Objective:To determine the effect of apatinib combined with Xiaoyan decoction for the treatment of non-squamous non-small cell lung cancer. Methods:Thirty-eight patients with non-squamous non-small cell lung cancer were randomly categorized into apatinib group (group A, 18 cases) and apatinib combined with Xiaoyan decoction group (group B, 20 cases). All patients did not under-go surgical treatment, radiotherapy, or chemotherapy during the study. Results:The median progression free survival (mPFS) of ad-vanced non-squamous non-small cell lung cancer patients reached up to 3 months. The mPFS, objective response rate, and disease control rate of the apatinib combined with Xiaoyan decoction group showed no significant difference and statistical significance (P>0.05). The apatinib combined with Xiaoyan decoction group was superior to the apatinib group with regard to alleviating clinical symp-toms and adverse reactions (P<0.05). Conclusion:Xiaoyan decoction combined with apatinib can improve the clinical symptoms of pa-tients and reduce the incidence of adverse reactions in the treatment of advanced non-squamous non-small cell lung cancer.

Objective:To investigate the in vitro effect of arsenic trioxide (As2O3) alone and in combination with dexamethasone (DXM), etoposide (VP-16), methotrexate (MTX), bortezomib (BTZ), and suberoylanilide hydroxamic acid (SAHA) on the growth of human cutaneous T cell lymphoma (CTCL) cells Hut-78 and Hut-102. Methods:Hut-78 and Hut-102 cells were cultured with different concentrations of As2O3, DXM, VP-16, MTX, BTZ, and SAHA alone and As2O3 in combination with DXM, VP-16, MTX, BTZ, or SAHA for 48 h. The effects of the different samples on Hut-78 and Hut-102 cell proliferation were determined by MTT assay. Analyses using CalcuSyn software were performed to determine whether the combination of As2O3 with DXM, VP-16, MTX, BTZ, or SAHA in-duced synergistic cytoxicity. Results:As2O3, DXM, VP-16, MTX, BTZ, and SAHA alone significantly inhibited the growth of Hut-78 and Hut-102 cells in a dose-dependent manner, with a 50%inhibiting concentration of 5μmol/L, 500μg/mL, 2.5μg/mL, 1μg/mL, 10μmol/L, and 2.5μmol/L individually after 48 h of culture. As2O3 with DXM, VP-16, MTX, BTZ, or SAHA showed remarkable antitu-mor efficacy compared with that of individual applications. Conclusion:As2O3 alone or combined with DXM, VP-16, MTX, BTZ, or SAHA significantly inhibited Hut-78 and Hut-102 cell growth in vitro. This study demonstrated that As2O3 with DXM, VP-16, MTX, BTZ, or SAHA presents synergistic antitumor effects on CTCL cells and may be an optimal regimen in clinical trials of CTCL.

Objective:To detect the inhibitory effects of CAL-101, a selective inhibitor of phosphoinostitide-3'-kinase delta (PI3Kδ), on Burkitt's lymphoma cell line Raji and diffused large B-cell lymphoma cell line SUDHL-10 and elucidate its relative mechanism. Methods:Raji and SUDHL-10 cells were treated with various concentrations of CAL-101. Methyl thiazolyl tetrazolium (MTT) assay was performed to determine the inhibitory effect of CAL-101 on lymphoma cells, and cell apoptosis was measured by Annexin V/PI and DAPI staining. Migration assays were performed with transwell to detect the migration of lymphoma cells derived from the stromal cell line HK. Western blot was used to detect the phosphorylation status of the ERK pathway. MTT and CalcuSyn software analyses were preformed to detect whether or not combining CAL-101 with bortezomib induces synergistic cytoxicity. Results:CAL-101 at con-centrations of 5, 10, 15, and 20μmol/L inhibited cell proliferation in a dose-dependent manner. The proliferation rates of the Raji cells treated with 5, 10, 15, and 20μmol/L for 48 h were 29.17%± 1.23%, 38.15%± 1.51%, 46.46%± 1.78%, and 55.8%± 2.01%, respec-tively, which were significantly higher (P<0.05) than that of the control group (1.15% ± 0.02%). Similar results were found in the SUDHL-10 cells after treatment with CAL-101 (P<0.05). CAL-101 also exerted an apoptotic effect on the lymphoma cells. The apop-totic rates of the Raji cells treated with CAL-101 for 21 h were 22.69%± 3.83%and 49.96%± 7.36%, respectively, which were signifi-cantly higher (P<0.05) than that of the control group (5.23%± 2.04%). Similar results were found in the SUDHL-10 cells (P<0.05). Treatment with 5 and 10 μmol/L CAL-101 dose-dependently inhibited the migration activity of lymphoma cells to stromal cells (P<0.05). Western blot analysis showed that the expression level of ERK phosphorylation protein was significantly downregulated in the cells treated with CAL-101. A synergistic effect between CAL-101 and bortezomib was verified. That is, these two drugs can signifi-cantly inhibit the proliferation of lymphoma cells with CI values less than 1. Conclusion:The PI3Kδ-specific inhibitor CAL-101 sup-pressed the proliferation of Raji and SUDHL-10 cells, induced apoptosis, and inhibited stromal cell-derived migration. This inhibitory effect may be induced by blocking the ERK pathway. Overall, our study indicated that CAL-101 is a novel and potential agent in the therapeutic strategy against aggressive B-cell lymphoma.

