Randomized Bendamustine-Rituximab(R) + Bortezomib Induction and R + Lenalidomide Maintenance for Mantle Cell Lymphoma.

While initial therapy of mantle cell lymphoma (MCL) is not standardized, bendamustine-rituximab (BR) is commonly used in older patients. Rituximab (R) maintenance following induction is often utilized. Thus, the open-label, randomized phase II ECOG-ACRIN Cancer Research Group E1411 trial was designed to test two questions: 1) Does addition of bortezomib to BR induction (BVR) and/or 2) addition of lenalidomide to rituximab (LR) maintenance improve progression-free survival (PFS) in patients with treatment-naïve MCL? From 2012-2016, 373 previously untreated patients, 87% ≥ 60 years old, were enrolled in this trial. At a median follow up of 7.5 years, there is no difference in the median PFS of BR compared to BVR (5.5 yrs vs. 6.4 yrs, HR 0.90, 90% CI 0.70, 1.16). There were no unexpected additional toxicities with BVR treatment compared to BR, with no impact on total dose/duration of treatment received. Independent of the induction treatment, addition of lenalidomide to rituximab did not significantly improve PFS, with median PFS in R vs LR (5.9 yrs vs 7.2 yrs, HR 0.84 90% CI 0.62, 1.15). The majority of patients completed the planned 24 cycles of LR at the scheduled dose. In summary, adding bortezomib to BR induction does not prolong PFS in treatment-naïve MCL, and LR maintenance was not associated with longer PFS compared with rituximab alone following BR. Nonetheless, the > 5 year median PFS outcomes in this prospective cooperative group trial indicate the efficacy of BR followed by rituximab maintenance as highly effective initial therapy for older MCL patients. (NCT01415752).

Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial.

BACKGROUND: Erlotinib is approved for the treatment of all patients with advanced non-small-cell lung cancer (NSCLC), but is most active in the treatment of EGFR mutant NSCLC. Cabozantinib, a small molecule tyrosine kinase inhibitor, targets MET, VEGFR, RET, ROS1, and AXL, which are implicated in lung cancer tumorigenesis. We compared the efficacy of cabozantinib alone or in combination with erlotinib versus erlotinib alone in patients with EGFR wild-type NSCLC. METHODS: This three group, randomised, controlled, open-label, multicentre, phase 2 trial was done in 37 academic and community oncology practices in the USA. Patients were eligible if they had received one or two previous treatments for advanced non-squamous, EGFR wild-type, NSCLC. Patients were stratified by performance status and line of therapy, and randomly assigned using permuted blocks within strata to receive open-label oral daily dosing of erlotinib (150 mg), cabozantinib (60 mg), or erlotinib (150 mg) and cabozantinib (40 mg). Imaging was done every 8 weeks. At the time of radiographic progression, there was optional crossover for patients in either single-drug group to receive combination treatment. The primary endpoint was to compare progression-free survival in patients given erlotinib alone versus cabozantinib alone, and in patients given erlotinib alone versus the combination of erlotinib plus cabozantinib. We assessed the primary endpoint in the per-protocol population, which was defined as all patients who were eligible, randomly assigned, and received at least one dose of treatment. The safety analysis population included all patients who received study treatment irrespective of eligibility. This trial is registered with ClinicalTrials.gov, number NCT01708954. FINDINGS: Between Feb 7, 2013, and July 1, 2014, we enrolled and randomly assigned 42 patients to erlotinib treatment, 40 patients to cabozantinib treatment, and 43 patients to erlotinib plus cabozantinib treatment, of whom 111 (89%) in total were included in the primary analysis (erlotinib [n=38], cabozantinib [n=38], erlotinib plus cabozantinib [n=35]). Compared with erlotinib alone (median 1·8 months [95% CI 1·7-2·2]), progression-free survival was significantly improved in the cabozantinib group (4·3 months [3·6-7·4]; hazard ratio [HR] 0·39, 80% CI 0·27-0·55; one-sided p=0·0003) and in the erlotinib plus cabozantinib group (4·7 months [2·4-7·4]; HR 0·37, 0·25-0·53; one-sided p=0·0003). Among participants included in the safety analysis of the erlotinib (n=40), cabozantinib (n=40), and erlotinib plus cabozantinib (n=39) groups, the most common grade 3 or 4 adverse events were diarrhoea (three [8%] cases in the erlotinib group vs three [8%] in the cabozantinib group vs 11 [28%] in the erlotinib plus cabozantinib group), hypertension (none vs ten [25%] vs one [3%]), fatigue (five [13%] vs six [15%] vs six [15%]), oral mucositis (none vs four [10%] vs one [3%]), and thromboembolic event (none vs three [8%] vs two [5%]). One death due to respiratory failure occurred in the cabozantinib group, deemed possibly related to either drug, and one death due to pneumonitis occurred in the erlotinib plus cabozantinib group, deemed related to either drug or the combination. INTERPRETATION: Despite its small sample size, this trial showed that, in patients with EGFR wild-type NSCLC, cabozantinib alone or combined with erlotinib has clinically meaningful, superior efficacy to that of erlotinib alone, with additional toxicity that was generally manageable. Cabozantinib-based regimens are promising for further investigation in this patient population. FUNDING: ECOG-ACRIN Cancer Research Group, National Cancer Institute of the National Institutes of Health.

