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The combination of cisplatin and pemetrexed remains the gold standard chemotherapy for malignant pleural mesothelioma (MPM), although resistance and poor response pose a significant challenge. Cytidine deaminase (CDA) is a key enzyme in the nucleotide salvage pathway and is involved in the adaptive stress response to chemotherapy. The cytidine analog capecitabine and its metabolite 5'-deoxy-5-fluorocytidine (5'-DFCR) are converted via CDA to 5-fluorouracil, which affects DNA and RNA metabolism. This study investigated a schedule-dependent treatment strategy, proposing that initial chemotherapy induces CDA expression, sensitizing cells to subsequent capecitabine treatment. Basal CDA protein expression was low in different mesothelioma cell lines but increased in the corresponding xenografts. Standard chemotherapy increased CDA protein levels in MPM cells in vitro and in vivo in a schedule-dependent manner. This was associated with epithelial-to-mesenchymal transition and with HIF-1alpha expression at the transcriptional level. In addition, pretreatment with cisplatin and pemetrexed in combination sensitized MPM xenografts to capecitabine. Analysis of a tissue microarray (TMA) consisting of samples from 98 human MPM patients revealed that most human MPM samples had negative CDA expression. While survival curves based on CDA expression in matched samples clearly separated, significance was not reached due to the limited sample size. In non-matched samples, CDA expression before but not after neoadjuvant therapy was significantly associated with worse overall survival. In conclusion, chemotherapy increases CDA expression in xenografts, which is consistent with our in vitro results in MPM and lung cancer. A subset of matched patient samples showed increased CDA expression after therapy, suggesting that a schedule-dependent treatment strategy based on chemotherapy and capecitabine may benefit a selected MPM patient population.
Subject(s)
Capecitabine , Cytidine Deaminase , Mesothelioma, Malignant , Pemetrexed , Pleural Neoplasms , Xenograft Model Antitumor Assays , Humans , Capecitabine/pharmacology , Animals , Cell Line, Tumor , Mesothelioma, Malignant/drug therapy , Mesothelioma, Malignant/metabolism , Mesothelioma, Malignant/pathology , Cytidine Deaminase/metabolism , Cytidine Deaminase/genetics , Mice , Pemetrexed/pharmacology , Pleural Neoplasms/drug therapy , Pleural Neoplasms/metabolism , Pleural Neoplasms/pathology , Cisplatin/pharmacology , Cisplatin/therapeutic use , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Epithelial-Mesenchymal Transition/drug effects , Mesothelioma/drug therapy , Mesothelioma/metabolism , Mesothelioma/pathology , Female , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Gene Expression Regulation, Neoplastic/drug effectsABSTRACT
Introduction: Malignant pleural mesothelioma (MPM) is a rare and universally lethal malignancy with limited treatment options. Immunotherapy with immune checkpoint inhibitors (ICIs) has recently been approved for unresectable MPM, but response to ICIs is heterogeneous, and reliable biomarkers for prospective selection of appropriate subpopulations likely to benefit from ICIs remain elusive. Methods: We performed multiscale integrative analyses of published primary tumor data set from The Cancer Genome Atlas (TCGA) and the French cohort E-MTAB-1719 to unravel the tumor immune microenvironment of MPM deficient in BAP1, one of the most frequently mutated tumor suppressor genes (TSGs) in the disease. The molecular profiling results were validated in independent cohorts of patients with MPM using immunohistochemistry and multiplex immunohistochemistry. Results: We revealed that BAP1 deficiency enriches immune-associated pathways in MPM, leading to increased mRNA signatures of interferon alfa/gamma response, activating dendritic cells, immune checkpoint receptors, and T-cell inflammation. This finding was confirmed in independent patient cohorts, where MPM tumors with low BAP1 levels are associated with an inflammatory tumor immune microenvironment characterized by increased exhausted precursor T-cells and macrophages but decreased myeloid-derived suppressor cells (MDSCs). In addition, BAP1low MPM cells are in close proximity to T cells and therefore can potentially be targeted with ICIs. Finally, we revealed that BAP1-proficient MPM is associated with a hyperactive mitogen-activated protein kinase (MAPK) pathway and may benefit from treatment with MEK inhibitors (MEKis). Conclusion: Our results suggest that BAP1 plays an immunomodulatory role in MPM and that BAP1-deficient MPM may benefit from immunotherapy, which merits further clinical investigation.
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Once considered "undruggable" due to the strong affinity of RAS proteins for GTP and the structural lack of a hydrophobic "pocket" for drug binding, the development of proprietary therapies for KRAS-mutant tumors has long been a challenging area of research. CRISPR technology, the most successful gene-editing tool to date, is increasingly being utilized in cancer research. Here, we provide a comprehensive review of the application of the CRISPR system in basic and translational research in KRAS-mutant cancer, summarizing recent advances in the mechanistic understanding of KRAS biology and the underlying principles of drug resistance, anti-tumor immunity, epigenetic regulatory networks, and synthetic lethality co-opted by mutant KRAS.
