CD161+CD127+CD8+ T cell subsets can predict the efficacy of anti-PD-1 immunotherapy in non-small cell lung cancer with diabetes mellitus.

The role of CD161+CD127+CD8+ T cells in non-small cell lung cancer (NSCLC) patients with diabetes remains unexplored. This study determined the prevalence, phenotype, and function of CD8+ T cell subsets in NSCLC with diabetes. We recruited NSCLC patients (n = 436) treated with anti-PD-1 immunotherapy as first-line treatment. The progression-free survival (PFS), overall survival (OS), T cells infiltration, and peripheral blood immunological characteristics were analyzed in NSCLC patients with or without diabetes. NSCLC patients with diabetes exhibited shorter PFS and OS (p = 0.0069 and p = 0.012, respectively) and significantly lower CD8+ T cells infiltration. Mass cytometry by time-of-flight (CyTOF) showed a higher percentage of CD161+CD127+CD8+ T cells among CD8+T cells in NSCLC with diabetes before anti-PD-1 treatment (p = 0.0071) than that in NSCLC without diabetes and this trend continued after anti-PD-1 treatment (p = 0.0393). Flow cytometry and multiple-immunofluorescence confirmed that NSCLC with diabetes had significantly higher CD161+CD127+CD8+ T cells to CD8+T cells ratios than NSCLC patients without diabetes. The RNA-sequencing analysis revealed immune-cytotoxic genes were reduced in the CD161+CD127+CD8+ T cell subset compared to CD161+CD127-CD8+ T cells in NSCLC with diabetes. CD161+CD127+CD8+ T cells exhibited more T cell-exhausted phenotypes in NSCLC with diabetes. NSCLC patients with diabetes with ≥ 6.3% CD161+CD127+CD8+ T cells to CD8+T cells ratios showed worse PFS. These findings indicate that diabetes is a risk factor for NSCLC patients who undergo anti-PD-1 immunotherapy.CD161+CD127+CD8+ T cells could be a key indicator of a poor prognosis in NSCLC with diabetes. Our findings would help in advancing anti-PD-1 therapy in NSCLC patients with diabetes.

Circular RNA circPHF16 enhances IL-17A expression and secretion by sequestering miR-378a-3p to activate the IL6ST axis in Graves' disease.

Interleukin-17A (IL-17A) plays a pivotal role in the pathogenesis of Graves' disease (GD), an autoimmune disorder affecting thyroid function, but the detailed regulatory mechanisms remain elusive. Circular RNAs (circRNAs) have emerged as key regulators of IL-17A expression and secretion in autoimmune diseases, yet their specific role in GD, especially within CD4 + T lymphocytes, are not well understood. In this study, a circRNA, circPHF16 (hsa_circ_0090364) was found to be highly expressed in the peripheral blood mononuclear cells and serum of GD patients. In vitro experiments in Jurkat T cells revealed that silencing of circPHF16 suppressed IL-17A expression and secretion, while overexpression of circPHF16 had the opposite effect. Furthermore, bioinformatics analysis demonstrated a circPHF16/miR-378a-3p/IL6ST pathway, in which circPHF16 regulates IL6ST expression, which, in turn, influences IL-17A expression and secretion by interacting with miR-378a-3p. In vivo studies in a mouse model of GD showed similar trends in molecular expression levels, consistent with competitive endogenous RNA interactions. Together the results of the study identify circPHF16 as a potential target in the development of new strategies for GD diagnosis and treatment, and thus, offer a theoretical foundation for clinical therapeutic approaches in GD.

Human Menstrual Blood-Derived Stem Cells Protect against Tacrolimus-Induced Islet Dysfunction via Cystathionine ß-Synthase Mediated IL-6/STAT3 Inactivation.

