Patient-Controlled Subcutaneous Analgesia with Hydromorphone versus Oral Oxycontin for Opioid Titration of Cancer Pain: A Prospective Multicenter Randomized Trial.

Background: Studies have shown that oral oxycontin tablets can be used for opioid titration. The European Society for Medical Oncology (ESMO) guidelines for adult cancer pain recommend opioid titration through the parenteral route, usually the intravenous or subcutaneous route. Patient-controlled subcutaneous analgesia (PCSA) with hydromorphone needs further evaluation for opioid titration. This prospective multicenter study was designed to compare the efficacy and safety of hydromorphone PCSA with oral oxycontin tablets for opioid titration of cancer pain. Patients and Methods: Eligible patients with cancer pain were randomly assigned in a 1:1 ratio to the PCSA group or the oxycontin group for dose titration. Different titration methods were given in both groups depending on whether the patient had an opioid tolerance. The primary endpoint of this study was time to successful titration (TST). Results: A total of 256 patients completed this study. The PCSA group had a significantly lower TST compared with the oxycontin group (median [95% confidence interval (CI)], 5.5[95% CI:2.5-11.5] hours vs.16.0 [95% CI:11.5-22.5] hours; p<0.001). The frequency (median; interquartile) of breakthrough pain (Btp) over 24 hours was significantly lower in the PCSA group (2.5;2.0-3.5) than in the oxycontin group.(3.0; 2.5-4.5) (p=0.04). The pain was evaluated by numeric rating scale (NRS) score at 12 hours after the start of titration. The pain score (median; interquartile) was significantly lower in the PCSA versus the oxycontin group (2.5;1.5-3.0) vs 4.5;3.0-6.0) (p=0.02). The equivalent dose of oral morphine (EDOM) for a successful titration was similar in both groups (p=0.29), but there was a significant improvement in quality of life (QoL) in both groups (p=0.03). No between-group difference in the incidence of opioid-related adverse effects was observed (p=0.32). Conclusion: Compared with oral oxycontin tablet, the use of PCSA with hydromorphone achieved a shorter titration duration for patients with cancer pain (p<0.001), without significantly increasing adverse events (p=0.32).

Study of cell and drug interactions based on dual-mode detection using SPR and fluorescence imaging.

The investigation of the interactions between cells and drugs forms a crucial aspect of biological and clinical medical studies. Generally, single-cell or local-cellular studies require a microscopic imaging system with high magnifications, which suffers from low detection throughputs and poor time responses. The study presented in this paper combined SPR and fluorescence to achieve cell localization, real-time monitoring of cell images and quantitative analysis of drugs. In order to obtain more comprehensive, accurate and real-time data, a dual-mode system based on surface plasmon resonance (SPR) and fluorescence was constructed based on a 4× magnification lens. This enables simultaneous studies of an entire cell and a specific region of the cell membrane. An adaptive adjustment algorithm was established for distorted SPR images, achieving temporal and spatial matching of the dual-mode detection. The combination of SPR and fluorescence not only achieved micro-detection but also complemented the qualitative or quantitative limitations of SPR or fluorescence method alone. In system characterization, the response signal of SPR was noticed to increase with the increasing concentration of EGF in stimulated cells. It indicated that this platform could be employed for quantitative detection of the cell membrane region. Upon addition of EGF, a peak in the SPR curve was observed, and the cells in the corresponding SPR image turned whiter. This indicated that the platform can simultaneously monitor the SPR response signal and image changes. The response time of fluorescence in EGF testing was several seconds earlier than SPR, revealing that signal transduction first occurred in the whole cell and then propagated to the cell membrane region. The inhibitory ability of Gefitinib on cells was verified in a fast and real-time manner within 20 min. The results indicated that the detection limit of this method was 20 IU/mL for EGF and 10 µg/mL for Gefitinib. In conclusion, this study demonstrates the advantages of SPR and fluorescence dual-mode techniques in the analysis of cell-drug interactions, as well as their strong potential in drug screening.

FPGA-based Lightweight QDS-CNN System for sEMG Gesture and Force Level Recognition.

