Cellular immunotherapy combined with platinum-based chemotherapy prolongs survival for non-small cell lung cancer patients.

Platinum-based chemotherapy is the primary treatment option for advanced non-small cell lung cancer (NSCLC) patients without a driver gene mutation, but its efficacy is still modest. Through a potential synergistic effect, autologous cellular immunotherapy (CIT) composed of cytokine-induced killer (CIK), natural killer (NK), and T cells might enhance it. NK cells exhibited in vitro cytotoxicity toward lung cancer cells (A549 cells) following platinum therapy. Using flow cytometry, the expression of MICA, MICB, DR4, DR5, CD112, and CD155 on lung cancer cells was assessed. In this retrospective cohort study, there were included 102 previously untreated stage IIIB/IV NSCLC patients ineligible for tyrosine kinase inhibitor (TKI) target therapy who received either chemotherapy alone (n=75) or combination therapy (n=27). The cytotoxicity of NK cells for A549 cells was increased obviously and a time-dependent enhancement of this effect was also observed. After platinum therapy, the levels of MICA, MICB, DR4, DR5, CD112, and CD155 on the surface of A549 cells were increased. In the combination group, the median PFS was 8.3 months, compared to 5.5 months in the control group (p=0.042); the median overall survival was 18.00 months, compared to 13.67 months in the combined group (p=0.003). The combination group had no obvious immune-related adverse effects. The combination of NK cells with platinum showed synergistic anticancer effects. Combining the two strategies increased survival with minor adverse effects. Incorporating CIT into conventional chemotherapy regimens may improve NSCLC treatment. However, additional evidence will require multicenter randomized controlled trials.

Genetic Variants in the ELOVL5 but not ELOVL2 Gene Associated with Polyunsaturated Fatty Acids in Han Chinese Breast Milk.

The present study was designed to examine the contributions of the fatty acid elongase (ELOVL) gene polymorphisms to the levels of polyunsaturated fatty acids (PUFAs) in breast milk. Two hundred and nine healthy Han Chinese mothers were included in the study. Carriers of minor alleles of SNPs (rs2397142 and rs9357760) in ELOVL5 were associated with higher levels of linoleic acid (LA), dihomo-γ-linolenic acid (DGLA), arachidonic acid (AA), docosatetraenoic acid (DTA), docosahexenoic acid (DHA), while in rs209512 of ELOVL5 the carriers of minor alleles had lower levels of DTA compared to major homozygote alleles (P ranged from 0.004-0.046), and genetically explained variability ranged from 3.2% for eicosapentaenoic acid (EPA) to 6.0% for LA. Our findings demonstrated that common variation in ELOVL5 gene encoding rate-limiting enzymes in the metabolism of PUFAs contribute to the PUFAs in breast milk.

Development of a humanized mouse model with functional human materno-fetal interface immunity.

Materno-fetal immunity possesses specialized characteristics to ensure pathogen clearance while maintaining tolerance to the semiallogeneic fetus. Most of our understanding on human materno-fetal immunity is based on conventional rodent models that may not precisely represent human immunological processes owing to the huge evolutionary divergence. Herein, we developed a pregnant human immune system (HIS) mouse model through busulfan preconditioning, which hosts multilineage human immune subset reconstitution at the materno-fetal interface. Human materno-fetal immunity exhibits a tolerogenic feature at the midgestation stage (embryonic day [E] 14.5), and human immune regulatory subsets were detected in the decidua. However, the immune system switches to an inflammatory profile at the late gestation stage (E19). A cell-cell interaction network contributing to the alternations in the human materno-fetal immune atmosphere was revealed based on single-cell RNA-Seq analysis, wherein human macrophages played crucial roles by secreting several immune regulatory mediators. Furthermore, depletion of Treg cells at E2.5 and E5.5 resulted in severe inflammation and fetus rejection. Collectively, these results demonstrate that the pregnant HIS mouse model permits the development of functional human materno-fetal immunity and offers a tool for human materno-fetal immunity investigation to facilitate drug discovery for reproductive disorders.

