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

Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion. Intratumoral hypoxia and genetic alterations can lead to HIF-1alpha overexpression, which has been associated with increased patient mortality in several cancer types. In preclinical studies, inhibition of HIF-1 activity has marked effects on tumour growth. Efforts are underway to identify inhibitors of HIF-1 and to test their efficacy as anticancer therapeutics.

Targeting HIF-1 for cancer therapy

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes.

For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy.

Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

/pdf/guidelines-for-the-use-and-interpretation-of-assays-for-ijf2t30pbq.pdf

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

/pdf/guidelines-for-the-use-and-interpretation-of-assays-for-28d1pi1jvo.pdf

Guidelines for the use and interpretation of assays for monitoring autophagy

The intrinsic limits of conventional cancer therapies prompted the development and application of various nanotechnologies for more effective and safer cancer treatment, herein referred to as cancer nanomedicine. Considerable technological success has been achieved in this field, but the main obstacles to nanomedicine becoming a new paradigm in cancer therapy stem from the complexities and heterogeneity of tumour biology, an incomplete understanding of nano-bio interactions and the challenges regarding chemistry, manufacturing and controls required for clinical translation and commercialization. This Review highlights the progress, challenges and opportunities in cancer nanomedicine and discusses novel engineering approaches that capitalize on our growing understanding of tumour biology and nano-bio interactions to develop more effective nanotherapeutics for cancer patients.

/pdf/cancer-nanomedicine-progress-challenges-and-opportunities-3dukbks14n.pdf

Cancer nanomedicine: progress, challenges and opportunities.

"Stromatogenesis" istheformation ofnewstroma occurring, inparallel withtheneoplastic process, atsites ofactive tumorinvasion, i.e., atthefreesurface ofadevelopingexophytic tumor, attheinvading tumorfront ofanadvancing endophytic tumor, andatsites oftumormetastasis, wherein thenewlyformed stroma disrupts thecontinuity ofnormalstructures, cleaving paths fortheinvading tumorcells. Stromais also present attheheart ofthetumor, butonlyasasecondary eventfollowing tumor advancement andsubsequent incorporation ofitsperiphery intoinnertumorareas. Thenewstroma, composed ofstromal cells andextracellular matrix (ECM),isloose andedematous attheexpanding tumorfronts, andrather dense incentral tumorareasandsites oftumormetastasis. Thestromal cells facing tumorinvasion areintensely proliferating (high MIB-1index) spindle-shaped cells, cc-smooth muscle actin positive, andloaded withthymidine phosphorylase (TP)andSPARC(secreted proteinacidic andrich incysteine). Theassociated ECM isrich incollagen III, SPARC, andnewbloodvessels (CD31)butisdepleted ofcollagen Iandfibronectin. These constitutional changes render stromatogenesis amenable totumorcell invasion and are, incases ofincipient neoplasia, aprospective criterion ofearly stromal invasion. Otherstromal cell orECM constituents, suchasthelactate dehydrogenase-5 (LDH5),theacidic fibroblast growth factor (aFGF), thebasic FGF(bFGF), andthecollagens IIandIV,remainunchanged, andothers arenegative: myosin, desmin, S-100 protein andepidermal growth factor receptor (EGFR). Themechanism ofstromatogenesis is obscure butisprobably stimulated byspecific stromatogenic growth factors, released byneoplastic andinflammatory cells. Itappears that theprocess isneither neoplastic norreactive, butrather isa,hereto unexplained, phenomenon ofhost's complicity in

i"Stromatogenesi s"" andTumor Progression

Pediatric soft tissue tumors should be always operated and sent for a biopsy.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ccr3.4080

Dermatofibrosarcoma protuberans in a child, that’s why soft tissue lesions are not always innocent in children

Merkel cell carcinoma is a rare neuroendocrine malignancy that arises from the dermis, in cases of immunocompromised, middle-aged patients or on skin exposed to sunlight. It only rarely presents in extra-cutaneous locations. We present the case of a 63-year-old female with a mass in the adipose tissue of the upper arm, without skin involvement and concurrent axillary lymph node enlargement. She was treated with wide excision and lymph node dissection; pathology led to the diagnosis of Merkel cell carcinoma, and she was subsequently submitted to adjuvant radiotherapy. No signs of recurrence are present 8 years postoperatively. Primary Merkel cell carcinoma can rarely be located in the adipose tissue without skin involvement. In cases of high suspicion, preoperative MRI scan can show the extent of the lesion, as well as lymph metastases.

Primary ectopic Merkel cell carcinoma without skin involvement-report of a case with prolonged survival.

<jats:p>
				    	    No Abstract
			            	</jats:p>

Is there any special imaging finding in a pedunculated focal nodular hyperplasia with suspected torsion?

Abstract PD-L1/PD-1 pathway is a major pathway exploited by human cancer types, which is a target for current immunotherapy. We investigated tumor microenvironmental factors involved in PD-L1 induction in prostate cancer (PC). We studied the expression of PD-L1 in a series of 66 PCs, in parallel with the expression of hypoxia- and acidity-related immunohistochemical markers (Hypoxia-inducible factor HIF1α, and lactate dehydrogenase LDHA) and tumor-infiltrating lymphocyte TIL density. Experiments with three PC cell lines, the 22Rv1, DU145, and PC3 were conducted focusing on the inducibility of PD-L1 by hypoxia, acidity, lymphocyte interactions, and radiation. In tissues, PD-L1 expression by cancer cells was directly related to PD-L1 expression by TILs and macrophages ( p &lt; 0.05), and the overexpression of HIF1α and LDH5 ( p &lt; 0.05). TIL density was inversely related to ΗΙF1α ( p = 0.02). Exposure of PC cell lines to hypoxia strongly induced PD-L1 and protein and mRNA levels, directly controlled by HIF1α function ( p &lt; 0.001). Irradiation with 20 Gy had no apparent effect on PD-L1 expression. Culturing PC cell lines with culture medium (CM) from PBMCs strongly induced PD-L1 at protein and mRNA levels, independently from HIF1α, which was also confirmed when cells were incubated with Interferon-γ ( p &lt; 0.001). It is concluded that the combination of anti-PD-L1/PD-1 immunotherapy with hypoxia/HIF-targeting may be important in the treatment of specific subgroups of PC patients. 

/pdf/hif1a-dependent-and-independent-pathways-regulate-the-1d0eq6ic.pdf

Alexandra Giatromanolaki

Papers

i"Stromatogenesi s"" andTumor Progression

Dermatofibrosarcoma protuberans in a child, that’s why soft tissue lesions are not always innocent in children

Primary ectopic Merkel cell carcinoma without skin involvement-report of a case with prolonged survival.

Is there any special imaging finding in a pedunculated focal nodular hyperplasia with suspected torsion?

HIF1α-dependent and independent pathways regulate the expression of PD-L1 in prostate cancer