3106 Background: Lung cancer is the leading cause for all cancer-related death, with NSCLC accounting for 85% of all cases. The oncogenic RET-fusion is identified in 1-2% of NSCLC patients. Several ...RET inhibitors have been approved. This pivotal phase II study aimed to evaluate the efficacy and safety of SY-5007, a novel, highly selective RET inhibitor, in Chinese patients with advanced, positive RET NSCLC. Methods: This trial enrolled two cohorts of patients with RET-fusion positive NSCLC. Cohort 1 comprised treatment-naive patients, and cohort 2 included those previously treated with systemic therapy. Both cohorts received oral SY-5007 at 160 mg twice daily in a 28-day cycle. Primary endpoint was overall response rate (ORR) assessed by blinded independent central review (BICR) per RESICST v1.1. Secondary endpoints included ORR assessed by investigators, disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: As of the data cutoff date on January 16, 2024, the trial enrolled 105 patients, with a median follow-up of 4.57 months (95% confidence interval CI 0.2-10.3). The BICR-assessed overall ORR was 77.1% (95% CI 67.9-84.8) and DCR was 83.8% (95% CI 75.3-90.3). The investigator-assessed overall ORR was 77.1% (95% CI 67.9-84.8) and DCR was 90.5% (95% CI 83.2-95.3). In treatment-naive patients (cohort 1, n=56), SY-5007 showed an ORR of 83.9% (95% CI 71.4-92.4) and a DCR of 91.1% (95% CI 80.4-97.0). In pre-treated patients (cohort 2, n=49), SY-5007 exhibited an ORR of 69.4% (95% CI 54.6-81.7) and a DCR of 89.8% (95% CI 77.8-96.6). For 29 patients with baseline brain metastasis, the ORR and DCR were 69.0% (95% CI 49.2-84.7) and 86.2% (95% CI 68.3-96.1). Meanwhile, the ORR and DCR for 76 patients without baseline brain metastasis were 80.3% (95% CI 69.5-88.5) and 92.1% (95% CI 83.6-97.0). Among 10 patients with baseline intracranial target lesions, intracranial ORR and DCR were 80.0% (95% CI 44.4-97.5) and 100% (95% CI 47.8-100). Median PFS, DoR or OS were not reached. Treatment-related adverse events (TRAEs) were reported in 96.2% of patients, with common events (≥ 30%) including increased AST, increased ALT, decreased neutrophil count, decreased white blood cell count and decreased platelet count. Grade ≥ 3 TRAEs and treatment-related serious adverse events were observed in 42.9% and 10.5% of patients. TRAE-induced dose interruption and dose reduction occurred in 39.0% and 23.8% of patients, respectively. TRAEs led to SY-5007 discontinuation in two patients (1.9%), with no deaths due to TRAE. Conclusions: SY-5007 demonstrated promising efficacy and safety for advanced NSCLC with positive RET. Clinical trial information: NCT05278364 .
Indigo alkaloids, such as indigo, indirubin and its derivatives, have been identified as effective antiviral compounds in Baphicacanthus cusia. Evidence suggests that the biosynthesis of indigo ...alkaloids in plants occurs via the shikimate pathway. The enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) is involved in plant metabolism; however, its underlying putative mechanism of regulating the production of indigo alkaloids is currently unknown.
One gene encoding EPSPS was isolated from B. cusia. Quantitative real-time PCR analysis revealed that BcEPSPS was expressed at the highest level in the stem and upregulated by methyl jasmonate (MeJA), salicylic acid (SA) and abscisic acid (ABA) treatment. The results of subcellular localization indicated that BcEPSPS is mainly expressed in both the plastids and cytosol, which has not been previously reported. An enzyme assay revealed that the heterogeneously expressed BcEPSPS protein catalysed the generation of 5-enolpyruvyl shikimate-3-phosphate. The overexpression of BcEPSPS in Isatis indigotica hairy roots resulted in the high accumulation of indigo alkaloids, such as indigo, secologanin, indole and isorhamnetin.
