Management Options in Triple-Negative Breast Cancer

Notorious for its poor prognosis and aggressive nature, triple-negative breast cancer (TNBC) is a heterogeneous disease entity. The nature of its biological specificity, which is similar to basal-like cancers, tumors arising in BRCA1 mutation carriers, and claudin-low cancers, is currently being explored in hopes of finding the targets for novel biologics and chemotherapeutic agents. In this review, we aim to give a broad overview of the disease’s nomenclature and epidemiology, as well as the basic mechanisms of emerging targeted therapies and their performance in clinical trials to date

CD24 Expression and differential resistance to chemotherapy in triple-negative breast cancer.

Breast cancer (BC) is a leading cause of cancer-related death in women. Adjuvant systemic chemotherapies are effective in reducing risks of recurrence and have contributed to reduced BC mortality. Although targeted adjuvant treatments determined by biomarkers for endocrine and HER2-directed therapies are largely successful, predicting clinical benefit from chemotherapy is more challenging. Drug resistance is a major reason for treatment failures. Efforts are ongoing to find biomarkers to select patients most likely to benefit from chemotherapy. Importantly, cell surface biomarkers CD44+/CD24- are linked to drug resistance in some reports, yet underlying mechanisms are largely unknown. This study focused on the potential role of CD24 expression in resistance to either docetaxel or doxorubicin in part by the use of triple-negative BC (TNBC) tissue microarrays. In vitro assays were also done to assess changes in CD24 expression and differential drug susceptibility after chemotherapy. Further, mouse tumor xenograft studies were done to confirm in vitro findings. Overall, the results show that patients with CD24-positive TNBC had significantly worse overall survival and disease-free survival after taxane-based treatment. Also, in vitro cell studies show that CD44+/CD24+/high cells are more resistant to docetaxel, while CD44+/CD24-/low cells are resistant to doxorubicin. Both in vitro and in vivo studies show that cells with CD24-knockdown are more sensitive to docetaxel, while CD24-overexpressing cells are more sensitive to doxorubicin. Further, mechanistic studies indicate that Bcl-2 and TGF-βR1 signaling via ATM-NDRG2 pathways regulate CD24. Hence, CD24 may be a biomarker to select chemotherapeutics and a target to overcome TNBC drug resistance

Gender Differences in and Factors Related to Self-Care Behaviors: A Cross-Sectional, Correlational Study of Patients With Heart Failure

Background Although self-care may reduce exacerbations of heart failure, reported rates of effective self-care in patients with heart failure are low. Modifiable factors, including psychosocial status, knowledge, and physical factors, are thought to influence heart failure self-care, but little is known about their combined impact on self-care. Objectives The objective of this study was to identify factors related to self-care behaviors in patients with heart failure. Design A cross-sectional, correlational study design was used. Participants and settings One hundred twenty-two patients (77 men and 45 women, mean age 60 ± 12 years old, 66% New York Heart Association functional class III/IV) were recruited from the outpatient clinics of an academic medical center and two community hospitals. Methods Data on self-care behaviors (Self-Care of Heart Failure Index), depressive symptoms, perceived control, self-care confidence, knowledge, functional status, and social support were collected. Factors related to self-care were examined using hierarchical multiple regression. Results Mean self-care behavior scores were less than 70 indicating the majority of men and women with HF did not consistently engage in self-care behaviors. Higher self-care confidence and perceived control and better heart failure management knowledge were associated with better self-care (r2 = .25, p \u3c .001). Higher perceived control and better knowledge were related to better self-care behaviors in men (r2 = .18, p = .001), while higher self-care confidence and poorer functional status were related to better self-care behaviors in women (r2 = .35, p \u3c .001). Conclusion This study demonstrates the substantial impact of modifiable factors such as confidence in one’s self-care abilities, perceived control, and knowledge on self-care behaviors. This study demonstrates that there are gender differences in factors affecting self-care, even though at baseline men and women have similar knowledge levels, physical, psychological, and behavioral status. Effective interventions focusing on modifiable factors and the unique characteristics of men and women should be provided to improve self-care behaviors in patients with heart failure

