Chocolate intake and muscle pain sensation: A randomized experimental study.

BACKGROUND: Chocolate, as a cocoa-derived product rich in flavanols, has been used for medical and anti-inflammatory purposes. Therefore, the aim of this study was to investigate if the ingestion of different percentages of cocoa products affects the experimentally induced pain caused by intramuscular hypertonic saline injections in the masseter muscle of healthy men and women. METHODS: This experimental randomized, double-blind, and controlled study included 15 young, healthy, and pain-free men and 15 age-matched women and involved three visits with at least a 1-week washout. Pain was induced twice at each visit with intramuscular injections of 0.2 mL hypertonic saline (5%), before and after intake of one of the different chocolate types: white (30% cocoa content), milk (34% cocoa content), and dark (70% cocoa content). Pain duration, pain area, peak pain, and pressure pain threshold (PPT) were assessed every fifth minute after each injection, up until 30 min after the initial injection. Descriptive and inferential statistics were performed using IBM® SPSS (Version 27); significance level was set to p<0.05. RESULTS: This study showed that intake of chocolate, no matter the type, reduced the induced pain intensity significantly more than no intake of chocolate (p<0.05, Tukey test). There were no differences between the chocolate types. Further, men showed a significantly greater pain reduction than women after intake of white chocolate (p<0.05, Tukey test). No other differences between pain characteristics or sexes were revealed. CONCLUSION: Intake of chocolate before a painful stimulus had a pain-reducing effect no matter the cocoa concentration. The results indicate that perhaps it is not the cocoa concentration (e.g., flavanols) alone that explains the positive effect on pain, but likely a combination of preference and taste-experience. Another possible explanation could be the composition of the chocolate, i.e. the concentration of the other ingredients such as sugar, soy, and vanilla. ClinicalTrials.gov Identifier: NCT05378984.

Lenalidomide-associated B-cell ALL: clinical and pathologic correlates and sensitivity to lenalidomide withdrawal.

Lenalidomide is an effective component of induction and maintenance therapy for multiple myeloma, though with a risk of secondary malignancies, including acute lymphoblastic leukemia (ALL). In contrast to therapy-related myeloid neoplasia, lenalidomide-associated lymphoblastic neoplasia remains poorly characterized. We conducted a dual institution retrospective study of 32 ALL cases that arose after lenalidomide maintenance (all B-lineage, 31/32 BCR::ABL-negative). B-cell ALL (B-ALL) was diagnosed at median 54 months (range, 5-119) after first exposure to lenalidomide and after median 42 months of cumulative lenalidomide exposure (range, 2-114). High incidence of TP53 mutations (9/19 evaluable cases) and low hypodiploidy (8/26 patients) were identified. Despite median age of 65 years and poor-risk B-ALL features observed in the cohort, rates of complete response (CR) or CR with incomplete hematologic recovery were high (25/28 patients receiving treatment). Median event-free survival was 35.4 months among treated patients (not reached among those undergoing allogeneic hematopoietic cell transplantation [HCT]). Sixteen patients remain alive without evidence of B-ALL after HCT or extended maintenance therapy. We also describe regression of B-ALL or immature B-cell populations with B-ALL immunophenotype after lenalidomide discontinuation in 5 patients, suggesting lenalidomide may drive leukemic progression even after initiation of lymphoblastic neoplasia and that lenalidomide withdrawal alone may be an appropriate first-line intervention in selected patients. Monitoring for early B-ALL-like proliferations may offer opportunities for lenalidomide withdrawal to prevent progression. Established combination chemotherapy regimens, newer surface antigen-targeted approaches, and allogeneic HCT are effective in many patients with lenalidomide-associated B-ALL and should be offered to medically fit patients.

Amide-to-Ester Substitution as a Strategy for Optimizing PROTAC Permeability and Cellular Activity.

Criteria for predicting the druglike properties of "beyond Rule of 5" Proteolysis Targeting Chimeras (PROTAC) degraders are underdeveloped. PROTAC components are often combined via amide couplings due to their reliability. Amides, however, can give rise to poor absorption, distribution, metabolism, and excretion (ADME) properties. We hypothesized that a bioisosteric amide-to-ester substitution could lead to improvements in both physicochemical properties and bioactivity. Using model compounds, bearing either amides or esters, we identify parameters for optimal lipophilicity and permeability. We applied these learnings to design a set of novel amide-to-ester-substituted, VHL-based BET degraders with the goal to increase permeability. Our ester PROTACs retained intracellular stability, were overall more potent degraders than their amide counterparts, and showed an earlier onset of the hook effect. These enhancements were driven by greater cell permeability rather than improvements in ternary complex formation. This largely unexplored amide-to-ester substitution provides a simple strategy to enhance PROTAC permeability and bioactivity and may prove beneficial to other beyond Ro5 molecules.