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BACKGROUND: The inducible Kras/p53 lung adenocarcinoma mouse model, which faithfully recapitulates human disease, is routinely initiated by the intratracheal instillation of a virus-based Cre recombinase delivery system. Handling virus-based delivery systems requires elevated biosafety levels, e.g., biosafety level 2 (BSL-2). However, in experimental animal research facilities, following exposure to viral vectors in a BSL-2 environment, rodents may not be reclassified to BSL-1 according to standard practice, preventing access to small animal micro-computed tomography (micro-CT) scanners that are typically housed in general access areas such as BSL-1 rooms. Therefore, our goal was to adapt the protocol so that the Cre-induced KP mouse model could be handled under BSL-1 conditions during the entire procedure. RESULTS: The Kras-Lox-STOP-Lox-G12D/p53 flox/flox (KP)-based lung adenocarcinoma mouse model was activated by intratracheal instillation of either an adenoviral-based or a gutless, adeno-associated viral-based Cre delivery system. Tumor growth was monitored over time by micro-CT. We have successfully substituted the virus-based Cre delivery system with a commercially available, gutless, adeno-associated, Cre-expressing vector that allows the KP mouse model to be handled and imaged in a BSL-1 facility. By optimizing the anesthesia protocol and switching to a microscope-guided vector instillation procedure, productivity was increased and procedure-related complications were significantly reduced. In addition, repeated micro-CT analysis of individual animals allowed us to monitor tumor growth longitudinally, dramatically reducing the number of animals required per experiment. Finally, we documented the evolution of tumor volume for different doses, which revealed that individual tumor nodules induced by low-titer AAV-Cre transductions can be monitored over time by micro-CT. CONCLUSION: Modifications to the anesthesia and instillation protocols increased the productivity of the original KP protocol. In addition, the switch to a gutless, adeno-associated, Cre-expressing vector allowed longitudinal monitoring of tumor growth under BSL-1 conditions, significantly reducing the number of animals required for an experiment, in line with the 3R principles.
Subject(s)
Adenocarcinoma of Lung , Lung Neoplasms , Mice , Animals , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Proto-Oncogene Proteins p21(ras)/genetics , Dependovirus/genetics , X-Ray Microtomography , Tumor Suppressor Protein p53 , Containment of Biohazards , Disease Models, Animal , Genetic Vectors/geneticsABSTRACT
Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the western blotting data shown in Fig. 5C, and the cell migration and invasion data shown in Figs. 3C and D and 6B and C were strikingly similar to data that had already appeared in other articles. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 38: 30713077, 2017; DOI: 10.3892/or.2017.5956].
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River sediment is vital in containing water pollution and strengthening water remediation. This paper has conducted a study on the microecological health assessment of the sediment and water body of Guixi River in Dianjiang, Chongqing, China, using metagenomics sequencing and microbial biological integrity index (M-IBI) technology. The analysis of physical and chemical characteristics shows that the concentration of TN varies from 2.62 to 9.76 mg/L in each sampling section, and the eutrophication of the water body is relatively severe. The proportion of Cyanobacteria in the sampling section at the sink entrance is higher than that of other sites, where there are outbreaks of water blooms and potential hazards to human health. The dominant functions of each site include carbon metabolism, TCA cycle, and pyruvate metabolism. In addition, the main virulence factors and antibiotic resistance genes in sediment are Type IV pili (VF0082), LOS (CVF494), MymA operon (CVF649), and macrolide resistance genes macB, tetracyclic tetA (58), and novA. Correlation analysis of environmental factors and microorganisms was also performed, and it was discovered that Thiothrix and Acidovorax had obvious gene expression in the nitrogen metabolism pathway, and the Guixi River Basin had a self-purification capacity. Finally, based on the microecological composition of sediment and physical and chemical characteristics of the water body, the health assessment was carried out, indicating that the main pollution area was Dianjiang Middle School and the watershed near the sewage treatment plant. The findings should theoretically support an in-depth assessment of the water environment's microecological health.
Subject(s)
Environmental Monitoring , Metagenomics , Rivers , Water Pollutants, Chemical , China , Water Pollutants, Chemical/analysis , Drug Resistance, Bacterial , Genes, Bacterial , HumansABSTRACT
Plant-based protein products, represented by "plant meat", are gaining more and more popularity as an alternative to animal proteins. In the present review, we aimed to update the current status of research and industrial growth of plant-based protein products, including plant-based meat, plant-based eggs, plant-based dairy products, and plant-based protein emulsion foods. Moreover, the common processing technology of plant-based protein products and its principles, as well as the emerging strategies, are given equal importance. The knowledge gap between the use of plant proteins and animal proteins is also described, such as poor functional properties, insufficient texture, low protein biomass, allergens, and off-flavors, etc. Furthermore, the nutritional and health benefits of plant-based protein products are highlighted. Lately, researchers are committed to exploring novel plant protein resources and high-quality proteins with enhanced properties through the latest scientific and technological interventions, including physical, chemical, enzyme, fermentation, germination, and protein interaction technology.