Objective:To investigate the clinical features, treatment strategies, and relative prognostic factors in 66 patients with solitary plasmacytoma (SP). Methods:The data of 644 patients, who were diagnosed with pathologically proven plasmacytoma in Tianjin Medical University Cancer Institute and Hospital between June 2000 and October 2012, were collected. Sixty-six of these patients (10.25%) were evaluated as SP, including 45 solitary bone plasmacytoma (SBP) and 21 extramedullary plasmacytoma (EMP). Results:SBP and EMP were the two clinical subsets of SP revealing the location of the lesion. SBP mostly occurred in the axial skeleton, whereas EMP was most frequently observed in the upper respiratory tract. The differences among tumor size, serum M-protein, and serumβ2-microglobulin exhibited statistical significance. Conclusion:Large tumor size (≥5 cm), positive serum M-protein, and serumβ2-microglobulin were the factors that affected the prognosis of SBP patients. Radiotherapy and serumβ2-microglobulin>3.5 mg/L were the favorable prognostic factors for EMP patients.

Objective To observe the clinical efficacy of Huajian-Badu membrane in the treatment of moderate and severe cancer pain. Methods The 80 malignant tumor patients with moderate to severe cancer pain from January 2016 to June 2017 in Tianjin University of Traditional Chinese Medicine First Teaching Hospital were recruited and randomly divided into the observation group and the control group, each of 40 cases. The control group were treated with Oxycodone Hydrochloride Prolonged-release Tablets, while the treatment group were treated with Huajian-Badu membrane on the basis of the treatment in control group. The pain relief, pain frequency, morphine consumption and quality of life (Karnofsky score), adverse reaction were evaluated between two groups before and after treatment. Results Compared with the control group, the total efficiency in the observation group was significantly higher (95.0％ vs. 80.0％, χ2=4.114, P=0.043). The frequency of breakthrough pain of two groups increased on the seventh and fourteenth treatment days(0.3 ± 0.6 times vs. 0.8 ± 0.7 times, t=-3.430 and 0.4 ± 0.6 times vs. 0.9 ± 0.8 times, t=-3.162), but the number of outbreaks of pain in the observation group significantly less than the control group (P<0.05 or P<0.01). The morphine injection dosage increased on the seventh and fourteenth treatment days (3.01 ± 4.28 g vs. 5.62 ± 6.37 g, t=-2.151 and 3.21 ± 4.32 g vs. 7.84 ± 7.76 g, t=-3.297), but the amount of the observtation group was significantly lower than that of control group (P<0.05 or P<0.01). The KPS score in the observation group increased significantly, and significantly higher than the control group on the seventh and fourteenth treatment days (73.0 ± 15.0 vs. 66.0 ± 12.0, t=2.305 and 77.0 ± 13.0 vs. 70.0 ± 15.0, t=2.230, P<0.05). The adverse reaction rate of the control group was 25％, while the the observation group was 20％. The difference between two groups was significant (χ2=0.287, P=0.592). Conclusions The Huajian-Badu membrane combined Oxycodone Hydrochloride Prolonged-release Tablets can improve the total effective rate of pain relief, reduce the number of outbreaks, reduce morphine consumption, improve patient KPS score of the patients with cancer pain.

