Therapy Treatment Strategies Research Articles

Effects of low impact elliptical training on knee osteoarthritis outcomes and knee joint space

Background: Different physical therapy treatment strategies are used to decrease the symptoms and reduce the severity of knee Osteoarthritis (OA). Low-impact elliptical training is like mobilizations, which increase nourishment and contribute to increased joint space. Objective: To determine the effects of low-impact elliptical training on knee osteoarthritis (OA) outcomes and knee joint space. Methods: Data for the randomized controlled trial (NCT05977374) was collected from 28 participants through a non-probability convenience sampling technique and randomized into group A: which received low-impact elliptical training along with conventional therapy, and group B: which received traditional physical therapy for 12 weeks. The outcomes were checked through a knee injury and Osteoarthritis Outcome Score (KOOS) pre and post-treatment at the 6th and 12th week and knee space was measured by X-rays pre and post-treatment at the 12th week only. Results: 51.92±9.106 years was the mean age of group A study participants, and 50.29±5.483 years for group B. Within-group analysis, all domains of the KOOS for the low-impact elliptical training group showed significant improvement (p≤0.005). Between-group analyses, all the domains of the KOOS showed a non-significant difference with p≥0.05. In the between-group analysis of the knee joint width of the medial and lateral spaces in pre- and post-observation, there was no significant difference noted, but within the group, significant improvement (p=0.007) was observed in the medial space for the LIET group only Conclusions: Elliptical training can be used to intervene in individuals with grade 1 and 2 knee osteoarthritis compared to conventional physical therapy for the alleviation of pain, stiffness, ADLs, sports, and QOL. Moreover, it may improve knee joint space. elliptical training; knee OA; knee outcome; pain

Molecular Imaging of Tumor-Infiltrating Lymphocytes in Living Animals Using a Novel mCD3 Fibronectin Scaffold.

The interaction between cancer cells and immune cells in the tumor microenvironment (TME) plays a crucial role in determining tumor growth, metastasis, and response to treatment. Tumor-infiltrating lymphocytes (TILs) in TME could be a predictive marker for treatment response in various therapeutic interventions, including chemotherapy and immunotherapy. Thus, imaging the tumor immune microenvironment is important for selecting the optimal treatment strategies in cancer therapy. The CD3 protein represents a promising target for diagnostic imaging of TILs in vivo to assess the immune state of the TME. Although many anti-CD3 antibodies have been explored for this application, the nonspecific immune activation by these antibodies limits their applications. To overcome this issue, we engineered a novel fibronectin III domain (FN3) protein binder (mCD3-FN3;11.8 kDa) against mouse CD3 antigen protein using a yeast display library to image TILs homing in vivo into the TME. We performed in vitro and in vivo assays to test the mCD3-FN3 binder purity as well as in vivo targetability in mouse models of syngeneic tumors. We used near-infrared 800 dye conjugated with mCD3-FN3 (IR800-mCD3-FN3) for in vivo tracking of TILs via optical imaging. We used three different syngeneic tumors in mice (mCD3+ EL4 tumor in C57BL/6 mice, mCD3- CT26 colon tumor, and mCD3- 4T1 breast tumor in BALB/c mice) for imaging TILs in vivo. C57BL/6 mice bearing EL4 tumors were separated into two groups (blocking [Blk] and nonblocking [Nblk]; n = 3 per group) and used for in vivo imaging. Blocking groups received 200 μg of unlabeled mCD3-FN3 2 h prior to the administration of IR800-mCD3-FN3 binder. Each mouse was administered with 25 μg of the IR800-mCD3-FN3 binder and tracked using an IVIS optical imaging system over time. C57BL/6/EL4 mice were imaged at 4 and 24 h post injection of the IR800-mCD3-FN3 binder, and mouse organs were collected at 24 h after final imaging and used for ex vivo histological imaging. In CT26 and 4T1 tumor models, TILs in TME were imaged 4, 24, and 48 h after binder injection. The NIR imaging of EL4 tumors showed that IR800-mCD3-FN3 can detect both TILs within the tumor and the tumor cells with a high signal-to-background ratio 24 h after initial binder injection with a total radiant efficiency (mean TRE ± SD) of 6.5 × 1010 ± 1.5 × 1010 [photons/s]/[μW/cm2]. The animals received preinjection of unlabeled mCD3-FN3(Blk) prior to IR800-mCD3-FN3 binder administration and showed a significant level of fluorescence signal reduction (mean TRE ± SD: 1.6 × 1010 ± 4.1 × 109) in the tumor when compared to the EL4-Nblk tumors (p = 0.006). The mouse group with CT26 and 4T1 tumors where the probe can only bind to TILs within the tumor showed a specific imaging signal (mean TRE ± SD) of 1.1 × 1011 ± 5.2 × 1010 and 9.5 × 1010 ± 4.6 × 1010, respectively, at 48 h p.i. For these groups, the ex vivo tumor-to-muscle ratios were 20- and 27-fold for CT26 and 4T1 tumors, respectively. These results clearly demonstrate the in vivo binding ability of the mCD3-FN3 binder to mCD3 marker expressed by T cells in the TME. The ex vivo histological analysis of tumors, and the organs of animals with EL4 tumors, and TILs imaging of CT26, and 4T1 tumors (at 48 p.i.) confirmed that the IR800-mCD3-FN3 probe was able to specifically bind to CD3 markers expressed by the T cells. In summary, both in vitro and in vivo data indicated that the engineered mCD3-FN3 binder by this study is a promising ligand for diagnostic imaging of tumors in vivo for the assessment of mCD3 expressing TILs in the TME. This can be used as a prognostic marker in evaluating tumor response to therapeutic intervention as well as a diagnostic marker in imaging tumor response to immune checkpoint blockade cancer therapies.

