Nursing Care Throughout the Chimeric Antigen Receptor T-Cell Therapy Process for Multiple Myeloma.

OBJECTIVES: Approvals of chimeric antigen receptor T-cell (CAR-T) therapies for relapsed/refractory multiple myeloma (RRMM) represent advancements in treatment options for a hard-to-treat population. Nursing care during CAR-T therapy is crucial for patients, their caregivers, and the broader CAR-T therapy care team. This manuscript provides an overview of the CAR-T therapy administration process and describes practical considerations for nursing professionals working with patients who receive CAR-T therapy. DATA SOURCES: Current literature describing CAR-T therapies for RRMM and published guidelines on nursing care during CAR-T therapy administration were identified from a PubMed database search. Literature was synthesized with practical considerations from nurses and nurse practitioners with expertise in the administration of CAR-T therapy for MM. A practical overview of the role of nursing professionals throughout all stages of CAR-T therapy administration for RRMM is provided. CONCLUSION: Planning, administration, and posttreatment monitoring for CAR-T therapy requires collaboration between nursing professionals and other healthcare providers as patients migrate between community oncology providers and specialized treatment centers. Nurses help with assessment of patient eligibility and patient and caregiver education before CAR-T therapy. They act in diverse roles across various settings involved in CAR-T therapy administration. Finally, nurses contribute to long-term identification and management of CAR-T-associated toxicities. IMPLICATIONS FOR NURSING PRACTICE: Nurses are crucial to the CAR-T therapy process and make significant contributions to optimizing patient care and subsequent outcomes.

The susceptibility of disulfide bonds to modification in keratin fibers undergoing tensile stress.

Cysteine residues perform a dual role in mammalian hairs. The majority help stabilize the overall assembly of keratins and their associated proteins, but a proportion of inter-molecular disulfide bonds are assumed to be associated with hair mechanical flexibility. Hair cortical microstructure is hierarchical, with a complex macro-molecular organization resulting in arrays of intermediate filaments at a scale of micrometres. Intermolecular disulfide bonds occur within filaments and between them and the surrounding matrix. Wool fibers provide a good model for studying various contributions of differently situated disulfide bonds to fiber mechanics. Within this context, it is not known if all intermolecular disulfide bonds contribute equally, and, if not, then do the disproportionally involved cysteine residues occur at common locations on proteins? In this study, fibers from Romney sheep were subjected to stretching or to their breaking point under wet or dry conditions to detect, through labeling, disulfide bonds that were broken more often than randomly. We found that some cysteines were labeled more often than randomly and that these vary with fiber water content (water disrupts protein-protein hydrogen bonds). Many of the identified cysteine residues were located close to the terminal ends of keratins (head or tail domains) and keratin-associated proteins. Some cysteines in the head and tail domains of type II keratin K85 were labeled in all experimental conditions. When inter-protein hydrogen bonds were disrupted under wet conditions, disulfide labeling occurred in the head domains of type II keratins, likely affecting keratin-keratin-associated protein interactions, and tail domains of the type I keratins, likely affecting keratin-keratin interactions. In contrast, in dry fibers (containing more protein-protein hydrogen bonding), disulfide labeling was also observed in the central domains of affected keratins. This central "rod" region is associated with keratin-keratin interactions between anti-parallel heterodimers in the tetramer of the intermediate filament.

Incidence and management of CAR-T neurotoxicity in patients with multiple myeloma treated with ciltacabtagene autoleucel in CARTITUDE studies.

Chimeric antigen receptor (CAR) T-cell therapies are highly effective for multiple myeloma (MM) but their impressive efficacy is associated with treatment-related neurotoxicities in some patients. In CARTITUDE-1, 5% of patients with MM reported movement and neurocognitive treatment-emergent adverse events (MNTs) with ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen-targeted CAR T-cell therapy. We assessed the associated factors for MNTs in CARTITUDE-1. Based on common features, patients who experienced MNTs were characterized by the presence of a combination of at least two variables: high tumor burden, grade ≥2 cytokine release syndrome (CRS) or any grade immune effector cell-associated neurotoxicity syndrome (ICANS) after cilta-cel infusion, and high CAR T-cell expansion/persistence. Strategies were implemented across the cilta-cel development program to monitor and manage patients with MNTs, including enhanced bridging therapy to reduce baseline tumor burden, early aggressive treatment of CRS and ICANS, handwriting assessments for early symptom detection, and extended monitoring/reporting time for neurotoxicity beyond 100 days post-infusion. After successful implementation of these strategies, the incidence of MNTs was reduced from 5% to <1% across the cilta-cel program, supporting its favorable benefit-risk profile for treatment of MM.

