Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of YK-029A in Treatment-Naive Patients With Advanced NSCLC Harboring EGFR Exon 20 Insertion Mutations: A Phase 1 Trial.

INTRODUCTION: Treatment options for treatment-naive patients with advanced NSCLC harboring EGFR exon 20 insertion (ex20ins) mutations are limited. This study evaluated the safety, tolerability, and pharmacokinetics of YK-029A, a third-generation EGFR tyrosine kinase inhibitor, and the preliminary efficacy of YK-029A in treatment-naive patients with EGFR ex20ins mutation. METHODS: This multicenter, dose-escalation, and dose-expansion phase 1 clinical trial enrolled patients with NSCLC harboring EGFR mutations. During the dose-escalation phase, YK-029A was orally administered using the traditional 3+3 principle at 50, 100, 150, 200, and 250 mg/d. In the dose-expansion phase, treatment-naive patients with EGFR ex20ins mutations were enrolled and administered YK-029A 200 mg/d. The primary end point was safety and tolerability. RESULTS: The safety analysis included 108 patients. No dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. The most common treatment-emergent adverse events were anemia (50.9%), diarrhea (49.1%), and rash (34.3%). There was minimal drug accumulation after multiple doses. A total of 28 treatment-naive patients with EGFR ex20ins mutations were enrolled in the dose-expansion and 26 were included in the efficacy analysis. According to the independent review committee evaluation, the objective response rate was 73.1% (95% confidence interval: 52.21%-88.43%), and the disease control rate was 92.3% (95% confidence interval: 74.87%-99.05%). CONCLUSIONS: YK-029A was found to have manageable safety and be tolerable in patients with NSCLC harboring EGFR mutations and have promising antitumor activity in untreated patients with EGFR ex20ins mutations.

Overexpression of Nta-miR6155 confers resistance to Phytophthora nicotianae and regulates growth in tobacco (Nicotiana tabacum L.).

Tobacco black shank induced by Phytophthora nicotianae causes significant yield losses in tobacco plants. MicroRNAs (miRNAs) play a pivotal role in plant biotic stress responses and have great potential in tobacco breeding for disease resistance. However, the roles of miRNAs in tobacco plants in response to P. nicotianae infection has not been well characterized. In this study, we found that Nta-miR6155, a miRNA specific to Solanaceae crops, was significantly induced in P. nicotianae infected tobacco. Some of predicted target genes of Nta-miR6155 were also observed to be involved in disease resistance. To further investigate the function of miR6155 in tobacco during P. nicotianae infection, Nta-miR6155 overexpression plants (miR6155-OE) were generated in the Honghua Dajinyuan tobacco variety (HD, the main cultivated tobacco variety in China). We found that the Nta-miR6155 overexpression enhanced the resistance in tobacco towards P. nicotianae infections. The level of reactive oxygen species (ROS) was significantly lower and antioxidant enzyme activities were significantly higher in miR6155-OE plants than those in control HD plants during P. nicotianae infection. In addition, we found that the accumulation of salicylic acid and the expression of salicylic acid biosynthesis and signal transduction-related genes is significantly higher in miR6155-OE plants in comparison to the control HD plants. Furthermore, we found that Nta-miR6155 cleaved target genes NtCIPK18 to modulate resistance towards P. nicotianae in tobacco plants. Additionally, phenotypic analysis of miR6155-OE plants showed that Nta-miR6155 could inhibit the growth of tobacco by suppressing nitrogen uptake and photosynthesis. In conclusion, our findings indicated that miR6155 plays a crucial role in the regulation of growth and resistance against P. nicotianae infections in tobacco plants.

Genome-Wide Identification and Expression Analysis of C3H Zinc Finger Family in Potato (Solanum tuberosum L.).

