The nutrition-related adverse events associated with immune checkpoint inhibitor treatment for patients with non-small cell lung cancer: A systematic review.

AIMS: Immune checkpoint inhibitor therapy used for lung cancer has significantly changed response and survival rates, however, the impact on patients' nutritional status remains largely unexplored. This review aims to identify common adverse events that increase nutrition risk induced in non-small cell lung cancer patients treated with immune checkpoint inhibitor therapy and assess impact on nutritional status. METHODS: PubMed, Medline and CINAHL were systematically searched in September 2023 for randomised controlled trials comparing immune checkpoint inhibitor treatment of non-small cell lung cancer to a control group. Treatment-related adverse events that increased nutrition impact symptoms identified in the patient-generated subjective global assessment and clinical guidelines were extracted and qualitatively analysed. Risk of bias was assessed using Cochrane Risk of Bias tool 2. RESULTS: Eleven eligible randomised controlled trial studies were identified and analysed. The data demonstrated immune checkpoint inhibitor treatment was associated with a lower percentage of reported nutrition impact symptoms, for example, decreased appetite, nausea, vomiting, compared to chemotherapy treatment. Conversely, immune checkpoint inhibitor treated patients recorded a greater percentage of immune-related adverse events that alter metabolism or nutrient absorption. CONCLUSION: Non-small cell lung cancer patients treated with immune checkpoint inhibitors still experience nutrition impact symptoms but less frequently than patients treated with chemotherapy. This combined with unique nutrition-related consequences from colitis and thyroid disorders induced by immune checkpoint inhibitor therapy indicates patients should be screened, assessed and interventions implemented to improve nutrition.

DFMO inhibition of neuroblastoma tumorigenesis.

BACKGROUND: Most high-risk neuroblastoma patients who relapse succumb to disease despite the existing therapy. We recently reported increased event-free and overall survival in neuroblastoma patients receiving difluoromethylornithine (DFMO) during maintenance therapy. The effect of DFMO on cellular processes associated with neuroblastoma tumorigenesis needs further elucidation. Previous studies have shown cytotoxicity with IC50 values >5-15 mM, these doses are physiologically unattainable in patients, prompting further mechanistic studies at therapeutic doses. METHODS: We characterized the effect of DFMO on cell viability, cell cycle, apoptosis, neurosphere formation, and protein expression in vitro using five established neuroblastoma cell lines (BE2C, CHLA-90, SHSY5Y, SMS-KCNR, and NGP) at clinically relevant doses of 0, 50, 100, 500, 1000, and 2500 µM. Limiting Dilution studies of tumor formation in murine models were performed. Statistical analysis was done using GraphPad and the level of significance set at p = 0.05. RESULTS: There was not a significant loss of cell viability or gain of apoptotic activity in the in vitro assays (p > 0.05). DFMO treatment initiated G1 to S phase cell cycle arrest. There was a dose-dependent decrease in frequency and size of neurospheres and a dose-dependent increase in beta-galactosidase activity in all cell lines. Tumor formation was decreased in xenografts both with DFMO-pretreated cells and in mice treated with DFMO. CONCLUSION: DFMO treatment is cytostatic at physiologically relevant doses and inhibits tumor initiation and progression in mice. This study suggests that DFMO, inhibits neuroblastoma by targeting cellular processes integral to neuroblastoma tumorigenesis at clinically relevant doses.

Development of a Digital Storytelling Intervention to Increase Breast, Cervical, and Colorectal Cancer Screening in the Hispanic/Latino Community: a Qualitative Evaluation.

Digital storytelling (DST) interventions may be one way to address disparities in cancer screening experienced by the Hispanic/Latino population. Digital stories are short, first-person narratives that include voice-over narration and images. With storytellers' permission, researchers can screen digital stories as a health intervention. Digital stories can inspire viewers to adopt or change their behavior, such as completing cancer screening. Rochester Healthy Community Partnership (a 20-year community-based participatory research partnership) together with eight Hispanic/Latino, Spanish speaking cancer survivors, co-survivors, or recently screened individuals, developed digital stories about breast, cervical, and colorectal cancer screening. Here, we describe our qualitative evaluation of the DST workshop. To understand what the storytellers thought viewers would find relatable in their digital stories, we applied Narrative Theory. We also assessed workshop successes and opportunities for improvement. We used the constant comparative method for data analysis. We learned that the storytellers anticipated their stories would be engaging and that viewers would connect with Hispanic/Latino cultural values. During the workshop, the storytellers felt like they were making an important contribution. The storytellers highlighted specific opportunities for improvement including sharing the stories more quickly after the workshop. Future research is needed to test whether this intervention follows the Narrative Theory causal pathway by persuading viewers to complete recommended cancer screenings.

AnimalTraits - a curated animal trait database for body mass, metabolic rate and brain size.

