Liposomes-enabled cancer chemoimmunotherapy.

Chemoimmunotherapy is an emerging paradigm in the clinic for treating several malignant diseases, such as non-small cell lung cancer, breast cancer, and large B-cell lymphoma. However, the efficacy of this strategy is still restricted by serious adverse events and a high therapeutic termination rate, presumably due to the lack of tumor-targeted distribution of both chemotherapeutic and immunotherapeutic agents. Targeted drug delivery has the potential to address this issue. Among the most promising nanocarriers in clinical translation, liposomes have drawn great attention in cancer chemoimmunotherapy in recent years. Liposomes-enabled cancer chemoimmunotherapy has made significant progress in clinics, with impressive therapeutic outcomes. This review summarizes the latest preclinical and clinical progress in liposome-enabled cancer chemoimmunotherapy and discusses the challenges and future directions of this field.

Degradation of bisphenol F by peroxymonosulfate activated with palladium-based catalysts.

In this study, supported Pd catalysts were prepared and used as heterogeneous catalysts for the activation of peroxymonosulfate (PMS) which successfully degrade bisphenol F (BPF). Among the supported catalysts (i.e., Pd/SiO2, Pd/CeO2, Pd/TiO2 and Pd/Al2O3), Pd/TiO2 exhibited the highest catalytic activity due to the high isoelectric point and high Pd0 content. Pd/TiO2 prepared by the deposition method leads to high Pd dispersion, which are the key factors for efficient BPF degradation. The influencing factors were investigated during the reaction process and two possible degradation pathways were proposed. Density functional theory (DFT) calculations demonstrate that stronger BPF adsorption and BPF degradation with lower reaction barrier occurs on smaller Pd particles. The catalytic activities are strongly dependent on the structural features of the catalysts. Both experiments and theoretical calculations prove that the reaction is actuated by electron transfer rather than radicals.

Novel insights on the Pd speciation in Pd/SSZ-13 and on the role of H2O in the Pd reduction by CO.

Pd speciation induced by the combined effect of CO and water on Pd/SSZ-13 samples prepared by both impregnation and ion exchange was examined by FT-IR spectroscopy of CO adsorbed at room temperature and at liquid nitrogen temperature on anhydrous and hydrated samples. Starting from the literature findings related to the CO reducing effect on Pd cations, the present work gives precise spectroscopic evidences on how water is necessary in this process not only for compensating with H+ the zeolite exchange sites set free by Pd reduction, but also for mobilizing isolated Pd2+/Pd+ cations and making possible the reduction reactions. The aggregation of some Pd+ sites, just formed by the reduction and mobilized by the hydration, gives rise to the formation of Pd2O particles. Also, Pd0(100) sites are observed with CO on hydrated sample, formed by the aggregation and reduction of isolated Pd cations. Moreover, Pd0(111) sites are formed on the surface of PdOx particles during CO outgassing. The observation of the combined effect of water and CO allowed to define assignments of IR bands related to carbonyls of Pd in different oxidation states and coordination degrees.

Bioactive nanocomposite hydrogel enhances postoperative immunotherapy and bone reconstruction for osteosarcoma treatment.

Osteosarcoma, a malignant bone tumor often characterized by high hedgehog signaling activity, residual tumor cells, and substantial bone defects, poses significant challenges to both treatment response and postsurgical recovery. Here, we developed a nanocomposite hydrogel for the sustained co-delivery of bioactive magnesium ions, anti-PD-L1 antibody (αPD-L1), and hedgehog pathway antagonist vismodegib, to eradicate residual tumor cells while promoting bone regeneration post-surgery. In a mouse model of tibia osteosarcoma, this hydrogel-mediated combination therapy led to remarkable tumor growth inhibition and hence increased animal survival by enhancing the activity of tumor-suppressed CD8+ T cells. Meanwhile, the implanted hydrogel improved the microenvironment of osteogenesis through long-term sustained release of Mg2+, facilitating bone defect repair by upregulating the expression of osteogenic genes. After 21 days, the expression levels of ALP, COL1, RUNX2, and BGLAP in the Vis-αPD-L1-Gel group were approximately 4.1, 5.1, 5.5, and 3.4 times higher than those of the control, respectively. We believe that this hydrogel-based combination therapy offers a potentially valuable strategy for treating osteosarcoma and addressing the tumor-related complex bone diseases.