Randomized, blinded trial of vitamin D3 for treating aromatase inhibitor-associated musculoskeletal symptoms (AIMSS).

The purpose of the study was to evaluate the efficacy and safety of vitamin D3 at 4000 IU/day as a treatment option for aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) when compared with the usual care dose of 600 IU D3. We conducted a single site randomized, double-blind, phase 3 clinical trial in women with AIMSS comparing change in symptoms, reproductive hormones and AI pharmacokinetics. Postmenopausal women ≥18 years with stages I-IIIA breast cancer, taking AI and experiencing AIMSS [breast cancer prevention trial symptom scale-musculoskeletal (BCPT-MS) subscale ≥1.5] were admitted. Following randomization, 116 patients had a run-in period of 1 month on 600 IU D3, then began the randomized assignment to either 600 IU D3 (n = 56) or 4000 IU D3 (n = 57) daily for 6 months. The primary endpoint was a change in AIMSS from baseline (after 1 month run-in) on the BCPT-MS (general MS pain, joint pain, muscle stiffness, range for each question: 0 = not at all to 4 = extremely). Groups had no statistically significant differences demographically or clinically. There were no discernable differences between the randomly allocated treatment groups at 6 months in measures of AIMSS, pharmacokinetics of anastrozole and letrozole, serum levels of reproductive hormones, or adverse events. We found no significant changes in AIMSS measures between women who took 4000 IU D3 daily compared with 600 IU D3. The 4000 IU D3 did not adversely affect reproductive hormone levels or the steady state pharmacokinetics of anastrozole or letrozole. In both groups, serum 25(OH)D remained in the recommended range for bone health (≥30 ng/mL) and safety (<50 ng/mL).

Structural and biochemical studies of SLIP1-SLBP identify DBP5 and eIF3g as SLIP1-binding proteins.

In metazoans, replication-dependent histone mRNAs end in a stem-loop structure instead of the poly(A) tail characteristic of all other mature mRNAs. This specialized 3' end is bound by stem-loop binding protein (SLBP), a protein that participates in the nuclear export and translation of histone mRNAs. The translational activity of SLBP is mediated by interaction with SLIP1, a middle domain of initiation factor 4G (MIF4G)-like protein that connects to translation initiation. We determined the 2.5 Å resolution crystal structure of zebrafish SLIP1 bound to the translation-activation domain of SLBP and identified the determinants of the recognition. We discovered a SLIP1-binding motif (SBM) in two additional proteins: the translation initiation factor eIF3g and the mRNA-export factor DBP5. We confirmed the binding of SLIP1 to DBP5 and eIF3g by pull-down assays and determined the 3.25 Å resolution structure of SLIP1 bound to the DBP5 SBM. The SBM-binding and homodimerization residues of SLIP1 are conserved in the MIF4G domain of CBP80/20-dependent translation initiation factor (CTIF). The results suggest how the SLIP1 homodimer or a SLIP1-CTIF heterodimer can function as platforms to bridge SLBP with SBM-containing proteins involved in different steps of mRNA metabolism.

Development of the research lifecycle model for library services.

QUESTION: Can the niche services of individual librarians across multiple libraries be developed into a suite of standard services available to all scientists that support the entire research lifecycle? SETTING: Services at a large, research-intensive state university campus are described. METHOD: Initial data were collected via concept mapping by librarians. Additional data were collected at conferences and meetings through interactive poster presentations. MAIN RESULTS: Services of interest to scientists for each of the stages in the research lifecycle were developed by the team to reflect the wide range of strengths of team members in aggregate. CONCLUSION: Input from researchers was the most effective tool for developing the model. A flexible research lifecycle model can be developed to match the needs of different service groups and the skills of different librarians.