Trait databases have become important resources for large-scale comparative studies in ecology and evolution. Here we introduce the AnimalTraits database, a curated database of body mass, metabolic rate and brain size, in standardised units, for terrestrial animals. The database has broad taxonomic breadth, including tetrapods, arthropods, molluscs and annelids from almost 2000 species and 1000 genera. All data recorded in the database are sourced from their original empirical publication, and the original metrics and measurements are included with each record. This allows for subsequent data transformations as required. We have included rich metadata to allow users to filter the dataset. The additional R scripts we provide will assist researchers with aggregating standardised observations into species-level trait values. Our goals are to provide this resource without restrictions, to keep the AnimalTraits database current, and to grow the number of relevant traits in the future.

Requirement for antiapoptotic MCL-1 during early erythropoiesis.

Although BCL-xL is critical to the survival of mature erythrocytes, it is still unclear whether other antiapoptotic molecules mediate survival during earlier stages of erythropoiesis. Here, we demonstrate that erythroid-specific Mcl1 deletion results in embryonic lethality beyond embryonic day 13.5 as a result of severe anemia caused by a lack of mature red blood cells (RBCs). Mcl1-deleted embryos exhibit stunted growth, ischemic necrosis, and decreased RBCs in the blood. Furthermore, we demonstrate that MCL-1 is only required during early definitive erythropoiesis; during later stages, developing erythrocytes become MCL-1 independent and upregulate the expression of BCL-xL. Functionally, MCL-1 relies upon its ability to prevent apoptosis to promote erythroid development because codeletion of the proapoptotic effectors Bax and Bak can overcome the requirement for MCL-1 expression. Furthermore, ectopic expression of human BCL2 in erythroid progenitors can compensate for Mcl1 deletion, indicating redundancy between these 2 antiapoptotic family members. These data clearly demonstrate a requirement for MCL-1 in promoting survival of early erythroid progenitors.

The Heme-Regulated Inhibitor Pathway Modulates Susceptibility of Poor Prognosis B-Lineage Acute Leukemia to BH3-Mimetics.

Antiapoptotic MCL1 is one of the most frequently amplified genes in human cancers and elevated expression confers resistance to many therapeutics including the BH3-mimetic agents ABT-199 and ABT-263. The antimalarial, dihydroartemisinin (DHA) translationally represses MCL-1 and synergizes with BH3-mimetics. To explore how DHA represses MCL-1, a genome-wide CRISPR screen identified that loss of genes in the heme synthesis pathway renders mouse BCR-ABL+ B-ALL cells resistant to DHA-induced death. Mechanistically, DHA disrupts the interaction between heme and the eIF2α kinase heme-regulated inhibitor (HRI) triggering the integrated stress response. Genetic ablation of Eif2ak1, which encodes HRI, blocks MCL-1 repression in response to DHA treatment and represses the synergistic killing of DHA and BH3-mimetics compared with wild-type leukemia. Furthermore, BTdCPU, a small-molecule activator of HRI, similarly triggers MCL-1 repression and synergizes with BH3-mimetics in mouse and human leukemia including both Ph+ and Ph-like B-ALL. Finally, combinatorial treatment of leukemia bearing mice with both BTdCPU and a BH3-mimetic extended survival and repressed MCL-1 in vivo. These findings reveal for the first time that the HRI-dependent cellular heme-sensing pathway can modulate apoptosis in leukemic cells by repressing MCL-1 and increasing their responsiveness to BH3-mimetics. This signaling pathway could represent a generalizable mechanism for repressing MCL-1 expression in malignant cells and sensitizing them to available therapeutics. IMPLICATIONS: The HRI-dependent cellular heme-sensing pathway can modulate apoptotic sensitivity in leukemic cells by repressing antiapoptotic MCL-1 and increasing their responsiveness to BH3-mimetics.

Effectiveness of Surgical Airway Training Laboratory and Assessment of Skill and Knowledge Fade in Surgical Airway Establishment Among Prehospital Providers.

OBJECTIVE: This study aimed to evaluate the effectiveness of surgical airway education composed of training using cadavers. The secondary aim was to evaluate the presence and degree of knowledge and skill fade 3 months after training. METHODS: Thirteen participants were recruited from a helicopter emergency medical services program. Participants were assessed at multiple points during training using a multiple-choice examination and a timed evaluation of the ability to establish a surgical airway. RESULTS: Training was effective at increasing knowledge and skill, with a mean increase in multiple-choice examination scores of 14.6 percentage points after training (P < .01) and a mean decrease in time to airway establishment of 26 seconds (P < .01). The training was not associated with the ability to establish a surgical airway in less than 40 seconds, with only 46% of participants able to do so. There was no evidence of knowledge or skill fade at 3 months after training. CONCLUSION: Surgical airway training that includes both didactic and clinical learning using human cadavers is effective at increasing both knowledge and skill. Additional training is needed to establish competency in consistently performing surgical airways in less than 40 seconds. No knowledge or skill fade was present at 3 months after training.