Transcription factors containing a CCCH structure (C3H) play important roles in plant growth and development, and their stress response, but research on the C3H gene family in potato has not been reported yet. In this study, we used bioinformatics to identify 50 C3H genes in potato and named them StC3H-1 to StC3H-50 according to their location on chromosomes, and we analyzed their physical and chemical properties, chromosome location, phylogenetic relationship, gene structure, collinearity relationship, and cis-regulatory element. The gene expression pattern analysis showed that many StC3H genes are involved in potato growth and development, and their response to diverse environmental stresses. Furthermore, RT-qPCR data showed that the expression of many StC3H genes was induced by high temperatures, indicating that StC3H genes may play important roles in potato response to heat stress. In addition, Some StC3H genes were predominantly expressed in the stolon and developing tubers, suggesting that these StC3H genes may be involved in the regulation of tuber development. Together, these results provide new information on StC3H genes and will be helpful for further revealing the function of StC3H genes in the heat stress response and tuber development in potato.

Transcriptome and functional analysis revealed the intervention of brassinosteroid in regulation of cold induced early flowering in tobacco.

Cold environmental conditions may often lead to the early flowering of plants, and the mechanism by cold-induced flowering remains poorly understood. Microscopy analysis in this study demonstrated that cold conditioning led to early flower bud differentiation in two tobacco strains and an Agilent Tobacco Gene Expression microarray was adapted for transcriptomic analysis on the stem tips of cold treated tobacco to gain insight into the molecular process underlying flowering in tobacco. The transcriptomic analysis showed that cold treatment of two flue-cured tobacco varieties (Xingyan 1 and YunYan 85) yielded 4176 and 5773 genes that were differentially expressed, respectively, with 2623 being commonly detected. Functional distribution revealed that the differentially expressed genes (DEGs) were mainly enriched in protein metabolism, RNA, stress, transport, and secondary metabolism. Genes involved in secondary metabolism, cell wall, and redox were nearly all up-regulated in response to the cold conditioning. Further analysis demonstrated that the central genes related to brassinosteroid biosynthetic pathway, circadian system, and flowering pathway were significantly enhanced in the cold treated tobacco. Phytochemical measurement and qRT-PCR revealed an increased accumulation of brassinolide and a decreased expression of the flowering locus c gene. Furthermore, we found that overexpression of NtBRI1 could induce early flowering in tobacco under normal condition. And low-temperature-induced early flowering in NtBRI1 overexpression plants were similar to that of normal condition. Consistently, low-temperature-induced early flowering is partially suppressed in NtBRI1 mutant. Together, the results suggest that cold could induce early flowering of tobacco by activating brassinosteroid signaling.

Efficacy and Safety of Denosumab Biosimilar QL1206 Versus Denosumab in Patients with Bone Metastases from Solid Tumors: A Randomized Phase III Trial.

BACKGROUND: Denosumab has been approved for the treatment of bone metastases from solid tumors. QL1206 is the first denosumab biosimilar and needs to be compared with denosumab in a phase III trial. OBJECTIVE: This phase III trial aims to compare the efficacy, safety, and pharmacokinetics between QL1206 and denosumab in patients with bone metastases from solid tumors. METHODS: This randomized, double-blind, phase III trial was conducted in 51 centers in China. Patients aged 18-80 years, with solid tumors and bone metastases, and an Eastern Cooperative Oncology Group performance status of 0-2 were eligible. This study was divided into a 13-week double-blind period, a 40-week open-label period, and a 20-week safety follow-up period. In the double-blind period, patients were randomly assigned (1:1) to receive three doses of QL1206 or denosumab (120 mg subcutaneously every 4 weeks, each). Randomization was stratified by tumor types, previous skeletal-related events, and current systemic anti-tumor therapy. In the open-label period, up to ten doses of QL1206 could be given in both groups. The primary endpoint was percentage change in urinary N-telopeptide/creatinine ratio (uNTX/uCr) from baseline to Week 13. Equivalence margins were ± 0.135. Secondary endpoints included percentage change in uNTX/uCr at Week 25 and 53, percentage change in serum bone-specific alkaline phosphatase at Week 13, 25, and 53, and time to on-study skeletal-related events. The safety profile was evaluated based on adverse events and immunogenicity. RESULTS: From September 2019 to January 2021, in the full analysis set, 717 patients were randomly assigned to receive QL1206 (n = 357) or denosumab (n = 360). Median percentage changes in uNTX/uCr at Week 13 in two groups were - 75.2% and - 75.8%, respectively. Least-squares mean difference in the natural log-transformed ratio of uNTX/uCr at Week 13 to baseline between the two groups was 0.012 (90% confidence interval - 0.078 to 0.103), within the equivalence margins. There were no differences in the secondary endpoints between the two groups (all p > 0.05). Adverse events, immunogenicity, and pharmacokinetics were similar in the two groups. CONCLUSIONS: Denosumab biosimilar QL1206 had promising efficacy, tolerable safety, and pharmacokinetics equivalent to denosumab and could benefit patients with bone metastases from solid tumors. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04550949, retrospectively registered on 16 September, 2020.