A preliminary analysis of library holdings as compared to the basic resources for pharmacy education list.

The catalogs of 11 university libraries were analyzed against the Basic Resources for Pharmaceutical Education (BRPE) to measure the percent coverage of the core total list as well as the core sublist. There is no clear trend in this data to link school age, size, or rank with percentage of coverage of the total list or the "First Purchase" core list when treated as independent variables. Approximately half of the schools have significantly higher percentages of core titles than statistically expected. Based on this data, it is difficult to predict what percentage of titles on the BRPE a library will contain.

Disentangling acceptance: Direct and indirect effects of partner acceptance on felt acceptance and relationship satisfaction.

Acceptance in intimate relationships predicts relationship satisfaction, as well as positive treatment outcomes in some couple interventions. However, little research has attempted to disentangle the dyadic effects of husbands' and wives' partner acceptance (i.e., acceptance of one's partner) and felt acceptance (i.e., felt sense of being accepted by one's partner) on relationship satisfaction. This study utilized a modified actor-partner interdependence mediation model (APIMeM) to examine whether the associations between acceptance of one's partner and each partner's relationship satisfaction are mediated by each partner's felt acceptance. We analyzed baseline self-report data from 209 heterosexual married couples who participated in a brief marital intervention in the United States. The final model supported the prediction that a person's acceptance of their partner would relate to their partner's relationship satisfaction through their partner's felt acceptance (i.e., an "accuracy effect") and to their own relationship satisfaction through their own felt acceptance (i.e., a "projection effect"). In all, the study demonstrates the utility of examining partner acceptance and felt acceptance as distinct, but related, constructs. Researchers and clinicians working with couples may consider conceptualizing, assessing, and even targeting partners and felt acceptance separately. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Associations between mother-infant bed-sharing practices and infant affect and behavior during the still-face paradigm.

Parents in the United States increasingly report bed-sharing with their infants (i.e., sleeping on a shared sleep surface), but the relationship between bed-sharing and child socioemotional outcomes are not well understood. The current study examines the links between mother-infant bed-sharing at 3 months and infant affect and behavior during a dyadic challenge task at 6 months. Further, we examine nighttime mother-infant contact at 3 months as a possible mechanism that may mediate linkages between bed-sharing and infant outcomes. Using observational data from a sample of 63 mother-infant dyads, we found that infants who bed-shared for any proportion of the observation period at 3 months displayed significantly more self-regulatory behaviors during the still-face episode of the Still-Face Paradigm (SFP) at 6 months, compared to non-bed-sharing infants. Also, infants of mothers who bed-shared for the entire observation period displayed significantly less negativity during the reunion episode than non-bed-sharing infants. There was no evidence that the relations between mother-infant bed-sharing practices and infant affect and behavior during the SFP were mediated through nighttime mother-infant contact. Results suggest that infant regulation at 6 months postpartum may vary based on early nighttime experiences, with bed-sharing potentially promoting more positive and well-regulated behavior during dyadic interaction.

Analysis of mRNA partitioning between the cytosol and endoplasmic reticulum compartments of mammalian cells.

All eukaryotic cells display a dramatic partitioning of mRNAs between the cytosol and endoplasmic reticulum (ER) compartments-mRNAs encoding secretory and integral membrane proteins are highly enriched on ER-bound ribosomes and mRNAs encoding cytoplasmic/nucleoplasmic proteins are enriched on cytosolic ribosomes. In current views, this partitioning phenomenon occurs through positive selection-mRNAs encoding signal sequence-bearing proteins are directed into the signal recognition particle pathway early in translation and trafficked as mRNA/ribosome/nascent polypeptide chain complexes to the ER. In the absence of an encoded signal sequence, mRNAs undergo continued translation on cytosolic ribosomes. Recent genome-wide analyses of mRNA partitioning between the cytosol and the ER compartments have identified subsets of mRNAs that are non-canonically partitioned to the ER-although lacking an encoded signal sequence, they are translated on ER-bound ribosomes. These findings suggest that multiple, and as yet unidentified, pathways exist for directing mRNA partitioning in the cell. In this contribution, we briefly review the literature describing the subcellular partitioning patterns of mRNAs and present a detailed methodology for studying this fundamental, yet poorly understood process.

Providing Breast Cancer Survivorship: Lessons Learned From a Pilot Project Implementation.

