Organ-specific metastasis of breast cancer: molecular and cellular mechanisms underlying lung metastasis

Background

Breast cancer (BC) is the most common type of cancer in women and the second cause of cancer-related mortality world-wide. The majority of BC-related deaths is due to metastasis. Bone, lung, brain and liver are the primary target sites of BC metastasis. The clinical implications and mechanisms underlying bone metastasis have been reviewed before. Given the fact that BC lung metastasis (BCLM) usually produces symptoms only after the lungs have been vastly occupied with metastatic tumor masses, it is of paramount importance for diagnostic and prognostic, as well as therapeutic purposes to comprehend the molecular and cellular mechanisms underlying BCLM. Here, we review current insights into the organ-specificity of BC metastasis, including the role of cancer stem cells in triggering BC spread, the traveling of tumor cells in the blood stream and their migration across endothelial barriers, their adaptation to the lung microenvironment and the initiation of metastatic colonization within the lung.

Conclusions

Detailed understanding of the mechanisms underlying BCLM will shed a new light on the identification of novel molecular targets to impede daunting pulmonary metastases in patients with breast cancer.

     

Age-Dependent Stability of Sensorimotor Functions in the Life-Extended <Emphasis Type="Italic">Drosophila</Emphasis> mutant <Emphasis Type="Italic">Methuselah</Emphasis>

Methuselah is a Drosophila mutant with a 35% increased lifespan. We examined the robustness of methuselah’s sensorimotor abilities in tethered flight as a function of age in experiments designed to test visuomotor synchronization and phototaxis in simulated flight. A total of 282 flies from different age groups (4 hours to 70 days) and genotypes (mth and w1118) were individually tethered under an infrared laser-sensor system that digitally recorded wing-beat frequency (WBF). We found that mth has a higher average WBF throughout most of its lifespan compared to parental control flies (w1118) and develops flight ability at a younger age. Its WBF at late life, however, is not significantly different than that of its parental control line. We further found that mth entrains during flight to motion of a visual grating significantly better than its parental line. These findings suggest that the mth gene not only delays chronological aging but enhances sensorimotor abilities critical to survival during early and middle, but not late life. Edited by Yong-Kyu Kim     

Liver transplant for hepatocellular carcinoma in the United States: Evolving trends over the last three decades

Hepatitis C virus infection has been the most common etiology in HCC‐related liver transplantation (LT). Since 2014, direct‐acting antivirals (DAAs) have dramatically improved HCV cure. We aimed to study the changing pattern of etiologies and impact in outcome in HCC‐related LT according to HCV treatment‐era through retrospective analysis of the Scientific Registry of Transplant Recipients (SRTR) database (1987‐2017). A total of 27 855 HCC‐related liver transplants were performed (median age 59 years, 77% male). In the DAA era (2014‐2017) there has been a 14.6% decrease in LT for HCV‐related HCC; however, HCV remains the most common etiology in 50% of cases. In the same era, there has been a 50% increase in LT for NAFLD‐related HCC. Overall survival was significantly worse for HCV‐related HCC compared to NAFLD‐related HCC during pre‐DAA era (2002‐2013; P = .031), but these differences disappeared in the DAA era. In addition, HCV patients had a significant improvement in survival when comparing the DAA era with IFN era (P < .001). Independent predictors of survival were significantly different in the pre‐DAA era (HCV, AFP, diabetes) than in the DAA era (tumor size). HCV‐related HCC continues to be the main indication for LT in the DAA era, but patients’ survival has significantly improved and is comparable to that of NAFLD‐related HCC.     

Restoration of Euglycemia After Duodenal Bypass Surgery Is Reliant on Central and Peripheral Inputs in Zucker fa/fa Rats

