The Remarkable Stability of Chimeric,Sialic Acid-derived α/δ-Peptides in Human Blood Plasma

Peptides are labile toward proteolytic enzymes, and structural modifications are often required to prolong their metabolic half-life and increase resistance. One modification is the incorporation of non-α-amino acids into the peptide to deter recognition by hydrolytic enzymes. We previously reported the synthesis of chimeric α/δ-peptides from glutamic acids (Glu) and the sialic acid derivative Neu2en. Conformational analyses revealed these constructs adopt secondary structures in water and may serve as conformational surrogates of polysialic acid. Polysialic acid is a tumor-associated polysaccharide and is correlated with cancer metastasis. Soluble polysialic acid is rapidly cleared from the blood limiting its potential for vaccine development. One motivation in developing structural surrogates of polysialic acid was to create constructs with increased bioavailability. Here, we report plasma stability profiles of Glu/Neu2en α/δ-peptides. DOTA was conjugated at the peptide N-termini by solid phase peptide synthesis, radiolabeled with ¹¹¹In, incubated in human blood plasma at 37 °C, and their degradation patterns monitored by cellulose acetate electrophoresis and radioactivity counting. Results indicate that these peptides exhibit a long half-life that is two- to three-orders of magnitude higher than natural α-peptides. These findings provide a viable platform for the synthesis of plasma stable, sialic acid-derived peptides that may find pharmaceutical application.     

论卫生船舶在登陆作战中的配置

在大规模登陆作战中需要大量的卫生船舶实施各种保障,因此必须对卫生船舶进行合理的配置,保证其既能有效地完成保障任务,又能避免重叠配置造成浪费．卫生船舶的配置应与指挥关系、保障任务战时分类相适应,具体配置时按医院船、卫生运输船、卫生救护艇的保障要求配置,并可根据保障任务的变化进行相应的调整．     

Critical evaluation of hepatic scintiangiography for neoplastic tumors of the liver.

Dynamic hepatic scintiangiography increases the specificity of diagnosis of space-occupying lesions of the liver seen on hepatic scintigraphy. The purpose of this study was to evaluate and compare critically this procedure with histologic and radiopaque diagnosis in the evaluation of suspected hepatic neoplasms. Ninety-two patients had hepatic scintiangiography, scintigraphy, and histologic certification. In ten of these patients the findings of radiopaque arteriography were compared with those of hepatic scintiangiography. In all ten patients with hepatoma, the scintiangiographic and histologic observations correlated; nine of these ten patients had a "tumor stain." Fifty-one of 59 patients with metastases to the liver had scinitangiograms that showed "tumor stain." In 2 of these 59 patients, scintiangiography revealed tumor vascularity whereas the results of scintigraphy were normal. In two of four patients with metastases and two of six patients with hepatomas, scintiangiograms revealed "tumor stain" that was not evident on radiopaque afteriography. Conclusions from this study are: (A) neoplastic arterialization or "tumor stain" is more readily detected by scintiangiography than by radiopaque arteriography; (B) a normal scintigram and a "tumor stain" on the scintiangiogram in a patient with a known primary neoplasm outside the liver is suggestive of hepatic metastases; and (C) a normal scintigram and scintiangiogram make neoplastic involvement of the liver improbable. Dynamic hepatic scintiangiography is a simple, clinically useful method for increasing the specificity of diagnosis of diagnosis of space-occupying lesions of the liver and should be part of the evaluation for possible neoplastic involvement.     

BMP2,3,4,5 mRNA在三叉神经中的表达分析

目的：明确 Ｂ Ｍ Ｐｓ 与外周神经的关系。方法：用原位杂交方法观察 Ｂ Ｍ Ｐ２,３,４,５ 的ｍ Ｒ Ｎ Ａ在三叉神经中的表达。结果：在外周神经（三叉神经）中均有 Ｂ Ｍ Ｐ２,３,４,５ ｍ Ｒ Ｎ Ａ 分布, Ｂ Ｍ Ｐ２,３,４,５ 的分布主要位于构成神经纤维髓鞘的雪旺细胞中;此外发现 Ｂ Ｍ Ｐ２ 在部分神经纤维中也有表达。结论：首次确定了 Ｂ Ｍ Ｐ２,３,４,５ 在外周神经中的表达和分布,揭示了 Ｂ Ｍ Ｐ２,３,４,５可能在外周神经的发育和再生以及形态结构的维持中发挥着调控作用。     