BACKGROUND: Many cancer survivors have gaps in knowledge of their disease and treatments received. OBJECTIVE: The goal of this project was to evaluate the development and implementation of a pilot breast cancer survivorship program aimed at decreasing the gap in patient knowledge of disease and treatment, from both the staff and patient perspectives. METHODS: A mixed methods approach used data from multiple sources: (1) historical data, (2) medical record review, (3) a mailed patient questionnaire, (4) 1:1 semistructured telephone interviews with patients, and (5) 1:1 semistructured interviews with staff members. RESULTS: The implementation of the pilot survivorship program resulted in increased patient knowledge of disease and treatments received. The majority of breast cancer survivors (80%) reported that the survivorship packet given at the end of treatment met most or all of their needs, and half reported that they did not feel they needed a 1:1 survivorship visit. The 20 staff interviews validated that most staff (80%) were able to accurately define cancer survivorship and aspects of providing survivorship care; however, 50% reported that they felt they needed more training. CONCLUSIONS: The pilot program was successful in increasing patient knowledge. Informal education and written material provided throughout the course of cancer care were found to meet most patient needs. Cancer center staff desire more training on providing survivorship care. IMPLICATIONS FOR PRACTICE: Survivorship care may be best provided through educational interventions began at diagnosis and provided on an ongoing basis.

SLIP1, a factor required for activation of histone mRNA translation by the stem-loop binding protein.

Replication-dependent histone mRNAs are the only eukaryotic cellular mRNAs that are not polyadenylated, ending instead in a conserved stem-loop. The 3' end of histone mRNA is required for histone mRNA translation, as is the stem-loop binding protein (SLBP), which binds the 3' end of histone mRNA. We have identified five conserved residues in a 15-amino-acid region in the amino-terminal portion of SLBP, each of which is required for translation. Using a yeast two-hybrid screen, we identified a novel protein, SLBP-interacting protein 1 (SLIP1), that specifically interacts with this region. Mutations in any of the residues required for translation reduces SLIP1 binding to SLBP. The expression of SLIP1 in Xenopus oocytes together with human SLBP stimulates translation of a reporter mRNA ending in the stem-loop but not a reporter with a poly(A) tail. The expression of SLIP1 in HeLa cells also stimulates the expression of a green fluorescent protein reporter mRNA ending in a stem-loop. RNA interference-mediated downregulation of endogenous SLIP1 reduces the rate of translation of endogenous histone mRNA and also reduces cell viability. SLIP1 may function by bridging the 3' end of the histone mRNA with the 5' end of the mRNA, similar to the mechanism of translation of polyadenylated mRNAs.

The International Prognostic Index assessed at relapse predicts outcomes of autologous transplantation for diffuse large-cell non-Hodgkin's lymphoma in second complete or partial remission.

Autologous hematopoietic stem cell transplantation (auto HSCT) has become the standard treatment for patients with relapsed diffuse large-cell non-Hodgkin's lymphoma (NHL) responding to conventional salvage chemotherapy. Nevertheless, more than half of these patients will relapse following auto HSCT and die. This study was undertaken to determine whether the International Prognostic Index (IPI) assessed at time of relapse (IPI-R) could be used to identify patients with greater probability for long-term survival following auto HSCT. Eighty patients, median age 47 years (range 19-68 years), with diffuse large cell lymphoma in either second complete remission (CR 2, n = 27) or partial remission (PR 2, n = 53) were treated between 1984 and 2002 with auto HSCT. Clinical features predictive of overall survival (OS) and progression-free survival (PFS) were analyzed. Post-auto HSCT, CR was achieved in 73 patients (91%). With a median follow-up of 5 years (range 1.0-14.2 years), OS and PFS at 5 years were 38% (95% confidence interval [CI] 27%-50%) and 32% (95% CI 22%-42%), respectively. Two risk groups with significantly different OS and PFS were identified by the IPI-R. The high-risk group (3, 4, or 5 IPI factors) had 2.0 times (95% CI 1.1-4.0, P = .03) the risk of death and 2.2 times (95% CI 1.2-4.0, P = .01) the risk of relapse as the low-risk group (0, 1, or 2 IPI factors). The median OS was 5 months versus 27 months and the median PFS was 2 months versus 8 months for the high- and low-risk IPI-R groups, respectively. In Cox regression analysis, high-risk IPI-R status (relative risk [RR] 2.4, 95% CI 1.2-4.8, P = .02) and bone marrow (BM) involvement at diagnosis (RR 2.9, 95% CI 1.3-6.4, P = .01) were independent predictors for poor OS. Similarly, high-risk IPI-R status (RR 2.5, 95% CI 1.3-4.7, P = .01) and BM involvement at diagnosis (RR 3.9, 95% CI 1.7-8.7, P = .001) were independent predictors for poor PFS. These results suggest that the IPI-R predicts OS and PFS following auto HSCT for patients with aggressive NHL in CR 2 or PR 2. Patients with high-risk IPI-R should be considered for novel therapeutic approaches.