Diabetes imposes a huge burden worldwide. Islet transplantation is an alternative therapy for diabetes. However, tacrolimus, a kind of immunosuppressant after organ transplantation, is closely related to post-transplant diabetes mellitus. Mesenchymal stem cells (MSCs) have attracted interest for their potential to alleviate diabetes. In vivo experiments revealed that human menstrual blood-derived stem cells (MenSCs) treatment improved tacrolimus-induced blood glucose, body weight, and glucose tolerance disorders in mice. RNA sequencing was used to analyze the potential therapeutic targets of MenSCs. In this study, we illustrated that cystathionine ß-synthase (CBS) contributed to tacrolimus -induced islet dysfunction. Using ß-cell lines (MIN6, ß-TC-6), we demonstrated that MenSCs ameliorated tacrolimus-induced islet dysfunction in vitro. Moreover, MenSC reduced the tacrolimus-induced elevation of CBS levels and significantly enhanced the viability, anti-apoptotic ability, glucose-stimulated insulin secretion (GSIS), and glycolytic flux of ß-cells. We further revealed that MenSCs exerted their therapeutic effects by inhibiting CBS expression to activate the IL6/JAK2/STAT3 pathway. In conclusion, we showed that MenSCs may be a potential strategy to improve tacrolimus-induced islet dysfunction.

Harvest residue recycling rather than slash-burning results in the enhancement of soil fertility and bacterial community stability in Eucalyptus plantations.

Deforestation and slash combustion have substantial adverse impacts on the atmosphere, soil and microbe. Despite this awareness, numerous individuals persist in opting for high-intensity Eucalyptus planting through slash-burning in pursuit of immediate profits while disregarding the environmental significance and destroying the soil. Slash-unburnt agriculture can effectively safeguard the ecological environment, and compared with slash-burning, there remains a limited understanding of its regulatory mechanisms on soil fertility and microbial community. Also, large uncertainty persists regarding the utilization of harvest residues. Thoroughly investigating these questions from various perspectives encompassing physical soil characteristics, nutrient availability, bacterial community structures, and stability is crucial. To explore the ecological advantages of slash-unburnt techniques on microorganisms and their associated ecosystems, we used two slash-unburnt (Unburnt) planting techniques: Spread (naturally and evenly covering the forest floor after logging) and Stack (residues are piled along contour lines) as well as the traditional slash Burnt method (Burnt) in a Eucalyptus plantation. A comparative analysis was conducted between the two methods. We observed that over a span of 4 years, despite the initial lower application of fertilizer in the Unburnt treatments compared with the Burnt treatment during the first 2 years, the Unburnt treatment gradually caught up or even surpassed and attained similar nutrient levels as the Burnt treatment. Alphaproteobacteria was the main phyla that indicated the difference in soil bacterial communities between Burnt and Unburnt treatments. The microbial networks also highlighted the significance of the Unburnt method, as it contributed to the preservation of crucial network nodes and the stability of soil bacterial communities. Therefore, rational utilization of harvest residue may effectively avoid the vast damage caused by slash-burning to Eucalyptus trees and the soil environment but may also increase the potential for restoring soil fertility, improving fertilizer utilization efficiency, and maintaining microbial community stability over time.

Case report: Prone positioning in the improvement of severe post-operative hypoxia following aortic dissection.

Postoperative hypoxemia after aortic dissection surgery presents a considerable clinical challenge, and acute respiratory distress syndrome (ARDS) is a common etiology. Prone positioning treatment has emerged as a potential intervention for improving respiratory function in this context. We report the case of a 27-year-old male who developed severe hypoxemia complicated by pulmonary embolism after aortic dissection surgery. He was diagnosed with postoperative hypoxemia combined with pulmonary embolism following aortic dissection. His respiratory status continued to deteriorate despite receiving standard postoperative care, thereby necessitating an alternative approach. Implementation of prone positioning treatment led to a substantial amelioration in his oxygenation and overall respiratory health, with a consistent hemodynamic state observed throughout the treatment. This technique resulted in significant relief in symptoms and improvement in respiratory parameters, facilitating successful extubation and, ultimately, discharge. This case underlines the possible efficacy of prone positioning therapy in managing severe hypoxia complicated by pulmonary embolism following aortic dissection surgery, warranting more thorough research to explore the potential of this treatment modality.