Deep learning (DL) has been used for electromyographic (EMG) signal recognition and achieved high accuracy for multiple classification tasks. However, implementation in resource-constrained prostheses and human-computer interaction devices remains challenging. To overcome these problems, this paper implemented a low-power system for EMG gesture and force level recognition using Zynq architecture. Firstly, a lightweight network model structure was proposed by Ultra-lightweight depth separable convolution (UL-DSC) and channel attention-global average pooling (CA-GAP) to reduce the computational complexity while maintaining accuracy. A wearable EMG acquisition device for real-time data acquisition was subsequently developed with size of 36mm×28mm×4mm. Finally, a highly parallelized dedicated hardware accelerator architecture was designed for inference computation. 18 gestures were tested, including force levels from 22 healthy subjects. The results indicate that the average accuracy rate was 94.92% for a model with 5.0k parameters and a size of 0.026MB. Specifically, the average recognition accuracy for static and force-level gestures was 98.47% and 89.92%, respectively. The proposed hardware accelerator architecture was deployed with 8-bit precision, a single-frame signal inference time of 41.9µs, a power consumption of 0.317W, and a data throughput of 78.6 GOP/s.

Efficacy of hyperthermic intrathoracic chemotherapy for initially diagnosed lung cancer with symptomatic malignant pleural effusion.

Initially diagnosed malignant pleural effusion (MPE) has different systematic treatments, and defining the best drainage regimen according to the responsiveness of MPE to different systematic treatments is important. This study compared the efficacy of hyperthermic intrathoracic chemotherapy (HITHOC) and pleural catheter drainage (IPCD) for initially diagnosed lung cancer with symptomatic MPE. We retrospectively reviewed the medical records of initially diagnosed lung cancer patients with symptomatic MPE between January 2018 and May 2022. The patients were treated with IPCD or HITHOC for local control of MPE after diagnosis. Systematic regimens were conducted during 1 month according to guidelines after local treatment. Intrathoracic MPE progression-free survival (iPFS) and overall survival (OS) were calculated, Univariate and multivariable Cox-regression were used to identify factors associated with iPFS and OS. A total of 33 patients were evaluated; 10 (30.3%) patients received IPCD, and 23 (69.7%) patients received HITHOC. No difference in the MPE control rate at 1 month was found between the IPCD group (90%) and HITHOC group (95.7%). However, this control rate was significantly higher in the HITHOC group (69.6%) than in the IPCD group (30%) at 3 months (P = 0.035). Multivariate analysis showed that receiving tyrosine kinase inhibitors (TKIs) or chemotherapy was a significant protective factor for iPFS (HR = 0.376, 95% CI 0.214-0.659, P = 0.007) and OS (HR = 0.321, 95% CI 0.174-0.594, P < 0.001). According to subgroup analysis, among patients treated with TKIs, those who received HITHOC had longer iPFS and OS than those who received IPCD (P = 0.011 and P = 0.002, respectively), but this difference was not found in the palliative care subgroup. Moreover, no patients treated with chemotherapy showed reaccumulation of MPE. Systematic TKIs or chemotherapy prolonged iPFS and OS for those initially diagnosed with lung cancer with symptomatic MPE. HITHOC prolonged iPFS and OS for those treated with systematic TKIs.

Cu-doped SnO2/rGO nanocomposites for ultrasensitive H2S detection at low temperature.

Hydrogen sulfide (H2S) detection remains a significant concern and the sensitivity, selectivity, and detection limit must be balanced at low temperatures. Herein, we utilized a facile solvothermal method to prepare Cu-doped SnO2/rGO nanocomposites that have emerged as promising candidate materials for H2S sensors. Characterization of the Cu-SnO2/rGO was carried out to determine its surface morphology, chemical composition, and crystal defects. The optimal sensor response for 10 ppm H2S was ~1415.7 at 120 °C, which was over 320 times higher than that seen for pristine SnO2 CQDs (Ra/Rg = 4.4) at 280 °C. Moreover, the sensor material exhibited excellent selectivity, a superior linear working range (R2 = 0.991, 1-150 ppm), a fast response time (31 s to 2 ppm), and ppb-level H2S detection (Ra/Rg = 1.26 to 50 ppb) at 120 °C. In addition, the sensor maintained a high performance even at extremely high humidity (90%) and showed outstanding long-term stability. These superb H2S sensing properties were attributed to catalytic sensitization by the Cu dopant and a synergistic effect of the Cu-SnO2 and rGO, which offered abundant active sites for O2 and H2S absorption and accelerated the transfer of electrons/holes.

