Multimodal Therapy Research Articles

Boron nitride nanotubes as carriers of genistein for multitherapeutic cancer treatment: A DFT study of electronic and solubility properties

Increasing cancer mortality statistics demand more accurate and efficient treatments. Nanostructures have proved to be promising choices in this regard. Nanotubes with large surface areas can play multiple roles from drug carriers in targeted drug delivery to beam absorbers in the photothermal method. While carbon nanotubes (CNTs) show cytotoxicity, Boron Nitride Nanotubes (BNNTs) offer wide bandgap and biocompatibility. In this study, we investigate the electronic and solvation properties of (5,5), (6,6), and (7,7) BNNTs computationally by the density functional theory. For multimodal therapy, we considered Iron (Fe) doping in the BNNT, which can be helpful in hyperthermia due to the magnetic moment of Fe. Our results show that doping has improved the band positions. Furthermore, we implemented an organic anticancer molecule, genistein, a metastasis inhibitor. All potent configurations connecting genistein with BNNT covalently demonstrated enhanced water solubility as compared to pristine and Fe-doped BNNTs. The results suggest that the (7,7) C3 complex is the most stable structure and the best drug carrier.

Highly Stable Near-Infrared II Luminescent Diradicaloids for Cancer Phototheranostics.

Near-infrared II (NIR-II) phototheranostic agents have become prominent agents for the early diagnosis and precise treatment of cancer. Organic open-shell diradicaloids with distinct structure and narrow band gap are promising candidates for phototherapeutic agents due to their strong spin-coupling effect and NIR light-harvesting capacity. However, achieving stable and efficient NIR-II luminescent diradicaloids is crucial yet rather challenging considering their high chemical reactivity and self-absorption. Herein, two highly stable NIR-II luminescent diradicaloids, 2PhNVDPP and PhNVDPP, were successfully fabricated by employing an acceptor planarization/π-conjugation extension and donor rotation strategy. After encapsulation into water-dispersible nanoparticles (NPs), 2PhNVDPP NPs exhibit NIR-II luminescence, high PCE of 53%, and improved photo/heat stability. In vivo experiments with 2PhNVDPP NPs demonstrated the clear visualization of blood vessels and tumors, as well as the successful NIR-II imaging-guided photothermal ablation of tumors. This study not only develops a pioneering stable diradicaloid phototherapeutic agent with NIR-II luminescence but also provides a unique perspective for the effectiveness of multimodal anticancer therapy.

Participants' perspectives on a multimodal stress management and comprehensive lifestyle modification program for patients with Crohn's disease-A qualitative interview study.

Crohn's disease (CD) is a type of inflammatory bowel disease (IBD) that is prevalent worldwide and associated with reduced quality of life for patients. Multimodal therapy approaches, which emphasize lifestyle modifications such as mindfulness and stress reduction, can be promising in enhancing health-related quality of life for IBD patients. However, research on multimodal therapy approaches for CD remains insufficient. This qualitative interview study is part of a mixed-methods approach that is embedded in a randomized controlled trial. It investigates the impact of a comprehensive 10-week day clinic lifestyle modification program on the health condition and quality of life of CD patients. Telephone interviews (n = 19) were conducted three months after the program to examine individuals' viewpoints on the intervention, including perceived changes and transfer of elements into daily life. Reflexive thematic analysis was performed using MAXQDA software. The results indicate that CD can have very individual and comprehensive impacts (psychological, physical, social), leading to reduced perceived quality of life and well-being. By participating in the program, patients wanted to find self-help options to complement conventional pharmacotherapy and actively manage their disease. Patients expressed high satisfaction with the program, feeling it provided valuable support for daily disease management. They were able to integrate adequate therapy elements into their routines to complement their care. Patients recognized significant improvements in various domains, mainly in the psychological domain, e.g., improved self-efficacy, symptom management, and, also partly physical/symptomatic and social improvements. A multimodal stress reduction and lifestyle modification day clinic appears to be beneficial as a complementary therapy for CD patients. It offers additional options and helps patients to address individual symptoms and needs, improve their understanding of the disease and their quality of life. Although promising, further research is needed to assess its long-term effects. ClinicalTrials.gov, identifier: NCT05182645.

