ABSTRACT
BACKGROUND: Breast cancer (BC) is the most common malignant disease in female patients worldwide. In HER-2+ BC patients, trastuzumab therapy is associated with a better prognosis. However, many HER-2+ BC patients experience recurrence or metastasis because of trastuzumab resistance. The mechanisms underlying trastuzumab resistance remain unclear. Recently, substantial evidence has suggested that exosomes are associated with drug resistance, and lncRNAs have attracted increasing attention due to their potential role in the regulation of trastuzumab resistance. METHODS: We collected the exosomes from the plasma of BC patients with and without trastuzumab resistance, sequenced the whole transcriptomes, identified differentially expressed lncRNAs, and identified lncRNA Linc00969, which was overexpressed in trastuzumab-resistant patients. Then, we established trastuzumab-resistant BC cell lines and explored the role of exosomal Linc00969 in trastuzumab resistance in vitro and in vivo by silencing or overexpressing Linc00969 and performing a series of functional analyses. Furthermore, to explore the mechanism by which exosomal Linc00969 contributes to trastuzumab resistance, we measured changes in HER-2, HUR and autophagy-related protein expression levels after regulating Linc00969 expression. In addition, we investigated the interaction between Linc00969 and HUR via pull-down and RIP assays and the effect of HUR on HER-2 expression and trastuzumab resistance after blocking HUR. RESULTS: We first found that exosomal lncRNA Linc00969 was overexpressed in trastuzumab-resistant BC patients and that exosome-mediated Linc00969 transfer could disseminate trastuzumab resistance in BC. Then, we found that silencing Linc00969 could reduce trastuzumab resistance and that overexpressing Linc00969 could enhance trastuzumab resistance. Furthermore, our results showed that Linc00969 could upregulate HER-2 expression at the protein level and maintain the stability of HER-2 mRNA by binding to HUR. Additionally, we found that exosomal Linc00969 could regulate trastuzumab resistance by inducing autophagy. CONCLUSIONS: In this study, we first identified that exosomal lncRNA Linc00969 could induce trastuzumab resistance by increasing HER-2 protein expression and mRNA stability by binding to HUR, and Linc00969 might also be involved in trastuzumab resistance by inducing autophagy. Our results elucidate a novel mechanism underlying trastuzumab resistance, and Linc00969 might be a new target for improving the treatment of HER-2+ BC patients.
Subject(s)
Breast Neoplasms , Exosomes , MicroRNAs , RNA, Long Noncoding , Female , Humans , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Line, Tumor , Exosomes/metabolism , MicroRNAs/genetics , RNA Stability , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Trastuzumab/pharmacology , Trastuzumab/therapeutic useABSTRACT
OBJECTIVE: The combination of stereotactic body radiation therapy (SBRT) and immune checkpoint inhibitors (ICIs) is actively being explored in advanced non-small-cell lung cancer (NSCLC) patients. However, little is known about the optimal fractionation and radiotherapy target lesions in this scenario. This study investigated the effect of SBRT on diverse organ lesions and radiotherapy dose fractionation regimens on the prognosis of advanced NSCLC patients receiving ICIs. METHODS: The medical records of advanced NSCLC patients consecutively treated with ICIs and SBRT were retrospectively reviewed at our institution from Dec. 2015 to Sep. 2021. Patients were grouped according to radiation sites. Progression-free survival (PFS) and overall survival (OS) were recorded using the Kaplan-Meier method and compared between different treatment groups using the log-rank (Mantel-Cox) test. RESULTS: A total of 124 advanced NSCLC patients receiving ICIs combined with SBRT were identified in this study. Radiation sites included lung lesions (lung group, n=43), bone metastases (bone