Proteasome inhibition with bortezomib is a validated approach to the treatment of multiple myeloma, but drug resistance often emerges and limits its utility in the retreatment setting. To begin to ...identify some of the mechanisms involved, we developed bortezomib-resistant myeloma cell lines that, unlike previously reported models, showed no β5 subunit mutations. Instead, up-regulation of the insulin-like growth factor (IGF)–1 axis was identified, with increased autocrine and paracrine secretion of IGF-1, leading to increased activation of the IGF-1 receptor (IGF-1R). Exogenous IGF-1 reduced cellular sensitivity to bortezomib, whereas pharmacologic or small hairpin RNA–mediated IGF-1R suppression enhanced bortezomib sensitivity in cell lines and patient samples. In vitro studies with OSI-906, a clinically relevant dual IGF-1R and insulin receptor inhibitor, showed it acted synergistically with bortezomib, and potently resensitized bortezomib-resistant cell lines and patient samples to bor-tezomib. Importantly, OSI-906 in combination with bortezomib also overcame bor-tezomib resistance in an in vivo model of myeloma. Taken together, these data support the hypothesis that signaling through the IGF-1/IGF-1R axis contributes to acquired bortezomib resistance, and provide a rationale for combining bortezomib with IGF-1R inhibitors like OSI-906 to overcome or possibly prevent the emergence of bortezomib-refractory disease in the clinic.
Objective: Pregaming is among the riskiest drinking behaviors in which college students engage, often leading to elevated blood alcohol levels and negative alcohol-related consequences. Yet, tailored ...interventions to reduce risk associated with pregaming are lacking. The present study was designed to develop and evaluate the efficacy of a brief, mobile-based intervention targeting heavy drinking during pregaming among college students, called Pregaming Awareness in College Environments (PACE). Method: PACE was developed using two innovations to facilitate behavior change: (a) a mobile-based application to increase intervention accessibility and (b) personalized pregaming-specific intervention content delivered using a harm reduction approach with cognitive behavioral skills training. After development and β-testing, we employed a randomized clinical trial with 485 college students who reported pregaming at least once per week in the past month (Mage = 19.98; 52.2% from minoritized racial and/or ethnic groups; 65.6% female). Participants were randomly assigned to PACE (n = 242) or a control condition website (n = 243), which consisted of general information about the effects of alcohol. Analysis assessed intervention effects on pregaming drinking, global drinking, and alcohol-related consequences at 6 and 14 weeks postintervention. Results: Although participants in both conditions reduced drinking, small and significant intervention effects favoring PACE were found at 6-week follow-up for overall drinking days, pregaming days, and alcohol-related consequences. Conclusions: Findings suggest the brief mobile PACE intervention has potential to address risky drinking, but more intensive pregaming-focused efforts may be necessary to achieve stronger and lasting effects among college students.
Public Health Significance Statement
Heavy drinking by college students cuts across multiple contexts, but one particularly risky one is pregaming, where large amounts of alcohol are consumed quickly often to get intoxicated prior to leaving for an intended destination, such as a bar, party, concert, sporting event, or date. Few interventions have attempted to directly address this ubiquitous behavior, which often leads to consequences for students both on the night of pregaming and in the long term. Changing pregaming drinking may help reduce drinking and lead to broader changes in drinking practices and reductions in alcohol-related harm for college students and other young adult groups.
Targeting B-cell receptor (BCR) signaling is a successful therapeutic strategy in mature B-cell malignancies. Precursor BCR (pre-BCR) signaling, which is critical during normal B lymphopoiesis, also ...plays an important role in pre-BCR+ B cell acute lymphoblastic leukemia (B-ALL). Here, we investigated the activity and mechanism of action of the BTK inhibitor ibrutinib in preclinical models of B-ALL. Pre-BCR+ ALL cells were exquisitely sensitive to ibrutinib at therapeutically relevant drug concentrations. In pre-BCR+ ALL, ibrutinib thwarted autonomous and induced pre-BCR signaling, resulting in deactivation of PI3K/Akt signaling. Ibrutinib modulated the expression of pre-BCR regulators (PTPN6, CD22, CD72, and PKCβ) and substantially reduced BCL6 levels. Ibrutinib inhibited ALL cell migration toward CXCL12 and beneath marrow stromal cells and reduced CD44 expression. CRISPR-Cas9 gene editing revealed that both BTK and B lymphocyte kinase (BLK) are relevant targets of ibrutinib in pre-BCR+ ALL. Consequently, in mouse xenograft models of pre-BCR+ ALL, ibrutinib treatment significantly prolonged survival. Combination treatment of ibrutinib with dexamethasone or vincristine demonstrated synergistic activity against pre-BCR+ ALL. These data corroborate ibrutinib as a promising targeted agent for pre-BCR+ ALL and highlight the importance of ibrutinib effects on alternative kinase targets.
