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Diffuse large B-cell lymphoma (DLBCL) is an aggressive, yet curable malignancy, that has had practice changing treatment approvals in both the frontline and relapsed setting in the last 5 years. Advent of novel therapeutic options in the recent years has added greater complexity in treatment selection and optimal sequencing given multiple treatments with the same therapeutic target or immunotherapeutic mechanism of action. Key features impacting treatment selection include the timing of relapse, eligibility for curative options in the second line setting, including chimeric antigen receptor T-cell therapy (CAR-T) and autologous stem cell transplant (auto-SCT), as well as considerations of mechanism of action and side effect profile. This article provides a comprehensive review on recently approved therapies for relapsed or refractory DLBCL, emerging cellular and non-cellular therapies, and a summary of our approach to the management of these patients.

Recent genetic and molecular classification of DLBCL has advanced our knowledge of disease biology, yet were not designed to predict early events and guide anticipatory selection of novel therapies. To address this unmet need, we used an integrative multiomic approach to identify a signature at diagnosis that will identify DLBCL at high risk of early clinical failure. Tumor biopsies from 444 newly diagnosed DLBCL were analyzed by WES and RNAseq. A combination of weighted gene correlation network analysis and differential gene expression analysis was used to identify a signature associated with high risk of early clinical failure independent of IPI and COO. Further analysis revealed the signature was associated with metabolic reprogramming and identified cases with a depleted immune microenvironment. Finally, WES data was integrated into the signature and we found that inclusion of ARID1A mutations resulted in identification of 45% of cases with an early clinical failure which was validated in external DLBCL cohorts. This novel and integrative approach is the first to identify a signature at diagnosis, in a real-world cohort of DLBCL, that identifies patients at high risk for early clinical failure and may have significant implications for design of therapeutic options.

Over the last two decades, the frontline therapy for mantle cell lymphoma (MCL) has evolved. However, the impact of subsequent lines of therapy on survival outcomes has not been well characterized. In this study, we investigated the treatment patterns and survival outcomes in patients with relapsed/refractory (R/R) MCL treated with second-line (2 L) therapy. Adult patients with newly diagnosed MCL from 2002 to 2015 were enrolled in a prospective cohort study. Clinical characteristics, 2 L treatment details, and outcomes were compared between patients who received 2 L treatment between 2003–2009 (Era 1), 2010–2014 (Era 2), and 2015–2021 (Era 3). 2 L treatment was heterogenous in all eras, and there was a substantial shift in the pattern of 2 L therapy over time. The estimated 2-year EFS rate was 21% (95% CI, 13–35), 40% (95% CI, 30–53), and 51% (95% CI, 37–68) in Era 1–3 respectively, and the 5-year OS rate was 31% (95% CI, 21–45), 37% (95% CI, 27–50), and 67% (95% CI, 54–83) in Era 1–3, respectively. These results provide real-world evidence on evolving treatment patterns of 2 L therapy based on the era of relapse. The changes in 2 L treatment correlated with improved EFS and OS, suggesting that treatment advances are associated with improved outcomes in patients with R/R MCL.

Up to 40% of diffuse large B-cell lymphoma (DLBCL) patients do not experience a durable response to frontline immunochemotherapy, and prospective identification of high-risk cases that may benefit from personalized therapeutic management remains an unmet need. Molecular phenotyping techniques have established a landscape of genomic variants in diagnostic DLBCL; however, these have not yet been applied in large-scale studies of relapsed/refractory DLBCL, resulting in incomplete characterization of mechanisms driving tumor progression and treatment resistance. Here, we performed an integrated multiomic analysis on 228 relapsed/refractory DLBCL samples, including 24 with serial biopsies. Refined cell-of-origin subtyping identified patients harboring GCB and DZsig+ relapsed/refractory tumors in cases with primary refractory disease with remarkably poor outcomes, and comparative analysis of genomic features between relapsed and diagnostic samples identified subtype-specific mechanisms of therapeutic resistance driven by frequent alteration to MYC , BCL2 , BCL6 , and TP53 among additional strong lymphoma driver genes. Tumor evolution dynamics suggest innate mechanisms of chemoresistance are present in many DLBCL tumors at diagnosis, and that relapsed/refractory tumors are primarily comprised of a homogenous clonal expansion with reduced tumor microenvironment activity. Adaptation of personalized therapeutic strategies targeting DLBCL subtype-specific resistance mechanisms should be considered to benefit these high-risk populations.

When a student struggles with a mathematics task, adults may rephrase or expand initial task instructions to clarify instructions or scaffold problem solving. Yet expanded instructions may not benefit all children, especially children with a mathematics learning disability (MLD). Here, we explore whether expanded instructions differentially affect fractions comparison performance for children with or without MLD. Fifth graders (N = 190) completed two consecutive sets of 24 fraction comparison items, each accompanied by initial or expanded instructions, respectively; and also completed vocabulary, spatial reasoning, verbal working memory, executive function, and number knowledge tasks. Results showed that fraction comparison performance was generally worse following expanded rather than initial instructions, particularly for difficult items or for children with MLD. Fixed ordered regressions showed that the strength of cognitive skills as predictors of performance varied depending on instructions format and MLD status, that the five cognitive predictors collectively accounted for more performance variation with initial compared to expanded instructions, and that vocabulary’s relative predictive strength as a single predictor increased when instructions were expanded, but only for children with mathematics difficulties. These findings support the notion that problem features differentially affect children with or without MLD and that not all children benefit from hearing expanded instructions for difficult mathematics tasks.

