Long-term Response Research Articles

Long-Term Outcomes of Rituximab-Treated Adult Patients with Podocytopathies

Background: Long-term outcomes of rituximab-treated adult patients with podocytopathies (either minimal change disease or focal segmental glomerulosclerosis) are largely unknown. Methods: A retrospective study at 30 nephrology departments from 15 countries worldwide included rituximab-treated adults with primary podocytopathies and a minimum clinical follow-up of 36 months. The primary outcome was relapse-free survival at 36 months. Results: 183 adult patients (n=64 with focal segmental glomerulosclerosis and n=119 with minimal change disease) with difficult-to-treat nephrotic syndrome (68% steroid-dependent/frequently relapsing, 22% steroid-resistant, 85% previously treated with two or more lines of immunosuppressive therapy) were treated with rituximab as part of a remission induction regimen. Complete or partial remission at 6 months after rituximab treatment was achieved in 82%. Eighty-three of 151 (55%) initial responders achieved long-term relapse-free survival over three years. Maintenance therapy with rituximab was associated with a better relapse-free survival (HR 2.05, 95% CI: 1.07-3.91), irrespective of the dosing regimen. At 36 months, 61% of initial responders receiving maintenance therapy with rituximab achieved long-term relapse-free survival and withdrawal of all concomitant immunosuppressive medication compared to 36% of patients without maintenance treatment (OR 2.69, 95% CI: 1.27-5.73). Relapses per year were reduced from an annual relapse rate of 1.0 (95% CI: 1.0-1.7) before to 0.17 (95% CI: 0.00-0.24) relapses/year after rituximab initiation. Over the 36 months of follow-up, a stable course of estimated glomerular filtration rate (eGFR) was observed in those who initially responded with either complete or partial remission, whereas non-responders experienced a reduction in eGFR reaching -11 (95% CI: -18 to -8) mL/min/1.73m2 . Conclusions: Rituximab facilitated achievement of initial and long-term response in a majority of adult patients with difficult-to-treat podocytopathies. Maintenance treatment with rituximab further associated with long-term relapse-free survival over three years. Non-response to initial rituximab treatment was associated with poor kidney prognosis.

Venetoclax triggers sublethal apoptotic signaling in venetoclax-resistant acute myeloid leukemia cells and induces vulnerability to PARP inhibition and azacitidine

Venetoclax plus azacitidine treatment is clinically beneficial for elderly and unfit acute myeloid leukemia (AML) patients. However, the treatment is rarely curative, and relapse due to resistant disease eventually emerges. Since no current clinically feasible treatments are known to be effective at the state of acquired venetoclax resistance, this is becoming a major challenge in AML treatment. Studying venetoclax-resistant AML cell lines, we observed that venetoclax induced sublethal apoptotic signaling and DNA damage even though cell survival and growth were unaffected. This effect could be due to venetoclax inducing a sublethal degree of mitochondrial outer membrane permeabilization. Based on these results, we hypothesized that the sublethal apoptotic signaling induced by venetoclax could constitute a vulnerability in venetoclax-resistant AML cells. This was supported by screens with a broad collection of drugs, where we observed a synergistic effect between venetoclax and PARP inhibition in venetoclax-resistant cells. Additionally, the venetoclax-PARP inhibitor combination prevented the acquisition of venetoclax resistance in treatment naïve AML cell lines. Furthermore, the addition of azacitidine to the venetoclax-PARP inhibitor combination enhanced venetoclax induced DNA damage and exhibited exceptional sensitivity and long-term responses in the venetoclax-resistant AML cell lines and samples from AML patients that had clinically relapsed under venetoclax-azacitidine therapy. In conclusion, we mechanistically identify a new vulnerability in acquired venetoclax-resistant AML cells and identify PARP inhibition as a potential therapeutic approach to overcome acquired venetoclax resistance in AML.