Highly efficient catalytic transfer hydrogenation for the conversion of nitrobenzene to aniline over PdO/TiO2: The key role of in situ switching from PdO to Pd.

The reduction of nitrobenzene to aniline is very important for both pollution control and chemical synthesis. Nevertheless, difficulties still remain in developing a catalytic system having high efficiency and selectivity for the production of aniline. Herein, it was found that PdO nanoparticles highly dispersed on TiO2 support (PdO/TiO2) functioned as a highly efficient catalyst for the reduction of nitrobenzene in the presence of NaBH4. Under favorable conditions, 95% of the added nitrobenzene (1 mmol/L) was reduced within 1 min with an ultra-low apparent activation energy of 10.8 kJ/mol by using 0.5%PdO/TiO2 as catalysts and 2 mmol/L of NaBH4 as reductants, and the selectivity to aniline even reached up to 98%. The active hydrogen species were perceived as dominant species during the hydrogenation of nitrobenzene by the results of isotope labeling experiments and ESR spectroscopic. A mechanism was proposed as follows: PdO activates the nitro groups and leads to in-situ generation of Pd, and the generated Pd acts as the reduction sites to produce active hydrogen species. In this catalytic system, nitrobenzene prefers to be adsorbed on the PdO nanoparticles of the PdO/TiO2 composite. Subsequently, the addition of NaBH4 results in in-situ generation of a Pd/PdO/TiO2 composite from the PdO/TiO2 composite, and the Pd nanoclusters would activate NaBH4 to generate active hydrogen species to attack the adsorbed nitro groups. This work will open up a new approach for the catalytic transfer hydrogenation of nitrobenzene to aniline in green chemistry.

Insight into the bimetallic structure sensibility of catalytic nitrate reduction over Pd-Cu nanocrystals.

Catalytic reduction of nitrate over bimetallic catalysts has emerged as a technology for sustainable treatment of nitrate-containing groundwater. However, the structure of bimetallic has been much less investigated for catalyst optimization. Herein, two main types of Pd-Cu bimetallic nanocrystal structures, heterostructure and intermetallic, were prepared and characterized using high-resolution transmission electron microscopy (HRTEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). The results show that two individual Pd and Cu nanocrystals with a mixed interface exist in the heterostructure nanocrystals, while Pd and Cu atoms are uniformly distributed across the intermetallic Pd-Cu nanocrystals. The catalytic nitrate reduction experiments were carried out in a semibatch reactor under constant hydrogen flow. The nitrate conversion rate of the heterostructure Pd-Cu nanocrystals supported on α-Al2O3, γ-Al2O3, SBA-15, and XC-72R exhibited 3.82-, 6.76-, 4.28-, 2.44-fold enhancements relative to the intermetallic nanocrystals, and the nitrogen and nitrite were the main products for the heterostructure and intermetallic Pd-Cu nanocrystals, respectively. This indicates that the catalytic nitrate reduction over Pd-Cu catalyst is sensitive to the bimetallic structures of the catalysts, and heterostructure bimetallic nanocrystals exhibit better catalytic performances on both the activity and selectivity, which may provide new insights into the design and optimization of catalysts to improve catalytic activity and selectivity for nitrate reduction in water.

Soluble PD-L1 as a novel biomarker predicts poor outcomes and disease progression in de novo myelodysplastic syndromes.

