IL-2-Free Tumor-Infiltrating Lymphocyte Therapy With PD-1 Blockade Demonstrates Potent Efficacy in Advanced Gynecologic Cancer

BACKGROUND: Tumor-infiltrating lymphocyte (TIL) therapy has been restricted by intensive lymphodepletion and high-dose intravenous interleukin-2 (IL-2) administration. To address these limitations, we conducted preclinical and clinical studies to evaluate the safety, antitumor activity, and pharmacokinetics of an innovative modified regimen in patients with advanced gynecologic cancer. METHODS: Patient-derived xenografts (PDX) were established from a local recurrent cervical cancer patient. TILs were expanded ex vivo from minced tumors without feeder cells in the modified TIL therapy regimen. Patients underwent low-dose cyclophosphamide lymphodepletion followed by TIL infusion without intravenous IL-2. The primary endpoint was safety; the secondary endpoints included objective response rate, duration of response, and T cell persistence. RESULTS: In matched patient-derived xenografts (PDX) models, homologous TILs efficiently reduced tumor size (p \u3c 0.0001) and underwent IL-2 absence in vivo. In the clinical section, all enrolled patients received TIL infusion using a modified TIL therapy regimen successfully with a manageable safety profile. Five (36%, 95% CI 16.3-61.2) out of 14 evaluable patients experienced objective responses, and three complete responses were ongoing at 19.5, 15.4, and 5.2 months, respectively. Responders had longer overall survival (OS) than non-responders (p = 0.036). Infused TILs showed continuous proliferation and long-term persistence in all patients and showed greater proliferation in responders which was indicated by the Morisita overlap index (MOI) of TCR clonotypes between infused TILs and peripheral T cells on day 14 (p = 0.004) and day 30 (p = 0.004). Higher alteration of the CD8 CONCLUSIONS: Our modified TIL therapy regimen demonstrated manageable safety, and TILs could survive and proliferate without IL-2 intravenous administration, showing potent efficacy in patients with advanced gynecologic cancer

Ultrasonography characteristics of cystic components in primary salivary gland tumors

Abstract Objectives The present study aimed to characterize the ultrasonography (US) features of cystic components in salivary gland tumors (SGTs). Materials and methods A total of 207 patients (218 lesions) with pathologically confirmed primary SGTs were analyzed. Preoperative US revealed the presence of cystic components in lesions. Lesion size, shape, margin, and US findings of the cystic components, including number, distribution, margin, occupying rate, and internal characteristics, were evaluated. Results Similarities were observed between the US performance of benign SGTs (B-SGTs) and malignant SGTs (M-SGTs) with cystic components. Differences in sex and age of patients, number, distribution, and internal characteristics of cystic components were statistically significant. For SGTs with cystic components, the proportions of M-SGTs to ill-defined margins (P = 0.002), eccentric distribution (P = 0.019), and none of the internal characteristics (P = 0.019) were significantly higher than those of B-SGTs. Younger age (P = 0.001), eccentric distribution (P = 0.034) and ill-defined margin (P < 0.001) were risk factors for diagnosing M-SGTs. Cystic component features needed to be combined with lesion indicators (border and shape) to improve diagnostic sensitivity. Conclusions US features of the B-SGTs and M-SGTs were significantly different. Cystic component is of interest in the US-related differential diagnosis of B-SGT and M-SGT. Clinical relevance Cystic components are potentially valuable in the differential diagnosis of B-SGTs and M-SGTs on US

Identification of an Autophagy-Related Signature for Prognosis and Immunotherapy Response Prediction in Ovarian Cancer

