A real-world study of recombinant human endostatin combined with PD-1/PD-L1 blockade and chemotherapy for patients with advanced non-small cell lung cancer negative for actionable molecular biomarkers.

The ongoing ENPOWER study exploring the efficacy and safety of the recombinant human endostatin (endostar) combined with programmed cell death 1 antibody sintilimab and chemotherapy showed encouraging efficacy and safety in advanced non-squamous non-small cell lung cancer. To evaluate the real-world efficacy and safety of endostar combined with immune checkpoint inhibitor and chemotherapy (EIC) for advanced non-squamous non-small cell lung cancer patients negative for actionable molecular biomarkers (NSCLCnm), patients with advanced NSCLCnm hospitalized to Zhejiang Provincial People's Hospital from January 2020 to December 2022 were screened for eligibility. The included patients were analyzed for the objective response rate (ORR) and disease control rate (DCR). The pre- and posttreatment expression levels of serum tumor associated biomarkers, chemokines and subpopulations of immune cells in peripheral blood were compared. For the 31 patients with advanced NSCLCnm treated with EIC, the median follow-up and treatment cycles were 18.0 months and 4, respectively. The ORR and DCR were 38.7% and 90.3%, respectively. For those who received EIC as first-line treatment, the ORR and DCR were 63.2% and 94.7%, respectively. EIC significantly decreased expression levels of carcinoma antigen 125, carcinoma embryonic antigen and cytokeratin 19 (P<0.05) in patients who were partial remission or stable disease. Among the 31 patients, 27 (87.1%) experienced at least 1 treatment-related adverse events, and 13 (41.9%) had the treatment-related adverse events of grade 3 or higher. No antiangiogenesis-related adverse events were observed. The current study showed that EIC was potentially effective for patients with NSCLCnm, especially when used as first-line therapy, and well tolerated.

Case Report: Life-threatening pancytopenia with tislelizumab followed by cerebral infarction in a patient with lung adenocarcinoma.

Immune checkpoint inhibitors (ICIs) are an integral antitumor therapy for many malignancies. Most patients show very good tolerability to ICIs; however, serious immune-related adverse events (irAEs) with ICIs have been well documented and prevent some patients from continuing ICIs or even become the direct cause of patient death. Cytopenia is a rare irAE but can be life-threatening. Here, we present the case of a 66-year-old male patient with metastatic lung adenocarcinoma who received two doses of chemotherapy + PD-1 antibody tislelizumab and developed pancytopenia after each dose. Although the first episode of pancytopenia resolved with a treatment regimen of granulocyte colony-stimulating factor (G-CSF), thrombopoietin (TPO), and red blood cell and platelet transfusion, the second episode showed extreme resistance to these treatments and improved only after the administration of steroids. His second pancytopenia episode resolved after a long course of treatment with methylprednisolone, G-CSF, TPO, hetrombopag and multiple red blood cell and platelet transfusions. However, he suffered a cerebral infarction when his platelet count was in the normal range and gradually recovered 1 week later. This case highlights the importance of the early recognition and management of hematological irAEs.

CD3 high and FoxP3 - tumor-infiltrating lymphocytes in the invasive margin as a favorable prognostic marker in patients with invasive urothelial carcinoma of the bladder.

Tumor-infiltrating lymphocytes (TILs) have been extensively explored as prognostic biomarkers and cellular immunotherapy methods in cancer patients. However, the prognostic significance of TILs in bladder cancer remains unresolved. We evaluated the prognostic effect of TILs in bladder cancer patients. Sixty-four bladder cancer patients who underwent surgical resection between 2018 and 2020 in Zhejiang Provincial People's Hospital were analyzed in this study. Immunohistochemistry was used to evaluate CD3, CD4, CD8, and FoxP3 expression on TILs in the invasive margin of tumor tissue, and the presence of TIL subsets was correlated with the disease-free survival (DFS) of bladder cancer patients. The relationship between clinical-pathological features and DFS were analyzed. A high level of CD3 + TILs (CD3 high TILs) ( P = 0.027) or negative expression of FoxP3 TILs (FoxP3 - TILs) ( P = 0.016) was significantly related to better DFS in bladder cancer patients. Those with CD3 high FoxP3 - TILs had the best prognosis compared to those with CD3 high FoxP3 + TILs or CD3 low FoxP3 - TILs ( P = 0.0035). Advanced age [HR 4.57, (1.86-11.25); P = 0.001], CD3 low TILs [HR 0.21, (0.06-0.71); P = 0.012], CD8 low TILs [HR 0.34, (0.12-0.94); P = 0.039], and FoxP3 + TILs [HR 10.11 (1.96-52.27); P = 0.006] in the invasive margin were associated with a worse prognosis (DFS) by multivariate analysis. In conclusion, we demonstrated that CD3 high , FoxP3 - , and CD3 high FoxP3 - TILs in the invasive margin were significantly associated with better DFS. CD8 high and CD4 high TILs in the invasive margin tended to predict better DFS in bladder cancer. Patients with CD4 high CD8 high TILs in the invasive margin were likely to have a better prognosis.