OGC SO37 - Pyloric drainage interventions for delayed gastric conduit emptying after oesophagectomy: A single centre analysis

Abstract Background Oesophagectomy in combination with perioperative multimodal therapy is the cornerstone of modern curative treatment for resectable oesophageal cancer. Delayed gastric emptying (DGE) is a common postoperative complication that results from the anatomical and physiological changes in the gastric conduit after an oesophageal resection. It is associated with an increased risk of pneumonia, anastomotic leak and prolonged hospital stay. Although several prophylactic pyloric drainage interventions have been postulated to mitigate the risk of DGE, the optimal modality remains debatable. This study aimed to define the incidence, evaluate prognostic factors, and characterise the management of DGE following oesophagectomy. Method Consecutive patients who underwent an oesophagectomy for oesophageal cancer between January 2022 and March 2024 were retrospectively identified from a hospital database. Pyloric drainage procedures consisted of expectant management, endoscopic/open pyloric Botox and pyloroplasty. Univariable and multivariable analyses were performed to define the incidence of DGE after each pyloric drainage modality, evaluate prognostic factors for DGE, and characterise the need for subsequent intervention in the management of DGE. Results The study cohort comprised 137 patients – mean age 66 years, male 78%. The incidence of DGE was 31%. Pyloroplasty had the lowest incidence of DGE (16%) followed by endoscopic botox (21%). Intra-operative pyloric drainage reduced the risk of DGE (p=0.03). The modality of prophylactic pyloric drainage used significantly influenced the risk of developing DGE (p=0.028). No significant differences were identified between patient demographics, operative approach, and oncological variables in the development of DGE. On multivariable analysis, pyloroplasty was associated with a reduced risk of DGE (OR 0.27, 95% CI 0.09 – 0.71). DGE did not influence overall survival. Conclusion DGE is a common postoperative complication which affects up to 39% of patients undergoing oesophagectomy. Patients who did not undergo a prophylactic pyloric drainage procedure during the index oesophagectomy were at an increased risk of developing DGE. Most patients with DGE (71%) require further intervention via endoscopy and botox injection. Pyloroplasty as a prophylactic drainage modality significantly reduced the risk of developing DGE compared to endoscopic botox. Further prospective randomised controlled trials are required to validate these findings.

Challenges in metastatic hepatocellular carcinoma: beyond tumor stage in guiding treatment.

Extrahepatic metastases in hepatocellular carcinoma (HCC) often signify a poor prognosis. This case details the five-year survival of a patient with HCC and adrenal metastasis managed with an aggressive multimodal approach, including ablation, systemic therapy, and surgical resection. Despite therapeutic advances, metastatic HCC management remains a clinical challenge, underscoring the need for individualized treatment strategies beyond traditional staging systems. Further research is essential to determine the role of surgical resection and other treatment modalities in the metastatic setting.

Clinical Evidence Regarding Spermidine–Hyaluronate Gel as a Novel Therapeutic Strategy in Vestibulodynia Management

Background: Vestibulodynia (VBD) represents a summation and overlapping of trigger factors (infections, hormonal disturbances, allergies, genetic aspects, psychological vulnerability, and others) with broad individual variability. As there are no standard treatment options for VBD, the disease is still in need of appropriate therapeutic tools. Objectives: A prospective observational trial was performed to confirm the efficacy of a topical gel containing a spermidine–hyaluronate complex (UBIGEL donna™) as either a stand-alone or companion treatment through a multicenter study on a large sample population. Methods: For women with VBD (n = 154), the treatment consisted of approximately two months (4 + 4 weeks) of applications according to the posology of UBIGEL. Evaluation of symptoms was performed on relevant clinical endpoints: dyspareunia and vulvovaginal pain/burning by a visual scale (VAS); vestibular trophism by a vestibular trophic health (VeTH) score; vulvoscopy through a cotton swab test; and the level of hypertonic pelvic floor by a physical graded assessment of levator ani hypertonus. Results: A total of 154 patients treated with UBIGEL donna™ showed significant improvements across all five evaluated parameters, including pain, dyspareunia, swab test results, muscle hypertonicity, and vestibular trophism. Pain and dyspareunia scores decreased by 46.5% and 33.5%, respectively, while significant improvements were also observed in the other parameters (p < 0.0001). These improvements were consistent across various stratifications, including age and disease duration. Conclusions: The findings of the present study suggest that UBIGEL donna™ is effective in alleviating pain and dyspareunia, as well as reducing vestibular hypersensitivity in women with VBD. Although UBIGEL donna™ alone cannot serve as a comprehensive substitute for all recommended therapies, we suggest that multimodal therapy strategies may be crucial for attaining substantial improvement in any aspect of the condition.

