Maintenance In Adults Research Articles

A plain language summary of the final analysis of the GRIFFIN study of daratumumab plus lenalidomide, bortezomib, and dexamethasone for people with newly diagnosed multiple myeloma.

This summary describes the final analysis of the GRIFFIN study. In this study, participants were newly diagnosed with a type of blood and bone marrow cancer called multiple myeloma, had never received any treatment, and were able to undergo an autologous stem cell transplant. The GRIFFIN study looked at adding the drug daratumumab (D) to a combination of standard treatments called RVd (lenalidomide [R], bortezomib [V], and dexamethasone [d]) during the treatment phases induction and consolidation, followed by daratumumab and lenalidomide (D-R) maintenance. Participants also received an autologous stem cell transplant to further help reduce multiple myeloma. The GRIFFIN study looked at whether D-RVd followed by D-R maintenance was better at killing multiple myeloma cells compared with RVd on its own followed by R maintenance on its own, and if treatments were safe. This summary also describes results from 2 other GRIFFIN publications: one that looked at participants with certain multiple myeloma characteristics or demographic factors that are associated with worse outcomes, and another that looked at how treatments impacted the participants' quality of life. At the time of the final analysis of GRIFFIN, participants who were treated with D-RVd followed by D-R maintenance had very low (undetectable) levels of multiple myeloma cells and multiple myeloma markers (biological signs) and were more likely to be alive without the multiple myeloma getting worse or coming back compared with participants who received standard RVd treatment followed by R maintenance. There was also a pattern of similar benefits achieved by participants who were at risk for worse outcomes. Additionally, participants who received D-RVd treatment followed by D-R maintenance reported less pain, less fatigue (extreme tiredness), and greater improvements in their ability to conduct daily physical activities. While some side effects (unwanted or unexpected effects of treatment) were higher with D-RVd, side effects in both groups were as expected, and adding daratumumab did not reduce a participant's ability to handle treatment. Results of the GRIFFIN study showed that D-RVd treatment followed by D-R maintenance was better at treating multiple myeloma than the standard treatment of RVd followed by R maintenance in adults with a new diagnosis of multiple myeloma who were able to receive an autologous stem cell transplant, with no unexpected side effects of treatment.Clinical Trial Registration: NCT02874742 (GRIFFIN) (ClinicalTrials.gov).

Elucidating a statistical learning brain network: Coordinate-based meta-analyses and functional connectivity profiles of artificial grammar learning in healthy adults

Abstract Language rehabilitation centers on modifying its use through experience-based neuroplasticity. Statistical learning of language is essential to its acquisition and likely its rehabilitation following brain injury, but its corresponding brain networks remain elusive. Coordinate-based meta-analyses were conducted to identify common and distinct brain activity across 25 studies coded for meta-data and experimental contrasts (Grammatical and Ungrammatical). The resultant brain regions served as seeds for profiling functional connectivity in large task-independent and task-dependent data sets. Hierarchical clustering of these profiles grouped brain regions into three subnetworks associated with statistical learning processes. Functional decoding clarified the mental operations associated with those subnetworks. Results support a left-dominant language sub-network and two cognitive control networks as scaffolds for language rule identification, maintenance, and application in healthy adults. These data suggest that cognitive control is necessary to track regularities across stimuli and imperative for rule identification and application of grammar. Future empirical investigation of these brain networks in language learning in individuals with brain injury will clarify their prognostic role in language recovery.

EPHB4-RASA1 Inhibition of PIEZO1 Ras Activation Drives Lymphatic Valvulogenesis.

EPHB4 (ephrin receptor B4) and the RASA1 (p120 Ras GTPase-activating protein) are necessary for the development of lymphatic vessel (LV) valves. However, precisely how EPHB4 and RASA1 regulate LV valve development is unknown. In this study, we examine the mechanisms by which EPHB4 and RASA1 regulate the development of LV valves. We used LV-specific inducible EPHB4-deficient mice and EPHB4 knockin mice that express a form of EPHB4 that is unable to bind RASA1 yet retains protein tyrosine kinase activity (EPHB4 2YP) to study the role of EPHB4 and RASA1 in LV valve development in the embryo and LV valve maintenance in adults. We also used human dermal lymphatic endothelial cells in vitro to study the role of EPHB4 and RASA1 as regulators of LV valve specification induced by oscillatory shear stress, considered the trigger for LV valve specification in vivo. LV valve specification, continued valve development postspecification, and LV valve maintenance were blocked upon induced loss of EPHB4 in LV. LV specification and maintenance were also impaired in EPHB4 2YP mice. Defects in LV development were reversed by inhibition of the Ras-MAPK (mitogen-activated protein kinase) signaling pathway. In human dermal lymphatic endothelial cells, loss of expression of EPHB4 or its ephrin b2 ligand, loss of expression of RASA1, and inhibition of physical interaction between EPHB4 and RASA1 resulted in dysregulated oscillatory shear stress-induced Ras-MAPK activation and impaired expression of LV specification markers that could be rescued by Ras-MAPK pathway inhibition. The same results were observed when human dermal lymphatic endothelial cells were stimulated with the Yoda1 agonist of the PIEZO1 oscillatory shear stress sensor. Although Yoda1 increased the number of LV valves when administered to wild-type embryos, it did not increase LV valve number when administered to EPHB4 2YP embryos. EPHB4 is necessary for LV valve specification, continued valve development postspecification, and valve maintenance. LV valve specification requires physical interaction between EPHB4 and RASA1 to limit activation of the Ras-MAPK pathway in lymphatic endothelial cells. Specifically, EPHB4-RASA1 physical interaction is necessary to dampen Ras-MAPK activation induced through the PIEZO1 oscillatory shear stress sensor. These findings reveal the mechanism by which EPHB4 and RASA1 regulate the development of LV valves.

