WRKY transcription factors play a key role in the tolerance of biotic and abiotic stresses across various crop species, but the function of some WRKY genes, particularly in tomato, remains ...unexplored. Here, we characterize the roles of a previously unstudied WRKY gene, SlWRKY8, in the resistance to pathogen infection and the tolerance to drought and salt stresses. Expression of SlWRKY8 was up‐regulated upon Pseudomonas syringae pv. tomato DC3000 (Pst. DC3000), abiotic stresses such as drought, salt and cold, as well as ABA and SA treatments. The SlWRKY8 protein was localized to the nucleus with no transcription activation in yeast, but it could activate W‐box‐dependent transcription in plants. The overexpression of SlWRKY8 in tomato conferred a greater resistance to the pathogen Pst. DC3000 and resulted in the increased transcription levels of two pathogen‐related genes SlPR1a1 and SlPR7. Moreover, transgenic plants displayed the alleviated wilting or chlorosis phenotype under drought and salt stresses, with higher levels of stress‐induced osmotic substances like proline and higher transcript levels of the stress‐responsive genes SlAREB, SlDREB2A and SlRD29. Stomatal aperature was smaller under drought stress in transgenic plants, maintaining higher water content in leaves compared with wild‐type plants. The oxidative pressure, indicated by the concentration of hydrogen peroxide (H2O2) and malondialdehyde (MDA), was also reduced in transgenic plants, where we also observed higher levels of antioxidant enzyme activities under stress. Overall, our results suggest that SlWRKY8 functions as a positive regulator in plant immunity against pathogen infection as well as in plant responses to drought and salt stresses.
This paper presents a novel design of ternary logic gates using carbon nanotube (CNT) FETs (CNTFETs). Ternary logic is a promising alternative to the conventional binary logic design technique, since ...it is possible to accomplish simplicity and energy efficiency in modern digital design due to the reduced circuit overhead such as interconnects and chip area. A resistive-load CNTFET-based ternary logic design has been proposed to implement ternary logic based on CNTFET. In this paper, a novel design technique for ternary logic gates based on CNTFETs is proposed and compared with the existing resistive-load CNTFET logic gate designs. Especially, the proposed ternary logic gate design technique combined with the conventional binary logic gate design technique provides an excellent speed and power consumption characteristics in datapath circuit such as full adder and multiplier. Extensive simulation results using SPICE are reported to show that the proposed ternary logic gates consume significantly lower power and delay than the previous resistive-load CNTFET gates implementations. In realistic circuit application, the utilization of the proposed ternary gates combined with binary gates results in over 90% reductions in terms of the power delay product.
Multimodality treatment provides modest survival benefits for patients with locally advanced (stage III) non-small-cell lung cancer (NSCLC). Nevertheless, preoperative immunotherapy has continuously ...been shown to be promising in treating resectable NSCLC.This phase 2 trial enrolled patients with AJCC-defined stage IIIA or T3-4N2 IIIB NSCLC deemed surgically resectable. Patients received three cycles of neoadjuvant treatment with intravenous PD-1 inhibitor toripalimab (240 mg), carboplatin (area under the curve 5), and pemetrexed (500 mg/m
2
for adenocarcinoma) or nab-paclitaxel (260 mg/m
2
for other subtypes) on day 1 of each 21-day cycle. Surgical resection was performed 4-5 weeks afterward. The primary endpoint was major pathological response (MPR), defined as less than 10% residual tumor remaining at the time of surgery.Thirty-three patients were enrolled, of whom 13 (39.4%) had T3-4N2 stage IIIB disease. Thirty (90.9%) patients underwent resection and all except one (96.7%) achieved R0 resection. Twenty patients (60.6%) in the intention-to-treat population achieved an MPR, including 15 patients (45.5%) who achieved a pathological complete response (pCR). The MPR and pCR rates in the per-protocol population were 66.7% and 50.0%, respectively. The surgical complications included three cases of arrhythmias, one case of a prolonged air leak, and one case of chylothorax. The most common grade 3 treatment-related adverse event (TRAE) was anemia (2, 6.1%). Severe TRAEs included one (3.0%) case of grade 3 peripheral neuropathy that resulted in surgical cancellation.Toripalimab plus platinum-based doublet chemotherapy yields a high MPR rate, manageable toxicity, and feasible resection in stage III NSCLC.Trial ClinicalTrials.gov (NCT04304248)
This paper presents a novel design of a ternary memory cell using carbon nanotube field-effect transistors (CNTFETs). Ternary logic is a promising alternative to conventional binary logic because it ...allows simplicity and energy efficiency in modern digital design due to the reduced circuit overhead in interconnects and chip area. In this paper, a novel design of a ternary memory cell based on CNTFETs is proposed; this cell uses a transmission gate for the write operation and a buffer for the read operation to make them separate. Chirality of the CNTFETs is utilized for threshold voltage control, thus avoiding the use of additional power supplies. Extensive simulation results using SPICE are reported to show that the two memory operations of the proposed ternary cell perform correctly at 0.9 V power supply. The static noise margin and read/write delay of the proposed ternary memory cell are also very good; by utilizing the latest CNTFET layout design tools, it is shown that the proposed ternary memory cell achieves a significant saving in area (41.6%) compared with its CMOS ternary counterpart at 32 nm.
