Search

Polatuzumab vedotin (Pola-V) is an antibody-drug conjugate directed to the CD79B subunit of the B-cell receptor (BCR). When combined with conventional immunochemotherapy, Pola-V improves outcomes in diffuse large B-cell lymphoma (DLBCL). To identify determinants of Pola-V sensitivity, we used CRISPR-Cas9 screening for genes that modulated Pola-V toxicity for lymphomas or the surface expression of its target, CD79B. Our results reveal the striking impact of CD79B glycosylation on Pola-V epitope availability on the lymphoma cell surface and on Pola-V toxicity. Genetic, pharmacological, and enzymatic approaches that remove sialic acid from N-linked glycans enhanced lymphoma killing by Pola-V. Pola-V toxicity was also modulated by KLHL6, an E3 ubiquitin ligase that is recurrently inactivated in germinal center derived lymphomas. We reveal how KLHL6 targets CD79B for degradation in normal and malignant germinal center B cells, thereby determining expression of the surface BCR complex. Our findings suggest precision medicine strategies to optimize Pola-V as a lymphoma therapeutic. Significance: These findings unravel the molecular basis of response heterogeneity to Pola-V and identify approaches that might be deployed therapeutically to enhance the efficacy of CD79B-specific tumor killing. In addition, they reveal a novel post-translational mechanism used by normal and malignant germinal center B cells to regulate expression of the BCR. See related commentary by Leveille, p. 1577 See related article by Meriranta et al., (©2024 American Association for Cancer Research.)

Multiple myeloma (MM) is an incurable plasma cell malignancy that exploits transcriptional networks driven by IRF4. We employ a multi-omics approach to discover IRF4 vulnerabilities, integrating functional genomics screening, spatial proteomics, and global chromatin mapping. ARID1A, a member of the SWI/SNF chromatin remodeling complex, is required for IRF4 expression and functionally associates with IRF4 protein on chromatin. Deleting Arid1a in activated murine B cells disrupts IRF4-dependent transcriptional networks and blocks plasma cell differentiation. Targeting SWI/SNF activity leads to rapid loss of IRF4-target gene expression and quenches global amplification of oncogenic gene expression by MYC, resulting in profound toxicity to MM cells. Notably, MM patients with aggressive disease bear the signature of SWI/SNF activity, and SMARCA2/4 inhibitors remain effective in immunomodulatory drug (IMiD)-resistant MM cells. Moreover, combinations of SWI/SNF and MEK inhibitors demonstrate synergistic toxicity to MM cells, providing a promising strategy for relapsed/refractory disease., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Rationale and Objective: This study aimed to develop a cosmesis scale to evaluate the cosmetic appearance of hemodialysis (HD) arteriovenous (AV) accesses from the perspective of the patient and clinician, which could be incorporated into clinical trials., Study Design: Using a modified Delphi process, two AV access cosmesis scale (AVACS) components were developed in a four-round Delphi panel consisting of two surveys and two consensus meetings with two rounds of patient consultation., Setting and Participants: The Delphi panel consisted of 15 voting members including five interventional or general nephrologists, five vascular surgeons, three interventional radiologists, and two vascular access nurse coordinators. Four patients experienced with vascular access were involved in patient question development., Analytical Approach: For a component to be included in the AVACS, it had to meet the prespecified panel consensus agreement of ⩾70%., Results: The clinician component of the AVACS includes nine questions on the following AV access features: scarring, skin discoloration, aneurysm/pseudoaneurysms and megafistula appearance. The patient component includes six questions about future vascular access decisions, interference with work or leisure activities, clothing choices, self-consciousness or attractiveness, emotional impact, and overall appearance., Limitations: Delphi panel methods are subjective by design, but with expert clinical opinion are used to develop classification systems and outcome measures. The developed scale requires further validation testing but is available for clinical trial use., Conclusions: While safety and efficacy are the primary concerns when evaluating AV access for HD, cosmesis is an important component of the ESKD patient experience. The AVACS has been designed to assess this important domain; it can be used to facilitate patient care and education about vascular access choice and maintenance. AVACS can also be used to inform future research on developing new techniques for AV access creation and maintenance, particularly as relates to AV access cosmesis., Competing Interests: Declaration of Conflicting InterestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The authors declare that they have no conflicts of interest regarding patents or royalties, stock/stock options, or first-degree relatives with any of these relationships related to this work. No reimbursement was received for the development of the manuscript.DR, VN, MM, CR, ED, CG, TV, SH, PB, LD and patients CS, DDR, FM, and MB (see acknowledgements) received remuneration from Becton Dickinson (BD) for their participation in the Delphi process.GW, AH, and NF are employees of CRG-EVERSANA Canada Inc., which was contracted by BD to facilitate the Delphi panel process and analyze the results.EK and DC are employees of the American Association of Kidney Patients (AAKP) which was contracted by BD to advise on patient input and recruited the Patient Ambassadors.DR is a consultant for BD and Gore Medical. VN is a consultant for the NACCME – Moderator for AV Access Webcast, supported by an educational grant from Medtronic. SH is a consultant/speaker for BD, Merit Medical, Medtronic, and Gore Medical. ED is a consultant for WL Gore, Angiodynamics, and 3M/KCI. ED is a scientific advisor for Boston Scientific. TY is a consultant for BD, WL Gore and Merit Medical and a scientific advisory board member of BD and Medtronic. CK is a consultant for BD and ACI/Humacyte and advisory board member for Boston Scientific. CL is a consultant for BD, Gore, and Medtronic.Other ConflictsED, KW, and TY are authors and ED is an editor for UpToDate.