Digital behaviour change intervention for weight loss maintenance in adults with obesity: a feasibility pilot study of eCHANGE

ABSTRACT Successful weight maintenance after weight loss is challenging. Digital interventions may facilitate behaviour change to prevent weight regain, however little is known about the acceptance and use of digital interventions in support of weight maintenance. This mixed methods study aims to evaluate user experiences, system use, and preliminary efficacy of eCHANGE, an application based self-management intervention for weight loss maintenance. A 3-month multi-site single group feasibility pilot study was conducted among adults (N = 60) with BMI ≥30 kg/m2, aiming to maintain weight after weight loss of ≥8%. User experiences and system use were examined through validated questionnaires, system use log data, and individual interviews (n = 15). Preliminary efficacy testing included body weight and patient reported outcome measures. Participants rated eCHANGE usability and usefulness as good in support of weight maintenance, with variation in usage. Analysis indicated that higher behavioural engagement scores were statistically significantly associated with frequency of technology usage. Weight loss was maintained by 83% of the participants at 3-months (i.e. defined as weight change of <3% of baseline body weight (kg)). Digital interventions, combining persuasive system design principles and behaviour change techniques, supporting self-regulation and maintenance of health behaviours, have the potential to facilitate weight maintenance after weight loss. Trial Registration: ClinicalTrials.gov NCT04537988 https://clinicaltrials.gov/ct2/show/NCT04537988

Transcription Factors Sox8 and Sox10 Contribute with Different Importance to the Maintenance of Mature Oligodendrocytes.

Myelin-forming oligodendrocytes in the vertebrate nervous system co-express the transcription factor Sox10 and its paralog Sox8. While Sox10 plays crucial roles throughout all stages of oligodendrocyte development, including terminal differentiation, the loss of Sox8 results in only mild and transient perturbations. Here, we aimed to elucidate the roles and interrelationships of these transcription factors in fully differentiated oligodendrocytes and myelin maintenance in adults. For that purpose, we conducted targeted deletions of Sox10, Sox8, or both in the brains of two-month-old mice. Three weeks post-deletion, none of the resulting mouse mutants exhibited significant alterations in oligodendrocyte numbers, myelin sheath counts, myelin ultrastructure, or myelin protein levels in the corpus callosum, despite efficient gene inactivation. However, differences were observed in the myelin gene expression in mice with Sox10 or combined Sox8/Sox10 deletion. RNA-sequencing analysis on dissected corpus callosum confirmed substantial alterations in the oligodendrocyte expression profile in mice with combined deletion and more subtle changes in mice with Sox10 deletion alone. Notably, Sox8 deletion did not affect any aspects of the expression profile related to the differentiated state of oligodendrocytes or myelin integrity. These findings extend our understanding of the roles of Sox8 and Sox10 in oligodendrocytes into adulthood and have important implications for the functional relationship between the paralogs and the underlying molecular mechanisms.

Association between plasma metal exposure and health span in very elderly adults: a prospective cohort study with mixture statistical approach.

Metals have been linked to a diverse spectrum of age-related diseases; however, the effects of metal exposure on health span remains largely unknown. This cohort study aims to determine the association between plasma metal and health span in elder adults aged ≥ 90years. The plasma concentrations of seven metals were measured at baseline in 300 elder adults. The end of the health span (EHS) was identified as the occurrence of one of eight major morbidities or mortality events. We used Cox regression to assess hazard ratios (HR). The combined effects of multiple metal mixtures were estimated using grouped-weighted quantile sum (GWQS), quantile g-computation (Q-gcomp), and Bayesian kernel machine regression (BKMR) methods. The estimated HR for EHS with an inter-quartile range (IQR) increment for selenium (Se) was 0.826 (95% confidence interval [CI]: 0.737-0.926); magnesium (Mg), 0.806 (95% CI: 0.691-0.941); iron (Fe), 0.756 (95% CI: 0.623-0.917), and copper (Cu), 0.856 (95% CI: 0.750-0.976). The P for trend of Se, Mg, and Fe were all < 0.05. In the mixture analyses, Q-gcomp showed a negative correlation with EHS (P = 0.904), with the sum of the negative coefficients being -0.211. Higher plasma Se, Mg, and Fe reduced the risk of premature end of health span, suggesting that essential metal elements played a role in health maintenance in elder adults.

