanowires) were controllably grown on a nickel foam substrate through a simple hydrothermal method combined with a subsequent phosphating treatment method. An electrocatalytic test indicated that the as-prepared 2D nanosheet array exhibited excellent activity and stability toward hydrogen evolution reaction under alkaline conditions, which offered a low overpotential of 99 mV at 10 mA/cm2 and a small Tafel slope of 70.4 mV/dec, whereas a competitive overpotential of 272 mV was required for oxygen evolution reaction. In addition, the 2D nanosheet array delivered a low cell voltage of 1.66 V at 10 mA/cm2 in a symmetric two-electrode system, implying its huge potential in overall water decomposition. The electrocatalytic performance is superior to the as-prepared 1D nanowire array and most of the Cu3P-related electrocatalysts previously reported. Experimental measurements and first-principles calculations show that the excellent performance of the 2D nanosheet array can be attributed to its unique 2D mesoporous structure and hybridization of cobalt, which not only provide a large electrochemically active surface and fast electrocatalytic reaction kinetics but also weaken the binding strength of electrocatalytic reaction intermediates. The present study provides a simple and controllable approach to synthesize Cu3P-based bimetallic phosphide nanostructures, which can be used as boosting Janus electrocatalysts for water decomposition.

Active Site Engineering in CoP@NC/Graphene Heterostructures Enabling Enhanced Hydrogen Evolution.

As the core of an electrocatalyst, the active site is critical to determine its catalytic performance in the hydrogen evolution reaction (HER). In this work, porous N-doped carbon-encapsulated CoP nanoparticles on both sides of graphene (CoP@NC/GR) are derived from a bimetallic metal-organic framework (MOF)@graphene oxide composite. Through active site engineering by tailoring the environment around CoP and engineering the structure, the HER activity of CoP@NC/GR heterostructures is significantly enhanced. Both X-ray photoelectron spectroscopy (XPS) results and density functional theory (DFT) calculations manifest that the electronic structure of CoP can be modulated by the carbon matrix of NC/GR, resulting in electron redistribution and a reduction in the adsorption energy of hydrogen (ΔGH*) from -0.53 to 0.04 eV. By engineering the sandwich-like structure, active sites in CoP@NC/GR are further increased by optimizing the Zn/Co ratio in the bimetallic MOF. Benefiting from this active site engineering, the CoP@NC/GR electrocatalyst exhibits small overpotentials of 105 mV in 0.5 M H2SO4 (or 125 mV in 1 M KOH) to 10 mA cm-2, accelerated HER kinetics with a low Tafel slope of 47.5 mV dec-1, and remarkable structural and HER stability.

N-6 methylation-related lncRNA is potential signature in lung adenocarcinoma and influences tumor microenvironment.

BACKGROUND: N-6 methylation (m6A) pushes forward an immense influence on the occurrence and development of lung adenocarcinoma (LUAD). However, the methylation on non-coding RNA in LUAD, especially long non-coding RNA (lncRNA), has not been received sufficient attention. METHODS: Spearman correlation analysis was used to screen lncRNA correlated with m6A regulators expression from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) repositories, respectively. Then, the least absolute shrinkage and selection operator (LASSO) was applied to build a risk signature consisting m6A-related lncRNA. Univariate and multivariate independent prognostic analysis were applied to evaluate the performance of signature in predicting patients' survival. Next, we applied Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) to conduct pathway enrichment analysis of 3344 different expression genes (DEGs). Finally, we set up a competing endogenous RNAs (ceRNA) network to this lncRNA. RESULTS: A total of 85 common lncRNAs were selected to acquire the components related to prognosis. The final risk signature established by LASSO regression contained 11 lncRNAs: ARHGEF26-AS1, COLCA1, CRNDE, DLGAP1-AS2, FENDRR, LINC00968, TMPO-AS1, TRG-AS1, MGC32805, RPARP-AS1, and TBX5-AS1. M6A-related lncRNA risk score could predict the prognostic of LUAD and was significantly associated with clinical pathological. And in the evaluation of lung adenocarcinoma tumor microenvironment (TME) by using ESTIMATE algorithm, we found a statistically significant correlation between risk score and stromal/immune cells. CONCLUSION: M6A-related lncRNA was a potential prognostic and therapy target for lung adenocarcinoma.

Neuropeptide S receptor 1 is a nonhormonal treatment target in endometriosis.

Endometriosis is a common chronic inflammatory condition causing pelvic pain and infertility in women, with limited treatment options and 50% heritability. We leveraged genetic analyses in two species with spontaneous endometriosis, humans and the rhesus macaque, to uncover treatment targets. We sequenced DNA from 32 human families contributing to a genetic linkage signal on chromosome 7p13-15 and observed significant overrepresentation of predicted deleterious low-frequency coding variants in NPSR1, the gene encoding neuropeptide S receptor 1, in cases (predominantly stage III/IV) versus controls (P = 7.8 × 10-4). Significant linkage to the region orthologous to human 7p13-15 was replicated in a pedigree of 849 rhesus macaques (P = 0.0095). Targeted association analyses in 3194 surgically confirmed, unrelated cases and 7060 controls revealed that a common insertion/deletion variant, rs142885915, was significantly associated with stage III/IV endometriosis (P = 5.2 × 10-5; odds ratio, 1.23; 95% CI, 1.09 to 1.39). Immunohistochemistry, qRT-PCR, and flow cytometry experiments demonstrated that NPSR1 was expressed in glandular epithelium from eutopic and ectopic endometrium, and on monocytes in peritoneal fluid. The NPSR1 inhibitor SHA 68R blocked NPSR1-mediated signaling, proinflammatory TNF-α release, and monocyte chemotaxis in vitro (P < 0.01), and led to a significant reduction of inflammatory cell infiltrate and abdominal pain (P < 0.05) in a mouse model of peritoneal inflammation as well as in a mouse model of endometriosis. We conclude that the NPSR1/NPS system is a genetically validated, nonhormonal target for the treatment of endometriosis with likely increased relevance to stage III/IV disease.

Cereblon pathway biomarkers and immune profiles in patients with myeloma receiving post-ASCT lenalidomide maintenance (LEOPARD).

LEOPARD was a single arm, phase II study of lenalidomide (LEN) and alternate day prednisolone maintenance in patients with newly diagnosed multiple myeloma (MM) following autologous stem cell transplantation (ASCT). Sixty patients were enrolled. Estimated median potential follow-up was 44 m, median PFS was 38.3 m, median OS was not reached (landmark 36 m OS: 71.4%). Correlative immunohistochemistry performed on pre-ASCT trephines demonstrated high MM tumor cereblon (total/cytoplasmic) was associated with superior OS (p = .045, p = .031, respectively), whereas high c-Myc was associated with inferior PFS (p = .04). Patients with high cereblon (total/nuclear) were more likely to improve depth of response, whereas patients with high c-Myc were less likely, suggesting alternative/more effective post-ASCT strategies for patients with high c-Myc need identification. Peripheral blood immune profiling (mass cytometry) informed a more sustained response to LEN maintenance, demonstrating enrichment of activated/cytotoxic NK cells and cytotoxic T cells in patients with durable responses, contrasting with enrichment of B-regs in early relapsers.