TMET-07. RADIORESISTANT GLIOBLASTOMA EVADES MITOCHONDRIAL LIPOTOXICITY THROUGH ALTERED DGKB AND DGAT1

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor, with a median survival of only 15 months despite multimodal therapy. Radiotherapy is a conventional therapy of GBM treatment, but the development of radioresistance often leads to tumor recurrence and treatment failure. To elucidate the molecular mechanisms underlying radioresistance in GBM, we established radioresistant GBM cell lines through repeated exposure to ionizing radiation. Transcriptomic analysis revealed that diacylglycerol kinase beta (DGKB), an enzyme that converts diacylglycerol (DAG) to phosphatidic acid, was significantly downregulated in radioresistant GBM cells. Functional studies demonstrated that knockdown of DGKB or expression of a kinase-dead DGKB mutant resulted in DAG accumulation and reduced fatty acid oxidation. Conversely, overexpression of DGKB activated fatty acid oxidation, increased reactive oxygen species (ROS) production, and sensitized GBM cells to radiation. Interestingly, we found that radiation upregulated the expression of diacylglycerol acyltransferase 1 (DGAT1), which catalyzes the conversion of DAG to triglycerides. Knockdown of DGAT1 using shRNA or miR-3918 mimic reduced lipid droplet formation and enhanced radiosensitivity both in vitro and in vivo. Furthermore, using Connectivity Map, we identified cladribine as a potential radiosensitizing agent that increases DGKB and decreases DGAT1. Cladribine effectively sensitized GBM cells to radiation and significantly prolonged the survival of mice bearing GBM xenografts. In conclusion, our study reveals a novel mechanism by which radioresistant GBM cells maintain lipid homeostasis through downregulation of DGKB and upregulation of DGAT1 to evade lethal mitochondrial lipotoxicity. Targeting the DGKB-DGAT1 axis represents a promising therapeutic strategy to overcome radioresistance and improve the outcomes of GBM patients.

Nanotechnology for Nasopharyngeal Cancer Therapy and Improving Drug Stability and Biodistribution

AbstractNasopharyngeal cancer (NPC) is a challenging malignancy with a poor prognosis due to late diagnosis and resistance to conventional treatments. Nanotechnology offers promising solutions to address these limitations by enabling targeted drug delivery, enhancing therapeutic efficacy, and facilitating multimodal treatment strategies. By leveraging the unique properties of nanomaterials and nanocarrier systems, innovative approaches for early detection, targeted treatment, and multimodal therapy can be developed, paving the way for more effective and personalized management of NPC. This review provides a comprehensive overview of recent developments and applications of nanotechnology in NPC therapy, focusing on improving drug stability, biodistribution, and targeted delivery to NPC tumors.

DDDR-18. TARGETTING GLIOBLASTOMA MULTIFORME USING A MULTIACTION ANTICANCER ANTI-INFLAMMATORY THERAPEUTIC STRATEGY

Abstract Glioblastoma multiforme (GBM) represents a significant challenge in adult brain tumor management, characterized by its aggressive nature and poor prognosis despite multimodal therapies. Current standard chemotherapy, Temozolomide (TMZ), offers limited survival benefits. In a recent breakthrough, the cyclic peptide cyclo-((2-Nal)-Leu-Ser-(2-Nal)-Arg) acetate (c2), initially developed for prostate cancer, demonstrates remarkable promise against GBM. By selectively inhibiting the inflammatory phospholipase enzyme sPLA2IIA, c2 significantly impedes GBM cell proliferation, surpassing TMZ efficacy in multiple resistant cell lines. Moreover, c2 exhibits potential to inhibit tumor growth and metastasis, confirmed in 3D tumoroid and wound healing assays. Mechanistic insights reveal modulation of crucial cellular pathways, including viral entry, cytoskeletal structure, and signaling cascades. Preclinical investigations demonstrate c2’s ability to penetrate the blood-brain barrier and attenuate tumor progression markers. At multiple levels, c2 is shown to target inhibition of ERBB2 and EGFR signalling and also have impacts on HIF1-NF-kB axis. This study proposes c2 as a potent anti-GBM candidate, warranting evaluations for its pharmacological profile, safety, and efficacy. With its potential to address the urgent need for effective GBM therapies, c2 holds promise as a significant advancement in GBM treatment, offering hope for improved patient outcomes.