Nkd1 functions downstream of Axin2 to attenuate Wnt signaling.

Wnt signaling is a crucial developmental pathway involved in early development as well as stem-cell maintenance in adults and its misregulation leads to numerous diseases. Thus, understanding the regulation of this pathway becomes vitally important. Axin2 and Nkd1 are widely utilized negative feedback regulators in Wnt signaling where Axin2 functions to destabilize cytoplasmic β-catenin, and Nkd1 functions to inhibit the nuclear localization of β-catenin. Here, we set out to further understand how Axin2 and Nkd1 regulate Wnt signaling by creating axin2gh1/gh1, nkd1gh2/gh2 single mutants and axin2gh1/gh1;nkd1gh2/gh2 double mutant zebrafish using sgRNA/Cas9. All three Wnt regulator mutants were viable and had impaired heart looping, neuromast migration defects, and behavior abnormalities in common, but there were no signs of synergy in the axin2gh1/gh1;nkd1gh2/gh2 double mutants. Further, Wnt target gene expression by qRT-PCR and RNA-seq, and protein expression by mass spectrometry demonstrated that the double axin2gh1/gh1;nkd1gh2/gh2 mutant resembled the nkd1gh2/gh2 phenotype demonstrating that Nkd1 functions downstream of Axin2. In support of this, the data further demonstrates that Axin2 uniquely alters the properties of β-catenin-dependent transcription having novel readouts of Wnt activity compared with nkd1gh2/gh2 or the axin2gh1/gh1;nkd1gh2/gh2 double mutant. We also investigated the sensitivity of the Wnt regulator mutants to exacerbated Wnt signaling, where the single mutants displayed characteristic heightened Wnt sensitivity, resulting in an eyeless phenotype. Surprisingly, this phenotype was rescued in the double mutant, where we speculate that cross-talk between Wnt/β-catenin and Wnt/Planar Cell Polarity pathways could lead to altered Wnt signaling in some scenarios. Collectively, the data emphasizes both the commonality and the complexity in the feedback regulation of Wnt signaling.

A WNT mimetic with broad spectrum FZD-specificity decreases fibrosis and improves function in a pulmonary damage model

BackgroundWnt/β-catenin signaling is critical for lung development and AT2 stem cell maintenance in adults, but excessive pathway activation has been associated with pulmonary fibrosis, both in animal models and human diseases such as idiopathic pulmonary fibrosis (IPF). IPF is a detrimental interstitial lung disease, and although two approved drugs limit functional decline, transplantation is the only treatment that extends survival, highlighting the need for regenerative therapies.MethodsUsing our antibody-based platform of Wnt/β-catenin modulators, we investigated the ability of a pathway antagonist and pathway activators to reduce pulmonary fibrosis in the acute bleomycin model, and we tested the ability of a WNT mimetic to affect alveolar organoid cultures.ResultsA WNT mimetic agonist with broad FZD-binding specificity (FZD1,2,5,7,8) potently expanded alveolar organoids. Upon therapeutic dosing, a broad FZD-binding specific Wnt mimetic decreased pulmonary inflammation and fibrosis and increased lung function in the bleomycin model, and it impacted multiple lung cell types in vivo.ConclusionsOur results highlight the unexpected capacity of a WNT mimetic to effect tissue repair after lung damage and support the continued development of Wnt/β-catenin pathway modulation for the treatment of pulmonary fibrosis.

Supporting Physical Activity Maintenance in Older Adults Following Supervised Group Exercise: A Mixed-Methods Study Among Culturally Diverse Older Adults.

Physical activity (PA) is important for prevention of falls and chronic disease in older adults. We aimed to examine the interrelated influences upon PA in culturally diverse older adults who completed a short-term exercise program, to inform maintenance strategies, using a mixed-methods design. Eighty-two past participants from the "Stepping On"© program were surveyed examining ongoing participation, social and cognitive determinants of PA, mental and physical functioning, and fear of falls. Semi-structured interviews were undertaken with 34 respondents regarding enablers and barriers, cultural factors, and preferences for PA. Data were collected in English, Chinese, Arabic, Punjabi, or Hindi. Cultural factors minimally affected PA participation. There was low perceived availability of PA opportunities. Health difficulties not only discouraged but also motivated participation. Social connection was a facilitator and could be used to support maintenance. Older adults may benefit from assistance in accessing PA opportunities and clinical guidance about the benefits of ongoing PA.