Glucocorticoids have been used for decades to treat lymphomas without an established mechanism of action. Using functional genomic, proteomic, and chemical screens, we discover that glucocorticoids inhibit oncogenic signaling by the B cell receptor (BCR), a recurrent feature of aggressive B cell malignancies, including diffuse large B cell lymphoma and Burkitt lymphoma. Glucocorticoids induce the glucocorticoid receptor (GR) to directly transactivate genes encoding negative regulators of BCR stability (LAPTM5; KLHL14) and the PI3 kinase pathway (INPP5D; DDIT4). GR directly represses transcription of CSK, a kinase that limits the activity of BCR-proximal Src-family kinases. CSK inhibition attenuates the constitutive BCR signaling of lymphomas by hyperactivating Src-family kinases, triggering their ubiquitination and degradation. With the knowledge that glucocorticoids disable oncogenic BCR signaling, they can now be deployed rationally to treat BCR-dependent aggressive lymphomas and used to construct mechanistically sound combination regimens with inhibitors of BTK, PI3 kinase, BCL2, and CSK., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Diffuse large B cell lymphoma (DLBCL) is an aggressive, profoundly heterogeneous cancer, presenting a challenge for precision medicine. Bruton's tyrosine kinase (BTK) inhibitors block B cell receptor (BCR) signaling and are particularly effective in certain molecular subtypes of DLBCL that rely on chronic active BCR signaling to promote oncogenic NF-κB. The MCD genetic subtype, which often acquires mutations in the BCR subunit, CD79B, and in the innate immune adapter, MYD88 L265P , typically resists chemotherapy but responds exceptionally to BTK inhibitors. However, the underlying mechanisms of response to BTK inhibitors are poorly understood. Herein, we find a non-canonical form of chronic selective autophagy in MCD DLBCL that targets ubiquitinated MYD88 L265P for degradation in a TBK1-dependent manner. MCD tumors acquire genetic and epigenetic alterations that attenuate this autophagic tumor suppressive pathway. In contrast, BTK inhibitors promote autophagic degradation of MYD88 L265P , thus explaining their exceptional clinical benefit in MCD DLBCL., Competing Interests: Declaration of interests T.O. received research funding from Gilead and Merck KGaA, is a consultant/received honoraria for/from Beigene, Roche, Janssen, Merck KGaA, Gilead, Kronos Bio and Abbvie (all not related to this work). Z.W. is a current employee at GSK. A.L.S III is a current employee at AstraZeneca and has stock options., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Diffuse large B-cell lymphoma (DLBCL) can be subdivided into the activated B-cell (ABC) and germinal center B cell-like (GCB) subtypes. Self-antigen engagement of B-cell receptors (BCR) in ABC tumors induces their clustering, thereby initiating chronic active signaling and activation of NF-κB and PI3 kinase. Constitutive BCR signaling is essential in some GCB tumors but primarily activates PI3 kinase. We devised genome-wide CRISPR-Cas9 screens to identify regulators of IRF4, a direct transcriptional target of NF-κB and an indicator of proximal BCR signaling in ABC DLBCL. Unexpectedly, inactivation of N-linked protein glycosylation by the oligosaccharyltransferase-B (OST-B) complex reduced IRF4 expression. OST-B inhibition of BCR glycosylation reduced BCR clustering and internalization while promoting its association with CD22, which attenuated PI3 kinase and NF-κB activation. By directly interfering with proximal BCR signaling, OST-B inactivation killed models of ABC and GCB DLBCL, supporting the development of selective OST-B inhibitors for the treatment of these aggressive cancers., Significance: DLBCL depends on constitutive BCR activation and signaling. There are currently no therapeutics that target the BCR directly and attenuate its pathologic signaling. Here, we unraveled a therapeutically exploitable, OST-B-dependent glycosylation pathway that drives BCR organization and proximal BCR signaling. This article is highlighted in the In This Issue feature, p. 1749., (©2023 American Association for Cancer Research.)

Oncogenic RAS mutations are common in multiple myeloma (MM), an incurable malignancy of plasma cells. However, the mechanisms of pathogenic RAS signaling in this disease remain enigmatic and difficult to inhibit therapeutically. We employ an unbiased proteogenomic approach to dissect RAS signaling in MM. We discover that mutant isoforms of RAS organize a signaling complex with the amino acid transporter, SLC3A2, and MTOR on endolysosomes, which directly activates mTORC1 by co-opting amino acid sensing pathways. MM tumors with high expression of mTORC1-dependent genes are more aggressive and enriched in RAS mutations, and we detect interactions between RAS and MTOR in MM patient tumors harboring mutant RAS isoforms. Inhibition of RAS-dependent mTORC1 activity synergizes with MEK and ERK inhibitors to quench pathogenic RAS signaling in MM cells. This study redefines the RAS pathway in MM and provides a mechanistic and rational basis to target this mode of RAS signaling., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction: Emerging research suggests that people with disabilities experience an increased risk of sexual violence. However, few studies have examined the relationship between disability types and various forms of sexual violence, involving either physical or nonphysical force., Methods: This cross-sectional study used nationally representative data from years 2011-2017 of the National Survey of Family Growth among women aged 18-44 years. Analyses were conducted in March 2020-June 2021. Using binary and multinomial logistic regression models, lifetime risk of sexual violence and experience of physical or nonphysical force at first intercourse were modeled as a function of disability type (sensory, physical, cognitive, or ≥2 disabilities). Models also controlled for relevant demographic confounders., Results: Women with any type of disability reported experiencing sexual violence in their lifetime approximately double the proportion of that experienced by nondisabled women (∼30% vs 16.9%), with women with multiple disabilities experiencing the greatest prevalence (42.1%) and risk (AOR=2.94, p<0.001) than nondisabled women. Women with cognitive disabilities or multiple disabilities were significantly more likely to experience either physical (cognitive: AOR=1.55, p<0.001; multiple: AOR=1.50, p<0.05) or nonphysical force (cognitive: AOR=2.28, p<0.01; multiple: AOR=2.74, p<0.001) during their first intercourse than nondisabled women., Conclusions: Results of this study suggest that future research should focus on the association between various types of disability and sexual violence. The development of inclusive evidence-based violence intervention and prevention programs for girls and women with disabilities is recommended., (Copyright © 2022 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

In diffuse large B cell lymphoma (DLBCL), tumors belonging to the ABC but not GCB gene expression subgroup rely upon chronic active B cell receptor signaling for viability, a dependency that is targetable by ibrutinib. A phase III trial ("Phoenix;" ClinicalTrials.gov: NCT01855750) showed a survival benefit of ibrutinib addition to R-CHOP chemotherapy in younger patients with non-GCB DLBCL, but the molecular basis for this benefit was unclear. Analysis of biopsies from Phoenix trial patients revealed three previously characterized genetic subtypes of DLBCL: MCD, BN2, and N1. The 3-year event-free survival of younger patients (age ≤60 years) treated with ibrutinib plus R-CHOP was 100% in the MCD and N1 subtypes while the survival of patients with these subtypes treated with R-CHOP alone was significantly inferior (42.9% and 50%, respectively). This work provides a mechanistic understanding of the benefit of ibrutinib addition to chemotherapy, supporting its use in younger patients with non-GCB DLBCL., Competing Interests: Declaration of interests L.M.S., G.W., and D.W.H. are inventors on an NIH patent application covering the LymphGen algorithm. L.M.S., G.W., D.W.H., W.H.W., S.B., and B.H. are inventors on an NIH patent application covering the use of BTK inhibitors in genetic subtypes of DLBCL. B.H., S.B., Y.F., J.V., and M.S. are employees of Johnson & Johnson., (Published by Elsevier Inc.)

Glycosylation of the surface immunoglobulin (Ig) variable region is a remarkable follicular lymphoma-associated feature rarely seen in normal B cells. Here, we define a subset of diffuse large B-cell lymphomas (DLBCLs) that acquire N-glycosylation sites selectively in the Ig complementarity-determining regions (CDRs) of the antigen-binding sites. Mass spectrometry and X-ray crystallography demonstrate how the inserted glycans are stalled at oligomannose-type structures because they are buried in the CDR loops. Acquisition of sites occurs in ∼50% of germinal-center B-cell-like DLBCL (GCB-DLBCL), mainly of the genetic EZB subtype, irrespective of IGHV-D-J use. This markedly contrasts with the activated B-cell-like DLBCL Ig, which rarely has sites in the CDR and does not seem to acquire oligomannose-type structures. Acquisition of CDR-located acceptor sites associates with mutations of epigenetic regulators and BCL2 translocations, indicating an origin shared with follicular lymphoma. Within the EZB subtype, these sites are associated with more rapid disease progression and with significant gene set enrichment of the B-cell receptor, PI3K/AKT/MTORC1 pathway, glucose metabolism, and MYC signaling pathways, particularly in the fraction devoid of MYC translocations. The oligomannose-type glycans on the lymphoma cells interact with the candidate lectin dendritic cell-specific intercellular adhesion molecule 3 grabbing non-integrin (DC-SIGN), mediating low-level signals, and lectin-expressing cells form clusters with lymphoma cells. Both clustering and signaling are inhibited by antibodies specifically targeting the DC-SIGN carbohydrate recognition domain. Oligomannosylation of the tumor Ig is a posttranslational modification that readily identifies a distinct GCB-DLBCL category with more aggressive clinical behavior, and it could be a potential precise therapeutic target via antibody-mediated inhibition of the tumor Ig interaction with DC-SIGN-expressing M2-polarized macrophages., (© 2021 by The American Society of Hematology.)

