Efficacy of Pyrotinib With/Without Trastuzumab in Treatment-Refractory, HER2-Positive Metastatic Colorectal Cancer: Result From a Prospective Observational Study.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is a promising therapeutic target in metastatic colorectal cancer (mCRC). This study was to evaluate the efficacy and safety of pyrotinib alone or pyrotinib with trastuzumab in patients with HER2-positive mCRC. PATIENTS AND METHODS: In this prospective observational study, patients with HER2 positive, Ras Sarcoma Viral Oncogene Homolog (RAS) wild type mCRC who received at least one standard treatment of palliative chemotherapy were enrolled. Patients were treated with oral pyrotinib alone or pyrotinib with trastuzumab. The primary endpoint was progression free survival (PFS), and the secondary endpoints were overall survival (OS), confirmed objective response rate (ORR), and safety. This trial is registered with chitcr.org, number ChiCTR2100046381. RESULTS: From February 15, 2021, to January 10, 2023, 32 patients were enrolled in this study. Twenty (62.5%) patients were treated with pyrotinib, while 12 (37.5%) received pyrotinib and trastuzumab. As of June 24, 2023, with a median follow-up of 11.0 months, the median PFS was 5.7 months (95%CI 4.5-10.2), while OS was not evaluable (NE), ORR and disease control rate (DCR were 34.4% and 87.5%. Patients' PFS in the pyrotinib plus trastuzumab subgroup and pyrotinib monotherapy group were 8.6 and 5.5 months, OS was not evaluable (NE) and 10.9 months, ORR was 50.0% and 25.0%, respectively. Most treatment-related adverse events (TRAEs) were grade 1-2, diarrhea was the most frequent TRAE (81.3%, 26/32). Grade 3 TRAEs occurred in 11 patients: 9 for diarrhea, 1 for nausea, and 1 for oral mucositis. CONCLUSION: Pyrotinib with or without trastuzumab showed promising anti-tumor activity and acceptable toxicities in treatment-refractory, HER2-positive mCRC.

Biological characteristics of pregnancy in captive Yangtze finless porpoises revealed by urinary metabolomics†.

The Yangtze finless porpoises (Neophocaena asiaeorientalis a.) are an endemic and critically endangered species in China. Intensive captive breeding is essential for understanding the biology of critically endangered species, especially their pregnancy characteristics, knowledge of which is crucial for effective breeding management. Urine metabolomics can reveal metabolic differences, arising from physiological changes across pregnancy stages. Therefore, we used the urinary metabolomic technology, to explore urinary metabolite changes in pregnant Yangtze finless porpoises. A total of 2281 metabolites were identified in all samples, which including organic acids and derivatives (24.45%), organoheterocyclic compounds (20.23%), benzenoids (18.05%), organic oxygen compounds (7.73%), and phenylpropanoids and polyketides (6.48%). There were 164, 387, and 522 metabolites demonstrating differential abundance during early pregnancy, mid pregnancy, and late pregnancy, respectively, from the levels observed in nonpregnancy. The levels of pregnenolone, 17α-hydroxyprogesterone, and tetrahydrocortisone were significantly higher during all pregnancy stages, indicating their important roles in fetal development. The differential metabolites between nonpregnancy and pregnancy were mainly associated with amino acid and carbohydrate metabolism. Moreover, metabolic activity varied across pregnancy stages; steroid hormone biosynthesis was predominant in early pregnancy, and amino acid biosynthesis and carbohydrate metabolism were predominant in mid pregnancy and late pregnancy, respectively. Our results provide new insights into metabolic characteristics in the Yangtze finless porpoises' urine during pregnancy, and indicate that the differential levels of urine metabolites can determine pregnancy in Yangtze finless porpoises, providing valuable information for the husbandry and management of pregnant Yangtze finless porpoises in captivity.

Synthetic high-energy computed tomography image via a Wasserstein generative adversarial network with the convolutional block attention module.