The function of BcEPSPS in catalysing the production of EPSP and regulating indigo alkaloid biosynthesis was revealed, which provided a distinct view of plant metabolic engineering. Our findings have practical implications for understanding the effect of BcEPSPS on active compound biosynthesis in B. cusia.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
9080
Background: Patients (pts) with brain metastases (BM) were usually unrepresented in clinical trials assessing the efficacy of PD-(L) 1 inhibitors. Here, we investigated the efficacy and safety ...of tislelizumab (TIS) plus chemotherapy in NSCLC pts with asymptomatic untreated BM or with stable BM after local radiotherapy. Methods: This multicenter, prospective, open-label phase 2 study enrolled systemic treatment-naïve pts with stage IV non-squamous (nsq) NSCLC without EGFR or ALK mutations who had BM. Pts received TIS combined with pemetrexed and carboplatin for 4 cycles, followed by maintenance TIS and pemetrexed. RECIST v1.1 and RANO-BM were applied for assessment for systematic and brain disease, respectively. The primary endpoint was the investigator-assessed 1-year PFS rate per RECIST v1.1. Results: 36 pts were enrolled with 77.8% having stage IVB disease, 25.0% liver metastases and 41.7% bone metastases. 29 (80.6%) pts were with untreated, asymptomatic brain metastases, and the other 7 (19.4%) received radiotherapy for BM previously. As of 30 Nov 2022, the median follow-up was 12.3 months. 1-year systematic PFS rate was 36.8% (95% CI, 18.0-55.7), with median PFS of 7.5 months (95% CI, 5.1-NE). Systematic ORR was 50.0% (95% CI, 31.9-68.1%). Median OS was not reached, with 1-year OS rate of 70.5% (95% CI, 51.7-83.1). For intracranial efficacy assessment per RANO-BM, 1-year intracranial PFS (iPFS) rate was 56.6 % (95% CI, 31.7-75.5), with 45.5% (95% CI, 19.4, 68.5) and 100% in pts with untreated and pretreated BM, respectively. Intracranial ORR was 56.7% (95% CI, 37.4-74.5%), with 53.8% (95% CI, 33.4-73.4%) in pts with untreated BM and 75% (95% CI, 19.4-99.4%) in pretreated BM. No grade 5 toxicities were observed. Grade 3-4 TRAEs occurred in 33.3% (12/36) of pts. 13.9% of pts experienced irAEs; grade 3-4 irAEs occurred in 2 (5.6%) pts. Conclusions: TIS plus chemotherapy yielded promising systematic and intracranial PFS, and was generally well tolerated in nsq-NSCLC pts with untreated or pretreated BM. Clinical trial information: NCT04507217 . Table: see text
Abstract only
e21077
Background: Previous studies indicated primary resistance to EGFR-TKIs might occur in EGFR co-mutation with other oncogenic alterations. However, the optimal therapeutic regimen ...for advanced NSCLC with EGFR co-mutation was still unknown. This respective observation study aimed to assess the efficacy and safety of the combination therapy with EGFR-TKI and chemotherapy in this sub-population. Methods: In this retrospectively study, from March 2017 to November 2019 advanced NSCLC patients with EGFR mutation detected using next-generation sequencing targeting 59 genes were screened for eligibility. We included patients of EGFR co-mutation with other oncogenic alterations receiving EGFR-TKI monotherapy or TKI plus chemotherapy as first-line therapy. The primary outcome was objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Disease control rate (DCR) and safety profile were considered to be the secondary endpoints. Results: Total 48 patients were enrolled. Among patients with concomitant mutation, the combination of chemotherapy with TKI was found to prolong mPFS (12.5 vs 7.3 months; HR, 0.38; 95%CI: 0.17-0.81; P = 0.012) compared with TKI monotherapy, with a trend of longer mOS (27.0 vs 22.4 months; HR, 0.40; 95%CI: 0.15-1.05; P = 0.062) and higher ORR (68.4% vs 44.8%, P = 0.113). The DCR were 100% in combination group and 93.1% in monotherapy group (P = 0.99). A proportion of 13.8% patients reported grade≥3 treatment-related adverse events in monotherapy group and 36.8% in combination group. Conclusions: EGFR co-mutation with other oncogenic alterations associated with poor treatment outcome with EGFR-TKI monotherapy. The combination of EGFR-TKI and chemotherapy was effective in this sub-population and side-effects were tolerable. The outcomes of this study should be confirmed by prospective clinical trials in future.