A comprehensive review of traditional uses, phytochemistry and pharmacology of Reynoutria genus.

OBJECTIVES: The genus Reynoutria belonging to the family Polygonaceae is widely distributed in the north temperate zone and used in folk medicine. It is administered as a sedative, tonic and digestive, also as a treatment for canities and alopecia. Herein, we reported a review on traditional uses, phytochemistry and pharmacology reported from 1985 up to early 2022. All the information and studies concerning Reynoutria plants were summarized from the library and digital databases (e.g. ScienceDirect, SciFinder, Medline PubMed, Google Scholar, and CNKI). KEY FINDINGS: A total of 185 articles on the genus Reynoutria have been collected. The phytochemical investigations of Reynoutria species revealed the presence of more than 277 chemical components, including stilbenoids, quinones, flavonoids, phenylpropanoids, phospholipids, lactones, phenolics and phenolic acids. Moreover, the compounds isolated from the genus Reynoutria possess a wide spectrum of pharmacology such as anti-atherosclerosis, anti-inflammatory, antioxidative, anticancer, neuroprotective, anti-virus and heart protection. SUMMARY: In this paper, the traditional uses, phytochemistry and pharmacology of genus Reynoutria were reviewed. As a source of traditional folk medicine, the Reynoutria genus have high medicinal value and they are widely used in medicine. Therefore, we hope our review can help genus Reynoutria get better development and utilization.

TM4SF1 promotes glioma malignancy through multiple mechanisms.

Transmembrane-4 L Six Family member 1 (TM4SF1) belongs to a family of integral membrane proteins implicated in cell growth and tumor progression. Glioma is the most common and aggressive malignant brain tumor in adults. In this study, we showed that TM4SF1 was highly expressed in glioma tumor tissues and cell lines. The expression levels of TM4SF1 were negatively correlated with patients' survival rates. Silencing TM4SF1 by RNA interference inhibited the proliferation, migration, and invasion of glioma cells. Moreover, TM4SF1 silencing induced glioma cell cycle arrest and early apoptosis. In contrast, overexpression of TM4SF1 in glioma cells exhibited the opposite effects. Mechanistically, we found that loss of TM4SF1 reduced phospho-ATK, Cyclin D1, Bcl-2, and MMP-9 levels in glioma cells. Taken together, these findings provide novel insights into glioma pathogenesis and suggest that TM4SF1 may represent a novel target for glioma intervention.

Immunotherapy of Cancer by Targeting Regulatory T cells.

Regulatory T (Treg) cells maintain immune homeostasis by inhibiting abnormal/overactive immune responses to both autogenic and nonautogenic antigens. Treg cells play an important role in immune tolerance, autoimmune diseases, infectious diseases, organ transplantation, and tumor diseases. Treg cells have two functional characteristics: T cell anergy and immunosuppression. Treg cells remain immune unresponsive to high concentrations of interleukin-2 and anti-CD3 monoclonal antibodies. In addition, the activation of Treg cells after TCR-mediated signal stimulation inhibits the activation and proliferation of effector T cells. In the process of tumor development, Treg cells accumulate locally in the tumor and lead to tumor escape by inducing anergy and immunosuppression. It is believed that targeted elimination of Treg cells can activate tumor-specific effector T cells and improve the efficiency of cancer immunotherapy. Therefore, inhibition/clearance of Treg cells is a promising strategy for enhancing antitumor immunity. Here, we review studies of cancer immunotherapies targeting Treg cells.

