Leukemia cells are protected from chemotherapy-induced apoptosis by their interactions with bone marrow mesenchymal stromal cells (BM-MSCs). Yet the underlying mechanisms associated with this ...protective effect remain unclear. Genome-wide gene expression profiling of BM-MSCs revealed that coculture with leukemia cells upregulated the transcription of genes associated with nuclear factor (NF)-κB signaling. Moreover, primary BM-MSCs from leukemia patients expressed NF-κB target genes at higher levels than their normal BM-MSC counterparts. The blockade of NF-κB activation via chemical agents or the overexpression of the mutant form of inhibitor κB-α (IκBα) in BM-MSCs markedly reduced the stromal-mediated drug resistance in leukemia cells in vitro and in vivo. In particular, our unique in vivo model of human leukemia BM microenvironment illustrated a direct link between NF-κB activation and stromal-associated chemoprotection. Mechanistic in vitro studies revealed that the interaction between vascular cell adhesion molecule 1 (VCAM-1) and very late antigen-4 (VLA-4) played an integral role in the activation of NF-κB in the stromal and tumor cell compartments. Together, these results suggest that reciprocal NF-κB activation in BM-MSCs and leukemia cells is essential for promoting chemoresistance in the transformed cells, and targeting NF-κB or VLA-4/VCAM-1 signaling could be a clinically relevant mechanism to overcome stroma-mediated chemoresistance in BM-resident leukemia cells.
•VCAM-1/VLA-4 triggers reciprocal NF-κB activation in leukemia and stromal cells and mediates cross-talk between leukemia and stromal cells.•VCAM-1/VLA-4 and NF-κB signaling plays a pivotal role in the development of leukemia chemoresistance.
•Veterans alcohol use and binge drinking declined throughout 12 months of the pandemic.•Pre-COVID PTSD associated with greater alcohol use and binge drinking.•Trends in substance use vary across ...racial/ethnic minority and female veterans.•Loneliness associated with reduced alcohol use and binge drinking over time.•Economic hardship and negative reactions to COVID associated with greater alcohol use and binge drinking.
The COVID-19 pandemic has had considerable behavioral health implications globally. One subgroup that may be of particular concern is U.S. veterans, who are susceptible to mental health and substance use concerns. The current study aimed to investigate changes in alcohol use and binge drinking before and during the first year of the pandemic among U.S. veterans, and how pre-pandemic mental health disorders, namely posttraumatic stress disorder (PTSD), and COVID-19-related factors like loneliness, negative reactions to COVID-19, and economic hardship influenced alcohol use trends.
1230 veterans were recruited in February 2020 as part of a larger survey study on veteran health behaviors. Veterans were asked to complete follow-up assessments throughout the pandemic at 6, 9, and 12- months.
Overall, veterans reported a significant decrease in alcohol use (IRR = 0.98) and binge drinking (IRR = 0.11) However, women, racial/ethnic minority veterans, and those with pre-existing PTSD exhibited smaller decreases in alcohol use and binge drinking and overall higher rates of use compared to men, White veterans, and those without PTSD. Both economic hardship and negative reactions to COVID-19 were associated with greater alcohol and binge drinking whereas loneliness showed a negative association with alcohol use and binge drinking.
Veterans reported decreases in alcohol use and binge drinking throughout the pandemic, with heterogeneity in these outcomes noted for higher risk groups. Special research and clinical attention should be given to the behavioral health care needs of veterans in the post-pandemic period.
Chemoimmunotherapy for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) is largely unchanged for decades. Both preclinical models and clinical data suggest the combination of ...lenalidomide and ibrutinib may have synergy in DLBCL, particularly in the non-germinal center B-cell-like subset.
We enrolled 60 patients with newly diagnosed non-germinal center B-cell-like DLBCL in this investigator-initiated, single-arm phase II trial of rituximab, lenalidomide, and ibrutinib (RLI) with the sequential addition of chemotherapy (ClinicalTrials.gov identifier: NCT02636322). Patients were treated with rituximab 375 mg/m
intravenous once on day 1, lenalidomide 25 mg once per day on days 1-10, and ibrutinib 560 mg once daily continuously of each 21-day cycle (RLI). After two cycles, standard chemotherapy was added to RLI for six additional cycles. The primary end points were overall response rate (ORR) after two cycles of RLI alone and complete response rate after completion of RLI with chemotherapy. In evaluable samples, circulating tumor DNA and DLBCL90 assays were performed.
