https://cancerbiologyprogram.med.wayne.edu/pdfs/hallmarks_cancer_article.pdf

Hallmarks of cancer: the next generation.

The hallmarks of cancer.

抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Recent data have expanded the concept that inflammation is a critical component of tumour progression. Many cancers arise from sites of infection, chronic irritation and inflammation. It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration. In addition, tumour cells have co-opted some of the signalling molecules of the innate immune system, such as selectins, chemokines and their receptors for invasion, migration and metastasis. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development.

Inflammation and cancer

The HER-2/neu oncogene is a member of the erbB-like oncogene family, and is related to, but distinct from, the epidermal growth factor receptor. This gene has been shown to be amplified in human breast cancer cell lines. In the current study, alterations of the gene in 189 primary human breast cancers were investigated. HER-2/neu was found to be amplified from 2- to greater than 20-fold in 30% of the tumors. Correlation of gene amplification with several disease parameters was evaluated. Amplification of the HER-2/neu gene was a significant predictor of both overall survival and time to relapse in patients with breast cancer. It retained its significance even when adjustments were made for other known prognostic factors. Moreover, HER-2/neu amplification had greater prognostic value than most currently used prognostic factors, including hormonal-receptor status, in lymph node-positive disease. These data indicate that this gene may play a role in the biologic behavior and/or pathogenesis of human breast cancer.

https://science.sciencemag.org/content/sci/235/4785/177.full.pdf

Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene

We have studied the binding of proteins to a synthetic DNA fragment corresponding to a 21 base pair sequence in the upstream region of the human c-myc gene. This sequence has previously been reported to bind the c-myc protein, thus representing a putative site for autoregulation of the c-myc gene (Ariga et al., 1989). Our electrophoretic mobility shift assays indicated that this DNA fragment binds to a factor present in nuclear extracts from HeLa cells. However, analysis of extracts from other cells indicated that this binding does not correlate with the presence of the c-myc protein. No binding was observed using c-myc protein translated in vitro. Also, anti-c-myc antibodies could not inhibit binding of this factor. These experiments indicate, that nucleotides -2193 to -2173 from the P1 promoter of the c-myc gene are able to bind a nuclear factor, and that this factor most likely does not include the c-myc protein.

Binding of a nuclear factor to the upstream region of the c-myc gene.

Lymphatic-to-blood vessel transdifferentiation in zebrafish

Understanding the pathological mechanisms unfolding after chronic traumatic brain injury (TBI) could reveal new therapeutic entry points. During the post-TBI sequel, the involvement of cerebrospinal fluid drainage through the meningeal lymphatic vessels was proposed. Here, we used K14-VEGFR3-Ig transgenic mice to analyze whether a developmental dysfunction of meningeal lymphatic vessels modifies post-TBI pathology. To this end, a moderate TBI was delivered by controlled cortical injury over the temporal lobe in male transgenic mice or their littermate controls. We performed MRI and a battery of behavioral tests over time to define the post-TBI trajectories. In vivo analyses were integrated by ex-vivo quantitative and morphometric examinations of the cortical lesion and glial cells. In post-TBI K14-VEGFR3-Ig mice, the recovery from motor deficits was protracted compared to littermates. This outcome is coherent with the observed slower hematoma clearance in transgenic mice during the first two weeks post-TBI. No other genotype-related behavioral differences were observed, and the volume of cortical lesions imaged by MRI in vivo, and confirmed by histology ex-vivo, were comparable in both groups. However, at the cellular level, post-TBI K14-VEGFR3-Ig mice exhibited an increased percentage of activated Iba1 microglia in the hippocampus and auditory cortex, areas that are proximal to the lesion. Although not impacting or modifying the structural brain damage and post-TBI behavior, a pre-existing dysfunction of meningeal lymphatic vessels is associated with morphological microglial activation over time, possibly representing a sub-clinical pathological imprint or a vulnerability factor. Our findings suggest that pre-existing mLV deficits could represent a possible risk factor for the overall outcome of TBI pathology. 

https://doi.org/10.1016/j.bbih.2022.100466

Significance of developmental meningeal lymphatic dysfunction in experimental post-traumatic injury

improved pulmonary compliance and gas exchange after lung transplantation. Aim: We report our clinical experience of FOB instillation of surfactant in severe RI after human lung transplantation. Methods: Retrospective review of 92 consecuetive lung or heart lung transplants performed at a single institution. Severe RI was defined as diffuse roentgenographic alveolar infiltrates, worsening hypoxaemia and decreased lung compliance within 72 hours of lung transplantation. One 5 ml vial of surfactant (Beractant Bovine Lung Extract, Abbott, Australasia Ptd. Ltd, 20mg/ml phospholipid) was instilled into each segmental bronchus upon diaqnosis of RI. Results: Five patients (all bilateral sequential) of mean age 49 years were diagnosed with RI and surfactant administered at a mean of 42 hours (range 2.3–98) post transplant. Mean graft ischaemic time was 414 minutes (range 232–625) and cardiopulmonary bypass time 167 minutes (range 0–210). Mean oxygen index (PaO2mmHg/FiO2) pre and 48 hours post surfactant was 70 and 223 respectively. Significant resolution of radiological infiltrates was evident in all cases within 24 hours. Successful extubation occurred at a mean of 15.8 days and survival is 100% at 16.2 months (range 1–49). Conclusions: Bronchoscopic instillation of surfactant improves oxygenation and prognosis following severe RI in lung transplant recipients. It represents a non-invasive therapeutic alternative to extra corporeal membrane oxygenation to significantly improve clinical outcome in RI.

Kari Alitalo

Papers

Binding of a nuclear factor to the upstream region of the c-myc gene.

Lymphatic-to-blood vessel transdifferentiation in zebrafish

Significance of developmental meningeal lymphatic dysfunction in experimental post-traumatic injury

Common anti-inflammatory and diverse smooth muscle cell effects of AAV-mediated angiopoietin-1 and -2 expression in rat cardiac allografts

The biology of vascular endothelial growth factors: [review]