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51.
V Cortés-Gallegos A Carranco I Sojo M Navarrette C Cervantes A Parra 《Fertility and sterility》1979,32(5):524-527
A radioimmunoassay to quantitate ethinylestradiol (EE-2) in both plasma and endometrium is described. In 29 women under sequential oral contraceptive therapy (chlormadinone acetate, 2 mg, plus mestranol, 80 microgram) for 6 to 84 months, a single blood sample and a single endometrial sample were simultaneously obtained on different days of the pseudomenstrual cycle. In 24 women under 40 years of age the mean plasma EE-2 concentrations were similar during the first (989 +/- 94 pg/ml) and the second half of the cycle (1053 +/- 186 pg/ml) (P greater than 0.05). A similar finding was observed with regard to mean endometrial EE-2 concentrations (3.55 +/- 2.1 and 5.89 +/- 1.7 microgram/gm of wet tissue, respectively). On the other hand, five women over 40 years of age had plasma EE-2 concentrations similar to those of the previous group, but the mean endometrial EE-2 concentrations was 0.9 +/- 0.6 microgram/gm of wet tissue (P less than 0.05). Although plasma follicle-stimulating hormone and luteinizing hormone did not show midcycle peak values, complete suppression of both gonadotropins was not observed. These results show that endometrium has a great ability to concentrate EE-2, and this ability seems to be greater in women below age 40 than above. Whether or not this observation might be related to the known higher incidence of endometrial cancer in women less than 40 years old who have been under chronic sequential oral contraceptive therapy cannot be disclosed from this limited number of determinations. 相似文献
52.
Zhiyuan Mao Pavlo A. Nesterenko Jami McLaughlin Weixian Deng Giselle Burton Sojo Donghui Cheng Miyako Noguchi William Chour Diana C. DeLucia Kathryn A. Finton Yu Qin Matthew B. Obusan Wendy Tran Liang Wang Nathanael J. Bangayan Lisa Ta Chia-Chun Chen Christopher S. Seet Gay M. Crooks John W. Phillips James R. Heath Roland K. Strong John K. Lee James A. Wohlschlegel Owen N. Witte 《Proceedings of the National Academy of Sciences of the United States of America》2022,119(31)
Tissue-specific antigens can serve as targets for adoptive T cell transfer-based cancer immunotherapy. Recognition of tumor by T cells is mediated by interaction between peptide–major histocompatibility complexes (pMHCs) and T cell receptors (TCRs). Revealing the identity of peptides bound to MHC is critical in discovering cognate TCRs and predicting potential toxicity. We performed multimodal immunopeptidomic analyses for human prostatic acid phosphatase (PAP), a well-recognized tissue antigen. Three physical methods, including mild acid elution, coimmunoprecipitation, and secreted MHC precipitation, were used to capture a thorough signature of PAP on HLA-A*02:01. Eleven PAP peptides that are potentially A*02:01-restricted were identified, including five predicted strong binders by NetMHCpan 4.0. Peripheral blood mononuclear cells (PBMCs) from more than 20 healthy donors were screened with the PAP peptides. Seven cognate TCRs were isolated which can recognize three distinct epitopes when expressed in PBMCs. One TCR shows reactivity toward cell lines expressing both full-length PAP and HLA-A*02:01. Our results show that a combined multimodal immunopeptidomic approach is productive in revealing target peptides and defining the cloned TCR sequences reactive with prostatic acid phosphatase epitopes.Tissue antigens are encoded by nonmutated genes but can serve as potential targets for cancer therapies (1–3). Adoptive T cell therapies reactive with tissue antigens have enabled clinical trials targeting MART1, NY-ESO-1, and WT1 (4). T cell receptor (TCR) immunotherapy has demonstrated its potential in treating different cancers.A major concern for TCR immunotherapy is toxicity on benign tissues. This “on-target off-tumor toxicity” is linked to expression of the target or cross-reactive antigens in normal organs. Several clinical trials have been discontinued because of observed off-tumor toxicities (4, 5).One way to minimize “on-target off-tumor” toxicity is to select tissue antigens expressed on nonessential organs. Patients with late-stage prostate cancers have often received a radical prostatectomy to remove the prostate gland (6). We chose prostatic acid phosphatase (PAP) among many previously defined prostate tissue antigens because 1) the expression of PAP is highly restricted to the prostate and prostate cancer (7), 2) PAP expression can be found in >95% of prostate cancers (8), 3) serum PAP elevation is found in >60% patients with relapsed prostate cancers (9), 4) an elevated level of PAP is a strong predictor for high-risk recurrence (10), and 5) the secreted form of PAP will not compete with TCR–PAP recognition, because the interaction is restricted to peptides bound to MHC I.Previous efforts to target PAP led to the first Food and Drug Administration–approved cancer vaccine, sipuleucel-T (Provenge) (11). Clinical trials showed a median improvement in overall survival of 4.1 mo in men with metastatic castration-resistant prostate cancer (11). Recent studies have also provided video evidence that T cells from sipuleucel-T-treated patients are capable of lysing PAP+ target cells (12). Neither the PAP epitopes presented nor the cognate TCR sequences have been defined at the molecular level. Recovery of TCRs that specifically recognize PAP epitopes could have potential therapeutic value. 相似文献
53.
We previously reported that intracellular oxidation-reduction (redox)
regulates NK cell functions and that IL-2-activated NK cells undergo
apoptosis upon contact with NK-sensitive target cells. We now report that
apoptosis in activated human NK cells is also regulated by redox. Thiol
deprivation increased apoptosis in NK cells induced by anti-Fas mAb or Fas
ligand-transfected cells, and pretreatment of cells with N- acetyl
cysteine, which increased intracellular glutathione, partially inhibited
the apoptosis and reversed the effect of thiol-deficient medium, suggesting
that Fas-induced apoptosis in NK cells is also redox sensitive. Thiol
deprivation did not alter cell surface Fas expression, but did increase
ceramide generation following Fas engagement. Although exogenous ceramides
induced apoptosis of NK cells, thiol depletion had no effect on this
apoptosis. Thiol deprivation increased CPP32 activation induced by Fas
engagement, but not by ceramides. These findings suggest that, if ceramide
is required for Fas-induced apoptosis, thiol deprivation affects the
Fas-mediated signaling pathway at the generation of ceramide and/or
upstream thereof. Though tyrosine phosphorylation following Fas engagement
was not significantly affected by thiol deprivation, tyrosine
dephosphorylation was delayed, suggesting that tyrosine phosphatases may
also be redox sensitive. The notion that dephosphorylation is important in
the Fas signaling pathway is supported by the finding that tyrosine
phosphatase inhibitors significantly enhanced both CPP32 activity and
apoptosis following Fas ligation. We conclude that events downstream of
tyrosine phosphorylation and upstream of CPP32 activation, including
tyrosine dephosphorylation and possibly ceramide generation, are sensitive
to regulation by redox in human NK cells, requiring a reducing environment
for optimal protection from apoptosis induced by Fas ligation.
相似文献
54.
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56.
应用免疫络化S-P法检测88例食管浸润世鳞癌P16蛋白的表达,结果P16蛋白阳性率为55.68%(49/88),其阳性颗粒位于细胞浆内;组织学Ⅰ、Ⅱ、Ⅲ级阳性率分予的85.71%(18/21)、55.13%(16/29)、39.47%(15/38)(P<0.01);淋巴结转移组和无转移组阳世事分别为36.36%(12/33),67.27%(37/55)(P<0.01);3年生存率P16蛋白阳性组和阴性组分别36%和16.67%。结果表明食管鳞癌中P16蛋白的表达可以反映肿瘤的分化程度和转移情况.提示P16蛋白的检测可作为食管鳞癌的重要预后指标之一。 相似文献
57.