Background
Hepatitis B core antibody (HBcAb) positivity is considered a prior hepatitis B virus (HBV) infection. However, little is known about the effect of HBcAb positivity on surgical safety for ...hilar cholangiocarcinoma (hCCA). The present study aims to investigate the role of HBcAb positivity on postoperative complications of hCCA.
Methods
A retrospective analysis was performed on the status of HBcAb positivity, liver fibrosis, perioperative surgical complications, and long‐term outcomes of hCCA patients with Hepatitis B surface antigen (HBsAg) negativity who underwent surgical treatment in Tongji Hospital from April 2012 to September 2019.
Results
HBcAb positivity with negative HBsAg occurs in 137 hCCA patients (63.1%). A total of 99 hCCA patients with negative HBsAg underwent extended hemihepatectomy, of whom 69 (69.7%) and 30 (30.3%) were HBcAb‐positive and HBcAb‐negative, respectively. Significant fibrosis was detected in 63.8% of the patients with HBcAb‐positive, which was markedly higher than those with HBcAb‐negative (36.7%) (p = 0.016). The postoperative complications and 90‐day mortality rates were 37.4% (37/99) and 8.1% (8/99), respectively. The incidence of postoperative complications in HBcAb‐positive patients (44.9%) was significantly higher than that in HBcAb‐negative patients (20.0%) (p = 0.018). All the patients who died within 30‐day after surgery were HBcAb‐positive. Multivariate analysis showed that the independent risk factors for complications were HBcAb positivity, preoperative cholangitis, portal occlusion >15 min, and significant fibrosis. There were no significant differences in recurrence‐free survival (RFS) and overall survival (OS) between HBcAb‐positive and HBcAb‐negative patients (p = 0.642 and p = 0.400, respectively).
Conclusions
HBcAb positivity is a common phenomenon in hCCA patients from China, a country with highly prevalent HBcAb positivity. The status of HBcAb‐positive markedly increases the incidence of postoperative complications after extended hemihepatectomy for hCCA patients.
The present study aims to evaluate the prevalence of HBcAb positivity in hCCA patients and explore the effect of HBcAb positivity on postoperative complications of hCCA patients after curative resection. Among all the 217 patients, 160 (73.7%) patients were HBcAb positive. Data of 99 HBsAg negative patients who underwent curative resection were analyzed, and the HBcAb positivity markedly increased the risk of postoperative complications and mortality after curative resection for hCCA. Surgeons should pay more attention to HBcAb status in hCCA patients with negative HBsAg, which could help them to select optimal surgical modalities.