The median age was 63.5 years (range, 29-83 years) with 28% age 70 years or older. The revised international prognostic index identified 42% as high risk, and 62% were double expressor of MYC and BCL2 protein. The ORR after two cycles of RLI was 86.2%, and the complete response rate at the end of RLI-chemotherapy was 94.5%. With a median follow-up of 31 months, the progression-free survival and overall survival were at 91.3% and 96.6% at 2 years, respectively.
Smart Start is the first study, to our knowledge, to treat newly diagnosed DLBCL with a targeted therapy combination before chemotherapy. RLI produced a high ORR, and RLI with chemotherapy resulted in durable responses. This establishes the potential for developing biologically driven and noncytotoxic first-line therapies for DLBCL.
•Co-use prevalence increased from 0.3% at W1 (age 11.5) to 9.5% at W10 (age 20.7).•Probability of co-use was higher among White than Hispanic or Asian participants.•Co-use was generally associated ...with poorer functioning in emerging adulthood.•There is some evidence of racial/ethnic disparities in co-use related outcomes.
Cannabis and tobacco co-use is a growing concern, yet little is known about its developmental course or associated outcomes during emerging adulthood. This study examines developmental trajectories of cannabis and tobacco co-use from adolescence to emerging adulthood, associations of co-use trajectories with four domains of functioning, and differences across racial/ethnic groups.
Survey data come from a racially/ethnically diverse and predominantly California-based cohort that completed 10 surveys from 2008 (wave 1: mean age 11.5; n = 6,509) to 2018 (wave 10: mean age 20.7; n = 2,429). Co-use was defined as use of both cannabis and tobacco (cigarettes or smokeless tobacco) in the past 30 days. Trajectories of use were examined using latent growth modeling in a structural equation modeling framework.
Prevalence of cannabis and tobacco co-use increased from 0.3% at wave 1 to 9.5% at wave 10, with average probabilities of co-use higher among non-Hispanic white versus Hispanic or Asian participants. Higher average probability of co-use was associated with greater delinquency, more mental health symptoms, and poorer physical health during emerging adulthood. Higher rate of change in the probability of co-use over time was associated with greater delinquency, but better social functioning and less physical ailments. There was some evidence of racial/ethnic disparities in functioning, even at similar levels of co-use.
Cannabis and tobacco co-use deserves greater attention, especially regarding its effects on functioning during emerging adulthood. Results also emphasize the need for future research to focus on racial/ethnic disparities related to co-use and associated outcomes.
A pyrochlore‐rich multiphase ceramic waste form was prepared by the alkoxide‐route and consolidated by sintering in air. Cerium (Ce) was used as a surrogate for plutonium (Pu), which was found in ...both the major pyrochlore and minor perovskite phases, but not the minor rutile phase. A synchrotron‐based fluorescence X‐ray absorption near‐edge spectroscopy (XANES) imaging technique was employed to determine the Ce oxidation state in each of the two Ce‐containing phases. It was shown that the major pyrochlore phase contains only tetravalent Ce, whereas the minor perovskite phase incorporates exclusively trivalent Ce. The effect of sintering atmosphere was also investigated, which revealed a very different phase assemblage when sintered in argon (Ar). A major perovskite phase was produced under Ar with a minor zirconolite‐4M phase, both containing trivalent Ce. The composition of the minor rutile phase remained the same whether it was sintered in air or Ar. The results demonstrate the importance of controlling the oxidation state of multivalent waste ions in the design of ceramic waste forms.
Adolescents and young adults in the United States are constantly exposed to substance-related media and advertising content. The current study seeks to explore, developmentally, how exposure to ...substance-related media content influences both normative beliefs about peer alcohol use and individual alcohol use. Youth (
N
= 4‚840; 50.6% female) were followed for ten years from age 12 to 22. Auto-regressive latent trajectory with structured residual (ALT-SR) models were used to explore within-person reciprocal associations between substance-related media content, descriptive norms, and alcohol use. Results indicated that‚ across adolescence and young adulthood, exposure to substance-related media content was associated with increased alcohol use via perceived alcohol norms. The pathway from media exposure to alcohol use was mediated by increased perceived norms for adolescents only. With screen time increasing over the last decade, it is important to invest resources into real-time interventions that address substance-related social media content as it relates to misperceived norms and to begin these interventions in early adolescence.