INNV-19. MULTIMODAL THERAPY FOR BRAF V600E MUTANT MELANOMA BRAIN METASTASES: CHARACTERIZATION OF CHRONOLOGICAL TREATMENT STRATEGIES AND ASSOCIATIONS WITH OVERALL SURVIVAL

Abstract BACKGROUND B-raf proto-oncogene (BRAF)-mutant melanoma brain metastases (BRAF MBM) are associated with poor prognosis. Amidst our large institutional experience treating patients with BRAF MBM with multimodality therapy, our aim was to identify disease and treatment-related prognostic features, accounting for longitudinal sequence of events, to inform clinical decision-making. METHODS We retrospectively reviewed electronic health records of 100 patients with primary cutaneous melanoma diagnosed with BRAF MBM. Demographic, disease, and clinical factors including treatment sequencing were tabulated. Descriptive statistics were used to summarize the study population and non-parametric tests were used to evaluate differences across groups. A multivariable Cox regression identified factors associated with overall survival (OS) following BRAF MBM diagnosis. RESULTS Median follow-up was 22 months and median OS was 33.5 months. Patients received an average [standard deviation (SD)] of 3.36 [1.06] unique therapies. After adjustment for covariates, greater number of brain metastases at initial diagnosis (hazard ratio (HR) 2.3 [1.14-4.62], p=0.01 for 3-10 metastases and HR 2.54 [1.01-6.36], p=0.04 for >10 metastases, respectively), receipt of combination IO and targeted therapy prior to BRAF MBM diagnosis (HR 2.91 [1.08-7.86], p=0.03), and receipt of no unique subsequent therapy after initial management strategy (HR 3.89 [1.48-10.16], p=0.005) were significantly associated with worse OS. CONCLUSIONS Despite heterogeneity in individual treatment sequences, patients with greater intracranial disease burden and those receiving combination targeted and immunotherapy prior to BRAF MBM diagnoses had the worst outcomes. Dynamic changes in therapy resistance may inform optimal treatment strategies for individuals with BRAF MBM.

NIMG-47. MULTI-INSTITUTIONAL VALIDATION OF AN AI-BASED MODEL FOR PREDICTION OF TUMOR INFILTRATION AND FUTURE RECURRENCE IN PATIENTS WITH GLIOBLASTOMA: RESULTS FROM THE RESPOND CONSORTIUM

Abstract BACKGROUND Glioblastoma is an infiltrative primary brain tumor with poor prognosis despite multimodal therapy. Recurrence is inevitable secondary to tumor cell infiltration in the peritumoral tissues, beyond contrast enhancing margins, which is the target for surgical resection. We hypothesize that a machine learning model constructed from a diverse, inter-institutional dataset can improve accuracy of generated tumor infiltration maps, thus guiding precision targeted therapies. METHODS 731 MRI scans of treatment-naïve glioblastoma patients from 10 institutions were included. All patients had pre-operative multiparametric-MRI (T1, T1Gd, T2, T2-FLAIR, ADC), and underwent complete resection of the enhancing tumor followed by standard-of-care chemoradiotherapy. 42 patients were used as an independent validation set, and 689 were used for training. Of these 239 patients had histopathologically confirmed recurrence with corresponding MRI scans, which were used as ground-truth for evaluating the location of recurrence using a leave-one-site-out (LSO) method. An AI model combining deep learning and SVM was used to develop a predictive model for infiltration. We validated the generalizability of our results in an unseen, multi-institutional data set. RESULTS Our model predicted locations of recurrence with odds ratio (99% CI) 37.6 (37.1-38.1) on the LSO testing set and 24.3 (23.4-25.2) on the validation set, indicating that areas labeled highly infiltrated were over 37 and 24 times more likely to coincide with future recurrence respectively. CONCLUSIONS We demonstrate that AI-based pattern analysis from multiparametric-MRI can predict tumor infiltration in peritumoral regions with high likelihood of recurrence by decrypting the visually imperceptible heterogeneity of peritumoral tissue. Model performance improved from training on a larger/diverse dataset and combining results of multiple AI methods. Independent validation confirmed the model’s ability to generalize to unseen data. We believe this will serve to advance AI-based biomarkers for predicting future recurrence and facilitate development of multi-modal targeted therapies in this era of precision neuro-oncology.