The use of Bruton tyrosine kinase (BTK) inhibitors to block B-cell receptor (BCR)-dependent NF-κB activation in lymphoid malignancies has been a major clinical advance, yet acquired therapeutic resistance is a recurring problem. We modeled the development of resistance to the BTK inhibitor ibrutinib in the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma, which relies on chronic active BCR signaling for survival. The primary mode of resistance was epigenetic, driven in part by the transcription factor TCF4. The resultant phenotypic shift altered BCR signaling such that the GTPase RAC2 substituted for BTK in the activation of phospholipase Cγ2, thereby sustaining NF-κB activity. The interaction of RAC2 with phospholipase Cγ2 was also increased in chronic lymphocytic leukemia cells from patients with persistent or progressive disease on BTK inhibitor treatment. We identified clinically available drugs that can treat epigenetic ibrutinib resistance, suggesting combination therapeutic strategies., Significance: In diffuse large B-cell lymphoma, we show that primary resistance to BTK inhibitors is due to epigenetic rather than genetic changes that circumvent the BTK blockade. We also observed this resistance mechanism in chronic lymphocytic leukemia, suggesting that epigenetic alterations may contribute more to BTK inhibitor resistance than currently thought. See related commentary by Pasqualucci, p. 555 . This article is highlighted in the In This Issue feature, p. 549 ., (©2021 American Association for Cancer Research.)

Fas is highly expressed on germinal center (GC) B cells, and mutations of FAS have been reported in diffuse large B cell lymphoma (DLBCL). Although GC-derived DLBCL has better overall outcomes than other DLBCL types, some cases are refractory, and the molecular basis for this is often unknown. We show that Fas is a strong cell-intrinsic regulator of GC B cells that promotes cell death in the light zone, likely via T follicular helper (Tfh) cell-derived Fas ligand. In the absence of Fas, GCs were more clonally diverse due to an accumulation of cells that did not demonstrably bind antigen. FAS alterations occurred most commonly in GC-derived DLBCL, were associated with inferior outcomes and an enrichment of Tfh cells, and co-occurred with deficiency in HVEM and PD-L1 that regulate the Tfh-B cell interaction. This work shows that Fas is critically required for GC homeostasis and suggests that loss of Tfh-mediated counterselection in the GC contributes to lethality in GC-derived lymphoma., Competing Interests: Disclosures:   N. Kotlov reported a patent to BostonGene issued. O. Plotnikova reported "BostonGene employee." G.A. Smith reported personal fees from AMGEN outside the submitted work. J.J. O'Shea reported "other" from Pfizer outside the submitted work. J.D. Phelan reported a patent to PCT/US2018/025377 pending. D.W. Scott reported personal fees from Abbvie, personal fees from AstraZeneca, personal fees from Celgene, personal fees from Janssen, grants from Janssen, and grants from NanoString outside the submitted work; in addition, D.W. Scott had a patent for molecularly subtype lymphoma pending with NanoString. No other disclosures were reported., (This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.)

Tumors frequently subvert major histocompatibility complex class I (MHC-I) peptide presentation to evade CD8 + T cell immunosurveillance, though how this is accomplished is not always well defined. To identify the global regulatory networks controlling antigen presentation, we employed genome-wide screening in human diffuse large B cell lymphomas (DLBCLs). This approach revealed dozens of genes that positively and negatively modulate MHC-I cell surface expression. Validated genes clustered in multiple pathways including cytokine signaling, mRNA processing, endosomal trafficking, and protein metabolism. Genes can exhibit lymphoma subtype- or tumor-specific MHC-I regulation, and a majority of primary DLBCL tumors displayed genetic alterations in multiple regulators. We established SUGT1 as a major positive regulator of both MHC-I and MHC-II cell surface expression. Further, pharmacological inhibition of two negative regulators of antigen presentation, EZH2 and thymidylate synthase, enhanced DLBCL MHC-I presentation. These and other genes represent potential targets for manipulating MHC-I immunosurveillance in cancers, infectious diseases, and autoimmunity., Competing Interests: Declaration of Interests N.P.R. and R.J.K. are now employees of Lyell Immunopharma and hold equity., (Published by Elsevier Inc.)

Breast ductal cytologic atypia is an important risk factor for sporadic breast cancer. Characterization of the associated normal breast tissue is needed to develop additional methods of risk assessment and new targets for breast cancer prevention. We conducted a prospective clinical trial evaluating women at normal-risk or at high-risk for sporadic breast cancer. Breast ductal cells were collected and studied cytologically and by gene expression profiling, and breast ductal architectural changes were studied by breast ductal endoscopy (BDE) and breast MRI. One hundred and forty subjects were studied, 70 at high risk (RR, 2.0-4.6) and 70 at normal risk. Cytologic atypia was present in 22.9% of high-risk and 25.7% of normal-risk subjects. Ductal endoscopy was performed in 89 subjects and revealed benign intraductal abnormalities, primarily intraductal fibrous webbing suggesting chronic inflammation, in 40.4% of high-risk and 5.4% of normal-risk subjects, respectively ( P 2 = 0.0002). Two high-risk subjects with atypia and no normal-risk subjects with atypia developed invasive breast cancer. Gene expression profiling of ductal cells showed comparable gene expression profiles without enriched expression of previously defined oncogenic signatures in subjects with cellular atypia compared with those without atypia, and in high-risk subjects compared with normal-risk subjects (FDR > 0.5). Cytologic ductal atypia in normal-risk subjects does not appear to be of clinical significance. Atypia in women at high risk may be associated with benign and malignant breast ductal abnormalities; these characteristics of high-risk ductal cells may not be reflected in gene expression profiles., (©2020 American Association for Cancer Research.)

Epstein-Barr virus (EBV) infects human B cells and reprograms them to allow virus replication and persistence. One key viral factor in this process is latent membrane protein 2A (LMP2A), which has been described as a B cell receptor (BCR) mimic promoting malignant transformation. However, how LMP2A signaling contributes to tumorigenesis remains elusive. By comparing LMP2A and BCR signaling in primary human B cells using phosphoproteomics and transcriptome profiling, we identified molecular mechanisms through which LMP2A affects B cell biology. Consistent with the literature, we found that LMP2A mimics a subset of BCR signaling events, including tyrosine phosphorylation of the kinase SYK, the calcium initiation complex consisting of BLNK, BTK, and PLCγ2, and its downstream transcription factor NFAT. However, the majority of LMP2A-induced signaling events markedly differed from those induced by BCR stimulation. These included differential phosphorylation of kinases, phosphatases, adaptor proteins, transcription factors such as nuclear factor κB (NF-κB) and TCF3, as well as widespread changes in the transcriptional output of LMP2A-expressing B cells. LMP2A affected apoptosis and cell-cycle checkpoints by dysregulating the expression of apoptosis regulators such as BCl-xL and the tumor suppressor retinoblastoma-associated protein 1 (RB1). LMP2A cooperated with MYC and mutant cyclin D3, two oncogenic drivers of Burkitt lymphoma, to promote proliferation and survival of primary human B cells by counteracting MYC-induced apoptosis and by inhibiting RB1 function, thereby promoting cell-cycle progression. Our results indicate that LMP2A is not a pure BCR mimic but rather rewires intracellular signaling in EBV-infected B cells that optimizes cell survival and proliferation, setting the stage for oncogenic transformation., Competing Interests: Competing interest statement: F.C. is a co-founder of enGene Statistics GmbH. T.O. reported grants from Merck KGaA, and Gilead, and personal fees from Merck KGaA, Roche, Kronos Bio, all outside the submitted work.