Background: Computed tomography (CT) is now universally applied into clinical practice with its non-invasive quality and reliability for lesion detection, which highly improves the diagnostic accuracy of patients with systemic diseases. Although low-dose CT reduces X-ray radiation dose and harm to the human body, it inevitably produces noise and artifacts that are detrimental to information acquisition and medical diagnosis for CT images. Methods: This paper proposes a Wasserstein generative adversarial network (WGAN) with a convolutional block attention module (CBAM) to realize a method of directly synthesizing high-energy CT (HECT) images through low-energy scanning, which greatly reduces X-ray radiation from high-energy scanning. Specifically, our proposed generator structure in WGAN consists of Visual Geometry Group Network (Vgg16), 9 residual blocks, upsampling and CBAM, a subsequent attention block. The convolutional block attention module is integrated into the generator for improving the denoising ability of the network as verified by our ablation comparison experiments. Results: Experimental results of the generator attention module ablation comparison indicate an optimization boost to the overall generator model, obtaining the synthesized high-energy CT with the best metric and denoising effect. In different methods comparison experiments, it can be clearly observed that our proposed method is superior in the peak signal-to-noise ratio (PSNR), structural similarity index measure (SSIM) and most of the statistics (average CT value and its standard deviation) compared to other methods. Because P<0.05, the samples are significantly different. The data distribution at the pixel level between the images synthesized by the method in this paper and the high-energy CT images is also most similar. Conclusions: Experimental results indicate that CBAM is able to suppress the noise and artifacts effectively and suggest that the image synthesized by the proposed method is closest to the high-energy CT image in terms of visual perception and objective evaluation metrics.

A bibliometric analysis of sepsis-induced myocardial dysfunction from 2002 to 2022.

Background: Sepsis-induced myocardial dysfunction (SIMD) has a significant contribution to sepsis-caused death in critically ill patients. In recent years, the number of published articles related to SIMD has increased rapidly. However, there was no literature that systematically analyzed and evaluated these documents. Thus, we aimed to lay a foundation for researchers to quickly understand the research hotspots, evolution processes and development trends in the SIMD field via a bibliometric analysis. Methods: Articles related to SIMD were retrieved and extracted from the Web of Science Core Collection on July 19th, 2022. CiteSpace (version 6.1.R2) and VOSviewer (version 1.6.18) were used for performing visual analysis. Results: A total of 1,076 articles were included. The number of SIMD-related articles published each year has increased significantly. These publications mainly came from 56 countries, led by China and the USA, and 461 institutions, but without stable and close cooperation. As authors, Li Chuanfu published the most articles, while Rudiger Alain had the most co-citations. Shock was the journal with the most studies, and Critical Care Medicine was the most commonly cited journal. All keywords were grouped into six clusters, some of which represented the current and developing research directions of SIMD as the molecular mechanisms. Conclusion: Research on SIMD is flourishing. It is necessary to strengthen cooperation and exchanges between countries and institutions. The molecular mechanisms of SIMD, especially oxidative stress and regulated cell death, will be critical subjects in the future.

The synthesis of high-energy CT images from low-energy CT images using an improved cycle generative adversarial network.

BACKGROUND: The dose of radiation a patient receives when undergoing dual-energy computed tomography (CT) is of significant concern to the medical community, and balancing the tradeoffs between the level of radiation used and the quality of CT images is challenging. This paper proposes a method of synthesizing high-energy CT (HECT) images from low-energy CT (LECT) images using a neural network that achieves an alternative to HECT scanning by employing an LECT scan, which greatly reduces the radiation dose a patient receives. METHODS: In the training phase, the proposed structure cyclically generates HECT and LECT images to improve the accuracy of extracting edge and texture features. Specifically, we combine multiple connection methods with channel attention (CA) and pixel attention (PA) mechanisms to improve the network's mapping ability of image features. In the prediction phase, we use a model consisting of only the network component that synthesizes HECT images from LECT images. RESULTS: Our proposed method was conducted on clinical hip CT image data sets from Guizhou Provincial People's Hospital. In a comparison with other available methods [a generative adversarial network (GAN), a residual encoder-to-decoder network with a visual geometry group (VGG) pretrained model (RED-VGG), a Wasserstein GAN (WGAN), and CycleGAN] in terms of metrics of peak signal-to-noise ratio (PSNR), structural similarity index measure (SSIM), normalized mean square error (NMSE), and a visual effect evaluation, the proposed method was found to perform better on each of these evaluation criteria. Compared with the results produced by CycleGAN, the proposed method improved the PSNR by 2.44%, the SSIM by 1.71%, and the NMSE by 15.2%. Furthermore, the differences in the statistical indicators are statistically significant, proving the strength of the proposed method. CONCLUSIONS: The proposed method synthesizes high-energy CT images from low-energy CT images, which significantly reduces both the cost of treatment and the radiation dose received by patients. Based on both image quality score metrics and visual effects comparisons, the results of the proposed method are superior to those obtained by other methods.