Distinct expression patterns of Hedgehog signaling components in mouse gustatory system during postnatal tongue development and adult homeostasis.

The Hedgehog (HH) pathway regulates embryonic development of anterior tongue taste fungiform papilla (FP) and the posterior circumvallate (CVP) and foliate (FOP) taste papillae. HH signaling also mediates taste organ maintenance and regeneration in adults. However, there are knowledge gaps in HH pathway component expression during postnatal taste organ differentiation and maturation. Importantly, the HH transcriptional effectors GLI1, GLI2 and GLI3 have not been investigated in early postnatal stages; the HH receptors PTCH1, GAS1, CDON and HHIP, required to either drive HH pathway activation or antagonism, also remain unexplored. Using lacZ reporter mouse models, we mapped expression of the HH ligand SHH, HH receptors, and GLI transcription factors in FP, CVP and FOP in early and late postnatal and adult stages. In adults we also studied the soft palate, and the geniculate and trigeminal ganglia, which extend afferent fibers to the anterior tongue. Shh and Gas1 are the only components that were consistently expressed within taste buds of all three papillae and the soft palate. In the first postnatal week, we observed broad expression of HH signaling components in FP and adjacent, non-taste filiform (FILIF) papillae in epithelium or stroma and tongue muscles. Notably, we observed elimination of Gli1 in FILIF and Gas1 in muscles, and downregulation of Ptch1 in lingual epithelium and of Cdon, Gas1 and Hhip in stroma from late postnatal stages. Further, HH receptor expression patterns in CVP and FOP epithelium differed from anterior FP. Among all the components, only known positive regulators of HH signaling, SHH, Ptch1, Gli1 and Gli2, were expressed in the ganglia. Our studies emphasize differential regulation of HH signaling in distinct postnatal developmental periods and in anterior versus posterior taste organs, and lay the foundation for functional studies to understand the roles of numerous HH signaling components in postnatal tongue development.

The Crohn's Disease Exclusion Diet: A Comprehensive Review of Evidence, Implementation Strategies, Practical Guidance, and Future Directions.

Dietary therapy is increasingly recognized for the management of Crohn's disease (CD) over recent years, including the use of exclusive enteral nutrition (EEN) as first-line therapy for pediatric CD according to current guidelines. The Crohn's disease exclusion diet (CDED) is a whole-food diet designed to reduce exposure to dietary components that are potentially pro-inflammatory, mediated by negative effects on the gut microbiota, immune response, and the intestinal barrier. The CDED has emerged as a valid alternative to EEN with cumulative evidence, including randomized controlled trials, supporting use for induction of remission and possibly maintenance in children and adults. We gathered a group of multidisciplinary experts, including pediatric and adult gastroenterologists, inflammatory bowel diseases (IBD) expert dietitians, and a psychologist to discuss the evidence, identify gaps, and provide insights into improving the use of CDED based on a comprehensive review of CDED literature and professional experience. This article reviews the management of CDED in both children and adults, long-term aspects of CDED, indications and contraindications, selecting the best candidates, identifying challenges with CDED, globalization, the role of the multidisciplinary team, especially of dietitian, and future directions. We concluded that CDED is an established dietary therapy that could serve as an alternative to EEN in many pediatric and adult cases, especially with mild to moderate disease. In severe disease, complicated phenotypes, or with extraintestinal involvement, CDED should be considered on a case-by-case basis, according to physician and dietitians' discretion. More studies are warranted to assess the efficacy of CDED in different scenarios.