•In B-ALL, cells that express a functional pre-BCR ibrutinib abrogate leukemia cell growth in vitro and in vivo.•Effects of ibrutinib in B-ALL not only are mediated through inhibition of BTK but also involve BLK inhibition.
In January 2018, the Center for Medicare and Medicaid Services (CMS) removed total knee arthroplasty (TKA) from the inpatient-only list. This impacted hospital reimbursement, Comprehensive Joint ...Replacement (CJR) bundle volumes, and bundle performance. We describe these impacts at an academic teaching hospital.
We reviewed CJR bundle data provided by CMS and internal databases to identify the shift in CJR TKA episode volume since January 2018, the impact on postacute care (PAC) utilization rates and readmissions, financial impact to the bundle, and impact on hospital reimbursement. We used data provided to CJR participants, internal hospital sources, and the Medicare Limited Data Set.
Between 2017 and 2018, CJR TKA episodes decreased from 91 to 51 (44% reduction). Inpatient PAC utilization was significantly higher in 2018 (20% vs 8%). The 90-day readmission rates increased from 5.5% to 12.7%. Average variance to target dropped from 15% to 5%. Average CMS reimbursement for TKA at our institution in 2019 was $14,823 for inpatients and $9299 for outpatients. We experienced $930,463 in decreased reimbursement from January 2018 to September 2019 as a result of the shift from inpatient to outpatient. In addition, we expect $625,143 in decreased incentive payments as higher functioning and lower cost outpatient TKAs are excluded from CJR.
Although CMS projected a minimal impact on CJR bundle participants, this has not been the case at our institution. We experienced reduced volumes, increased PAC utilization, and a substantial financial impact. We expect a similar outcome when CMS removes total hip arthroplasty from the inpatient-only list.
Gene-expression profiling has been used to define 3 molecular subtypes of diffuse large B-cell lymphoma (DLBCL), termed germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, and ...primary mediastinal B-cell lymphoma (PMBL). To investigate whether these DLBCL subtypes arise by distinct pathogenetic mechanisms, we analyzed 203 DLBCL biopsy samples by high-resolution, genome-wide copy number analysis coupled with gene-expression profiling. Of 272 recurrent chromosomal aberrations that were associated with gene-expression alterations, 30 were used differentially by the DLBCL subtypes (P < 0.006). An amplicon on chromosome 19 was detected in 26% of ABC DLBCLs but in only 3% of GCB DLBCLs and PMBLs. A highly up-regulated gene in this amplicon was SPIB, which encodes an ETS family transcription factor. Knockdown of SPIB by RNA interference was toxic to ABC DLBCL cell lines but not to GCB DLBCL, PMBL, or myeloma cell lines, strongly implicating SPIB as an oncogene involved in the pathogenesis of ABC DLBCL. Deletion of the INK4a/ARF tumor suppressor locus and trisomy 3 also occurred almost exclusively in ABC DLBCLs and was associated with inferior outcome within this subtype. FOXP1 emerged as a potential oncogene in ABC DLBCL that was up-regulated by trisomy 3 and by more focal high-level amplifications. In GCB DLBCL, amplification of the oncogenic mir-17-92 microRNA cluster and deletion of the tumor suppressor PTEN were recurrent, but these events did not occur in ABC DLBCL. Together, these data provide genetic evidence that the DLBCL subtypes are distinct diseases that use different oncogenic pathways.
Background and Objectives
Behavioral health issues, such as substance use, depression, and social isolation, are of grave concern during COVID‐19, especially for vulnerable populations. One such ...population is US veterans, who have high rates of pre‐existing behavioral health conditions and may thus be at‐risk for poorer outcomes. The current study aimed to investigate substance use among US veterans during COVID‐19 as a function of pre‐existing depression, loneliness, and social support.
Methods
We investigated the relationship between pre‐pandemic depression and substance use during COVID‐19 using linear (alcohol) and logistic (cannabis) regression among a large sample of US veterans (N = 1230). We then tested if loneliness and social support moderated these effects.
Results
Though there was a decrease in alcohol and cannabis use among the overall sample, veterans who screened for depression prior to the pandemic exhibited higher levels of substance use after the pandemic's onset. Loneliness compounded the effects of depression on rates of alcohol use. Social support was not protective for the effects of depression on either alcohol or cannabis use.
Discussion and Conclusions
Veterans with pre‐existing depression may be in need of attention for substance use behaviors. Interventions aimed at alleviating loneliness among veterans may be useful in mitigating alcohol use, but not cannabis use, amid COVID‐19.