Design, Analysis and Experiment of the Fiber Push-Out Device Based on Piezoelectric Actuator.

In this study, a fiber push-out device based on a piezoelectric actuator was designed, analyzed and tested, and its experimental environment was designed. The piezoelectric actuator includes a flexible beam. By using response surface analysis (RSM), taking the large displacement as the objective function and on the premise of meeting the strength requirements, the structural parameters of the flexible beam were analyzed. In the process of fiber push-out, the interfacial shear stress was estimated by establishing the system integrating the fiber-matrix-composite three-phase model and the piezoelectric actuator model using the analytic method, and the theoretical analysis results of the fiber interface mechanical properties were given. A prototype of the system was made, and the performance tests of the piezoelectric actuator and the fiber push-out device were carried out. The test results showed that the designed piezoelectric actuator can achieve a stepping resolution of 6.67 µm and a maximum displacement of about 100 µm at the input voltage of 150 V, which is consistent with the design results. The extrusion test of a single fiber was carried out using a piezoelectric actuator. The mechanical properties of the interfacial layer during the push-out process were measured and the interfacial shear strength was calculated, which is consistent with the theoretical analysis results. Finally, based on the mechanical properties obtained from the test, the loading failure process of the fiber was simulated by finite element analysis, which well explained the failure process of the fiber, thus verifying the feasibility of the designed fiber push-out device.

Synthesis of methanesulfone-containing tetrasubstituted carbon stereocenters.

A methanesulfonylation reaction for the synthesis of sulfone-containing tetrasubstituted carbon stereocenters is described for the first time by simple treatment of indanedione-chromanone synthons with Et3N and easily accessible MsCl without any use of organometallic chemistry. This technology gave the corresponding valuable chromone-based 2-methanesulfonylated 1,3-indanediones in good yields (up to 89% yield) under mild conditions. The present work provides an attractive strategy for the construction of biologically interesting sulfone-containing tetrasubstituted carbon stereocenters, which might be valuable in medicinal chemistry.

Clinical effects and molecular mechanisms of lncRNA MNX1-AS1 in malignant tumors.

With continuous disclosure of the significance of long non-coding RNAs (lncRNAs) in gene expression, the role of lncRNAs in malignant tumors has attracted extensive attention of scholars. Many types of studies found that lncRNA MNX1-AS1 is an over-expressed lncRNA in various malignant tumors. Results also indicate that MNX1-AS1 participates in the biological processes of cancers. Recent studies found that lncRNA MNX1-AS1 has high sensitivities and specificities in tumor tissues and plasma and may be a potential diagnostic biomarker and prognostic predictor. The biological functions of lncRNA MNX1-AS1 and its mechanisms of function in tumors were comprehensively reviewed in this article to lay a molecular foundation for future clinical applications of MNX1-AS1.

Addition of an Emotionally Stable Node in the SOSa-SPSa Model for Group Emotional Contagion of Panic in Public Health Emergency: Implications for Epidemic Emergency Responses.