Effects of dietary PUFA patterns and FADS genotype on breast milk PUFAs in Chinese lactating mothers.

BACKGROUND: Breastfeeding affects the growth and development of infants, and polyunsaturated fatty acids (PUFAs) play a crucial role in this process. To explore the factors influencing the PUFA concentration in breast milk, we conducted research on two aspects: dietary fatty acid patterns and single nucleotide polymorphisms (SNPs) in maternal fatty acid desaturase genes. METHODS: Three hundred seventy Chinese Han lactating mothers were recruited. A dietary semi-quantitative food frequency questionnaire (FFQ) was used to investigate the dietary intake of lactating mothers from 22 to 25 days postpartum for 1 year. Meanwhile, breast milk samples were collected from the participants and tested for the concentrations of 8 PUFAs and 10 SNP genotypes. We sought to determine the effect of dietary PUFA patterns and SNPs on breast milk PUFAs. We used SPSS 24.0 statistical software for data analysis. Statistical tests were all bilateral tests, with P < 0.05 as statistically significant. RESULTS: Under the same dietary background, PUFA contents in breast milk expressed by most major allele homozygote mothers tended to be higher than that expressed by their counterparts who carried minor allele genes. Moreover, under the same gene background, PUFA contents in breast milk expressed by the mother's intake of essential PUFA pattern tended to be higher than that expressed by their counterparts who took the other two kinds of dietary. CONCLUSIONS: Our study suggests that different genotypes and dietary PUFA patterns affect PUFA levels in breast milk. We recommend that lactating mothers consume enough essential fatty acids to ensure that their infants ingest sufficient PUFAs.

Shikonin impairs T lymphocyte proliferation and thymopoiesis while it may increase myeloid-derived suppressor cells to alleviate immune responses.

Shikonin (SHK) has multifaceted physiological functions, including antitumor, anti-inflammatory, and antimicrobial effects. Recently, SHK has been shown to affect immune responses; however, its detailed immune modulatory function in vivo remains unclear. In this study, we demonstrated that SHK not only inhibited T cell proliferation in vitro, but also intensively inhibited thymopoiesis and eliminated CD4/CD8 double-positive thymic progenitor cells in vivo. Treatment of mice with SHK resulted in immune profile alterations, which promoted myelosis in the bone marrow and increased inhibitory immune cells in central immune organs. A decrease in T cells and B cells was observed in the spleen. Using a murine allogenic skin transplantation model, we revealed that short-term treatment of recipients with SHK significantly inhibited skin graft rejection, in which the levels of myeloid-derived suppressor cells (MDSC) were markedly increased. Taken together, our study suggests that SHK can efficiently eliminate proliferating T cells and inhibit thymopoiesis while promoting the generation of MDSC, indicating its potential role in alleviating immune responses in allogeneic organ/cell transplantation.

Cardiac damage in autoimmune diseases: Target organ involvement that cannot be ignored.

Autoimmune diseases are diseases that cause damage to the body's own tissues as a result of immune dysfunction, often involving multiple organs and systems. The heart is one of the common target organs of autoimmune diseases. The whole structure of the heart can be affected, causing microcirculatory disorders, arrhythmias, pericardial damage, myocarditis, myocardial fibrosis, and impaired valvular function. However, early clinical manifestations of autoimmune heart damage are often overlooked because they are insidious or have no typical features. The damage is often severe and irreversible when symptoms are apparent, even life-threatening. Therefore, early detection and treatment of heart damage in autoimmune diseases is particularly important. Herein, we review the clinical features and mechanisms of cardiac damage in common rheumatic diseases.

Identification of Treponema pallidum-specific protein biomarkers in syphilis patient serum using mass spectrometry.