TMET-15. INVESTIGATING THE IL4I1-AHR AXIS IN GLIOBLASTOMA METABOLISM

Abstract Glioblastoma (GB) is the most frequent and malignant form of primary brain tumors in adults. Despite multi-modal therapy consisting of surgery, radio- and chemotherapy, tumors recur and overall survival remains poor. Previously, we identified that besides the classical tryptophan-catabolizing enzyme tryptophan-2,3-dioxygenase (TDO2), the L-amino acid oxidase interleukin-4-induced 1 (IL4I1) is able to activate the transcription factor aryl hydrocarbon receptor (AHR) via production of downstream metabolites. Activation of the AHR in GB may promote tumor progression e.g. by inhibiting anti-tumor immune responses. In this study, we aim to elucidate further the specific effects of the metabolic enzyme IL4I1 and its metabolites on AHR activation in GB. Further, we set out to identify and validate novel AHR target genes downstream of IL4I1. Harnessing the IL4I1-AHR axis might lead to the development of novel therapy strategies helping to overcome resistance in GB in the future.

STEM-19. TARGETINGGIHCG LNCRNA IN GLIOBLASTOMA STEM CELLS: A POTENTIAL THERAPEUTIC STRATEGY

Abstract Glioblastoma multiforme (GBM) remains the most lethal and prevalent primary brain tumor worldwide. Despite advances in understanding its biology and multimodal therapy options, the overall prognosis for GBM patients remains bleak, primarily due to the high recurrence rate, which is intimately linked to tumor resistance against standard therapeutic interventions. Glioblastoma stem cells (GSCs) contribute to therapeutic resistance and cellular heterogeneity through their self-renewal properties and ability to adapt. Thus, identifying new molecular targets driving GBM progression is crucial for developing effective therapies. Recent advancements in genome biology have revealed that long non-coding RNAs (lncRNAs) play roles in various biological functions, and the dysregulation of numerous lncRNAs has been shown to be associated with specific cancers. To identify GSC-associated lncRNAs, a comprehensive analysis was performed using single-cell RNA sequencing datasets from GBM tumors, GBM organoids, GSC-enriched GBM tumors, as well as normal human brain samples. A chromatin-enriched lncRNA, GIHCG, was identified as being highly expressed in GSCs compared to non-neoplastic neural stem cells. The GIHCG gene, located on human chromosome 12q14.1, is frequently amplified in glioblastoma and impacts overall survival. Bioinformatic and functional analyses revealed that GIHCG is amplified in 13% of GBM patient samples, and high expression of GIHCG is a negative prognostic marker for GBM patients, with significantly reduced overall survival compared to the low expression group. In addition, the depletion of GIHCG significantly reduced GSC proliferation and migration. Further, the knockdown of GIHCG decreased both mRNA and protein expression levels of critical GSC stemness factors, including SOX2, NESTIN, and OLIG2. Moreover, GIHCG depletion reduced the sphere formation capacity of GSCs, demonstrating the functional importance of GIHCG in the maintenance of GSC stemness. These results indicate that GIHCG is essential for GSC proliferation, migration, and stemness, underscoring its potential therapeutic value in RNA-based therapies for combating glioblastoma malignancy.

Variability and repeatability of spinal manipulation force-time characteristics in thoracic spinal manipulation on a manikin.