Mediastinal gray zone lymphoma (MGZL) has immunopathologic features between classical Hodgkin lymphoma (cHL) and primary mediastinal thymic B-cell lymphoma (PMBL), leading to uncertainty regarding its biological relationship to these entities. We performed gene expression profiling from patients with MGZL (20), cHL (18), and PMBL (17) and show MGZL clusters between cHL and PMBL. Expression signatures reveal germinal B-cell and IFN regulatory factor 4 (IRF4) signatures were relatively low in MGZL and cHL compared with PMBL, indicating downregulation of the B-cell program in MGZL, a hallmark of cHL. T-cell and macrophage signatures were higher in MGZL and cHL compared with PMBL, consistent with infiltrating immune cells, which are found in cHL. The NFκB signature was higher in MGZL than PMBL, and like cHL, MGZL and PMBL express NFκB inducing kinase (NIK), indicating noncanonical signaling. These findings indicate that while MGZL has distinctive clustering, it is biologically closer to cHL., Competing Interests: Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed.

Patients with severe COVID-19 have a hyperinflammatory immune response suggestive of macrophage activation. Bruton tyrosine kinase (BTK) regulates macrophage signaling and activation. Acalabrutinib, a selective BTK inhibitor, was administered off-label to 19 patients hospitalized with severe COVID-19 (11 on supplemental oxygen; 8 on mechanical ventilation), 18 of whom had increasing oxygen requirements at baseline. Over a 10-14 day treatment course, acalabrutinib improved oxygenation in a majority of patients, often within 1-3 days, and had no discernable toxicity. Measures of inflammation - C-reactive protein and IL-6 - normalized quickly in most patients, as did lymphopenia, in correlation with improved oxygenation. At the end of acalabrutinib treatment, 8/11 (72.7%) patients in the supplemental oxygen cohort had been discharged on room air, and 4/8 (50%) patients in the mechanical ventilation cohort had been successfully extubated, with 2/8 (25%) discharged on room air. Ex vivo analysis revealed significantly elevated BTK activity, as evidenced by autophosphorylation, and increased IL-6 production in blood monocytes from patients with severe COVID-19 compared with blood monocytes from healthy volunteers. These results suggest that targeting excessive host inflammation with a BTK inhibitor is a therapeutic strategy in severe COVID-19 and has led to a confirmatory international prospective randomized controlled clinical trial., (Copyright © 2020, American Association for the Advancement of Science.)

The development of precision medicine approaches for diffuse large B cell lymphoma (DLBCL) is confounded by its pronounced genetic, phenotypic, and clinical heterogeneity. Recent multiplatform genomic studies revealed the existence of genetic subtypes of DLBCL using clustering methodologies. Here, we describe an algorithm that determines the probability that a patient's lymphoma belongs to one of seven genetic subtypes based on its genetic features. This classification reveals genetic similarities between these DLBCL subtypes and various indolent and extranodal lymphoma types, suggesting a shared pathogenesis. These genetic subtypes also have distinct gene expression profiles, immune microenvironments, and outcomes following immunochemotherapy. Functional analysis of genetic subtype models highlights distinct vulnerabilities to targeted therapy, supporting the use of this classification in precision medicine trials., Competing Interests: Declaration of Interests G.W.W., D.W.H., and L.M.S. are inventors on an NIH patent application that is based on the work presented herein. D.W.S. was a consultant for Abbvie, Celgene, and Janssen; received research funding from NanoString Technologies, Janssen, and Roche/Genentech. Authors are included on additional patents, some of which are licensed by NanoString Technologies., (Published by Elsevier Inc.)

The KLHL14 gene acquires frequent inactivating mutations in mature B cell malignancies, especially in the MYD88 L265P , CD79B mutant (MCD) genetic subtype of diffuse large B cell lymphoma (DLBCL), which relies on B cell receptor (BCR) signaling for survival. However, the pathogenic role of KLHL14 in DLBCL and its molecular function are largely unknown. Here, we report that KLHL14 is in close proximity to the BCR in the endoplasmic reticulum of MCD cell line models and promotes the turnover of immature glycoforms of BCR subunits, reducing total cellular BCR levels. Loss of KLHL14 confers relative resistance to the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and promotes assembly of the MYD88-TLR9-BCR (My-T-BCR) supercomplex, which initiates prosurvival NF-κB activation. Consequently, KLHL14 inactivation allows MCD cells to maintain NF-κB signaling in the presence of ibrutinib. These findings reinforce the central role of My-T-BCR-dependent NF-κB signaling in MCD DLBCL and suggest that the genetic status of KLHL14 should be considered in clinical trials testing inhibitors of BTK and BCR signaling mediators in DLBCL., Competing Interests: The authors declare no competing interest.

Objectives: To explore the relationship between congenital cytomegalovirus (CMV) and inattention and hyperactivity among school-aged children., Methods: The Behavior Assessment System for Children, Second Edition, parent- and self-report, was completed among children with symptomatic congenital CMV (ScCMV) (n = 36), asymptomatic congenital CMV (AcCMV) (n = 76), and controls (n = 29) enrolled in a longitudinal cohort. The proportions of children with ScCMV, AcCMV, and controls with Attention Problems or Hyperactivity T-scores ever ≥ 65 were compared. Mean T-scores in these domains were also compared and adjusted for IQ., Results: Children with AcCMV did not differ from controls in the proportion of children with elevated Attention Problems or Hyperactivity T-scores or in mean Attention Problems or Hyperactivity T-scores. Children with ScCMV had a higher proportion of elevated Attention Problems T-scores compared with the AcCMV group but not controls. There were no differences in the proportions of children with elevated Hyperactivity T-scores between ScCMV and AcCMV or control groups. Children with ScCMV had higher mean Attention Problems T-scores versus those with AcCMV and controls and higher mean Hyperactivity T-scores versus those with AcCMV but not controls. After adjustment for IQ, differences in mean Attention Problems or Hyperactivity T-scores were no longer significant., Conclusion: Children with AcCMV are not at increased risk of inattention or hyperactivity compared with controls. However, our study suggests an increased prevalence of inattention and hyperactivity among children with ScCMV. Differences in IQ were confirmed to have a confounding effect. Evaluation for attention-deficit/hyperactivity disorder may be warranted in this population.

