Specific TCR profiles predict clinical outcome of adjuvant EGFR-TKIs for resected EGFR-mutant non-small cell lung cancer.

BACKGROUND: ADJUVANT-CTONG1104 reported a favorable survival outcome from adjuvant gefitinib treatment over chemotherapy in EGFR-mutant non-small cell lung cancer (NSCLC) patients. However, heterogeneous benefit from EGFR-TKIs and chemotherapy demands further biomarker exploration for patient selection. Previously, we identified certain TCR sequences with predictive value for adjuvant therapies from the CTONG1104 trial and found a relationship between the TCR repertoire and genetic variations. It remains unknown which TCR sequences could further enhance the prediction for only adjuvant EGFR-TKI. METHODS: In this study, 57 tumor and 12 tumor-adjacent samples, respectively, from gefitinib-treated patients in the CTONG1104 were collected for TCR ß gene sequencing. We attempted to constitute a predictive model for prognosis and favorable adjuvant EGFR-TKI outcome for patients with early-stage NSCLC and EGFR mutations. RESULTS: The TCR rearrangements demonstrated significant prediction for overall survival (OS). A combined model of high frequent Vß7-3Jß2-5 and Vß24-1Jß2-1 with lower frequent Vß5-6Jß2-7 and Vß28Jß2-2 constituted the best value for predicting OS (P < 0.001; Hazard Ratio [HR] = 9.65, 95% confidence interval [CI]: 2.27 to 41.12) or DFS (P = 0.02; HR = 2.61, 95% CI: 1.13 to 6.03). In Cox regression analyses, when multiple clinical data were included, the risk score remained an independent prognostic predictor for OS (P = 0.003; HR = 9.49; 95% CI: 2.21 to 40.92) and DFS (P = 0.015; HR = 3.13; 95% CI: 1.25 to 7.87). CONCLUSIONS: In this study, a predictive model was constituted with specific TCR sequences for prognosis prediction and gefitinib benefit in the ADJUVANT-CTONG1104 trial. We provide a potential immune biomarker for EGFR-mutant NSCLC patients who might benefit from an adjuvant EGFR-TKI.

Porcine circovirus type 2 capsid protein induces unfolded protein response with subsequent activation of apoptosis.

Porcine circovirus type 2 (PCV2) has recently been reported to elicit the unfolded protein response (UPR) via activation of the PERK/eIF2α (RNA-activated protein kinase-like endoplasmic reticulum (ER) kinase/eukaryotic initiation factor 2α) pathway. This study attempted to examine which viral protein might be involved in inducing UPR and whether this cellular event would lead to apoptosis of the cells expressing the viral protein. By transient expression, we found that both replicase (Rep) and capsid (Cap) proteins of PCV2 could induce ER stress as shown by increased phosphorylation of PERK with subsequent activation of the eIF2α-ATF4 (activating transcription factor 4)-CHOP (CCAAT/enhancer-binding protein homologous protein) axis. Cap expression, but not Rep, significantly reduced anti-apoptotic B-cell lymphoma-2 (Bcl-2) and increased caspase-3 cleavage, possibly due to increased expression of CHOP. Since knockdown of PERK by RNA interference clearly reduced Cap-induced CHOP expression, caspase-3 cleavage, and apoptotic cell death possibly by partially rescuing Bcl-2 expression, we propose that there is connection between Cap-induced UPR and apoptosis via the PERK/eIF2α/ATF4/CHOP/Bcl-2 pathway. This study, together with our earlier studies, provides insight into the mechanisms underlying PCV2 pathogenesis.

[Response of indica rice spikelet differentiation and degeneration to air temperature and solar radiation of different sowing dates]. / ç±¼ç¨»é¢–èŠ±åˆ†åŒ–ä¸Žé€€åŒ–å¯¹ä¸åŒæ’­æœŸæ¸©å ‰çš„å“åº”.

In this study, three rice varieties, including three-line hybrid indica rice Wuyou308 and Tianyouhuazhan, and inbred indica rice Huanghuazhan were used to investigate the effects of air temperature and solar radiation on rice growth duration and spikelet differentiation and degeneration. Ten sowing-date treatments were conducted in this field experiment. The results showed that the growth duration of three indica rice varieties were more sensitive to air temperature than to day-length. With average temperature increase of 1 ℃, panicle initiation advanced 1.5 days, but the panicle growth duration had no significant correlation with the temperature and day-length. The number of spikelets and differentiated spikelets revealed significant differences among different sowing dates. Increases in average temperature, maximum temperature, minimum temperature, effective accumulated temperature, temperature gap and the solar radiation benefited dry matter accumulation and spikelet differentiation of all varieties. With increases of effective accumulated temperature, diurnal temperature gap and solar radiation by 50 ℃, 1 ℃, 50 MJ·m-2 during panicle initiation stage, the number of differentiated spikelets increased 10.5, 14.3, 17.1 respectively. The rate of degenerated spikelets had a quadratic correlation with air temperature, extreme high and low temperature aggravated spikelets degeneration, and low temperature stress made worse effect than high temperature stress. The rate of spikelet degeneration dramatically rose with the temperature falling below the critical temperature, the critical effective accumulated temperature, daily average temperature, daily maximum temperature and minimum temperature during panicle initiation were 550-600 ℃, 24.0-26.0 ℃, 32.0-34.0 ℃, 21.0-23.0 ℃, respectively. In practice, the natural condition of appropriate high temperature, large diurnal temperature gap and strong solar radiation were conducive to spikelet differentiation, and hindered the spikelet degeneration.

