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Background: Hodgkin's lymphoma (HL) survivors who undergo radiotherapy experience increased risks of second cancers (SC) and cardiac sequelae. To reduce such risks, extended-field radiotherapy (RT) for HL has largely been replaced by involved field radiotherapy (IFRT). While it has generally been assumed that IFRT will reduce SC risks, there are few data that quantify the reduction in dose to normal tissues associated with modern RT practice for patients with mediastinal HL, and no estimates of the expected reduction in SC risk.

BACKGROUND.Estimates of radiation‐related second cancer risk among Hodgkin lymphoma survivors are largely based on radiation therapy (RT) fields and doses no longer in use, and these estimates do not account for differences in normal tissue dose among individual patients. This study gives individualized estimates for the risks of lung and female breast cancer expected with contemporary involved‐field RT and low‐dose (20 Gy) RT for mediastinal Hodgkin lymphoma.METHODS.Three RT plans were constructed for 37 consecutive patients with mediastinal Hodgkin lymphoma: 35 Gy mantle RT, 35 Gy involved‐field RT (IFRT), and 20 Gy IFRT. For each of the 111 RT plans, individual‐level dosimetry data were incorporated into a cell initiation/inactivation/proliferation model to estimate the excess relative risk (ERR) and cumulative incidence of radiation‐induced second cancer.RESULTS.ERR estimates were compatible with results of epidemiological studies. Compared with 35 Gy mantle radiation therapy, 35 Gy IFRT was predicted to reduce the 20‐year ERRs of breast and lung cancer by 63% and 21%, respectively, primarily because of lower normal tissue doses with the omission of axillary RT. Low‐dose (20 Gy) IFRT was associated with a 77% and 57% decrease in these ERRs. Patient‐specific differences in normal tissue dose with IFRT led to 11‐fold and 3.6‐fold variations among individual's estimates of breast and lung cancer ERR, respectively.CONCLUSIONS.Contemporary IFRT is predicted to substantially reduce risk of secondary breast and lung cancer compared with mantle RT, with considerable variation in risk among individuals. Individualized prospective risk estimates could facilitate patient‐specific counseling and the development of more effective RT techniques. Cancer 2007. © 2007 American Cancer Society.

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Unsupervised learning has been a long-standing goal of machine learning and is especially important for medical image analysis, where the learning can compensate for the scarcity of labeled datasets. A promising subclass of unsupervised learning is self-supervised learning, which aims to learn salient features using the raw input as the learning signal. In this paper, we use a contrastive self-supervised learning method Chen et al. ( 2020a) that achieved state-of-the-art results on natural-scene images, and apply this method to digital histopathology by collecting and training on 60 histopathology datasets without any labels. We find that combining multiple multi-organ datasets with different types of staining and resolution properties improves the quality of the learned features. Furthermore, we find drastically subsampling a dataset (e.g., using1% of the available image patches) does not negatively impact the learned representations, unlike training on natural-scene images. Linear classifiers trained on top of the learned features show that networks pretrained on digital histopathology datasets perform better than ImageNet pretrained networks, boosting task performances up to 7.5% in accuracy and 8.9% in F 1 . These findings may also be useful when applying newer contrastive techniques to histopathology data. Pretrained PyTorch models are made publicly available at https://github.com/ozanciga/self-supervised-histopathology.

Thousands of circular RNAs (circRNAs) have been recently discovered in cumulus cells and oocytes from several species. However, the expression and function of circRNA during porcine oocyte meiotic maturation have been never examined. Here, we separately identified 7,067 and 637 circRNAs in both cumulus cells and oocytes via deep sequencing and bioinformatic analysis. Further analysis revealed that a faction of circRNAs is differentially expressed (DE) in a developmental stage-specific manner. The host genes of DE circRNAs are markedly enriched to multiple signaling pathways associated with cumulus cell function and oocyte maturation. Additionally, most DE circRNAs harbor several miRNA targets, suggesting that these DE circRNAs potentially act as miRNA sponge. Importantly, we found that maternal circARMC4 knockdown by siRNA microinjection caused a severely impaired chromosome alignment, and significantly inhibited first polar body extrusion and early embryo development. Taken together, these results demonstrate for the first time that circRNAs are abundantly and dynamically expressed in a developmental stage-specific manner in cumulus cells and oocytes, and maternally expressed circARMC4 is essential for porcine oocyte meiotic maturation and early embryo development.

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Summary N6-Methyladenosine (m6A) regulates oocyte-to-embryo transition and the reprogramming of somatic cells into induced pluripotent stem cells. However, the role of m6A methylation in porcine early embryonic development and its reprogramming characteristics in somatic cell nuclear transfer (SCNT) embryos are yet to be known. Here, we showed that m6A methylation was essential for normal early embryonic development and its aberrant reprogramming in SCNT embryos. We identified a persistent occurrence of m6A methylation in embryos between 1-cell to blastocyst stages and m6A levels abruptly increased during the morula-to-blastocyst transition. Cycloleucine (methylation inhibitor, 20 mM) treatment efficiently reduced m6A levels, significantly decreased the rates of 4-cell embryos and blastocysts, and disrupted normal lineage allocation. Moreover, cycloleucine treatment also led to higher levels in both apoptosis and autophagy in blastocysts. Furthermore, m6A levels in SCNT embryos at the 4-cell and 8-cell stages were significantly lower than that in parthenogenetic activation (PA) embryos, suggesting an abnormal reprogramming of m6A methylation in SCNT embryos. Correspondingly, expression levels of m6A writers (METTL3 and METTL14) and eraser (FTO) were apparently higher in SCNT 8-cell embryos compared with their PA counterparts. Taken together, these results indicated that aberrant nuclear transfer-mediated reprogramming of m6A methylation was involved in regulating porcine early embryonic development.