Purpose: Percutaneous ablation techniques, including microwave ablation (MWA) and radiofrequency ablation (RFA), have become important minimally invasive treatment options for liver cancer. This systematic review compared MWA with RFA for treatment of liver cancer., Methods: The systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search of MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials was conducted for randomized and observational studies published from 2006 onwards. A random-effects model was used for meta-analyses and local tumor progression (LTP), technique efficacy, overall survival (OS), disease-free survival (DFS), intrahepatic de novo lesions (IDL), extrahepatic metastases (EHM), length of stay (LOS), and complications were analyzed. Subgroup and sensitivity analyses were also conducted., Results: Of 1379 studies identified, 28 randomized and observational studies met inclusion criteria. The main analysis demonstrated that LTP was significantly reduced by 30% with MWA versus RFA (RR=0.70; P=0.02) (all studies) and by 45% with MWA versus RFA (RR=0.55; P=0.007) (randomized studies only). There were no significant differences between MWA and RFA for other efficacy and safety outcomes. Higher frequency (2450 MHz) and larger tumor size (≥2.5 cm) are amongst variables that may be associated with improved outcomes for MWA. Sensitivity analyses were generally congruent with the main results., Conclusion: MWA is at least as safe and effective as RFA for treating liver cancer and demonstrated significantly reduced LTP rates. Future studies should assess time and costs associated with these two treatment modalities., Competing Interests: SG, JWC, MBG, and JFA are employees of Ethicon, Inc. (manufacturer of Neuwave microwave ablation instrumentation). RAQ, NCF, BS, and GWJW are employees of Cornerstone Research Group, who were sponsored to perform this study by Ethicon, Inc. MBG reports stocks and stock options from Johnson & Johnson during the conduct of the study. The authors report no other conflicts of interest in this work.

Patients in a hospital step-down unit require a level of care that is between that of the intensive care unit (ICU) and that of the general ward. While many patients remain physiologically stabilized, others will suffer clinical emergencies and be readmitted to the ICU, with a subsequent high risk of mortality. Had the associated physiological deterioration been detected early, the emergency may have been less severe or avoided entirely. Current clinical monitoring is largely heuristic, requiring manual calculation of risk scores and the use of heuristic decision criteria. Technical drawbacks include ignoring the time-series dynamics of physiological measurements, and lacking patient-specificity (i.e., personalization of models to the individual patient). In this paper, we demonstrate how Gaussian process regression models can supplement current monitoring practice by providing interpretable and intuitive illustrations of erratic vital-sign volatility. These personalized volatility metrics may provide significantly advanced warning of deterioration, while minimizing the false alarms that induce so-called alarm fatigue. While many AI-based approaches to healthcare are criticized for being uninterpretable "black-box" methods, the cause of alarms generated from the proposed methods are explicitly interpretable and intuitive. We conclude that intelligent computational inference using methods such as those proposed can enhance current clinical decision making and potentially save lives.

Although generally curable with intensive chemotherapy in resource-rich settings, Burkitt lymphoma (BL) remains a deadly disease in older patients and in sub-Saharan Africa. Epstein-Barr virus (EBV) positivity is a feature in more than 90% of cases in malaria-endemic regions, and up to 30% elsewhere. However, the molecular features of BL have not been comprehensively evaluated when taking into account tumor EBV status or geographic origin. Through an integrative analysis of whole-genome and transcriptome data, we show a striking genome-wide increase in aberrant somatic hypermutation in EBV-positive tumors, supporting a link between EBV and activation-induced cytidine deaminase (AICDA) activity. In addition to identifying novel candidate BL genes such as SIN3A , USP7 , and CHD8 , we demonstrate that EBV-positive tumors had significantly fewer driver mutations, especially among genes with roles in apoptosis. We also found immunoglobulin variable region genes that were disproportionally used to encode clonal B-cell receptors (BCRs) in the tumors. These include IGHV4-34, known to produce autoreactive antibodies, and IGKV3-20, a feature described in other B-cell malignancies but not yet in BL. Our results suggest that tumor EBV status defines a specific BL phenotype irrespective of geographic origin, with particular molecular properties and distinct pathogenic mechanisms. The novel mutation patterns identified here imply rational use of DNA-damaging chemotherapy in some patients with BL and targeted agents such as the CDK4/6 inhibitor palbociclib in others, whereas the importance of BCR signaling in BL strengthens the potential benefit of inhibitors for PI3K, Syk, and Src family kinases among these patients., (© 2019 by The American Society of Hematology.)

Doxorubicin (DOX) is a widely used drug for cancer treatment as a chemotherapeutic agent. However, the cellular and integrative mechanism of DOX-induced immunometabolism is unclear. Two-month-old male C57BL/6J mice were divided into high- and low-dose DOX-treated groups with a maintained saline control group. The first group was injected with a high dose of DOX (H-DOX; 15 mg·kg -1 ·wk -1 ), and the second group was injected with 7.5 mg·kg -1 ·wk -1 as a latent low dose of DOX (LL-DOX). H-DOX treatment led to complete mortality in 2 wk and 70% survival in the LL-DOX group compared with the saline control group. Therefore, an additional group of mice was injected with an acute high dose of DOX (AH-DOX) and euthanized at 24 h to compare with LL-DOX and saline control groups. The LL-DOX and AH-DOX groups showed obvious apoptosis and dysfunctional and structural changes in cardiac tissue. Splenic contraction was evident in AH-DOX- and LL-DOX-treated mice, indicating the systems-wide impact of DOX on integrative organs of the spleen, which is essential for cardiac homeostasis and repair. DOX dysregulated splenic-enriched immune-sensitive lipoxygenase and cyclooxygenase in the spleen and left ventricle compared with the saline control group. As a result, lipoxygenase-dependent D- and E-series resolvin precursors, such as 16HDoHE, 4HDoHE, and 12-HEPE, as well as cyclooxygenase-mediated PG species (PGD 2 , PGE 2, and 6-keto-PG 2α ) were decreased in the left ventricle, suggestive of defective immunometabolism. Both AH-DOX and LL-DOX induced splenic contraction and expansion of red pulp with decreased CD169 + metallophilic macrophages. AH-DOX intoxicated macrophages in the spleen by depleting CD169 + cells in the acute setting and sustained the splenic macrophage loss in the chronic phase in the LL-DOX group. Thus, DOX triggers a vicious cycle of splenocardiac cachexia to facilitate defective immunometabolism and irreversible macrophage toxicity and thereby impaired the inflammation-resolution program. NEW & NOTEWORTHY Doxorubicin (DOX) triggered splenic mass loss and decreased CD169 with germinal center contraction in acute and chronic exposure. Cardiac toxicity of DOX is marked with dysregulation of immunometabolism and thereby impaired resolution of inflammation. DOX suppressed physiological levels of cytokines and chemokines with signs of splenocardiac cachexia.