Single-cell transcriptional profiling reveals cell type-specific responses to duck reovirus infection in the Bursa of Fabricius of Cairna moschata

Duck reovirus (DRV) is a universal waterfowl virus that causes significant economic losses in the duck industry. However, the role of the host innate immune response of the Bursa of Fabricius to DRV infection is largely unknown. In the present study, we constructed a single-cell resolution transcriptomic atlas of the Bursa of Fabricius of Cairna moschata after infection with HN10 (a novel DRV). Ten cell-type marker genes were used to annotate the cell type, indicating a high degree of cell heterogeneity in the Bursa of Fabricius. Most of the innate and adaptive immune system-related genes were highly expressed in T cells, B cells, neutrophils, macrophages, and DCs. In the Bursa of Fabricius, the proportions of DCs and macrophages were largely increased by HN10 infection at 14 d, suggesting that DCs and macrophages play important roles in the long-term viral response. Notably, a number of innate and adaptive immune system-related genes were highly expressed at 24 h after HN10 infection, indicating that the Bursa of Fabricius has a very strong immune function even in the early developmental stage. In the immune system, the NOD-like receptor signaling pathway and RIG-I-like receptor signaling pathway were significantly activated at the early stage of HN10 infection, while the Toll-like receptor signaling pathway was significantly activated at the late stage. Enrichment analysis suggested that different immune signaling pathways play roles in specific developmental stages. Our data provide an opportunity to reveal the immune response to DRV infection at the single-cell level.

Real-World Clinical Outcomes of Treatment With Olaparib for BRCA1/2 Mutation-Positive Metastatic Breast Cancer in Japanese Patients.

Background Olaparib is effective in the treatment of metastatic breast cancer (MBC) patients, mainly confirmed by deleterious germline BRCA mutations. However, real-world data are scarce. Methodology A total of 10 cases from our institute and 17 cases from the relevant Japanese literature were reviewed. All 27 patients had MBC with confirmed deleterious germline BRCA mutations. Tumor reduction, response duration, disease-free interval (DFI), overall survival (OS), and safety were assessed. Additionally, exploratory research was conducted on the characteristics of a subgroup of patients who had a long-term response to olaparib. Results In the 10 cases from two Juntendo hospitals who received olaparib from July 2018 to December 2021, the median age was 48 years (range = 37-63 years). The same numbers of BRCA1 and BRCA2 mutations and the same ratios of luminal and triple negative (TN) breast cancer cases were observed. The metastatic sites, mainly visceral, included the lungs (n = 4), liver (n = 5), and bone (n = 6). The median duration of drug use was four months (range = 1-36 months). The median number of treatment regimens from metastasis to olaparib administration was 2.0 (range = 1-9 regimens). The median DFI was 21 months (range = 0-106 months). The median OS was not reached (range = 16-191 months). In the subgroup analysis of six cases in which olaparib was effective for four months or more, there was a case where DFI was longer than 100 months. Treatment-related toxicities (TRTs) included neutropenia (n = 5; 50%), anemia (n = 4; 40%), thrombocytopenia (n = 2; 20%), nausea (n = 1; 10%), and fatigue (n = 1; 10%). CTCAE (version 5.0) grade ≥3 TRTs included anemia (n = 1; 10%) and neutropenia (n = 5; 50%). On the other hand, neutropenia was previously said to be as low as 27.3%, lower than anemia (40.0%), in a population including various races. We additionally examined another 17 cases from the Japanese literature. Conclusions To our knowledge, this study reports the first real-world data of Japanese patients with MBC and confirmed deleterious germline BRCA mutations. Our data showed that olaparib is effective in the real world. The incidence of neutropenia seemed higher in Japanese patients.

Unifying creep and fatigue modeling of composites: A time-homogenized micromechanical framework with viscoplasticity and cohesive damage