The role of the compromised immune microenvironment, including immune checkpoints, in myelodysplastic syndromes (MDS) has been identified as critical This study aimed to investigate the expression patterns of immune checkpoints, particularly soluble PD-1/PD-L1 (sPD-1/sPD-L1) as well as PD-1 on effector T cell subsets, and assess their prognostic value and potential regulatory roles in MDS. 161 MDS patients were enrolled, including 129 patients were primarily diagnosed with de novo MDS, together with 59 MDS patients who underwent hypomethylating agents (HMAs) therapy. Plasma sPD-L1 level was elevated in newly diagnosed MDS patients, which was also found to be associated with MDS disease progression that further increase in higher IPSS-R score group. Patients with increased sPD-L1 expression at diagnosis exhibited notably poorer overall survival, and multivariate Cox analysis indicated that elevated sPD-L1 was an independent risk factor. Furthermore, the levels of multiple cytokines and membrane-bound PD-1 on T cells were found to correlate with sPD-1/sPD-L1 levels in plasma. Importantly, we also found sPD-L1 levels significantly increased in MDS patients who showed progression of disease following HMAs therapy. In conclusion, we found elevated plasma sPD-L1 levels in MDS patients are associated with disease progression and poorer overall survival. This study showed that sPD-L1 is a potential biomarker for prognosis and a target for immunotherapy in MDS.

Biomarker role of thyroid irAE and PD-L1 positivity in predicting PD-1 blockade efficacy in patients with non-small cell lung cancer.

Thyroid immune-related adverse events (irAEs) are associated with programmed cell death protein 1 (PD-1) blockade efficacy in non-small cell lung cancer (NSCLC). However, their independence from PD-L1 expression and quantitative impact on predicting PD-1 blockade efficacy remain unexplored. This multicenter, retrospective, longitudinal study from Korea included 71 metastatic NSCLC patients who underwent PD-L1 expression and thyroid function testing during PD-1 blockade. Disease progression by the Response Evaluation Criteria for Solid Tumors was the main outcome. Three-stage analyses were performed: (1) multivariate Cox regression models adjusted for PD-L1 expression according to thyroid irAEs; (2) subgroup analyses; (3) regrouping and comparing predictivity of current and alternative staging. Patients with thyroid irAE + exhibited a longer progression-free survival [7/20 vs. 34/51, adjusted HR 0.19 (0.07-0.47); P < 0.001] than those with thyroid irAE-, independent of PD-L1 expression; the results remained across most subgroups without interaction. The three groups showed different adjusted HR for disease progression (Group 1: PD L1 + and thyroid irAE + ; Group 2: PD-L1 + or thyroid irAE + : 5.08 [1.48-17.34]; Group 3: PD-L1- and thyroid irAE- : 30.49 [6.60-140.78]). Alternative staging (Group 1 in stage IVB → stage IVA; Group 3 in stage IVA → stage IVB) improved the prognostic value (PVE: 21.7% vs. 6.44%; C-index: 0.706 vs. 0.617) compared with the 8th Tumor-Node-Metastasis staging. Our study suggests thyroid irAEs and PD-L1 expression are independent biomarkers that improve predicting PD-1 blockade efficacy in NSCLC. Thyroid irAEs would be helpful to identify NSCLC patients who benefit from PD-1 blockade in early course of treatment.

First-line pembrolizumab with or without chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma: 5-year follow-up of the Japanese population of KEYNOTE­048.