Substrate Stiffness Controls Osteoblastic and Chondrocytic Differentiation of Mesenchymal Stem Cells without Exogenous Stimuli.

Stem cell fate has been linked to the mechanical properties of their underlying substrate, affecting mechanoreceptors and ultimately leading to downstream biological response. Studies have used polymers to mimic the stiffness of extracellular matrix as well as of individual tissues and shown mesenchymal stem cells (MSCs) could be directed along specific lineages. In this study, we examined the role of stiffness in MSC differentiation to two closely related cell phenotypes: osteoblast and chondrocyte. We prepared four methyl acrylate/methyl methacrylate (MA/MMA) polymer surfaces with elastic moduli ranging from 0.1 MPa to 310 MPa by altering monomer concentration. MSCs were cultured in media without exogenous growth factors and their biological responses were compared to committed chondrocytes and osteoblasts. Both chondrogenic and osteogenic markers were elevated when MSCs were grown on substrates with stiffness <10 MPa. Like chondrocytes, MSCs on lower stiffness substrates showed elevated expression of ACAN, SOX9, and COL2 and proteoglycan content; COMP was elevated in MSCs but reduced in chondrocytes. Substrate stiffness altered levels of RUNX2 mRNA, alkaline phosphatase specific activity, osteocalcin, and osteoprotegerin in osteoblasts, decreasing levels on the least stiff substrate. Expression of integrin subunits α1, α2, α5, αv, ß1, and ß3 changed in a stiffness- and cell type-dependent manner. Silencing of integrin subunit beta 1 (ITGB1) in MSCs abolished both osteoblastic and chondrogenic differentiation in response to substrate stiffness. Our results suggest that substrate stiffness is an important mediator of osteoblastic and chondrogenic differentiation, and integrin ß1 plays a pivotal role in this process.

Rural Print Media and a Tailored Advocacy Intervention for Smoke-Free Policy.

PURPOSE: To examine frequency, prominence, and content of local print media after a 4-year policy advocacy intervention. DESIGN: This was a controlled community-based trial. SETTING: The study took place in 39 rural counties (22 intervention, 17 comparison). SUBJECTS: Subjects consisted of 2525 newspaper articles monitored over 18 quarters (July 2007 to December 2011). INTERVENTION: One key element of the tailored policy advocacy intervention delivered by community advisors was building demand for smoke-free policy via media advocacy strategies. MEASURES: Media clips were coded to assess number of articles; percent of tobacco-related articles on the front page or bold heading section; percent of pro-health articles; and percent of articles with secondhand smoke (SHS)-relevant topics or themes. ANALYSIS: Coded data were entered into Atlas.ti software. Article frequencies and attributes were compared between groups and over time using negative binomial regression for longitudinal data, with county-level demographics as covariates. RESULTS: In the last 3 years, there were approximately twice as many articles in intervention than in comparison counties. Media clips from newspapers in intervention counties were between 1.4 and 2 times more likely to have front page placement and percent of relevant topic or theme than were those in comparison counties. There was no difference in rate of pro-health articles by group. CONCLUSION: The policy advocacy intervention to promote smoke-free policy increased media attention to SHS and may have increased public awareness of issues related to smoke-free policy.

Change in surface roughness by dynamic shape-memory acrylate networks enhances osteoblast differentiation.

Microscale surface roughness has been shown to enhance osseointegration of titanium implants through increased osteoblast differentiation while osteoblast proliferation remains greater on smooth titanium. Taking advantage of these phenomena, we developed a shape memory (meth)acrylate copolymer with thermomechanical properties that created a time-dependent dynamic surface change from smooth to rough under in vitro cell culture conditions and evaluated the effect of the shape recovery on osteoblast response. Rough topographies were created using soft lithography techniques to mimic those found on clinically-used Ti surfaces (machined smooth; acid-etched; grit-blasted). The surface roughness was then reduced to smooth via compression and shown to fully recover within 24 h in culture conditions. When grown under static conditions, osteoblast number, alkaline phosphatase specific activity (ALP), and osteoprotegerin (OPG) and vascular endothelial growth factor (VEGF) production were unaffected by polymer surface roughness, but osteocalcin (OCN) was increased on the grit-blasted polymer mimic. Under dynamic conditions, DNA was reduced but OCN and OPG were increased on the compressed grit-blasted polymer at 3 days compared to static surfaces. The present study indicates that responses to polymer surface are sensitive to time-dependent changes in topography. The use of a shape memory polymer with dynamic surface roughness may improve osseointegration.