Aim: To screen novel biomarkers in serum of syphilis patients using a mass spectrometry-based method. Materials & methods: Sera were collected from 18 syphilis patients and divided into three groups. Every six serum samples (before and after treatment) in each group were pooled and detected by mass spectrometry. Results: Twenty-five unique peptides corresponding to 15 Treponema pallidum proteins were discovered. Among them, Tp0369 was discovered as a promising biomarker candidate in this study. Tp0524 and Tp0984 levels decreased 0.38-fold and 0.51-fold after BPG treatment, respectively, which may be related to disease outcomes of syphilis. Conclusion: These findings confirmed the presence of detectable T. pallidum protein in patients' serum, which could promote the development of syphilis diagnostics.

Correlation of circulating tumor DNA EGFR mutation levels with clinical outcomes in patients with advanced lung adenocarcinoma.

BACKGROUND: Circulating tumor DNA (ctDNA) is a promising biomarker for non-invasive epidermal growth factor receptor mutations (EGFRm) detection in lung cancer patients, but existing methods have limitations in sensitivity and availability. In this study, we used the ΔCt value (mutant cycle threshold [Ct] value-internal control Ct value) generated during the polymerase chain reaction (PCR) assay to convert super-amplification-refractory mutation system (superARMS) from a qualitative method to a semi-quantitative method named reformed-superARMS (R-superARMS), and evaluated its performance in detecting EGFRm in plasma ctDNA in patients with advanced lung adenocarcinoma. METHODS: A total of 41 pairs of tissues and plasma samples were obtained from lung adenocarcinoma patients who had known EGFRm in tumor tissue and were previously untreated. EGFRm in ctDNA was identified by using superARMS. Through making use of ΔCt value generated during the detection process of superARMS, we indirectly transform this qualitative detection method into a semi-quantitative PCR detection method, named R-superARMS. Both qualitative and quantitative analyses of the data were performed. Kaplan-Meier analysis was performed to estimate the progression-free survival (PFS) and overall survival (OS). Fisher exact test was used for categorical variables. RESULTS: The concordance rate of EGFRm in tumor tissues and matched plasma samples was 68.3% (28/41). At baseline, EGFRm-positive patients were divided into two groups according to the cut-off ΔCt value of EGFRm set at 8.11. A significant difference in the median OS (mOS) between the two groups was observed (EGFRm ΔCt ≤8.11 vs. >8.11: not reached vs. 11.0 months; log-rank P = 0.024). Patients were divided into mutation clearance (MC) group and mutation incomplete clearance (MIC) group according to whether the ΔCt value of EGFRm test turned negative after 1 month of treatment. We found that there was also a significant difference in mOS (not reached vs. 10.4 months; log-rank P = 0.021) between MC group and MIC group. Although there was no significant difference in PFS between the two groups, the two curves were separated and the PFS of MC group tended to be higher than the MIC group (not reached vs. 27.5 months; log-rank P = 0.088). Furthermore, EGFRm-positive patients were divided into two groups according to the cut-off of the changes in ΔCt value of EGFRm after 1 month of treatment, which was set at 4.89. A significant difference in the mOS between the two groups was observed (change value of ΔCt >4.89 vs. ≤4.89: not reached vs. 11.0 months; log-rank P = 0.014). CONCLUSIONS: Detecting EGFRm in ctDNA using R-superARMS can identify patients who are more likely sensitive to targeted therapy, reflect the molecular load of patients, and predict the therapeutic efficacy and clinical outcomes of patients.

Heterogeneous nuclear ribonucleoprotein A2/B1 is a negative regulator of human breast cancer metastasis by maintaining the balance of multiple genes and pathways.

