N-acetyl-cysteine reduces neointimal thickening and procoagulant activity after balloon-induced injury in abdominal aortae of New Zealand white rabbits

BACKGROUND: Procoagulant activity and oxidative stress generated by balloon injury to normal vessels promote the migration of medial smooth muscle cells and their proliferation in the intima. We hypothesised that administering levo N-acetyl-cysteine (NAC) i.v. at the time of injury, and s.c. before and after injury would reduce neointimal formation 4 weeks later and would regulate procoagulant activity in vessels with neointima undergoing ballooning a second time. METHODS AND RESULTS: at the time of injury rabbits received: NAC, unfractionated heparin (HEP) or both (NAC + HEP). Neointimal thickening at 28 days, calculated as the ratio between the intimal and medial area, was attenuated after NAC, HEP and NAC+HEP by 39%, 30% and 47% respectively when compared to untreated injured animals (CONTROLS) (p <0.05). At 28 days, bound thrombin activity and platelet adhesion 1 h after a repeated balloon injury decreased in animals receiving NAC, HEP and NAC+HEP bv 54%, 63% and 64% for thrombin activity (p <0.05 vs CONTROLS), and by 56%, 66% and 75% respectively for 111Indium-platelet deposition (p <0.05 vs CONTROLS). CONCLUSIONS: NAC in-vivo was effective in reducing neointimal thickening and procoagulant response after balloon injury.     

Inhibition of multiple vascular endothelial growth factor receptors (VEGFR) blocks lymph node metastases but inhibition of VEGFR-2 is sufficient to sensitize tumor cells to platinum-based chemotherapeutics

Vascular endothelial growth factor receptors (VEGFR) have important roles in cancer, affecting blood and lymphatic vessel functionality as well as tumor cells themselves. We compared the efficacy of a VEGFR tyrosine kinase inhibitor, PTK787/ZK222584 (PTK/ZK), which targets the three VEGFRs, with blocking antibodies directed against VEGFR-2 (DC101) or VEGF-A (Pab85618) in a metastatic melanoma model. Although all inhibitors exerted comparable effects on primary tumor growth, only PTK/ZK significantly reduced lymph node metastasis formation. A comparable decrease in lymphatic vessel density following blockade of VEGFR-2 (DC101) or the three VEGFRs (PTK/ZK) was observed in the metastases. However, the functionality of lymphatics surrounding the primary tumor was more significantly disrupted by PTK/ZK, indicating the importance of multiple VEGFRs in the metastatic process. The antimetastatic properties of PTK/ZK were confirmed in a breast carcinoma model. B16/BL6 tumor cells express VEGF ligands and their receptors. Blockade of a VEGFR-1 autocrine loop with PTK/ZK inhibited tumor cell migration. Furthermore, the tumor cells also showed enhanced sensitivity to platinum-based chemotherapy in combination with PTK/ZK, indicating that autocrine VEGFRs are promoting tumor cell migration and survival. In summary, our results suggest that, in addition to blocking angiogenesis, combined inhibition of the three VEGFRs may more efficiently target other aspects of tumor pathophysiology, including lymphatic vessel functionality, tumor cell dissemination, survival pathways, and response to chemotherapeutic compounds.     

The enamel matrix derivative (Emdogain) enhances human tongue carcinoma cells gelatinase production, migration and metastasis formation

Enamel matrix derivative Emdogain (EMD) is widely used in periodontal treatment to regenerate lost connective tissue and to improve the attachment of the teeth. Gelatinases (MMP-2 and -9) have an essential role in the promotion and progression of oral cancer growth and metastasis formation. We studied the effects of EMD on human tongue squamous cell carcinoma (HSC-3) cells in vitro and in vivo. In vitro, EMD (100 microg/ml and 200 microg/ml) remarkably induced the MMP-2 and -9 production from HSC-3 cells analysed by zymography and enzyme-linked immunosorbent assay. EMD also slightly induced the MMP-2 and -9 production from benign human mucosal keratinocytes (HMK). Furthermore, EMD clearly induced the transmigration of HSC-3 cells but had no effect on the HMK migration in transwell assays. The in vitro wound closure of HSC-3 cells was notably accelerated by EMD, whereas it had only minor effect on the wound closure of HMKs. The migration of both cell lines was inhibited by a selective cyclic anti-gelatinolytic peptide CTT-2. EMD had no effect on HSC-3 cell proliferation or apoptosis and only a limited effect on cell attachment to various extracellular matrix components. The in vivo mice experiment revealed that EMD substantially induced HSC-3 xenograft metastasis formation. Our results suggest that the use of EMD for patients with oral mucosal carcinomas or premalignant lesions should be carefully considered, possibly avoided.     