Objective:To investigate the association between serum levels of thyroglobulin (Tg), thyroid stimulating hormone (TSH) and antibodies and lymph node metastasis (LNM) in papillary thyroid cancer (PTC) .Methods:A total of 1 502 patients with PTC who were admitted to the Department of Breast and Thyroid Surgery of the First Affiliated Hospital of Chongqing Medical University from Jan. 2019 to Jan. 2022 were retrospectively enrolled, including males ( n=431), females ( n=1 071), aged < 55 years ( n=1 271), and ≥ 55 years old ( n=231). All patients were pathologically confirmed to have PTC after surgery. Univariate analysis was performed on the general data of patients and the indexes in the postoperative pathology report and the LNM group, and the data of P<0.05 in the analysis were included in the regression analysis to determine the independent risk factors of cervical LNM in PTC patients. Patients were divided into 8 subgroups according to the different statuses of the three thyroid antibodies (TGAb, TPOAb, TRAb) : [ (+) indicates positive; (-) indicates negative]. According to the order of TGAb, TPOAb, and TRAb, there are the following 8 states, 1 (+++) ; 2 (---) ; 3 (++-) ; 4 (+--) ; 5 (+-+) ; 6 (-+-) ; 7 (-++) ; 8 (--+). The differences in general clinical information, Tg and TSH between the two groups were compared, and the receiver operating characteristic curve (ROC) curve of Tg in the diagnosis of PTC lymph node metastasis was constructed, and regression analysis was used to explore the diagnostic value of serological indicators in the diagnosis of cervical LNM in PTC. Results:In this study, compared with the non-metastasis group, there were 308 males (33.2%) and 225 patients (24.3%) with bilateral PTC in metastasis group. The mean serum Tg value was (25.5±2.1) ng/mL and the TSH level was significantly increased ( P<0.05), and the results of binary logistic regression analysis showed that males ( OR=1.57, P<0.001), bilateral PTC ( OR=1.448, P<0.001), non-papillary carcinoma (>10 mm) ( OR=1.745, P<0.001) and increased Tg level ( OR=1.007, P=0.002) were independent risk factors for cervical lymph node metastasis in PTC patients, and the area under the ROC curve of Tg in the evaluation of cervical lymph node metastasis was 0.634 [95% CI (0.636, 0.691), P<0.05], while the TSH status was 0.56-1.39 ( OR=0.375, P=0.013). 1.40-2.29 ( OR=0.422, P=0.003) ; 2.30-5.91 ( OR=0.466, P=0.004) ; ≥5.91 ( OR=0.41, P=0.001) was not a risk factor. Conclusion:Male sex, bilateral thyroid cancer, non-papillary carcinoma (>10 mm), and preoperative serum Tg>29.8 ng/mL are the influencing factors of LNM in PTC patients.

Objective To investigate the effect of CAL?101, a selective inhibitor of PI3Kδ, in combination with bortezomib on the proliferation and apoptosis in human mantle cell lymphoma cell lines Z138, HBL?2 and Jeko?1 in vitro, to explore its mechanisms and provide the foundation for effective treatment strategies against mantle cell lymphoma. Methods MTT assay was applied to detect the inhibitory effects of CAL?101 and bortezomib either alone or combined on Z138, HBL?2 and Jeko?1 cells. Calcusyn software was used to analyze the synergistic cytotoxicity. Western blot was used to detect the expression of PI3K?p110σ and p?Akt, Akt, p?ERK and ERK proteins after the cells were exposed to different concentrations of CAL?101. Flow cytometry was employed to assess the apoptosis rate. NF?κB kit was used to determine the changes of location of NF?κB P65, and Western blot was applied to detect the level of caswpase?3 and the phosphorylation of Akt in different groups. Results CAL?101 and BTZ inhibited the proliferation of Z138, HBL?2 and Jeko?1 cells in a dose? and time?dependent manner. CAL?101/BTZ combination induced significantly synergistic cytotoxicity in the MCL cells. The results of Western blot assay showed that CAL?101 significantly blocked the phosphorylation of Akt and ERK in the MCL cell lines. In addition, CAL?101 combined with BTZ induced pronounced apoptosis (P<0.01). For example, after the Z138 cells exposed to the drugs for 48 h, the apoptosis rates of the control, CAL?101, BTZ and CAL?101+BTZ groups were:(2.6±1.8)%, (40.0±3.0)%, (34.0±1.0)%, and (67.4±1.0)%, respectively; and when drug treatment was given to HBL?2 cells over 96 h, the apoptosis rates of these four cell groups were (7.4±0.6)%,(30.7±5.7)%, (12.0±1.0)%, and (85.0±4.0)%, respectively. The combination therapy contributed to the enhanced inactivity of nuclear factor?κB ( NF?κB) and Akt inactivation in the MCL cell lines (P<0.05), however, the casepase?3 activity was up?regulated. Conclusions The combination of CAL?101 and bortezomib is muchmore effective in inhibiting proliferation and promoting apoptosis of mantle cell lymphoma cell lines ( Z138, HBL?2 and Jeko?1) , which may be mediated through inhibiting PI3K/Akt signaling pathway and the transcription of NF?κB.