Subject(s)
Dairy Products , Meat , Animals , EggsABSTRACT
Background: Artificial intelligence-assisted colonoscopy (AIAC) has been proposed and validated in recent years, but the effectiveness of clinic application remains unclear since it was only validated in some clinical trials rather than normal conditions. In addition, previous clinical trials were mostly concerned with colorectal polyp identification, while fewer studies are focusing on adenoma identification and polyps size measurement. In this study, we validated the effectiveness of AIAC in the clinical environment and further investigated its capacity for adenoma identification and polyps size measurement. Methods: The information of 174 continued patients who went for coloscopy in Chongqing Rongchang District People's hospital with detected colon polyps was retrospectively collected, and their coloscopy images were divided into three validation datasets, polyps dataset, polyps/adenomas dataset (all containing narrow band image, NBI images), and polyp size measurement dataset (images with biopsy forceps and polyps) to assess the competence of the artificial intelligence system, and compare its diagnostic ability with endoscopists with different experiences. Results: A total of 174 patients were included, and the sensitivity of the colorectal polyp recognition model was 99.40%, the accuracy of the colorectal adenoma diagnostic model was 93.06%, which was higher than that of endoscopists, and the mean absolute error of the polyp size measurement model was 0.62 mm and the mean relative error was 10.89%, which was lower than that of endoscopists. Conclusion: Artificial intelligence-assisted model demonstrated higher competence compared with endoscopists and stable diagnosis ability in clinical use.
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Malignant pleural mesothelioma (MPM) is a lethal malignancy etiologically caused by asbestos exposure, for which there are few effective treatment options. Although asbestos carcinogenesis is associated with reactive oxygen species (ROS), the bona fide oncogenic signaling pathways that regulate ROS homeostasis and bypass ROS-evoked apoptosis in MPM are poorly understood. In this study, we demonstrate that the mitogen-activated protein kinase (MAPK) pathway RAS-RAF-MEK-ERK is hyperactive and a molecular driver of MPM, independent of histological subtypes and genetic heterogeneity. Suppression of MAPK signaling by clinically approved MEK inhibitors (MEKi) elicits PARP1 to protect MPM cells from the cytotoxic effects of MAPK pathway blockage. Mechanistically, MEKi induces impairment of homologous recombination (HR) repair proficiency and mitochondrial metabolic activity, which is counterbalanced by pleiotropic PARP1. Consequently, the combination of MEK with PARP inhibitors enhances apoptotic cell death in vitro and in vivo that occurs through coordinated upregulation of cytotoxic ROS in MPM cells, suggesting a mechanism-based, readily translatable strategy to treat this daunting disease. Collectively, our studies uncover a previously unrecognized scenario that hyperactivation of the MAPK pathway is an essential feature of MPM and provide unprecedented evidence that MAPK signaling cooperates with PARP1 to homeostatically maintain ROS levels and escape ROS-mediated apoptosis.
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The Kelch-like ECH-associated protein 1/nuclear factor erythroid-derived 2-like 2 (KEAP1/NRF2) pathway is well recognized as a key regulator of redox homeostasis, protecting cells from oxidative stress and xenobiotics under physiological circumstances. Cancer cells often hijack this pathway during initiation and progression, with aberrant KEAP1-NRF2 activity predominantly observed in non-small cell lung cancer (NSCLC), suggesting that cell/tissue-of-origin is likely to influence the genetic selection during malignant transformation. Hyperactivation of NRF2 confers a multi-faceted role, and recently, increasing evidence shows that a close interplay between metabolic reprogramming and tumor immunity remodelling contributes to its aggressiveness, treatment resistance (radio-/chemo-/immune-therapy) and susceptibility to metastases. Here, we discuss in detail the special metabolic and immune fitness enabled by KEAP1-NRF2 aberration in NSCLC. Furthermore, we summarize the similarities and differences in the dysregulated KEAP1-NRF2 pathway between two major histo-subtypes of NSCLC, provide mechanistic insights on the poor response to immunotherapy despite their high immunogenicity, and outline evolving strategies to treat this recalcitrant cancer subset. Finally, we integrate bioinformatic analysis of publicly available datasets to illustrate the new partners/effectors in NRF2-addicted cancer cells, which may provide new insights into context-directed treatment.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Kelch-Like ECH-Associated Protein 1 , Lung Neoplasms , NF-E2-Related Factor 2 , Humans , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Gene Expression Regulation, Neoplastic , Kelch-Like ECH-Associated Protein 1/genetics , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , NF-E2-Related Factor 2/metabolism , Oxidative StressABSTRACT
BACKGROUND: Solvent tolerance is a desired feature of microorganisms for their application in biotechnology. Organic solvent-tolerant microorganisms are able to thrive in the presence of organic solvents. Several mechanisms have been proposed to elucidate their intrinsic tolerance to organic solvents. OBJECTIVE: The present review aims to summarize the state of the art of the roles of membrane proteins in microbial organic solvent tolerance. Strategies and challenges for improving the protective function of membrane proteins in organic solvent stress are also proposed. RESULTS: Membrane proteins related to transporter, signal transduction, and material and energy metabolism are involved in solvent tolerance. Optimization of the expression level of membrane proteins and engineering of membrane proteins are utilized to tackle the toxicity caused by organic solvents. CONCLUSIONS: Membrane proteins occupy a strikingly important position in microbial solvent tolerance. Further research on novel methods in membrane proteins, trade-offs among overexpression and toxicity of membrane proteins and solvent yield, and a direct relationship between signaling pathways and solvent tolerance will advance the utilization of organic solvent-tolerant microorganisms in biotechnology.