GPRC5A is a potential prognostic biomarker and correlates with immune cell infiltration in non-small cell lung cancer.

Background: The tumor microenvironment (TME) plays an important role in tumor progression and immunotherapy responses in non-small cell lung cancer (NSCLC). The programmed cell death 1 (PD-1)/ programmed cell death-ligand 1 (PD-L1) checkpoint is a central mediator of immunosuppression in the TME. However, there is still a need to identify additional biomarkers that could reflect the difference in TME and PD-L1 expression in NSCLC patients. To this end, we focused on the expression of G-protein-coupled receptor family C group 5 type A (GPRC5A) in NSCLC. GPRC5A, is a retinoic acid-inducible gene that plays multiple roles in NSCLC. However, little is known about the role of GPRC5A in regulating the TME and PD-L1. Our objective was to describe the critical role of GPRC5A expression in NSCLC in the setting of immune cell infiltration. Methods: We identified the relationship between GPRC5A expression and the clinicopathologic characteristics of NSCLC patients in the Fudan University Shanghai Cancer Center (FUSCC) cohort. Furthermore, we validated GPRC5A as a predictive biomarker by using public databases to reveal the relationship between GPRC5A expression and immune cell infiltration. To correlate the expression of GPRC5A with the spatial distribution of PD-L1 in NSCLC samples, we performed multiplex immunohistochemistry (mIHC). Results: Low GPRC5A expression is associated with earlier pathological stage (pStage). Analysis of immune cell infiltration indicates there is a relationship between low GPRC5A expression and increased infiltration of CD8+ T cells, activated CD4+ T cells, and M1 macrophages within the TME. Furthermore, low GPRC5A expression is associated with an increased immunophenotype score (IPS) in NSCLC. Additionally, analysis of mIHC reveals there is a correlation between low GPRC5A expression and spatial distribution of tumoral PD-L1 expression. Conclusions: Our study revealed the relationship between low expression of GPRC5A and earlier pStage in NSCLC. Furthermore, we observed that low expression of GPRC5A is associated with increased infiltration of immune cells, higher IPS, and spatial distribution of PD-L1-positive tumor cells. Therefore, we speculate that low expression of GPRC5A is associated with immunotherapy, but further validation is still required.

Why Do People Watch Pornography? Cross-Cultural Validation of the Pornography Use Motivations Scale (PUMS) and Its Short Form (PUMS-8).

Motivations for pornography use may vary across gender identities, sexual orientations, and geographical regions, warranting examination to promote individual and public health. The aims of this study were to validate the Pornography Use Motivations Scale (PUMS) in a diverse, multicultural sample, and develop a short form (PUMS-8) that can assess a wide range of pornography use motivations. Using data from 42 countries (N = 75,117; Mage = 32.07; SDage = 12.37), enabled us to thoroughly evaluate the dimensionality, validity, and reliability of the Pornography Use Motivations Scale (PUMS), leading to the development of the more concise PUMS-8 short scale. Additionally, language-, nationality-, gender-, and sexual-orientation-based measurement invariance tests were conducted to test the comparability across groups. Both the PUMS and the PUMS-8 assess eight pornography use motivations, and both demonstrated excellent psychometric properties. Sexual Pleasure emerged as the most frequent motivation for pornography use across countries, genders, and sexual orientations, while differences were observed concerning other motivations (e.g. self-exploration was more prevalent among gender-diverse individuals than men or women). The motivational background of pornography use showed high similarity in the examined countries. Both the PUMS and the PUMS-8 are reliable and valid measurement tools to assess different types of motivations for pornography use across countries, genders, and sexual orientations. Both scales are recommended for use in research and clinical settings.