Recent Advancements in Physiological, Biochemical, and Multimodal Sensors Based on Flexible Substrates: Strategies, Technologies, and Integrations.

Flexible wearable devices have been widely used in biomedical applications, the Internet of Things, and other fields, attracting the attention of many researchers. The physiological and biochemical information on the human body reflects various health states, providing essential data for human health examination and personalized medical treatment. Meanwhile, physiological and biochemical information reveals the moving state and position of the human body, and it is the data basis for realizing human-computer interactions. Flexible wearable physiological and biochemical sensors provide real-time, human-friendly monitoring because of their light weight, wearability, and high flexibility. This paper reviews the latest advancements, strategies, and technologies of flexibly wearable physiological and biochemical sensors (pressure, strain, humidity, saliva, sweat, and tears). Next, we systematically summarize the integration principles of flexible physiological and biochemical sensors with the current research progress. Finally, important directions and challenges of physiological, biochemical, and multimodal sensors are proposed to realize their potential applications for human movement, health monitoring, and personalized medicine.

Pd/Pt-Bimetallic-Nanoparticle-Doped In2O3 Hollow Microspheres for Rapid and Sensitive H2S Sensing at Low Temperature.

H2S is a poisonous gas that is widespread in nature and human activities. Its rapid and sensitive detection is essential to prevent it from damaging health. Herein, we report Pd- and Pt-bimetallic-nanoparticle-doped In2O3 hollow microspheres that are synthesized using solvothermal and in situ reduction methods for H2S detection. The structure of as-synthesized 1 at% Pd/Pt-In2O3 comprises porous hollow microspheres assembled from In2O3 nanosheets with Pd and Pt bimetallic nanoparticles loaded on its surface. The response of 1 at% Pd/Pt-In2O3 to 5 ppm H2S is 140 (70 times that of pure In2O3), and the response time is 3 s at a low temperature of 50 °C. In addition, it can detect trace H2S (as low as 50 ppb) and has superior selectivity and an excellent anti-interference ability. These outstanding gas-sensing performances of 1 at% Pd/Pt-In2O3 are attributed to the chemical sensitization of Pt, the electronic sensitization of Pd, and the synergistic effect between them. This work supplements the research of In2O3-based H2S sensors and proves that Pd- and Pt-bimetallic-doped In2O3 can be applied in the detection of H2S.

Multichannel Flexible Pulse Perception Array for Intelligent Disease Diagnosis System.

Pressure sensors with high sensitivity, a wide linear range, and a quick response time are critical for building an intelligent disease diagnosis system that directly detects and recognizes pulse signals for medical and health applications. However, conventional pressure sensors have limited sensitivity and nonideal response ranges. We proposed a multichannel flexible pulse perception array based on polyimide/multiwalled carbon nanotube-polydimethylsiloxane nanocomposite/polyimide (PI/MPN/PI) sandwich-structure pressure sensor that can be applied for remote disease diagnosis. Furthermore, we established a mechanical model at the molecular level and guided the preparation of MPN. At the structural level, we achieved high sensitivity (35.02 kPa-1) and a broad response range (0-18 kPa) based on a pyramid-like bilayer microstructure with different upper and lower surfaces. A 27-channel (3 × 9) high-density sensor array was integrated at the device level, which can extract the spatial and temporal distribution information on a pulse. Furthermore, two intelligent algorithms were developed for extracting six-dimensional pulse information and automatic pulse recognition (the recognition rate reaches 97.8%). The results indicate that intelligent disease diagnosis systems have great potential applications in wearable healthcare devices.