Subject(s)
Membrane Proteins , Membrane Transport Proteins , Solvents , Membrane Proteins/metabolism , Membrane Transport Proteins/metabolism , Energy MetabolismABSTRACT
The rapid development of 5G, big data, and Internet of Things (IoT) technologies is urgently required for novel non-volatile memory devices with low power consumption, fast read/write speed, and high reliability, which are crucial for high-performance computing. Ferroelectric memory has undergone extensive investigation as a viable alternative for commercial applications since the post-Moore era. However, conventional perovskite-structure ferroelectrics (e.g., PbZr x Ti1- x O3) encounter severe limitations for high-density integration owing to the size effect of ferroelectricity and incompatibility with complementary metal-oxide-semiconductor technology. Since 2011, the ferroelectric field has been primarily focused on HfO2-based ferroelectric thin films owing to their exceptional scalability. Several reviews discussing the control of ferroelectricity and device applications exist. It is believed that a comprehensive understanding of mechanisms based on industrial requirements and concerns is necessary, such as the wake-up effect and fatigue mechanism. These mechanisms reflect the atomic structures of the materials as well as the device physics. Herein, a review focusing on phase stability and domain structure is presented. In addition, the recent progress in related ferroelectric memory devices and their challenges is briefly discussed.
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Objective:To investigate the value of number of negative lymph nodes (NLNs) in predicting the prognosis of patients with esophageal cancer after neoadjuvant therapy and the construction of nomogram prodiction model.Methods:The retrospective cohort study was conducted. The clinicopathological data of 1 924 patients with esophageal cancer after neoadjuvant therapy uploaded to the Surveillance, Epidemiology, and End Results Database of the National Cancer Institute from 2004 to 2015 were collected. There were 1 624 males and 300 females, aged 63 (range, 23?85)years. All 1 924 patients were randomly divided into the training dataset of 1 348 cases and the validation dataset of 576 cases with a ratio of 7:3 based on random number method in the R software (3.6.2 version). The training dataset was used to constructed the nomogram predic-tion model, and the validation dataset was used to validate the performance of the nomogrram prediction model. The optimal cutoff values of number of NLNs and number of examined lymph nodes (ELNs) were 8, 14 and 10, 14, respectively, determined by the X-tile software (3.6.1 version), and then data of NLNs and ELNs were converted into classification variables. Observation indicators: (1) clinicopathological characteristics of patients in the training dataset and the validation dataset; (2) survival of patients in the training dataset and the validation dataset; (3) prognostic factors analysis of patients in the training dataset; (4) survival of patients in subgroup of the training dataset; (5) prognostic factors analysis in subgroup of the training dataset; (6) construction of nomogram prediction model and calibration curve. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was conducted using the t test. Measurement data with skewed distribution were represented as M(range), and comparison between groups was conducted using the Mann-Whitney U test. Count data were described as absolute numbers, and comparison between groups was conducted using the chi-square test. The Kaplan-Meier method was used to draw survival curve and Log-Rank test was used for survival analysis. The COX proportional hazard model was used for univariate and multivariate analyses. Based on the results of multivariate analysis, the nomogram prediction model was constructed. The prediction efficacy of nomogram prediction model was evaluated using the area under curve (AUC) of the receiver operating characteristic curve and the Harrell′s c index. Errors of the nomogram prediction model in predicting survival of patients for the training dataset and the validation dataset were evaluated using the calibration curve. Results:(1) Clinicopathological characteristics of patients in the training dataset and the validation dataset. There was no significant difference in clinicopatholo-gical characteristics between the 1 348 patients of the training dataset and the 576 patients of the validation dataset ( P>0.05). (2) Survival of patients in the training dataset and the validation dataset. All 1 924 patients were followed up for 50(range, 3?140)months, with 3-year and 5-year cumulative survival rate as 59.4% and 49.5%, respectively. The 3-year cumulative survival rate of patients