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

Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.

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Tumour exosome integrins determine organotropic metastasis

Bevacizumab plus Irinotecan,Fluorouracil,and Leucovorin for Metastatic Colorectal Cancer

Genomic analysis provides insights into the role of copy number variation in disease, but most methods are not designed to resolve mixed populations of cells. In tumours, where genetic heterogeneity is common, very important information may be lost that would be useful for reconstructing evolutionary history. Here we show that with flow-sorted nuclei, whole genome amplification and next generation sequencing we can accurately quantify genomic copy number within an individual nucleus. We apply single-nucleus sequencing to investigate tumour population structure and evolution in two human breast cancer cases. Analysis of 100 single cells from a polygenomic tumour revealed three distinct clonal subpopulations that probably represent sequential clonal expansions. Additional analysis of 100 single cells from a monogenomic primary tumour and its liver metastasis indicated that a single clonal expansion formed the primary tumour and seeded the metastasis. In both primary tumours, we also identified an unexpectedly abundant subpopulation of genetically diverse 'pseudodiploid' cells that do not travel to the metastatic site. In contrast to gradual models of tumour progression, our data indicate that tumours grow by punctuated clonal expansions with few persistent intermediates.

/pdf/tumour-evolution-inferred-by-single-cell-sequencing-2d93wjd7r9.pdf

Tumour evolution inferred by single-cell sequencing

Of the many types of human papillomavirus (HPV), more than 30 infect the genital tract. The association between certain oncogenic (high-risk) strains of HPV and cervical cancer is well established. Although HPV is essential to the transformation of cervical epithelial cells, it is not sufficient, and a variety of cofactors and molecular events influence whether cervical cancer will develop. Early detection and treatment of precancerous lesions can prevent progression to cervical cancer. Identification of precancerous lesions has been primarily by cytologic screening of cervical cells. Cellular abnormalities, however, may be missed or may not be sufficiently distinct, and a portion of patients with borderline or mildly dyskaryotic cytomorphology will have higher-grade disease identified by subsequent colposcopy and biopsy. Sensitive and specific molecular techniques that detect HPV DNA and distinguish high-risk HPV types from low-risk HPV types have been introduced as an adjunct to cytology. Earlier detection of high-risk HPV types may improve triage, treatment, and follow-up in infected patients. Currently, the clearest role for HPV DNA testing is to improve diagnostic accuracy and limit unnecessary colposcopy in patients with borderline or mildly abnormal cytologic test results.

Human Papillomavirus and Cervical Cancer

Filamentous inclusions (F1) are unusual, irregularly shaped cytoplasmic inclusions, which are mostly found in acinar cell carcinomas of the pancreas and are consequently thought to be an abnormal zymogen granule type. This study describes identical inclusions in acinar, centroacinar, and small duct epithelial cells from nonneoplastic pancreas, as well as those found in tumor cells from a mixed acinar-endocrine pancreatic carcinoma. An ultrastructural and immunogold labeling demonstration indicates that these inclusions are aggregates of intermediate filaments immunoreacting with the anti-cyto-keratin AE1/AE3 mixture and with V9 clone anti-vimentin monoclonal antibodies. Their pleomorphic appearance, variable immunoreactivity, and frequent association with lipid droplets and secondary lysosomes, mostly of the angulate type, led to the hypothesis that the F1 undergo a degenerative remodeling pathway similar to that proposed for hepatic Mal-lory bodies. A survey of the literature on Fl and human tumors sugge...

Filamentous inclusions in nonneoplastic and neoplastic pancreas: an ultrastructural and immunogold labeling study.

Is radical surgery always curative in pancreatic neuroendocrine tumors? A cure model survival analysis.

The intermediate filament (IF) proteins present in the normal and pathological exocrine human pancreas were studied by immunolocalization using antibodies to cytokeratins (CKs) and vimentin. Acinar cells of normal pancreas showed a presence of simple CKs 8 and 18. Duct epithelium consistently expressed CKs 7, 8, 18 and 19 whereas centroacinar cells were rather low in CK 7. A subpopulation of CK 4 cells was detected in inter-intralobular ducts. In addition, some ducts contained individual cells or groups of cells that were positive for the stratification-related CKs (CKs 4, 5, 13, 15, 16). All pancreatic ductal adenocarcinomas regularly expressed CKs 7, 8, 18, 19 and were also positive for the 34 beta E12 antibody. Cytokeratin 4 was detected in a minor population of tumor cells. Pancreatic carcinoma also contained minor amounts of stratification-related CKs in variable combinations. Mucinous cystoadenocarcinoma showed the presence of CKs 7, 8, 18, 19 and was also positive for 34 beta E12, whereas the serous microcystic tumor presented CKs 8, 18, 19 and a variable amount of CKs 4 and 7. The duct-ductular alterations of the exocrine pancreas contained a different combination and distribution of CK isoforms similar to normal pancreatic ductal system. Mucinous hypertrophy and pyloric gland metaplasia reacted with antibodies to CKs 7, 8, 18 and 19. Vimentin was focally present both in normal and neoplastic tissue. Our results indicate that pancreatic ducts are characterized by an intrinsic "biliary-pancreatic duct type" immunoprofile (CKs 7, 8, 18 and 19), in contrast to acinar cells expressing exclusively CKs 8 and 18. We also detected a subpopulation of ducts regularly expressing CK 4. Surprisingly, several stratification-related CKs were detected both in normal and neoplastic exocrine pancreas. Moreover, the differentiation phenotypes of pancreatic tumors were reminiscent of normal cellular compartments.

Expression of intermediate filaments in normal and neoplastic exocrine pancreas

To the Editor: Alcohol-induced chronic pancreatitis is the most frequent form of chronic pancreatitis in Italy (l), as in most Western countries (2). Less common forms seen are idiopathic and hereditary chronic pancreatitis and that secondary to hypercalcemia (1-3). The clinical and histological features of these forms are well documented (1,3,4). We recently saw a jaundiced patient who was thought to have cancer of the head of the pancreas. Histological examination of the resected pancreas segment, however, excluded the presence of cancer and revealed an uncommon form of chronic pancreatitis. In this report, we describe this extremely rare case.

Donatella Santini

Papers

Filamentous inclusions in nonneoplastic and neoplastic pancreas: an ultrastructural and immunogold labeling study.

Is radical surgery always curative in pancreatic neuroendocrine tumors? A cure model survival analysis.

Expression of intermediate filaments in normal and neoplastic exocrine pancreas

An unusual case of chronic pancreatitis of possible immune origin.

WHO 2010 classification of pancreatic endocrine tumors. is the new always better than the old