Abstract 14432: Self-Care Clustering in Adults With Type 1 Diabetes

Poor glycemic control in type 1 diabetes (T1D) may result in cardiovascular disease. Self-care, or the process of maintaining health through health-promoting behaviors and managing illnesses when changes are detected, may improve glycemic control and outcomes. However, self-care in T1D is ill-defined. We examined how self-care maintenance, monitoring, and management cluster in adults with T1D and identified unique characteristics of individuals within each cluster. Adults ( n =200, 27% Black, 61% female) with T1D (median[IQR] age: 35 [22] years, T1D duration: 19 [19] years, insulin pump use: 68%) reported personal, clinical and social determinants of health (SDH; modified PRAPARE tool, scored 0-22; higher is worse) and the Self-Care of Diabetes Inventory (3 self-care scales: maintenance, monitoring, management; 1 confidence scale; scored 0-100; scores ≥ 70 are adequate). Cluster analysis was performed with self-care domains as criteria via Ward’s method. To compare clusters, Kruskal-Wallis and chi-square tests were used for continuous and categorical variables, respectively. Three self-care clusters were found and labeled: Mastery (n= 70, 70% White, insulin pump use: 63%, median [IQR] age: 41 [28] years, T1D: 22 [22] years, Self-Care Maintenance: 85.4 [10.4], Monitoring: 82.4 [8.8], Management: 72.2 [13.9], Confidence: 95.5 [11.4], SDH: 2 [2]); Inconsistent (n= 112, 75% White, Insulin Pump use: 75%, median[IQR] age: 34 [22] years, T1D: 19 [18] years, Self-Care Maintenance: 79.2 [12.5], Monitoring: 67.7 [11.8], Management: 58.3 [13.9], Confidence: 88.6 [15.9], SDH: 3 [2]); and Novice (n= 18, 39% White, Insulin pump use: 44%, median[IQR] age: 25 [9] years, T1D: 14 [10] years, Self-Care Maintenance: 53.1 [9.9], Monitoring: 52.9 [13.2], Management: 44.4 [9.7], Confidence: 64.8 [27.8], SDH: 6 [7]). Significant differences were found for age (p&lt;.001), race (p&lt;.01), insulin pump use (p&lt;.05), Self-Care Maintenance (p&lt;.001), Self-Care Monitoring (p&lt;.001), Self-Care Management (p&lt;.001), Self-Care Confidence (p&lt;.001), and SDH (p&lt;.01). No differences were found in T1D duration. Three distinct profiles of self-care were found in this sample of adults with T1D. Older patients using insulin pumps with fewer SDH risk were more likely to master self-care.

Chemotherapy-Sparing Induction Followed By Consolidation and Maintenance with Blinatumomab and Concurrent Oral Tyrosine Kinase Inhibitor Therapy for Newly-Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Primary Endpoint Results from the Blissphall Study

Background: Oral ABL-targeted kinase inhibitors (TKIs) have transformed treatment of BCR::ABL+ (Philadelphia chromosome-positive, Ph+) acute lymphoblastic leukemia (ALL). Induction (IND) w/ corticosteroids (CS) and dasatinib (DAS) alone results in morphologic complete response (mCR) rates approaching 100% but low rates of measurable residual disease (MRD) negativity; addition of intensive chemotherapy to TKIs adds risks of myelosuppression. DAS + the CD3/CD19 bispecific T-cell engager blinatumomab (BLIN) is effective consolidation (CONSOL) for Ph+ ALL, though ABL kinase mutations conferring resistance can arise early in therapy (Foà, NEJM, 2020). We designed a phase II study of BLIN as part of a chemotherapy sparing strategy in pts w/ Ph+ ALL (BLISSPHALL), introducing BLIN as early as 6 weeks into treatment for pts in mCR, w/ aim of expediting MRD clearance and suppressing resistant clones early in disease course, and including a maintenance (MAINT) phase of BLIN + TKI for pts in molecular response. Methods: We conducted a multicenter trial of TKI + CS IND and TKI + BLIN CONSOL + MAINT in adults (≥18 yrs) w/ newly-diagnosed (ND) Ph+ ALL (NCT04329325). Study schema is depicted in Figure 1. Pts received CS pre-phase w/ prednisone (PRED) or dexamethasone (DEX) followed by modified GIMEMA LAL1205 IND (DEX + DAS 140 mg/d w/ DAS dose adjustments or TKI change per protocol) w/ intrathecal methotrexate (IT MTX) d22, 43 and bone marrow (BM) MRD assessments including FACS and BCR::ABL1 PCR. Pts in mCR on d43 could proceed to CONSOL w/ 3 cycles (C) of TKI + BLIN 28 mcg/d IVCI, d1-28, w/ 14d off BLIN between cycles and BM MRD assessment/IT MTX after each cycle. TKI was given continuously including between BLIN cycles. Pts in protocol-defined complete molecular response (CMR; MRD negative by FACS and no detectable BCR::ABL1 transcripts) after CONSOL could proceed to MAINT (C4-7 BLIN + TKI, 28d off between cycles). The primary objective is to determine the proportion of evaluable pts achieving CMR by the end of CONSOL (≤ 3C BLIN + TKI). Secondary objectives include safety/toxicity of BLIN + DAS, duration of CMR, incidence of relapse, event-free/overall survival. Toxicities were defined by CTCAE v5.0. Results: 17 pts enrolled (12 women, 5 men) w/ median age 50 yrs (range 22-87); BCR::ABL1 transcript type p190 (n=15) or p210 (n=2). Median follow-up 11.7 months (range 3-24). All began DAS 140 mg/d as initial TKI; 4 changed TKI for DAS intolerance per protocol (bosutinib, n=2; ponatinib [PON], n=2) and remained on study; TKI was changed to PON in 1 other pt to optimize BCR::ABL1 transcript suppression pre-allogeneic transplant (alloHCT) and that pt was withdrawn from study. Two had interruption or delay of BLIN due to toxicity (grade [G] 3 transaminase elevation, n=1; G2 cytokine release syndrome, n=1); BLIN was resumed in both. Figure 2 lists nonhematologic adverse effects (AEs) seen in ≥2 pts at least possibly related to TKI or BLIN while on study. One pt developed G3 pancreatitis after DAS was changed to PON; TKI was changed back to DAS. There were no G4-5 AEs. All pts (100%) achieved mCR during IND (median d22). Ten achieved CMR to date (5 during IND, 5 during CONSOL) and 6 did not achieve CMR; determination pending in 1 pt. By FACS, 16/17 achieved BM MRD negativity; 13/14 evaluable pts had no evidence of malignant clonal IgH rearrangement (IgHR) by next generation sequencing (NGS). Notably, 3 pts w/ persistent low-level BCR::ABL1 transcripts had no evidence of malignant clonal IgHR by NGS but were withdrawn post-CONSOL as protocol required BCR::ABL1 PCR negativity to proceed to MAINT. Two pts relapsed, both after achieving CMR (one declined CONSOL and self-discontinued TKI; one had extramedullary (EM) relapse w/ ABL T315I mutation). Four pts underwent alloHCT in CR1 (rising MRD levels on study leading to change in therapy, n=1; persistent BCR::ABL1 PCR positivity, n=2; IKZF1 plus phenotype, n=1); one underwent alloHCT in CR2 following EM relapse. Conclusions: DAS + CS IND w/ addition of BLIN to TKI in mCR leads to high rates of deep molecular response w/ low risk of early relapse and low rates of severe regimen-related toxicity in pts w/ ND Ph+ ALL. Use of PON (vs DAS) as initial TKI w/ BLIN may further suppress resistant clones. Further f/u is needed to confirm durability of CMR w/ BLIN + TKI CONSOL ± MAINT in absence of alloHCT and whether pts w/ persistent BCR::ABL1 PCR positivity and no malignant clonal IgHR by NGS exhibit similar outcomes to those in CMR.

