Predicting adults likely to develop heart failure using readily available clinical information: An analysis of heart failure incidence using the NHEFS.

BACKGROUND: Heart failure is a heavy burden on the health care system in the United States. Once heart failure develops, the quality of life and longevity are dramatically affected. As such, its prevention is critical for the well-being of at risk patients. We evaluated the predictive ability of readily available clinical information to identify those likely to develop heart failure. METHODS: We used a classification and regression tree (CART) model to determine the top predictors for heart failure incidence using the NHANES Epidemiologic Follow-up Study (NHEFS). The identified predictors were hypertension, diabetes, obesity, and myocardial infarction (MI). We evaluated the relationship between these variables and incident heart failure by the product-limit method and Cox models. All analyses incorporated the complex sample design to provide population estimates. RESULTS: We analyzed data from 14,407 adults in the NHEFS. Participants with diabetes, MI, hypertension, or obesity had a higher incidence of heart failure than those without risk factors, with diabetes and MI being the most potent predictors. Individuals with multiple risk factors had a higher incidence of heart failure as well as a higher hazard ratio than those with just one risk factor. Combinations that included diabetes and MI had the highest incidence rates of heart failure per 1000 person years and the highest hazard ratios for incident heart failure. CONCLUSIONS: Having diabetes, MI, hypertension or obesity significantly increased the risk for incident heart failure, especially combinations including diabetes and MI. This suggests that individuals with these conditions, singly or in combination, should be prioritized in efforts to predict and prevent heart failure incidence.

Manganese-catalyzed late-stage aliphatic C-H azidation.

We report a manganese-catalyzed aliphatic C-H azidation reaction that can efficiently convert secondary, tertiary, and benzylic C-H bonds to the corresponding azides. The method utilizes aqueous sodium azide solution as the azide source and can be performed under air. Besides its operational simplicity, the potential of this method for late-stage functionalization has been demonstrated by successful azidation of various bioactive molecules with yields up to 74%, including the important drugs pregabalin, memantine, and the antimalarial artemisinin. Azidation of celestolide with a chiral manganese salen catalyst afforded the azide product in 70% ee, representing a Mn-catalyzed enantioselective aliphatic C-H azidation reaction. Considering the versatile roles of organic azides in modern chemistry and the ubiquity of aliphatic C-H bonds in organic molecules, we envision that this Mn-azidation method will find wide application in organic synthesis, drug discovery, and chemical biology.

Kaempferol, a Phytoprogestin, Induces a Subset of Progesterone-Regulated Genes in the Uterus.

Progesterone functions as a steroid hormone involved in female reproductive physiology. While some reproductive disorders manifest with symptoms that can be treated by progesterone or synthetic progestins, recent data suggest that women also seek botanical supplements to alleviate these symptoms. However, botanical supplements are not regulated by the U.S. Food and Drug Administration and therefore it is important to characterize and quantify the inherent active compounds and biological targets of supplements within cellular and animal systems. In this study, we analyzed the effect of two natural products, the flavonoids, apigenin and kaempferol, to determine their relationship to progesterone treatment in vivo. According to immunohistochemical analysis of uterine tissue, kaempferol and apigenin have some progestogenic activity, but do not act in exactly the same manner as progesterone. More specifically, kaempferol treatment did not induce HAND2, did not change proliferation, and induced ZBTB16 expression. Additionally, while apigenin treatment did not appear to dramatically affect transcripts, kaempferol treatment altered some transcripts (44%) in a similar manner to progesterone treatment but had some unique effects as well. Kaempferol regulated primarily unfolded protein response, androgen response, and interferon-related transcripts in a similar manner to progesterone. However, the effects of progesterone were more significant in regulating thousands of transcripts making kaempferol a selective modifier of signaling in the mouse uterus. In summary, the phytoprogestins, apigenin and kaempferol, have progestogenic activity in vivo but also act uniquely.

Home-Built Spinning Apparatus for Drying Agarose-Based Imaging Mass Spectrometry Samples.

Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) is a useful technique for mapping the spatial distribution of molecules across biological samples. Sample preparation is crucial for MALDI-IMS; samples must be flat, dry, and cocrystallized with a matrix prior to analysis. Agarose-based samples can be difficult to consistently prepare as they are susceptible to environmental changes, which can lead to inconsistent drying and wrinkling on the sample surface. Small height differences may cause low ionization of target analytes or introduce artifacts in imaging data depending on the instrument used for analysis. To overcome the variations, a home-built robotic spinner was constructed and applied to agarose-based samples. This robotic spinner is inexpensive and easy to assemble, and when it was applied to agarose-based samples, accelerated the drying process and reduced wrinkles, improving the overall quality of the resulting IMS data.

Fallopian tube secreted protein affects ovarian metabolites in high grade serous ovarian cancer.

High grade serous ovarian cancer (HGSOC), the most lethal histotype of ovarian cancer, frequently arises from fallopian tube epithelial cells (FTE). Once transformed, tumorigenic FTE often migrate specifically to the ovary, completing the crucial primary metastatic step and allowing the formation of the ovarian tumors after which HGSOC was originally named. As only the fimbriated distal ends of the fallopian tube that reside in close proximity to the ovary develop precursor lesions such as serous tubal intraepithelial carcinomas, this suggests that the process of transformation and primary metastasis to the ovary is impacted by the local microenvironment. We hypothesize that chemical cues, including small molecules and proteins, may help stimulate the migration of tumorigenic FTE to the ovary. However, the specific mediators of this process are still poorly understood, despite a recent growth in interest in the tumor microenvironment. Our previous work utilized imaging mass spectrometry (IMS) to identify the release of norepinephrine (NE) from the ovary in co-cultures of tumorigenic FTE cells with an ovarian explant. We predicted that tumorigenic FTE cells secreted a biomolecule, not produced or produced with low expression by non-tumorigenic cells, that stimulated the ovary to release NE. As such, we utilized an IMS mass-guided bioassay, using NE release as our biological marker, and bottom-up proteomics to demonstrate that a secreted protein, SPARC, is a factor produced by tumorigenic FTE responsible for enhancing release of ovarian NE and influencing primary metastasis of HGSOC. This discovery highlights the bidirectional interplay between different types of biomolecules in the fallopian tube and ovarian microenvironment and their combined roles in primary metastasis and disease progression.