Novel anti-Acanthamoeba effects elicited by a repurposed poly (ADP-ribose) polymerase inhibitor AZ9482.

Introduction: Acanthamoeba infection is a serious public health concern, necessitating the development of effective and safe anti-Acanthamoeba chemotherapies. Poly (ADP-ribose) polymerases (PARPs) govern a colossal amount of biological processes, such as DNA damage repair, protein degradation and apoptosis. Multiple PARP-targeted compounds have been approved for cancer treatment. However, repurposing of PARP inhibitors to treat Acanthamoeba is poorly understood. Methods: In the present study, we attempted to fill these knowledge gaps by performing anti-Acanthamoeba efficacy assays, cell biology experiments, bioinformatics, and transcriptomic analyses. Results: Using a homology model of Acanthamoeba poly (ADP-ribose) polymerases (PARPs), molecular docking of approved drugs revealed three potential inhibitory compounds: olaparib, venadaparib and AZ9482. In particular, venadaparib exhibited superior docking scores (-13.71) and favorable predicted binding free energy (-89.28 kcal/mol), followed by AZ9482, which showed a docking score of -13.20 and a binding free energy of -92.13 kcal/mol. Notably, the positively charged cyclopropylamine in venadaparib established a salt bridge (through E535) and a hydrogen bond (via N531) within the binding pocket. For comparison, AZ9482 was well stacked by the surrounding aromatic residues including H625, Y652, Y659 and Y670. In an assessment of trophozoites viability, AZ9482 exhibited a dose-and time-dependent anti-trophozoite effect by suppressing Acanthamoeba PARP activity, unlike olaparib and venadaparib. An Annexin V-fluorescein isothiocyanate/propidium iodide apoptosis assay revealed AZ9482 induced trophozoite necrotic cell death rather than apoptosis. Transcriptomics analyses conducted on Acanthamoeba trophozoites treated with AZ9482 demonstrated an atlas of differentially regulated proteins and genes, and found that AZ9482 rapidly upregulates a multitude of DNA damage repair pathways in trophozoites, and intriguingly downregulates several virulent genes. Analyzing gene expression related to DNA damage repair pathway and the rate of apurinic/apyrimidinic (AP) sites indicated DNA damage efficacy and repair modulation in Acanthamoeba trophozoites following AZ9482 treatment. Discussion: Collectively, these findings highlight AZ9482, as a structurally unique PARP inhibitor, provides a promising prototype for advancing anti-Acanthamoeba drug research.

A single-arm, multicenter, phase 2 clinical study of recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate (MRG002) in HER2-positive unresectable locally advanced or metastatic urothelial carcinoma.

BACKGROUND: MRG002 is a novel HER2-targeted antibody-drug conjugate being investigated in the MRG002-006 trial to evaluate the efficacy and safety in HER2-positive urothelial carcinoma patients. METHODS: This is an open-label, single-arm, multicenter phase II study. Eligibility criteria included: histologically confirmed HER2 IHC 2 + or 3 + UC, prior received ≥ 1 standard treatment. Patients in this study received MRG002 every 3 weeks until progressive disease or unacceptable toxicity. The primary endpoint was confirmed ORR per RECIST 1.1. RESULTS: As of February 24, 2023, a total of 43 patients were enrolled. The median age was 60. 9 patients were dosed at 2.6 mg/kg and 34 patients were dosed at 2.2 mg/kg. At baseline, most patients (29/43) received ≥ 2 lines of treatment and 35 (81.4%) patients had prior ICI therapy. FISH test was performed in 41 patients and 9 (22.0%) were positive. By the cut-off date, 41 patients were evaluable and the ORR was 53% (95%CI：38.9%-67.5%), with 6.9% CR, and the DCR was 83.7% (95%CI：70.0%-91.9%). The median PFS and OS for the 43 patients were 7.0 months (95%CI：5.4-NE) and 14.9 months (95%CI：11.9-NE), respectively. The ORR was 77.8% in 9 patients with positive HER2 FISH results. Most common treatment-related AEs were anemia (51.2%), alopecia (44.2%) and neutropenia (39.5%); most were grade 1 or 2. CONCLUSION: Preliminary results of MRG002 demonstrated a clinically meaningful response in pretreated HER-2 positive unresectable locally advanced or metastatic UC patients. MRG002 at 2.2 mg/kg was well tolerated with a manageable toxicity.