Quantitative systems pharmacology (QSP) models aim to describe mechanistically the pathophysiology of disease and predict the effects of therapies on that disease. For most drug development applications, it is important to predict not only the mean response to an intervention but also the distribution of responses, due to inter-patient variability. Given the necessary complexity of QSP models, and the sparsity of relevant human data, the parameters of QSP models are often not well determined. One approach to overcome these limitations is to develop alternative virtual patients (VPs) and virtual populations (Vpops), which allow for the exploration of parametric uncertainty and reproduce inter-patient variability in response to perturbation. Here we evaluated approaches to improve the efficiency of generating Vpops. We aimed to generate Vpops without sacrificing diversity of the VPs' pathophysiologies and phenotypes. To do this, we built upon a previously published approach (Allen et al., 2016) by (a) incorporating alternative optimization algorithms (genetic algorithm and Metropolis-Hastings) or alternatively (b) augmenting the optimized objective function. Each method improved the baseline algorithm by requiring significantly fewer plausible patients (precursors to VPs) to create a reasonable Vpop., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Study Question: Among infertile women undergoing ovarian stimulation, is allostatic load (AL), a measure of chronic physiological stress, associated with subsequent fertility and pregnancy outcomes?, Summary Answer: AL at baseline was not associated with conception, spontaneous abortion or live birth, however, it was significantly associated with increased odds of pre-eclampsia and preterm birth among women who had a live birth in the study., What Is Known Already: Several studies have linked AL during pregnancy to adverse outcomes including preterm birth and pre-eclampsia, hypothesizing that it may contribute to well-documented disparities in pregnancy and birth outcomes. However, AL biomarkers change over the course of pregnancy, raising questions as to whether gestational AL assessment is a valid measure of cumulative physiologic stress starting long before pregnancy. To better understand how AL may impact reproductive outcomes, AL measurement in the non-pregnant state (i.e. prior to conception) is needed., Study Design, Size, Duration: A secondary data analysis based on data from 836 women who participated in Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS), a multi-center, randomized clinical trial of ovarian stimulation conducted from 2011 to 2014., Participants/materials, Setting, Methods: Ovulatory women with unexplained infertility (ages 18-40) were enrolled and at baseline, biological and anthropometric measures were collected. AL scores were calculated as a composite of the following baseline variables determined a priori: BMI, waist-to-hip ratio, systolic blood pressure, diastolic blood pressure, dehydroepiandrosterone sulfate, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, C-reactive protein and HOMA score. Participants received ovarian stimulation for up to four cycles and if they conceived, were followed throughout pregnancy. We fit multi-variable logistic regression models examining AL (one-tailed and two-tailed) in relation to the following reproductive outcomes: conception, spontaneous abortion, live birth, pre-eclampsia, preterm birth and low birthweight., Main Results and the Role of Chance: Adjusting for covariates, a unit increase in two-tailed AL score was associated with 62% increased odds of pre-eclampsia (OR: 1.62, 95% CI: 1.14, 2.38) 44% increased odds of preterm birth (OR: 1.44, 95% CI: 1.02, 2.08), and 39% increased odds of low birthweight (OR: 1.39, 95% CI: 0.99, 1.97). The relationship between AL and preterm birth was mediated by pre-eclampsia (P = 0.0003). In one-tailed AL analyses, associations were similar, but slightly attenuated. AL was not associated with fertility outcomes (conception, spontaneous abortion, live birth)., Limitations, Reasons for Caution: Results may not be generalizable to fertile women who conceive naturally or women with other types of infertility. Comparisons to previous, related work are difficult because variables included in AL composite measures vary across studies. AL may be indicative of overall poor health, rather than being specific to chronic physiological stress., Wider Implications of the Findings: Our results suggest that chronic physiological stress may not impact success of ovarian stimulation, however, they confirm and extend previous work suggesting that AL is associated with adverse pregnancy outcomes. Physiological dysregulation due to chronic stress has been proposed as a possible mechanism underlying disparities in birth outcomes, which are currently poorly understood. Assessing biomarkers of physiological dysregulation pre-conception or in early pregnancy, may help to identify women at risk of adverse pregnancy outcomes, particularly pre-eclampsia., Study Funding/competing Interest(s): Support for AMIGOS was provided by: U10 HD39005, U10 HD38992, U10 HD27049, U10 HD38998, U10 HD055942, HD055944, U10 HD055936 and U10HD055925. Support for the current analysis was provided by T32ES007271, R25HD075737, P30ES001247 and P30ES005022. This research was made possible by funding by American Recovery and Reinvestment Act. The content is solely the responsibility of the authors and does not necessarily represent the official views of NICHD, NIEHS or NIH. E.B., W.V., O.M., R.A., M.R., V.B., G.W.B., C.C., E.E., S.K., R.U., P.C, H.Z., N.S. and S.T. have nothing to disclose. R.L. reported serving as a consultant to Abbvie, Bayer, Kindex, Odega, Millendo and Fractyl and serving as a site investigator and receiving grants from Ferring. K.H. reported receiving grants from Roche Diagnostics and Ferring. R.R. reported a grant from AbbVie. M.D. reported being on the Board of Directors of and a stockholder in Advanced Reproductive Care., Trial Registration Number: Clinical Trials.gov number: NCT01044862.

B cell receptor (BCR) signalling has emerged as a therapeutic target in B cell lymphomas, but inhibiting this pathway in diffuse large B cell lymphoma (DLBCL) has benefited only a subset of patients 1 . Gene expression profiling identified two major subtypes of DLBCL, known as germinal centre B cell-like and activated B cell-like (ABC) 2,3 , that show poor outcomes after immunochemotherapy in ABC. Autoantigens drive BCR-dependent activation of NF-κB in ABC DLBCL through a kinase signalling cascade of SYK, BTK and PKCβ to promote the assembly of the CARD11-BCL10-MALT1 adaptor complex, which recruits and activates IκB kinase 4-6 . Genome sequencing revealed gain-of-function mutations that target the CD79A and CD79B BCR subunits and the Toll-like receptor signalling adaptor MYD88 5,7 , with MYD88(L265P) being the most prevalent isoform. In a clinical trial, the BTK inhibitor ibrutinib produced responses in 37% of cases of ABC 1 . The most striking response rate (80%) was observed in tumours with both CD79B and MYD88(L265P) mutations, but how these mutations cooperate to promote dependence on BCR signalling remains unclear. Here we used genome-wide CRISPR-Cas9 screening and functional proteomics to determine the molecular basis of exceptional clinical responses to ibrutinib. We discovered a new mode of oncogenic BCR signalling in ibrutinib-responsive cell lines and biopsies, coordinated by a multiprotein supercomplex formed by MYD88, TLR9 and the BCR (hereafter termed the My-T-BCR supercomplex). The My-T-BCR supercomplex co-localizes with mTOR on endolysosomes, where it drives pro-survival NF-κB and mTOR signalling. Inhibitors of BCR and mTOR signalling cooperatively decreased the formation and function of the My-T-BCR supercomplex, providing mechanistic insight into their synergistic toxicity for My-T-BCR + DLBCL cells. My-T-BCR supercomplexes characterized ibrutinib-responsive malignancies and distinguished ibrutinib responders from non-responders. Our data provide a framework for the rational design of oncogenic signalling inhibitors in molecularly defined subsets of DLBCL.