The functions of EZH2 in immune cells: Principles for novel immunotherapies.

Enhancer of zeste homolog 2 (EZH2) is aberrantly expressed or mutated in multiple types of cancer cells and plays an oncogenic role in tumorigenesis and development in most cancers. Results from pilot clinical studies have implied that EZH2 inhibitors have therapeutic potential against some cancers. However, the exact mechanisms by which EZH2 plays oncogenic roles and EZH2 inhibition exerts anticancer effects are incompletely understood. To date, the findings of studies focusing on EZH2 and cancer cells have failed to fully explain the observations in preclinical and clinical studies. Therefore, recent studies about the roles of EZH2 in cancers have shifted from cancer cells to immune cells. The human immune system is a complex network comprising multiple subpopulations of immune cells. Immune cells communicate and interact with cancer cells during cancer development and treatment, dictating the fate of cancer cells. Elucidating the roles of EZH2 in immune cells, especially in cancer patients, promises the identification of novel immunotherapeutic strategies or priming of existing immunotherapies against cancer. Hence, we reviewed the studies focusing on the involvement of EZH2 in various immune cells, aiming to provide ideas for immunotherapies targeting EZH2 in immune cells.

Effect of shoe wearing time and midsole hardness on ground reaction forces, ankle stability and perceived comfort in basketball landing.

This study examined the effect of wearing time on comfort perception and landing biomechanics of basketball shoes with different midsole hardness. Fifteen basketball players performed drop landing and layup first step while wearing shoes of different wearing time (new, 2-, 4-, 6- and 8-week) and hardness (soft, medium and hard). Two-way ANOVA with repeated measures was performed on GRF, ankle kinematic and comfort perception variables. Increased wearing time was associated with poorer force attenuation and comfort perception during landing activities (p < 0.05). The new shoes had significantly smaller forefoot (2- and 4-week) and rearfoot peak GRF impacts (all time conditions) in drop landing and smaller rearfoot peak GRF impact (6- and 8-week) in layup; shoes with 4-week of wearing time had significantly better perceptions of forefoot cushioning, forefoot stability, rearfoot cushioning, rearfoot stability and overall comfort than the new shoes (p < 0.05). Compared with hard shoes, the soft shoes had better rearfoot cushioning but poorer forefoot cushioning (p < 0.05). Shoe hardness and wearing time would play an influential role in GRF and comfort perception, but not in ankle kinematics. Although shoe cushioning performance would decrease even after a short wearing period, the best comfort perception was found at 4-week wearing time.

Anti-cancer effects of curcumin on lung cancer through the inhibition of EZH2 and NOTCH1.

Curcumin is potentially therapeutic for malignant diseases. The mechanisms of this effect might involve a combination of antioxidant, immunomodulatory, proapoptotic, and antiangiogenic activities. However, the exact mechanisms are not fully understood. In the present study, we provided evidences that curcumin suppressed the expression of enhancer of zeste homolog 2 (EZH2) in lung cancer cells both transcriptionally and post-transcriptionally. Curcumin inhibited the expression of EZH2 through microRNA (miR)-let 7c and miR-101. Curcumin decreased the expression of NOTCH1 through the inhibition of EZH2. There was a reciprocal regulation between EZH2 and NOTCH1 in lung cancer cells. These observations suggest that curcumin inhibits lung cancer growth and metastasis at least partly through the inhibition of EZH2 and NOTCH1.

Evidence for transcriptional interference in a dual-luciferase reporter system.