Preventative and curative treatment of venous thromboembolic disease in cancer patients

Cancer-associated venous thromboembolism (CAT) is common in patients with cancer and associated with significant morbidity and mortality. The incidence of CAT continues to rise, complicating patient care and burdening healthcare systems. Patients with cancer experiencing VTE face poorer prognoses, making prevention and effective management imperative. This narrative review synthesizes evidence on thromboprophylaxis in ambulatory patients with cancer receiving systemic therapy and acute treatment strategies for CAT. Risk assessment models (e.g., Khorana score) aid in identifying high-risk patients who may benefit from thromboprophylaxis. Pharmacological thromboprophylaxis with low molecular weight heparins (LMWHs) direct oral anticoagulants (DOACs) has been shown to reduce the risk of CAT without significantly increasing the risk of bleeding complications. However, implementation of risk-based strategies remains limited in clinical practice. For acute CAT management, LMWHs have been the standard of care, but DOACs are increasingly favored due to their convenience and efficacy. However, challenges persist, including bleeding risks and drug interactions. Emerging therapies targeting Factor XI inhibitors present promising alternatives, potentially addressing current limitations in anticoagulation management for CAT.

Impact of Immunosuppressive Therapy, Vaccination, and Monoclonal Antibody Use With Outcomes in Liver and Kidney Transplant Recipients With COVID-19: A Retrospective Study.

Patients who have undergone solid organ transplantation are at an elevated risk of severe coronavirus disease (COVID-19) because of post-transplantation immunosuppressive therapy. However, optimization of vaccination, modification of immunosuppression, and implementation of monoclonal antibody (mAb) therapy in transplant recipients with COVID-19 is uncertain. A retrospective cross-sectional study was conducted on patients who underwent liver or kidney transplants and were diagnosed with COVID-19. The association of several vaccine doses, mycophenolate therapy, and mAB therapy with mortality outcomes after COVID-19 diagnosis (3 and 6 months), hospitalization, and length of hospital stay were assessed. This study included 255 patients with a median age of 59 (23-89) were included. Many COVID-19 vaccine doses were not associated with any outcome; however, patients with a liver transplanted with mycophenolate had higher 3-month (19% vs. 0%; p = 0.02) and 6-month (21% vs. 0%; p = 0.01) mortality rates than those who did not. In addition, transplant recipients who received mAb therapy for COVID-19 were less likely to be hospitalized (37% vs. 68%; p < 0.001). For organ transplant recipients with COVID-19, vaccination alone may not be an optimal strategy for preventing serious outcomes. Rather, the types of organ transplant, immunosuppressive therapy (particularly mycophenolate), and COVID-19 treatment strategy should be synergistically considered to promote an optimal therapeutic dynamic for a vulnerable population.

From metabolic byproduct to immune modulator: the role of lactate in tumor immune escape.

Lactic acid, a key metabolic byproduct within the tumor microenvironment, has garnered significant attention for its role in immune evasion mechanisms. Tumor cells produce and release large amounts of lactic acid into the tumor microenvironment through aberrant glycolysis via the Warburg effect, leading to a drop in pH. Elevated lactic acid levels profoundly suppress proliferation capacity, cytotoxic functions, and migratory abilities of immune effector cells such as macrophages and natural killer cells at the tumor site. Moreover, lactic acid can modulate the expression of surface molecules on immune cells, interfering with their recognition and attack of tumor cells, and it regulates signaling pathways that promote the expansion and enhanced function of immunosuppressive cells like regulatory T cells, thereby fostering immune tolerance within the tumor microenvironment. Current research is actively exploring strategies targeting lactic acid metabolism to ameliorate tumor immune evasion. Key approaches under investigation include inhibiting the activity of critical enzymes in lactic acid production to reduce its synthesis or blocking lactate transporters to alter intracellular and extracellular lactate distribution. These methods hold promise when combined with existing immunotherapies such as immune checkpoint inhibitors and chimeric antigen receptor T-cell therapies to enhance the immune system's ability to eliminate tumor cells. This could pave the way for novel combinatorial treatment strategies in clinical cancer therapy, effectively overcoming tumor immune evasion phenomena, and ultimately improving overall treatment efficacy.