A micromechanical model for simulating failure of unidirectional composites under cyclic loading has been developed and tested. To efficiently pass through the loading signal, a two-scale temporal framework with adaptive stepping is proposed, with a varying step size between macro time steps, and a fixed number of equally spaced micro time steps in between. With the focus on matrix dominated failure under off-axis loading, viscoplasticity and microcracking are included in the model for the polymer matrix, while carbon fibers are modeled as elastic. For a proper representation of viscous deformation in the matrix under cyclic loading, a two-scale version of the Eindhoven Glassy Polymer constitutive model is formulated, that is based on time homogenization with an effective time increment. The failure state of the representative volume element is reached by the initiation and damaging of cohesive microcracks. Cyclic and static degradation are represented by using Dávila’s fatigue damage function, which is built on top of Turon’s quasi-static cohesive model. The model results are compared with available experimental data on unidirectional carbon/PEEK composites tested at different stress levels, load ratios, frequencies and off-axis angles. Plasticity controlled and crack growth controlled failure mechanisms, characteristic of the long-term response of polymeric composites, are captured by the model, as well as their distinct frequency dependence. As a limit case, the model is able to reproduce the time to failure in creep loading, where the heterogeneous microstructure and viscoplastic flow of the matrix trigger the evolution of quasi-static damage. However, for the studied material system, the present model does not accurately reproduce the load ratio dependence and the off-axis angle dependence of the crack growth controlled failure mechanism.

Long-term breast cancer response to CDK4/6 inhibition defined by TP53-mediated geroconversion

Inhibition of CDK4/6 kinases has led to improved outcomes in breast cancer. Nevertheless, only a minority of patients experience long-term disease control. Using a large, clinically annotated cohort of patients with metastatic hormone receptor-positive (HR+) breast cancer, we identify TP53 loss (27.6%) and MDM2 amplification (6.4%) to be associated with lack of long-term disease control. Human breast cancer models reveal that p53 loss does not alter CDK4/6 activity or G1 blockade but instead promotes drug-insensitive p130 phosphorylation by CDK2. The persistence of phospho-p130 prevents DREAM complex assembly, enabling cell-cycle re-entry and tumor progression. Inhibitors of CDK2 can overcome p53 loss, leading to geroconversion and manifestation of senescence phenotypes. Complete inhibition of both CDK4/6 and CDK2 kinases appears to be necessary to facilitate long-term response across genomically diverse HR+ breast cancers.

C. elegans behavior, fitness, and lifespan, are modulated by AWB/ASH-dependent death perception.

The ability of the nervous system to initiate intricate goal-directed behaviors in response to environmental stimuli is essential for metazoan survival. In this study, we demonstrate that the nematode Caenorhabditis elegans perceives and reacts to dead conspecifics. The exposure to C. elegans corpses as well as corpse lysates activates sensory neurons AWB and ASH, triggering a glutamate-and acetylcholine-dependent signaling cascade that regulates both immediate (aversion) and long-term (survival) responses to the presence of a death signature. We identify increased adenosine monophosphate (AMP) and cysteine concentrations as chemical fingerprints for the presence of metazoan corpses and show that death cue sensing by AWB and ASH leads to physiological changes which promote reproduction at the expense of lifespan. Our findings illuminate a novel signaling paradigm that allows organisms to detect and interpret the environmental enrichment of intracellular metabolites as a death cue.

Efficacy of echolaser smart interface-guided laser ablation in volume reduction of symptomatic benign thyroid nodules.

The management of benign symptomatic thyroid nodules until recent years has been limited to surgery, radioactive iodine treatment, or surveillance which is associated with the burden of morbidity of complications or symptom non-relief as well as cost. Laser ablation has emerged as a minimally invasive alternative, this uses laser energy to thermally ablate nodule tissue, leading to volume reduction and symptom relief. Long-term treatment response data is growing but remains limited in the United States. Our study aims to quantify the effectiveness of laser ablation in reducing the volume of thyroid nodules over a 12 to 18-month period. Retrospective review of data was conducted for 63 adults with cytologically benign, solid symptomatic thyroid nodules ranging from 1.333 cm3 to 103.794 cm3 in volume. Ultrasound-guided laser thermal ablation was performed on all nodules using EchoLaser X4 Smart Interface device with 1064 nm diode laser to deliver total ablation energy (joules), calculated per device guidelines. Serial sonographic volume measurements were conducted 1 month, 3 -6 months, 6 - 12 months, and 12 to 18 months post-ablation intervals. Study cohort was comprised of 63 thyroid nodules. reduction in nodule volume increased progressively over time, with median reductions of 46.05% [STD 21.8] at 1 month, 60.33% [STD 20.1] at 3-6 months, 68.69% [STD 18.8] at 6-12 months, and 64.04% [STD 19.27] at 12-18 months. A total of 62, 56, 42, and 17 nodules had available data for analysis at these respective intervals. This study demonstrated a marked progressive reduction of thyroid nodule volume following ablation. The treatment appears to be consistently effective in reducing symptoms across a wide range of nodule sizes, although the degree of volume reduction varies. The results of our study underscore the potential of laser ablation as a viable treatment option for thyroid nodules, with a sustained reduction in nodule volume observed over an extended post-procedure period.

