The investigation on sialic acid-modified pectin nanoparticles loaded with oxymatrine for orally targeting and inhibiting the of ulcerative colitis.

The aim of the study was to develop an oral targeting drug delivery system (OTDDS) of oxymatrine (OMT) to effectively treat ulcerative colitis (UC). The OTDDS of OMT (OMT/SA-NPs) was constructed with OMT, pectin, Ca2+, chitosan (CS) and sialic acid (SA). The obtained particles were characterized in terms of particle size, zeta potential, morphology, drug loading, encapsulation efficiency, drug release and stability. The average size of OMT/SA-NPs was 255.0 nm with a zeta potential of -12.4 mV. The loading content and encapsulation efficiency of OMT/SA-NPs were 14.65% and 84.83%, respectively. The particle size of OMT/SA-NPs changed slightly in the gastrointestinal tract. The nanoparticles can delivery most of the drug to the colon region. In vitro cell experiments showed that the SA-NPs had excellent biocompatibility and anti-inflammation, and the uptake of SA-NPs by RAW 264.7 cells was time and concentration-dependent. The conjugated SA can help the internalization of NPs into target cells. In vivo experiments showed that OMT/SA-NPs had a superior anti-inflammation effect and the effect of reducing UC, which was attributed to the delivery most of OMT to the colonic lumen, the specific targeting and retention in colitis site and the combined anti-inflammation of OMT and NPs.

Spatial distribution dynamics for Epimedium brevicornum Maxim. from 1970 to 2020.

At different time scales, a species will experience diverse distribution changes. For Epimedium brevicornum Maxim, the phenomenon is obvious, but the understanding of the spatial dynamics of E. brevicornum under distinct time scales is poor. In this study, we modeled the potential distribution for E. brevicornum for five time scales, 1970-1979, 1980-1989, 1990-1999, 2000-2009, and 2010-2019, with different occurrence data, and the Kuenm package was used to optimize the parameter combination. Then, SDM tools and a Venn diagram were utilized to simulate the changes in highly suitable areas and spatial dynamics, respectively. Comprehensive results show that temperature seasonality (BIO4, 37.54%) has the greatest effect on the distribution of E. brevicornum, followed by minimum temperature (TMIN, 21.42%). The areas of distribution for E. brevicornum are 35.06 × 105 km2, 25.7 × 105 km2, 67.64 × 105 km2, 27.29 × 105 km2, and 9.87× 105 km2, which are mainly concentrated in Gansu, Shaanxi, Shanxi, and Henan, respectively. In addition, the largest regions for expansion, stability, and contraction under various time scales are 5.6 × 105 km2, 3.54 × 105 km2, and 3.47 × 105 km2, respectively. These changes indicate that approximately 7.96% of the regions are highly stable, and three critical counties, Wanyuan, Chenggu, and Hechuan, and Xixiang, have become significant areas for migration. Overall, our results indicate that there are different spatial distribution patterns and dynamics for E. brevicornum for different time scales. Given these results, this study also proposes comprehensive strategies for the conservation and management of E. brevicornum, which will further improve the current resource utilization status.

Meta-analysis of the relationship between montelukast use and neuropsychiatric events in patients with allergic airway disease.

Use of montelukast, as a cause of neuropsychiatric events, in patients with asthma or allergic rhinitis is controversial, and comprehensive statistical analyses verifying this relationship remain lacking. To better understand the relationship between montelukast and neuropsychiatric events, it is vital to guide patients in the effective use of the drug, especially in children whose mothers are concerned about its side effects. In this study, randomized controlled trials (RCTs) investigating montelukast and neuropsychiatric events were retrieved from a literature search of the Medline (1966 to February 2023), Embase (1974 to February 2023), Web of Science, and other related databases. After screening, 18 RCTs were ultimately included in a meta-analysis to merge statistics, which demonstrated no significant increase in neuropsychiatric events compared with placebo. A similar pattern of adverse neuropsychiatric events was observed in patients grouped according to age, with headache being the most common adverse neuropsychiatric event. Overall, montelukast did not significantly increase neuropsychiatric events in patients with allergic rhinitis and/or asthma compared with placebo. Large-sample RCTs are needed to verify the association between neuropsychiatric events and montelukast use in children, and attention is also devoted to FDA warnings.

Integrated UPLC-Q-TOF-MS and network pharmacology approach-driven quality marker discovery of Danggui Shaoyao San for primary dysmenorrhea.