Long-term effects of tocilizumab on retinal and choroidal inflammation in Birdshot uveitis

BackgroundTocilizumab (TCZ), an interleukin-6 receptor antagonist, is approved for treating rheumatic diseases and has demonstrated efficacy in managing refractory non-infectious uveitis (NIU). This retrospective study aimed to investigate the long-term effects of TCZ on inflammation in the retinal and choroidal compartments in Birdshot NIU.MethodsEight patients (16 eyes) received TCZ and were included in the analysis. The primary outcomes measured were inflammatory activity in the retina and choroid, assessed by fluorescein angiography (FA) and indocyanine green angiography (ICGA) using the Angiography Scoring for Uveitis Working Group at baseline, 6, 12, 24, and 36 months.ResultsThe mean follow-up time with TCZ treatment was 33 months. At baseline, the median FA score was 14 (quartiles: 10.25, 15.25), which significantly decreased over time (at 36 months: 8 (5.5, 11); p = 0.004). In contrast, the ICGA score significantly increased within the first year (median at baseline: 5 (4.75, 7.25); at 6 months: 7 (6, 9.25); at 12 months: 7 (6.5, 9.25); p = 0.002), but returned to baseline levels after two years (at 24 months: 5 (5, 6.5); at 36 months: 5.5 (4, 7.5)). Central retinal thickness (CRT) improved significantly after 6 months (median at baseline: 295 µm (275, 322); at 6 months: 275 µm (251, 308); p = 0.01).ConclusionTCZ is effective in reducing retinal vasculitis and CRT in refractory Birdshot uveitis over time, but might be less effective in managing choroidal inflammation. Further studies are needed to determine the optimal treatment strategies for TCZ therapy in NIU.

State-of-the-art therapy and innovative treatment strategies in esophageal squamous cell cancer

SummaryRecent advances in the development of new therapeutic agents and the execution of numerous randomized controlled trials have changed the landscape of systemic therapy approaches in patients with esophageal squamous cell cancer (ESCC). Particularly the inclusion of immunotherapy permits clinicians to improve patient management in multiple settings. This review gives an overview of standard-of-care treatment and sheds light on new therapeutic options, recently approved treatments, and ongoing trials.

Evaluating corticosteroid treatment strategies for cardiac sarcoidosis: analysis of the nationwide claims-based JROAD-DPC dataset

Abstract Background Corticosteroid-based immunosuppressive therapy is the cornerstone of treatment for cardiac sarcoidosis (CS), aimed at preventing severe adverse events including death, heart failure and lethal arrhythmic events. Nevertheless, data on the optimal initial dosing, appropriate tapering schedules, suitable maintenance dosages, and the recurrence rates among patients are insufficient. Purpose This study sought to scrutinize real-world data on corticosteroid therapy regimen for CS and to reassess optimal treatment protocols. Methods From the Japanese Diagnosis Procedure Combination database, 6,282 patients with hospitalized CS were identified between 2012 and 2022. Among them, 3,067 CS patients who were initiated on corticosteroid therapy during hospitalization were analyzed. We examined the baseline patient characteristics and treatment strategies for corticosteroid therapy, including starting dose, tapering period, maintenance dose, and their correlation with the onset of adverse events. Results The cohort had a mean age was 63±11 years, and 1,256 patients (41.0 %) were female. The starting dose of corticosteroids was 30.3±6.9 mg, with 88.6% of patients receiving a dose of ≧30 mg/day. The doses of corticosteroids at 30, 60, 90, 120, 150 and 180 days post-discharge were 21.4±9.8, 15.7±6.9, 12.2±5.7, 10.4±5.0, 9.3±4.5 and 9.0±4.6 mg, respectively. By day 180, 83.7% of the patients were maintained on ≦10 mg/day. However, 17.1 % of patients required an increase in corticosteroid dosage during the tapering course, primarily due to exacerbation of sarcoidosis. When analyzing only the group without corticosteroid escalation up to 180 days post-discharge, the average corticosteroid dose was 8.7±3.8 mg, with 95.3% of patients on ≦10 mg/day. We observed 965 re-hospitalization (31.5 %) during follow-up, with 58.8% of these patients having corticosteroid escalation to ≧30 mg, and 12.8% of patients received second-line immunosuppressive therapy, such as methotrexate. Conclusion The majority of CS patients were initiated on a corticosteroid regimen of 30 mg/day, which was subsequently tapered to below 10 mg/day by day 180. However, non-negligible number of patients experienced clinical events or relapse, underscoring the necessity for vigilant follow-up during corticosteroid therapy.Figure