Comprehensive proteogenomic characterization of rare kidney tumors.

Non-clear cell renal cell carcinomas (non-ccRCCs) encompass diverse malignant and benign tumors. Refinement of differential diagnosis biomarkers, markers for early prognosis of aggressive disease, and therapeutic targets to complement immunotherapy are current clinical needs. Multi-omics analyses of 48 non-ccRCCs compared with 103 ccRCCs reveal proteogenomic, phosphorylation, glycosylation, and metabolic aberrations in RCC subtypes. RCCs with high genome instability display overexpression of IGF2BP3 and PYCR1. Integration of single-cell and bulk transcriptome data predicts diverse cell-of-origin and clarifies RCC subtype-specific proteogenomic signatures. Expression of biomarkers MAPRE3, ADGRF5, and GPNMB differentiates renal oncocytoma from chromophobe RCC, and PIGR and SOSTDC1 distinguish papillary RCC from MTSCC. This study expands our knowledge of proteogenomic signatures, biomarkers, and potential therapeutic targets in non-ccRCC.

Trace amounts of palladium catalysed the Suzuki-Miyaura reaction of deactivated and hindered aryl chlorides.

Electron-rich and hindered aryl chlorides are the most challenging substrates in Suzuki-Miyaura cross-coupling (SMC) reactions. Herein, we report a highly efficient catalytic system for the SMC reaction using trace amounts of commercially available catalysts [Pd(PPh3)4/(t-Bu)PCy2; Pd loading as low as 9.5 × 10-5 mol%]. This catalytic system can efficiently couple deactivated and sterically hindered aryl chlorides with various substituted phenylboronic acids, even in one-pot multiple coupling reactions (yield of products up to 92%). The impact of solvents on SMC reactions and the mechanisms of by-product formation in aryl boronic acid couplings are analyzed using density functional theory (DFT). Utilizing trace amounts of commercially available catalysts avoids complex synthesis, reduces costs, and minimizes metal residues.

The genome of Lespedeza potaninii reveals biased subgenome evolution and drought adaptation.

Lespedeza potaninii, a xerophytic subshrub belonging to the legume family, is native to the Tengger Desert and is highly adapted to drought. It has important ecological value due to its drought adaptability, but the underlying molecular mechanisms remain largely unknown. Here, we report a 1.24 Gb chromosome-scale assembly of the L. potaninii genome (contig N50=15.75 Mb). Our results indicate that L. potaninii underwent an allopolyploid event with two subgenomes, A and B, presenting asymmetric evolution and B subgenome dominance. We estimate that the two diploid progenitors of L. potaninii diverged around 3.6 MYA and merged around 1.0 MYA. We revealed that the expansion of hub genes associated with drought responses, such as the binding partner 1 of accelerated cell death 11 (ACD11) (BPA1), facilitated environmental adaptations of L. potaninii to desert habitats. We found a novel function of the BPA1 family in abiotic stress tolerance in addition to the known role in regulating the plant immune response, which could improve drought tolerance by positively regulating reactive oxygen species homeostasis in plants. We revealed that bZIP transcription factors could bind to the BPA1 promoter and activate its transcription. Our work fills the genomic data gap in the Lespedeza genus and the tribe Desmodieae, which should provide both theoretical support in the study of drought tolerance and in the molecular breeding of legume crops.