Efficacy and safety of osimertinib for patients with EGFR-mutated NSCLC: a systematic review and meta-analysis of randomized controlled studies.

BACKGROUND: Osimertinib is a recently approved third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR-T790M resistance mutations. The aim of the present meta-analysis was to investigate the efficacy and safety of osimertinib for patients with EGFR-mutated non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Databases were searched for randomized controlled studies that reported the efficacy and safety of osimertinib versus other treatments (chemotherapy, other EGFR-TKIs, etc.) in treating EGFR-mutated NSCLC. The measured effects included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), central nervous system progression-free survival (CNS-PFS), and overall survival (OS). Additional outcome was the incidence of adverse event. Relative risk (RR) for incidence and hazard ratio (HR) for survival outcomes were pooled. RESULTS: Seven studies containing 3335 participants were finally included. Osimertinib tended to improve ORR and DCR (RRs >1) as compared with other treatments. Osimertinib was also a significant protective factor for PFS, CNS-PFS, and OS (HRs <1 and p < .05). Osimertinib showed similar advantages in improving tumor response and patient survival when used as first-line, second-line, and third-line/adjuvant therapy, respectively, as compared with other treatments (RRs >1 for ORR and DCR; HRs <1 for PFS, CNS-PFS, and OS). Osimertinib also had better therapeutic effects as compared with chemotherapy, other EGFR TKIs, docetaxel + bevacizumab, and placebo, respectively. The five most common adverse events with pooled incidence > 20% were diarrhea, rash, nail effects, dry skin, and stomatitis, yet the pooled incidence of serious adverse events was less than 2%. CONCLUSIONS: This meta-analysis suggests that osimertinib has a positive effect in disease control and survival for patients with EGFR-mutated NSCLC with acceptable toxicities.

Facile Hydrothermal Synthesis of SnO2 Nanoflowers for Low-Concentration Formaldehyde Detection.

In this work, SnO2 nanoflowers were prepared by a simple one-step hydrothermal process. The morphology and structure of SnO2 nanoflowers were characterized by SEM, TEM, Raman spectroscopy, and XRD, which demonstrated the good crystallinity of the SnO2 tetrahedron structure of the as-synthesized materials. In addition, the sensing properties of SnO2 nanoflowers were studied in detail. It was found that the SnO2 nanoflower-based gas sensor exhibits excellent gas response (9.2 to 120 ppm), fast response and recovery (2/15 s to 6 ppm), good linearity of correlation between response (S) vs. concentration (C) (lgS = 0.505 lgC - 0.147, R2 = 0.9863), superb repeatability, and selectivity at 300 °C. The outstanding performance can also be attributed to the high specific surface area ratio and size of SnO2 nanoflowers close to the thickness of the electron depletion layer that can provide abundant active sites, promote the rate of interaction, and make it easier for gas molecules to diffuse into the interior of the material. Therefore, SnO2 nanoflowers can be an ideal sensing material for real-time monitoring of low-concentration HCHO.

A compact gas chromatography platform for detection of multicomponent volatile organic compounds biomarkers.

Some human exhaled volatile organic compounds (VOCs) can be employed to diagnose related human endogenous diseases as characteristic biomarkers, which is expected to be applied to rapid screening and grading because of their non-invasive and cost-effective advantages. In this study, we developed a compact gas chromatography (GC) platform mainly composed of an integrated silicon-based micro-column chip using micro-electromechanical system techniques and a miniaturized metal oxide semiconductor gas detector. In addition, the sampling/switching valve with related components and embedded microcontrollers was used for airflow control. The fabricated system selectively detected the five VOCs (pentane, acetone, toluene, octane, and decane) considered the typical endogenous disease biomarkers. In the experiments, the functional parameters of the system were investigated, and the optimum temperature conditions of the system for separation were determined. The results show that the system can successfully test the studied five VOCs as low as 1 ppm. In addition, the influence of interfering gas (carbon dioxide and ammonia) on the system for the VOC mixture is also investigated. Moreover, to prove the possibility of breath analysis of the fabricated system, the detection performance of isoprene and acetone at the ppb level is studied. Then, the concentration changes of the isoprene at the ppb concentration for human breath are successfully detected in the system. Therefore, we believe that the prepared compact GC system has potential applications in the human endogenous disease diagnosis for the VOC biomarkers.