Bioinformatics investigation of the prognostic value and mechanistic role of CD9 in glioma

In recent years, CD9 has been extensively studied as a potential biomarker for cancer. However, the biological role of CD9 in gliomas remains unclear. This study investigates the function of CD9 in gliomas and its molecular mechanisms. Utilizing pan-cancer analysis with TCGA, CGGA, and GEO databases, differential expression of CD9 was observed in 11 tumor types within the TCGA cohort, and it was associated with patient survival rates. Analysis of the CGGA glioma database revealed that patients with high CD9 expression had lower survival rates. The area under the ROC curve (AUC) for GSE16011 was greater than 0.7, indicating a high discriminative ability. Through gene set enrichment analysis (GSEA), immune-related analysis, and CD9 mutation detection, CD9 was found to have the strongest correlation with neutrophil involvement (cor = 0.30, P < 0.05), and the high CD9 expression group exhibited higher rejection responses and TIDE scores, suggesting a lower likelihood of successful immunotherapy. The high CD9 expression group was more sensitive to 81 drugs, indicating potential therapeutic effects for gliomas. Furthermore, overexpression of CD9 in gliomas may be associated with gene mutations. Down-regulation or up-regulation of CD9 expression in the glioblastoma cell line LN229 showed that CD9 could positively regulate the migratory ability of LN229 cells. Further, several marker genes, such as VEGFR-2, TGF-β1, CASP1 and PI3K, were down regulated in CD9 knockdown cell lines and up regulated in CD9 overexpression cell lines, compared with control cell line. This study preliminarily explores the role of CD9 in gliomas and its prognostic value, providing new insights for personalized treatment strategies in glioma therapy.

Unraveling the neuroprotective potential of scalp electroacupuncture in ischemic stroke: A key role for electrical stimulation

This study aims to explore the neuroprotective effects of scalp Electroacupuncture (EA) on ischemic stroke, with a specific focus on the role of electrical stimulation (ES). Employing a rat model of middle cerebral artery occlusion (MCAO), we used methods such as Triphenyl tetrazolium chloride staining, micro-CT scanning, Enzyme linked immunosorbent assay (ELISA), and immunofluorescence to assess the impacts of EA. We further conducted RNA-seq analysis and in vitro experiments with organotypic brain slices and cerebral organoids to explore the underlying mechanisms. Our research revealed that EA notably reduced cerebral infarct volume and improved regional cerebral blood flow in rats following MCAO. Micro-CT imaging showed improved vascular integrity in EA-treated groups. Histological analyses, including HE staining, indicated reduced brain tissue damage. ELISA demonstrated a decrease in pro-inflammatory cytokines TNF-α, IL-1β, and IL-6, suggesting improved blood–brain barrier function. Immunofluorescence and Western blot analyses revealed that EA treatment significantly inhibited microglial and astrocytic overactivation. RNA-seq analysis of brain tissues highlighted a downregulation of immune pathways and inflammatory responses, confirming the neuroprotective role of EA. This was further corroborated by in vitro experiments using organotypic brain slices and cerebral organoids, which showcased the efficacy of electrical stimulation in reducing neuroinflammation and protecting neuronal cells. The study highlights the potential of scalp EA, particularly its ES component, in treating ischemic stroke. It provides new insights into the mechanisms of EA, emphasizing its efficacy in neuroprotection and modulation of neuroinflammation, and suggests avenues for optimized treatment strategies in stroke therapy.