Mitsugumin 53 (MG53) is a tripartite motif family protein that has been reported to attenuate injury via membrane repair in different organs. Contrast-induced acute kidney injury (CI-AKI) is a common ...complication caused by the administration of iodinated contrast media (CM). While the cytotoxicity induced by CM leading to tubular cell death may be initiated by cell membrane damage, we wondered whether MG53 alleviates CI-AKI. This study was designed to investigate the effect of MG53 on CI-AKI and the underlying mechanism. A rat model of CI-AKI was established, and CI-AKI induced the translocation of MG53 from serum to injury sites on the renal proximal tubular (RPT) epithelia, as illustrated by immunoblot analysis and immunohistochemical staining. Moreover, pretreatment of rats with recombinant human MG53 protein (rhMG53, 2 mg/mL) alleviated iopromide-induced injury in the kidney, which was determined by measuring serum creatinine, blood urea nitrogen and renal histological changes. In vitro studies demonstrated that exposure of RPT cells to iopromide (20, 40, and 80 mg/mL) caused cell membrane injury and cell death, which were attenuated by rhMG53 (10 and 50 μg/mL). Mechanistically, MG53 translocated to the injury site on RPT cells and bound to phosphatidylserine to protect RPT cells from iopromide-induced injury. In conclusion, MG53 protects against CI-AKI through cell membrane repair and reducing cell apoptosis; therefore, rhMG53 might be a potential effective means to treat or prevent CI-AKI.
Background
The efficacy of adjuvant targeted therapy for operable lung cancer is still under debate. Comprehensive genetic profiling is needed for detecting co‐mutations in resected epidermal growth ...factor receptor (EGFR)‐mutated lung adenocarcinoma (ADC), which may interfere the efficacy of adjuvant tyrosine kinase inhibitor (TKI) treatment.
Materials and Methods
Mutation profiling of 416 cancer‐relevant genes was conducted for 139 resected stage I–IIIa lung ADCs with EGFR mutations using targeted next‐generation sequencing. Co‐mutation profiles were systematically analyzed.
Results
Rare EGFR alterations other than exon 19 deletion and L858R, such as L861Q (∼3%) and G719A (∼2%), were identified at low frequencies. Approximately 10% of patients had mutations in EGFR exon 20 that could confer resistance to first‐generation TKIs. Ninety‐one percent of patients harbored at least one co‐mutation in addition to the major EGFR mutation. TP53 was the top mutated gene and was found more frequently mutated at later stage. Markedly, NF1 mutations were found only in stage II–III ADCs. Conversely, RB1 mutations were more frequent in stage I ADCs, whereas APC mutations were observed exclusively in this group. Thirty‐four percent of patients with EGFR TKI‐sensitizing mutations had genetic alterations involving EGFR downstream effectors or bypass pathways that could affect the response to EGFR TKIs, such as PIK3CA, BRCA1, and NOTCH1.
Conclusion
Operable lung ADCs with EGFR TKI‐sensitizing mutations are associated with a high proportion of co‐mutations. Mutation profiling of these resected tumors could facilitate in determining the applicability and efficacy of adjuvant EGFR TKI therapeutic strategy.
Implications for Practice
The efficacy of adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy for lung cancer harboring EGFR mutation after surgical resection is still under debate. Next‐generation sequencing of 416 cancer‐relevant genes in 139 resected lung cancers revealed the co‐mutational landscape with background EGFR mutation. Notably, the study identified potential EGFR TKI‐resistant mutations in 34.71% of patients with a drug‐sensitizing EGFR mutation and who were naive in terms of targeted therapy. A comprehensive mutation profiling of these resected tumors could facilitate in determining the applicability and efficacy of adjuvant EGFR TKI therapeutic strategy for these patients.