Mapping the accessibility of the disulfide crosslink network in the wool fiber cortex.

The disulfide bond network within the cortex of mammalian hair has a critical influence on the physical and mechanical characteristics of the fiber. The location, pattern, and accessibility of free and crosslinked cysteines underpin the properties of this network, but have been very difficult to map and understand, because traditional protein extraction techniques require the disruption of these disulfide bonds. Cysteine accessibility in both trichocyte keratins and keratin associated proteins (KAPs) of wool was investigated using staged labeling, where reductants and chaotropic agents were used to expose cysteines in a stepwise fashion according to their accessibility. Cysteines thus exposed were labeled with distinguishable alkylation agents. Proteomic profiling was used to map peptide modifications and thereby explore the role of KAPs in crosslinking keratins. Labeled cysteines from KAPs were detected when wool was extracted with reductant only. Among them were sequences from the end domains of KAPs, indicating that those cysteines were easily accessible in the fiber and could be involved in forming interdisulfide linkages with keratins or with other KAPs. Some of the identified peptides were from the rod domains of Types I and II keratins, with their cysteines positioned on the exposed surface of the α-helix. Peptides were also identified from keratin head and tail domains, demonstrating that they are not buried within the filament structure and, hence, have a possible role in forming disulfide linkages. From this study, a deeper understanding of the accessibility and potential reactivity of cysteine residues in the wool fiber cortex was obtained.

Calpain-2-mediated PTEN degradation contributes to BDNF-induced stimulation of dendritic protein synthesis.

Memory consolidation has been suggested to be protein synthesis dependent. Previous data indicate that BDNF-induced dendritic protein synthesis is a key event in memory formation through activation of the mammalian target of rapamycin (mTOR) pathway. BDNF also activates calpain, a calcium-dependent cysteine protease, which has been shown to play a critical role in learning and memory. This study was therefore directed at testing the hypothesis that calpain activity is required for BDNF-stimulated local protein synthesis, and at identifying the underlying molecular mechanism. In rat hippocampal slices, cortical synaptoneurosomes, and cultured neurons, BDNF-induced mTOR pathway activation and protein translation were blocked by calpain inhibition. BDNF treatment rapidly reduced levels of hamartin and tuberin, negative regulators of mTOR, in a calpain-dependent manner. Treatment of brain homogenates with purified calpain-1 and calpain-2 truncated both proteins. BDNF treatment increased phosphorylation of both Akt and ERK, but only the effect on Akt was blocked by calpain inhibition. Levels of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a phosphatase that inactivates Akt, were decreased following BDNF treatment, and calpain inhibition reversed this effect. Calpain-2, but not calpain-1, treatment of brain homogenates resulted in PTEN degradation. In cultured cortical neurons, knockdown of calpain-2, but not calpain-1, by small interfering RNA completely suppressed the effect of BDNF on mTOR activation. Our results reveal a critical role for calpain-2 in BDNF-induced mTOR signaling and dendritic protein synthesis via PTEN, hamartin, and tuberin degradation. This mechanism therefore provides a link between proteolysis and protein synthesis that might contribute to synaptic plasticity.

Rural print media portrayal of secondhand smoke and smoke-free policy.

The purpose of this article is to describe how the print media portrays secondhand smoke and smoke-free policy in rural communities. Baseline print media clips from an ongoing 5-year study of smoke-free policy development in 40 rural communities were analyzed. The authors hypothesized that community population size would be positively associated with media favorability toward smoke-free policy. Conversely, pounds of tobacco produced and adult smoking prevalence would be negatively associated with media favorability. There was a positive correlation between population size and percentage of articles favorable toward smoke-free policy. The authors did not find a correlation between adult smoking or tobacco produced and media favorability toward smoke-free policy, but we did find a positive relationship between tobacco produced and percentage of pro-tobacco articles and a negative relationship between adult smoking prevalence and percentage of articles about health/comfort. Implications for targeting pro-health media in rural communities as well as policy-based initiatives for tobacco control are discussed.

Efforts to quit smoking by parents of children with asthma.

The objective of this project was to assess the prevalence of (1) tobacco smoke exposure at home among children with asthma and (2) efforts to quit smoking by their parents. We employed a cross sectional survey of 622 parents of children diagnosed by a doctor with asthma. Seventy-five percent of parents reported smoke-free homes. Overall, 85% of parents pledged to keep smoke-free homes, 92% in existing smoke-free homes and 64% in homes with smoke.