The short version of the Sexual Distress Scale (SDS-3): Measurement invariance across countries, gender identities, and sexual orientations.

Background: The three-item Sexual Distress Scale (SDS-3) has been frequently used to assess distress related to sexuality in public health surveys and research on sexual wellbeing. However, its psychometric properties and measurement invariance across cultural, gender and sexual subgroups have not yet been examined. This multinational study aimed to validate the SDS-3 and test its psychometric properties, including measurement invariance across language, country, gender identity, and sexual orientation groups. Methods: We used global survey data from 82,243 individuals (Mean age=32.39 years; 40.3 % men, 57.0 % women, 2.8 % non-binary, and 0.6 % other genders) participating in the International Sexual Survey (ISS; https://internationalsexsurvey.org/) across 42 countries and 26 languages. Participants completed the SDS-3, as well as questions regarding sociodemographic characteristics, including gender identity and sexual orientation. Results: Confirmatory factor analysis (CFA) supported a unidimensional factor structure for the SDS-3, and multi-group CFA (MGCFA) suggested that this factor structure was invariant across countries, languages, gender identities, and sexual orientations. Cronbach's α for the unidimensional score was 0.83 (range between 0.76 and 0.89), and McDonald's ω was 0.84 (range between 0.76 and 0.90). Participants who did not experience sexual problems had significantly lower SDS-3 total scores (M = 2.99; SD=2.54) compared to those who reported sexual problems (M = 5.60; SD=3.00), with a large effect size (Cohen's d = 1.01 [95 % CI=-1.03, -0.98]; p < 0.001). Conclusion: The SDS-3 has a unidimensional factor structure and appears to be valid and reliable for measuring sexual distress among individuals from different countries, gender identities, and sexual orientations.

Thyroid cancer and cardiovascular diseases: a Mendelian randomization study.

Background: Multiple observational studies have shown associations between thyroid cancer (TC) and cardiovascular diseases (CVDs). However, the results were inconsistent, and the potential causal genetic relationship remains unclear. Methods: The genetic instruments of TC and CVDs were derived from data obtained through genome-wide association studies (GWAS). We performed the two-sample Mendelian randomization(MR) methods to investigate the causality of TC on CVDs. Summary-level statistics for CVDs, including heart failure (HF), atrial fibrillation (AF), coronary artery disease (CAD), myocardial infarction (MI), ischemic stroke (IS) and venous thromboembolism (VTE). The primary method employed in this MR analysis was the Inverse Variance Weighted (IVW) approach, and four additional algorithms were used: MR-Egger, weighted median, simple mode, and weighted mode. Additionally, we assessed the reliability of the causal relationship through pleiotropy, heterogeneity and leave-one-out sensitivity analysis. Results: In this MR analysis, we only detected causality of genetically predicted TC on HF (IVW method, odds ratio (OR) = 1.00134, 95% confidence interval (CI): 1.00023-1.00244, p = 0.017). However, There were no causal associations of TC with CAD, MI, AF, IS, and VTE. Conclusion: Our results confirmed the causal association between TC and HF. It is crucial to closely monitor the incidence of HF in TC patients and give comprehensive clinical intervention based on conventional treatment.

Impacts of different slash disposals on soil and water erosion of high-intensity management Eucalyptus grandis × urophylla plantation.