group, n=24), and brain metastases (brain group, n=57). Compared with the brain group, the mean PFS (mPFS) in the lung group was significantly prolonged by 13.3 months (8.5 months vs. 21.8 months, HR=0.51, 95%CI: 0.28-0.92, P=0.0195), and that in the bone group prolonged by 9.5 months with a 43% reduction in the risk of disease progression (8.5 months vs. 18.0 months, HR=0.57, 95%CI: 0.29-1.13, P=0.1095). The mPFS in the lung group was prolonged by 3.8 months as compared with that in the bone group. The mean OS (mOS) in the lung and bone groups was longer than that of the brain group, and the risk of death decreased by up to 60% in the lung and bone groups as compared with that of the brain group. When SBRT was concurrently given with ICIs, the mPFS in the lung and brain groups were significantly longer than that of the bone group (29.6 months vs. 16.5 months vs. 12.1 months). When SBRT with 8-12 Gy per fraction was combined with ICIs, the mPFS in the lung group was significantly prolonged as compared with that of the bone and brain groups (25.4 months vs. 15.2 months vs. 12.0 months). Among patients receiving SBRT on lung lesions and brain metastases, the mPFS in the concurrent group was longer than that of the SBRTâICIs group (29.6 months vs. 11.4 months, P=0.0003 and 12.1 months vs. 8.9 months, P=0.2559). Among patients receiving SBRT with <8 Gy and 8-12 Gy per fraction, the mPFS in the concurrent group was also longer than that of the SBRTâICIs group (20.1 months vs. 5.3 months, P=0.0033 and 24.0 months vs. 13.4 months, P=0.1311). The disease control rates of the lung, bone, and brain groups were 90.7%, 83.3%, and 70.1%, respectively. CONCLUSION: The study demonstrated that the addition of SBRT on lung lesions versus bone and brain metastases to ICIs improved the prognosis in advanced NSCLC patients. This improvement was related to the sequence of radiotherapy combined with ICIs and the radiotherapy fractionation regimens. Dose fractionation regimens of 8-12 Gy per fraction and lung lesions as radiotherapy targets might be the appropriate choice for advanced NSCLC patients receiving ICIs combined with SBRT.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Radiosurgery , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/radiotherapy , Lung Neoplasms/drug therapy , Lung Neoplasms/radiotherapy , Immune Checkpoint Inhibitors , Retrospective Studies , Radiosurgery/methodsABSTRACT
Radioresistance is the major factor of glioblastoma multiforme (GBM) treatment failure and relapse. Hypoxia and autophagy are linked to radioresistance and poor prognosis in solid tumors, but mechanisms remain unknown. Thus, we hypothesize that hypoxia may activate autophagy through two critical factors, HIF1A and Beclin-1, resulting in radioresistance of GBM in vitro and in vivo. In this study, we first demonstrated that HIF1A was overexpressed in GBM tissues and predicted a poor prognosis via bioinformatics. Secondly, we determined that hypoxia induced high expression of HIF1A and upregulated levels of Beclin-1 and autophagy, while HIF1A knockdown by shRNA reduced the expression of Beclin-1. Then we revealed the crosstalk and mechanisms of HIF1A-associated-Beclin-1 in three aspects: (a) transcriptional regulation, (b) protein interaction, and (c) HIF1A/BNIP3/Beclin-1 signaling pathway. Furthermore, we confirmed that silencing HIF1A enhanced the radiosensitivity of GBM in vitro and in vivo. Additionally, Beclin-1 suppression by 3-MA could reverse radioresistance induced by HIF1A under hypoxia. In conclusion, we demonstrated that hypoxia triggered autophagy via HIF1A-associated Beclin-1, resulting in radioresistance in GBM. HIF1A knockdown improved GBM radiosensitivity, and silencing Beclin-1 could reverse HIF1A-induced radioresistance under hypoxic conditions. These findings may help us comprehend the molecular underpinnings of hypoxia-induced autophagy and provide a novel perspective and prospective treatment for GBM radiosensitization.