Evaluation of Typical Volatile Organic Compounds Levels in New Vehicles under Static and Driving Conditions.

In modern societies, the air quality in vehicles has received extensive attention because a lot of time is spent within the indoor air compartment of vehicles. In order to further understand the level of air quality under different conditions in new vehicles, the vehicle interior air quality (VIAQ) in new vehicles with three different brands was investigated under static and driving conditions, respectively. Air sampling and analysis are conducted under the requirement of HJ/T 400-2007. Static vehicle tests demonstrate that with the increasing of vehicle interior air temperature in sunshine conditions, a higher concentration and different types of volatile organic compounds (VOCs) release from the interior materials than that in the environment test chamber, including alkanes, alcohols, ketones, benzenes, alkenes, aldehydes, esters and naphthalene. Driving vehicle tests demonstrate that the concentration of VOCs and total VOCs (TVOC) inside vehicles exposed to high temperatures will be reduced to the same level as that in the environment test chamber after a period of driving. The air pollutants mainly include alkanes and aromatic hydrocarbons. However, the change trends of VOCs and TVOC vary under different conditions according to various kinds of factors, such as vehicle model, driving speed, air exchange rate, temperature, and types of substance with different boiling points inside the vehicles.

Ultralow detection limit and ultrafast response/recovery of the H2 gas sensor based on Pd-doped rGO/ZnO-SnO2 from hydrothermal synthesis.

Hydrogen (H2) sensors are of great significance in hydrogen energy development and hydrogen safety monitoring. However, achieving fast and effective detection of low concentrations of hydrogen is a key problem to be solved in hydrogen sensing. In this work, we combined the excellent gas sensing properties of tin(IV) oxide (SnO2) and zinc oxide (ZnO) with the outstanding electrical properties of reduced graphene oxide (rGO) and prepared palladium (Pd)-doped rGO/ZnO-SnO2 nanocomposites by a hydrothermal method. The crystal structure, structural morphology, and elemental composition of the material were characterized by FE-SEM, TEM, XRD, XPS, Raman spectroscopy, and N2 adsorption-desorption. The results showed that the Pd-doped ZnO-SnO2 composites were successfully synthesized and uniformly coated on the surface of the rGO. The hydrogen gas sensing performance of the sensor prepared in this work was investigated, and the results showed that, compared with the pure Pd-doped ZnO-SnO2 sensor, the Pd-doped rGO/ZnO-SnO2 sensor modified with 3 wt% rGO had better hydrogen (H2)-sensing response of 9.4-100 ppm H2 at 380 °C. In addition, this sensor had extremely low time parameters (the response time and recovery time for 100 ppm H2 at 380 °C were 4 s and 8 s, respectively) and an extremely low detection limit (50 ppb). Moreover, the sensor exhibited outstanding repeatability and restoration. According to the analysis of the sensing mechanism of this nanocomposite, the enhanced sensing performance of the Pd-doped rGO/ZnO-SnO2 sensor is mainly due to the heterostructure of rGO, ZnO, and SnO2, the excellent electrical and physical properties of rGO and the synergy between rGO and Pd.

Real-Time Detection of LAMP Products of African Swine Fever Virus Using Fluorescence and Surface Plasmon Resonance Method.