Sentiment contagion is similar to an infectious disease that spreads in a crowd. In this study, we explore the law of emotional infection under sudden public events by SIR model. The paper adds an emotionally stable node and establishes a group emotional infection model of U-SOSPa-SPSOa model. Simulation results show that our model is reasonable and can better explain the entire contagion process by considering four groups (unsusceptible-susceptible-optimistic-pessimistic) of people. Our theoretical results show: When the pessimists were below the critical value of 0.34, the number of negative emotional groups first increased and then decreased. As the proportion increases, the emotional peak of pessimists increases. The cure probability θo has the least influence on the P(t), and at the same time, under the action of θp, the P(t) reaches the stable state first. The increase of the risk coefficient can promote the pessimist infection. When the degree of risk is low, the rate of emotional infection is increased. When the degree of risk is high, the rate of infection is slowed. Therefore, system customizers and related managers can improve the efficiency of stable groups, adjust the proportion of initial negative emotions, control the infection of the spontaneous infection process, and directly deal with negative emotions. They can carry out treatment and other means to stabilize group emotions and maintain social stability.

Diagnostic significance of serum periostin in eosinophilic chronic sinusitis with nasal polyps.

OBJECTIVES: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous disease. Eosinophilic CRSwNP (ENP) exhibits a strong tendency for recurrence after surgery. Given that the treatment strategy of ENP differs from that of non-eosinophilic CRSwNP (nENP), clinical diagnostic criteria that distinguish ENP from nENP are needed. METHODS: In total, 94 CRSwNP patients were enrolled in the cohort. Factors associated with ENP were determined with regression analysis, and optimal cutoff points of the predictors were determined by a receiver operating characteristic curve. RESULTS: Serum periostin levels, blood eosinophils and basophils counts significantly differed between ENP and nENP. A combination of the cut-off values for the three predictors, including absolute blood eosinophil and basophil counts, yielded a sensitivity of 79.2% and 70.8%, and a specificity of 84.8% and 73.9%, respectively. Serum periostin levels yielded a sensitivity of 72.9% and a specificity of 60.9% for the diagnosis of ENP. The predicted probability of periostin in combination with blood eosinophils and basophils counts (AUC, 0.872) exhibited moderate accuracy. In addition, patients with ENP displayed an increased prevalence of smoking. CONCLUSIONS: Periostin in combination with blood eosinophils and basophils counts has the potential to better refine current CRSwNP phenotypes.

The Role of Periostin in the Occurrence and Progression of Eosinophilic Chronic Sinusitis with Nasal Polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a highly heterogeneous disease with different host defence responses. However, whether periostin and vascular endothelial growth factor (VEGF) are similarly impaired in patients with eosinophilic CRSwNP (ENP) and those with non-eosinophilic CRSwNP (nENP) remains unclear. We sought to evaluate the expression and possible modulation of periostin and VEGF, regulated on activation normal T expressed and secreted (RANTES) and eotaxin-2 in the polyp tissues from 30 patients with ENP and from 36 patients with nENP and in middle turbinate tissues from 12 control subjects. We found that ENP tissues exhibited a significantly increased expression of periostin and VEGF compared with tissues from patients with nENP and control subjects (P < 0.05, respectively). Accordingly, the expression of VEGF, RANTES, and eotaxin-2 in ENP fibroblasts was significantly up-regulated after stimulation with up-regulated periostin in vitro, but the expression of VEGF and RANTES was significantly inhibited by stimulation with down-regulated periostin. Our findings suggest that periostin might play an important role in the occurrence and progression of ENP and might be a potential therapeutic target.

The association between methylated CDKN2A and cervical carcinogenesis, and its diagnostic value in cervical cancer: a meta-analysis.