mRNA translation is compartmentalized to the endoplasmic reticulum following physiological inhibition of cap-dependent translation.

Eukaryotic cells utilize a cycle of ribosome trafficking on the endoplasmic reticulum (ER) to partition mRNAs between the cytosol and ER compartments. In this process, ribosomes engaged in the synthesis of signal sequence-bearing proteins are trafficked to the endoplasmic reticulum via the signal-recognition particle pathway and are released from the ER upon translation termination. Though the processes governing ribosome trafficking to the ER are well understood, little is known regarding the complementary ribosome release process. In this study, Coxsackie B virus (CBV) infection was used to inactivate the initiation stage of protein synthesis, thereby limiting translation to the elongation and termination stages. Ribosome partitioning between the cytosol and ER compartments was examined to determine the role of termination in ribosome release from the ER. CBV infection resulted in efficient cleavage of eIF4G and PABP, coincident with polyribosome breakdown in the cytosol and ER compartments. Termination resulted in the continued association of ribosomes with the ER compartment, rather than the expected process of ribosome release. Analyses of ribosome/mRNA loading patterns in the cytosol and ER revealed that CBV infection was accompanied by a suppression of mRNA translation in the cytosol and the sustained, although reduced, translation in the ER compartment. Direct biosynthetic labeling experiments demonstrated that protein synthesis on the ER was enhanced relative to the cytosol following CBV infection. In total, these data demonstrate that ribosome and mRNA release from the ER is regulated independent of translation termination and identify the ER as a privileged site for protein synthesis.

Pathways for compartmentalizing protein synthesis in eukaryotic cells: the template-partitioning model.

mRNAs encoding signal sequences are translated on endoplasmic reticulum (ER) -- bound ribosomes, whereas mRNAs encoding cytosolic proteins are translated on cytosolic ribosomes. The partitioning of mRNAs to the ER occurs by positive selection; cytosolic ribosomes engaged in the translation of signal-sequence-bearing proteins are engaged by the signal-recognition particle (SRP) pathway and subsequently trafficked to the ER. Studies have demonstrated that, in addition to the SRP pathway, mRNAs encoding cytosolic proteins can also be partitioned to the ER, suggesting that RNA partitioning in the eukaryotic cell is a complex process requiring the activity of multiple RNA-partitioning pathways. In this review, key findings on this topic are discussed, and the template-partitioning model, describing a hypothetical mechanism for RNA partitioning in the eukaryotic cell, is proposed.

Partitioning and translation of mRNAs encoding soluble proteins on membrane-bound ribosomes.

In eukaryotic cells, it is generally accepted that protein synthesis is compartmentalized; soluble proteins are synthesized on free ribosomes, whereas secretory and membrane proteins are synthesized on endoplasmic reticulum (ER)-bound ribosomes. The partitioning of mRNAs that accompanies such compartmentalization arises early in protein synthesis, when ribosomes engaged in the translation of mRNAs encoding signal-sequence-bearing proteins are targeted to the ER. In this report, we use multiple cell fractionation protocols, in combination with cDNA microarray, nuclease protection, and Northern blot analyses, to assess the distribution of mRNAs between free and ER-bound ribosomes. We find a broad representation of mRNAs encoding soluble proteins in the ER fraction, with a subset of such mRNAs displaying substantial ER partitioning. In addition, we present evidence that membrane-bound ribosomes engage in the translation of mRNAs encoding soluble proteins. Single-cell in situ hybridization analysis of the subcellular distribution of mRNAs encoding ER-localized and soluble proteins identify two overall patterns of mRNA distribution in the cell-endoplasmic reticular and cytosolic. However, both partitioning patterns include a distinct perinuclear component. These results identify previously unappreciated roles for membrane-bound ribosomes in the subcellular compartmentalization of protein synthesis and indicate possible functions for the perinuclear membrane domain in mRNA sorting in the cell.