BACKGROUND: Previously reported results from phase III KEYNOTE-048 demonstrated similar or improved overall survival (OS) with pembrolizumab or pembrolizumab-chemotherapy versus cetuximab-chemotherapy (EXTREME) in Japanese patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). We report results in Japanese patients from KEYNOTE-048 after 5 years of follow-up. METHODS: Patients with R/M HNSCC of the oropharynx, oral cavity, hypopharynx, or larynx were randomly assigned 1:1:1 to pembrolizumab, pembrolizumab-chemotherapy, or EXTREME. Primary endpoints were OS and progression-free survival. Efficacy was evaluated in the programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20, PD-L1 CPS ≥ 1, and total Japanese populations. RESULTS: In Japan, 67 patients were enrolled (pembrolizumab, n = 23; pembrolizumab-chemotherapy, n = 25; EXTREME, n = 19). Median follow-up was 71.0 months (range, 61.2-81.5); data cutoff, February 21, 2022. 5-year OS rates with pembrolizumab versus EXTREME were 35.7% versus 12.5% (hazard ratio [HR] 0.38; 95% CI 0.13-1.05), 23.8% versus 12.5% (HR 0.70; 95% CI 0.34-1.45), and 30.4% versus 10.5% (HR 0.54; 95% CI 0.27-1.07) in the PD-L1 CPS ≥ 20, CPS ≥ 1, and total Japanese populations, respectively. 5-year OS rates with pembrolizumab-chemotherapy versus EXTREME were 20.0% versus 14.3% (HR 0.79; 95% CI 0.27-2.33), 10.5% versus 14.3% (HR 1.18; 95% CI 0.56-2.48), and 8.0% versus 12.5% (HR 1.11; 95% CI 0.57-2.16) in the PD-L1 CPS ≥ 20, CPS ≥ 1, and total Japanese populations, respectively. CONCLUSION: After 5 years of follow-up, pembrolizumab and pembrolizumab-chemotherapy showed long-term clinical benefits; results further support these treatments as first-line options for Japanese patients with R/M HNSCC. CLINICAL TRIAL REGISTRATION: NCT02358031.

Interplay of α-Synuclein Oligomers and Endoplasmic Reticulum Stress in Parkinson'S Disease: Insights into Cellular Dysfunctions.

Oligomeric forms of α-synuclein (α-syn) are critical in the formation of α-synuclein fibrils, exhibiting neurotoxic properties that are pivotal in the pathogenesis of Parkinson's disease (PD). A salient feature of this pathology is the disruption of the protein folding capacity of the endoplasmic reticulum (ER), leading to a perturbation in the ER's protein quality control mechanisms. The accumulation of unfolded or misfolded proteins instigates ER stress. However, the onset of ER stress and the consequent activation of the Unfolded Protein Response (UPR) and Endoplasmic Reticulum-Associated Degradation (ERAD) pathways do not merely culminate in apoptosis when they fail to restore cellular homeostasis. More critically, this condition initiates a cascade of reactions involving ER-related structures and organelles, resulting in multifaceted cellular damage and, potentially, a feedback loop that precipitates neuroinflammation. In this review, we elucidate the interplay between UPR and ERAD, as well as the intricate crosstalk among the ER and other organelles such as mitochondria, lysosomes, and the Golgi apparatus, underscoring their roles in the neurodegenerative process.

Current progress of anti­PD­1/PDL1 immunotherapy for glioblastoma (Review).

Glioblastoma (GBM) is the most common central nervous system malignancy in adults. GBM may be classified as grade IV diffuse astrocytoma according to the 2021 World Health Organization revised classification of central nervous system tumors, which means it is the most aggressive, invasive, undifferentiated type of tumor. Immune checkpoint blockade (ICB), particularly anti­programmed cell death protein­1 (PD­1)/PD­1 ligand­1 immunotherapy, has been confirmed to be successful across several tumor types. However, in GBM, this treatment is still uncommon and the efficacy is unpredictable, and <10% of patients show long­term responses. Recently, numerous studies have been conducted to explore what factors may indicate or affect the ICB response rate in GBM, including molecular alterations, immune expression signatures and immune infiltration. The present review aimed to summarize the current progress to improve the understanding of immunotherapy for GBM.

Enhancements in Parkinson's Disease Management: Leveraging Levodopa Optimization and Surgical Breakthroughs.