BACKGROUND: Cervical cancer is the second deadliest gynecologic malignancy, characterized by apparently precancerous lesions and cervical intraepithelial neoplasia (CIN), and having a long course from the development of CIN to cervical cancer. Cyclin-dependent kinase inhibitor 2A (CDKN2A) is a well-documented tumor suppressor gene and is commonly methylated in cervical cancer. However, the relationship between methylated CDKN2A and carcinogenesis in cervical cancer is inconsistent, and the diagnostic accuracy of methylated CDKN2A is underinvestigated. In this study, we attempted to quantify the association between CDKN2A methylation and the carcinogenesis of cervical cancer, and its diagnostic power. METHODS: We systematically reviewed four electronic databases and identified 26 studies involving 1,490 cervical cancers, 1,291 CINs, and 964 controls. A pooled odds ratio (OR) with corresponding 95% confidence intervals (95% CI) was calculated to evaluate the association between methylated CDKN2A and the carcinogenesis of cervical cancer. Specificity, sensitivity, the area under the receiver operating characteristic curve, and the diagnostic odds ratio were computed to assess the effect of methylated CDKN2A in the diagnosis of cervical cancer. RESULTS: Our results indicated an upward trend in the methylation frequency of CDKN2A in the carcinogenesis of cervical cancer (cancer vs control: OR =23.67, 95% CI =15.54-36.06; cancer vs CIN: OR =2.53, 95% CI =1.79-3.5; CIN vs control: OR =9.68, 95% CI =5.82-16.02). The specificity, sensitivity, area under the receiver operating characteristic curve, and diagnostic odds ratio were 0.99 (95% CI: 0.97-0.99), 0.36 (95% CI: 0.28-0.45), 0.93 (95% CI: 0.91-0.95), and 43 (95% CI: 19-98), respectively. CONCLUSION: Our findings indicate that abnormal CDKN2A methylation may be strongly correlated with the pathogenesis of cervical cancer. Our results also demonstrate that CDKN2A methylation might serve as an early detector of cervical cancer. These findings require further confirmation.

Structure-activity study of quinazoline derivatives leading to the discovery of potent EGFR-T790M inhibitors.

We have developed a series of 6, 7-disubstituted-4-(arylamino) quinazoline derivatives that functioned as irreversible EGFR inhibitors, and these compounds exhibited excellent enzyme inhibition potency. As compared with afatinib, some of them showed significantly enhanced activities towards H1975 cells (EGFR-T790M). Furthermore, the optimized compounds 7q and 8f also demonstrated good pharmacokinetic profiles, oral bioavailability as well as excellent in vivo efficacy in H1975 and HCC827 xenografts at a non-toxic dose. Based on the improved safety and efficacy against EGFR-T790M resistance, 7q and 8f are promising candidates for further studies.

Simultaneous genotyping of HPA-17w to -21w by PCR-SSP in Chinese Cantonese.

Studies have reported the polymorphism of human platelet antigen (HPA)-17w, -18w, -19w, -20w, and -21w. However, the distribution of these five antigens in Chinese Cantonese is still unknown. In this study, we designed new sequence-specific primers for HPA-19w to -21w and used published primers for HPA-17w and -18w to develop a polymerase chain reaction with the sequence-specific primers (PCR-SSP) method for simultaneously genotyping HPA-17w to -21w. A total of 820 unrelated Cantonese apheresis platelet donors in Guangzhou were involved in this study. Among the five HPAs, complete a/a homozygosity was observed for HPA-17w to -20w with an allele frequency of 1.0000. For HPA-21w, nine individuals (9/820, 1.10%) were found to be HPA-21a/bw heterozygous and the allele frequencies of HPA-21a and HPA-21bw were 0.9945 (1631/1640) and 0.0055 (9/1640), respectively. The reliability of the PCR-SSP method was determined by comparing with the genotyping results by DNA sequencing, and no inconsistencies were observed between the two methods. This study provides a reliable PCR-SSP method for simultaneously genotyping HPA-17w to -21w and could improve HPA-matched platelet transfusion in Chinese Cantonese.

Synthesis and in vivo SAR study of indolin-2-one-based multi-targeted inhibitors as potential anticancer agents.

A series of indolin-2-one analogues were designed and synthesized, and all of them exhibited excellent in vitro potency. The structure and in vivo activity or toxicity relationship (in-vivo SAR) investigation of indolin-2-one structural analogues was carried out. In vivo efficacy studies indicated that 3b significantly suppressed tumor growth in HT-29 and NCI-H460 xenografts without causing significant loss of body weight. Kinase assay showed that compound 3b effectively inhibited the VEGFR-2, VEGFR-3, FLT3, Ret and PDGFR-ß kinases, but had little effect on the VEGFR-1 kinase. Besides, 3b showed higher selectivity for VEGFR-2 compared with PDGFR-ß. On the basis of its selectivity and safety properties, 3b was identified as a drug candidate for the treatment of cancer.