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy, but some patients have a very indolent evolution. This heterogeneous course is related, in part, to the different biological characteristics of conventional MCL (cMCL) and the distinct subgroup of leukemic nonnodal MCL (nnMCL). Robust criteria to distinguish these MCL subtypes and additional biological parameters that influence their evolution are not well defined. We describe a novel molecular assay that reliably distinguishes cMCL and nnMCL using blood samples. We trained a 16-gene assay (L-MCL16 assay) on the NanoString platform using 19 purified leukemic samples. The locked assay was applied to an independent cohort of 70 MCL patients with leukemic presentation. The assay assigned 37% of cases to nnMCL and 56% to cMCL. nnMCL and cMCL differed in nodal presentation, lactate dehydrogenase, immunoglobulin heavy chain gene mutational status, management options, genomic complexity, and CDKN2A / ATM deletions, but the proportion with 17p/ TP53 aberrations was similar in both subgroups. Sequential samples showed that assay prediction was stable over time. nnMCL had a better overall survival (OS) than cMCL (3-year OS 92% vs 69%; P = .006) from the time of diagnosis and longer time to first treatment. Genomic complexity and TP53 / CDKN2A aberrations predicted for shorter OS in the entire series and cMCL, whereas only genomic complexity was associated with shorter time to first treatment and OS in nnMCL. In conclusion, the newly developed assay robustly recognizes the 2 molecular subtypes of MCL in leukemic samples. Its combination with genetic alterations improves the prognostic evaluation and may provide useful biological information for management decisions., (© 2018 by The American Society of Hematology.)

Introduction and Hypothesis: The objective was to prospectively characterize dynamic pelvic 3-Tesla magnetic resonance imaging (dp3T MRI) findings in nulligravida women and characterize changes 6 months after delivery in the same woman., Methods: In this prospective study, nulligravida women seeking assisted reproductive technology for pregnancy were recruited. After physical examination by Pelvic Organ Prolapse Quantification (POP-Q), Brink assessment and measures including the Pelvic Floor Distress Inventory-20 and Pelvic Floor Impact Questionnaire-7, pre-pregnancy dp3T MRI at rest, with strain, and evacuation were performed. Assessments were repeated ≥6 months postpartum. Analysis included Welch and paired t tests for continuous variables, Fisher's exact test for differences in categorical outcomes, and paired t tests for postpartum symptoms., Results: Nineteen subjects (mean ± SD age, 31 ± 5 years) completed baseline clinical and dp3T MRI studies, 15 delivered and 10 (30.5 ± 3 years) completed pre-pregnancy and post-delivery clinical and dp3T MRI assessments. There were no significant changes in scores of validated questionnaires (all p > 0.05) or on POP-Q measures post-delivery. Two (20%) subjects without pre-pregnancy levator tears had tears on MRI post-delivery. MRI measures of pelvic organ descent were increased post-delivery. Seventeen pelvic soft-tissue parameters increased by greater than 10% post-delivery, including 5 out of 70 (7.1%), 17 out of 110 (15.5%), and 50 out of 110 (45.5%) values exceeding thresholds at rest, strain, and evacuation respectively., Conclusions: Dynamic pelvic 3T MRI detected levator tears and increased pelvic organ descent, which can be directly attributed to pregnancy and delivery.

Background: Diffuse large B-cell lymphomas (DLBCLs) are phenotypically and genetically heterogeneous. Gene-expression profiling has identified subgroups of DLBCL (activated B-cell-like [ABC], germinal-center B-cell-like [GCB], and unclassified) according to cell of origin that are associated with a differential response to chemotherapy and targeted agents. We sought to extend these findings by identifying genetic subtypes of DLBCL based on shared genomic abnormalities and to uncover therapeutic vulnerabilities based on tumor genetics., Methods: We studied 574 DLBCL biopsy samples using exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes to identify genes with recurrent aberrations. We developed and implemented an algorithm to discover genetic subtypes based on the co-occurrence of genetic alterations., Results: We identified four prominent genetic subtypes in DLBCL, termed MCD (based on the co-occurrence of MYD88 L265P and CD79B mutations), BN2 (based on BCL6 fusions and NOTCH2 mutations), N1 (based on NOTCH1 mutations), and EZB (based on EZH2 mutations and BCL2 translocations). Genetic aberrations in multiple genes distinguished each genetic subtype from other DLBCLs. These subtypes differed phenotypically, as judged by differences in gene-expression signatures and responses to immunochemotherapy, with favorable survival in the BN2 and EZB subtypes and inferior outcomes in the MCD and N1 subtypes. Analysis of genetic pathways suggested that MCD and BN2 DLBCLs rely on "chronic active" B-cell receptor signaling that is amenable to therapeutic inhibition., Conclusions: We uncovered genetic subtypes of DLBCL with distinct genotypic, epigenetic, and clinical characteristics, providing a potential nosology for precision-medicine strategies in DLBCL. (Funded by the Intramural Research Program of the National Institutes of Health and others.).

Gaussian process regression (GPR) provides a means to generate flexible personalized models of time series of patient vital signs. These models can perform useful clinical inference in ways that population-based models cannot. A challenge for the use of personalized models is that they must be amenable to a wide range of parameterizations, to accommodate the plausible physiology of any patient in the population. Additionally, optimal performance is typically achieved when models are regularized in light of the knowledge of the physiology of the individual patient. In this paper, we describe a method to build GP models with varying complexity (via covariance kernels) and regularization (via fixed priors over hyperparameters) on a patient-specific level, for the purpose of robust vital-sign forecasting. To this end, our results present evidence in support of two main hypotheses: 1) the use of patient-specific models can outperform population-based models for useful clinical tasks, such as vital-sign forecasting; and 2) the optimal values of (hyper)parameters of these models are best determined by sophisticated methods of optimization, due to high correlation between dimensions of the search space. The resulting models are sufficiently robust to inform clinicians of a patient's vital-sign trajectory and warn of imminent deterioration.