Background: Ovarian cancer (OC) is one of the most malignant tumors in the female reproductive system, with a poor prognosis. Various responses to treatments including chemotherapy and immunotherapy are observed among patients due to their individual characteristics. Applicable prognostic markers could make it easier to refine risk stratification for OC patients. Autophagy is closely implicated in the occurrence and development of tumors, including OC. Whether autophagy -related genes can be used as prognostic markers for OC patients remains unclear. Methods: The gene transcriptome data of 374 OC patients were downloaded from The Cancer Genome Atlas (TCGA) database. The correlation between the autophagy levels and outcomes of OC patients was identified through the single sample gene set enrichment analysis (ssGSEA). Recognized molecular markers of autophagy in different clinical specimens were detected by immunohistochemistry (IHC) assay. The gene set enrichment analysis (GSEA), ESTIMATE, and CIBERSORT analysis were applied to explore the correlation of autophagy with the tumor immune microenvironment (TIME). Single-cell RNA-sequencing (scRNA-seq) data from seven OC patients were included for characterizing cell-cell interaction patterns of autophagy-high or low tumor cells. Machine learning, Stepwise Cox regression and LASSO-Cox analysis were used to screen autophagy hub genes, which were used to establish an autophagy-related signature for prognosis evaluation. Four tumor immunotherapy cohorts were obtained from the GEO (Gene Expression Omnibus) database and the literature for autophagy risk score validation. Results: The autophagy levels were closely related to the prognosis of the OC patients. Additionally, the autophagy levels were correlated with TIME status including immune score, and immune-cell infiltration. The scRNA-seq analysis found that tumor cells with high or low autophagy levels had different interactions with immune cells, especially macrophages. Eight autophagy-hub genes (ZFYVE1, AMBRA1, LAMP2, TRAF6, PDPK1, ATG2B, DAPK1 and TP53INP2) were screened for an autophagy-related signature. According to this signature, higher risk score was correlated with poor prognosis and better immunotherapy response in the OC patients. Conclusions: The autophagy-related signature is applicable to predict the prognosis and immune checkpoint inhibitors (ICIs) therapy efficiency in OC patients. It is possible to identify OC patients who will respond to ICIs therapy and have a favorable prognosis, although more verification is needed

Sohlh1 and Lhx8 are prominent biomarkers to estimate the primordial follicle pool in mice

Abstract Efficient evaluation of the primordial follicle pool (PFP) of mammalian models is an essential subject in biomedical research relating to ovarian physiology and pathogenesis. Our recent study has identified a gene signature including Sohlh1, Nobox, Lhx8, Tbpl2, Stk31, Padi6, and Vrtn strongly correlated with ovarian reserve by using bioinformatics analysis. Aimed to investigate the validity of these candidate biomarkers for evaluating the PFP, we utilized an OR comparison model to decode the relationship between the numbers of PFP and candidate biomarkers in the present study. Our results suggest that these biomarkers Sohlh1, Nobox, Lhx8, Tbpl2, Stk31, Padi6, and Vrtn possess independent potential to evaluate the number of the PFP. And the combination of Sohlh1 and Lhx8 can be used as the optimal biomarkers for rapid assessment of the PFP in the murine ovary. Our findings provide a new perspective for evaluating the PFP of the ovary in animal studies and the clinic

Tamarixinin A Alleviates Joint Destruction of Rheumatoid Arthritis by Blockade of MAPK and NF-κB Activation

Background: Tamarixinin A, a natural tannin isolated from Myricaria bracteata, has been confirmed to have moderate anti-inflammatory effects in vitro and in vivo. However, how it effects rheumatoid arthritis (RA) is still unknown. Therefore, the aim of this study is to investigate the therapeutic effects of tamarixinin A on experimental RA, and explore the underlying mechanism.Methods: The anti-arthritic effects of tamarixinin A were evaluated on collagen-induced arthritis (CIA) mice and adjuvant-induced arthritis (AIA) rats. The hind paw thickness, inflammatory cytokine levels in serum, and histopathological assessments were determined. The arthritis score was evaluated. Activation of p38 and p65 in AIA rats was also determined. The anti-inflammatory effect in vitro was also tested in LPS induced macrophages, and its related anti-inflammatory signaling pathways were explored.Results: Treatment with tamarixinin A significantly suppressed the progression and development of RA in CIA mice and AIA rats. Both in CIA mice and AIA rats, arthritis scores decreased, paw swelling and thickness were reduced, and joint destruction was alleviated. In AIA rats, tamarixinin A significantly inhibited the expression of p38, p-p38 and p65. In addition, tamarixinin A inhibited the production of pro-inflammatory mediators, the phosphorylation of p38, ERK, JNK and p65, as well as the nuclear translocation of p38 in LPS- induced macrophages.Conclusion: Tamarixinin A is a potential effective candidate compound for human RA treatment, which executes anti-arthritic effects potentially through down-regulating MAPK and NF-κB signal pathway activation