ABSTRACT
Breast cancer is the most common malignant disease in female patients worldwide and can spread to almost every place in the human body, most frequently metastasizing to lymph nodes, bones, lungs, liver and brain. The liver is a common metastatic location for solid cancers as a whole, and it is also the third most common metastatic site for breast cancer. Breast cancer liver metastasis (BCLM) is a complex process. Although the hepatic microenvironment and liver sinusoidal structure are crucial factors for the initial arrest of breast cancer and progression within the liver, the biological basis of BCLM remains to be elucidated. Importantly, further understanding of the interaction between breast cancer cells and hepatic microenvironment in the liver metastasis of breast cancer will suggest ways for the development of effective therapy and prevention strategies for BCLM. In this review, we provide an overview of the recent advances in the understanding of the molecular mechanisms of the hepatic microenvironment in BCLM formation and discuss current systemic therapies for treating patients with BCLM as well as potential therapeutic development based on the liver microenvironment-associated signaling proteins governing BCLM.
ABSTRACT
We propose a dual gated recurrent unit neural network based on nonlinear equalizer (dual-GRU NLE) for radio-over-fiber (ROF) communication systems. The dual equalization scheme is mainly based upon GRU algorithm, which can be trained via two steps including I-GRU and Q-GRU. By using the dual-GRU equalizer, 60-Gbps 64-QAM signal generation and transmission over 10-km SMF and 1.2-m wireless link at 81-GHz can be achieved. For the digital signal processing (DSP) at receiver, comparison between CMMA equalizer, Volterra equalizer, and dual-GRU equalizer are demonstrated. The results indicate that the proposed dual-GRU NLE significantly mitigates the nonlinear distortions. The dual-GRU equalizer has a better BER performance in receiver sensitivity than the traditional CMMA and Volterra equalizer. At the expense of large complexity, an improvement of receiver sensitivity can be achieved as much as 1 dB compared with Volterra equalizer at the BER of 2×10-2. To the best of our knowledge, this is the first time to propose a novel dual-GRU equalizer, which is promising for the development in millimeter-wave photonics for B5G applications and beyond.
ABSTRACT
Breast cancer (BC) is the most common cancer in females and BC brain metastasis (BCBM) is considered as the second most frequent brain metastasis. Although the advanced treatment has significantly prolonged the survival in BC patients, the prognosis of BCBM is still poor. The management of BCBM remains challenging. Systemic treatments are important to maintain control of central nervous system disease and improve patients' survival. BCBM medical treatment is a rapidly advancing area of research. With the emergence of new targeted drugs, more options are provided for the treatment of BM. This review features currently available BCBM treatment strategies and outlines novel drugs and ongoing clinical trials that may be available in the future. These treatment strategies are discovered to be more efficacious and potent, and present a paradigm shift in the management of BCBMs.
ABSTRACT
BACKGROUND: The COVID-19 pandemic is a significant worldwide health crisis. Breast cancer patients with COVID-19 are fragile and require particular clinical care. This study aimed to identify the clinical characteristics of breast cancer patients with COVID-19 and the risks associated with anti-cancer treatment. METHODS: The medical records of breast cancer patients with laboratory-confirmed COVID-19 were collected among 9559 COVID-19 patients from seven designated hospitals from 13th January to 18th March 2020 in Hubei, China. Univariate and multivariate analyses were performed to assess risk factors for COVID-19 severity. RESULTS: Of the 45 breast cancer patients with COVID-19, 33 (73.3%) developed non-severe COVID-19, while 12 (26.7%) developed severe COVID-19, of which 3 (6.7%) patients died. The median age was 62 years, and 3 (6.7%) patients had stage IV breast cancer. Univariate analysis showed that age over 75 and the Eastern Cooperative Oncology Group (ECOG) score were associated with COVID-19 disease severity (P < 0.05). Multivariate analysis showed that patients who received chemotherapy within 7 days had a significantly higher risk for severe COVID-19 (logistic regression model: RR = 13.886, 95% CI 1.014-190.243, P = 0.049; Cox proportional hazards model: HR = 13.909, 95% CI 1.086-178.150, P = 0.043), with more pronounced neutropenia and higher LDH, CRP and procalcitonin levels than other patients (P < 0.05). CONCLUSIONS: In our breast cancer cohort, the severity of COVID-19 could be associated with baseline factors such as age over 75 and ECOG scores. Chemotherapy within 7 days before symptom onset could be a risk factor for severe COVID-19, reflected by neutropenia and elevated LDH, CRP and procalcitonin levels.
Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , COVID-19/diagnosis , Neutropenia/etiology , SARS-CoV-2/isolation & purification , Aged , Aged, 80 and over , Breast Neoplasms/complications , Breast Neoplasms/mortality , C-Reactive Protein , China/epidemiology , Female , Humans , L-Lactate Dehydrogenase/blood , Middle Aged , Neutropenia/epidemiology , Pandemics , Procalcitonin/blood , Retrospective Studies , Risk Factors , Treatment OutcomeABSTRACT
Granulocytes are key players in cancer metastasis. While tumor-induced de novo expansion of immunosuppressive myeloid-derived suppressor cells (MDSCs) is well-described, the fate and contribution of terminally differentiated mature neutrophils to the metastatic process remain poorly understood. Here, we show that in experimental metastatic cancer models, CXCR4hiCD62Llo aged neutrophils accumulate via disruption of neutrophil circadian homeostasis and direct stimulation of neutrophil aging mediated by angiotensin II. Compared to CXCR4loCD62Lhi naive neutrophils, aged neutrophils more robustly promote tumor migration and support metastasis through the increased release of several metastasis-promoting factors, including neutrophil extracellular traps (NETs), reactive oxygen species, vascular endothelial growth factors, and metalloproteinases (MMP-9). Adoptive transfer of aged neutrophils significantly enhanced metastasis of breast (4T1) and melanoma (B16LS9) cancer cells to the liver, and these effects were predominantly mediated by NETs. Our results highlight that in addition to modulating MDSC production, targeting aged neutrophil clearance and homeostasis may be effective in reducing cancer metastasis.
Subject(s)
Extracellular Traps , Melanoma , Myeloid-Derived Suppressor Cells , Aged , Granulocytes , Humans , L-Selectin , Neutrophils , Receptors, CXCR4ABSTRACT
A novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread across the world, prompting the World Health Organization to declare the coronavirus disease of 2019 (COVID-19) a public health emergency of international concern. Cancer patients are regarded as a highly vulnerable population to SARS-CoV-2 infection and development of more severe COVID-19 symptoms, which is possibly due to the systemic immunosuppressive state caused directly by tumor growth and indirectly by effects of anticancer treatment. Currently, much effort has been directed toward studying the pathogenesis and treatment of COVID-19, but the risk profiles, prognoses, and treatment outcomes in cancer patients remain unclear. Based on the current literature, we summarize the risk profiles, clinical and biochemical characteristics, and therapy outcomes of COVID-19 infections in cancer patients. The challenges in the clinical care of cancer patients with COVID-19 are discussed. The goal of this review is to stimulate research to better understand the biological impact and prognoses of COVID-19 infections in cancer patients, thus facilitating improvement of the clinical management of these patients.
Subject(s)
COVID-19/complications , COVID-19/therapy , Neoplasms/complications , Neoplasms/immunology , Anti-Inflammatory Agents/therapeutic use , Antineoplastic Agents/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/diagnosis , COVID-19/virology , Case-Control Studies , Disease Progression , Female , Humans , Immunization, Passive , Immunocompromised Host/immunology , Immunoglobulins, Intravenous/therapeutic use , Male , Neoplasms/therapy , Neoplasms/virology , Oxygen/therapeutic use , Prognosis , Risk Assessment , Risk Factors , SARS-CoV-2/genetics , Severity of Illness Index , COVID-19 SerotherapyABSTRACT
When liquids flow in the pipelines, the onset of cavitation can be characterized by a variant of the Euler number known as the cavitation number (CN), which is based on the velocity and denoted by C in this paper. Conventionally, cavitation is considered to be induced when C ~ 1. However, experimental observations and several pipe bursts indicate that the CN may incorrectly predict the onset of cavitation. For example, when leakage occurs in the pipeline or a valve in the pipeline is opened, the resultant pressure loss generates a dynamic pressure wave with a small amplitude, which may lead to bubble formation, even though C ~ 1 is not satisfied. Hence, this paper proposes another CN based on the amplitude of the generated dynamic pressure wave, rather than the velocity, for ascertaining the onset of cavitation. The validity of the proposed CN was verified through experiments and a case study. The results indicated that the proposed CN can be effectively used for cavitation prediction induced by pressure fluctuations and for investigating phenomena such as pressure fluctuation, leakage, and corrosion in liquid pipelines, tanks, and pressure vessels, as well as the safety design of liquefied natural gas tanks and tankers.
