Molecular classification reveals the sensitivity of lung adenocarcinoma to radiotherapy and immunotherapy: multi-omics clustering based on similarity network fusion.

BACKGROUND: Due to individual differences in tumors and immune systems, the response rate to immunotherapy is low in lung adenocarcinoma (LUAD) patients. Combinations with other therapeutic strategies improve the efficacy of immunotherapy in LUAD patients. Although radioimmunotherapy has been demonstrated to effectively suppress tumors, the underlying mechanisms still need to be investigated. METHODS: Total RNA from LUAD cells was sequenced before and after radiotherapy to identify differentially expressed radiation-associated genes. The similarity network fusion (SNF) algorithm was applied for molecular classification based on radiation-related genes, immune-related genes, methylation data, and somatic mutation data. The changes in gene expression, prognosis, immune cell infiltration, radiosensitivity, chemosensitivity, and sensitivity to immunotherapy were assessed for each subtype. RESULTS: We used the SNF algorithm and multi-omics data to divide TCGA-LUAD patients into three subtypes. Patients with the CS3 subtype had the best prognosis, while those with the CS1 and CS2 subtypes had poorer prognoses. Among the strains tested, CS2 exhibited the most elevated immune cell infiltration and expression of immune checkpoint genes, while CS1 exhibited the least. Patients in the CS2 subgroup were more likely to respond to PD-1 immunotherapy. The CS2 patients were most sensitive to docetaxel and cisplatin, while the CS1 patients were most sensitive to paclitaxel. Experimental validation of signature genes in the CS2 subtype showed that inhibiting the expression of RHCG and TRPA1 could enhance the sensitivity of lung cancer cells to radiation. CONCLUSIONS: In summary, this study identified a risk classifier based on multi-omics data that can guide treatment selection for LUAD patients.

[Intradermal needling and acupuncture in prevention and treatment of leukopenia after chemotherapy with spleen-kidney deficiency: a randomized controlled trial].

OBJECTIVE: To compare the clinical effect of intradermal needling and acupuncture in prevention and treatment of leukopenia after chemotherapy with spleen-kidney deficiency. METHODS: A total of 90 patients with malignant tumor who received chemotherapy were randomly divided into a intradermal needling group (30 cases, 1 case dropped out), an acupuncture group (30 cases, 2 cases dropped out, 1 case was eliminated) and a control group (30 cases). The control group received conventional symptomatic treatment after chemotherapy. On the basis of the treatment in the control group, the intradermal needling group received intradermal needling at Guanyuan (CV 4), Dazhui (GV 14) and bilateral Geshu (BL 17), Zusanli (ST 36)，Shenshu (BL 23), the needles were retained for 48 h, once every other day. On the basis of the treatment in the control group, the acupuncture group received conventional acupuncture at the same acupoints as the intradermal needling group, once every other day. The treatment started from the first day of chemotherapy, for a total of 2 weeks in the three groups. The white blood cell count, neutrophil count, hemoglobin content, platelet count and Karnofsky performance status (KPS) score before treatment and on 3rd, 7th, 14th, and 21st days after treatment were compared among the three groups. The incidence and grading of leukopenia and the usage of leukocyte-boosting drug during chemotherapy cycle was recorded. RESULTS: On 7th day after treatment, the white blood cell count in the intradermal needling group and the acupuncture group was higher than that in the control group (P<0.01, P<0.05). On the 14th day after treatment, the hemoglobin content in the intradermal needling group and the acupuncture group was higher than that in the control group (P<0.01). On the 7th, 14th, and 21st days after treatment, the platelet count in the acupuncture group was higher than that in the control group (P<0.01), on the 14th and 21st days after treatment, the platelet count in the intradermal needling group was higher than that in the control group (P<0.01). There was no statistically significant difference among the three groups after treatment in terms of neutrophil count, KPS score, incidence and grading of leukopenia, and the usage of leukocyte-boosting drug (P>0.05). CONCLUSION: Both intradermal needling and acupuncture can effectively increase peripheral blood white blood cell count, hemoglobin content and platelet count during chemotherapy cycle, reduce the toxicity of chemotherapy drug to bone marrow hematopoietic function, and alleviate bone marrow suppression after chemotherapy. The two treatments are equally effective.

Pan-cell death-related signature reveals tumor immune microenvironment and optimizes personalized therapy alternations in lung adenocarcinoma.

