To investigate the mechanism of immune response in mouse macrophage induced by Pneumococcal heat shock protein 40 (HSP40).After recombinant HSP40 (rHSP40) underwent expression detection and purification, lipopolysaccharide (LPS) was removed from it. Then rHSP40 was used to stimulate bone marrow derived macrophages (BMDMs) derived from C57BL/6 wild-type mice. The mRNA levels of tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), IL-1β, IL-23p19, IL-12p40, IL-12p35 and IL-10 in BMDMs were determined by reverse transcription PCR; the expressions of TNF-α, IL-6 and IL-12p40 were measured by ELISA. After stimulated by rHSP40, the levels of TNF-α and IL-6 expressed by wide-type, TLR2-/- and TLR4-/- BMDMs were detected by ELISA. The effects of the pretreatment of mitogen-activated protein kinases (MAPK) inhibitors on the secretion of TNF-α and IL-6 induced by rHSP40 were also evaluated by ELISA in BMDMs. The phosphorylation levels of p38MAPK and c-Jun N-terminal kinase (JNK) were determined by Western blotting.The rHSP40 protein reached a purity of more than 90%. It significantly enhanced the phosphorylation levels of p38MAPK and JNK as well as the expressions of TNF-α and IL-6. The p38MAPK and JNK inhibitors significantly suppressed the expressions of TNF-α and IL-6. The expressions of TNF-α and IL-6 in TLR4-/- BMDMs significantly decreased compared with wide-type BMDMs.HSP40-induced immune response of mouse macrophages is regulated by p38MAPK and JNK signaling pathways, and this induction process depends on TLR4.
Background Laparoscopic localization of gastrointestinal tumors has long been an important objective. This study aimed to evaluate the clinical application of a magnetic tracer technique during laparoscopic-assisted surgery.Methods Fifty-seven patients with gastrointestinal tumors, who voluntarily underwent endoscopic marking between May 2019 and May 2020, were enrolled. A magnetic ring was clamped onto tissues adjacent to the lesion and released during preoperative endoscopy. Then, another magnet ring or laparoscopic instrument was delivered to the wall of the digestive tract contralateral to the lesion and attracted, thus achieving accurate intraoperative localization. Observational evaluation included data regarding preoperative marking, intraoperative localization, operation, and safety.Results Fifty-six of the 57 (98.2%) patients with gastric tumors (n = 35), duodenal tumors (n = 1), and colorectal tumors (n = 20), successfully underwent marking, localization, and resection. The mean margins of proximal and distal resection of colorectal tumors were 106 and 78 mm, respectively. The mean (± SD) duration of endoscopic marking and laparoscopic localization for gastric/duodenal and colorectal tumors were 5.3 ± 0.3, 1.0 ± 0.1, 5.5 ± 0.4, and 1.0 ± 0.1 min, respectively. No complications occurred in 56 of the 57 patients.Conclusions The magnetic tracer technique demonstrated promising potential as a localization method for gastrointestinal tumors, with superior safety, effectiveness, rapidity, and convenience.
This technical report outlines our submission system for the CHiME-8 NOTSOFAR-1 Challenge. The primary difficulty of this challenge is the dataset recorded across various conference rooms, which captures real-world complexities such as high overlap rates, background noises, a variable number of speakers, and natural conversation styles. To address these issues, we optimized the system in several aspects: For front-end speech signal processing, we introduced a data-driven joint training method for diarization and separation (JDS) to enhance audio quality. Additionally, we also integrated traditional guided source separation (GSS) for multi-channel track to provide complementary information for the JDS. For back-end speech recognition, we enhanced Whisper with WavLM, ConvNeXt, and Transformer innovations, applying multi-task training and Noise KLD augmentation, to significantly advance ASR robustness and accuracy. Our system attained a Time-Constrained minimum Permutation Word Error Rate (tcpWER) of 14.265% and 22.989% on the CHiME-8 NOTSOFAR-1 Dev-set-2 multi-channel and single-channel tracks, respectively.