ABSTRACT
BACKGROUND: The prevalence of gene translocation in some mesenchymal tumors can be used as highly specific molecular diagnostic markers in clinic and pathology. EWSR1 is a partner gene in a large, diverse range of mesenchymal tumors. CASE DESCRIPTION: This paper describes the case of a 31-year-old man who was diagnosed with a primary intracranial mesenchymal tumor with EWSR1-CREM gene fusion and eventually returned to a normal live with no signs of tumor recurrence or metastasis after treatment, including surgery therapy, radiotherapy, and 6 cycles of vincristine-doxorubicin-cyclophosphamide chemotherapy, even though the classification and grade of the tumor are still controversial. CONCLUSIONS: This case is a novel entity of intracranial mesenchymal neoplasm with EWSR1-CREM gene fusion which was confirmed by histopathology, molecular pathology, and next-generation sequencing (NGS). The literature review shows only 5 cases of intracranial tumor harboring EWSR1-CREM gene fusion with similar features. With the further application of molecular pathology and NGS in clinical practice, there will be more intracranial mesenchymal tumor cases with EWSR1-CREM gene fusion found in the future, which may lead to further understanding of the diagnosis and clinical features of this neoplasm.
Subject(s)
Biomarkers, Tumor/genetics , Brain Neoplasms/genetics , Cyclic AMP Response Element Modulator/genetics , Gene Fusion/genetics , RNA-Binding Protein EWS/genetics , Adult , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/therapy , Humans , Male , Mesenchymal Stem Cells/pathologyABSTRACT
Drag reduction performance was studied with a rotating disk instrument in the laboratory, and experiments show that there is an initial rapid growth stage and stability stage for drag reduction ratio change. The higher the rotational speed, the larger the initial drag reduction ratio is; the larger the concentration, the shorter the drag reduction stabilization time is. Under high concentration and high speed, the drag reduction onset time is short. Because of the shear degradation, the Reynolds number should be taken into account during use. Through a comparison of diesel properties after adding agents with national standard, it is confirmed that drag reduction agents could be used in this pipeline.
ABSTRACT
The angiotensin II type I receptor (AGTR1) has a strong influence on tumor growth, angiogenesis, inflammation and immunity. However, the role of AGTR1 on lymph node metastasis (LNM) in breast cancer, which correlates with tumor progression and patient survival, has not been examined. AGTR1 was highly expressed in lymph node-positive tumor tissues, which was confirmed by the Oncomine database. Next, inhibition of AGTR1 reduced tumor growth and LNM in orthotopic xenografts by bioluminescence imaging (BLI). Losartan, an AGTR1-specific inhibitor, decreased the chemokine pair CXCR4/SDF-1α levels invivo and inhibited AGTR1-induced cell migration and invasion invitro. Finally, the molecular mechanism of AGTR1-induced cell migration and LNM was assessed by knocking down AGTR1 in normal cells or CXCR4 in AGTR1high cells. AGTR1-silenced cells treated with losartan showed lower CXCR4 expression. AGTR1 overexpression caused the upregulation of FAK/RhoA signaling molecules, while knocking down CXCR4 in AGTR1high cells downregulated these molecules. Collectively, AGTR1 promotes LNM by increasing the chemokine pair CXCR4/SDF-1α and tumor cell migration and invasion. The potential mechanism of AGTR1-mediated cell movement relies on activating the FAK/RhoA pathway. Our study indicated that inhibiting AGTR1 may be a potential therapeutic target for LNM in early-stage breast cancer.