Yield potential, pharmaceutical compounds production and stress tolerance capacity are 3 classes of traits that determine the quality of medicinal plants. The autotetraploid
has greater yield, higher ...bioactive lignan accumulation and enhanced stress tolerance compared with its diploid progenitor. Here we show that the transcription factor
WRKY34, with higher expression levels in tetraploid than in diploid
, has large pleiotropic effects on an array of traits, including biomass growth rates, lignan biosynthesis, as well as salt and drought stress tolerance. Integrated analysis of transcriptome and metabolome profiling demonstrated that
expression had far-reaching consequences on both primary and secondary metabolism, reprograming carbon flux towards phenylpropanoids, such as lignans and flavonoids. Transcript-metabolite correlation analysis was applied to construct the regulatory network of
WRKY34 for lignan biosynthesis. One candidate target
4CL3, a key rate-limiting enzyme of lignan biosynthesis as indicated in our previous study, has been demonstrated to indeed be activated by
WRKY34. Collectively, the results indicate that the differentially expressed
WRKY34 has contributed significantly to the polyploidy vigor of
, and manipulation of this gene will facilitate comprehensive improvements of
herb.
Abstract Over the past century, the field of antibody discovery has undergone significant evolution, excluding the current exploration stage of artificial intelligence‐based antibody generation and ...the often overlooked non‐animal sourced antibody discovery, which typically requires mature in vitro affinity and the selection of high‐quality antigen formulations. This journey has traversed various stages, from methods involving serum‐based antibody acquisition, the isolation of B cells capable of perpetual antibody production through hybridoma technology, to the in‐depth exploration of genetic material using the phage display system, and the current stage involving diverse single B cell screening techniques. Additionally, the emergence of machine learning has brought impressive scientific and technological breakthroughs across research domains, proving to be a powerful application in the field of antibody discovery. However, each technique comes with its limitations, such as variability and control challenges in serum‐based acquisition, lengthy and difficult hybridoma‐derived antibody development, potential limitations in sequence and epitope diversity due to immunization biases in phage display techniques, and costly single B cell screening. Protein mass spectrometry sequencing, with shorter acquisition time and lower costs, is seen as a shortcut by diagnostic companies, impacting traditional antibody development. In diagnostic antibody development, methodological differences in downstream assays and the impact of constant regions outside the Fv core are often neglected. This paper deeply analyzes challenges, proposing innovative strategies for the next generation of diagnostic antibody development. Aimed at moving closer to the gold standard of antibody discovery, these strategies enhance the competitiveness of diagnostic reagent products.
Suo Quan Wan (SQW) is a Chinese traditional prescription that has been used in clinical treatment of lower urinary tract symptoms for centuries. However, scientific basis of SQW efficacy and ...mechanism is still needed. This study investigated the effect of SQW on bladder function and transient receptor potential vanilloid 1 (TRPV1) expression in the bladder of rats with bladder outlet obstruction (BOO). The induced changes in bladder function in overactive bladder (OAB) rat model were observed following different periods of outlet obstruction to obtain an appropriate rat model.
This study was carried out in two parts. In the first part, female Sprague-Dawley rats received sham operations or partial BOO operations. Two, four, and six weeks later, the OAB model groups and control were subjected to urodynamic tests to measure differences in bladder functions. Once the appropriate rat model was obtained, the second part of the experiment was performed. The rat model was recreated and treated with SQW. Urodynamic assessment was conducted, and the bladders of the rats were then removed. Immunofluorescence staining, real-time PCR, and Western blot were performed to localize and quantify the expression of TRPV1 in the bladder.
Results of the first part indicated that at 2 and 4 weeks, the OAB model group exhibited significant differences in urodynamic parameters, including bladder pressure, maximum voiding pressure, and maximum bladder capacity, compared with the sham group. At 4 and 6 weeks, the OAB model group exhibited significant differences in residual volume (RV) and non-voiding contraction frequency. Six-week OAB model group showed much more RV but less voiding efficiency when compared with 6-week sham group or 2-and 4-week OAB model group. Rats that underwent BOO exhibited similarities with the compensated state before four weeks and may have entered decompensated state at six weeks. Studies conducted with 4-week OAB model were appropriate. In part two of the experiment, unstable bladder in the OAB model group recovered bladder stability after SQW treatment, accompanied by improved bladder hypertrophy, as well as corrected urodynamic parameters. Expression of TRPV1 mRNA and proteins in the bladder was significantly greater in the OAB model group than that in the control group, which subsequently decreased significantly with SQW treatment in BOO-induced rats.
SQW can modulate the expression of TRPV1 in accordance with the recovery of bladder function.
Chatbot Application on Cryptocurrency Xie, Qitao; Tan, Dayuan; Zhu, Ting ...