Danggui Shaoyao San (DSS), a famous prescription, has been clinically proved to be effective in treating primary dysmenorrhea (PD). Currently there is no valid quality control data available for DSS. The main aim of the current research was to explore quality markers (Q-markers) of DSS. The chemical constituents of DSS were qualitatively identified using ultra-performance liquid chromatography tandem quadrupole time of flight mass spectrometry (UPLC-Q-TOF-MS) technology. On this basis, the targets of DSS and PD were predicted and screened using the TCMSP, SwissTargetPrediction, GeneCards, OMIM and TTD databases. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis was performed on the core intersection targets using string and Cytoscape 3.7.1 software. Then molecular docking was conducted to screen the Q-markers of DSS in PD. A total of 126 chemical constituents, including 22 organic acids, 14 phthalides, 24 monoterpenoids, five sesquiterpene lactones, 22 triterpenoids, four phenylpropanoids and 35 other compounds were preliminarily characterized. According to network pharmacology prediction analysis, six compounds containing polyporenic acid C, senkyunolide P, alisol B 23-acetate, naringenin, gallic acid, ferulic acid and albiflorin were regarded as Q-markers of DSS. The present research established an integrative UPLC-Q-TOF-MS and network pharmacology method to discover the latent Q-markers of DSS and provided a theoretical data for the follow-up quality control of DSS.

Phylogenomic analyses based on the plastid genome and concatenated nrDNA sequence data reveal cytonuclear discordance in genus Atractylodes (Asteraceae: Carduoideae).

Atractylodes species are widely distributed across East Asia and are cultivated as medicinal herbs in China, Japan, and Korea. Their unclear morphological characteristics and low levels of genetic divergence obscure the taxonomic relationships among these species. In this study, 24 plant samples were collected representing five species of Atractylodes located in China; of these, 23 belonged to members of the A. lancea complex. High-throughput sequencing was used to obtain the concatenated nrDNA sequences (18S-ITS1-5.8S-ITS2-28S) and plastid genomes. The concatenated nrDNA sequence lengths for all the Atractylodes species were 5,849 bp, and the GC content was 55%. The lengths of the whole plastid genome sequences ranged from 152,138 bp (A. chinensis) to 153,268 bp (A. lancea), while their insertion/deletion sites were mainly distributed in the intergenic regions. Furthermore, 33, 34, 36, 31, and 32 tandem repeat sequences, as well as 30, 30, 29, 30, and 30 SSR loci, were detected in A. chinensis, A. koreana, A. lancea, A. japonica, and A. macrocephala, respectively. In addition to these findings, a considerable number of heteroplasmic variations were detected in the plastid genomes, implying a complicated phylogenetic history for Atractylodes. The results of the phylogenetic analysis involving concatenated nrDNA sequences showed that A. lancea and A. japonica formed two separate clades, with A. chinensis and A. koreana constituting their sister clade, while A. lancea, A. koreana, A. chinensis, and A. japonica were found based on plastid datasets to represent a mixed clade on the phylogenetic tree. Phylogenetic network analysis suggested that A. lancea may have hybridized with the common ancestor of A. chinensis and A. japonica, while ABBA-BABA tests of SNPs in the plastid genomes showed that A. chinensis was more closely related to A. japonica than to A. lancea. This study reveals the extensive discordance and complexity of the relationships across the members of the A. lancea complex (A. lancea, A. chinensis, A. koreana, and A. japonica) according to cytonuclear genomic data; this may be caused by interspecific hybridization or gene introgression.

Integrated Serum Pharmacochemistry, Metabolomics, and Network Pharmacology to Reveal the Material Basis and Mechanism of Danggui Shaoyao San in the Treatment of Primary Dysmenorrhea.