with number of NLNs as <8, 8?14 and >14 in the training dataset was 46.7%, 62.0% and 66.0%, respectively, and the 5-year cumulative survival rate was 38.1%, 52.1% and 59.7%, respectively. There was a significant difference in the survival of these patients in the training dataset ( χ2=33.70, P<0.05). The 3-year cumulative survival rate of patients with number of NLNs as <8, 8?14 and >14 in the validation dataset was 51.1%, 54.9% and 71.2%, respectively, and the 5-year cumulative survival rate was 39.3%, 42.5% and 55.7%, respectively. There was a significant difference in the survival of these patients in the validation dataset ( χ2=14.49, P<0.05). The 3-year cumulative survival rate of patients with number of ELNs as <10, 10?14 and >14 in the training dataset was 53.9%, 60.0% and 62.7%, respectively, and the 5-year cumulative survival rate was 44.7%, 49.1% and 56.9%, respectively. There was a significant difference in the survival of these patients in the training dataset ( χ2=9.88, P<0.05). The 3-year cumulative survival rate of patients with number of ELNs as <10, 10?14 and >14 in the validation dataset was 56.2%, 47.9% and 69.3%, respectively, and the 5-year cumula-tive survival rate was 44.9%, 38.4% and 51.9%, respectively. There was a significant difference in the survival of these patients in the validation dataset ( χ2=9.30, P<0.05). (3) Prognostic factors analysis of patients in the training dataset. Results of multivariate analysis showed that gender, neoadjuvant pathological (yp) T staging, ypN staging (stage N1, stage N2, stage N3) and number of NLNs (8?14, >14) were independent influencing factors for the prognosis of patients with esophageal cancer after neoadjuvant therapy ( hazard ratio=0.65, 1.44, 1.96, 2.41, 4.12, 0.69, 0.56, 95% confidence interval as 0.49?0.87, 1.17?1.78, 1.59?2.42, 1.84?3.14, 2.89?5.88, 0.56?0.86, 0.45?0.70, P<0.05). (4) Survival of patients in subgroup of the training dataset. Of the patients with NLNs in the training dataset, the 3-year cumulative survival rate of patients with number of NLNs as <8, 8?14 and >14 was 61.1%, 71.6% and 76.8%, respectively, and the 5-year cumulative survival rate was 50.7%, 59.9% and 70.1%, respectively. There was a significant difference in the survival of these patients in the training dataset ( χ2=12.66, P<0.05). Of the patients with positive lymph nodes in the training dataset, the 3-year cumulative survival rate of patients with number of NLNs as <8, 8?14 and >14 was 26.1%, 42.9% and 44.7%, respectively, and the 5-year cumulative survival rate was 20.0%, 36.5% and 39.3%, respectively. There was a significant difference in the survival of these patients in the training dataset ( χ2=20.39, P<0.05). (5) Prognostic factors analysis in subgroup of the training dataset. Results of multivariate analysis in patients with NLNs in the training dataset showed that gender, ypT staging and number of NLNs (>14) were independent influencing factors for the prognosis of patients with esophageal cancer after neoadju-vant therapy ( hazard ratio=0.67, 1.44, 0.56, 95% confidence interval as 0.47?0.96, 1.09?1.90, 0.41?0.77, P<0.05). Results of multi-variate analysis in patients with positive lymph nodes in the training dataset showed that race as others, histological grade as G2, ypN staging as stage N3 and number of NLNs (8?14, >14) were independent influencing factors for the prognosis of patients with esophageal cancer after neoadjuvant therapy ( hazard ratio=2.73, 0.70, 2.08, 0.63, 0.59, 95% confidence interval as 1.43?5.21, 0.54?0.91, 1.44?3.02, 0.46?0.87, 0.44?0.78, P<0.05). (6) Construction of nomogram prediction model and calibration curve. Based on the multivariate analysis of prognosis in patients of the training dataset ,the nomogram prediction model for the prognosis of patients with esophageal cancer after neoadju-vant treatment was constructed based on the indicators of gender, ypT staging, ypN staging and number of NLNs. The AUC of nomogram prediction model in predicting the 3-, 5-year cumulative survival rate of patients in the training dataset and the validation dataset was 0.70, 0. 70 and 0.71, 0.71, respectively. The Harrell′s c index of nomogram prediction model of patients in the training dataset and the validation dataset was 0.66 and 0.63, respectively. Results of calibration curve showed that the predicted value of the nomogram prediction model of patients in the training dataset and the validation dataset was in good agreement with the actual observed value. Conclusion:The number of NLNs is an independent influencing factor for the prognosis of esophageal cancer patients after neoadjuvant therapy, and the nomogram prediction model based on number of NLNs can predict the prognosis of esophageal cancer patients after neoadjuvant therapy.
