Cisplatin, doxorubicin and fluorouracil (5-FU), drugs belonging to different chemical classes, have been extensively used for chemotherapy of various cancers. Despite extensive investigations into their hepatotoxicity, there is very limited information on their effects on the structure and ultra-structure of liver cells in vivo. Here, we demonstrate for the first time, the effects of these three anticancer drugs on rat liver toxicity using both light and electron microscopy. Light microscopic observations revealed that higher doses of cisplatin and doxorubicin caused massive hepatotoxicity compared to 5-FU treatment, including dissolution of hepatic cords, focal inflammation and necrotic tissues. Interestingly, low doses also exhibited abnormal changes, including periportal fibrosis, degeneration of hepatic cords and increased apoptosis. These changes were confirmed at ultrastructural level, including vesiculated rough endoplasmic reticulum and atrophied mitochondria with ill-differentiated cisternae, dense collection of macrophages and lymphocytes as well as fibrocytes with collagenous fibrils manifesting early sign of fibrosis, especially in response to cisplatin and doxorubicin -treatment. Our results provide in vivo evidence, at ultrastructural level, of direct hepatotoxicity caused by cisplatin, doxorubicin and 5-FU at both light and electron microscopi. These results can guide the design of appropriate treatment regimen to reduce the hepatotoxic effects of these anticancer drugs.

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Key Points Question What are the national prevalence, frequency, and main types of discrimination that adult patients report experiencing in the US health care system? Findings In this nationally representative cross-sectional survey study, 21% of 2137 US adult survey respondents indicated that they had experienced discrimination in the health care system, and 72% of those who had experienced discrimination reported experiencing it more than once. Racial/ethnic discrimination was the most frequently reported type of discrimination respondents experienced. Meaning Experiences of discrimination in the health care system appear to be more common than previously recognized and deserve considerable attention.

Background In the past decade, Lynn Etheredge presented a vision for the Learning Health System (LHS) as an opportunity for increasing the value of health care via rapid learning from data and immediate translation to practice and policy. An LHS is defined in the literature as a system that seeks to continuously generate and apply evidence, innovation, quality, and value in health care. Objective This review aimed to examine themes in the literature and rhetoric on the LHS in the past decade to understand efforts to realize the LHS in practice and to identify gaps and opportunities to continue to take the LHS forward. Methods We conducted a thematic analysis in 2018 to analyze progress and opportunities over time as compared with the initial Knowledge Gaps and Uncertainties proposed in 2007. Results We found that the literature on the LHS has increased over the past decade, with most articles focused on theory and implementation; articles have been increasingly concerned with policy. Conclusions There is a need for attention to understanding the ethical and social implications of the LHS and for exploring opportunities to ensure that these implications are salient in implementation, practice, and policy efforts.

The hyaluronan receptor CD44 plays an important role in facilitating invasion and metastasis of a variety of tumors, including breast carcinomas. CD44 functions as a bioactive signaling transmitter. Although a number of studies have implicated CD44 in breast tumor invasion, the evidence is still circumstantial. We have developed a tetracycline-regulated CD44s (standard form) system in the weakly metastatic breast cancer cell MCF7, which exhibits low endogenous expression of CD44 and generated a new cell line, MCF7F-B5. Induction of CD44s alone affected the growth characteristics of MCF7F-B5 cells by increasing their abilities to proliferate, migrate, and invade in vitro. In addition, we have identified and validated cortactin as a novel transcriptional target of hyaluronan/CD44s signaling in underpinning breast tumor invasion. To test these observations in vivo, we developed a doxycycline (DOX)-regulated CD44s breast cancer xenograft model. Induction of CD44s did not affect the growth rate or local invasion of the primary tumor. However, although no mice from the ؉DOX group developed metastasis, 8 of 11 mice from the ؊DOX group developed secondary tumors to the liver only. Interestingly, metastatic breast tumors expressed high levels of CD44. This study provides in vivo evidence for the role of the standard form of CD44 in promoting breast tumor invasion and metastasis to the liver. Breast cancer cells metastasize from the original tumor site through the vasculature to distant organs such as the liver, lungs, brain, and bones. These cells also invade and exfoliate into body cavities, especially the pleural space, where they grow in suspension within effusions.1 Invasion is the defining event for cancer and the recurring step in the metastatic process. Cell invasion depends, in great part, on the ability of invading cells to attach to and then detach from various types of cells and extracellular components. Although moving to secondary sites, tumor cells use a new set of adhesion, migration, and homing proteins. The adhesion molecule CD44 (also known as homing protein, PGP-1, Hermes antigen, and HUTCH-1) is the principal cell surface receptor for hyaluronic acid (HA), although other extracellular matrix (ECM) proteins, including collagen, fibronectin, and osteopontin, can bind CD44.2 Via its interaction with HA, CD44 functions as a bioactive signaling transmitter, leading to diverse effects on cellular adhesion, migration, and invasion-all of which are important processes in cancer progression as well as in hematopoietic development and wound healing. [3][4][5] CD44 is a ubiquitous multistructural and multifunctional cell surface adhesion molecule involved in cell-cell and cell-matrix interactions. It is the most studied alternatively spliced gene in cancer. Of its 20 exons, the first and last five exons are constant, whereas the 10 intermediate exons are subject to alternative splicing, resulting in the generation of a variable region. Differential utilization of the 10 variable region exons generates multiple i...