Survival among patients with composite and sequential lymphoma between primary mediastinal lymphoma/diffuse large B-cell lymphoma and classical Hodgkin lymphoma: A population-based study.

BACKGROUND: Data on composite and sequential lymphoma between primary mediastinal lymphoma/diffuse large B-cell lymphoma (LBCL) and classical Hodgkin lymphoma (cHL) are rare. METHODS: We identified 25 cases with composite lymphoma (CL), 116 cases developing LBCL as a second primary cancer after cHL (cHL-LBCL), and 74 cases developing cHL as a second primary cancer after LBCL (LBCL-cHL) from the Surveillance, Epidemiology, and End Results (SEER) 18 database. Comparisons of overall survival (OS) and lymphoma cause-specific survival (CSS) between patients with cHL-LBCL or cHL-LBCL and their de novo counterparts were performed. RESULTS: The 5-year OS of patients with CL was 74.8 %. No significant difference in unadjusted OS and lymphoma CSS were observed between patients with de novo LBCL (LBCL-1 group) and patients with cHL-LBCL. However, the age- and stage-adjusted cHL-LBCL group had inferior OS and lymphoma CSS compared with that in the LBCL-1 group. The unadjusted and adjusted OS and lymphoma CSS in the LBCL-cHL group were significantly worse than patients with de novo cHL. CONCLUSIONS: CL between LBCL and cHL may have good outcomes. cHL survivors had poorer outcomes after a LBCL diagnosis versus patients with LBCL-1. Significantly poor outcomes were observed in patients with LBCL-cHL compared with patients with de novo cHL.

Protective immunity induced by the vaccination of recombinant Proteus mirabilis OmpA expressed in Pichia pastoris.

Proteus mirabilis (P. mirabilis) is a zoonotic pathogen that has recently presented a rising infection rate in the poultry industry. To develop an effective vaccine to protect chickens against P. mirabilis infection, OmpA, one of the major outer membrane proteins of P. mirabilis, was expressed in Pichia pastoris. The concentration of the expressed recombinant OmpA protein reached 8.0µg/mL after induction for 96h with 1.0% methanol in the culture. In addition, OmpA protein was confirmed by SDS-PAGE and Western blot analysis using the antibody against Escherichia coli-expressed OmpA protein. Taishan Pinus massoniana pollen polysaccharide, a known plant-derived adjuvant, was mixed into the recombinant OmpA protein to prepare the OmpA subunit vaccine. We then subcutaneously inoculated this vaccine into chickens to examine the immunoprotective effects. ELISA analysis indicated that an excellent antibody response against OmpA was elicited in the vaccinated chickens. Moreover, a high protection rate of 80.0% was observed in the vaccinated group, which was subsequently challenged with P. mirabilis. The results suggest that the eukaryotic P. mirabilis OmpA was an ideal candidate protein for developing an effective subunit vaccine against P. mirabilis infection.

Distribution of the type I interferon in different organs of chicken digestive system.