Novel Mutations Widen the Phenotypic Spectrum of Slow Skeletal/β‐Cardiac Myosin (MYH7) Distal Myopathy

Laing early onset distal myopathy and myosin storage myopathy are caused by mutations of slow skeletal/β‐cardiac myosin heavy chain encoded by the gene MYH7, as is a common form of familial hypertrophic/dilated cardiomyopathy. The mechanisms by which different phenotypes are produced by mutations in MYH7, even in the same region of the gene, are not known. To explore the clinical spectrum and pathobiology, we screened the MYH7 gene in 88 patients from 21 previously unpublished families presenting with distal or generalized skeletal muscle weakness, with or without cardiac involvement. Twelve novel mutations have been identified in thirteen families. In one of these families, the father of the proband was found to be a mosaic for the MYH7 mutation. In eight cases, de novo mutation appeared to have occurred, which was proven in four. The presenting complaint was footdrop, sometimes leading to delayed walking or tripping, in members of 17 families (81%), with other presentations including cardiomyopathy in infancy, generalized floppiness, and scoliosis. Cardiac involvement as well as skeletal muscle weakness was identified in nine of 21 families. Spinal involvement such as scoliosis or rigidity was identified in 12 (57%). This report widens the clinical and pathological phenotypes, and the genetics of MYH7 mutations leading to skeletal muscle diseases.     

Co-activation of PIK3CA and Yap promotes development of hepatocellular and cholangiocellular tumors in mouse and human liver

Activation of the PI3K and Yes-associated protein (Yap) signaling pathways has been independently reported in human hepatocellular carcinoma (HCC). However, the oncogenic interactions between these two cascades in hepatocarcinogenesis remain undetermined. To assess the consequences of the crosstalk between the PI3K and Yap pathways along liver carcinogenesis, we generated a mouse model characterized by combined overexpression of activated mutant forms of PIK3CA (PIK3CAH1047R) and Yap (YapS127A) in the mouse liver using hydrodynamic transfection (PIK3CA/Yap). In addition, suppression of PI3K and Yap pathways was conducted in human HCC and cholangiocarcinoma (CCA) cell lines. We found that concomitant activation of PI3K and Yap pathways triggered rapid liver tumor development in mice. Histologically, tumors were pure HCC, CCA, or mixed HCC/CCA. At the molecular level, PIK3CA/Yap tumors were characterized by activation of the mTORC1/2, ERK/MAPK, and Notch pathways. Simultaneous activation of PI3K and Yap pathways frequently occurred in human liver tumor specimens and their combined suppression was highly detrimental for the growth of HCC and CCA cell lines. In conclusion, our study demonstrates the oncogenic cooperation between PI3K and Yap pathways along liver carcinogenesis. The PIK3CA/Yap mouse represents an important preclinical liver tumor model for the development of novel therapeutics against this malignancy.     

Catheter-aided extraction of a steel coil accidentally lodged in the right ventricle

In one case a steel coil similar to the Gianturco coil accidentally lodged in the outflow tract of the right ventricle during the embolization of a pulmonary arteriovenous fistula. Extraction of the coil with an intravascular foreign body retrieval set (Cook Inc., Bloomington Ind.) was unsuccessful because the extraction wire broke. An improvised device was then employed, using a Cordis 8 French multipurpose catheter and a single stainless steel wire designed for surgical osteosynthesis. The steel coil was successfully caught by the device and pulled out via the femoral vein.     

Polyaniline as pH-sensitive component in plasticized PVC membranes

The pH and redox sensitivity of electrically conducting polymer films consisting of a mixture of polyaniline (PANI) and plasticized poly(vinyl chloride) (PVC) have been studied with potentiometry, UV–vis spectroscopy and energy dispersive X-ray analysis (EDXA). It is well known that PANI is highly H⁺-selective and can easily be dissolved in many organic solvents with functionalized organic acids. PANI is therefore very suitable to be used as a H⁺-sensitive component in plasticized PVC membranes. In this work, we have studied the behaviour of PANI as the H⁺-sensitive component in plasticized PVC membranes as well as the influence of added lipophilic salts, tridodecylmethylammonium chloride (TDMACl) and potassium tetrakis(4-chlorophenyl)borate (KTpClPB), on the pH and redox sensitivity of these membranes. The pH sensitivity was studied between pH 2 and 9. The electrode membranes were prepared according to the all-solid-state electrode configuration by placing the membrane directly on a glassy carbon substrate. The PANI content in the membranes was varied from 0% to 100% (m/m) and the TDMACl and KTpClPB content from 0% to 40% (m/m). PANI was dissolved in tetrahydrofuran (THF) with phosphoric acid dihexadecyl ester. It was found that appropriate amounts of plasticized PVC decreases the hysteresis effect of pure PANI that was observed in the potentiometric measurements. It is also shown that TDMACl facilitates the emeraldine salt (ES)–emeraldine base (EB) transition of PANI while KTpClPB hinders it and allows PANI to stay in the conducting ES form even at pH 9. Differences in the redox sensitivity of membranes containing TDMACl and KTpClPB will also be discussed.     

免疫靶向药物治疗非小细胞肺癌的最新研究进展

随着精准医学和生物技术的发展,除了EGFR基因,非小细胞肺癌中ALK、BRAF、HER2、KRAS、MEK1、MET、NRAS、PIK3CA、RET、ROS1等多个基因突变的研究也逐渐取得更大突破。相比化疗时代,靶向和免疫治疗显著延长了晚期非小细胞肺癌患者的生存时间,使晚期转移性肺癌患者的中位生存期延长至23～27个月,5年生存率达14.6%以上。2020年,非小细胞肺癌新药的进展和获批均呈现井喷状态,特别是靶向和免疫治疗领域产生了范式转变,每一项成功的数据都为晚期非小细胞肺癌患者的生存带来了更多的选择和希望。本文拟对2020年新上市和获批一线治疗非小细胞肺癌的免疫靶向新药进行介绍和总结,以期为临床用药提供一定的理论基础。