Gastrointestinal bypass surgeries that result in rerouting and subsequent exclusion of nutrients from the duodenum appear to rapidly alleviate hyperglycemia and hyperinsulinemia independent of weight loss. While the mechanism(s) responsible for normalization of glucose homeostasis remains to be fully elucidated, this rapid normalization coupled with the well-known effects of vagal inputs into glucose homeostasis suggests a neurohormonally mediated mechanism. Our results show that duodenal bypass surgery on obese, insulin-resistant Zucker fa/fa rats restored insulin sensitivity in both liver and peripheral tissues independent of body weight. Restoration of normoglycemia was attributable to an enhancement in key insulin-signaling molecules, including insulin receptor substrate-2, and substrate metabolism through a multifaceted mechanism involving activation of AMP-activated protein kinase and downregulation of key regulatory genes involved in both lipid and glucose metabolism. Importantly, while central nervous system–derived vagal nerves were not essential for restoration of insulin sensitivity, rapid normalization in hepatic gluconeogenic capacity and basal hepatic glucose production required intact vagal innervation. Lastly, duodenal bypass surgery selectively altered the tissue concentration of intestinally derived glucoregulatory hormone peptides in a segment-specific manner. The present data highlight and support the significance of vagal inputs and intestinal hormone peptides toward normalization of glucose and lipid homeostasis after duodenal bypass surgery.Obesity is commonly associated with insulin resistance and type 2 diabetes (1). The most effective therapy for alleviating obesity is bariatric surgery (2). In addition to its long-term impact on body weight, a rapid restoration of euglycemia is observed in diabetic patients preceding substantial weight loss (3,4). Despite widespread appreciation of this phenomenon, little is known regarding the underlying mechanism(s). Because insulin resistance is usually a prerequisite for the development of type 2 diabetes, bariatric surgery likely improves insulin sensitivity. To this end, alterations in hormonal milieu and glucomodulatory effects mediated by the gut-brain axis represent two plausible mechanisms. For evaluation of these mechanisms, glucose clamp studies were undertaken in Zucker fa/fa (ZF) rats after duodenal-jejunal bypass surgery (DJB) with and without total subdiaphragmatic vagotomy (TSV). Furthermore, to determine whether improvement in glucoregulation is in part mediated by changes in intestinally derived hormone peptides, we assessed circulating and tissue concentration of a select set of intestinal factors. Our data indicate that DJB was sufficient to rapidly restore euglycemia in ZF rats. This normalization was attributable to improved lipid metabolism, altered patterning of intestinally derived hormones, and insulin sensitivity but was independent of body weight, food intake, and augmented insulin secretion. Importantly, denervation studies underscored the importance of central nervous system (CNS)-derived vagal inputs with respect to hepatic gluconeogenic capacity and regulation of hepatic glucose production (HGP) after DJB.     

The utility of neural network in the diagnosis of Cheyne-Stokes respiration

The aim of this study was to design a diagnostic model to identify patients with Cheyne-Stokes respiration (CSR-CSA) based on indices of oximetric spectral analysis. A retrospective analysis of oximetric recordings of 213 sleep studies conducted over a one-year period at a Veterans Affairs medical facility was performed. A probabilistic neural network (PNN) was developed from salient features of the oximetric spectral analysis, desaturation events and the delta index. A fivefold cross-validation was used to assess the accuracy of the neural network in identifying CSR-CSA. When compared to overnight polysomnography, the PNN achieved a sensitivity of 100% (95% confidence interval [CI] 85%-100%) and a specificity of 99% (95% 97%-100%) with a corresponding area under the curve of 99% (95% CI 99%-100%). When combined with overnight pulse oximetry, PNN offers an accurate and easily applicable tool to detect CSR-CSA.     

Treatment of Evan’s syndrome by leflunomide and desmopressin in a mixed-breed dog

A 9-year-old, male, mixed-breed dog was presented with severe lethargy, pale and icterus mucous membranes, gingival hemorrhage, and hematochezia. On physical examination, petechiae and echimosis on the penis were observed. The complete blood count revealed severe regenerative anemia and thrombocytopenia. Urinalysis indicated hemoglobinuria and bilirobinuria, and abdominal sonography showed splenomegaly. A series of diagnostic tests was performed based on the suspicion of Evan’s syndrome (concurrent immune-mediated anemia and thrombocytopenia). The therapeutic program was started with prednisolone combined with leflunomide followed by desmopressin and erythropoietin, lasted 1?month, and the animal showed progressive recovery. During 6?months follow-up, no complications were detected in the mentioned case.     

Medication Adherence: Tailoring the Analysis to the Data

The purpose of this paper is to explore more comprehensive methods to analyze antiretroviral non-adherence data. Using illustrative data and simulations, we investigated the value of using binary logistic regression (LR; dichotomized at 0% non-adherence) versus a hurdle model (combination of LR plus generalized linear model for >0% non-adherence) versus a zero-inflated negative binomial (ZINB) model (simultaneously modeling 0% non-adherence and >0% non-adherence). In simulation studies, the hurdle and ZINB models had similar power but both had higher power in comparison to LR alone. The hurdle model had higher power than ZINB in settings where covariate effects were restricted to one or the other part of the model (0% non-adherence or degree of non-adherence). Use of the hurdle and ZINB models are powerful and valuable approaches in analyzing adherence data which yield a more complete picture than LR alone. We recommend adoption of this methodology for future antiretroviral adherence research.     

Periosteal osteoblastoma: report of a case with a rare histopathologic presentation and review of the literature

Osteoblastoma is an uncommon benign bone tumor most commonly located in the vertebral column or metaphysis of a long bone. Periosteal location is rare. We report a periosteal-based osteoblastoma, arising from the proximal tibia, in a 20-year-old woman who presented with knee swelling and pain of 2-year duration. Imaging studies showed a metaphyseal surface-based lesion with patchy radiodensities. The cortico-medullary junction was intact. The lesion was totally excised. Histopathologic evaluation disclosed immature bone and osteoid deposition in a vascularized stroma, associated with numerous osteoblasts and osteoclasts rimming the bony trabeculae. Plate-like arrangements of cartilage in the margin of the neoplastic tissue were also identified. At 16 months postoperatively, the patient was well without recurrence. Although extremely unusual, the presence of cartilage does not necessarily exclude the diagnosis of osteoblastoma.