An immunohistochemical study of keratin expression in ameloblastoma from a Kenyan population

OBJECTIVES: Ameloblastomas appear to exhibit biological heterogeneity and, except in the case of malignancy, histological appearances that do not always allow their behaviour to be predicted. The aim of this study was to assess keratin expression in African ameloblastomas and to correlate this with their clinical and histological features. MATERIALS AND METHODS: Expression of simple keratins 7, 8, 18 and 19; cornification keratins 1 and 10; basal and differentiation keratins 5 and 14 and hyperproliferation-related keratins 6 and 16 in 14-39 cases of ameloblastoma was assessed by immunohistochemical methods. RESULTS: There was patchy expression of keratin 7 in the suprabasal and stellate reticulum-like cells in some cases. All cases showed similar weak expression for keratins 8 and 18 in suprabasal and stellate reticulum-like cells but none showed keratin 1 or 10 expression. There was intense expression of keratins 5, 14 and 19 by all tumour cells suggesting that they may retain basal cell characteristics with a potential for proliferation. No consistent relationship was seen between histological types and keratin expression pattern. However, keratins 6 and 16, expressed by suprabasal and stellate reticulum-like cells, showed a marked variation within and between cases, with the highest levels of expression in squamous strands. CONCLUSIONS: We propose that squamous strands may represent the sites of most active growth within individual tumours and expression of keratins 6, 16 and 19 may be predictors of rapid growth. There is a need for further investigation of this in longitudinal clinical studies.     

The contribution of activated factor XIII to fibrinolytic resistance in experimental pulmonary embolism

BACKGROUND: The resistance of thrombi to fibrinolysis induced by plasminogen activators remains a major impediment to the successful treatment of thrombotic diseases. This study examines the contribution of activated factor XIII (factor XIIIa) to fibrinolytic resistance in experimental pulmonary embolism. METHODS AND RESULTS: The fibrinolytic effects of specific inhibitors of factor XIIIa-mediated fibrin-fibrin cross-linking and alpha2-antiplasmin-fibrin cross-linking were measured in anesthetized ferrets with pulmonary emboli. Five experimental groups were treated with heparin (100 U/kg) and/or tissue plasminogen activator (TPA, 1 mg/kg) and the percent (mean+/-SD) lysis of emboli was determined: (1) control, normal factor XIIIa activity (14.1+/-4. 8% lysis); (2) inhibited factor XIIIa activity (42.7+/-7.4%); (3) normal factor XIIIa activity+TPA (32.3+/-7.7%); (4) inhibited factor XIIIa activity+TPA (76.0+/-11.9%); and (5) inhibited alpha2-antiplasmin-fibrin cross-linking+TPA (54.7+/-3.9%). Inhibition of factor XIIIa activity increased endogenous lysis markedly (group 1 versus 2; P<0.0001), to a level comparable to that achieved with TPA (group 2 versus 3; P<0.05). Among groups receiving TPA, selective inhibition of factor XIII-mediated alpha2-antiplasmin-fibrin cross-linking enhanced lysis (group 3 versus 5; P<0.0005). Complete inhibition of factor XIIIa also amplified lysis (group 3 versus 4; P<0.0001) and had greater effects than inhibition of alpha2-antiplasmin cross-linking alone (group 4 versus 5; P<0.0005). No significant fibrinogen degradation occurred in any group. CONCLUSIONS: Factor XIIIa-mediated fibrin-fibrin and alpha2-antiplasmin-fibrin cross-linking both caused experimental pulmonary emboli to resist endogenous and TPA-induced fibrinolysis. This suggests that factor XIIIa may play a critical role in regulating fibrinolysis in human thrombosis.     

A new era for radiolabeled antibodies in cancer?

Radioimmunotherapy (RIT), a therapy targeted to tumor cells, is a modality that can currently deliver radiation to tumor cells at levels 3-50-times higher than to the normal tissue with the next highest dose. RIT appears promising for future cancer therapy. Clinical responses in patients with advanced cancer have frequently been achieved with RIT as a single agent. Extended complete remissions and even increased survival have been achieved in lymphoma. Similar results in other cancers seem likely with RIT in combination therapy.     