2019 IEEE Conference on Computational Intelligence for Financial Engineering & Economics (CIFEr)
Conference Proceeding
Odprti dostop
Many chatbots have been developed that provide a multitude of services through a wide range of methods. A chatbot is a brand-new conversational agent in the highspeed changing technology world. With ...the advance of Artificial Intelligence and machine learning, chatbots are becoming more and more popular. A chatbot is the extension of human interface mediums such as the phone and social platforms. Similarly, Cryptocurrency is a new extension of digital or virtual currency designed to work as a medium of exchange. In the current digital exchanging world, investors and interested parties are eager to know more information about, and the capabilites of, this new type of currency. One of the potential paths to retrieve the info automatically and quickly is through a chatbot. We explored the open source python library, Chatterbot, to apply Itchat API (a WeChat interface) with the aim of building a robot chatting application, I&C Chat, on the topic of cryptocurrency. First, we collected question and answer pairs datasets from Quora websites. Furthermore, we also created API calls to query the real time quote for the top 25 cryptocurrencies. Then we used the collected data to train our chatbot and implemented a logic adapter to receive the price quote of cryptocurrencies based on the incoming question. The Itchat API method will return the best matched answer to the asking party automatically. The response time of different questions has been investigated. The results imply that this application is quite useful, feasible and beneficial to the digital currency world.
Suo Quan Wan (SQW) is an effective traditional Chinese prescription on treated lower urinary tract symptoms (LUTS), and has been proved have modulation effect on the expression of transient receptor ...potential vanilloid 1 (TRPV1) in accordance with the recovery of bladder function of overactive bladder rat. This study further investigated the mechanism of SQW modulated TRPV1 signaling and bladder function using TRPV1 knockout (KO) mice.
Study was conducted using wild type and TRPV1 KO mice. The KO animals were grouped into KO group and SQW treated group. We applied in vivo cystometrogram recording techniques to analyze voiding control of the urinary bladder, as well as in vitro organ bath to study bladder distension response to various compounds, which subsequently elicited normal smooth muscle excitation. Real-time polymerase chain reaction and western blot analysis were performed to quantify the expression of TRPV1 and P2X3 in the bladder. ATP released from bladder strips was measured using the luciferin-luciferase ATP bioluminescence assay kit.
KO preparation inhibited decrease micturition times, while micturition interval and volume were increased. Results of urodynamic record of the TRPV1
mice during NS infusion showed reduced bladder pressure and contraction which exhibited decreased response to α, β-me ATP, KCl, and carbachol and no response to CAP. The ATP released by the TRPV1
mice from strips of bladder smooth muscles was significantly reduced, along with no TRPV1 expression and reduced expression level of P2X3 in the bladder. SQW could increase ATP release in some degree, while had no effect on TRPV1 and P2X3 expression. SQW could improve bladder pressure slightly, while make no significantly effects on the force response to α,β-meATP, CAP, carbachol in gradient concentration, and KCl, as well as MBC and voiding activities.
TRPV1 plays an important role in urinary bladder mechanosensitivity. The effective SQW is hard to play its proper role on bladder function of mice without TRPV1.
Mobile network that millions of people use every day is one of the most complex systems in the world. Optimization of mobile network to meet exploding customer demand and reduce capital/operation ...expenditures poses great challenges. Despite recent progress, application of deep reinforcement learning (DRL) to complex real world problem still remains unsolved, given data scarcity, partial observability, risk and complex rules/dynamics in real world, as well as the huge reality gap between simulation and real world. To bridge the reality gap, we introduce a Sim-to-Real framework to directly transfer learning from simulation to real world via graph convolutional neural network (CNN) - by abstracting partially observable mobile network into graph, then distilling domain-variant irregular graph into domain-invariant tensor in locally Euclidean space as input to CNN -, domain randomization and multi-task learning. We use a novel self-play mechanism to encourage competition among DRL agents for best record on multiple tasks via simulated annealing, just like athletes compete for world record in decathlon. We also propose a decentralized multi-agent, competitive and cooperative DRL method to coordinate the actions of multi-cells to maximize global reward and minimize negative impact to neighbor cells. Using 6 field trials on commercial mobile networks, we demonstrate for the first time that a DRL agent can successfully transfer learning from simulation to complex real world problem with imperfect information, complex rules/dynamics, huge state/action space, and multi-agent interactions, without any training in the real world.
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