The dual-luciferase reporter assay is widely used for microRNA target identification and the functional validation of predicted targets. To determine whether curcumin regulates expression of the histone methyltransferase enhancer of zeste homolog 2 (EZH2) by targeting its 3'untranslated region (3'UTR), two luciferase reporter systems containing exactly the same sequence of the EZH2 3'UTR were used to perform dual-luciferase reporter assays. Surprisingly, there were certain discrepancies between the luciferase activities derived from these two reporter constructs. We normalized luciferase activity to an internal control to determine the amount of the reporter construct successfully transfected into cells, induced a transcriptional block with flavopiridol, quantified renilla luciferase mRNA levels, and compared the absolute luciferase activity among the different groups. The results suggested that curcumin promoted the transcription of the luciferase genes located downstream of the simian vacuolating virus 40 (SV40) early enhancer/promoter, but not those located downstream of the human cytomegalovirus (CMV) immediate-early or the herpes simplex virus thymidine kinase (HSV-TK) promoters. These results explain the discrepancies between the two luciferase reporter systems. The current study underscores the importance of taking caution when interpreting the results of dual-luciferase reporter assays and provides strategies to overcome the potential pitfall accompanying dual-luciferase reporter systems.

Propofol promotes cell apoptosis via inhibiting HOTAIR mediated mTOR pathway in cervical cancer.

OBJECTIVES: Cervical cancer is one of the most common gynecologic malignant tumors. Propofol has been proposed to play a role of antitumor in various cancers. However, the functions and mechanisms of Propofol in cervical cancer is still not clear. METHODS: In vitro, the different concentrations of propofol were co-incubated with cervical cancer cell lines, including Hela, Caski and C-33A cells respectively. The pcDNA-HOTAIR plasmid was transfected into cells after the treatment of 10 µg/ml propofol. The cell viability and apoptosis were detected by MTT assay and TUNEL method. In vivo, propofol was injected into mice of transplantation tumor with Caski cells or with pcDNA-HOTAIR treated Caski cells. RESULTS: Propofol significantly decreased the cell viability and increased the cell apoptosis in Hela, Caski and C-33A cells, while HOTAIR overexpression promoted cell viability and inhibits cell apoptosis. mTOR/p70S6K protein expression levels were also markedly reduced by propofol but the effects were reversed with pcDNA-HOTAIR. In vivo, propofol inhibited the tumor size but had no inhibition effect in HOTAIR overexpression group. CONCLUSION: Propofol inhibited tumor size, cell viability and promoted cell apoptosis via inhibiting mTOR/p70S6K pathway mediated by HOTAIR in cervical cancer.

Propofol exerts anti-hepatocellular carcinoma by microvesicle-mediated transfer of miR-142-3p from macrophage to cancer cells.

OBJECTIVE: We previously confirmed that propofol directly inhibited the viability, proliferation, and invasiveness of hepatocellular carcinoma cells in vitro. In this study, we investigated the mechanism underlying the anti-HCC effects of propofol. METHODS: In vivo antitumor activity was investigated in tumor-bearing mice following an intraperitoneal injection of propofol, with or without clodrolip. The co-culture system was used to verify that miR-142-3p was transported from macrophages to HCC cells. A miR-142-3p inhibitor was used to down-regulate the expression of miR-142-3p. RESULTS: Propofol drastically inhibited tumor growth in tomor-bearing mice through macrophage activation, and stimulated tumor-associated macrophages (TAMs) to secrete microvesicles (MVs), which delivered miR-142-3p to HCC cells, resulting in the inhibition of HCC cell invasion. In addition, MVs collected from the plasma of the tumor-bearing mice injected with propofol suppressed tumor growth. More importantly, down-regulation of the expression miR-142-3p reversed the effect of propofol on HCC cell migration. CONCLUSIONS: This study reveals a novel role for propofol in the inhibition of HCC through MV-mediated transfer of miR-142-3p from macrophages to cancer cells in vivo.

[The nitrate and temperature impact analysis in the detection of COD by UV spectrum].

Configured standard solution of chemical oxygen demand with potassium hydrogen phthalate was used as experimental subjects, collected ultraviolet absorption spectra of the standard solution in the range of 1,800 mg x L(-1), were collected, and PLS (partial least squares) algorithm was used to establish the correction model of different spectral region, the results showed that. The model in the spectral region of 265-310 nm had the highest correlation and smallest error; In order to eliminate the impact of nitrates and temperature on the detection of the COD , studied the changes of the UV absorption spectrum with different concentrations of sodium standard solution and different temperature. The results showed that absorption of nitrate in 208-238 nm was apparent, and the model for spectral region of 265-310 nm was free from the influence of nitrate; In the full range of spectrum, temperature rising leads to an increase in absorbance, thus the temperature compensation model was established for the different spectral region through predictive analysis.