Association of Pork Intake with Cognitive Performance in Older Adults Enrolled in the National Health and Nutrition Examination Survey (NHANES), 2011-2014 Data Cycles.

Pork provides higher levels of several nutrients important for cognitive maintenance in older adults. A pilot clinical study suggests the addition of moderate amounts of pork to a Mediterranean-style diet improves cognition in older adults. There is an absence of observational research that isolates effects of pork from other red meats. To examine the relationship of pork intake on cognitive performance in older adults. Cross-sectional data from the U.S. National Health and Nutrition Examination Survey (NHANES) 2011-2014 cycles were used in these analyses. Pork intake was assessed using data from two non-consecutive 24-h dietary recalls. Cognitive function was assessed by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word Learning, CERAD Delayed Recall, Animal Fluency, and Digital Substitution tests. Statistical analyses were adjusted for sample weighting and survey design variables to account for the complex design. Student t-tests (continuous variables) and Pearson chi-squared tests (categorical variables) were employed to compare participant characteristics between the low and normal cognitive performance groups. Logistic regression was used to determine the relationship of pork intake (low, medium, and high) with prevalence of low cognitive performance, with the non-consumer group as the referent category. Pork intake was not beneficially or detrimentally associated performance on the any of the cognitive tests in both the crude and multivariate models (p > 0.05). Prospective cohort investigations and larger/longer-term clinical trials are needed to fully elucidate effects of pork intake on cognition in older adults.

Global role of IGF2BP1 in controlling the expression of Wnt/β-catenin-regulated genes in colorectal cancer cells.

Introduction: Wnt/β-catenin signaling controls cell division and lineage specification during embryonic development, and is crucial for stem cells maintenance and gut tissue regeneration in adults. Aberrant activation of Wnt/β-catenin signaling is also essential for the pathogenesis of a variety of malignancies. The RNA-binding protein IGF2BP1 is a transcriptional target of Wnt/β-catenin signaling, normally expressed during development and often reactivated in cancer cells, where it regulates the stability of oncogenic mRNA. Methods: In this study, we employed iCLIP and RNA sequencing techniques to investigate the role of IGF2BP1 in the post-transcriptional regulation of Wnt/β-catenin-induced genes at a global level within colorectal cancer (CRC) cells characterized by constitutively active Wnt/β-catenin signaling. Results and Discussion: In our study, we show that, in contrast to normal cells, CRC cells exhibit a much stronger dependency on IGF2BP1 expression for Wnt/β-catenin-regulated genes. We show that both untransformed and CRC cells have their unique subsets of Wnt/β-catenin-regulated genes that IGF2BP1 directly controls through binding to their mRNA. Our iCLIP analysis revealed a significant change in the IGF2BP1-binding sites throughout the target transcriptomes and a significant change in the enrichment of 6-mer motifs associated with IGF2BP1 binding in response to Wnt/β-catenin signaling. Our study also revealed a signature of IGF2BP1-regulated genes that are significantly associated with colon cancer-free survival in humans, as well as potential targets for CRC treatment. Overall, this study highlights the complex and context-dependent regulation of Wnt/β-catenin signaling target genes by IGF2BP1 in non-transformed and CRC cells and identifies potential targets for colon cancer treatment.