Subject(s)
Breast Neoplasms/pathology , Chemokine CXCL12/metabolism , Lymph Nodes/pathology , Receptor, Angiotensin, Type 1/metabolism , Receptors, CXCR4/metabolism , Animals , Breast Neoplasms/drug therapy , Cell Movement , Chemokine CXCL12/genetics , Female , Focal Adhesion Protein-Tyrosine Kinases/genetics , Gene Expression Regulation, Neoplastic/drug effects , Humans , Losartan/administration & dosage , Losartan/pharmacology , Lymphatic Metastasis , Mice , Mice, Nude , Middle Aged , Neoplasm Invasiveness , Neoplasms, Experimental , Receptor, Angiotensin, Type 1/genetics , Receptors, CXCR4/genetics , Signal Transduction , Up-Regulation , rhoA GTP-Binding Protein/genetics , rhoA GTP-Binding Protein/metabolismABSTRACT
RATIONALE: Primary cardiac tumors are very rare, and angiosarcoma accounts for about 33% of all primary malignant cardiac tumors. Primary cardiac epithelioid angiosarcoma is a highly aggressive and difficult to diagnose tumor, with early systemic metastasis and poor prognosis. PATIENT CONCERNS: A 35-year-old Han male experienced sudden severe palpitation and moderate dyspnea. The patient received a whole body F-18 fluoro-deoxyglucose positron emission tomography (18F-FDG PET)/computed tomography (CT) scan, the scan showed a large mass in the right atrium (RA) and numerous pulmonary nodules in both lungs. DIAGNOSES: The patient was diagnosed as right atrial epithelioid angiosarcoma with multiple pulmonary metastasis by pulmonary biopsy through CT-guided percutaneous transthoracic fine needle aspiration. INTERVENTIONS: The patient received a cycle of chemotherapy with docetaxel and gemcitabine, followed by another cycle with epirubicin and ifosfamide. OUTCOMES: The chemotherapy was ineffective. After the two cycles, the bilateral pleural effusion steadily increased, the patient had severe dyspnea and palpitation, and died three weeks later, with an overall survival of 2.5 months. LESSONS: Primary angiosarcoma of heart is a very rare and aggressive disease, and its diagnosis and treatment are difficult. Most patients may have systemic metastasis at diagnosis, and have a very short survival without surgical resection. Hence, early diagnosis and surgical resection is extremely important to treat this disease.
Subject(s)
Heart Neoplasms/diagnostic imaging , Hemangioendothelioma, Epithelioid/diagnostic imaging , Hemangiosarcoma/diagnostic imaging , Lung Neoplasms/diagnostic imaging , Lung/diagnostic imaging , Positron Emission Tomography Computed Tomography/methods , Adult , Biopsy/methods , Dyspnea/diagnostic imaging , Dyspnea/etiology , Fluorodeoxyglucose F18 , Heart Atria/diagnostic imaging , Heart Atria/pathology , Heart Neoplasms/complications , Heart Neoplasms/pathology , Hemangioendothelioma, Epithelioid/complications , Hemangioendothelioma, Epithelioid/secondary , Hemangiosarcoma/complications , Hemangiosarcoma/secondary , Humans , Lung/pathology , Lung Neoplasms/complications , Lung Neoplasms/secondary , MaleABSTRACT
RATIONALE: Brain metastasis (BM) is a rising challenge in forward-looking oncology, as its treatment choices are very limited, especially, after the failure of local treatment schemes. PATIENT CONCERNS: We report on a 39-year-old Chinese woman who was diagnosed with stage IV triple-negative breast cancer(TNBC) with multiple brain, lung, and bone metastases. She had previously, undergone whole-brain radiation therapy. Paclitaxel, platinum, UTD1, capecitabine, gemcitabine, vinorelbine, and single-agent apatinib were then administered as first- to fifth-line therapies. She exhibited progression each time after a short period of disease stabilization. DIAGNOSES: Triple-negative breast cancer. INTERVENTIONS: The patient chose treatment with apatinib+CPT-11+S-1 as the sixth-line therapy. OUTCOMES: A remarkable response of the brain, and lung metastases, and alleviation of the brain edema were achieved, and these effects persisted for 7 months. LESSONS: We describe the significant anti-tumor effect of apatinib + CPT-11 + S-1 against BMs from breast cancer. This report is the first to suggest potential approaches to BM treatment using this scheme and describes the effects of an apatinib-containing regimen on BMs.