Fallopian tube initiation of high grade serous ovarian cancer and ovarian metastasis: Mechanisms and therapeutic implications.

Ovarian cancer is the most lethal gynecologic malignancy and the fifth leading cause of cancer-related death in women. Although outcomes have improved in recent years, there remains an unmet clinical need to understand the early pathogenesis of ovarian cancer in order to identify new diagnostic approaches and agents of chemoprevention and chemotherapy. While high grade serous ovarian cancer (HGSOC), the most abundant histotype, was initially thought to arise from the ovarian surface epithelium, there is an increasing body of evidence suggesting that HGSOC originates in the fallopian tube. With this new understanding of cell of origin, understanding of disease development requires analysis with a novel perspective. Currently, factors that drive the initiation and migration of dysplastic tubal epithelial cells from the fallopian tube to the ovary are not yet fully defined. These factors include common mutations to fallopian tube epithelial cells, as well as factors originating from both the fallopian tube and ovary which are capable of inducing transformation and dissemination in said cells. Here, we review these changes, their causative agents, and various potential means of intervention.

Chemotherapy-associated neutropenic enterocolitis of the transverse colon post right hemicolectomy.

Neutropenic enterocolitis (NE) is a life-threatening infection of the immunocompromised. NE ubiquitously affects the cecum, often with involvement of the ascending colon and ileum. Classically, NE is associated with high mortality leading to the frequent use of aggressive treatment strategies including surgery. Although conservative approaches are often successful, there are currently no standardized treatment guidelines for NE and it is unclear when such strategies should be implemented. Here, we describe a patient with suspected chemotherapy-associated NE despite having previously undergone a right hemicolectomy. As computed tomography imaging failed to provide a conclusive diagnosis, we performed a gentle endoscopic evaluation that affirmed a diagnosis of NE of the transverse colon, and suggested the patient would benefit from conservative treatment. This case demonstrates that endoscopy can be a safe and useful tool in the diagnosis of NE, and is an important reminder that NE can affect any part of the gastrointestinal tract.

Ileal carcinoid tumor represents after prolonged remission as a solitary breast mass.

While the metastatic spread of breast cancer is well documented, the breast is seldom a site for metastasis. Non-mammillary cancers can involve the breast or axilla, though this is exceedingly rare with few reported instances. Here, we present the case of a 62-year-old woman who attended an outpatient breast clinic with a history of an ileal carcinoid tumor complicated by multi-organ metastasis. Her disease was in clinical remission for several years, though she recently re-presented with a single solitary lesion to the breast that was later confirmed as a recurrence of her carcinoid tumor. This serves as an important reminder that the breast can indeed be a site for metastasis. As metastatic breast lesions can often be difficult to diagnose, it is essential to obtain a thorough medical history in order to determine the appropriate clinical course.

Non-implant associated primary cutaneous anaplastic large cell lymphoma of the breast.

Anaplastic large cell lymphomas (ALCL) comprise a group of rare, related T-cell neoplasms that typically present on the extremities. Infrequently, cutaneous ALCL can involve the breast, where it is near ubiquitously associated with breast implants. Here, we present the rare case of a 70-year-old woman with primary cutaneous ALCL of the breast with no history of breast augmentation. This serves as an important reminder that in some instances, breast ALCL can be idiopathic. Further, given the potential for malignancy, any changes to the breast skin should be diagnosed quickly in order to ensure rapid delivery of the appropriate treatment.

Loss of PTEN in Fallopian Tube Epithelium Results in Multicellular Tumor Spheroid Formation and Metastasis to the Ovary.

High-grade serous ovarian cancer (HGSOC) can originate in the fallopian tube and then spread to the ovary. Our objective was to evaluate the role of multicellular tumor spheroids (MTS) in ovarian metastasis. By testing a panel of murine oviductal epithelial (MOE) cells with genetic alterations mimicking those seen in HGSOC, we found that loss of PTEN allowed MTS formation under ultra-low adhesion conditions. Confirming these results in vivo, MTS-like structures were observed in the oviducts of PAX8Cre/+ PTENflox/flox mice. MOE PTENshRNA cells could incorporate up to 25% wild type cells into MTS, while higher percentages of wild type cells resulted in a loss of MTS formation. MTS formation allowed MOE PTENshRNA cells to survive better under ultra-low adhesion conditions than control cells. MTS also attached to the ovarian stroma, as would be exposed during ovulation. Interestingly, MTS more robustly cleared monolayers of murine ovarian surface epithelia than murine ovarian fibroblasts. When xenografted into the ovarian bursa, OVCAR8 MTS were able to form tumors in the ovary at a similar rate as an equal number of OVCAR8 cells grown on traditional cell culture plastic. In conclusion, loss of a single gene (PTEN) allows the fallopian tube epithelia to form MTS, which survive better under ultra-low adhesion conditions, attach to the extracellular matrix exposed during ovulation, and colonize the ovary. These results suggest that MTS may contribute to seeding of the ovary in HGSOC patients.