Scientific Significance
Our findings are among the first to report tangible behavioral health outcomes experienced by US veterans as a result of COVID‐19. Results can help inform treatment efforts for veterans who are struggling with substance use during and post‐pandemic.
A role for B-cell-receptor (BCR) signalling in lymphomagenesis has been inferred by studying immunoglobulin genes in human lymphomas and by engineering mouse models, but genetic and functional ...evidence for its oncogenic role in human lymphomas is needed. Here we describe a form of 'chronic active' BCR signalling that is required for cell survival in the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). The signalling adaptor CARD11 is required for constitutive NF- B pathway activity and survival in ABC DLBCL. Roughly 10% of ABC DLBCLs have mutant CARD11 isoforms that activate NF- B, but the mechanism that engages wild-type CARD11 in other ABC DLBCLs was unknown. An RNA interference genetic screen revealed that a BCR signalling component, Bruton's tyrosine kinase, is essential for the survival of ABC DLBCLs with wild-type CARD11. In addition, knockdown of proximal BCR subunits (IgM, Ig- , CD79A and CD79B) killed ABC DLBCLs with wild-type CARD11 but not other lymphomas. The BCRs in these ABC DLBCLs formed prominent clusters in the plasma membrane with low diffusion, similarly to BCRs in antigen-stimulated normal B cells. Somatic mutations affecting the immunoreceptor tyrosine-based activation motif (ITAM) signalling modules of CD79B and CD79A were detected frequently in ABC DLBCL biopsy samples but rarely in other DLBCLs and never in Burkitt's lymphoma or mucosa-associated lymphoid tissue lymphoma. In 18% of ABC DLBCLs, one functionally critical residue of CD79B, the first ITAM tyrosine, was mutated. These mutations increased surface BCR expression and attenuated Lyn kinase, a feedback inhibitor of BCR signalling. These findings establish chronic active BCR signalling as a new pathogenetic mechanism in ABC DLBCL, suggesting several therapeutic strategies.
To examine prospective, bidirectional associations between homelessness and substance use frequency among young adults receiving substance use treatment in the United States. We also investigated ...potential differences across demographic subgroups.
Young adults (
= 3717,
age = 20.1, 28% female, 7.3% sexual/gender minority, and 37% non-Hispanic White) receiving substance use treatment in the U.S. completed assessments at intake, 3 months, 6 months, and 12 months post-intake. Latent growth curve models with structured residuals (LGC-SR) were used to examine cross-lagged associations between homeless days and frequency of substance use and associated problems. Models were stratified by sex, race/ethnicity, and sexual and/or gender minority status.
Overall, days spent homeless (
-0.19,
= 0.046) and substance use frequency (
-6.19,
< 0.001) significantly decreased during treatment, with no significant cross-lagged associations between homeless days and substance use frequency. However, results differed by race and ethnicity. For non-Hispanic White young adults, greater substance use at treatment entry was associated with steeper declines in homeless days between-persons (
= -0.14,
= 0.04). For African Americans, homeless days at treatment entry were associated with greater increases in substance use between-persons (
= 0.29,
= 0.04). No significant differences were found by sex or sexual/gender minority status.
Despite overall declines in homelessness and substance use during treatment, these outcomes may unfold differently for non-Hispanic White and African American young adults. More support may be needed for African American young adults reporting homelessness at treatment entry.
Abstract Background It is unclear whether a positive skin patch test for metal allergy in patients with skin hypersensitivity to metals is associated with an increased risk of total knee arthroplasty ...(TKA) failure. Our aim was to determine whether patients with a history of metal allergy who had a positive skin patch test (SPT+) had worse outcomes after primary TKA compared with those with a negative skin patch test and compared with controls. Methods Over 12 years, 127 patients underwent 161 TKA after skin patch testing (SPT; 56 were positive). Cases were matched by age, gender, body mass index, American Society of Anesthesiologists score, implant type, and implant manufacturer to 161 control knee arthroplasties without any prior history of metal allergy and no SPT. Median follow-up was 5.3 years. Differences in outcome measures were assessed between groups. Results Patients with a SPT+ to metal did not have a higher complication, reoperation, or revision rates compared with patients with a SPT− and matched controls. Survivorship free of revision at 5 years was 98.1% for SPT+; 100% for SPT−; 97.6% for SPT+ controls, 99.0% for SPT− controls. There was no statistically significant difference in postoperative pain between SPT+ and SPT− patients and matched controls. Conclusion This study was designed to evaluate the effect of metal hypersensitivity on TKA outcomes and the role of SPT in patients before TKA. In this study, a SPT+ for metals was of little practical value in predicting the midterm outcome after TKA and cannot be strongly recommended as a method to guide the selection of implant type.
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