Danggui Shaoyao San (DSS), a well-known formula, has been successfully applied in treating primary dysmenorrhea (PD) in China. However, its material basis and mechanism are still unrevealed. This current research aims to reveal the material basis and mechanism of DSS in treating PD by an integrative approach of serum pharmacochemistry, metabolomics, and network pharmacology. The results showed that DSS markedly relieved the physiological and pathological symptoms of PD as confirmed by the improvement of writhing behavior, inhibition of uterine edema, callback of clinical biochemical indexes, and metabolic profiles. Furthermore, a metabolomic analysis demonstrated that the therapeutic effect of DSS was attributed to the modulation of arachidonic acid metabolism, pentose and glucuronate interconversions, and phenylalanine metabolism. Meanwhile, 23 blood ingredients were identified after the oral administration of DSS. By analyzing the correlation coefficient of the identified biomarkers and blood components, active compounds closely associated with core metabolic pathways were extracted. Taking these active compounds as a basis, network pharmacology prediction was executed. It was found that active components of DSS including alisol B,23-acetate, chlorogenic acid, levistilide A, cianidanol, senkyunolide A, atractylenolide II, and sedanolide, were germane to steroid hormone biosynthesis, arachidonic acid metabolism, sphingolipid signaling pathway, etc. Interestingly, PTGS2 and PTGS1 related to the arachidonic acid metabolism may be pivotal targets of DSS. The current study proved that the integration of serum pharmacochemistry, metabolomics, and network pharmacology, was a powerful approach to investigate the material basis and the molecular mechanisms of DSS, and provided a solid basis for DSS application.

Biological Ingredient Analysis of Traditional Herbal Patent Medicine Fuke Desheng Wan Using the Shotgun Metabarcoding Approach.

With the widespread use of traditional medicine around the world, the safety and efficacy of traditional herbal patent medicine have become an increasing concern to the public. However, it is difficult to supervise the authenticity of herbal materials in mixed herbal products according to the current quality standards, especially for traditional herbal patent medicine, with a distinct variance in the dosage of herbal materials. This study utilized the shotgun metabarcoding approach to analyze the biological ingredients of Fuke Desheng Wan (FKDSW), which is an effective traditional herbal product for the treatment of dysmenorrhea. Six herbal materials were collected, and a lab-made mock FKDSW sample was produced to establish a method for the authentication assessment of biological ingredients in traditional herbal patent medicine based on shotgun metabarcoding. Furthermore, four commercial FKDSW samples were collected to verify the practicality of the shotgun metabarcoding approach. Then, a total of 52.16 Gb raw data for 174 million paired-end reads was generated using the Illumina NovaSeq sequencing platform. Meanwhile, 228, 23, and 14 operational taxonomic units (OTUs) were obtained for the ITS2, matK, and rbcL regions, respectively, after bioinformatic analysis. Moreover, no differences were evident between the assembly sequences obtained via shotgun metabarcoding and their corresponding reference sequences of the same species obtained via Sanger sequencing, except for part of the ITS2 and matK assembly sequences of Paeonia lactiflora Pall., Saussurea costus (Falc.) Lipsch. and Bupleurum chinense DC. with 1-6 different bases. The identification results showed that all six prescribed ingredients were successfully detected and that the non-authentic ingredient of Bupleuri Radix (Chaihu, Bupleurum chinense DC. or Bupleurum scorzonerifolium Willd.) was found in all the commercial samples, namely Bupleurum falcatum L. Here, 25 weed species representing 16 genera of ten families were detected. Moreover, 26 fungal genera belonging to 17 families were found in both lab-made and commercial FKDSW samples. This study demonstrated that the shotgun metabarcoding approach could overcome the biased PCR amplification and authenticate the biological ingredients of traditional herbal patent medicine with a distinct variance in the dosage of the herbal materials. Therefore, this provides an appropriate evaluation method for improving the safety and efficacy of traditional herbal patent medicine.

The complete chloroplast genome of Atractylodes japonica Koidz. ex Kitam. and its phylogenetic inference.

Atractylodes japonica Koidz. ex Kitam. is a perennial herbal plant, and its dried rhizomes have been widely used as traditional medicine in China and Japan. In this study, we assembled and annotated the complete chloroplast (cp) genome sequence of A. japonica using the high-throughput sequencing approach. The cp genome of A. japonica is 153,208 bp in length with the overall GC content of 37.7%, including two inverted repeat (IR) regions of 25,147 bp, which was separated by a large single-copy (LSC) region of 84,255 bp and a small single-copy (SSC) region of 18,659 bp. 113 unique genes were annotated in the genome, including 80 protein-coding genes, 29 represented tRNA genes, and four denoted rRNA genes. A maximum-likelihood phylogenetic analysis with 38 complete cp sequences showed that Atractylodes formed a monophyletic clade, and A. japonica and A. koreana formed a subclade in Atractylodes. This study provides the chloroplast genome structure features and phylogenetic relationship of A. japonica.