Tetrandrine suppresses human glioma growth by inhibiting cell survival, proliferation and tumour angiogenesis through attenuating STAT3 phosphorylation.

Tetrandrine (Tet), a bisbenzylisoquinoline alkaloid, has been reported to possess anti-tumour activity. However, its effects on human glioma remain unknown. In this study, we demonstrated that Tet inhibited human glioma cell growth in vitro and in vivo. It has been hypothesised that Tet inhibits glioma growth by affecting glioma cell survival, proliferation and vasculature in and around the xenograft tumour in the chick CAM model and signal transducer and activator of transcription 3 (STAT3) mediated these activities. Therefore, we conducted a detailed analysis of the inhibitory effects of Tet on cell survival using a TUNEL assay and flow cytometric analysis; on cell proliferation based on the expression of proliferating cell nuclear antigen; and on angiogenesis using a CAM anti-angiogenesis assay. We used western blotting to investigate the role of STAT3 on the anti-glioma activities of Tet. The results revealed that Tet inhibited survival and proliferation in human glioma cells, impaired tumour angiogenesis and decreased the expression of phosphorylated STAT3 and its downstream proteins. In sum, our data indicate that STAT3 is involved in Tet-induced the regression of glioma growth by activating tumour cell apoptosis, inhibiting glioma cell proliferation and inhibiting angiogenesis.

Low pH-induced changes of antioxidant enzyme and ATPase activities in the roots of rice (Oryza sativa L.) seedlings.

Soil acidification is the main problem in the current rice production. Here, the effects of low pH on the root growth, reactive oxygen species metabolism, plasma membrane functions, and the transcript levels of the related genes were investigated in rice seedlings (Oryza sativa L.) in a hydroponic system at pH 3.5, 4.5, and 5.5. There were two hybrid rice cultivars in this trial, including Yongyou 12 (YY12, a japonica hybrid) and Zhongzheyou 1 (ZZY1, an indica hybrid). Higher H+ activity markedly decreased root length, the proportion of fine roots, and dry matter production, but induced a significant accumulation of hydrogen peroxide (H2O2), and led to serious lipid peroxidation in the roots of the two varieties. The transcript levels of copper/zinc superoxide dismutase 1 (Cu/Zn SOD1), copper/zinc superoxide dismutase 2 (Cu/Zn SOD2), catalase A (CATA) and catalase B (CATB) genes in YY12 and ZZY1 roots were significantly down-regulated after low pH exposure for two weeks. Meanwhile, a significant decrease was observed in the expression of the P-type Ca2+-ATPases in roots at pH 3.5. The activities of antioxidant enzymes (SOD, CAT) and plasma membrane (PM) Ca2+-ATPase in the two varieties were dramatically inhibited by strong rhizosphere acidification. However, the expression levels of ascorbate peroxidase 1 (APX1) and PM H+-ATPase isoform 7 were up-regulated under H+ stress compared with the control. Significantly higher activities of APX and PM H+-ATPase could contribute to the adaptation of rice roots to low pH.

[Effects of exogenous nitric oxide on active oxygen metabolism and photosynthetic characteristics of tomato seedlings under cadmium stress].

A hydroponic experiment was conducted to study the effects of exogenous sodium nitroprusside (SNP), a NO donor, on the active oxygen metabolism and photosynthetic characteristics of tomato (Lycopersicon esculentum Mill.) seedlings under Cd stress. The results showed that under the stress, applying 100 micromol x L(-1) SNP promoted the activities of plant superoxide dismutase (SOD) and catalase (CAT) significantly, increased the leaf- and root calcium (Ca) and iron (Fe) contents and the leaf chlorophyll content, net photosynthetic rate (P(n)), transpiration rate (T(r)), and stomatal conductance (G(s)), and decreased the contents of H2O2 and MDA and the concentration of intercellular CO2 (C(i)). The addition of hemoglobin, a NO scavenger, eliminated the effects of SNP, while applying 100 micromol x L(-1) sodium nitrate or nitrite (the decomposition products of NO or its donor SNP) or 100 micromol x L(-1) sodium ferrocyanide (an analog of SNP) had no significant alleviation effects on Cd stress. This study suggested that exogenous NO could promote the scavenging of reactive oxygen, keep the mineral nutrition in balance, and alleviate the damage of Cd stress to the leaf photosynthetic apparatus, making the tomato seedlings preserve their photosynthetic efficiency.