摘要
背景 辅助靶向治疗对可手术肺癌的疗效仍在争论中。在可切除的表皮生长因子受体 (EGFR) 突变肺腺癌 (ADC) 中检测共突变需要全面的遗传分析，这可能会影响辅助酪氨酸激酶抑制剂 (TKI) 治疗的疗效。
材料和方法 使用靶向的下一代测序技术，对 139 个具有 EGFR 突变的可切除的 I‐IIIa 期肺 ADC 进行416 个癌症相关基因突变分析。系统地分析了共突变谱。
结果 除了外显子 19 缺失和 L858R 外的罕见EGFR 改变，如 L861Q(~3%) 和 G719A(~2%)，较低频率被发现。大约 10% 的患者发生 EGFR 外显子 20 突变，这可能导致对第一代 TKI 耐药。除主要EGFR突变外，91% 的患者出现至少一种共突变。TP53是最常见的突变基因，在后期的突变频率较高。显然的是，NF1突变只在 II‐III 期 ADC 中发现。相反，RB1 突变在 I 期 ADC 中更为频发，而仅在该组中观察到 APC 突变。34% EGFR TKI 敏感突变患者的遗传变异涉及 EGFR 下游效应靶点或旁路途径，可能影响对 EGFR TKI 的反应，如PIK3CA、BRCA1，和NOTCH1。
结论 具有 EGFR TKI 敏感突变的可手术肺 ADC 与高比例的共突变相关。这些可切除肿瘤的突变谱有助于确定辅助 EGFR TKI 治疗策略的适用性和有效性。
实践意义:辅助表皮生长因子受体 (EGFR) 酪氨酸激酶抑制剂 (TKI) 治疗肺癌术后EGFR突变的疗效仍存在争议。在 139 例可切除的肺癌中，对 416 个癌症相关基因进行的下一代测序揭示了EGFR突变背景下的共突变图景。值得注意的是，该研究在 34.71% 的药物敏感性EGFR突变患者中发现了潜在的 EGFR TKI 耐药突变，而这些患者缺乏靶向治疗方面的经验。对这些可切除肿瘤进行全面的突变谱分析有助于确定辅助 EGFR TKI 治疗策略对这些患者的适用性和有效性。
The best treatment option for patients with operable lung cancer is debatable. In this study, a comprehensive mutation profiling was performed on resected EGFR‐mutated lung adenocarcinoma using next‐generation sequencing that targeted cancer‐relevant genes to identify potential candidates for adjuvant tyrosine kinase inihibitors treatment post‐operation.
Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare type of non-small cell lung cancer. In this study, we retrospectively reviewed the data from 74 consecutive patients with pulmonary ...LELC and investigated the prognostic value of pretreatment monocyte-to-lymphocyte ratio (MLR). The cut-off value determined by ROC curve for MLR was 0.262. According to this cut-off value, 36 (48.6%) patients had lower MLR value (<0.262) at diagnosis. There was no significant correlation between MLR level and gender, age, smoking history, stage, and lactate dehydrogenase (LDH) level. The 2-year, 5-year, and 10-year OS rate were 86%, 72%, and 61%, respectively; the 2-year, 5-year, and 10-year PFS rate were 71%, 63%, and 49%, respectively. In univariate analysis, advanced stage, elevated LDH level, and higher MLR value (> = 0.262) were significantly associated with poor OS and PFS. In a multivariate Cox regression model that included stage, LDH and MLR level, all of these three factors were found to be independent prognostic factors for both PFS and OS. In patients who received radical surgery, MLR level remained significantly correlated with OS and PFS. In conclusion, we firstly demonstrated that pretreatment MLR can be used as a useful independent prognostic marker in patients with pulmonary LELC, and might guide us to optimize the treatment strategies. However, due to the relatively rarity of this disease and the limitation of a retrospective study, further prospective studies performed in multicenter are necessary to validate the prognostic value of MLR in pulmonary LELC.
The snub-nosed monkey genus Rhinopithecus includes five closely related species distributed across altitudinal gradients from 800 to 4,500 m. Rhinopithecus bieti, Rhinopithecus roxellana, and ...Rhinopithecus strykeri inhabit high-altitude habitats, whereas Rhinopithecus brelichi and Rhinopithecus avunculus inhabit lowland regions. We report the de novo whole-genome sequence of R. bieti and genomic sequences for the four other species. Eight shared substitutions were found in six genes related to lung function, DNA repair, and angiogenesis in the high-altitude snub-nosed monkeys. Functional assays showed that the high-altitude variant of CDT1 (Ala537Val) renders cells more resistant to UV irradiation, and the high-altitude variants of RNASE4 (Asn89Lys and Thr128Ile) confer enhanced ability to induce endothelial tube formation in vitro. Genomic scans in the R. bieti and R. roxellana populations identified signatures of selection between and within populations at genes involved in functions relevant to high-altitude adaptation. These results provide valuable insights into the adaptation to high altitude in the snub-nosed monkeys.
The human lens is comprised largely of crystallin proteins assembled into a highly ordered, interactive macro-structure essential for lens transparency and refractive index. Any disruption of intra- ...or inter-protein interactions will alter this delicate structure, exposing hydrophobic surfaces, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness worldwide, affecting tens of millions of people, and currently the only treatment is surgical removal of cataractous lenses. The precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. We further show that lanosterol treatment could reduce cataract severity and increase transparency in dissected rabbit cataractous lenses in vitro and cataract severity in vivo in dogs. Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.
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