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Objective:To explore the clinical effect of the modified Quaba flap on reconstruction of the soft tissue defects in distal hand and foot.Methods:From August 2013 to March 2022, 36 cases of soft tissue defect in distal hand and foot were reconstructed by the modified Quaba flap in the Department of Microrepair and Reconstruction of Orthopaedic Centre, the First Affiliated Hospital of Xinjiang Medical University. There were 24 males and 12 females, aged 18 to 58 years old with an average age of 35.6 years old. The sizes of defect were 1.5 cm × 0.5 cm - 5.0 cm × 3.0 cm, including 28 in hand and 8 in foot. Of the defects, 26 were traumatic soft tissue defects, 5 were chronic hand infection and 5 were after resection of hand tumour. The sizes of flap employed were 5.0 cm × 1.5 cm - 10.0 cm × 6.5 cm. Method of optimization included: (1) Extended the paddle of propeller flap or made the rotation point being further; (2) Determined the perforator vessel that entered the pedicle, and made the perforating point as the location of rotation hence to maximise a blood flow; (3) Improved the pedicle mobility and reduced the angle of rotation of the flap; (4) The superficial vein in the pedicle was retained in the modified Quaba flap; (5) Properly retained the fascia tissue of the pedicle; (6) "Skinned-tail" design for the pedicle. All patients entered scheduled follow-up reviews at outpatient clinic and by telephone or WeChat interviews. Colour, texture, wound healing, complications at donor site and hand function were evaluated.Results:All flaps survived. The donor sites were directly closed in 27 patients, and skin grafts were applied in 9 patients. All patients were entered postoperative follow-up for 3-36(mean 24) months. All flaps had good colour and texture but with poor sensation. Wounds healed at the first attention. Hand functions(28 cases) were evaluated according to the Evaluation Trial Standards of Upper Limb Partial Functional of Hand Surgery of Chinese Medical Association. Hand function appeared excellent in 23 patients, good in 3 and fair in 2, with an excellent and good rate at 92.9%. Motion of all metacarpophalangeal joints were satisfactory. Flexion of metacarpophalangeal joints ranged from 65° to 90°, with an average of 80°. Dorsal extension ranged from 0° to 20° (mean 8°), without obvious joint pain. Foot functions(8 cases) were evaluated according to hallux metatarsophalangeal-interphalangeal scale of the American Orthopaedic Foot and Ankle Society (AOFAS), 6 patients were in excellent and 2 in good.Conclusion:Modified Quaba flap is easy to harvest and with stable and reliable blood circulation. The optimised methods can extend the length of the paddle of the flap and shorten the rotation point. They are very effective methods in reconstruction of the soft tissue defect in distal hand and foot.
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Objective:To explore the clinical effect of keystone flap (KF) on repair of soft tissue defects at the donor site after flap transfer.Methods:From October 2020 to December 2022, in the Department of Microsurgical Rapair of First Affiliated Hospital of Xinjiang Medical University, 12 patients were repaired with KF after transfer of flaps. There were 3 donor sites for lateral thigh myocutaneous flap, 3 for sural nerve nutrient vascular flap, 4 for latissimus dorsi myocutaneous flap and 2 for medial supramalleolar island flap. Size of the KF was 15.0 cm × 12.0 cm-30.0 cm × 20.0 cm. Types of KF were: 3 of type I, 5 of type IIA, 2 of type IIB and 2 of type Sydney Melanoma Unit (SMU) modification KF design. Four patients were reviewed by telephone follow-up, 5 by WeChat and 3 with outpatient clinic visits to observe the appearance of the transferred KF and postoperative complications. Appearance of flaps was scored and analysed using Vancouver Scar Scale (VSS) and Scar Cosmesis Assessment and Rating (SCAR) .Results:The average follow-up period was 15.9 (2-27) months. The colour and texture of the transferred KF were similar to that of the surrounding skin, together with good sensation recovery. No complication such as osteofascial compartment syndrome, necrosis, wound dehiscence and venous congestion occurred in all patients. At the final follow-up, the scores for VSS was 2.17±0.58 and the score for SCAR was 5.33±1.23, with satisfactory repairing outcomes.Conclusion:As a relay flap, the KF is a simple and effective flap for reconstruction of the defects at the donor site and it can avoid complications that can be caused by direct closure of the soft tissue defect or a wound dehiscence after skin grafting.