67Cu-2IT-BAT-Lym-1 pharmacokinetics, radiation dosimetry, toxicity and tumor regression in patients with lymphoma.

Lym-1, a monoclonal antibody that preferentially targets malignant lymphocytes, has induced therapeutic responses and prolonged survival in patients with non-Hodgkin's lymphoma when labeled with 1311. Radiometal-labeled antibodies provide higher tumor radiation doses than corresponding 1311 antibodies. 67Cu has an exceptional combination of properties desirable for radioimmunotherapy, including gamma and beta emissions for imaging and therapy, respectively, a biocompatible half-time and absence of pathways contributing to myelotoxicity. The radioimmunoconjugate, 67Cu-21T-BAT-Lym-1, has been shown to be efficacious in nude mice bearing human Burkitt's lymphoma (Raji) xenografts. Based on these results, a clinical study of the pharmacokinetics and dosimetry of 67Cu-21T-BAT-Lym-1 in patients with lymphoma was initiated. METHODS: Eleven patients with advanced stage 3 or 4 lymphoma were given a preload dose of unmodified Lym-1, then an imaging dose of 126-533 MBq (3.4-14.4 mCi) 67Cu-21T-BAT-Lym-1. Total Lym-1 ranged from 25 to 70 mg dependent on the specific activity of the radioimmunoconjugate and was infused at a rate of 0.5-1 mg/min. Imaging, physical examination, including caliper measurement of superficial tumors, and analysis of blood, urine and fecal samples were performed for a period of 6-13 d after infusion to assess pharmacokinetics, radiation dosimetry, toxicity and tumor regression. RESULTS: In 7 patients, in whom superficial tumors had been accurately measured, tumors regressed from 18% to 75% (mean 48%) within several days of 67Cu-21T-BAT-Lym-1 infusion. The uptake and biological half-time of 67Cu-21T-BAT-Lym-1 in tumors were greater than those of normal tissues, except the mean liver half-time exceeded the mean tumor half-time. The mean tumor-to-marrow radiation ratio was 32:1, tumor-to-total body was 24:1 and tumor-to-liver was 1.5:1. Images were of very good quality; tumors and normal organs were readily identified. Mild and transient Lym-1 toxicity occurred in 6 patients; 1 patient developed a human antimouse antibody. There were no significant changes in blood counts or serum chemistries indicative of radiation toxicity. CONCLUSION: Because of the long residence time of 67Cu-21T-BAT-Lym-1 in tumors, high therapeutic ratios were achieved and, remarkably, numerous tumor regressions were observed after imaging doses. The results indicate considerable therapeutic potential for 67Cu-21T-BAT-Lym-1.     

Breast cancer–derived GM-CSF regulates arginase 1 in myeloid cells to promote an immunosuppressive microenvironment

Tumor-infiltrating myeloid cells contribute to the development of the immunosuppressive tumor microenvironment. Myeloid cell expression of arginase 1 (ARG1) promotes a protumor phenotype by inhibiting T cell function and depleting extracellular l-arginine, but the mechanism underlying this expression, especially in breast cancer, is poorly understood. In breast cancer clinical samples and in our mouse models, we identified tumor-derived GM-CSF as the primary regulator of myeloid cell ARG1 expression and local immune suppression through a gene-KO screen of breast tumor cell–produced factors. The induction of myeloid cell ARG1 required GM-CSF and a low pH environment. GM-CSF signaling through STAT3 and p38 MAPK and acid signaling through cAMP were required to activate myeloid cell ARG1 expression in a STAT6-independent manner. Importantly, breast tumor cell–derived GM-CSF promoted tumor progression by inhibiting host antitumor immunity, driving a significant accumulation of ARG1-expressing myeloid cells compared with lung and melanoma tumors with minimal GM-CSF expression. Blockade of tumoral GM-CSF enhanced the efficacy of tumor-specific adoptive T cell therapy and immune checkpoint blockade. Taken together, we show that breast tumor cell–derived GM-CSF contributes to the development of the immunosuppressive breast cancer microenvironment by regulating myeloid cell ARG1 expression and can be targeted to enhance breast cancer immunotherapy.