Long-term responses of intertidal and subtidal seagrasses to anthropogenic disturbances and sea warming in the northwestern pacific coast

Long-term ecological research is imperative for comprehensively understanding how ecosystems respond to environmental changes over time. This study examined the long-term responses of seagrasses (Zostera japonica, Z. marina, and Z caespitosa) in intertidal and subtidal zones to anthropogenic disturbances and sea warming on the southern coast of the Korean peninsula over 15 years (2008–2022). Dramatic declines in the intertidal seagrasses were observed due to human activities such as clam harvesting and oyster cultivation, resulting in the disappearance of almost all Z. japonica in intertidal zones. Subtidal seagrasses, including Z. marina and Z. caespitosa decreased gradually throughout the study period. The biomass and canopy height of the subtidal Z. marina showed an inverse trend against water temperature. In addition, water temperature anomalies such as marine heat waves (MHWs) caused abrupt declines of seagrasses within both the intertidal and subtidal zones. Annually repeated and acute human-induced disturbances were the primary threat to the intertidal seagrass species. Nevertheless, the subtidal seagrasses were primarily affected by unpredictable summer MHWs as well as gradual rising water temperatures, with MHWs causing more dramatic alterations in the coastal seagrass ecosystems compared to gradual SST rising. The continuous decline of seagrasses due to natural and human-induced disturbances will alter the structure of shallow coastal ecosystems, leading to significant changes in the ecosystem services they provide. The results of this study underscore the importance of management actions in coastal seagrass ecosystems and highlight the need to predict future impacts of ongoing climate change.

Transcriptomic insights into mycorrhizal interactions with tomato root: a comparative study of short- and long-term post-inoculation responses.

Arbuscular mycorrhiza (AM) refers to a symbiotic association between plant roots and fungi that enhances the uptake of mineral nutrients from the soil and enables the plant to tolerate abiotic and biotic stresses. Although previously reported RNA-seq analyses have identified large numbers of AM-responsive genes in model plants, such as Solanum lycopersicum L., further studies are underway to comprehensively understand the complex interactions between plant roots and AM, especially in terms of the short- and long-term responses after inoculation. Herein, we used RNA-seq technology to obtain the transcriptomes of tomato roots inoculated with the fungus Rhizophagus irregularis at 7 and 30days post inoculation (dpi). Of the 1,019 differentially expressed genes (DEGs) in tomato roots, 635 genes showed differential expressions between mycorrhizal and non-mycorrhizal associations at the two time points. The number of upregulated DEGs far exceeded the number of downregulated ones at 7 dpi, and this difference decreased at 30dpi. Several notable genes were particularly involved in the plant defense, plant growth and development, ion transport, and biological processes, namely, GABAT, AGP, POD, NQO1, MT4, MTA, and AROGP3. In addition, the Kyoto encyclopedia of genes and genomes pathway enrichment analysis revealed that some of the genes were involved in different pathways, including those of ascorbic acid (AFRR, GME1, and APX), metabolism (CYP, GAPC2, and CAM2), and sterols (CYC1 and HMGR), as well as genes related to cell division and cell cycle (CDKB2 and PCNA). These findings provide valuable new data on AM-responsive genes in tomato roots at both short- and long-term postinoculation stages, enabling the deciphering of biological interactions between tomato roots and symbiotic fungi.