[Research on chemical oxygen demand optical detection method based on the combination of multi-source spectral characteristics].

A novel method based on multi-source spectral characteristics of the combination is proposed for chemical oxygen demand detection. First, the ultraviolet and near infrared spectrum of the actual water samples are collected respectively. After pretreatment of the spectrum data, the features of the spectrum are extracted by the nonnegative matrix factorization algorithm for training after normalization. Particle swarm and least squares support vector machines algorithm are applied to predicting chemical oxygen demand of the validation set of water samples. The effect of spectrum's base number on the predicted results is discussed. The experimental results show that the best base number of the ultraviolet spectrum is 5, the best base number of the near infrared spectrum is 2; The validation set correlation coefficient of the prediction model is 0.999 8, and the root mean square error of prediction is 3.26 mg x L(-1). Experimental results demonstrate that the nonnegative matrix factorization algorithm is more suitable for feature extraction of spectral data, and the least squares support vector machines algorithm as a quantitative model correction method of the actual water samples can get good prediction accuracy with different feature extraction methods (principal component analysis, independent component analysis), spectroscopic methods (ultraviolet spectrum method, near infrared spectrum method) and different combination pattern (data direct combination, combining data first, then feature extraction) respectively.

Propofol inhibits the adhesion of hepatocellular carcinoma cells by upregulating microRNA-199a and downregulating MMP-9 expression.

BACKGROUND: Propofol is one of the extensively and commonly used intravenous anesthetics and has the ability to influence the proliferation, motility, and invasiveness of many cancer cells. In this study, the effects of propofol on hepatocellular carcinoma cells invasion ability were examined. METHODS: We assessed the invasion ability of HepG2 cells in vitro by determining enzyme activity and protein expression of MMP-9 using gelatin zymography assay and Western blot. The real-time PCR was used to evaluate the effect of propofol on microRNA-199a (miR-199a) expression, and miR-199a-2 precursor to evaluate whether over-expression of miR-199a can affect MMP-9 expression. Finally, the effect of miR-199a on propofol-induced anti-tumor activity using anti-miR-199a was assessed. RESULTS: Propofol significantly elevated the expression of miR-199a and inhibited the invasiveness of HepG2 cells. Propofol also efficiently decreased enzyme activity and protein expression of MMP-9. Moreover, the over-expression of miR-199a decreased MMP-9 protein level. Interestingly, the neutralization of miR-199a by anti-miR-199a antibody reversed the effect of propofol on alleviation of tumor invasiveness and inhibition of MMP-9 activity in HepG2 cells. CONCLUSION: Propofol decreases hepatocellular carcinoma cell invasiveness, which is partly due to the down-regulation of MMP-9 expression by miR-199a.

Propofol induces apoptosis of hepatocellular carcinoma cells by upregulation of microRNA-199a expression.

Propofol is one of the extensively commonly used intravenous anaesthetic agents. The effects of Propofol on hepatocellular carcinoma (HCC) growth inhibition and apoptosis have been examined. The techniques used were the MTT assay, flow cytometry, real-time PCR to assess miR-199a expression, as also caspase-8 and caspase-9 activity in HepG2 cells treated with Propofol. Finally, we evaluated the effect of miR-199a on Propofol-induced anti-tumour activity using anti-miR-199a. Propofol efficiently inhibited the growth of HCC cells, but was less toxic to normal hepatic cells. It induced apoptosis and increased expression of miR-199a. Activation of caspase-8 and caspase-9 suggested that both extrinsic and intrinsic pathways are involved in Propofol-induced apoptosis. Anti-miR-199a reversed the effect of Propofol on apoptosis and activation of caspase-8 and caspase-9 in HepG2 cells. Propofol can effectively induce apoptosis of HCC cells and modulation of miR-199a possibly contributes to the anti-tumour action of Propofol. Hence, Propofol might be an effective drug for HCC.

[The turbidity and pH impact analysis of low concentration water chemical oxygen demand ultraviolet absorption detection].