Ninety-six first grade students in an urban school system were tested in October and May on reading, mathematics, and their understanding of sequences of letters and numbers. A time lag analysis was subsequently conducted. In such analyses, cross-correlations between the first measurement of one variable and the second measurement of another are compared. The larger of the correlations indicates the direction of the relationship; i.e., which variable is most likely to be causal. Correlations of the fall scores on the number sequences with spring scores on the mathematics concepts scale were significant, while correlations of the fall mathematics concepts scores with spring number sequence scores were negligible. This indicates that understanding such complex sequences has a directional effect on understanding mathematics concepts. Fall-spring cross-correlations for the letter sequences and reading test, although significant, did not differ, and hence provided no indication of the direction of the relationship. Potential explanations were discussed.

The ability to detect a pattern within a sequence of ordered units, defined as patterning, is a skill that is central to learning mathematics and influential in reading. Although the importance of patterning has been demonstrated, there has been limited research investigating the cognitive components of patterning. Studies suggested that cognitive flexibility and working memory may underlie patterning. A construct similar to patterning, fluid intelligence, has also been linked to executive function, which includes working memory, inhibition, and cognitive flexibility. However, fluid intelligence seems to be most highly related to working memory. The main goal of the study was to examine the role of working memory, inhibition, and cognitive flexibility in first-grade children’s patterning ability. We found that only cognitive flexibility was significantly related to patterning. This suggests that the ability to switch one’s thinking is involved in understanding patterns. In addition, the study tested the relation between executive function skills, patterning, reading fluency, and reading comprehension. We found that working memory was related to reading fluency and both working memory and inhibition were related to and uniquely predicted reading comprehension. Lastly, cognitive flexibility was significantly related to inhibition and working memory; however, inhibition and working memory were not related to one another.

The International Stem Cell Initiative compared several commonly used approaches to assess human pluripotent stem cells (PSC). PluriTest predicts pluripotency through bioinformatic analysis of the transcriptomes of undifferentiated cells, whereas, embryoid body (EB) formation in vitro and teratoma formation in vivo provide direct tests of differentiation. Here we report that EB assays, analyzed after differentiation under neutral conditions and under conditions promoting differentiation to ectoderm, mesoderm, or endoderm lineages, are sufficient to assess the differentiation potential of PSCs. However, teratoma analysis by histologic examination and by TeratoScore, which estimates differential gene expression in each tumor, not only measures differentiation but also allows insight into a PSC’s malignant potential. Each of the assays can be used to predict pluripotent differentiation potential but, at this stage of assay development, only the teratoma assay provides an assessment of pluripotency and malignant potential, which are both relevant to the pre-clinical safety assessment of PSCs. The International Stem Cell Initiative tests methods in a multisite study to detect pluripotency and teratoma formation (PluriTest, Embryoid Body and Teratoma methods) in human pluripotent stem cells. Here, the authors provide guidelines for their application: only the teratoma assay offers evidence of malignant potential.

Pseudomonas aeruginosa is an opportunistic pathogen capable of stably adapting to the antiseptic octenidine by an unknown mechanism. Here we characterise this adaptation, both in the laboratory and a simulated clinical setting, and identify a novel antiseptic resistance mechanism. In both settings, 2 to 4-fold increase in octenidine tolerance was associated with stable mutations and a specific 12 base pair deletion in a putative Tet-repressor family gene (smvR), associated with a constitutive increase in expression of the Major Facilitator Superfamily (MFS) efflux pump SmvA. Adaptation to higher octenidine concentrations led to additional stable mutations, most frequently in phosphatidylserine synthase pssA and occasionally in phosphatidylglycerophosphate synthase pgsA genes, resulting in octenidine tolerance 16- to 256-fold higher than parental strains. Metabolic changes were consistent with mitigation of oxidative stress and altered plasma membrane composition and order. Mutations in SmvAR and phospholipid synthases enable higher level, synergistic tolerance of octenidine.Bock et al. characterise the adaptation of Pseudomonas aeruginosa to the antiseptic octenidine, using whole genome sequencing, gene expression studies and metabolomics. They attribute this increased tolerance to synergistic changes in efflux and plasma membrane composition via mutations in SmvR, the regulator of MFS efflux pump SmvA, and in phospholipid pathway proteins PssA and PgsA.

Background Studies examining the association between in utero Zika virus (ZIKV) exposure and child neurodevelopmental outcomes have produced varied results. Methods We aimed to assess neurodevelopmental outcomes among normocephalic children born from pregnant people enrolled in the Zika in Pregnancy in Honduras (ZIPH) cohort study, July–December 2016. Enrollment occurred during the first prenatal visit. Exposure was defined as prenatal ZIKV IgM and/or ZIKV RNA result at enrollment. Normocephalic children, >6 months old, were selected for longitudinal follow-up using the Bayley Scales of Infant and Toddler Development (BSID-III) and the Ages & Stages Questionnaires: Social-Emotional (ASQ:SE-2). Results One hundred fifty-two children were assessed; after exclusion, 60 were exposed and 72 were unexposed to ZIKV during pregnancy. Twenty children in the exposed group and 21 children in the unexposed group had a composite score <85 in any of the BSID-III domains. Although exposed children had lower cognitive and language scores, differences were not statistically significant. For ASQ:SE-2 assessment, there were not statistically significant differences between groups. Conclusions This study found no statistically significant differences in the neurodevelopment of normocephalic children between in utero ZIKV exposed and unexposed. Nevertheless, long-term monitoring of children with in utero ZIKV exposure is warranted. Impact This study found no statistically significant differences in the neurodevelopment in normocephalic children with in utero Zika virus exposure compared to unexposed children, although the exposed group showed lower cognitive and language scores that persisted after adjustment by maternal age and education and after excluding children born preterm and low birth weight from the analysis. Children with prenatal Zika virus exposure, including those normocephalic and have no evidence of abnormalities at birth, should be monitored for neurodevelopmental delays. Follow-up is important to be able to detect developmental abnormalities that might not be detected earlier in life.