[Serum allergen-specific IgE in patients with eosinophilic nasal polyps].

OBJECTIVE: To investigate the relationship between airborne allergen and patients with nasal polyps (NP). METHOD: Eighty-three cases of patients with NP were classified into the eosinophilic group(ENP) and non eosinophilic group (nENP) in terms of the EOS count in NP specimen, all patients underwent specific-IgE test with standardized allergens and the results were analyzed. RESULT: The specific-IgE positive rate was 59.26% in ENP group and 23.21% in the nENP group respectively (P < 0.01), and the positive rate of ENP was statistical significance compared with nENP. The dust mite was the most prevalent airborne allergen in ENP group. CONCLUSION: The perennial airborne allergens may play a certain role in the etiology and pathogenesis of NP.

Noncovalent attachment of NAD+ cofactor onto carbon nanotubes for preparation of integrated dehydrogenase-based electrochemical biosensors.

This study describes a facile approach to the preparation of integrated dehydrogenase-based electrochemical biosensors through noncovalent attachment of an oxidized form of beta-nicotinamide adenine dinucleotide (NAD(+)) onto carbon nanotubes with the interaction between the adenine subunit in NAD(+) molecules and multiwalled carbon nanotubes (MWCNTs). X-ray photoelectron spectroscopic and cyclic voltammetric results suggest that NAD(+) is noncovalently attached onto MWCNTs to form an NAD(+)/MWCNT composite that acts as the electronic transducer for the integrated dehydrogenase-based electrochemical biosensors. With glucose dehydrogenase (GDH) as a model dehydrogenase-based recognition unit, electrochemical studies reveal that glucose is readily oxidized at the GDH/NAD(+)/MWCNT-modified electrode without addition of NAD(+) in the phosphate buffer. The potential for the oxidation of glucose at the GDH/NAD(+)/MWCNT-modified electrode remains very close to that for NADH oxidation at the MWCNT-modified electrode, but it is more negative than those for the oxidation of glucose at the MWCNT-modified electrode and for NADH oxidation at a bare glassy carbon electrode. These results demonstrate that NAD(+) molecules stably attached onto MWCNTs efficiently act as the cofactor for the dehydrogenases. MWCNTs employed here not only serve as the electronic transducer and the support to confine NAD(+) cofactor onto the electrode surface, but also act as the electrocatalyst for NADH oxidation in the dehydrogenase-based electrochemical biosensors. At the GDH/NAD(+)/MWCNT-based glucose biosensor, the current is linear with the concentration of glucose being within a concentration range from 10 to 300 microM with a limit of detection down to 4.81 microM (S/N = 3). This study offers a facile and versatile approach to the development of integrated dehydrogenase-based electrochemical devices, such as electrochemical biosensors and biofuel cells.

[Expression of proteinase cathepsin L1 gene of Schistosoma japonicum in Escherichia coli].

OBJECTIVE: To express the proteinase cathepsin L1 gene of Schistosoma japonicum (SjCL1) in Escherichia coli JM109 cells. METHODS: The SjCL1 gene was amplified from the recombinant plasmid pcDNA3-SjCL1 by PCR. The gene was cloned into a prokaryotic expression vector pGEX4T-1 to construct a recombinant plasmid pGEX-SjCL1. The E. coli JM109 cells were transformed with the recombinant plasmid pGEX-SjCL1 and the transformants were induced by IPTG to express the recombinant protein, the target protein was then identified by SDS-PAGE and Western blotting. RESULTS: A 1 kb length PCR product was obtained and a recombinant plasmid pGEX-SjCL1 was constructed. The expression product was detected by SDS-PAGE and Western blotting and an expression band about 62000 was found. CONCLUSION: The SjCL1 gene is effectively expressed in the E. coli JM109 cells.