Feedback of biochemical indexes of blood sugar control by swimming exercise / Feedback dos índices bioquímicos de controle de açúcar no sangue por exercícios de natação / Feedback de los índices bioquímicos del control del azúcar en sangre mediante el ejercicio de natación

ABSTRACT Introduction: According to the metabolic characteristics of ultra-long-distance swimming and the characteristics of energy utilization and absorption during exercise, we have formulated a nutritional supplement plan for crossing to study the influence of swimming sports on blood sugar and give biochemical feedback indicators. Objective: To lay a foundation for studying the nutrition supplement rules during long-term exercise by taking the athletes' blood after training to determine the changes in blood sugar, adjusting and determining the nutritional supplement plan during training. Methods: We monitor athletes' physical function changes and biochemical indicators during training and study the changes of these biochemical indicators and athletes' physical functions after long-term swimming exercises to scientifically arrange the exercise intensity and load during the training period. Results: The urine indexes after exercise did not change much, reflecting the exercise load's low intensity. The changes in blood lactic acid and blood urea indexes after exercise also confirmed this. During the training period, the athletes' hemoglobin and red blood cell parameters are in the ideal range, indicating that the athlete's physical function is in good condition. During the training period, the training load intensity and load are reasonable according to ultra-long-distance swimming's energy supply characteristics. After training, the changes in blood glucose indicators reflect that the nutritional supplement program we formulated for athletes is reasonable and feasible. Conclusions: By monitoring the blood sugar and biochemical indicators of swimmers, it can help athletes to arrange exercise intensity scientifically and load during the training period, to better carry out open water competitions in China, and to arrange training and scientific nutrition during the training period scientifically. Lay the foundation for the establishment of nutrition supplement theory and training theory for super long-time sports. Level of evidence II; Therapeutic studies - investigation of treatment results.

RESUMEN Introducción: De acuerdo con las características metabólicas de la natación de ultra larga distancia y las características de utilización y absorción de energía durante el ejercicio, hemos formulado un plan de complementos nutricionales para estudiar la influencia de los deportes de natación en el azúcar en sangre y dar indicadores de retroalimentación bioquímica. Objetivo: Sentar las bases para el estudio de las reglas de los suplementos nutricionales durante el ejercicio a largo plazo mediante la extracción de sangre de los atletas después del entrenamiento para determinar los cambios en el azúcar en sangre, ajustando y determinando el plan de suplementos nutricionales durante el entrenamiento. Métodos: monitoreamos los cambios en la función física de los atletas y los indicadores bioquímicos durante el entrenamiento y estudiamos los cambios de estos indicadores bioquímicos y las funciones físicas de los atletas después de ejercicios de natación de larga distancia para organizar científicamente la intensidad y la carga del ejercicio durante el período de entrenamiento. Resultados: Los índices de orina después del ejercicio no cambiaron mucho, lo que refleja la baja intensidad de la carga de ejercicio. Los cambios en los índices de ácido láctico y urea en sangre después del ejercicio también lo confirmaron. Durante el período de entrenamiento, los parámetros de hemoglobina y glóbulos rojos de los atletas están en el rango ideal, lo que indica que la función física del atleta está en buenas condiciones. Durante el período de entrenamiento, la intensidad de la carga de entrenamiento y la carga son razonables de acuerdo con las características de suministro de energía de la natación de ultra larga distancia. Después del entrenamiento, los cambios en los indicadores de glucosa en sangre reflejan que el programa de suplementos nutricionales que formulamos para los atletas es razonable y factible. Conclusiones: monitorear los indicadores bioquímicos y de azúcar en sangre de los nadadores, puede ayudar a los atletas a organizar científicamente la intensidad del ejercicio y la carga durante el período de entrenamiento, a realizar mejor las competiciones en aguas abiertas en China y a organizar el entrenamiento y la nutrición científica durante el período de entrenamiento. Sentar las bases para el establecimiento de la teoría de los suplementos nutricionales y la teoría del entrenamiento para deportes de larga duración. Nivel de evidencia II; Estudios terapéuticos: investigación de los resultados del tratamiento.