Late Pleistocene to early Holocene vegetation and environmental changes in the tropical Leizhou Peninsula, South China: New evidence from the n-alkane record

Understanding past long-term vegetation responses to regional or even global climate change and forcing mechanisms is essential to future climate change projections. However, due to the lack of long-term terrestrial sedimentary records, there are few studies focusing on vegetation changes in tropical southern China since the last glacial period, especially from the perspective of peat n-alkane records. Here, we have presented a peat core record from the Xialu peatland in the northern Leizhou Peninsula, and n-alkanes were investigated in conjunction with multiple proxy indicators. Our results showed that the organic matter sources were mainly a mixture of aquatic and terrestrial vegetation, with terrestrial vegetation accounting for most of the bulk organic matter composition. From ∼44.1 to 29 cal kyr BP, the organic matter source was mainly dominated by terrestrial vegetation, which corresponds to warm and humid conditions. From 29 to 14 cal kyr BP, the input of the terrestrial vegetation was reduced, the aquatic vegetation input increased, implying cool and dry conditions. From 14 to 9.3 cal kyr BP, the climate gradually became warmer and wetter, and terrestrial vegetation dominated in this area. Overall, the climatic conditions from the Xialu peatland were generally consistent with other records from adjacent areas. Our results suggest that, during the Last Glacial Maximum (LGM), a substantial drop in regional and global sea levels may have been the main cause of drought in tropical southern China on orbital timescales. Meanwhile, several climatic fluctuations on millennial timescales could have been influenced by the variability of the North Atlantic Meridional Overturning Circulation (AMOC) and migration of the Intertropical Convergence Zone (ITCZ).

Intracranial outcomes following neurosurgical resection in patients with brain metastases secondary to HER2-positive breast cancer versus other subtypes.

Neurosurgical resection serves an important role in select patients with breast cancer and brain metastases but can delay systemic therapy and yield complications. Consequently, identification of patients most likely to benefit from surgery is important. Given the poorer long-term intracranial responses to radiotherapy sometimes observed in HER2-positive (HER2 +) patients, we investigated whether neurosurgical resection is differentially beneficial in this population. We identified 633 patients with newly diagnosed brain metastases arising from breast cancer managed at Brigham and Women's Hospital/Dana-Farber Cancer Institute between 2010 and 2022. Patients were stratified by breast cancer subtype: HER2 + (N = 189), hormone receptor positive (HR +)/HER2- (N = 267), and triple negative (N = 177). Per-patient and per-metastasis outcomes were evaluated; interaction models assessing the impact of neurosurgical resection by subtype were constructed. Relative to HR + /HER2- subtype, omission of upfront neurosurgical resection in patients with HER2 + disease was associated with increased subsequent utilization of salvage stereotactic radiation, whole brain radiotherapy, and craniotomy (interaction HR 2.02 [95% CI, 1.04-3.93], p = 0.04; HR 3.92 [95% CI, 1.24-12.40], p = 0.02; HR 4.98 [95% CI, 1.34-18.58], p = 0.02, respectively). Tumors stemming from HER2 + versus HR + /HER2- primaries displayed increased local recurrence when upfront neurosurgical resection was omitted (interaction HR 3.62 [95% CI, 1.06-12.38], p = 0.04). No such associations were noted when comparing triple negative to HR + /HER2- subtype (p-interaction > 0.05 in all cases). Patients with HER2 + disease and brain metastases may disproportionately benefit from upfront neurosurgical resection relative to other subtypes. If validated, our results may suggest a lower threshold to consider surgery in brain metastases secondary to HER2 + breast cancer.

Exceptional sustained long-term complete response to Tepotinib in a MET-amplified advanced intrahepatic biliary tract cancer failing Durvalumab plusCisplatin and Gemcitabine.