OBJECTIVE: Distribution of the type I interferon in different organs of the chicken digestive system. MATERIAL AND METHODS: In order to obtain a certain length (274 bp) of a fragment, a pair of primers was designed according to the conserved nucleotide sequence of gallus IFNAR-1 (EU477527.1) fragment that was published by the GenBank. The fragment was cloned by pEASY-T1 and amplified by relative fluorescence quantitative PCR with SYBR Green I; according to the results, we made a standard curve. The experimental group took interferon orally, while the control group took equivalent physiological saline orally, then we used relative fluorescence quantitative PCR to detect the copies of the IFNAR-1 gene of the palate, tongue, esophagus, craw, glandular stomach, duodenum and rectum of the experimental group and control group. Copies of the IFNAR-1 gene of those organs were calculated by Ct value. Finally, all the chickens were infected with the Newcastle Disease Virus after 48 hours. RESULTS: The results showed that the IFNAR-1 gene had the most expression in the esophagus. In the experiment of interferon antiviral activity detection, the chickens which took interferon orally were healthier than the other group. CONCLUSIONS: It is confirmed that the interferon receptor did exist in the digestive organs. However, according to the physical and chemical properties of interferon, interferon is easily inactivated in the acid and alkali environment, by pepsin and trypsin, so the absorption site for interferon exists in organs above the craw, especially in the esophagus and tongue.

Development and validation of HPLC-UV-MS method for the control of four anti-diabetic drugs in suspected counterfeit products.

An HPLC-UV method has been developed for the determination of valibose, miglitol, voglibose and acarbose, the four anti-diabetic drugs. The separation was accomplished successfully by using reversed phase chromatography (Prevail carbohydrate column, 250 mm x 4.6 mm, 5 microm) with a gradient acetonitrile-phosphate buffer solution (pH 8.0) at a wavelength of 210 nm. Furthermore, the method of a high-performance liquid chromatography coupled with ESI-MS in positive ionization mode has been established. These two methods were successfully applied to the assay and qualitative detection of four alpha-glucosidase inhibitors in the potential counterfeit anti-diabetic drugs.

[Genetic mapping of the intergenomic translocated "taigu" genic sterility gene (Ms2)].

The "Taigu" genic sterility gene Ms2 located on the short arm of the 4D chromosome of common wheat (AABBDD) originally incorporated into hexoploid triticale (AABBRR) and durum wheat (AABB) through intergenomic translocation in distant hybridization was introduced back into the genomes of common wheat. The dominant male sterility was expressed normally in the new "Taigu" genic sterile wheat carrying the intergenomically translocated Ms2, and the female fertility mechanism in its male sterile plants was normal as well. Observation of the chromosome configuration at meiosis of pollen mother cells (PMC) of the young ears of the sterile plants showed that they were euploid plants (2n = 42). No configurations different from those of the "Taigu" genic sterility gene located at the original locus were noticed of the Ms2 intergenomically translocated back into the common wheat. In systematic test crosses with marker genes the intergenomically translocated gene Ms2 was found to be linked with the dominant dwarf marker in common wheat Rht3 and, consequently, remapped and located on the short arm of the 4B chromosome of common wheat with a distance of 9.7 cM from Rht3. The new locus was designated as Ms2 (4BS). Discussions are given of the fate of Ms2 during translocation in the hexoploid triticale, the exchange of the names for 4A and 4B chromosomes in common wheat and the possible exploitation of the new locus Ms2 (4BS), and the following speculations are made: (a) In genic genes of allopolyploid organisms the donor chromosomes tend to be intergenomically translocated to their physiologically and evolutionarily close chromosomes with the same order number and the same arm; (b) it is confirmed that the 7th International Conference of Wheat Genetics was right to exchange the names between chromosomes 4A and 4B of common wheat in 1988; and (c) as a new genetic marker and a breeding tool for all the chromosome B-carrying species in the tribe of Triticeae, Ms2(4BS) may have wide application in building and expanding the gene pool of germplasm resources of various species of wheat.