Qualitative investigation of the speech-language therapy experiences of individuals who covertly stutter.

PURPOSE: Individuals who covertly stutter have a unique experience of stuttering that involves concealing the core behaviors of stuttering (e.g., repetitions, prolongations, and blocks). From the listener's perspective, covert stuttering results in minimum typical, overt stuttering behaviors. However, from the speaker's perspective, covert stuttering often increases the cognitive and emotional impact of stuttering. This study explores the speech-language therapy experiences of individuals who covertly stutter in order to improve treatment recommendations and best practice. METHODS: This investigation is a qualitative analysis of individuals' speech-language therapy experiences as persons who covertly stutter. Real-time video interviews were conducted with the use of open-ended phenomenological interview questions. Interviews were transcribed and thematic analysis of interview transcripts was conducted to investigate the speech-language therapy experiences of the participants. RESULTS: The participants indicated that stuttering therapy was most impactful when it included explicit goals and activities, personalized selection of therapy techniques or strategies beyond fluency techniques, encouraged self-education, and educated those in the person's environment. CONCLUSION: The evidence suggests individualized therapy based on each client's unique manifestation of covert stuttering is beneficial; while, fluency-focused stuttering therapy is often incongruent with the needs of persons who covertly stutter. Therapeutic implications and recommendations for speech-language pathologists are discussed.

A 20-Year-Old-Trauma Patient With Suspected Malignant Hyperthermia Following Induction With Succinylcholine: A Case Study.

Malignant hyperthermia (MH) is a life-threatening hypermetabolic state that can occur following induction with depolarizing neuromuscular blockade and volatile anesthesia gases. Because succinylcholine is a common choice for prehospital and emergency department inductions, it is important for staff to be able to recognize and effectively treat an MH crisis. This case study highlights a 20-year-old male trauma patient who presented to a Level I trauma center and was intubated for declining mental status. He developed suspected MH following his anesthetic induction with succinylcholine. The following outlines the case, clinical identification of MH, and treatment.

PDE8 Is Expressed in Human Airway Smooth Muscle and Selectively Regulates cAMP Signaling by ß2-Adrenergic Receptors and Adenylyl Cyclase 6.

Two cAMP signaling compartments centered on adenylyl cyclase (AC) exist in human airway smooth muscle (HASM) cells, one containing ß2-adrenergic receptor AC6 and another containing E prostanoid receptor AC2. We hypothesized that different PDE isozymes selectively regulate cAMP signaling in each compartment. According to RNA-sequencing data, 18 of 24 PDE genes were expressed in primary HASM cells derived from age- and sex-matched donors with and without asthma. PDE8A was the third most abundant of the cAMP-degrading PDE genes, after PDE4A and PDE1A. Knockdown of PDE8A using shRNA evoked twofold greater cAMP responses to 1 µM forskolin in the presence of 3-isobutyl-1-methylxanthine. Overexpression of AC2 did not alter this response, but overexpression of AC6 increased cAMP responses an additional 80%. We examined cAMP dynamics in live HASM cells using a fluorescence sensor. PF-04957325, a PDE8-selective inhibitor, increased basal cAMP concentrations by itself, indicating a significant basal level of cAMP synthesis. In the presence of an AC inhibitor to reduce basal signaling, PF-04957325 accelerated cAMP production and increased the inhibition of cell proliferation induced by isoproterenol, but it had no effect on cAMP concentrations or cell proliferation regulated by prostaglandin E2. Lipid raft fractionation of HASM cells revealed PDE8A immunoreactivity in buoyant fractions containing caveolin-1 and AC5/6 immunoreactivity. Thus, PDE8 is expressed in lipid rafts of HASM cells, where it specifically regulates ß2-adrenergic receptor AC6 signaling without effects on signaling by the E prostanoid receptors 2/4-AC2 complex. In airway diseases such as asthma and chronic obstructive pulmonary disease, PDE8 may represent a novel therapeutic target to modulate HASM responsiveness and airway remodeling.

Use of complementary and alternative medicines and supplements by Mexican-origin patients in a U.S.-Mexico border HIV clinic.

This article draws from a study investigating the influence of institutional and psychosocial factors on adherence to antiretroviral (ARV) medications by Mexican-origin persons living with HIV (PWLH) on the U.S.-Mexico border and seeking treatment at a clinic in El Paso, Texas. Among 113 participants, many individuals reported using complementary and alternative medicines (CAM) to support general health and their immune systems and to address symptoms of HIV-related diseases and ARV side effects. CAM were seen as complementing ARV treatment; however, CAM use was often not reported to health care providers out of concern about disapproval and loss of care privileges. This finding challenges researchers and providers to consider seriously how Hispanic populations, with their CAM use, may exhibit the hybridization of health and healing. Information on CAM use needs to be available to providers to assess the benefits and contraindications of use and to develop realistic and effective care strategies.