Biliary tract cancers (BTCs) are a diverse group of malignancies with varied genetic backgrounds. The prevalence of intrahepatic cholangiocarcinoma (iCC) is increasing, particularly in Western countries. Despite advancements in treatments, the prognosis for BTC remains poor. Recent molecular profiling has revealed that up to 40% of iCC cases have targetable genetic alterations. MET amplification, although rare, presents a significant target for therapy. A 25-year-old female with a history of ulcerative colitis presented with shoulder pain and a positron emission tomography-computed tomography (PET-CT) scan revealed an enlarged liver and multiple metastases. Histopathological analysis diagnosed poorly differentiated adenocarcinoma. First-line therapy with Cisplatin, Gemcitabine, and Durvalumab resulted in disease progression. Molecular profiling identified a TP53 mutation and MET amplification. Based on these findings, Tepotinib was initiated. Tepotinib treatment led to a significant reduction in tumor size and normalization of CA 19-9 levels within 2 months, achieving a complete metabolic remission lasting up to 17 months. The treatment was well tolerated with minimal side effects. MET-amplified BTCs are exceedingly rare, and evidence for targeted treatment is limited. This case demonstrates the efficacy of Tepotinib in a young patient with MET-amplified iCC, showing a long-term response and suggesting a potential new standard treatment option for this molecularly defined entity. This case also highlights the aggressive nature of MET-amplified tumors and the need for targeted second-line therapies. Tepotinib showed remarkable efficacy in treating MET-amplified intrahepatic cholangiocarcinoma, underscoring the importance of molecular profiling in BTCs and suggesting a potential new therapeutic approach for this rare cancer subtype.

B-086 Evaluation of Long-Term Adaptive Immune Responses Specific to SARS-CoV-2: Effect of Various Vaccination and Omicron Exposure

Abstract Background The immune response to SARS-CoV-2 becomes increasingly complex as individuals receive different combinations of vaccines and encounter breakthrough infections. Our study aims to describe the immunogenicity observed over a two-year period in healthy individuals who completed two-dose series and then experienced booster and/or Omicron infection. Methods In June 2023, we recruited 78 healthcare workers who had previously participated in clinical research initiated in March 2021 at a single medical center. At 1, 5, 11, and 25 months after second dose, we assessed SARS-CoV-2-specific humoral and cellular immune responses using commercially available immunoassays and surrogate virus neutralization tests, along with interferon gamma (IFN-γ)-based enzyme-linked immunosorbent spot (ELIspot) assay using SARS-CoV-2 spike peptide pools. Results As the humoral immune response was monitored longitudinally, robust antibody production persisted after the third antigen exposure, in contrast to the rapid decline observed between the second and third dose injections. All immune metrics tended to increase as the number of vaccine doses increased. We also found a trend toward increased humoral immune response in the homologous mRNA-based vaccine group and enhanced cellular immune response in the vector-based primary series with mRNA booster heterologous combination group. Interestingly, no significant difference was found between Omicron exposure through breakthrough infection and bivalent vaccination. Omicron exposure significantly increased the breadth of neutralizing activity, while it did not significantly alter the cross-reactivity in the cellular immune response. Conclusions We identified individuals with diminished neutralization, aiding decisions for future vaccination prioritization. In addition, our findings suggest the role of cellular immunity as an important correlate of long-term protection through cross-reactivity to emerging variants.

Association Between Single-Dose and Longer Term Clinical Response to Stimulants in Attention-Deficit/Hyperactivity Disorder: A Systematic Review of Randomized Controlled Trials.

Objectives: Stimulants, such as methylphenidate (MPH) and amphetamines, represent the first-line pharmacological option for attention-deficit/hyperactivity disorder (ADHD). Randomized controlled trials (RCTs) have demonstrated beneficial effects at a group level but could not identify characteristics consistently associated with varying individual response. Thus, more individualized approaches are needed. Experimental studies have suggested that the neurobiological response to a single dose is indicative of longer term response. It is unclear whether this also applies to clinical measures. Methods: We carried out a systematic review of RCTs testing the association between the clinical response to a single dose of stimulants and longer term improvement. Potentially suitable single-dose RCTs were identified from the MED-ADHD data set, the European ADHD Guidelines Group RCT Data set (https://med-adhd.org/), as updated on February 1, 2024. Quality assessment was carried out using the Cochrane Risk of Bias (RoB) 2.0 tool. Results: A total of 63 single-dose RCTs (94% testing MPH, 85% in children) were identified. Among these, only a secondary analysis of an RCT tested the association between acute and longer term clinical response. This showed that the clinical improvement after a single dose of MPH was significantly associated with symptom improvement after a 4-week MPH treatment in 46 children (89% males) with ADHD. The risk of bias was rated as moderate. A further RCT used near-infrared spectroscopy, thus did not meet the inclusion criteria, and reported an association between brain changes under a single-dose and longer term clinical response in 22 children (82% males) with ADHD. The remaining RCTs only reported single-dose effects on neuropsychological, neuroimaging, or neurophysiological measures. Conclusion: This systematic review highlighted an important gap in the current knowledge. Investigating how acute and long-term response may be related can foster our understanding of stimulant mechanism of action and help develop stratification approaches for more tailored treatment strategies. Future studies need to investigate potential age- and sex-related differences.