Experiments were performed to assess the ability of bencianol (ZY15051) to reverse contractions of human basilar arteries in vitro that were induced by a wide range of substances implicated in the aetiology of migraine and cerebral arterial spasm. Bencianol caused a dose-related (1-100 micrograms ml-1) reversal of contractions induced by 5-hydroxytryptamine, noradrenaline, angiotensin II, prostaglandin F2 alpha, and U-46619 (a thromboxane-A2 mimetic). Bencianol was more effective against contractions induced by EC50 compared to maximal concentrations of each agent, and was least effective against the thromboxane-A2 mimetic, U-46619. In addition, contractions induced by thromboxane-A2-like substances generated from guinea-pig lungs were also reversed by bencianol but only at the highest concentration used (100 micrograms ml-1). The relevance of this action of bencianol to migraine and cerebral arterial spasm is discussed. 相似文献
58.
59.
Kazumi Sojo Yoshihiro Sawaki Hisashi Hattori Hideki Mizutani Minoru Ueda 《Journal of cranio-maxillo-facial surgery》2005,33(4):238-245
BACKGROUND: With a hypothesis that "angiogenesis occurs before osteogenesis," an experimental study using a rat model was carried out. Histological and immunohistochemical examinations of vascular endothelial growth factor (VEGF) and bone morphogenetic protein-2, -4 (BMP-2, -4) were performed at the margins of bone formation after femoral bone lengthening. MATERIAL AND METHODS: Thirty-five Wistar rats weighing 380-400 g (11-week-old males) were used. An external fixator was applied on the femur, and an osteotomy performed under general anaesthesia. Five days after the operation, femoral lengthening was initiated at a rate of 0.8 mm/day for 8 days. The rats were sacrificed just after distraction was completed, and at 1, 3, 5, 7, 9 and 14 days after distraction. The specimens from these rats were stained with haematoxylin-eosin, VEGF, and BMP-2, -4 immunohistochemical staining, and were investigated. RESULTS: Expression of VEGF was observed in the woven bone at the osteogenetic front and near to osteoblasts around the newly formed bone. On the other hand, expressions of BMP-2, -4 were seen in the hypertrophic chondrocytes. In the same specimen, the VEGF area was further away from the bone stump than the BMP-2, -4 areas. CONCLUSION: These results confirm the hypothesis that angiogenesis is induced before osteogenesis. 相似文献
60.
Sperm nitric oxide and motility: the effects of nitric oxide synthase stimulation and inhibition 总被引:2,自引:1,他引:2
Nitric oxide (NO) is synthesized from L-arginine by a family of enzymes
known as the nitric oxide synthases (NOS). We have recently shown a NOS
similar to constitutive brain NOS (bNOS) and endothelial NOS (ecNOS) to be
present in spermatozoa. The aim of this study is to investigate NO
production by human spermatozoa and the effects of stimulation and
inhibition of NOS. This was carried out using the Iso-NO, an isolated NO
meter and sensor, which provides rapid, accurate and direct measurements of
NO. Semen samples with normozoospermic and asthenozoospermic profiles were
prepared using a direct swim-up technique. Basal concentrations of NO and
stimulated NO production were measured after exposure to the calcium
ionophore (A23187; 0.01-10 microM) a potent activator of constitutive NOS.
NO production in human spermatozoa was significantly increased by the
addition of A23187 30 seconds after stimulation. Furthermore, this response
was greatly diminished by pre-incubating the samples with competitive
inhibitors of L-arginine, the substrate for NOS, before treatment with
calcium ionophore. In the presence of N(G)-nitro-L-arginine methyl ester
(L- NAME), N(G)-nitro-L-arginine (L-NA) or N(G)-methyl-L-arginine (L-NMMA;
all at 10 microM), NO production was inhibited with a rank order of potency
L-NAME > L-NMMA > L-NA which is in accordance with the inhibition of
an endothelial type of constitutive NOS.
相似文献