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brain Neoplasms/drug therapy , Brain Neoplasms/secondary , Camptothecin/analogs & derivatives , Oxonic Acid/administration & dosage , Pyridines/administration & dosage , Tegafur/administration & dosage , Triple Negative Breast Neoplasms/drug therapy , Adult , Brain Edema/drug therapy , Brain Edema/pathology , Brain Neoplasms/pathology , Camptothecin/administration & dosage , Disease Progression , Drug Combinations , Female , Humans , Irinotecan , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lung Neoplasms/secondary , Neoplasm Staging , Triple Negative Breast Neoplasms/pathologyABSTRACT
Despite promising in vitro evidence for effective glioblastoma treatment, most drugs are hindered from entering the central nervous system because of the presence of the blood-brain barrier (BBB). Thus, successful modification of drug delivery and novel therapeutic strategies are needed to overcome this obstacle. Extracellular vesicles (EVs), cell-derived membrane-encapsulated structures with diameters ranging from 50 to 1000 nm, have been explored as the drug delivery system to deliver their cargo to the brain tissue. Moreover, tumor targeting and selective drug delivery has been facilitated by engineering their parent cells to secrete modified EVs. However, the method suffers from many shortcomings including poor repeatability and complex and time-consuming operations. In this context, we present an easy-to-adapt and highly versatile methodology to modify EVs with an engineered peptide capable of recognition and eradication of glioma. On the basis of molecular recognition between phospholipids on EV lipid bilayer membranes and ApoA-I mimetic peptides, we have developed methotrexate (MTX)-loaded EVs functionalized with therapeutic [Lys-Leu-Ala (KLA)] and targeted [low-density lipoprotein (LDL)] peptides. In vitro experiments demonstrated that EVs decorated with LDL or KLA-LDL could obviously ameliorate their uptake by human primary glioma cell line U87 and permeation into three-dimensional glioma spheroids in contrast to blank EVs, and consequently, the treatment outcome of the payload is improved. Both ex vivo and in vivo imaging experiments revealed that peptide LDL could obviously promote EV extravasation across the BBB and distribution in the glioma site. Furthermore, compared with the mice administrated with MTX and MTX@EVs, MTX@EVs-KLA-LDL-treated mice showed the longest median survival period. In conclusion, functionalizing with the peptide onto EV surfaces may provide a substantial advancement in the application of EVs for selective target binding as well as therapeutic effects for brain tumor treatment.
Subject(s)
Methotrexate/chemistry , Animals , Cell Line, Tumor , Extracellular Vesicles , Glioblastoma , Humans , Mice , PeptidesABSTRACT
We propose an optical line terminal (OLT)-centralized sampling frequency offset (SFO) compensation scheme for adaptively-modulated OFDM-PON systems. By using the proposed SFO scheme, the phase rotation and inter-symbol interference (ISI) caused by SFOs between OLT and multiple optical network units (ONUs) can be centrally compensated in the OLT, which reduces the complexity of ONUs. Firstly, the optimal fast Fourier transform (FFT) size is identified in the intensity-modulated and direct-detection (IMDD) OFDM system in the presence of SFO. Then, the proposed SFO compensation scheme including phase rotation modulation (PRM) and length-adaptive OFDM frame has been experimentally demonstrated in the downlink transmission of an adaptively modulated optical OFDM with the optimal FFT size. The experimental results show that up to ± 300 ppm SFO can be successfully compensated without introducing any receiver performance penalties.