Factors influencing normal blood pressure maintenance in young adults.

Despite an alarming increase in the prevalence of hypertension among Chinese young adults, longitudinal studies investigating factors that affect the maintenance of normal blood pressure (BP) in this population are lacking. Our study aimed to address this knowledge gap. A total of 7100 participants from the Kailuan Study who had normal BP and were aged<30 years at their first physical examination between 2006 and 2016 were included in this study. Cox proportional hazards regression models were used to assess hazard ratios (HR), and 95% confidence intervals (CI) were calculated to assess the associations between influencing factors and the maintenance of normal BP in young adults. Analyses were stratified by sex. During the follow-up period (mean, 7.98 years), 1921 participants (27.06%) maintained normal BP. Higher education levels (HR, 1.11; 95% CI, 1.00-1.22), low salt intake (HR, 1.25; 95% CI, 1.04-1.51), being underweight (HR, 1.16; 95% CI, 1.02-1.31), and having normal weight (HR, 1.19; 95% CI, 1.01-1.39), normal blood glucose (HR, 1.22; 95% CI, 1.02-1.46), and no family history of hypertension (HR, 1.65; 95% CI, 1.41-1.92) at baseline were found to be associated with maintaining normal BP. Compared with female smokers, female non-smokers had 1.68 times higher odds of maintaining normal BP. This study identified factors that influence the maintenance of normal BP in the young population in China. This information can assist clinicians in establishing comprehensive and effective primary prevention measures for hypertension.

Predictors of loneliness onset and maintenance in European older adults during the COVID-19 pandemic.

Loneliness is a major public health concern. Duration of loneliness is associated with severity of health outcomes, and further research is needed to direct interventions and social policy. This study aimed to identify predictors of the onset vs. the maintenance of loneliness in older adults before and during the pandemic using longitudinal data from the Survey of Health, Age, and Retirement in Europe (SHARE). Groupings of persistent, situational, and no loneliness were based on self-reports from an ordinary pre-pandemic SHARE wave and a peri-pandemic telephone interview. Predictors were identified and compared in three hierarchical binary regression analyses, with independent variables added in blocks of geographic region, demographics, pre-pandemic social network, pre-pandemic health, pandemic-related individual, and country level variables. Self-reported loneliness levels for the persistent, situational, and no loneliness groups were stable and distinct through 7 years preceding the pre-pandemic baseline measure. Shared predictors were chronic diseases, female sex, depression, and no cohabitant partner. Persistent loneliness was uniquely predicted by low network satisfaction (OR: 2.04), functional limitations (OR: 1.40), and a longer country-level isolation period for older adults (OR: 1.24). Interventions may target persons with depression, functional limitations, chronic health issues, and no cohabitant partner. The added burden of the length of isolation on those who are already lonely should be taken into account when employing social policies that target older adults. Further research should distinguish between situational and persistent loneliness, and seek to identify predictors of chronic loneliness onset.

Mediating effects of heart rate variability on the association between chronic stress, cardiorespiratory fitness and working memory maintenance

