<h2>Abstract</h2><h3>Purpose</h3> To explore the association of the effective dose to immune cells (EDIC) with disease control, lymphopenia, and toxicity in patients with non-small cell lung cancer (NSCLC) and identify methods to reduce EDIC. <h3>Methods</h3> We abstracted data from all patients with locally advanced NSCLC treated with chemoradiation with or without consolidative immunotherapy over a ten-year period. Associations between EDIC and progression-free survival (PFS) and overall survival (OS) were modeled with Cox proportional hazards and Kaplan-Meier method. Logistic regression was used to model predictors of lymphopenia and higher EDIC. Analyses were performed with EDIC as a continuous and categorical variable. Lymphopenia was graded per CTCAE v5.0. <h3>Results</h3> Overall, 786 patients were included (228 of which received consolidative immunotherapy); median EDIC was 4.7 Gy. Patients with EDIC < 4.7 Gy had a longer median PFS (15.3 vs. 9.0 months; p < 0.001) and OS (34.2 vs. 22.4 months; p < 0.001). On multivariable modeling, EDIC correlated with inferior PFS (HR 1.08, 95 % CI 1.01–1.14, p = 0.014) and OS (HR 1.10, 95 % CI 1.04–1.18, p = 0.002). EDIC was predictive of grade 4 lymphopenia (OR 1.16, 95 % CI 1.02–1.33, p = 0.026). EDIC ≥ 4.7 Gy was associated with increased grade 2 + pneumonitis (6-month incidence: 26 % vs 20 %, p = 0.04) and unplanned hospitalizations (90-day incidence: 40 % vs 30 %, p = 0.002). Compared to protons, photon therapy was associated with EDIC ≥ 4.7 Gy (OR 5.26, 95 % CI 3.71–7.69, p < 0.001) in multivariable modeling. <h3>Conclusions</h3> EDIC is associated with inferior disease outcomes, treatment-related toxicity, and the development of severe lymphopenia. Proton therapy is associated with lower EDIC. Further investigations to limit radiation dose to the immune system appear warranted. 

The Effective Radiation Dose to Immune Cells Predicts Lymphopenia and Inferior Cancer Control in Locally Advanced NSCLC.

Comprehensive study on thermal decomposition mechanism and interaction of 3-Nitro-1,2,4-Triazol-5-One/Poly-3-nitromethyl-3-methyloxetane plastic bonded explosives

Theoretical investigation on interface interaction and properties of 3-nitro-1,2,4-triazol-5-one (NTO)/fluoropolymer polymer-bonded explosives (PBXs)

Study on thermolysis and interaction of NTO/HMX: innovation of a mixed explosive model. 

Multi-aspect simulation insight on thermolysis mechanism and interaction of NTO/HMX-based plastic-bonded explosives: a new conception of the mixed explosive model.

Pipemidic acid (PPA), one of the most prominent medications of the second generation of quinolones, has broad-spectrum antibacterial activity. Due to its low solubility and short half-life, it has led to a poor efficacy and numerous side effects. Multicomponent crystals have been proven to be an effective strategy for tuning the dissolution property of pharmaceuticals. Herein, multicomponent crystals of PPA with salicylic acid (SAA), gentian acid (GA), protocatechuic acid (PCA), caffeic acid (CAA), and saccharin (SAC) were synthesized. All the multicomponent crystals were characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), and thermal analysis including differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Hirshfeld Surface (HS) analysis showed that compared with PPA trihydrate, the contribution of the strong interaction in the multicomponent crystal structure to maintain the crystal structure tended to be weakened, indicating that the multicomponent crystal may increase the apparent solubility of PPA. Moreover, all the multicomponent crystals exhibit increased solubility and decelerated intrinsic dissolution rate (IDR). Specifically, the PPA-SAA and PPA-GA salts demonstrate the most significant solubility improvement in the pH 6.8 buffer by 640.98% and 213.11% when compared to the pure PPA trihydrate, respectively. For the other hydrates of the three salts (PPA-PCA salt hydrate, PPA-CAA salt hydrate, and PPA-SAC salt hydrate), the solubility increased by 45.90%, 13.11%, and 165.57%, respectively. Further, in vitro dissolution experiment results revealed that the IDR values of the multicomponent crystals (PPA-SAA salt, PPA-GA salt, PPA-PCA salt hydrate, PPA-CAA salt hydrate, and PPA-SAC salt hydrate) were 2.40, 2.14, 1.57, 1.53, and 2.80 mg/cm2/min, respectively, which were all less than that of the PPA trihydrate (5.24 mg/cm2/min). This causes the multicomponent crystals to release at a slower rate, thus improving bioavailability. Molecular dynamics simulation results indicate that the solubilizing effect is caused by the lower lattice energy and full exposure of hydrophilic groups caused by molecular assembly. Different from the cyclic supramolecular synthons in other multicomponent crystals from structure point, the ones in PPA-SAA salts are chain-like synthons, which may be one of the main reasons for the most significant increase in its apparent solubility. Stability tests showed that all multicomponent crystals exhibited excellent stability over 8 weeks at accelerated storage conditions (40 °C and 75% RH). This work demonstrates that multicomponent crystals can offer a promising potential to slow the release rate and enhance the solubility for these defective pharmaceuticals. 