Identifying the Cellular Target of Cordyheptapeptide A and Synthetic Derivatives.

Cordyheptapeptide A is a lipophilic cyclic peptide from the prized Cordyceps fungal genus that shows potent cytotoxicity in multiple cancer cell lines. To better understand the bioactivity and physicochemical properties of cordyheptapeptide A with the ultimate goal of identifying its cellular target, we developed a solid-phase synthesis of this multiply N-methylated cyclic heptapeptide which enabled rapid access to both side chain- and backbone-modified derivatives. Removal of one of the backbone amide N-methyl (N-Me) groups maintained bioactivity, while membrane permeability was also preserved due to the formation of a new intramolecular hydrogen bond in a low dielectric solvent. Based on its cytotoxicity profile in the NCI-60 cell line panel, as well as its phenotype in a microscopy-based cytological assay, we hypothesized that cordyheptapeptide was acting on cells as a protein synthesis inhibitor. Further studies revealed the molecular target of cordyheptapeptide A to be the eukaryotic translation elongation factor 1A (eEF1A), a target shared by other lipophilic cyclic peptide natural products. This work offers a strategy to study and improve cyclic peptide natural products while highlighting the ability of these lipophilic compounds to effectively inhibit intracellular disease targets.

The Long Shadow: Collateral Impact and Finding Resilience Amidst a Global Pandemic Pediatric Palliative Care Social Work During COVID-19.

This manuscript illuminates the nuanced ways in which the COVID-19 pandemic has impacted the pediatric palliative care social work role and clinical care in caring for children with life-limiting illnesses and their families throughout the country. The authors discuss memorable moments, logistical impacts, telehealth usage, decision-making experiences, end of life care, bereavement practices, specialized interventions, and self-care. The paper concludes with lessons learned and practical recommendations for the future.

Understanding and Improving the Membrane Permeability of VH032-Based PROTACs.

Proteolysis targeting chimeras (PROTACs) are catalytic heterobifunctional molecules that can selectively degrade a protein of interest by recruiting a ubiquitin E3 ligase to the target, leading to its ubiquitylation and degradation by the proteasome. Most degraders lie outside the chemical space associated with most membrane-permeable drugs. Although many PROTACs have been described with potent activity in cells, our understanding of the relationship between structure and permeability in these compounds remains limited. Here, we describe a label-free method for assessing the permeability of several VH032-based PROTACs and their components by combining a parallel artificial membrane permeability assay (PAMPA) and a lipophilic permeability efficiency (LPE) metric. Our results show that the combination of these two cell-free membrane permeability assays provides new insight into PROTAC structure-permeability relationships and offers a conceptual framework for predicting the physicochemical properties of PROTACs in order to better inform the design of more permeable and more effective degraders.

Drug-Like Properties in Macrocycles above MW 1000: Backbone Rigidity versus Side-Chain Lipophilicity.

Large macrocyclic peptides can achieve surprisingly high membrane permeability, although the properties that govern permeability in this chemical space are only beginning to come into focus. We generated two libraries of cyclic decapeptides with stable cross-ß conformations, and found that peptoid substitutions within the ß-turns of the macrocycle preserved the rigidity of the parent scaffold, whereas peptoid substitutions in the opposing ß-strands led to "chameleonic" species that were rigid in nonpolar media but highly flexible in water. Both rigid and chameleonic compounds showed high permeability over a wide lipophilicity range, with peak permeabilities differing significantly depending on scaffold rigidity. Our findings indicate that modulating lipophilicity can be used to engineer favorable ADME properties into both rigid and flexible macrocyclic peptides, and that scaffold rigidity can be used to tune optimal lipophilicity.

Conducting Psychosocial Intervention Research among Adolescents and Young Adults with Cancer: Lessons from the PRISM Randomized Clinical Trial.

BACKGROUND: Adolescents and young adults (AYAs) with cancer have poor psychosocial outcomes, in part because their limited participation in clinical trials precludes intervention-testing. We previously reported results of a successful randomized trial testing an AYA-targeted psychosocial intervention. Here, we aimed to describe strategies learned during the trial's conduct. METHODS: We summarized data from the medical record and staff field notes regarding reasons for participation/non-participation. We conducted two focus groups with study staff; directed content analyses identified strategies for success. RESULTS: 92 AYAs enrolled (77% of approached; n = 50 Usual Care (control), n = 49 PRISM (intervention)). In eligible families who declined participation (n = 22 AYAs, n = 8 parents), the AYAs more commonly had advanced cancer (n = 11 (37%) declined vs. n = 25 (26%) enrolled). AYA reasons for non-enrollment were predominantly "not interested"; parents worried participation was "too burdensome." Staff strategies for accrual included having significant time to introduce the study and underscoring a desire to learn from the patient. After enrollment, AYAs who discontinued participation were more commonly assigned to control (n = 5 (10%) control vs. n = 2 (4%) intervention). Only n = 1 AYA chose to discontinue participation after receiving the intervention. CONCLUSIONS: Efforts to engage AYAs prior to and during studies may help with accrual and retention.