Contemporary National Incidence and Outcomes of Acute Limb Ischemia

Acute limb ischemia (ALI) is a morbid and deadly diagnosis. However, existing epidemiologic studies describing ALI predate the introduction of the Affordable Care Act in 2010 and direct oral anticoagulants in 2011. Thus, we synergized the National Inpatient Sample (NIS) and United States Census to define contemporary trends in the incidence, treatment, and outcomes of ALI in the US. We included emergent admissions of adults with primary diagnosis of lower extremity ALI in survey-weighted NIS data (2005-2020). Mann-Kendal trend test evaluated ALI incidence (primary outcome), anticoagulation usage, insurance coverage, revascularization type, and in-hospital amputation/death. Multivariable logistic regression quantified covariate associations with in-hospital amputation/death. Of the 582,322,862 estimated hospitalizations in the NIS, 227,440 met the inclusion criteria (mean age 68.80years, 49.94% women, 76.66% White). ALI incidence peaked in 2006 (7.16/100,000 person-years) but has declined since 2015 to 4.16/100,000 person-years in 2020 (ptrend=0.008). Endovascular revascularization, anticoagulation, and Medicaid coverage increased, while self-pay insurance decreased (ptrend < 0.05). Amputation rates significantly decreased from 8.04 to 6.54% (ptrend=0.01) while death rate remained at 5.59% (ptrend=0.16) over the study period. Prehospitalization anticoagulation was associated with decreased amputation (adjusted odds ratio [aOR]=0.74 (95% confidence interval [CI] 0.65-0.84)) and death (aOR=0.50 (95% CI 0.43-0.57)). When controlling for covariates, women had a higher risk of death (aOR=1.17 (95% CI 1.07-1.27), P<0.0001), while Black patients had a higher risk of amputation (aOR=1.24 (95% CI 1.10-1.41), P<0.0001). Our US population based epidemiological study demonstrates that ALI incidence and in-hospital amputation rates are decreasing, while mortality remains unchanged. We further highlight the ongoing need for ALI investigation specifically as it relates to access to care, antithrombotic therapy use, treatment strategy, and strategies to combat gender and racial disparities.

Identification of Immune Infiltration-related Molecular Features in Ovarian Cancer Patients and Experimental Validation of Immune Response Molecular Mechanisms through Integrated WGCNA, Machine Learning, and Single-cell Sequencing Analysis.

Ovarian cancer is one of the most common gynecological malignancies globally, and immunotherapy has emerged as a promising treatment strategy in recent years. However, the effectiveness of immunotherapy is often limited by immune escape mechanisms. To unravel the immune response mechanisms in ovarian cancer, this study aimed to employ integrated Weighted Gene Co-expression Network Analysis (WGCNA), machine learning, and single-- cell sequencing analysis to systematically investigate immune infiltration-related molecular features in ovarian cancer patients and experimentally validate the molecular mechanisms of the immune response. This research may provide a new theoretical foundation and treatment strategy for immune-based therapies in ovarian cancer. Relevant ovarian cancer datasets were collected from public databases. The ConsensusCluster- Plus and ggplot2 R packages were used to perform dimensionality reduction and clustering analysis of immune infiltration-related genes. Various algorithms were employed to select the best ovarian cancer prognostic model with OC consistency. The prognostic value of angiogenesis and immune-related gene expression was evaluated through Kaplan-Meier survival analysis, and the impact of immune infiltration on immune function in ovarian cancer patients was assessed. Functional pathways were identified using the Gene Set Enrichment Analysis (GSEA) method, and the infiltration abundance of immune and stromal components was inferred using the single-sample Gene Set Enrichment Analysis (ssGSEA) method. The influence of angiogenesis on the cellular level of Ovarian Cancer (OC) was explored in single- cell sequencing data, followed by in vitro cell experiments for further validation. The effect of the angiogenesis model on OC was evaluated through the above-mentioned research and experiments, aiming to investigate the mechanism of targeted therapy strategies in ovarian cancer. Immune-related data were collected from ovarian cancer patients in this study. Through WGCNA analysis, the MEturquoise module was identified, and a total of 1018 hub genes were determined. A prediction model was constructed using machine learning, with CoxBoost+StepCox selected as the best model, leading to the identification of 10 genes associated with ovarian cancer. Patients with high AIDPS had shorter survival time, and GSEA analysis revealed enrichment in immune-related pathways. Single-sample gene set enrichment analysis demonstrated increased immune cell infiltration and malignant stromal changes in the high AIDPS group. Results from in vitro cell experiments showed that silencing RPL31 inhibited the proliferation and migration of ovarian cancer cells while enhancing immune response capability. AIDPS holds significant clinical significance in Ovarian Cancer (OC) with poor prognosis observed in patients with high AIDPS. These patients exhibit more significant genomic variations, denser immune cell infiltration, and greater tolerance toward immune therapy. Importantly, inhibiting the expression of RPL31, a key component of AIDPS, can significantly suppress the proliferation, migration, and invasive properties of ovarian cancer cells, while stimulating the cytotoxicity of effector T cells and promoting immune response, thus slowing down the progression of ovarian cancer.