Parkinson's disease (PD) is a complex neurological condition caused due to inheritance, environment, and behavior among various other parameters. The onset, diagnosis, course of therapy, and future of PD are thoroughly examined in this comprehensive review. This review also insights into pathogenic mechanisms of reactive microgliosis, Lewy bodies, and their functions in the evolution of PD. It addresses interaction complexity with genetic mutations, especially in genes such as UCH-L1, parkin, and α-synuclein, which illuminates changes in the manner dopaminergic cells handle proteins and use proteases. One of the emerging therapeutic routes that are being investigated is neuroprotective medicines that aim to prevent the aggregation of α-synuclein and interventions that modify the progression of diseases. The review concludes by stressing the dynamic nature of PD research and the potential game-changing impact of precision medicines on current approaches to therapy. This raises the improved outcomes and life quality for those with PD. Potential treatments for severe PD include new surgical methods like Deep Brain Stimulation (DBS). Further, exploration of non-motor manifestations, such as cognitive impairment, autonomic dysfunction, and others, is covered in this review article. These symptoms have a significant impact on patients' quality of life. One of the emerging therapeutic routes that are being investigated is neuroprotective medicines that aim to prevent the aggregation of α-synuclein and interventions that modify the progression of diseases. The review concludes by stressing the dynamic nature of PD research and the potential game-changing impact of precision medicines on current approaches to therapy.

Tumor-Activated Neutrophils Promote Lung Cancer Progression through the IL-8/PD-L1 Pathway.

BACKGROUND: Lung cancer remains a major global health threat due to its complex microenvironment, particularly the role of neutrophils, which are crucial for tumor development and immune evasion mechanisms. This study aimed to delve into the impact of lung cancer cell-conditioned media on neutrophil functions and their potential implications for lung cancer progression. METHODS: Employing in vitro experimental models, this study has analyzed the effects of lung cancer cell-conditioned media on neutrophil IL-8 and IFN-γ secretion, apoptosis, PD-L1 expression, and T-cell proliferation by using techniques, such as ELISA, flow cytometry, immunofluorescence, and CFSE proliferation assay. The roles of IL-8/PD-L1 in regulating neutrophil functions were further explored using inhibitors for IL-8 and PD-L1. RESULTS: Lung cancer cell lines were found to secrete higher levels of IL-8 compared to normal lung epithelial cells. The conditioned media from lung cancer cells significantly reduced apoptosis in neutrophils, increased PD-L1 expression, and suppressed T-cell proliferation and IFN-γ secretion. These effects were partially reversed in the presence of IL-8 inhibitors in Tumor Tissue Culture Supernatants (TTCS), while being further enhanced by IL-8. Both apoptosis and PD-L1 expression in neutrophils demonstrated dose-dependency to TTCS. Additionally, CFSE proliferation assay results further confirmed the inhibitory effect of lung cancer cell-conditioned media on T-cell proliferation. CONCLUSION: This study has revealed lung cancer cell-conditioned media to modulate neutrophil functions through regulating factors, such as IL-8, thereby affecting immune regulation and tumor progression in the lung cancer microenvironment.

Glucose-6-phosphate dehydrogenase deficiency detection using fluorocytometric assay: Evaluation after 1 year of clinical implementation.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common enzymopathy that affects red blood cells (RBCs) and renders them susceptible to oxidative stress. G6PD deficiency can cause hemolytic anemia, especially after exposure to certain drugs or infections. The diagnosis of G6PD deficiency is usually based on spectrophotometric measurement of enzyme activity, but this method has limitations in heterozygous females and in patients with other hematological disorders. In this study, we evaluated the use of flow cytometry as an alternative method for detecting G6PD deficiency in 514 samples (265 females and 249 males) from a clinical laboratory. We compared the results of flow cytometry with those of spectrophotometry and molecular analysis, and assessed the performance of flow cytometry in different subgroups of patients. We found that flow cytometry was able to identify G6PD deficiency in most cases, with high sensitivity and specificity. Flow cytometry also allowed the quantification of the percentage of G6PD-deficient RBCs, which varied among heterozygous females due to X-chromosome inactivation. Moreover, flow cytometry detected several cases of G6PD deficiency that were missed by spectrophotometry, especially in heterozygous females with normal or subnormal enzyme activity. However, flow cytometry also showed some false negative results, mainly in patients with sickle cell disease. Therefore, flow cytometry is a reliable and efficient tool for screening G6PD deficiency, but some precautions should be taken in interpreting the results in patients with other hematological conditions.