African swine fever (ASF) is a swine disease with a very high fatality rate caused by a complex double-stranded DNA virus. The fluorescence PCR detection method is widely used for virus nucleic acid detection. Surface plasmon resonance (SPR) is a label-free and real-time detection method, unlike the fluorescence PCR detection method. In this research, we detected the loop-mediated isothermal amplification (LAMP) products of the African swine fever virus by using the SPR and fluorescence methods separately and simultaneously. By comparing the positive and negative control results, we found that the SPR response unit is completely different before and after the LAMP process. In addition, the fluorescence results on a chip showed that with an increase in the concentration of the sample, the cycle threshold (CT) value decreased, which is consistent with commercial instruments. Both the decline rate of the SPR response unit and the CT value of the fluorescence realized were used to distinguish the positive control from the negative control and water, which indicates that the SPR method can be combined with fluorescence to detect LAMP products. This research provides a label-free and simple method for detecting LAMP products.

Multi-Dimensional Feature Combination Method for Continuous Blood Pressure Measurement Based on Wrist PPG Sensor.

The cuff-less blood pressure (BP) monitoring method based on photoplethysmo- gram (PPG) makes it possible for long-term BP monitoring to prevent and treat cardiovascular and cerebrovascular events. In this paper, a portable BP prediction system based on feature combination and artificial neural network (ANN) is implemented. The robustness of the model is improved from three aspects. Firstly, an adaptive peak extraction algorithm was used to improve the accuracy of peaks and troughs detection. Secondly, multi-dimensional features were extracted and fused, including three groups of PPG-based features and one group of demographics-based features. Finally, a two-layer feedforward artificial neural networks algorithm was used for regression. Thirty-three subjects distributed in the three BP groups were recruited. The proposed method passed the European Society of Hypertension International Protocol revision 2010 (ESP-IP2). Experimental results show that the proposed method exhibits good accuracy for a diverse population with an estimation error of -0.07 ± 4.47 mmHg for SBP and 0.00 ± 3.61 mmHg for DBP. Moreover, the model tracked the BP of two subjects for half a month, laying the foundation work for daily BP monitoring. This work will contribute to the long-term wellness management and rehabilitation process, enabling timely detection and improvement of the user's physical health.

Effectiveness and safety of chemotherapy combined with immunomodulatory therapies for multiple myeloma: A protocol for systematic review and meta-analysis.

BACKGROUND: Multiple myeloma (MM) is considered one of the prevalent malignant plasma cell diseases affecting people. In essence, maintenance treatment is valuable for prolonging the survival time of patients experiencing MM. The majority of the currently used treatment protocols for MM are founded on a combination of chemotherapy and immunomodulatory drugs, of which immunomodulatory drugs seems to be one of the most active drugs. However, in the literature, chemotherapy combined with immunomodulatory therapies have not been unambiguously proven. To systematically appraise and synthesize these results, the present investigation will evaluate whether combining chemotherapy with immunomodulatory therapies an effective and safe approach to treating patients with MM. METHODS: Two authors relied in 7 different databases: PubMed, EMBASE, Cochrane Library, Web of Science, WanFang Database, Chinese Biomedical Literature Database, China National Knowledge Infrastructure and for studies on chemotherapy's effectiveness when combined with immunomodulatory therapies. The authors only considered studies published up to December 16, 2021 and only those written in English or Chinese. They will also carry out selection of studies, extraction of data, along with assessing risk of bias. Besides, they will also use RevMan V.5.3 to conduct data synthesis. They will establish heterogeneity using the I2 test. At the same time, the authors will evaluate publication bias by making a funnel plot and conducting the Begg as well as Egger tests. ETHICS AND DISSEMINATION: The present study will not necessitate ethics approval since it will be funded on already published works. OSF REGISTRATION NUMBER: 10.17605/OSF.IO/X7DE4.

Design and Characterization of a Microfluidic Circuit for Air Particulate Matter Separation.

Air microfluidic circuits have been widely concerned in the separation of atmospheric particulate matter, especially for portable particulate matter separation detection devices. Currently, no systematic approach for the design and optimization of an air-microfluidic system for PM separation has been reported in the literature. In this paper, a two-stage air microfluidic circuit is designed. The design process is divided into two stages: first, the preliminary design of the structure is completed according to aerodynamic theory. Then, the influences of various factors (such as flow channel width, tilt angle, flow rate, etc.) on the collection efficiency and particle wall loss are explored through numerical analysis to complete the optimization design of the structure. Finally, the air microfluidic circuit is prepared by MEMS processing technology and the particulate matter separation experiments are carried out. The developed two-stage air microfluidic circuit can realize the efficient separation of PM10 and PM2.5. Thus, the important factors affecting the collection efficiency and particle wall loss of air microfluidic circuit are clarified, and a systematic design theory method is formed.