Background: The slash disposal-burning forest-in high-intensity management Eucalyptus grandis × urophylla plantation has accelerated soil degradation. Statement of the problem: Slash disposals is a contributing factor, but its specific role in the correlation between rainfall-runoff and soil erosion remains elusive. Objectives: his study investigated the characteristics of rainfall-runoff and soil erosion resistance in different methods of slash disposals in plantation. Methods: Three methods of slash disposal, namely burning forest (BF), moving away (MA), and spreading evenly (SE), were established. A field simulation experiment of rainfall was conducted, and path analysis was used. Results: The findings revealed that the water holding, infiltrating properties and the time the rainfall-runoff generated of SE were increased by approximately 10∼20 %, 100 %, and 80 %, respectively, compared with BF and MA. Water loss, soil loss and nutrient loss were significantly reduced by 62.23 % and 61.56 %, 69.06 % and 49.55 %, and 58.8 % and 65.42 % in SE and BF compared to MA. Path analysis suggested that different from BF and MA, the correlation between soil water properties and rainfall-runoff factors in SE was weakened, simultaneously considering the result that SE had the lower proportions of silt for sediment component (75.31 %), it stabilized the soil structure. Conclusions and prospect: Consequently, SE mitigated the erosion force by reducing rainfall-runoff and enhancing the anti-erosion of soil through improved water properties, making it a viable slash disposal. This work provides a detailed description of the soil erosion characteristics of plantation, including water, soil, and nutrient losses caused by rainfall-runoff, as well as the soil anti-erosion due to different slash disposals. These findings offer valuable insights for the management of high-intensity Eucalyptus grandis × urophylla plantations.

Using three-dimensional model-based tumour volume change to predict the symptom improvement in patients with renal cell cancer.

In our recent study, we explored the efficacy of three-dimensional (3D) measurement of tumor volume in predicting the improvement of quality of life (QoL) in patients suffering from renal cell cancer (RCC), who were treated with axitinib and anti-PD-L1 antibodies. This study encompassed 18 RCC patients, including 10 men and 8 women, with an average age of 56.83 ± 9.94 years. By utilizing 3D Slicer software, we analyzed pre- and post-treatment CT scans to assess changes in tumor volume. Patients' QoL was evaluated through the FKSI-DRS questionnaire. Our findings revealed that 3D models for all patients were successfully created, and there was a moderate agreement between treatment response classifications based on RECIST 1.1 criteria and volumetric analysis (kappa = 0.556, p = 0.001). Notably, nine patients reported a clinically meaningful improvement in QoL following the treatment. Interestingly, the change in tumor volume as indicated by the 3D model showed a higher area under the curve in predicting QoL improvement compared to the change in diameter measured by CT, although this difference was not statistically significant (z = 0.593, p = 0.553). Furthermore, a multivariable analysis identified the change in tumor volume based on the 3D model as an independent predictor of QoL improvement (odds ratio = 1.073, 95% CI 1.002-1.149, p = 0.045).In conclusion, our study suggests that the change in tumor volume measured by a 3D model may be a more effective predictor of symptom improvement in RCC patients than traditional CT-based diameter measurements. This offers a novel approach for assessing treatment response and patient well-being, presenting a significant advancement in the field of RCC treatment.

Effect of folA gene in human breast milk-derived Limosilactobacillus reuteri on its folate biosynthesis.

Introduction: Folate supplementation is crucial for the human body, and the chemically synthesized folic acid might have undesirable side effects. The use of molecular breeding methods to modify the genes related to the biosynthesis of folate by probiotics to increase folate production is currently a focus of research. Methods: In this study, the folate-producing strain of Limosilactobacillus reuteri B1-28 was isolated from human breast milk, and the difference between B1-28 and folA gene deletion strain ΔFolA was investigated by phenotyping, in vitro probiotic evaluation, metabolism and transcriptome analysis. Results: The results showed that the folate producted by the ΔFolA was 2-3 folds that of the B1-28. Scanning electron microscope showed that ΔFolA had rougher surface, and the acid-producing capacity (p = 0.0008) and adhesion properties (p = 0.0096) were significantly enhanced than B1-28. Transcriptomic analysis revealed that differentially expressed genes were mainly involved in three pathways, among which the biosynthesis of ribosome and aminoacyl-tRNA occurred in the key metabolic pathways. Metabolomics analysis showed that folA affected 5 metabolic pathways, involving 89 different metabolites. Discussion: In conclusion, the editing of a key gene of folA in folate biosynthesis pathway provides a feasible pathway to improve folate biosynthesis in breast milk-derived probiotics.