Window of opportunity trials with immune checkpoint inhibitors in triple-negative breast cancer.

Patients with triple-negative breast cancer (TNBC) have a relatively poor clinical outcome. The immune checkpoint inhibitor (ICI) pembrolizumab combined with chemotherapy is the current standard of care in TNBC patients with stage II and III. Monotherapy with ICIs has not been comprehensively assessed in the neoadjuvant setting in TNBC patients, given unfavorable results in metastatic trials. ICIs, however, have been tested in the window of opportunity (WOO) before surgery or standard chemotherapy-based neoadjuvant treatment. The WOO design is well suited to assess an ICI alone or in combination with other ICIs, targeted therapy, radiotherapy or cryotherapy, and measure their pharmacodynamic and clinical effect in this treatment-naive population. Some patients show a good response to ICIs in WOO studies. Biomarkers like tumor-infiltrating lymphocytes, programmed death ligand-1, and interferon-γ signature may predict activity and may identify patients likely to benefit from ICIs. Moreover, an increase in tumor-infiltrating lymphocytes, programmed death ligand-1 expression or T cell receptor expansion following administration of ICIs in the WOO setting could potentially inform of immunotherapy benefit, which would allow tailoring further treatment. This article reviews WOO trials that assessed immunotherapy in the early-stage TNBC population, and how these results could be translated to test de-escalation strategies of neoadjuvant chemotherapy and immunotherapy without compromising a patient's prognosis.

Efficacy of PD-1 inhibitor with neoadjuvant chemotherapy in hypopharyngeal and oropharyngeal cancer.

Objective: This study is aimed to evaluate the efficacy and safety of PD-1 inhibitors combined with neoadjuvant chemotherapy in patients with locally advanced hypopharyngeal and oropharyngeal cancer prior to surgical resection. Methods: This retrospective analysis included 42 patients diagnosed with locally advanced hypopharyngeal and oropharyngeal cancer. The efficacy, safety, survival, and laryngeal preservation rate were evaluated. Results: A total of 42 patients were included in this retrospective analysis, of whom 28 had hypopharyngeal cancer and 14 had oropharyngeal cancer. Of the 42 patients, 14 (33.3%) achieved a pathological complete response (PCR) at the primary site, 20 (47.6%) achieved a major pathological response (MPR), and 8 (19%) had an incomplete pathological response (IPR) at the primary lesion. A PCR at both the primary site and the neck lymph nodes was observed in 9 patients (21.4%). The laryngeal preservation rate was 92.9% (26/28) in patients with hypopharyngeal cancer. The median follow-up time was 10.5 months. The median progression-free survival (PFS) was 26.42 months (95% CI, 23.416-29.424), and the median overall survival (OS) was 27.1 months (95% CI, 24.316-29.884). The 1-year PFS rate was 83.1%, and the 1-year OS rate was 85.9%. Conclusion: Combination therapy with PD-1 inhibitors and neoadjuvant chemotherapy has demonstrated superior efficacy and safety as a preoperative treatment for locally advanced hypopharyngeal and oropharyngeal cancer. Notably, this treatment regimen does not increase the risk of severe postoperative complications and has shown promising results in improving laryngeal preservation rates.

Precision Imaging in Neurodegeneration: The Superiority of Diffusion Tensor Imaging Over Conventional MRI in Differentiating Parkinson's Disease From Atypical Parkinsonian Syndromes.