RESUMO Introdução: De acordo com as características metabólicas da natação de ultra longa distância e as características de utilização e absorção de energia durante o exercício, formulamos um plano de suplemento nutricional para estudar a influência dos esportes de natação no açúcar no sangue e fornecer indicadores de feedback bioquímico. Objetivo: Estabelecer as bases para o estudo das regras de suplementos nutricionais durante exercícios de longa duração, retirando sangue de atletas após o treinamento para determinar as mudanças na glicemia, ajustando e determinando o plano de suplementação nutricional durante o treinamento. Métodos: monitoramos as mudanças na função física e nos indicadores bioquímicos dos atletas durante o treinamento e estudamos as mudanças nesses indicadores bioquímicos e nas funções físicas dos atletas após exercícios de natação de longa distância para organizar cientificamente a intensidade e a carga do exercício durante o período de treinamento. Resultados: As taxas de urina após o exercício não mudaram muito, refletindo a baixa intensidade da carga de exercício. Alterações nos índices de uréia e ácido láctico no sangue após o exercício também confirmaram isso. Durante o período de treinamento, os parâmetros de hemoglobina e hemácias dos atletas estão na faixa ideal, indicando que a função física do atleta está em boas condições. Durante o período de treinamento, a intensidade da carga de treinamento e a carga são razoáveis de acordo com as características da fonte de alimentação da natação de ultra longa distância. Após o treinamento, as mudanças nos indicadores de glicose no sangue refletem que o programa de suplementos nutricionais que formulamos para atletas é razoável e viável. Conclusões: monitorar os indicadores bioquímicos e de açúcar no sangue de nadadores pode ajudar os atletas a organizar cientificamente a intensidade e carga do exercício durante o período de treinamento, conduzir melhor competições em águas abertas na China e organizar treinamento e nutrição científica durante o período de treinamento. Estabelecendo as bases para o estabelecimento da teoria dos suplementos nutricionais e da teoria do treinamento para esportes de longa duração. Nível de evidência II; Estudos terapêuticos: investigação dos resultados do tratamento.

The complete chloroplast genome of Atractylodes koreana (Nakai) Kitam and its phylogenetic analysis.

Atractylodes koreana (Nakai) Kitam is a perennial herb of Asteraceae, mainly distributed in China and Korea, which is the main adulterant of traditional herbal medicine 'Cangzhu'. In the present study, we reported the complete chloroplast (cp) genome of A. koreana with the total length of 153,232 bp, which is consisted of four regions, including one large single copy (LSC) region of 84,250 bp, one small single copy (SSC) region of 18,690 bp, and two inverted repeat regions (IRa and IRb) of 25,146 bp. The GC content of the complete cp genome is 37.7%. A total of 110 unique genes were annotated, comprising 79 protein-coding genes, 27 transfer RNA (tRNA) genes and four ribosome RNA (rRNA) genes. Moreover, nine protein-coding genes contained one intron and three protein-coding genes (clpP, ycf3, and rps12) contained two introns. The phylogenetic analysis indicated that A. koreana is a sister group of A. chinensis and A. lancea.

WITHDRAWN: The role of sustainable urban employee basic medical insurance in health risk appraisal of urban residents.

Ahead of Print article withdrawn by publisher.

A Smartphone-Based Cursor Position System in Cross-Device Interaction Using Machine Learning Techniques.

The use of mobile devices, especially smartphones, has become popular in recent years. There is an increasing need for cross-device interaction techniques that seamlessly integrate mobile devices and large display devices together. This paper develops a novel cross-device cursor position system that maps a mobile device's movement on a flat surface to a cursor's movement on a large display. The system allows a user to directly manipulate objects on a large display device through a mobile device and supports seamless cross-device data sharing without physical distance restrictions. To achieve this, we utilize sound localization to initialize the mobile device position as the starting location of a cursor on the large screen. Then, the mobile device's movement is detected through an accelerometer and is accordingly translated to the cursor's movement on the large display using machine learning models. In total, 63 features and 10 classifiers were employed to construct the machine learning models for movement detection. The evaluation results have demonstrated that three classifiers, in particular, gradient boosting, linear discriminant analysis (LDA), and naïve Bayes, are suitable for detecting the movement of a mobile device.

The serine hydroxymethyltransferase-2 (SHMT2) initiates lymphoma development through epigenetic tumor suppressor silencing.

Cancer cells adapt their metabolic activities to support growth and proliferation. However, increased activity of metabolic enzymes is not usually considered an initiating event in the malignant process. Here, we investigate the possible role of the enzyme serine hydroxymethyltransferase-2 (SHMT2) in lymphoma initiation. SHMT2 localizes to the most frequent region of copy number gains at chromosome 12q14.1 in lymphoma. Elevated expression of SHMT2 cooperates with BCL2 in lymphoma development; loss or inhibition of SHMT2 impairs lymphoma cell survival. SHMT2 catalyzes the conversion of serine to glycine and produces an activated one-carbon unit that can be used to support S-adenosyl methionine synthesis. SHMT2 induces changes in DNA and histone methylation patterns leading to promoter silencing of previously uncharacterized mutational genes, such as SASH1 and PTPRM. Together, our findings reveal that amplification of SHMT2 in cooperation with BCL2 is sufficient in the initiation of lymphomagenesis through epigenetic tumor suppressor silencing.