P4.11E.24 Clinical Features of Long-Term Response (LTR) to Immune Checkpoint Inhibitors (ICIs) in Patients with Advanced or Recurrent NSCLC

P4.11E.24 Clinical Features of Long-Term Response (LTR) to Immune Checkpoint Inhibitors (ICIs) in Patients with Advanced or Recurrent NSCLC

138P Long-term motor responses to disease-modifying therapies in spinal muscular atrophy (SMA) adults: a prospective study

138P Long-term motor responses to disease-modifying therapies in spinal muscular atrophy (SMA) adults: a prospective study

Self-Assembling Peptides for Vaccine Adjuvant Discovery

Vaccination is credited as a significant medical achievement contributing to the decline in morbidity and mortality of infectious diseases. Traditional vaccines composed of inactivated and live-attenuated whole pathogens confer the induction of potent and long-term immune responses; however, traditional vaccines pose a high risk of eliciting autoimmune and allergic responses as well as inflammations. New modern vaccines, such as subunit vaccines, employ minimum pathogenic components (such as carbohydrates, proteins, or peptides), overcome the drawbacks of traditional vaccines and stimulate effective immunity against infections. However, the low immunogenicity of subunit vaccines requires effective immune stimulants (adjuvants), which are an indispensable factor in vaccine development. Although there are several approved adjuvants in human vaccines, the challenges of matching and designing appropriate adjuvants for specific vaccines, along with managing the side effects and toxicity of existing adjuvants in humans, are driving the development of new adjuvants. Self-assembling peptides are a promising biomaterial rapidly emerging in the fields of biomedicine, vaccination and material science. Here, peptides self-assemble into ordered supramolecular structures, forming different building blocks in nanoparticle size, including fibrils, tapes, nanotubes, micelles, hydrogels or nanocages, with great biostability, biocompatibility, low toxicity and effectiveness at controlled release. Self-assembling peptides are effective immunostimulatory agents used in vaccine development to enhance and prolong immune responses. This review describes the predominant structures of self-assembling peptides and summarises their recent applications as vaccine adjuvants. Challenges and future perspectives on self-assembled peptides as vaccine adjuvants are also highlighted.

349P Comparison of short- and long-term proteomic response to the fast skeletal myosin inhibitor, sevasemten (EDG-5506), in Becker muscular dystrophy (BMD)

349P Comparison of short- and long-term proteomic response to the fast skeletal myosin inhibitor, sevasemten (EDG-5506), in Becker muscular dystrophy (BMD)

Finite element modeling and analysis of tire creep test

Abstract The tire is one of the most complex components of the vehicle, which justifies strict standards and regulations set by governments worldwide to ensure the performance, durability, and reliability of tires approved for use in the transport sector. Among these requirements, tire durability testing involves the assessment of short-and long-term tire response to determine optimum conditions of use and service life. Therefore, this paper focuses on the creep performance of tires using the finite element method in ABAQUS. As a case study, a selected tire with visco-hyperelastic rubber compounds and linear elastic reinforcements is subjected to a constant prescribed force for a period of time, and the resulting strain evolution is recorded till the release of the applied load. Several parameters are accounted for, such as the inflation pressure, material characteristic times, and load amplitude. The post-processing of results enabled the prediction of the overall creep response of the tire over time with respect to the prescribed load. The knowledge gained in this study can be exploited to predict tire failure caused by excessive strain and pinpoint the areas of the tire that are the most exposed to creep failure.