CXCR6-positive circulating mucosal-associated invariant T cells can identify patients with non-small cell lung cancer responding to anti-PD-1 immunotherapy.

BACKGROUND: Mucosal-associated invariant T (MAIT) cells have been reported to regulate tumor immunity. However, the immune characteristics of MAIT cells in non-small cell lung cancer (NSCLC) and their correlation with the treatment efficacy of immune checkpoint inhibitors (ICIs) remain unclear. PATIENTS AND METHODS: In this study, we performed single-cell RNA sequencing (scRNA-seq), flow cytometry, and multiplex immunofluorescence assays to determine the proportion and characteristics of CD8+MAIT cells in patients with metastatic NSCLC who did and did not respond to anti-PD-1 therapy. Survival analyses were employed to determine the effects of MAIT proportion and C-X-C chemokine receptor 6 (CXCR6) expression on the prognosis of patients with advanced NSCLC. RESULTS: The proportion of activated and proliferating CD8+MAIT cells were significantly higher in responders-derived peripheral blood mononuclear cells (PBMCs) and lung tissues before anti-PD-1 therapy, with enhanced expression of cytotoxicity-related genes including CCL4, KLRG1, PRF1, NCR3, NKG7, GZMB, and KLRK1. The responders' peripheral and tumor-infiltrating CD8+MAIT cells showed an upregulated CXCR6 expression. Similarly, CXCR6+CD8+MAIT cells from responders showed higher expression of cytotoxicity-related genes, such as CST7, GNLY, KLRG1, NKG7, and PRF1. Patients with ≥15.1% CD8+MAIT cells to CD8+T cells ratio and ≥35.9% CXCR6+CD8+MAIT cells to CD8+MAIT cells ratio in peripheral blood showed better progression-free survival (PFS) after immunotherapy. The role of CD8+MAIT cells in lung cancer immunotherapy was potentially mediated by classical/non-classical monocytes through the CXCL16-CXCR6 axis. CONCLUSION: CD8+MAIT cells are a potential predictive biomarker for patients with NSCLC responding to anti-PD-1 therapy. The correlation between CD8+MAIT cells and immunotherapy sensitivity may be ascribed to high CXCR6 expression.

Advances in the composition, efficacy, and mimicking of human milk phospholipids.

Phospholipids are the essential components of human milk, contributing to the enhancement of cognitive development, regulation of immune functions, and mitigation of elevated cholesterol levels. Infant formulas supplemented with phospholipids can change the composition, content, and globule membrane structure of milk lipids, improving their digestive properties and nutritional value. However, mimicking phospholipids in infant formulas is currently limited, and the supplemented standards of phospholipid species and amounts in infant formulas are unknown. Consequently, there is a significant difference between the phospholipids in infant formulas and those in human milk. This article reviews the recent progress in human milk phospholipid research, aiming to describe the composition, content, and positive effects of human milk phospholipids, as well as summarises the dietary sources of phospholipid supplementation and the current state of human milk phospholipid mimicking in infant formulas. This review provides clear directions for research on mimicking human milk phospholipids and evaluating the nutritional functions of phospholipids in infants.

Progress in triacylglycerol isomer detection in milk lipids.

In triacylglycerols (TAGs), position differences of fatty acids on the glycerol skeleton produce various TAG isomers. These TAG isomers have different pathways of digestion, absorption, and utilization in infants, thereby affecting TAG nutritional properties of TAGs. Here, we review the progress of research on methods for detecting TAG isomers, and identify direction and thought for improving these methods, including novel chromatographic combinations, perfect algorithm, and improved equipment. The ensuing optimization of these methods is expected to provide robust guarantee for the gradual improvement of milk-derived TAG isomer detection, and is an important prerequisite for infant formula to mimic the structured lipids of human milk.