The Oncogenic Action of NRF2 Depends on De-glycation by Fructosamine-3-Kinase.

The NRF2 transcription factor controls a cell stress program that is implicated in cancer and there is great interest in targeting NRF2 for therapy. We show that NRF2 activity depends on Fructosamine-3-kinase (FN3K)-a kinase that triggers protein de-glycation. In its absence, NRF2 is extensively glycated, unstable, and defective at binding to small MAF proteins and transcriptional activation. Moreover, the development of hepatocellular carcinoma triggered by MYC and Keap1 inactivation depends on FN3K in vivo. N-acetyl cysteine treatment partially rescues the effects of FN3K loss on NRF2 driven tumor phenotypes indicating a key role for NRF2-mediated redox balance. Mass spectrometry reveals that other proteins undergo FN3K-sensitive glycation, including translation factors, heat shock proteins, and histones. How glycation affects their functions remains to be defined. In summary, our study reveals a surprising role for the glycation of cellular proteins and implicates FN3K as targetable modulator of NRF2 activity in cancer.

Noncovalent inhibitors reveal BTK gatekeeper and auto-inhibitory residues that control its transforming activity.

Inhibition of Bruton tyrosine kinase (BTK) is a breakthrough therapy for certain B cell lymphomas and B cell chronic lymphatic leukemia. Covalent BTK inhibitors (e.g., ibrutinib) bind to cysteine C481, and mutations of this residue confer clinical resistance. This has led to the development of noncovalent BTK inhibitors that do not require binding to cysteine C481. These new compounds are now entering clinical trials. In a systematic BTK mutagenesis screen, we identify residues that are critical for the activity of noncovalent inhibitors. These include a gatekeeper residue (T474) and mutations in the kinase domain. Strikingly, co-occurrence of gatekeeper and kinase domain lesions (L512M, E513G, F517L, L547P) in cis results in a 10- to 15-fold gain of BTK kinase activity and de novo transforming potential in vitro and in vivo. Computational BTK structure analyses reveal how these lesions disrupt an intramolecular mechanism that attenuates BTK activation. Our findings anticipate clinical resistance mechanisms to a new class of noncovalent BTK inhibitors and reveal intramolecular mechanisms that constrain BTK's transforming potential.

Enlarging spin-dependent transverse displacement of surface plasmon polaritons focus.

By introducing additional spin angular momentum (SAM) induced spiral phase, the spin-dependent transverse displacement of surface plasmon polaritons (SPPs) focus is effectively enlarged. The separation between the SPPs focuses generated by left circularly polarized (LCP) light and right circularly polarized (RCP) light reaches 1500 nm, which is six times larger than the previously reported values with semicircular plasmonic lens. The relationship between the displacement of the SPPs focus and the total spiral phase that consisted of the intrinsic and the additional spiral phase is theoretically established. Furthermore, the flexibility and versatility of the proposed mechanism is demonstrated by reversing or continuously controlling the SPPs focus. These findings hold great promise for spin-based plasmonic devices and the related applications, such as on-chip communication.

Analysis of the activity and safety of weekly low-dose bevacizumab-based regimens in heavily pretreated patients with metastatic breast cancer.