Neem Leaf Extract Exhibits Anti-Aging and Antioxidant Effects from Yeast to Human Cells

Neem leaves have long been used in traditional medicine for promoting longevity. However, the precise mechanisms underlying their anti-aging effects remain elusive. In this study, we investigated the impact of neem leaf extract (NLE) extracted from a 50% ethanol solution on the chronological lifespan of Saccharomyces cerevisiae, revealing an extension in lifespan, heightened oxidative stress resistance, and a reduction in reactive oxygen species. To discern the active compounds in NLE, LC/MS and the GNPS platform were employed. The majority of identified active compounds were found to be flavonoids. Subsequently, compound-target pharmacological networks were constructed using the STP and STITCH platforms for both S. cerevisiae and Homo sapiens. GOMF and KEGG enrichment analyses of the predicted targets revealed that “oxidoreductase activity” was among the top enriched terms in both yeast and human cells. These suggested a potential regulation of oxidative stress response (OSR) by NLE. RNA-seq analysis of NLE-treated yeast corroborated the anti-oxidative effect, with “oxidoreductase activity” and “oxidation-reduction process” ranking high in enriched GO terms. Notably, CTT1, encoding catalase, emerged as the most significantly up-regulated gene within the “oxidoreductase activity” cluster. In a ctt1 null mutant, the enhanced oxidative stress resistance and extended lifespan induced by NLE were nullified. For human cells, NLE pretreatment demonstrated a decrease in reactive oxygen species levels and senescence-associated β-galactosidase activity in HeLa cells, indicative of anti-aging and anti-oxidative effects. This study unveils the anti-aging and anti-oxidative properties of NLE while delving into their mechanisms, providing novel insights for pharmacological interventions in aging using phytochemicals

Rolling Up Gold Nanoparticle-Dressed DNA Origami into Three-Dimensional Plasmonic Chiral Nanostructures

Construction of three-dimensional (3D) plasmonic architectures using structural DNA nanotechnology is an emerging multidisciplinary area of research. This technology excels in controlling spatial addressability at sub-10 nm resolution, which has thus far been beyond the reach of traditional top-down techniques. In this paper, we demonstrate the realization of 3D plasmonic chiral nanostructures through programmable transformation of gold nanoparticle (AuNP)-dressed DNA origami. AuNPs were assembled along two linear chains on a two-dimensional rectangular DNA origami sheet with well-controlled positions and particle spacing. By rational rolling of the 2D origami template, the AuNPs can be automatically arranged in a helical geometry, suggesting the possibility of achieving engineerable chiral nanomaterials in the visible range

Japanese Encephalitis Disease Burden and Clinical Features of Japanese Encephalitis in Four Cities in the People's Republic of China

The incidence rate of Japanese encephalitis (JE) in the People's Republic of China has decreased substantially with the wide use of JE vaccine, but the accuracy of JE reporting is uncertain. We established active surveillance for acute meningitis and encephalitis syndrome (AMES) in four prefectures in China during 2006–2008 and performed JE laboratory testing on AMES cases identified from six sentinel hospitals in each prefecture. We estimated JE incidence for each prefecture by applying age-adjusted and season-adjusted JE positivity rates from sentinel hospitals to the total AMES resident cases. We identified 4,513 AMES cases, including 3,561 (79%) among residents of four prefectures. Among 2,294 AMES cases from sentinel hospitals, we identified 213 (9.2%) laboratory-confirmed JE cases. Adjusted estimates of JE incidence per 100,000 persons ranged from 0.08 in Shijiazhuang to 1.58 in Guigang. Active surveillance and laboratory confirmation provides a better estimate of the actual JE disease burden and should be used to further refine JE prevention strategies