Impact of emotional states on tinnitus sound therapy efficacy based on ECG signals and emotion recognition model

BackgroundDiagnosis and severity assessment of tinnitus are mostly based on the patient's descriptions and subjective questionnaires, which lacks objective means of diagnosis and assessment bases, the accuracy of which fluctuates with the clarity of the patient's description. This complicates the timely modification of treatment strategies or therapeutic music to improve treatment efficacy. New methodWe employed a novel random convolutional kernel-based method for electrocardiogram (ECG) signal analysis to identify patients' emotional states during Music Tinnitus Sound Therapy (Music-TST) sessions. Then analyzed correlations between emotional changes in different treatment phase and Tinnitus Handicap Inventory (THI) score differences to determine the impact of emotions on tinnitus treatment efficacy. ResultsThis study revealed a significant correlation between patients' emotion changes during Music-TST and the therapy's effectiveness. Changes in arousal and dominance dimension, were strongly linked to THI variations. These findings highlight the substantial impact of emotional responses on sound therapy's efficacy, offering a new perspective for understanding and optimizing tinnitus treatment. Comparison with existing methodsCompared to existing methods, we proposed an objective indicator to assess the progress of sound therapy, the indicator could also be used to provide feedback to optimize sound therapy music. ConclusionsThis study revealed the critical role of emotion changes in tinnitus sound therapy. By integrating objective ECG-based emotion analysis with traditional subjective scale like THI, we present an innovative approach to assess and potentially optimize therapy effectiveness. This finding could lead to more personalized and effective treatment strategies for tinnitus sound therapy.

Tailored Treatment Strategies in First Line Therapy for Ovarian Cancer Patients: A Critical Review of the Literature.

Ovarian cancer (OC) is a significant cause of cancer-related mortality in women globally, with a five-year survival rate of approximately 49%. Standard therapy involves cytoreductive surgery followed by chemotherapy. Its poor prognosis has driven interest in alternative therapies such as targeted molecular agents like bevacizumab and poly (ADP-ribose) polymerase inhibitors (PARPi). This review systematically searched PubMed from January 2018 to December 2023 for studies on PARPi in OC. Emphasis was on identifying relevant Phase III trials, extracting data on study design, patient demographics, and outcomes. Special focus was on assessing PARPi efficacy, safety, impact on quality of life, and ongoing trials, including those on Clinicaltrials.gov. The efficacy of PARPi in first-line therapy for OC has been extensively studied. Trials like SOLO-1, PRIMA, and ATHENA-MONO have demonstrated significant improvements in progression-free survival (PFS) and overall survival (OS), particularly in patients with BRCA mutations. Additionally, the combination of PARPi with other agents like bevacizumab has shown promising results in extending PFS. However, PARPi treatment is associated with various adverse effects, including hematologic toxicities like anemia, thrombocytopenia, and neutropenia. While most adverse events are manageable, some patients may require dose adjustments or discontinuation of treatment. Importantly, PARPi maintenance therapy has not adversely affected health-related quality of life (HRQoL), with studies reporting similar HRQoL scores between PARPi-treated and placebo-treated patients. PARPi offer effective treatment with manageable side effects, suitable even for medically fragile patients. Individualized dosing can optimize benefits while minimizing adverse events. Exploring diverse treatment approaches, particularly in patients with limited life expectancy or high disease burden, could improve outcomes. Ongoing research is investigating alternative therapies and combinations to broaden treatment options. Combining bevacizumab with PARPi may be justified for first-line and recurrent maintenance therapy. Regardless of mutational status, PARPi should be considered for maintenance therapy in newly diagnosed advanced OC. Platinum sensitivity remains crucial for treatment decisions and predicting survival outcomes.

The Importance of Early Physical Therapy Intervention in Fighting Post-surgical Sequelae in a Patient with Cerebral Abscess

The primary objective of this research was to highlight the importance of early physical therapy intervention in fighting neurological sequelae following surgical intervention and improving the patient's level of independence in cases of cerebral abscess. The study was based on identifying the degree of neuro-motor impairment immediately after the surgery, followed by establishing a specific physical therapy intervention strategy based on the identified manifestations. The subjects included in the study had a common clinical diagnosis of cerebral abscess and the presence of neurological sequelae post-surgery. The physical therapy approach consisted of neuro-proprioceptive facilitation techniques and methods, considered the most effective in such pathologies. The results obtained from the initial and final evaluations of the patients included in the study and their interpretationhighlighted that the early application of neuro-motor and proprioceptive facilitation techniques allowed achieving favorable results and reaching the proposed objectives.