BACKGROUND: Currently, there are no standard regimens for metastatic breast cancer patients (MBC) who have failed ≥ 3 chemotherapy treatments. The aim of this study was to assess whether weekly low-dose bevacizumab-based regimens were well tolerated and would improve efficacy in MBC patients who had failed numerous therapies. METHODS: Seventeen patients with MBC who were heavily pretreated with a median of five regimens of therapy (range 1-10) between 2012 and 2016 were included in the analysis. Bevacizumab was administered at a dose of 100 mg intravenously once a week combined with one or two types of chemotherapeutic drugs until confirmed disease progression or an intolerable adverse event was observed. Patient characteristics, objective response rate, clinical benefit rate, progression-free survival, and toxicity were assessed. RESULTS: All 17 patients had been pretreated with taxane-based and anthracycline-based chemotherapy. Weekly low-dose bevacizumab combined with one or two types of chemotherapeutic drugs, which had usually not been previously used (e.g. etoposide, irinotecan, pemetrexed, methotrexate, and nab-paclitaxel), was administered. Three patients achieved a partial response, while one had stable disease for > 24 weeks, and the clinical benefit rate was 23.5%. Median progression-free survival was 3.4 months (95% confidence interval 2.0-4.8). The most common hematological adverse events were neutropenia, anemia, and thrombocytopenia. Bevacizumab-related adverse events included grade 1 bleeding (17.6%) and grade 2 hypertension (5.9%). CONCLUSIONS: Weekly low-dose bevacizumab combined with chemotherapy shows a relatively favorable clinical response and tolerable toxicity, providing a feasible option for heavily pretreated MBC patients.

Atomic Force Microscopy Study of the Anti-inflammatory Effects of Triptolide on Rheumatoid Arthritis Fibroblast-like Synoviocytes.

High-resolution atomic force microscopy (AFM) was used for the in situ evaluation of the anti-inflammatory effects of triptolide on rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) to understand the anti-RA effects of triptolide, based on the morphological and biophysical changes observed in RA-FLS. RA-FLS have been reported to play a primary role in inflammatory bone destruction during the development of RA and thus are regarded as an important target for RA treatment. Triptolide pretreatment significantly inhibited tumor necrosis factor-α-induced expression of the interleukin (IL)-1ß, IL-6, and IL-8 genes in MH7A cells. Using AFM, we showed that triptolide-induced morphological damage in MH7A cells by inducing significant ultrastructure changes in the membrane, which were closely related to triptolide-induced apoptosis in MH7A cells. Using force measurements determined with AFM, triptolide was shown to increase the stiffness of MH7A cells. These findings not only revealed the strong anti-inflammatory effects of triptolide on RA-FLS, highlighting triptolide as a potential anti-RA agent, but also revealed the possible use of AFM for studying anti-inflammatory responses in RA-FLS, which we expect to be developed into a potential tool for anti-RA drug studies in RA-FLS.

RNA Interference of IQ Motif Containing GTPase-Activating Protein 3 (IQGAP3) Inhibits Cell Proliferation and Invasion in Breast Carcinoma Cells.

Breast cancer is a highly prevalent disease affecting women. The association of IQ motif containing GTPase-activating protein 3 (IQGAP3) and breast cancer is poorly defined. Here we reported that IQGAP3 is a key regulator of cell proliferation and metastasis during breast cancer progression. The expression of IQGAP3 was significantly increased in breast tissues compared to nontumor tissues at both protein and mRNA levels. Furthermore, IQGAP3 had a high expression level in ZR-75-30 and BT474 compared to other breast cancer cell lines. Depletion of IQGAP3 through RNA interference in ZR-75-30 and BT474 significantly inhibited cell proliferation. More importantly, IQGAP3 silencing in breast cancer cells notably repressed cell migration and invasion. Further analysis suggested that inhibition of cell proliferation and metastasis was associated with some proteins, including p53, MMP9, Snail, CDC42, p-ERK1/2, KIF2C, KIF4A, PCNA, and Twist. Since expression of IQGAP3 seems to be associated with the pathogenesis of breast cancer and suppression of it can inhibit cancer cell growth and metastasis, IQGAP3 may be a potential therapeutic target in human breast cancer.

The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development.

The gene encoding the lysine-specific histone methyltransferase KMT2D has emerged as one of the most frequently mutated genes in follicular lymphoma and diffuse large B cell lymphoma; however, the biological consequences of KMT2D mutations on lymphoma development are not known. Here we show that KMT2D functions as a bona fide tumor suppressor and that its genetic ablation in B cells promotes lymphoma development in mice. KMT2D deficiency also delays germinal center involution and impedes B cell differentiation and class switch recombination. Integrative genomic analyses indicate that KMT2D affects methylation of lysine 4 on histone H3 (H3K4) and expression of a set of genes, including those in the CD40, JAK-STAT, Toll-like receptor and B cell receptor signaling pathways. Notably, other KMT2D target genes include frequently mutated tumor suppressor genes such as TNFAIP3, SOCS3 and TNFRSF14. Therefore, KMT2D mutations may promote malignant outgrowth by perturbing the expression of tumor suppressor genes that control B cell-activating pathways.