Lipophilic Permeability Efficiency Reconciles the Opposing Roles of Lipophilicity in Membrane Permeability and Aqueous Solubility.

As drug discovery moves increasingly toward previously "undruggable" targets such as protein-protein interactions, lead compounds are becoming larger and more lipophilic. Although increasing lipophilicity can improve membrane permeability, it can also incur serious liabilities, including poor water solubility, increased toxicity, and faster metabolic clearance. Here we introduce a new efficiency metric, especially relevant to "beyond rule of 5" molecules, that captures, in a simple, unitless value, these opposing effects of lipophilicity on molecular properties. Lipophilic permeability efficiency (LPE) is defined as log D7.4dec/w - mlipocLogP + bscaffold, where log D7.4dec/w is the experimental decadiene-water distribution coefficient (pH 7.4), cLogP is the calculated octanol-water partition coefficient, and mlipo and bscaffold are scaling factors to standardize LPE values across different cLogP metrics and scaffolds. Using a variety of peptidic and nonpeptidic macrocycle drugs, we show that LPE provides a functional assessment of the efficiency with which a compound achieves passive membrane permeability at a given lipophilicity.

Provider Perspectives on Use of Medical Marijuana in Children With Cancer.

BACKGROUND: Although medical marijuana (MM) may have utility in the supportive care of children with serious illness, it remains controversial. We investigated interdisciplinary provider perspectives on legal MM use in children with cancer. METHODS: We sent a 32-item, cross-sectional survey to 654 pediatric oncology providers in Illinois, Massachusetts, and Washington characterizing MM practices, knowledge, attitudes, and barriers. Forty-eight percent responded; 44% (n = 288) were included in analyses. Providers were stratified by status as legally eligible to certify (ETC) for MM. We used Fisher's exact and Wilcoxon rank tests and univariate and multivariate logistic regression models for group comparisons. RESULTS: The provider median age was 35 years (range 22-70 years); 33% were ETC (83 physicians; 13 Washington state advance practice providers). Thirty percent of providers received ≥1 request for MM in the previous month. Notably, only 5% of all providers knew state-specific regulations. ETC providers were more likely to know that MM is against federal laws (P < .0001). Whereas most providers (92%) reported willingness to help children with cancer access MM, in adjusted models, ETC providers were less likely to indicate approval of patient MM use by smoking, oral formulations, as cancer-directed therapy, or to manage symptoms (P < .005 for all). Forty-six percent of all providers cited the absence of standards around formulations, potency, or dosing to be the greatest barrier to recommending MM. CONCLUSIONS: Most pediatric oncology providers are willing to consider MM use in children with cancer and receive frequent inquiries. However, ETC providers endorse less favorable attitudes overall. The absence of standards is an important barrier to recommending MM.

Promoting Resilience in Stress Management for Parents (PRISM-P): An intervention for caregivers of youth with serious illness.

INTRODUCTION: It is well-known that parental stress and coping impacts the well-being of children with serious illness. The current study aimed to evaluate the feasibility and satisfaction of a novel resilience promoting intervention, the Promoting Resilience in Stress Management Intervention for Parents (PRISM-P) among parents of adolescents and young adults with Type 1 diabetes or cancer. Secondary analyses explored the effect of the PRISM-P on parent-reported resilience and distress. METHOD: The PRISM-P includes 4 short skills-based modules, delivered in either 2 or 4 separate, individual sessions. English-speaking parents of adolescents with cancer or Type 1 diabetes were eligible. Feasibility was conservatively defined as a completion rate of 80%; satisfaction was qualitatively evaluated based upon parent feedback regarding intervention content, timing, and format. Resilience and distress were assessed pre- and postintervention with the Connor Davidson Resilience Scale and the Kessler-6 Psychological Distress Scale. RESULTS: Twelve of 24 caregivers of youth with diabetes (50%) and 13 of 15 caregivers of youth with cancer (87%) agreed to participate. Nine of 12 (75%) and 9 of 13 (64%) completed all PRISM-P modules, respectively. Among those who completed the intervention, qualitative satisfaction was high. Parent-reported resilience and distress scores improved after the intervention. Effect sizes for both groups indicated a moderate intervention effect. DISCUSSION: Ultimately, the PRISM-P intervention was well accepted and impactful among parents who completed it. However, attrition rates were higher than anticipated, suggesting alternative or less time-intensive formats may be more feasible. (PsycINFO Database Record