Background Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra, leading to motor and non-motor symptoms. Atypical parkinsonian syndromes (APS), including progressive supranuclear palsy (PSP) and essential tremor (ET), present with overlapping clinical features, making differential diagnosis challenging. Conventional MRI has limitations in distinguishing PD from APS, necessitating advanced imaging techniques like diffusion tensor imaging (DTI) for more accurate diagnosis. Objectives This retrospective study aimed to evaluate the diagnostic accuracy of DTI in diagnosing PD and APS, particularly assessing its ability to differentiate these conditions from each other compared to conventional MRI. Additionally, the study sought to determine if DTI could diagnose PD in cases where conventional MRI results were normal, thereby highlighting the potential role of DTI in enhancing diagnostic precision in neurodegenerative disorders. Methodology The study included 30 patients with clinically diagnosed PD or APS who underwent both conventional MRI and DTI. Data were collected retrospectively. Imaging was performed using a Philips Multiva 1.5-Tesla MRI scanner (Philips, Amsterdam, Netherlands). DTI sequences were analyzed for fractional anisotropy (FA) values in the substantia nigra, superior cerebellar peduncle, middle cerebellar peduncle, transverse pontine fibers, and dentate nucleus. The FA values were compared with established normal values, and the findings from DTI were correlated with clinical diagnoses and conventional MRI results. Results Among the 30 patients, 53.3% were clinically diagnosed with PD and 46.7% with APS, including PSP and ET. Conventional MRI findings were normal in 46.7% of cases, indicating its limitations in detecting early or subtle changes in neurodegenerative disorders. In contrast, DTI identified abnormalities in 83.3% of cases, demonstrating its superior diagnostic sensitivity. DTI detected significant FA value reductions in the substantia nigra in PD patients (mean FA: 0.440), which is consistent with the degeneration of dopaminergic neurons characteristic of PD. In PSP patients, the superior cerebellar peduncle showed marked FA reductions (mean FA: 0.523), correlating with the clinical features of PSP, such as bradykinesia and postural instability. ET was identified by reduced FA values in the superior cerebellar peduncle and dentate nucleus, distinguishing it from other forms of parkinsonism. DTI was particularly effective in cases where conventional MRI results were inconclusive or normal, identifying early-stage PD and differentiating it from APS with greater accuracy. The study demonstrated a sensitivity of 95.8% and specificity of 93.8% for DTI in differentiating PD from APS compared to conventional MRI. Conclusion This study highlights DTI as a superior imaging modality for the early diagnosis and differentiation of parkinsonian disorders, particularly when conventional MRI results are inconclusive. DTI's ability to detect significant microstructural changes in specific brain regions, evidenced by FA value reductions, enhances diagnostic accuracy. Incorporating DTI into routine clinical practice is essential for accurate differentiation between PD and APS, facilitating better patient management.

Progression patterns in patients with advanced hepatocellular carcinoma treated with local therapy, targeted drugs, and PD-1/PD-L1 inhibitors.

Introduction: To explore the progression patterns of advanced hepatocellular carcinoma (HCC) in patients treated with a combination of local therapies, targeted drugs, and PD-1/PD-L1 inhibitors. Material and methods: A retrospective study involving 86 patients with Barcelona Clinic Liver Cancer stage C HCC was conducted between August 2018 and April 2022. All patients received local therapy, targeted drugs, and PD-1/PD-L1 inhibitors. Disease progression was evaluated using computed tomography or magnetic resonance imaging after combination therapy. Peripheral blood immune cells were analyzed using flow cytometry. Results: For intrahepatic progression, the median time to first progression was 5.3 months in 60 patients (95% confidence interval (CI): 2.3-7.1 months), and the median time to second progression was 9.3 months in 40 patients (95% CI: 4.8-11.8 months, p < 0.0001). For extrahepatic progression, the median time to first progression was 5.8 months in 61 patients (95% CI: 1.6-8.4 months), and the median time to second progression was 8.7 months in 39 patients (95% CI: 4.5-10.9 months, p < 0.0001). The common sites of extrahepatic progression are the lymph nodes and lungs. The percentages of PD-1+ cells gradually decreased after combination treatment but then gradually increased at follow-up in extrahepatic progression. The percentages of CD3+ T cells, CD3+CD4+ T cells, CD3+CD8+ T cells and CD16+CD56+ cells exhibited different trends in intrahepatic and extrahepatic progression. Conclusions: After combination treatment, patients with advanced HCC exhibit different characteristics of disease progression and composition of peripheral blood immune cells. Lymph nodes and lungs were the most susceptible sites for disease progression.

