Carbon Ion Radiotherapy Induce Metabolic Inhibition After Functional Imaging-Guided Simultaneous Integrated Boost for Prostate Cancer

PurposeAs local recurrence remains a challenge and the advantages of the simultaneous integrated boost (SIB) technique have been validated in photon radiotherapy, we applied the SIB technique to CIRT. The aim was to investigate the metabolomic changes of the CIRT with concurrent androgen deprivation therapy (ADT) in localized prostate cancer (PCa) and the unique metabolic effect of the SIB technique.Material and MethodsThis study enrolled 24 pathologically confirmed PCa patients. All patients went through CIRT with concurrent ADT. The gross target volume (GTV) boost was defined as positive lesions on both 68Ga-PSMA PET/CT and mpMRI images. Urine samples collected before and after CIRT were analyzed by the Q-TOF UPLC-MS/MS system. R platform and MetDNA were used for peak detection and identification. Statistical analysis and metabolic pathway analysis were performed on Metaboanalyst.ResultsThe metabolite profiles were significantly altered after CIRT. The most significantly altered metabolic pathway is PSMA participated alanine, aspartate and glutamate metabolism. Metabolites in this pathway showed a trend to be better suppressed in the SIB group. A total of 11 identified metabolites were significantly discriminative between two groups and all of them were better down-regulated in the SIB group. Meanwhile, among these metabolites, three metabolites in DNA damage and repair related purine metabolism were down-regulated to a greater extent in the SIB group.ConclusionMetabolic dysfunction was one of the typical characteristics of PCa. CIRT with ADT showed a powerful inhibition of PCa metabolism, especially in PSMA participated metabolic pathway. The SIB CIRT showed even better performance on down-regulation of most metabolism than uniform-dose-distribution CIRT. Meanwhile, the SIB CIRT also showed its unique superiority to inhibit purine metabolism. PSMA PET/CT guided SIB CIRT showed its potentials to further benefit PCa patients

Effects of the gradually decreasing low temperature stress on the chloroplast membrane related indexes in cucumber seedling(渐降低温胁迫对黄瓜幼苗叶绿体膜相关指标的影响)

为了进一步说明模拟自然界温度渐降低温胁迫的冷害作用的机理，以黄瓜品种“津优1号”为试材，以直降低温胁迫（昼温/夜温= (10±0. 5)℃/(5±0. 5)℃）为对照CK，常温（昼温/夜温= (25±0. 5)℃/(18±0. 5)℃）为对照CK1，研究渐降低温胁迫（即以1℃ • h-1的平均降温速度进行降温处理）对黄瓜幼苗叶绿体膜相关指标的影响.结果表明：(1)Ca2+-ATPase和Mg2+-ATPase活性在低温胁迫过程中呈先上升后下降趋势，随着低温胁迫的进程，渐降低温胁迫下2种酶活性下降的幅度明显低于直降低温胁迫.(2)经过低温胁迫，冷害指数、叶绿体膜蛋白质量浓度和叶绿素质量浓度显著下降.(3)处理T的冷害指数、膜蛋白和叶绿素质量浓度、Ca2+-ATPase和Mg2+-AT-Pase活性均显著高于CK.总之，渐降低温胁迫可以减少叶绿体膜的损伤，增强抵御低温逆境胁迫的能力

Signalling input from divergent pathways subverts B cell transformation

Malignant transformation of cells typically involves several genetic lesions, whose combined activity gives rise to cancer1. Here we analyse 1,148 patient-derived B-cell leukaemia (B-ALL) samples, and find that individual mutations do not promote leukaemogenesis unless they converge on one single oncogenic pathway that is characteristic of the differentiation stage of transformed B cells. Mutations that are not aligned with this central oncogenic driver activate divergent pathways and subvert transformation. Oncogenic lesions in B-ALL frequently mimic signalling through cytokine receptors at the pro-B-cell stage (via activation of the signal-transduction protein STAT5)2-4 or pre-B-cell receptors in more mature cells (via activation of the protein kinase ERK)5-8. STAT5- and ERK-activating lesions are found frequently, but occur together in only around 3% of cases (P = 2.2 × 10-16). Single-cell mutation and phospho-protein analyses reveal the segregation of oncogenic STAT5 and ERK activation to competing clones. STAT5 and ERK engage opposing biochemical and transcriptional programs that are orchestrated by the transcription factors MYC and BCL6, respectively. Genetic reactivation of the divergent (suppressed) pathway comes at the expense of the principal oncogenic driver and reverses transformation. Conversely, deletion of divergent pathway components accelerates leukaemogenesis. Thus, persistence of divergent signalling pathways represents a powerful barrier to transformation, while convergence on one principal driver defines a central event in leukaemia initiation. Pharmacological reactivation of suppressed divergent circuits synergizes strongly with inhibition of the principal oncogenic driver. Hence, reactivation of divergent pathways can be leveraged as a previously unrecognized strategy to enhance treatment responses