Young adulthood is a demanding developmental stage during which an individual is required to learn to adequately respond to physical and psychosocial stressors (Malter Cohen et al., 2013). High degrees of chronic stress have been shown to have detrimental effects on physical and mental health outcomes in young adults, accompanied by decreases in academic achievement and subjective well-being (Bayram &amp; Bilgel, 2008; Malter Cohen et al., 2013). While effects of acute stress on neurocognitive functioning have been examined, documentation on effects of prolonged stress exposure on working memory is scarce. While chronic stress may impair working memory, empirical evidence supports the assumption that exercise targeting cardiorespiratory fitness has the potential to buffer harmful effects of stress on working memory performance (Loprinzi &amp; Frith, 2019). According to the Neurovisceral Integration Theory, shared neurophysiological areas are involved in cardiac autonomic control as well as the modulation of attentional and emotional regulatory processing (Forte et al., 2019). Therefore, heart rate-variability (HRV) may be a physiological correlate mediating the association between chronic stress, cardiorespiratory fitness and working memory maintenance.&#x0D; The present study investigated the mediating role of resting heart rate-variability on the association between chronic stress, cardiorespiratory fitness and working memory maintenance in young healthy adults.&#x0D; Working memory maintenance was assessed in N = 115 healthy adults (48% female) aged 18 to 35 years (M = 24.1, SD = 3.8) using a modified version of the Sternberg task with low (3 items) and high cognitive load (6 items). Additionally, the Åstrand test was conducted on a bicycle ergometer to estimate maximal oxygen consumption (VO2max). Resting HRV was recorded using electrocardiography. The LF/HF ratio was extracted for mediation analyses.&#x0D; Path analysis revealed a significant association between cardiorespiratory fitness and accuracy on high cognitive load trials, but not on trials with low cognitive load. Levels of perceived chronic stress showed a trend for a positive association with working memory maintenance, independently of cognitive load. The pattern of results remained unchanged after introduction of HRV as a mediator.&#x0D; Results indicate that despite young adulthood being characterized by peak cognitive performance, cardiorespiratory fitness influences working memory maintenance. The lack of mediating effects of HRV, indicates that this association cannot be explained by vagal influences on memory processing driven by the autonomic nervous system. As working memory is crucial for performance in many real-life domains, such as workplace and learning environments in general maintenance and promotion of cardiorespiratory fitness is encouraged.&#x0D; References&#x0D; Bayram, N., &amp; Bilgel, N. (2008). The prevalence and socio-demographic correlations of depression, anxiety and stress among a group of university students. Social Psychiatry and Psychiatric Epidemiology, 43(8), 667-672. https://doi.org/10.1007/s00127-008-0345-x&#x0D; Forte, G., Favieri, F., &amp; Casagrande, M. (2019). Heart rate variability and cognitive function: A systematic review [Mini Review]. Frontiers in Neuroscience, 13, Article 710. https://doi.org/10.3389/fnins.2019.00710&#x0D; Loprinzi, P. D., &amp; Frith, E. (2019). Protective and therapeutic effects of exercise on stress-induced memory impairment. Journal of Physiological Sciences, 69(1), 1-12. https://doi.org/10.1007/s12576-018-0638-0&#x0D; Malter Cohen, M., Tottenham, N., &amp; Casey, B. J. (2013). Translational developmental studies of stress on brain and behavior: Implications for adolescent mental health and illness? Neuroscience, 249, 53-62. https://doi.org/https://doi.org/10.1016/j.neuroscience.2013.01.023

Does heart rate variability mediate the association between chronic stress, cardiorespiratory fitness, and working memory in young adults?

Young adulthood is a demanding development phase rendering individuals at risk for high levels of stress. While chronic stress may impair working memory maintenance, cardiorespiratory fitness is suggested to have a protective effect. Heart rate variability (HRV) contributes to this cognitive domain, but also retaliates to stress and aerobic exercise. Therefore, the present study investigated the mediating role of resting HRV on the association between chronic stress, cardiorespiratory fitness, and working memory maintenance in young healthy adults. Healthy participants (N=115, 48% female) aged 18-35 years (M=24.1, SD=3.8) completed the Åstrand test on a bicycle ergometer to estimate maximal oxygen consumption [ (ml/min/kg)]. In addition, working memory maintenance was assessed using the modified Sternberg task with low (three items) and high cognitive load (six items). Using electrocardiography, HRV was recorded and the LF/HF ratio was extracted for mediation analyses. Path analysis revealed that cardiorespiratory fitness was significantly associated with accuracy on high cognitive load trials (β=0.19, p=0.035), but not on trials with low cognitive load. Perceived levels of chronic stress failed to show a significant association with working memory maintenance, independently of cognitive load. The pattern of results remained unchanged after introduction of HRV as a mediator (β=0.18, p=0.045). In conclusion, higher cardiorespiratory fitness is associated with better maintenance of verbal information in working memory. However, this association cannot be explained by vagal influences on memory processing driven by the autonomic nervous system.

Dietary Intake of 91 Individual Polyphenols and 5-Year Body Weight Change in the EPIC-PANACEA Cohort.

Polyphenols are bioactive compounds from plants with antioxidant properties that may have a protective role against body weight gain, with adipose tissue and systemic oxidative stress as potential targets. We aimed to investigate the dietary intake of individual polyphenols and their association with 5-year body weight change in a sub-cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC). This study included 349,165 adult participants from nine European countries. Polyphenol intake was estimated through country-specific validated dietary questionnaires and the Phenol-Explorer database. Body weight was obtained at recruitment and after a mean follow-up time of 5 years. Associations were estimated using multilevel mixed linear regression models. From 91 polyphenols included, the majority (n = 67) were inversely associated with 5-year body weight change after FDR-correction (q < 0.05). The greatest inverse associations were observed for quercetin 3-O-rhamnoside (change in weight for doubling in intake: −0.071 (95% CI: −0.085; −0.056) kg/5 years). Only 13 polyphenols showed positive associations with body weight gain, mainly from the subclass hydroxycinnamic acids (HCAs) with coffee as the main dietary source, such as 4-caffeoylquinic acid (0.029 (95% CI: 0.021; 0.038) kg/5 years). Individual polyphenols with fruit, tea, cocoa and whole grain cereals as the main dietary sources may contribute to body weight maintenance in adults. Individual HCAs may have different roles in body weight change depending on their dietary source.