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This study aimed to systematically evaluate the efficacy and safety of different Chinese medicine injections combined with conventional western medicine for stable angina pectoris. PubMed, Cochrane Library, EMbase, Web of Science, CNKI, Wanfang, VIP, and SinoMed were searched to collect randomized controlled trial(RCT) of Chinese medicine injection combined with conventio-nal western medicine in the treatment of stable angina pectoris from the inception of the databases to July 8, 2022. Two researchers independently screened the literature, extracted the data, and evaluated the risk of bias of the included studies. Stata 15.1 was used for network Meta-analysis. A total of 52 RCTs were included, involving 4 828 patients treated by 9 Chinese medicine injections(Danhong Injection, Salvia Miltiorrhiza Polyphenol Hydrochloride Injection, Tanshinone Sodium Ⅱ_A Sulfonate Injection, Salvia Miltiorrhiza Ligustrazine Injection, Dazhu Hongjingtian Injection, Puerarin Injection, Safflower Yellow Pigment Injection, Shenmai Injection and Xuesaitong Injection). The network Meta-analysis showed that:(1)in terms of improving the efficacy of angina pectoris, the surface under the cumulative ranking curve(SUCRA) followed the order of conventional western medicine combined with Salvia Miltiorrhiza Ligustrazine Injection>Tanshinone Sodium Ⅱ_A Sulfonate Injection>Danhong Injection>Salvia Miltiorrhiza Polyphenol Hydrochloride Injection>Xuesaitong Injection>Shenmai Injection>Puerarin Injection>Safflower Yellow Pigment Injection>Dazhu Hongjingtian Injection;(2)in terms of improving the efficacy of electrocardiogram(ECG), SUCRA followed the order of conventional western medicine combined with Salvia Miltiorrhiza Ligustrazine Injection>Puerarin Injection>Danhong Injection>Salvia Miltiorrhiza Polyphenol Hydrochloride Injection>Shenmai Injection>Xuesaitong Injection>Safflower Yellow Pigment Injection>Tanshinone Sodium Ⅱ_A Sulfonate Injection>Dazhu Hongjingtian Injection;(3)in terms of increasing high-density lipoprotein cholesterol(HDL-C), SUCRA followed the order of conventional western medicine combined with Danhong Injection>Shenmai Injection>Safflower Yellow Pigment Injection>Xuesaitong Injection>Tanshinone Sodium Ⅱ_A Sulfonate Injection>Dazhu Hongjingtian Injection;(4)in terms of lowering low-density lipoprotein cholesterol(LDL-C), SUCRA followed the order of conventional western medicine combined with Safflower Yellow Pigment Injection>Danhong Injection>Shenmai Injection>Tanshinone Sodium Ⅱ_A Sulfonate Injection>Dazhu Hongjingtian Injection>Xuesaitong Injection;(5)in terms of safety, the overall adverse reactions of Chinese medicine injection combined with conventional western medicine were less than those of the control group. Current evidence indicated that Chinese medicine injection combined with conventional western medicine could improve the curative effect of stable angina pectoris with higher safety. Limited by the number and quality of included studies, the above conclusion needed to be verified by more high-quality studies.
Subject(s)
Humans , Angina, Stable/drug therapy , Medicine, Chinese Traditional , Network Meta-Analysis , Drugs, Chinese Herbal , Salvia miltiorrhiza , CholesterolABSTRACT
Adaptions to therapeutic pressures exerted on cancer cells enable malignant progression of the tumor, culminating in escape from programmed cell death and development of resistant diseases. A common form of cancer adaptation is non-genetic alterations that exploit mechanisms already present in cancer cells and do not require genetic modifications that can also lead to resistance mechanisms. Epithelial-to-mesenchymal transition (EMT) is one of the most prevalent mechanisms of adaptive drug resistance and resulting cancer treatment failure, driven by epigenetic reprogramming and EMT-specific transcription factors. A recent breakthrough in cancer treatment is the development of KRASG12C inhibitors, which herald a new era of therapy by knocking out a unique substitution of an oncogenic driver. However, these highly selective agents targeting KRASG12C, such as FDA-approved sotorasib (AMG510) and adagrasib (MRTX849), inevitably encounter multiple mechanisms of drug resistance. In addition to EMT, cancer cells can hijack or rewire the sophisticated signaling networks that physiologically control cell proliferation, growth, and differentiation to promote malignant cancer cell phenotypes, suggesting that inhibition of multiple interconnected signaling pathways may be required to block tumor progression on KRASG12C inhibitor therapy. Furthermore, the tumor microenvironment (TME) of cancer cells, such as tumor-infiltrating lymphocytes (TILs), contribute significantly to immune escape and tumor progression, suggesting a therapeutic approach that targets not only cancer cells but also the TME. Deciphering and targeting cancer adaptions promises mechanistic insights into tumor pathobiology and improved clinical management of KRASG12C-mutant cancer. This review presents recent advances in non-genetic adaptations leading to resistance to KRASG12C inhibitors, with a focus on oncogenic pathway rewiring, TME, and EMT.