Expert consensus on the diagnosis and treatment of respiratory diseases exacerbated by nonsteroidal anti-inflammatory drugs （2024, Chengdu）

Non-steroidal anti-inflammatory drugs-exacerbated respiratory disease （N-ERD） is a chronic respiratory disease characterized by eosinophilic inflammation, featuring chronic rhinosinusitis （CRS）, asthma, and intolerance to cyclooxygenase 1 （COX-1） inhibitors. The use of these medications can lead to an acute worsening of rhinitis and asthma symptoms. This condition has not yet received sufficient attention in China, with a high rate of misdiagnosis and a lack of related research. The Chinese Rhinology Research Group convened a group of leading young experts in otolaryngology from across the country, based on the latest domestic and international evidence-based medical practices to formulate this consensus.The consensus covers the epidemiology, pathogenesis, clinical manifestations, diagnostic methods, and treatment strategies for N-ERD, including pharmacotherapy, surgery, biologic treatments, and desensitization therapy. The goal is to improve recognition of N-ERD, reduce misdiagnosis, and enhance treatment outcomes.

Positive feedback regulation between glycolysis and histone lactylation drives oncogenesis in pancreatic ductal adenocarcinoma

BackgroundMetabolic reprogramming and epigenetic alterations contribute to the aggressiveness of pancreatic ductal adenocarcinoma (PDAC). Lactate-dependent histone modification is a new type of histone mark, which links glycolysis metabolite to the epigenetic process of lactylation. However, the role of histone lactylation in PDAC remains unclear.MethodsThe level of histone lactylation in PDAC was identified by western blot and immunohistochemistry, and its relationship with the overall survival was evaluated using a Kaplan-Meier survival plot. The participation of histone lactylation in the growth and progression of PDAC was confirmed through inhibition of histone lactylation by glycolysis inhibitors or lactate dehydrogenase A (LDHA) knockdown both in vitro and in vivo. The potential writers and erasers of histone lactylation in PDAC were identified by western blot and functional experiments. The potential target genes of H3K18 lactylation (H3K18la) were screened by CUT&Tag and RNA-seq analyses. The candidate target genes TTK protein kinase (TTK) and BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) were validated through ChIP-qPCR, RT-qPCR and western blot analyses. Next, the effects of these two genes in PDAC were confirmed by knockdown or overexpression. The interaction between TTK and LDHA was identified by Co-IP assay.ResultsHistone lactylation, especially H3K18la level was elevated in PDAC, and the high level of H3K18la was associated with poor prognosis. The suppression of glycolytic activity by different kinds of inhibitors or LDHA knockdown contributed to the anti-tumor effects of PDAC in vitro and in vivo. E1A binding protein p300 (P300) and histone deacetylase 2 were the potential writer and eraser of histone lactylation in PDAC cells, respectively. H3K18la was enriched at the promoters and activated the transcription of mitotic checkpoint regulators TTK and BUB1B. Interestingly, TTK and BUB1B could elevate the expression of P300 which in turn increased glycolysis. Moreover, TTK phosphorylated LDHA at tyrosine 239 (Y239) and activated LDHA, and subsequently upregulated lactate and H3K18la levels.ConclusionsThe glycolysis-H3K18la-TTK/BUB1B positive feedback loop exacerbates dysfunction in PDAC. These findings delivered a new exploration and significant inter-relationship between lactate metabolic reprogramming and epigenetic regulation, which might pave the way toward novel lactylation treatment strategies in PDAC therapy.

Retrospective Analysis of Steady-State Sodium Valproate Plasma Concentrations in Chinese Patients With Bipolar Disorder: Impact of Demographic and Clinical Characteristics.

This study comprehensively examined the demographic and clinical characteristics of patients undergoing valproic acid therapy and explored their potential impact on plasma valproic acid concentrations. All enrolled patients were administered the extended-release formulation. An in-depth investigation of factors, including dose, age, sex, body mass index, co-administered medications, and laboratory test findings, was conducted to evaluate their potential influence on study outcomes. In total, 164 patients met the inclusion criteria and were included in the analysis. The patient age ranged from 13 to 60 years, with a median age of 25.71 years. Most patients (89%) received a daily dose of 1 g valproic acid. Co-administered psychiatric medications included aripiprazole, quetiapine, and lorazepam. Laboratory test results, such as hemoglobin and transaminase levels, were also collected as part of the study. The average plasma valproic acid plasma concentration was 79.8 mg/L. The dose significantly affected valproic acid concentrations, as a higher percentage of measurements exceeded the therapeutic range at a daily dose of 1 g. Furthermore, females exhibited significantly higher valproic acid concentrations compared with males at the same dose ( P < 0.05). However, different age groups showed no statistically significant differences in valproic acid concentrations ( P > 0.05). The co-administered antipsychotic and antidepressant medications significantly affected valproate concentrations, as reflected in the multiple regression model ( P < 0.01). This study offers valuable insights into the demographic and clinical characteristics of patients undergoing valproic acid therapy. It highlights the influence of dose, sex, and concomitant medications on plasma valproic acid concentrations. Overall, these findings can help guide dose adjustments and implement personalized treatment strategies in valproic acid therapy.