Objective To investigate the effect of CAL?101, a selective inhibitor of PI3Kδ, in combination with bortezomib on the proliferation and apoptosis in human mantle cell lymphoma cell lines Z138, HBL?2 and Jeko?1 in vitro, to explore its mechanisms and provide the foundation for effective treatment strategies against mantle cell lymphoma. Methods MTT assay was applied to detect the inhibitory effects of CAL?101 and bortezomib either alone or combined on Z138, HBL?2 and Jeko?1 cells. Calcusyn software was used to analyze the synergistic cytotoxicity. Western blot was used to detect the expression of PI3K?p110σ and p?Akt, Akt, p?ERK and ERK proteins after the cells were exposed to different concentrations of CAL?101. Flow cytometry was employed to assess the apoptosis rate. NF?κB kit was used to determine the changes of location of NF?κB P65, and Western blot was applied to detect the level of caswpase?3 and the phosphorylation of Akt in different groups. Results CAL?101 and BTZ inhibited the proliferation of Z138, HBL?2 and Jeko?1 cells in a dose? and time?dependent manner. CAL?101/BTZ combination induced significantly synergistic cytotoxicity in the MCL cells. The results of Western blot assay showed that CAL?101 significantly blocked the phosphorylation of Akt and ERK in the MCL cell lines. In addition, CAL?101 combined with BTZ induced pronounced apoptosis (P<0.01). For example, after the Z138 cells exposed to the drugs for 48 h, the apoptosis rates of the control, CAL?101, BTZ and CAL?101+BTZ groups were:(2.6±1.8)%, (40.0±3.0)%, (34.0±1.0)%, and (67.4±1.0)%, respectively; and when drug treatment was given to HBL?2 cells over 96 h, the apoptosis rates of these four cell groups were (7.4±0.6)%,(30.7±5.7)%, (12.0±1.0)%, and (85.0±4.0)%, respectively. The combination therapy contributed to the enhanced inactivity of nuclear factor?κB ( NF?κB) and Akt inactivation in the MCL cell lines (P<0.05), however, the casepase?3 activity was up?regulated. Conclusions The combination of CAL?101 and bortezomib is muchmore effective in inhibiting proliferation and promoting apoptosis of mantle cell lymphoma cell lines ( Z138, HBL?2 and Jeko?1) , which may be mediated through inhibiting PI3K/Akt signaling pathway and the transcription of NF?κB.

OBJECTIVETo investigate the effect of CAL-101, a selective inhibitor of PI3Kδ, in combination with bortezomib on the proliferation and apoptosis in human mantle cell lymphoma cell lines Z138, HBL-2 and Jeko-1 in vitro, to explore its mechanisms and provide the foundation for effective treatment strategies against mantle cell lymphoma.

METHODSMTT assay was applied to detect the inhibitory effects of CAL-101 and bortezomib either alone or combined on Z138, HBL-2 and Jeko-1 cells. Calcusyn software was used to analyze the synergistic cytotoxicity. Western blot was used to detect the expression of PI3K-p110σ and p-Akt, Akt, p-ERK and ERK proteins after the cells were exposed to different concentrations of CAL-101. Flow cytometry was employed to assess the apoptosis rate. NF-κB kit was used to determine the changes of location of NF-κB P65, and Western blot was applied to detect the level of caswpase-3 and the phosphorylation of Akt in different groups.