As part of multimodal therapy, spinal manipulation (SM) is a recommended and effective treatment for musculoskeletal pain. However, the underlying physiological mechanisms for pain relief are largely unknown. SM thrusts can be described and quantified using force-time characteristics (e.g. preload force, peak force, thrust speed, thrust duration, and thrust impulse). If these biomechanical parameters of SM are important for clinical outcomes, a large variability in the delivery of SM could lead to inconsistent responses and could thereby potentially mask a significant clinical effect. Our goal was to determine variability, and repeatability of thoracic spinal manipulation (SM) force-time profiles in a sample of Swiss chiropractors. All interventions were performed on a human analogue manikin. Participating chiropractors received three case scenarios with the following scenarios: 50-year-old male patient, 30-year-old male athlete, and a 70-year-old female patient, each presenting with uncomplicated musculoskeletal thoracic pain. Clinicians were asked to perform three consecutive thoracic SM thrusts for each of the scenarios and repeated the same interventions after 24-48h. Eighty-one chiropractors participated in the study, including 32 females (39.5%) with a mean age of 45.22 ± 12.96years. The variability in SM force-time characteristics between clinicians was substantial, with preload forces ranging from 4.50 to 450.25 N and peak forces ranging from 146.08 to 1285.17 N. Significant differences between case scenarios were observed for peak force (p < 0.0001), maximum thrust speed (p = 0.0002), and thrust impulse (p = 0.0004). Except for thrust duration, repeatability within and between sessions was fair to excellent (ICCs between 0.578 and 0.957). Substantial variability in application of SM was evident across clinicians and between case scenarios. Despite substantial clinician-dependent variability, the high repeatability of thoracic SM thrusts suggests a level of standardization in SM delivery, indicating that chiropractors might have 'their' individual force-time profile that they are capable to reproduce. Further research based on these findings should explore how to enhance the consistency, effectiveness, and safety of thoracic SM delivered clinically to humans.

Two-year Local and Distant Control of Malignant Peripheral Nerve Sheath Tumor (MPNST) in NF1 Patients After Multiple Recurrences: A Case Report

Malignant peripheral nerve sheath tumors (MPNSTs) are rare, biologically high-grade sarcomas that tend to recur and metastasize. The known risk factors for MPNSTs include neurofibromatosis type 1, highly aggressive MPNSTs, and dismal survival outcomes. Multimodality therapies, including surgical resection, radiotherapy, chemotherapy, targeted therapy, and combination therapy, are available. This case report describes a young woman with NF1 who was referred to us with a history of three local recurrences of MPNSTs in the proximal part of her left thigh after several surgical attempts. Successful local and distant control was achieved via preoperative radiotherapy and chemotherapy prior to the latest surgery. With preoperative RT and chemotherapy, more long-term and successful local and distant control was achieved, particularly in high-risk NF1- associated MPNST patients with a history of recurrence. Trials with larger sample sizes may show improvements in local control (LC), disease-free survival (DFS), and overall survival (OS) with neoadjuvant interventions in such patients.

The effects of multimodal versus opioid-only analgesia on pain control and opioid exposure for inpatient acute pancreatitis: A retrospective cohort study.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Acute pancreatitis (AP) is a common gastrointestinal condition that carries a significant financial and physical burden for patients due to the painful presentation and frequent need for hospitalization. Treatment varies in the type and route of analgesic used. Unmanaged pain can lead to worsening health outcomes and prolonged admissions. Further research is needed to understand current practices for managing AP. This study was a retrospective, exploratory, single-center cohort study. Patients admitted to an internal medicine unit with AP from September 1, 2020, to December 31, 2021, were included. Our primary outcome was the change in pain scores during the first 24-hours after administration of the first pain-relieving medication. Secondary outcomes included change in pain scores within the first 12-hours, time to oral tolerance, characterization of analgesic orders, comparison of median pain scores by home analgesic usage, and specific inpatient opioid use. One hundred sixty-nine patients were screened, and 94 were included in the study. Forty-four patients were assigned to the multimodal cohort and 50 patients to the opioid-only cohort. Changes in pain scores per unit of time, assessed by a mixed-effects model, within the first 24 hours were -0.080 (SE, 0.018) in the multimodal cohort and -0.090 (SE, 0.014) in the opioid-only cohort (P = 0.780). Morphine milligram equivalents (MME) administered in the multimodal and opioid-only cohorts were 24.50 (interquartile range [IQR], 51.75) and 52.5 (IQR, 68.5) (P = 0.001), respectively. There was no significant difference in the change in pain scores between patients receiving multimodal therapy and those receiving opioids only. Significantly fewer MME were administered in the multimodal group, suggesting that multimodal therapy can be opioid-sparing in AP.