B-cell non-Hodgkin lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL, such as diffuse ...large B-cell lymphoma, have been comprehensively interrogated at the genomic level, but rarer subtypes, such as mantle cell lymphoma, remain less extensively characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared using the same methodology to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genomic landscapes of 685 B-NHL tumors at high depth, including diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, and Burkitt lymphoma. We identified conserved hallmarks of B-NHL that were deregulated in the majority of tumors from each subtype, including frequent genetic deregulation of the ubiquitin proteasome system. In addition, we identified subtype-specific patterns of genetic alterations, including clusters of co-occurring mutations and DNA copy number alterations. The cumulative burden of mutations within a single cluster were more discriminatory of B-NHL subtypes than individual mutations, implicating likely patterns of genetic cooperation that contribute to disease etiology. We therefore provide the first cross-sectional analysis of mutations and DNA copy number alterations across major B-NHL subtypes and a framework of co-occurring genetic alterations that deregulate genetic hallmarks and likely cooperate in lymphomagenesis.
Poly-victimization is common among youth experiencing homelessness (YEH) and youth in substance use treatment. To date, studies have not examined poly-victimization among these two intersecting ...populations.
To examine heterogeneity in lifetime victimization experiences among youth reporting homelessness at substance use treatment entry; identify demographic predictors of victimization class membership; and associations between victimization and clinical characteristics at treatment intake.
1270 adolescents and young adults reporting past 90-day homelessness in a nationwide substance use treatment data set.
Latent Class Analysis (LCA) and logistic regression were used to examine heterogeneity in poly-victimization experiences, and associations with demographics and clinical characteristics for males and females.
Four victimization classes emerged for males, and five victimization classes emerged for females. The prevalence of victimization and trauma characteristics were higher for females, except physical victimization, which was higher for males. Age, race/ethnicity, and sexual minority status were related to poly-victimization class membership, but not consistently across classes. Compared to low or single victimization classes, youth in the poly-victimization class had higher odds of post-traumatic stress disorder, major depressive disorder, and exchange sex (among females); Poly-victimization class membership was not associated with duration of recent homelessness or substance use disorder diagnoses, when compared to low/less complex victimization.
High rates of lifetime victimization were found for YEH in substance use treatment, with rates generally higher among females. Trauma-informed interventions are needed to address complex victimization experiences and poor mental health among unstably housed youth in treatment.
•Four victimization classes were identified for males, and five for females.•Prevalence of victimization types was generally higher for females.•Poly-victimization was related to mental health diagnoses at treatment intake.•Poly-victimization was not consistently related to substance use disorder diagnoses.
Environmental DNA (eDNA) is an emerging approach for detecting species, yet numerous methodological questions remain unanswered. Here we examined how time to filtration (0–48 h after collection) and ...sample storage (open vs. chilled in the dark) influenced detection and measured eDNA concentration. Water samples kept in the dark and chilled had no significant decrease in detection or eDNA concentration relative to those filtered immediately upon return from the field. Water samples exposed to light and ambient air temperature had non-detections beginning at 1 h, the majority of these samples were below the limit of detection (LOD) by 6 h, and eDNA was undetectable in these samples by 24 h. These results have important implications for eDNA research where immediate access to refrigeration is not available, or for fieldwork that requires extended sampling time (e.g., canoeing a river). Further, we report faster eDNA degradation times under ambient conditions than some previous aquaria or mesocosm studies, suggesting an ongoing need to study mechanisms related to eDNA persistence and sample storage.
Hybridisation can be an important driver of evolutionary change, but hybridisation with invasive species can have adverse effects on native biodiversity. While hybridisation has been documented ...across taxa, there is limited understanding of ecological factors promoting patterns of hybridisation and the spatial distribution of hybrid individuals. We combined the results of ecological niche modelling (ENM) and restriction site‐associated DNA sequencing to test theories of niche conservatism and biotic resistance on the success of invasion, admixture, and extent of introgression between native and non‐native fishes. We related Maxent predictions of habitat suitability based on the native ranges of invasive Eastern Banded Killifish (Fundulus diaphanus diaphanus Lesueur 1817) and native Western Banded Killifish (Fundulus diaphanus menona Jordan and Copeland 1877) to admixture indices of individual Banded Killifish. We found that Eastern Banded Killifish predominated at sites predicted as suitable from their ENM, consistent with niche conservatism. Admixed individuals were more common as Eastern Banded Killifish habitat suitability declined. We also found that Eastern Banded Killifish were most common at sites closest to the presumed source of this invasion, whereas the proportion of admixed individuals increased with distance from the source of invasion. Lastly, we found little evidence that habitat suitability for Western Banded Killifish provides biotic resistance from either displacement by, or admixture with, invasive Eastern Banded Killifish. Our study demonstrates that ENMs can inform conservation‐relevant outcomes between native and invasive taxa while emphasising the importance of protecting isolated Western Banded Killifish populations from invasive conspecifics.
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