Hesperidin delays cell cycle progression into the G0/G1 phase via suspension of MAPK signaling pathway in intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (iCCA) derived from epithelial cells of bile ducts is highly aggressive tumor. Hesperidin extracted from citrus fruits is a promising antitumor compound. The purpose of this study is to explore molecular mechanism by which hesperidin affects cholangiocarcinoma progression. Cellular functional experiments were performed and subcutaneous transplant xenograft model was established. Our findings indicated that hesperidin suppressed iCCA cell proliferation in time- and concentration-dependent manners. Hesperidin treatment induced cell cycle arrest at G0/G1 phase, whereas it has no effect on cell apoptosis. Further, data revealed that hesperidin attenuated MEK5 and ERK5 phosphorylation and inhibited ERK5 nuclear localization by reducing MEKK2 activity in MAPK signaling pathway. It could cause alterations in expression of the downstream genes, including CDK4, CDK6 (cell cycle protein kinases), Cyclin D1 (a G1/S checkpoint), P21, and P27 (two G1-checkpoint CDK inhibitors), thereby arresting cell cycle distribution of iCCA cells in the G0/G1 phase. BIX02189 treatment, a specific inhibitor of MEK5, in combination with hesperidin displayed synergistic inhibitory effects on cell cycle arrest and gene expressions. Furthermore, hesperidin administration alone or in combination with MEK5 inhibitor BIX02189 restrained iCCA tumor growth in vivo. Taken together, these results confirmed that hesperidin regulated the expression of cell cycle-related genes by inhibiting the activation of MEKK2/MEK5/ERK5 signaling pathway, inducing iCCA cell cycle arrest at the G0/G1 phase. Our study provides a theoretical foundation and experimental basis for further development of hesperidin as a therapeutic agent for iCCA treatment.

The status of WIF1 methylation in cell-free DNA is associated with the insusceptibility for gefitinib in the treatment of lung cancer.

BACKGROUND: Targeted cancer therapy has shed light on the treatment of tumor, especially for patients with non-small cell lung cancer. However, only a limited portion of NSCLC patients carrying specific mutations showed an ideal drug response. In addition, DNA methylation status showed a great potential for cancer detection and prognosis prediction. METHODS: Bisulfite sequencing was performed to analyze the DNA methylation of WIF1 promoter in cfDNA and tumor tissue samples collected from NSCLC patients. PFS and OS analyses were carried out to evaluate the prognosis of gefitinib treatment in patients with differential levels of WIF1 DNA methylation. Quantitative real-time PCR was used to analyze the expression of WIF1 mRNA, while immunohistochemistry was performed to assess the expression of WIF1 protein. Furthermore, ELISA was carried out to evaluate the WIF1 activity in plasma. RESULTS: The DNA methylation level of WIF1 promoter was lower in the cfDNA of NSCLC patients with a complete or partial response to gefitinib, and NSCLC patients with hypomethylated WIF1 showed better PFS and OS. The DNA methylation of WIF1 promoter in the resected tumor tissues was consistent with WIF1 DNA methylation in cfDNA, indicating that cfDNA was mainly derived from lung cancer tissues. As a result, the expression of WIF1 in tissue samples and the WIF1 activity in plasma was inhibited in patients with hypermethylated WIF1. Moreover, the cell viability of gefitinib-resistant cells was decreased by the suppressed WIF1 methylation in vitro. And the expression level of WIF1 mRNA was higher in gefitinib-resistant cells overexpressing ALKBH5, a known suppressor of WIF1 methylation. CONCLUSION: In summary, the findings of this study demonstrated that the level of WIF1 methylation in cfDNA was associated with the insusceptibility of gefitinib in the treatment of lung cancer.