Multimodal Physical Therapy Management of Subcoracoid Impingement: A Case Report With One-Year Follow-Up and Ultrasound Measurement of Coracohumeral Distance

Multimodal Physical Therapy Management of Subcoracoid Impingement: A Case Report With One-Year Follow-Up and Ultrasound Measurement of Coracohumeral Distance

A diselenide MOF-based nanomotor dual-driven by carbon monoxide and near-infrared-II light for multimodal tumor-targeted therapy

A diselenide MOF-based nanomotor dual-driven by carbon monoxide and near-infrared-II light for multimodal tumor-targeted therapy

Active rest with exercise for pharmacy workers: an ergonomic approach to prevent musculoskeletal injury risk

This study aims to carefully review published articles examining the effect of active rest with exercise to prevent the risk of musculoskeletal injuries among pharmacy workers. Using the systematic literature review method, data were obtained from a thorough search on Google Scholar. The keywords were "Active Rest AND Exercise AND Injury Risk AND Musculoskeletal AND Pharmacy Worker AND Ergonomics". Additionally, inclusion and exclusion criteria were applied to select articles that align with the study objective. For example, it focused on articles indexed in the Scopus database and published between 2019 and 2024. For standard operationalization, this study followed the PRISMA method. Based on the search results, 6,850 articles were found from various sources. Furthermore, the articles went through several stages of the screening process, in which 8 articles that fit the theme and met the inclusion requirements were selected. The results of this study found that active rest programs had a positive impact on the work productivity, physical activity, and physical fitness of pharmacy workers. In addition, an occupational safety and health (OSH) program, a supportive work environment, and the promotion of an active lifestyle with exercise were also important in improving productivity. Adjustment of active rest programs for specific types of workers, effective behavior change interventions, ergonomic education, and multimodal physical therapy have been shown to reduce the risk of musculoskeletal disorders. The findings of this study support the assumption that a comprehensive intervention program can prevent musculoskeletal injuries, improve employee well-being and comfort, and provide guidance for healthcare practitioners and pharmaceutical company managers in designing effective active rest programs.

ASAP1 and ARF1 regulate myogenic differentiation in rhabdomyosarcoma by modulating TAZ activity.

Despite aggressive, multimodal therapies, the prognosis of patients with refractory or recurrent rhabdomyosarcoma (RMS) has not improved in four decades. Because RMS resembles skeletal muscle precursor cells, differentiation-inducing therapy has been proposed for patients with advanced disease. In RAS-mutant PAX fusion-negative RMS (FN-FMS) preclinical models, MEK1/2 inhibition (MEKi) induces differentiation, slows tumor growth, and extends survival. However, the response is short-lived. A better understanding of the molecular mechanisms regulating FN-RMS differentiation could improve differentiation therapy. Here, we identified a role in FN-RMS differentiation for ASAP1, an ARF GTPase-activating protein (ARF GAP) with both pro-invasive and tumor suppressor functions. We found that ASAP1 knockdown inhibited differentiation in FN-RMS cells. Interestingly, knockdown of the GTPases ARF1 or ARF5, targets of ASAP1 GAP activity, also blocked differentiation of FN-RMS. We discovered that loss of ARF pathway components blocked myogenic transcription factor expression. Therefore, we examined the effects on transcriptional regulators. MEKi led to the phosphorylation and inactivation of WWTR1 (TAZ), a homolog of the pro-proliferative transcriptional co-activator YAP1 regulated by the Hippo pathway. However, loss of ASAP1 or ARF1 blocked this inactivation, which inhibits MEKi-induced differentiation. Finally, MEKi-induced differentiation was rescued by dual knockdown of ASAP1 and WWTR1. This study shows that ASAP1 and ARF1 are necessary for myogenic differentiation, providing a deeper understanding of differentiation in FN-RMS and illuminating an opportunity to advance differentiation therapy. Implications: ASAP1 and ARF1 regulate MEKi-induced differentiation of FN-RMS cells by modulating WWTR1 (TAZ) activity, supporting YAP1/TAZ inhibition as a FN-RMS differentiation therapy strategy.