RESULTSCAL-101 and BTZ inhibited the proliferation of Z138, HBL-2 and Jeko-1 cells in a dose- and time-dependent manner. CAL-101/BTZ combination induced significantly synergistic cytotoxicity in the MCL cells. The results of Western blot assay showed that CAL-101 significantly blocked the phosphorylation of Akt and ERK in the MCL cell lines. In addition, CAL-101 combined with BTZ induced pronounced apoptosis (P < 0.01). For example, after the Z138 cells exposed to the drugs for 48 h, the apoptosis rates of the control, CAL-101, BTZ and CAL-101 + BTZ groups were: (2.6 ± 1.8)%, (40.0 ± 3.0)%, (34.0 ± 1.0)%, and (67.4 ± 1.0)%, respectively; and when drug treatment was given to HBL-2 cells over 96 h, the apoptosis rates of these four cell groups were (7.4 ± 0.6)%, (30.7 ± 5.7)%, (12.0 ± 1.0)%, and (85.0 ± 4.0)%, respectively. The combination therapy contributed to the enhanced inactivity of nuclear factor-κB (NF-κB) and Akt inactivation in the MCL cell lines (P < 0.05), however, the casepase-3 activity was up-regulated.

CONCLUSIONSThe combination of CAL-101 and bortezomib is muchmore effective in inhibiting proliferation and promoting apoptosis of mantle cell lymphoma cell lines (Z138, HBL-2 and Jeko-1), which may be mediated through inhibiting PI3K/Akt signaling pathway and the transcription of NF-κB.

Antineoplastic Agents ; pharmacology ; Antineoplastic Combined Chemotherapy Protocols ; pharmacology ; Apoptosis ; drug effects ; Blotting, Western ; Boronic Acids ; Bortezomib ; pharmacology ; Caspase 3 ; metabolism ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Class Ia Phosphatidylinositol 3-Kinase ; antagonists & inhibitors ; Dose-Response Relationship, Drug ; Drug Synergism ; Formazans ; Humans ; Lymphoma, Mantle-Cell ; drug therapy ; pathology ; MAP Kinase Signaling System ; drug effects ; NF-kappa B ; metabolism ; Neoplasm Proteins ; metabolism ; Phosphatidylinositol 3-Kinases ; metabolism ; Phosphorylation ; drug effects ; Proto-Oncogene Proteins c-akt ; metabolism ; Purines ; administration & dosage ; pharmacology ; Pyrazines ; Quinazolinones ; administration & dosage ; pharmacology ; Signal Transduction ; Software ; Tetrazolium Salts

OBJECTIVETo investigate the proliferation inhibitory role and mechanism of PI3Kδ inhibitor CAL-101 on multiple myeloma (MM) cells, and to provide new therapeutic options for MM treatment.

METHODSMM cell lines U266 and RPMI8226 cells were treated with various concentrations of CAL-101. MTT assay and CalcuSyn software were performed to determine the inhibitory effect of CAL-101 and the synergistic effect with PCI- 32765, SAHA (suberoylanilide hydroxamic acid), BTZ (Bortezomib) on MM cells. The protein expression level of p-AKT, p-ERK, AKT, ERK and PI3Kδ processed by CAL-101 were analyzed by Western blot.

RESULTSCAL-101 at concentration of 15, 20, 25, 30 and 40 μmol/L could induce significant dose-dependent proliferation inhibition on U266 cells after treatment for 48 hours. The cell proliferation inhibition rates were (33.54 ± 1.23)%, (41.72 ± 1.78)%, (53.67 ± 2.01)%, (68.97 ± 2.11)% and (79.25 ± 1.92)%, respectively. Similar results were found in RPMI8226 cell line. Western blots showed high expression level of p-AKT, p-ERK, AKT, ERK and PI3Kδ in cell lines and MM primary cells. p-AKT and p-ERK protein expression levels were down-regulated significantly by CAL-101 treatment. Synergistic effect has been verified between CAL-101 and PCI-32765, SAHA and Bortezomib in U266 cell line, and PCI-32765, Bortezomib in RPMI8226 cell line with CI values less than 1.

CONCLUSIONCAL-101 could inhibit proliferation of MM cell lines. High levels of p-AKT, p-ERK, AKT, ERK and PI3Kδ protein expression were observed in both cell lines and primary cells. Down-regulation of p-AKT and p-ERK probably related with the mechanism of CAL-101 in MM cell proliferation inhibition. CAL-101 has significant synergistic effect with PCI-32765, SAHA and BTZ.

Boronic Acids ; Bortezomib ; Cell Line, Tumor ; Cell Proliferation ; Down-Regulation ; Humans ; Multiple Myeloma ; pathology ; Phosphatidylinositol 3-Kinases ; antagonists & inhibitors ; Protein Kinase Inhibitors ; pharmacology ; Purines ; pharmacology ; Pyrazines ; Pyrazoles ; Pyrimidines ; Quinazolinones ; pharmacology