New Insights into the Solubilization of Multicomponent Crystals: A Case Study of Pipemidic Acid

Theoretical investigation on the intermolecular interactions between 3-nitro-1,2,4-triazol-5-one and 2,6-diamino-3,5-dinitropyrazine-1-oxide using DFT methods

Impact of Radiation Dose to the Immune System on Disease Progression and Survival for Early-Stage Non-Small Cell Lung Cancer Treated with Stereotactic Body Radiation Therapy.

Abnormal histone modifications (HMs) can promote the occurrence of breast cancer. To elucidate the relationship between HMs and gene expression, we analyzed HM binding patterns and calculated their signal changes between breast tumor cells and normal cells. On this basis, the influences of HM signal changes on the expression changes of breast cancer-related genes were estimated by three different methods. The results showed that H3K79me2 and H3K36me3 may contribute more to gene expression changes. Subsequently, 2109 genes with differential H3K79me2 or H3K36me3 levels during cancerogenesis were identified by the Shannon entropy and submitted to perform functional enrichment analyses. Enrichment analyses displayed that these genes were involved in pathways in cancer, human papillomavirus infection, and viral carcinogenesis. Univariate Cox, LASSO, and multivariate Cox regression analyses were then adopted, and nine potential breast cancer-related driver genes were extracted from the genes with differential H3K79me2/H3K36me3 levels in the TCGA cohort. To facilitate the application, the expression levels of nine driver genes were transformed into a risk score model, and its robustness was tested via time-dependent receiver operating characteristic curves in the TCGA dataset and an independent GEO dataset. At last, the distribution levels of H3K79me2 and H3K36me3 in the nine driver genes were reanalyzed in the two cell lines and the regions with significant signal changes were located.

The risk model construction of the genes regulated by H3K36me3 and H3K79me2 in breast cancer

Lung adenocarcinoma is one of the deadliest tumors because the lack of effective diagnosis and treatment methods. Some studies have found that N6-methyladenosine (m6A) RNA methylation regulators, as a dynamic chemical modification, affects the occurrence and development of lung adenocarcinoma. However, the potential mechanisms of the differentially expressed m6A-regulated genes in different subtypes of lung adenocarcinoma and the tumor microenvironment remain unclear. Gene expression data, mutation data and corresponding clinical data of LUAD patients were downloaded from TCGA database. Based on the expression of 38 m6A-regulated genes, differentially expressed m6A genes were searched. According to the differentially expressed m6A-regulated genes, we identified two distinct m6A patterns by consensus clustering. The relative infiltration levels of 23 immune cells were quantified by the single-sample gene set enrichment analysis (ssGSEA) algorithm. The stromal and immune scores were evaluated by using of ESTIMATE algorithm. The prognosis model of m6A-related immune genes was established by LASSO-Cox regression. Survival analysis and receiver operating characteristic curve were used to evaluate prognostic models. The 19 differentially expressed m6A regulators were found. LUAD samples were divided into two subtypes based on the 19 differentially expressed m6A-regulated genes. One subtype, which survived better, had higher immune infiltration and immune scores, and lower tumor purity. In addition, the 5 differentially expressed immune prognostic genes between the two clusters were identified to build a risk score model. Kaplan-Meier survival analysis showed that the low-risk group had better survival than the high-risk group. The ROC confirmed the predictive accuracy of our established model. 

M6A RNA Methylation Modification and Tumor Immune Microenvironment in Lung Adenocarcinoma

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Theoretical investigation on the intermolecular interactions between 3-nitro-1,2,4-triazol-5-one and 2,6-diamino-3,5-dinitropyrazine-1-oxide using DFT methods

Impact of Radiation Dose to the Immune System on Disease Progression and Survival for Early-Stage Non-Small Cell Lung Cancer Treated with Stereotactic Body Radiation Therapy.

The risk model construction of the genes regulated by H3K36me3 and H3K79me2 in breast cancer

M6A RNA Methylation Modification and Tumor Immune Microenvironment in Lung Adenocarcinoma