Context-restricted PD-(L)1 checkpoint agonism by CTLA4-Ig therapies inhibits T cell activity.

T cell surface CTLA4 sequesters the costimulatory ligands CD80 and CD86 on antigen-presenting cells (APCs) to prevent autoimmunity. Therapeutic immunosuppression by recombinant CTLA4-immunoglobulin (Ig) fusion proteins, including abatacept, is also attributed to CD80/CD86 blockade. Recent studies show that CTLA4-Ig binding to APC surface cis-CD80:PD-L1 complexes can release the inhibitory ligand PD-L1, but whether this contributes to T cell inhibition remains unclear. Here, we show that PD-L1 liberation by CTLA4-Ig is strictly limited, both in extent and context, relative to PD-L1-competing anti-CD80 antibodies. At APC surface CD80:PD-L1 ratios exceeding 2:1, CTLA4-Ig therapies fail to release PD-L1 regardless of their CD80 affinity. Additionally, introducing flexibility into CTLA4-Ig by modifying its rigid homodimer interface produces biologics that retain bivalent CD80 binding without dissociating cis-bound PD-L1. These findings demonstrate that CTLA4-Ig therapies liberate PD-L1 through a CD80 reorientation mechanism that imposes a strict context dependence to their PD-1 checkpoint agonism and resultant T cell inhibition.

Prognostic value of systemic inflammation response index in cancer patients treated with PD-1/PD-L1 immune checkpoint inhibitors: a meta-analysis.

BACKGROUND: The prognostic significance of the systemic inflammatory response index (SIRI) in patients with cancer receiving programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) has been widely investigated; however, the results have been conflicting. As such, the present meta-analysis aimed to analyze the precise significance of the SIRI in predicting prognosis in patients with cancer undergoing ICI therapy. METHODS: A comprehensive literature search of the Web of Science, PubMed, Embase, and Cochrane Library databases for relevant studies, published from inception to April 25, 2024, was performed. The SIRI was analyzed for its prognostic utility in patients undergoing ICI therapy by calculating combined hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). RESULTS: Six studies comprising 1133 patients were included in the analysis. Pooled data revealed that a higher SIRI was significantly associated with poor overall survival (OS) (HR 1.96 [95% CI 1.55-2.47]; p < 0.001) and progression-free survival (PFS) (HR 1.41 [95% CI 1.19-1.67]; p < 0.001) for patients who underwent PD-1/PD-L1 ICI treatment. Subgroup analysis revealed that SIRI was markedly associated with dismal OS and PFS, independent of sample size, cut-off value, and survival analysis (p < 0.05). The findings were verified to be robust against publication bias and sensitivity analyses. CONCLUSION: In summary, an elevated SIRI was significantly associated with OS and PFS in patients with cancer undergoing PD-1/PD-L1 ICI treatment. SIRI may a candidate indicator for predicting the prognosis of patients undergoing ICI therapy.

To our knowledge, this meta-analysis is the first to analyze the utility of the SIRI in predicting the prognosis of patients with cancer undergoing ICI therapy.Pooled data demonstrated that a higher SIRI was significantly associated with OS and PFS in patients with cancer undergoing PD-1/PD-L1 ICI treatment.SIRI may be a candidate indicator for predicting the prognosis of patients undergoing ICI therapy.