Prostaglandins are formed by enzymatic and non-enzymatic mechanisms. They have been detected in human ovarian follicular fluid (HFF), a medium rich in growth factors and nutrients important for oocyte growth and fertility. However, the comprehensive identification of HFF prostaglandins has not been addressed. Here we use hybrid triple quadrupole time-of-flight and triple quadrupole mass spectrometers to comprehensively analyze prostaglandins in HFF. We identified PGE1, PGE2, PGF2α, and other prostaglandins synthesized via prostaglandin-endoperoxide synthase (i.e. Cox) cascades. We also identified specific PGF2α isomers (F2-isoprostanes) and PGF3α analogs whose structures are inconsistent with Cox-dependent formation. A prospective cohort pilot study of infertility patient subtypes revealed two potential associations. F2-isoprostanes are decreased in the diminished ovarian reserve subtype and elevated PGF2α may be associated with decreased live birth. Other than PGF2α, only body mass index >25kg/m 2 correlated with poor in vitro fertilization outcome. Our studies suggest that HFF contains prostaglandins formed from at least two mechanisms, which may correlate with distinct clinical parameters., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: While female sexual dysfunction is a frequent occurrence, characteristics in infertile women are not well delineated. Furthermore, the impact of infertility etiology on the characteristics in women with differing androgen levels observed in women with polycystic ovary syndrome and unexplained infertility has not been assessed., Objective: The objective of the study was to determine the characteristics of sexual dysfunction in women with polycystic ovary syndrome and unexplained infertility., Study Design: A secondary data analysis was performed on 2 of Eunice Kennedy Shriver National Institute of Child Health and Human Development Cooperative Reproductive Medicine Networks clinical trials: Pregnancy in Polycystic Ovary Syndrome Study II and Assessment of Multiple Intrauterine Gestations From Ovarian Stimulation. Both protocols assessed female sexual function using the Female Sexual Function Inventory and the Female Sexual Distress Scale., Results: Women with polycystic ovary syndrome had higher weight and body mass index than women with unexplained infertility (each P < .001), greater phenotypic (Ferriman-Gallwey hirsutism score, sebum score, and acne score; each P < .001), and hormonal (testosterone, free testosterone, and dehydroepiandrosterone; each P < .001) evidence of androgen excess. Sexual function scores, as assessed by the Female Sexual Function Inventory, were nearly identical. The Female Sexual Distress Scale total score was higher in women with polycystic ovary syndrome. The mean Female Sexual Function Inventory total score increased slightly as the free androgen index increased, mainly as a result of the desire subscore. This association was more pronounced in the women with unexplained infertility., Conclusion: Reproductive-age women with infertility associated with polycystic ovary syndrome and unexplained infertility, despite phenotypic and biochemical differences in androgenic manifestations, do not manifest clinically significant differences in sexual function., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Randomized, multicenter, open-label, phase 2/3 trial investigating lenalidomide versus investigator's choice (IC) in relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Experimental Design: Patients with DLBCL who received ≥2 prior therapies were stratified by DLBCL subtype [germinal center B-cell (GCB) vs. non-GCB; determined by immunohistochemistry (IHC)] and then randomized 1:1 to lenalidomide (25 mg/day, 21 days of 28-day cycle) or IC (gemcitabine, rituximab, etoposide, or oxaliplatin). Crossover to lenalidomide was permitted for IC-treated patients with radiologically confirmed progressive disease. The primary endpoint was overall response rate (ORR). Progression-free survival (PFS), overall survival, and subtype analysis [GCB vs. activated B-cell (ABC)] using gene expression profiling (GEP) were exploratory endpoints. Results: Stage 1: 102 DLBCL patients (by IHC: non-GCB, n = 54; GCB, n = 48) received ≥1 dose of lenalidomide or IC. Hematologic treatment-emergent adverse events with lenalidomide versus IC included neutropenia (42.6%; 36.4%), anemia (33.3%; 47.3%), thrombocytopenia (24.1%; 43.6%), and leukopenia (5.6%; 12.7%), respectively. Overall, lenalidomide-treated patients had an ORR of 27.5% versus 11.8% in IC (ORRs were similar regardless of IHC-defined DLBCL subtype). Median PFS was increased in patients receiving lenalidomide (13.6 weeks) versus IC (7.9 weeks; P = 0.041), with greater improvements in non-GCB patients (15.1 vs. 7.1 weeks, respectively; P = 0.021) compared with GCB (10.1 vs. 9.0 weeks, respectively; P = 0.550). Conclusions: The clinical benefit of lenalidomide monotherapy in DLBCL patients was more evident in the non-GCB subtype. Exploratory analyses suggest that this preferential benefit was more pronounced in the GEP-defined ABC population, demonstrating a need for additional studies of lenalidomide in DLBCL using GEP subtyping. Clin Cancer Res; 23(15); 4127-37. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Robust continuous monitoring of patient vital signs (VS) is limited by artefactual data yielding measurements that are not representative of the patient's physiology. These artefacts are typified by several distinct "archetypes". We present several of these archetypal artefacts for heart rate (HR) monitoring, and propose a light weight, real-time algorithm to remove the majority of these artefacts. Most artefacts are not identifiable by their values in absolute terms, but instead by their values relative to other measurements nearby in time. We model temporally-proximate measurements as independent and identically distributed (i.i.d.) samples from a Gamma distribution. Measurements with low likelihood with respect to the distribution are candidates for artefact removal. This lightweight algorithm is important for real-time deployment on wearable sensors, which are becoming increasingly common in hospital and home care. The clinical applicability of artefact-removal is demonstrated in its ability to enhance patient deterioration detection. A Kalman filter-based patient monitoring algorithm is shown to improve early warning of deterioration when the proposed artefact-removal algorithm is used. We demonstrate this real-time system with patient data from a clinical trial that we have undertaken.

Purpose Mantle cell lymphoma is an aggressive B-cell neoplasm that displays heterogeneous outcomes after treatment. In 2003, the Lymphoma/Leukemia Molecular Profiling Project described a powerful biomarker-the proliferation signature-using gene expression in fresh frozen material. Herein, we describe the training and validation of a new assay that measures the proliferation signature in RNA derived from routinely available formalin-fixed paraffin-embedded (FFPE) biopsies. Methods Forty-seven FFPE biopsies were used to train an assay on the NanoString platform, using microarray gene expression data of matched fresh frozen biopsies as a gold standard. The locked assay was applied to pretreatment FFPE lymph node biopsies from an independent cohort of 110 patients uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. Seventeen biopsies were tested across three laboratories to assess assay reproducibility. Results The MCL35 assay, which contained a 17-gene proliferation signature, yielded gene expression of sufficient quality to assign an assay score and risk group in 108 (98%) of 110 archival FFPE biopsies. The MCL35 assay assigned patients to high-risk (26%), standard-risk (29%), and low-risk (45%) groups, with different lengths of overall survival (OS): a median of 1.1, 2.6, and 8.6 years, respectively (log-rank for trend, P < .001). In multivariable analysis, these risk groups and the Mantle Cell Lymphoma International Prognostic Index were independently associated with OS ( P < .001 for both variables). Concordance of risk assignment across the three independent laboratories was 100%. Conclusion The newly developed and validated MCL35 assay for FFPE biopsies uses the proliferation signature to define groups of patients with significantly different OS independent of the Mantle Cell Lymphoma International Prognostic Index. Importantly, the analytic and clinical validity of this assay defines it as a reliable biomarker to support risk-adapted clinical trials.

Janus kinases (JAKs) classically signal by activating STAT transcription factors but can also regulate gene expression by epigenetically phosphorylating histone H3 on tyrosine 41 (H3Y41-P). In diffuse large B-cell lymphomas (DLBCLs), JAK signaling is a feature of the activated B-cell (ABC) subtype and is triggered by autocrine production of IL-6 and IL-10. Whether this signaling involves STAT activation, epigenetic modification of chromatin, or both mechanisms is unknown. Here we use genetic and pharmacological inhibition to show that JAK1 signaling sustains the survival of ABC DLBCL cells. Whereas STAT3 contributed to the survival of ABC DLBCL cell lines, forced STAT3 activity could not protect these cells from death following JAK1 inhibition, suggesting epigenetic JAK1 action. JAK1 regulated the expression of nearly 3,000 genes in ABC DLBCL cells, and the chromatin surrounding many of these genes was modified by H3Y41-P marks that were diminished by JAK1 inhibition. These JAK1 epigenetic target genes encode important regulators of ABC DLBCL proliferation and survival, including IRF4, MYD88, and MYC. A small molecule JAK1 inhibitor cooperated with the BTK inhibitor ibrutinib in reducing IRF4 levels and acted synergistically to kill ABC DLBCL cells, suggesting that this combination should be evaluated in clinical trials., Competing Interests: Dr. Levine and Dr. Staudt separately collaborated with the same laboratory and have therefore appeared as coauthors on a paper published as Sanda et al. (2013) TYK2-STAT1-BCL2 pathway dependence in T-cell acute lymphoblastic leukemia. Cancer Discov 3(5):564–577, although they did so independently and without knowledge of each other’s participation in this study.