Configuration standard solution in the concentration range of 1 - 25 mg x L(-1) of potassium hydrogen phthalate was used as experimental subject, Ultraviolet absorption spectra was collected, the COD quantitative analysis model was established by partial least squares with different pretreatment methods and the turbidity of the compensation effect analysis was given. The results show the model uses smoothing first derivative pretreatment method, internal cross validation RMSECV root mean square value of 0.122 27, principal component number 4, the square of the prediction model correlation coefficient is 0.999 8, and the relative prediction error is in the range of 0.03%-1.7%; for 0-100 NTU's turbidity solution, the relative standard deviation RSD is 2.3% after compensation; with pH in the range of 3-10, influence can be ignored.

[Guiding values of facial nerve 3D-TOF-MRA and 3D-FIESTA scan for primary hemifacial spasm operation].

OBJECTIVE: To explore the operative guiding values of facial nerve three-dimensional time-of-flight magnetic resonance angiography (3D-TOF-MRA) and three-dimensional fast imaging employing steady state acquisition three-dimensional fast imaging employing steady state acquisition (3D-FIESTA) scan. METHODS: A total of 125 cases of primary hemifacial spasm was treated at our hospital from 2004 to 2012. Among them, 80 cases received preoperative facial nerve MRA scan. The imaging and intraoperative findings were compared to determine the responsible blood vessels. RESULTS: Responsible blood vessels were found in all 80 cases. Sixty patients (75%) had the involvement of single vessel of anterior inferior cerebellar artery (AICA, n = 57), posterior inferior cerebellar artery (PICA, n = 1), superior cerebellar artery (SCA, n = 1) and vertebral artery (VA, n = 1). Two or more vessels were implicated in 9 patients (11.25%). The culprits were AICA+ internal auditory artery (n = 8) and PICA+ internal auditory artery (n = 1). The source of responsible vessels of 11 cases could not be determined before surgery. Through intraoperative anatomy, 59 patients had single vessel lesions, including AICA (n = 53), PICA (n = 4), SCA (n = 1) and VA (n = 1). Among 14 cases of multiple vessels, there were AICA + internal auditory artery (n = 7), internal auditory artery + PICA (n = 2), AICA + brain stem perforating artery (n = 3) and AICA + vein (n = 2). Seven cases were uncertain. No significant statistical difference existed between two groups. CONCLUSION: Facial nerve 3D-TOF-MRA and 3D-FIESTA scan can identify the status of responsible blood vessels to guide operations.

[Determination of chemical oxygen demand in water using near infrared transmission and UV absorbance method].

Chemical oxygen demand (COD) is a synthetical indicator which represents the degree of organic pollution in water. The near-infrared (NIR) transmission and the UV absorbance method based on photoelectric detection technology and spectroscopy analysis have some advantages such as high precision, speed, non-contact, no secondary pollution etc compared to conventional wet chemical method. The NIR transmission spectra and UV absorbance spectra of standard solution configured with phthalate hydrogen potassium were collected respectively by MPA FTIR spectrometer (Bruker Optics Inc.) made in Germany and AvaSpec-2048-2 UV spectrometer (Avantes Inc.) made in Netherlands. After different pretreatment to the spectra, COD quantitative analysis model was established using partial least squares regression (PLS) and linear regression. The statistical analysis of COD quantitative model was implemented, and the result showed that UV absorbance method had a higher relevance but lower forecast accuracy and precision than NIR transmission method.

[Recognition and management of hidden related vessel during the operation of microvascular decompression for hemifacial spasm].

OBJECTIVE: To investigate the recognition and approach of the hidden related vascular in hemifacial spasm patients during the operation of microvascular decompression. METHODS: The clinical records of 85 patients of hemifacial spasm were analyzed at our hospital. The hidden related vessel was found in 7 patients. REZ (root entry zone) was surrounded by Teflon cotton slice to separate the vessel from REZ. RESULTS: There were 7 patients of hidden related vessel in 85 patients. And the related vessels were anteroinferior cerebellar artery and its branches. The symptoms became totally relieved after operation and there was no recurrence. CONCLUSION: The microvascular decompression is an effectively treatment for hemifacial spasm patients. Searching for the related vessel (particularly hidden related vessel) is the most important part of the operation. An effective decompression of REZ is the key point of operation.