ABSTRACT
The histone H3 lysine 36 (H3K36) methyltransferase NSD3, a neighboring gene of FGFR1, has been identified as a critical genetic driver of lung squamous cell carcinoma (LUSC). However, the molecular characteristics, especially the immunological roles of NSD3 in driving carcinogenesis, are poorly understood. In this study, we systematically integrated multi-omics data (e.g., genome, transcriptome, proteome, and TMA array) to dissect the immunological profiles in NSD3-amplified LUSC. Next, pharmaco-transcriptomic correlation analysis was implemented to identify the molecular underpinnings and therapeutic vulnerabilities in LUSC. We revealed that NSD3-amplified LUSC presents a non-inflamed tumor immune microenvironment (TIME) state in multiple independent LUSC patient cohorts. Predictably, elevated NSD3 expression was correlated with a worse immunotherapy outcome. Further molecular characterizations revealed that the high activity of unfolded protein response (UPR) signaling might be a pivotal mediator for the non-immunogenic phenotype of NSD3-amplified LUSC. Concordantly, we showed that NSD3-amplified LUSCs exhibited a more sensitive phenotype to compounds targeting UPR branches than the wild-type group. In brief, our multi-level analyses point to a previously unappreciated immunological role for NSD3 and provide therapeutic rationales for NSD3-amplified squamous lung cancer.
ABSTRACT
Malignant pleural mesothelioma (MPM) is a rare but aggressive thoracic malignancy with limited treatment options. One of the standard treatments for MPM is chemotherapy, which consists of concurrent treatment with pemetrexed and cisplatin. Pemetrexed limits tumor growth by inhibiting critical metabolic enzymes involved in nucleotide synthesis. Cisplatin causes direct DNA damage, such as intra-strand and inter-strand cross-links, which are repaired by the nucleotide excision repair pathway, which depends on relatively high nucleotide levels. We hypothesized that prolonged pretreatment with pemetrexed might deplete nucleotide pools, thereby sensitizing cancer cells to subsequent cisplatin treatment. The MPM cell lines ACC-MESO-1 and NCI-H28 were treated for 72 h with pemetrexed. Three treatment schedules were evaluated by initiating 24 h of cisplatin treatment at 0 h (concomitant), 24 h, and 48 h relative to pemetrexed treatment, resulting in either concomitant administration or pemetrexed pretreatment for 24 h or 48 h, respectively. Multicolor flow cytometry was performed to detect γH2AX (phosphorylation of histone H2AX), a surrogate marker for the activation of the DNA damage response pathway. DAPI staining of DNA was used to analyze cell cycle distribution. Forward and side scatter intensity was used to distinguish subpopulations based on cellular size and granularity, respectively. Our study revealed that prolonged pemetrexed pretreatment for 48 h prior to cisplatin significantly reduced long-term cell growth. Specifically, pretreatment for 48 h with pemetrexed induced a cell cycle arrest, mainly in the G2/M phase, accumulation of persistent DNA damage, and induction of a senescence phenotype. The present study demonstrates that optimizing the treatment schedule by pretreatment with pemetrexed increases the efficacy of the pemetrexed-cisplatin combination therapy in MPM. We show that the observed benefits are associated with the persistence of treatment-induced DNA damage. Our study suggests that an adjustment of the treatment schedule could improve the efficacy of the standard chemotherapy regimen for MPM and might improve patient outcomes.
Subject(s)
Lung Neoplasms , Mesothelioma, Malignant , Mesothelioma , Pleural Neoplasms , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cisplatin/pharmacology , Cisplatin/therapeutic use , Histones , Humans , Lung Neoplasms/pathology , Mesothelioma/drug therapy , Mesothelioma/pathology , Nucleotides , Pemetrexed/pharmacology , Pemetrexed/therapeutic use , Pleural Neoplasms/drug therapy , Pleural Neoplasms/pathologyABSTRACT
Poor solubility of wheat gluten proteins (WG) has negative impact on functional attributes such as gelation and emulsification, which limits it use in the food industry. In this study, WG underwent different degrees of phosphorylation using sodium tripolyphosphate (STP). Phosphoric acid groups were successfully incorporated in the WG via covalent bonding (C-N-P and C-O-P) involving hydroxyl and primary amino groups from WG. The introduction of phosphoric acid groups increased the negative charge of phosphorylation-WG, which caused the enhancement of electrostatic repulsion between proteins and reduced the droplet size in emulsions, thereby allowing proteins to be more efficiently dispersed in the solution system. The change of structure induced with phosphorylation improved hydration of protein, making the WG with higher solubility, thereby resulting in the improvement of its emulsification, foaming, thermal stability, and rheological properties. Therefore, WG can be modified by phosphorylation which caused an overall improvement of functional properties, thus facilitating the expansion of WG applications.