14516 Background: Mutations in the EGFR gene appear to confer sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Genetic polymorphisms are more prevalent than mutations in human genome. We evaluated the association of polymorphisms in the EGFR gene with the clinical outcomes in the patients with advanced NSCLC treated with gefitinib, an EGFR-TKI. Methods: Candidate polymorphic loci approach was used to determine the functional polymorphisms within the EGFR gene range. Four most representative tagging single nucleotide polymorphisms (SNPs), one well-known CA simple sequence repeat (CA-SSR) in intron 1, and several common SNPs in the region encoding tyrosine kinase domain of EGFR were included in our study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and directly DNA sequencing approach were used to determine the genotypes of 84 advanced NSCLC patients treated with gefitinib. Results: Rs2293347 in exon 25 and CA-SSR in intron 1 were addressed by the candidate loci approach. For rs2293347, the clinical benefit rates were 71.2% and 37.5% (P = 0.0043) in wild-type (G/G genotype) and variation allele carriers (A/G or A/A genotypes). The progression-free survival were 11 months and 3 months (P = 0.0018), respectively, while the results for overall survival were similar. For CA-SSR, the clinical benefit rate was 88.5% in patients carrying at least one shorter CA repeat allele [≤16 (CA)n], and 48.3% in patients carrying two longer CA repeat alleles [>16 (CA)n] (P = 0.0005). However, CA- SSR polymorphism was not found to be associated with the progression-free survival and overall survival. Conclusions: Rs2293347 and CA-SSR polymorphisms may be predictive for clinical outcomes in patients with advanced NSCLC treated with gefitinib. No significant financial relationships to disclose.
e13529 Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) play a key role in the management of advanced non-small cell lung cancer (NSCLC). Numerous investigations have demonstrated an association between the presence of somatic mutations in EGFR and the sensitivity to gefitinib or erlotinib in NSCLC. Since genetic polymorphisms are more prevalent than mutations in human genome, some of them may be more practical as genetic biomarkers to predict the sensitivity to EGFR-TKIs. The FAS-FASL system plays crucial role in apoptotic signaling in many tumor cells. Here, we assessed the possibility that single nucleotide polymorphisms (SNPs) in FAS and FASL could be used to predict the sensitivity to gefitinib in patients with advanced NSCLC. Methods: Candidate polymorphic loci approach was used to determine the functional polymorphisms. SNPs in the promoter region of the FAS (−1377G/A and −670A/G) and FASL (−844T/C) were assessed in 88 advanced NSCLC patients treated with gefitinib. The Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The association between genotypes and sensitivity to gefitinib was validated by statistical tests. Results: For FAS -1377G/A, the clinical benefit rates (CBR) of gefitinib in advanced NSCLC patients were 31.3%, 61.1% or 74.3% (p = 0.014) in AA, GA or GG genotypes, respectively. For FAS −670A/G, the CBR were 32.0%, 78.0% or 57.9% (p = 0.001) in GG, AG or AA genotypes. For FASL - 844T/C, the CBR were 65.2%, 57.1% or 50% (p = 0.276) in CC, CT or TT genotypes. FAS -670 GG genotype carriers also had a significantly shorter survival time after the treatment of gefitinib than variation allele carriers (AG or AA genotypes), the overall survival time were 26 and 47 months (p = 0.012), respectively. Conclusions: FAS -1377G/A and -670A/G polymorphisms may be predictive for sensitivity to gefitinib in patients with advanced NSCLC. No significant financial relationships to disclose.
Lung cancer is the leading cause of death from cancer in the world. The treatment remains one of the most challenging tasks in the medical world. The discovery and development of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) have had a major impact in the treatment of non small cell lung cancer (NSCLC). But the efficacy of EGFR-TKI in EGFR wild-type patients is limited, and the limited EGFR mutation incidence also prompts researchers to study what is the best treatment choice for patients with NSCLC who are negative for EGFR mutations. This review will discuss the research status in treatment choice for EGFR wild-type NSCLC. 肺癌是癌症死亡的主要原因。肺癌的治疗仍是医疗界最具挑战性的任务之一。表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor-tyrosine kinase inhibitor, EGFR-TKI）的发现和发展，对非小细胞肺癌（non-small cell lung cancer, NSCLC）的治疗产生了重大影响。但EGFR-TKI对EGFR野生型NSCLC的疗效较差，而有限的EGFR突变率也促使研究者们不断探索EGFR野生型NSCLC的最佳的治疗选择。本文将对EGFR野生型 NSCLC的治疗现状进行综述。
Abstract Our study aims to excavate the role of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in myocardial infarction (MI), especially in an ischemia/reperfusion injury model and the underlying mechanism involving the MALAT1-miR144 axis. Our results demonstrated that the expression of MALAT1 has a higher level, while miR-144 expression significantly reduced in myocardial tissue after MI and also in left anterior descending (LAD)-ligation mice. This result was confirmed in vitro studies in HL-1 cardiomyocytes followed with hypoxia/reoxygenation. In addition, overexpression of MALAT1 by MALAT1-pcDNA injection into the mice with LAD increased myocardial apoptosis in vivo, while this effect was attenuated by miR-144 mimic. Bioinformatics analysis exhibits that 3′-UTR of MALAT1 is targeted to the miR-144-3p. Up-regulation miR-144 blunted the hypoxia- or MALAT1-induced cell apoptosis. In conclusion, the expression of MALAT1 was increased, whereas miR-144 expression was down-regulated in the myocardium after AMI. MALAT1 up-regulation plays a critical role in promoting cardiomyocytes apoptosis via targeting miR-144.
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