作者: Kong, Zhihua ; Su, Zhenhong ; Lu, Yiyu ; Zhou, Yingxing ; Liu, Jin ; Cheng, Binbin ; Xiao, Jian ; Wang, Wei ; Chen, Jianjun ; Wang, Shuanghu ; Shi, Yaru ; Fei, Xiaoting ; Shao, Chuxiao

In this work, a series of bifunctional PD-L1/CD73 (cluster of differentiation 73) small-molecule inhibitors were designed and synthesized. Among them, CC-5 showed the strongest PD-L1 inhibitory effects with an IC₅₀ of 6 nM and potent anti-CD73 activity with an IC₅₀ of 0.773 μM. The high PD-L1/CD73 inhibitory activity of CC-5 was further confirmed by SPR assays with K_D of 182 nM for human PD-L1 and 101 nM for CD73, respectively. Importantly, CC-5 significantly suppressed tumor growth in a CT26 and B16-F10 tumor model with TGI of 64.3% and 39.6%, respectively. Immunohistochemical (IHC) and flow cytometry analysis of tumor-infiltrating lymphocytes (TILs) indicated that CC-5 exerted anticancer effects via activating the tumor immune microenvironment. Collectively, CC-5 represents the first dual PD-L1/CD73 inhibitor worthy of further research as a bifunctional immunotherapeutic agent.

2019-01-01·Medical Archives

Comparison of Topical and Subcutaneous Bupivacaine Infiltration with Subcutaneous Ketamine on Postoperative Pain in Total Abdominal Hysterectomy

Article

作者: Kamali, Alireza ; Shokrpour, Maryam ; Maktabi, Maryam ; Jelodar, Hamede Taghavi

INTRODUCTIONHysterectomy is one of the most common surgical procedures. Problems such as severe pelvic pain, irregular or heavy bleeding and uterine cancer from those that may be used to treat them no choice but to remove the uterus by surgery. Abdominal pain after abdominal hysterectomy, the most common complaints of patients undergoing this type of surgery is considered.AIMThis study aimed to compare the effects of bupivacaine into the subcutaneous tissue and skin ketamine for pain control after surgery in patients undergoing abdominal hysterectomy was performed under general anesthesia.METHODSThis study is a randomized, double-blind clinical trial involving 99 women scheduled for TAH referred to tertiary centers was performed. Group A: 5 mL of 0.25% bupivacaine into the subcutaneous tissue and, Group II: 100 mg ketamine skin and subcutaneous tissue with cc5 volume injection, groups of three: cc5 distilled water was injected into the subcutaneous tissue and. The average duration of analgesia and pain and pain score were recorded.RESULTSThe average duration of analgesia in group K 65.1±8.8, in the bupivacaine group 65.4±8.7 and in the placebo group 57.6±5.5, which, according to P Value≤0.01 is a significant difference between the three groups were observed, so that the pain in the placebo group for a significant period of ketamine and bupivacaine groups is lower, while that between ketamine and bupivacaine in terms of the average duration of analgesia was no significant difference not.CONCLUSIONThe results of our study indicate that the use of bupivacaine and ketamine effective in reducing postoperative pain in patients undergoing abdominal hysterectomy tissue and further doses of ketamine and bupivacaine single dose resulted in a significant reduction of postoperative pain patients were compared to the placebo group.

1991-01-01·The Journal of Steroid Biochemistry and Molecular Biology2区 · 生物学

Effects of long-term treatment with estradiol or clomiphene citrate on bone maintenance, and pituitary and uterine weights in ovariectomized rats

2区 · 生物学

Article

作者: J.L. Brown ; M.F. Nelson ; P.K. Chakraborty ; C.B. Ruff ; A.S. Mitchell

Long-term estrogen replacement therapy in postmenopausal women can bring relief to hot flushes and reduce loss of bone mass due to osteoporosis, however, such treatment often can cause uterine hyperplasia and other undesirable effects. This study compared changes in bone mineral content (BMC), uterine weight, pituitary weight and pituitary gonadotropin content in the ovariectomized rat model following treatment with estradiol (E2) or two levels of clomiphene citrate (CC), an estrogen agonist/antagonist. Groups (n = 8-12) of adult ovariectomized (OVX) rat were implanted with E2 pellets (5 micrograms/day) or injected subcutaneously with CC at 1 mg/kg body wt (CC-1) or 5 mg/kg body wt (CC-5) twice weekly for 12 months. Placebo implanted OVX and intact (INT) female rats served as negative and positive controls, respectively. Following treatment, the uterus, pituitary gland and right femur were collected from each animal. E2 treatment increased (P less than 0.05) uterine weight compared to all other treatment groups, while both CC doses increased uterine weight over the OVX group only (E2, 0.24 +/- 0.03; INT, 0.14 +/- 0.01; CC-1, 0.06 +/- 0.01; CC-5, 0.07 +/- 0.01; and OVX, 0.02 +/- 0.01 g per 100 g body wt). Pituitary weight was increased 15-fold (P less than 0.05) by E2 treatment over all other treatment groups (E2, 65.7 +/- 13.9; INT, 4.0 +/- 0.5; CC-1, 3.3 +/- 0.03; CC-5, 2.7 +/- 0.02; and OVX, 2.9 +/- 0.02 mg per 100 g body wt). Both E2 and CC treatments reduced pituitary luteinizing hormone and follicle stimulating hormone content (micrograms/pit) to INT levels and were lower (P less than 0.05) than OVX levels. Mean BMC of E2, CC-1- or CC-5-treated rats was greater (P less than 0.05) than that of either the INT or OVX groups, while INT animals had a higher BMC compared to OVX animals (E2, 0.027 +/- 0.003; CC-1, 0.026 +/- 0.001; CC-5, 0.028 +/- 0.001; INT, 0.021 +/- 0.001; and OVX, 0.017 +/- 0.001 g/cm per 100 g body wt). These data indicate that CC has the potential to reduce bone mineral loss without causing other undesirable effects, including uterine hyperstimulation, and thus needs to be further investigated.

100 项与 CC-5 相关的药物交易

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