This study constructed a comprehensive analysis of cell death modules in eliminating aberrant cells and remodeling tumor microenvironment (TME). Consensus analysis was performed in 490 lung adenocarcinoma (LUAD) patients based on 4 types of cell death prognostic genes. Intersection method divided these LUAD samples into 5 cell death risk (CDR) clusters, and COX regression analysis were used to construct the CDR signature (CDRSig) with risk scores. Significant differences of TME phenotypes, clinical factors, genome variations, radiosensitivity and immunotherapy sensitivity were observed in different CDR clusters. Patients with higher risk scores in the CDRSig tended to be immune-excluded or immune-desert, and those with lower risk scores were more sensitive to radiotherapy and immunotherapy. The results from mouse model showed that intense expression of the high-risk gene PFKP was associated with low CD8+ T cell infiltration upon radiotherapy and anti-PD-L1 treatment. Deficient assays in vitro confirmed that PFKP downregulation enhanced cGAS/STING pathway activation and radiosensitivity in LUAD cells. In conclusion, our studies originally performed a comprehensive cell death analysis, suggesting the importance of CDR patterns in reprogramming TME and providing novel clues for LUAD personalized therapies.

Association of Antihypertensive Drug-Related Gene Polymorphisms with Stroke in the Chinese Hypertensive Population.

Background: Antihypertensive therapy is crucial for preventing stroke in hypertensive patients. However, the efficacy of antihypertensive therapy varies across individuals, partially due to therapy-related genetic variations among individuals. We investigated the association of antihypertensive drug-related gene polymorphism with stroke in patients with hypertension. Methods: Demographic information, medication, and outcome data were obtained from a hypertensive patient management system, and a PCR fluorescence probe technique was used to detect 7 gene polymorphic loci (CYP2D6∗10, ADRB1, CYP2C9∗3, AGTR1, ACE, CYP3A5∗3, and NPPA), and these loci were compared between patients with and without stroke. Logistic regression was performed to analyze the association of these genetic variations with stroke risk in hypertensive patients while controlling for potential factors. Results: The prevalence of stroke in the hypertensive population in Changsha County of Hunan Province was 2.75%. The mutation frequencies of ADRB1 (1165G > C), CYP2D6∗10, CYP2C9∗3, AGTR1 (1166A > C), ACE (I/D), NPPA (2238T > C), and CYP3A5∗3 were 74.43%, 57.23%, 4.26%, 5.71%, 31.62%, 1.17%, and 69.58%, respectively. Univariate analysis revealed that ADRB1 polymorphism was associated with stroke (χ2 = 8.659, P < 0.05), with a higher stroke risk in the CC group than in the GC and GG groups (GC + GG). Multivariate unconditional logistic regression analysis showed that the CC genotype in ADRB1 (vs. the GC + GG genotype) was associated with an increased risk of stroke [odds ratio (OR) = 1.184, P<0.05] in hypertensive patients. No association was observed between CYP2D6∗10, CYP2C9∗3, AGTR1 (1166A > C), ACE (I/D), CYP3A5∗3, and NPPA (2238T > C) polymorphisms and stroke. Conclusions: ADRB1 (1165G > C) gene polymorphism is associated with the risk of stroke in Chinese hypertensive patients. The CC genotype is correlated with a higher risk of stroke than the GC + GG genotype.

hsa-miR-1301-3p Promotes the Proliferation and Migration of Nonsmall Cell Lung Cancer Cells and Reduces Radiosensitivity via Targeting Homeodomain-Only Protein Homeobox.

Background: There is increasing evidence that abnormal expression of microRNAs is involved in the occurrence and progression of tumors. In previous experiments, we found that the content of hsa-miR-1301-3p in tumor tissues of patients with nonsmall cell lung cancer (NSCLC) showed an obvious upward trend compared with that in normal tissues. We performed a detailed study on the impact and underlying mechanism of hsa-miR-1301-3p in NSCLC cells. Methods: The impact of hsa-miR-1301-3p on NSCLC cell proliferation, apoptosis, migration, and invasion was examined using colony formation, flow cytometry, modified Boyden chamber, and wound healing assays. Different doses of radiation were applied to NSCLC cells to investigate their sensitivity to radiotherapy. The potential target gene of hsa-miR-1301-3p was determined by dual-luciferase reporter assay and immunoblotting. Result: hsa-miR-1301-3p was upregulated in NSCLC tissues and cells. hsa-miR-1301-3p effectively promoted the rapid proliferation, migration, and invasion of NSCLC cells, while inhibiting apoptosis. It also induced radioresistance in NSCLC cells. hsa-miR-1301-3p targeted the homeodomain-only protein homeobox (HOPX) mRNA 3' untranslated region and inhibited its transcription in NSCLC cells. Exogenous HOPX overexpression antagonized the mechanism by which hsa-miR-1301-3p regulates NSCLC cell proliferation, metastasis, and apoptosis. Conclusions: hsa-miR-1301-3p plays an oncogenic role in the occurrence and development of NSCLC. By targeting HOPX, hsa-miR-1301-3p can not only promote the proliferation and metastasis of NSCLC cells, but also alleviate apoptosis and reduce radiosensitivity.