ABSTRACT
In this paper, we develop a novel transfer latent support vector machine for joint recognition and localization of actions by using Web images and weakly annotated training videos. The model takes training videos which are only annotated with action labels as input for alleviating the laborious and time-consuming manual annotations of action locations. Since the ground-truth of action locations in videos are not available, the locations are modeled as latent variables in our method and are inferred during both training and testing phrases. For the purpose of improving the localization accuracy with some prior information of action locations, we collect a number of Web images which are annotated with both action labels and action locations to learn a discriminative model by enforcing the local similarities between videos and Web images. A structural transformation based on randomized clustering forest is used to map the Web images to videos for handling the heterogeneous features of Web images and videos. Experiments on two public action datasets demonstrate the effectiveness of the proposed model for both action localization and action recognition.
ABSTRACT
In cross-view action recognition, what you saw in one view is different from what you recognize in another view, since the data distribution even the feature space can change from one view to another. In this paper, we address the problem of transferring action models learned in one view (source view) to another different view (target view), where action instances from these two views are represented by heterogeneous features. A novel learning method, called heterogeneous transfer discriminant-analysis of canonical correlations (HTDCC), is proposed to discover a discriminative common feature space for linking source view and target view to transfer knowledge between them. Two projection matrices are learned to, respectively, map data from the source view and the target view into a common feature space via simultaneously minimizing the canonical correlations of interclass training data, maximizing the canonical correlations of intraclass training data, and reducing the data distribution mismatch between the source and target views in the common feature space. In our method, the source view and the target view neither share any common features nor have any corresponding action instances. Moreover, our HTDCC method is capable of handling only a few or even no labeled samples available in the target view, and can also be easily extended to the situation of multiple source views. We additionally propose a weighting learning framework for multiple source views adaptation to effectively leverage action knowledge learned from multiple source views for the recognition task in the target view. Under this framework, different source views are assigned different weights according to their different relevances to the target view. Each weight represents how contributive the corresponding source view is to the target view. Extensive experiments on the IXMAS data set demonstrate the effectiveness of HTDCC on learning the common feature space for heterogeneous cross-view action recognition. In addition, the weighting learning framework can achieve promising results on automatically adapting multiple transferred source-view knowledge to the target view.
ABSTRACT
PURPOSE: The aim of this study was to investigate the association between polymorphic variants of DNA repair genes with the susceptibility of acute oral mucositis (OM) in nasopharyngeal carcinoma (NPC) patients treated with radiotherapy. MATERIALS AND METHODS: The study population consisted of 120 NPC patients treated with intensity-modulated radiation therapy (IMRT). Among them 70 patients also received concurrent chemotherapy. Genotypes in DNA repair genes Ku70 c.-1310C>G (rs2267437), Ku70 c.1781G> T (rs132788), Ku80 c.2099-2408G> A (rs3835), Ku80 c.*841G> A (rs2440) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) c.2888 + 713C> T (rs2213178) were determined by polymerase chain reaction combined with the restriction fragment length polymorphism (PCR-RFLP) technique. Mucositis was scored using the Common Terminology Criteria (CTC) for Adverse Events v.3.0 scale. The population was divided into the CTC0-2 group (CTC toxicity grade 0, 1 and 2) and the CTC3 + group (CTC toxicity grade 3 and above). Odd ratios (OR) and 95% confidence intervals (CI) were calculated using the multivariate logistic regression analysis. RESULTS: A significant difference in Ku70 c.1781G> T genotype distribution was observed between the CTC0-2 and CTC3 + groups for the 120 patients analyzed. The GG carriers were at higher risks for severe OM (CTC3+) compared with the TT homozygotes (OR = 3.000, 95% CI = 1.287-6.994, p = 0.011). No association was found between Ku70 (c.-1310C> G), Ku80 (c.2099-2408G> A, c.*841G> A), DNA-PKcs (c.2888 + 713 C > T) and the development of severe oral mucositis. Stratification analyses for the 50 patients treated with radiation alone further confirmed the association between the variant genotype of GG and severe OM (OR = 5.128, 95% CI = 1.183-22.238, p = 0.029). Concurrent radiochemotherapy increased the risk of severe OM for both the TT homozygotes and GG genotypes. CONCLUSIONS: Our study suggests that the Ku70 c.1781G> T polymorphism may be a susceptibility factor for radiation-induced oral mucositis in Chinese nasopharyngeal carcinoma patients.