BACKGROUND: Heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 is an important RNA-binding protein that affects the RNA processing, splicing, transport and stability of many genes. hnRNPA2/B1 is expressed during proliferation and metastasis of various cancer types and promotes such processes. However, the precise role and mechanism of hnRNPA2/B1 in breast cancer remain unclear. METHODS: The association of hnRNPA2/B1 with breast cancer metastasis was assessed using tissue chips, mouse models and publicly available data. The role and mechanism of hnRNPA2/B1 in breast cancer metastasis were studied in cell lines and mouse models. FINDINGS: In contrast to other cancer research findings, hnRNPA2/B1 expression was negatively correlated with breast cancer metastasis. hnRNPA2/B1 inhibited MDA-MB-231 triple-negative breast cancer (TNBC) cell metastasis in vitro and in vivo. hnRNPA2/B1 knockout activated ERK-MAPK/Twist and GR-beta/TCF4 pathways but inhibited STAT3 and WNT/TCF4 signalling pathways. Profilin 2 (PFN2) promoted breast cancer cell migration and invasion, whereas hnRNPA2/B1 bound directly to the UAGGG locus in the 3'-untranslated region of PFN2 mRNA and reduced the stability of PFN2 mRNA. INTERPRETATION: Our data supported the role of hnRNPA2/B1 in tumour metastasis risk and survival prediction in patients with breast cancer. The inhibitory role of hnRNPA2/B1 in metastasis was a balance of downstream multiple genes and signalling pathways. PFN2 downregulation by hnRNPA2/B1 might partly explain the inhibitory mechanism of hnRNPA2/B1 in breast cancer metastasis. Therefore, hnRNPA2/B1 might be used as a new prognostic biomarker and valuable molecular target for breast cancer treatments.

Dietary patterns affect maternal macronutrient intake levels and the fatty acid profile of breast milk in lactating Chinese mothers.

OBJECTIVES: Fatty acids (FA) in human milk play an important role in meeting the nutritional demands and promoting the growth and development of breastfeeding infants. Breast milk FA is sensitive to maternal dietary habits, and dietary patterns are better used to explain the effect of diet on FA. Few studies have examined the association between maternal dietary patterns and the FA components of breast milk in developing countries. In this study, we aimed to determine whether dietary patterns affect the FA profile of breast milk in lactating Chinese mothers with the overall goal to optimize the management of infant feeding. METHODS: A total of 274 lactating women ranging from 22 d to 6 mo postpartum were included, and samples of their breast milk were collected together with completed questionnaires. Using a principal component analysis, four dietary patterns were identified in a rotated component matrix. FA profiles were detected using capillary gas chromatography and presented as the percentage by weight of total FA. RESULTS: Maternal intake of energy, carbohydrates, and proteins showed differences between the different dietary patterns. In addition, there were significant differences in the total proportions of saturated, polyunsaturated, and ω-6 polyunsaturated fatty acids in breast milk among the four patterns (P < 0.001; P = 0.025; P = 0.038, respectively). CONCLUSIONS: The results demonstrate that maternal dietary patterns can affect macronutrient intake levels and milk FA profiles in lactating Chinese women. These results are of great significance in understanding how a maternal diet can both improve maternal macronutrient intake and the FA nutritional status of breast milk.

Differential expression of filamin A and its clinical significance in breast cancer.

Changes in filamin A (FLNa) expression contribute to the development and progression of numerous malignancies. However, in vitro studies of breast cancer have shown conflicting results. Thus, the present study aimed to detect the expression of FLNa in breast cancer tissue samples and the association with clinicopathological data, in order to provide insightful ex vivo data. A total of 96 breast cancer and distant normal breast tissues and 20 benign tumor tissue specimens were subjected to immunohistochemistry or reverse transcription polymerase chain reaction (RT-PCR) analysis of FLNa expression. Clinicopathological data were collected to analyze the association with FLNa expression. The FLNa protein was overexpressed in breast cancer tissues compared with distant normal mammary gland and benign breast tissues. The FLNa protein was expressed in 63.5% of breast cancer, with positive rates of 36, 66.7 and 84.6%, respectively, in stage I, II and III breast cancer patients (P<0.05). Overexpression of the FLNa protein was associated with advanced stage, lymph node metastasis, vascular or neural invasion, menstruation state and other risk stratifications for breast cancer. The overexpression of FLNa in breast cancer was validated by RT-PCR, indicating transcriptional regulation of FLNa overexpression in breast cancer. FLNa mRNA and protein were overexpressed in breast cancer tissues, which was associated with advanced stage, lymph node metastasis and vascular or neural invasion of breast cancer, suggesting that FLNa contributes to breast cancer development and progression.