Abstract 1531: TIL analysis demonstrates different mechanisms underlying PD-1 resistance in animal models

Abstract Despite the tremendous success of PD-1 immunotherapy in treating cancer, resistance to the therapy is an inevitable risk. One of the major mechanisms underlying this resistance is alterations in the tumor microenvironment, including tumor-infiltrating lymphocyte (TIL) profiling changes after anti-PD1 treatment. To better understand the mechanism of PD-1 resistance, characterization of TILs in the tumor microenvironment was explored. First, immune cell profiling was performed in syngeneic tumor models established by 19 cancer cell lines without anti-PD-1 treatment. Depending on the tumor model, absolute numbers of CD45+ cells and immune cell subsets varied. Moreover, stratifying the analysis based on tumor size (100 mm3 to 3000 mm3) revealed alterations in the proportion of immune cell percentages in MC38 tumors, which implies alterations in TIL frequency during cancer progression. Next, we investigated the TIL profile in two PD-1 resistant models: a hPD-1 antibody-induced resistant model and a syngeneic model in aged mice. The hPD-1 antibody resistant model was induced by multiple rounds of hPD-1 antibody retreatment on MC38 tumor-bearing humanized B-hPD-1/hPD-L1 mice. Efficacy results from this model further validated their resistance to hPD-1 treatment (0% tumor growth inhibition (TGI)), while the control group, which was not serially treated, showed substantial tumor inhibition (82.2% TGI). Next, mPD-1 antibody resistance was evaluated in aged wild-type mice. While mPD-1 efficacy on MC38-bearing young mice was approximately 85.5% TGI, the efficacy of this treatment in aged mice yielded only 6% TGI. TIL analysis in these models was subsequently performed: in the hPD-1-treated control mice that were responsive to anti-PD1 treatment, the numbers of total T cells, cytotoxic T cells (CD8+) and MHC II positive cells were increased, while the anti-tumor effector cells in the serially treated resistant mice were either unchanged (total T cells and MHC II positive cells) or decreased (CD8+ cells); strikingly, an increase in inhibitory myeloid-derived suppressor cell (MDSC) populations was also observed in the resistant model post-treatment. In the anti-PD1 treated aged mice, the frequency of TILs was unchanged upon mPD-1 treatment, suggesting that resistance in aged mice may be due to non-responsiveness of the immune cells. In sum, our results demonstrate different mechanisms underlying anti-PD-1 resistance, and suggest that a more thorough analysis of the TILs present in the tumor microenvironment could predict the responsiveness to PD-1 therapy and inform treatment strategies. Citation Format: Sha Qiao, Yujia Liu, Wei Liu, Wenqian Pan, Xiaofei Zhou, Linlin Wang, Mengya Chai, Yujie Liu, Hao Yang, Zhaoxue Yu. TIL analysis demonstrates different mechanisms underlying PD-1 resistance in animal models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1531.

Innovative Nanoparticulate Strategies in Colon Cancer Treatment: A Paradigm Shift.

As a major public health issue, colorectal cancer causes 9.4% of total cancer-related deaths and comprises 10% of new cancer diagnoses worldwide. In the year 2023, an estimated 153,020 people are expected to receive an identification of colorectal cancer (CRC), resulting in roughly 52,550 fatalities anticipated as a result of this illness. Among those impacted, approximately 19,550 cases and 3750 deaths are projected to occur in individuals under the age of 50. Irinotecan (IRN) is a compound derived from the chemical structure of camptothecin, a compound known for its action in inhibiting DNA topoisomerase I. It is employed in the treatment strategy for CRC therapies. Comprehensive in vivo and in vitro studies have robustly substantiated the anticancer efficacy of these compounds against colon cancer cell lines. Blending irinotecan in conjunction with other therapeutic cancer agents such as oxaliplatin, imiquimod, and 5 fluorouracil enhanced cytotoxicity and improved chemotherapeutic efficacy. Nevertheless, it is linked to certain serious complications and side effects. Utilizing nano-formulated prodrugs within "all-in-one" carrier-free self-assemblies presents an effective method to modify the pharmacokinetics and safety portfolio of cytotoxic chemotherapeutics. This review focuses on elucidating the mechanism of action, exploring synergistic effects, and innovating novel delivery approaches to enhance the therapeutic efficacy of irinotecan.