In vitro evaluation of bi-layer silk fibroin scaffolds for gastrointestinal tissue engineering

Silk fibroin scaffolds were investigated for their ability to support attachment, proliferation, and differentiation of human gastrointestinal epithelial and smooth muscle cell lines in order to ascertain their potential for tissue engineering. A bi-layer silk fibroin matrix composed of a porous silk fibroin foam annealed to a homogeneous silk fibroin film was evaluated in parallel with small intestinal submucosa scaffolds. AlamarBlue analysis revealed that silk fibroin scaffolds supported significantly higher levels of small intestinal smooth muscle cell, colon smooth muscle cell, and esophageal smooth muscle cell attachment in comparison to small intestinal submucosa. Following 7 days of culture, relative numbers of each smooth muscle cell population maintained on both scaffold groups were significantly elevated over respective 1-day levels—indicative of cell proliferation. Real-time reverse transcription polymerase chain reaction and immunohistochemical analyses demonstrated that both silk fibroin and small intestinal submucosa scaffolds were permissive for contractile differentiation of small intestinal smooth muscle cell, colon smooth muscle cell, esophageal smooth muscle cell as determined by significant upregulation of α-smooth muscle actin and SM22α messenger RNA and protein expression levels following transforming growth factor-β1 stimulation. AlamarBlue analysis demonstrated that both matrix groups supported similar degrees of attachment and proliferation of gastrointestinal epithelial cell lines including colonic T84 cells and esophageal epithelial cells. Following 14 days of culture on both matrices, spontaneous differentiation of T84 cells toward an enterocyte lineage was confirmed by expression of brush border enzymes, lactase, and maltase, as determined by real-time reverse transcription polymerase chain reaction and immunohistochemical analyses. In contrast to small intestinal submucosa scaffolds, silk fibroin scaffolds supported spontaneous differentiation of esophageal epithelial cells toward a suprabasal cell lineage as indicated by significant upregulation of cytokeratin 4 and cytokeratin 13 messenger RNA transcript levels. In addition, esophageal epithelial cells maintained on silk fibroin scaffolds also produced significantly higher involucrin messenger RNA transcript levels in comparison to small intestinal submucosa counterparts, indicating an increased propensity for superficial, squamous cell specification. Collectively, these data provide evidence for the potential of silk fibroin scaffolds for gastrointestinal tissue engineering applications

Tadpole Galaxies in the Hubble Ultra Deep Field

Tadpole galaxies have a head-tail shape with a large clump of star formation at the head and a diffuse tail or streak of stars off to one side. We measured the head and tail masses, ages, surface brightnesses, and sizes for 66 tadpoles in the Hubble Ultra Deep Field (UDF), and we looked at the distribution of neighbor densities and tadpole orientations with respect to neighbors. The heads have masses of 10^7-10^8 Msun and photometric ages of ~0.1 Gyr for z~2. The tails have slightly larger masses than the heads, and comparable or slightly older ages. The most obvious interpretation of tadpoles as young merger remnants is difficult to verify. They have no enhanced proximity to other resolved galaxies as a class, and the heads, typically less than 0.2 kpc in diameter, usually have no obvious double-core structure. Another possibility is ram pressure interaction between a gas-rich galaxy and a diffuse cosmological flow. Ram pressure can trigger star formation on one side of a galaxy disk, giving the tadpole shape when viewed edge-on. Ram pressure can also strip away gas from a galaxy and put it into a tail, which then forms new stars and gravitationally drags along old stars with it. Such an effect might have been observed already in the Virgo cluster. Another possibility is that tadpoles are edge-on disks with large, off-center clumps. Analogous lop-sided star formation in UDF clump clusters are shown.Comment: 19 pages, 16 figures, ApJ in press, vol 722, October 10, 201

Marital Status as an Independent Predictor of Event-Free Survival of Patients with Heart Failure

Background: Depressive symptoms are a well-known predictor of mortality in patients with heart failure, and positive spousal support is associated with improved outcomes in these patients. However, in the context of depressive symptoms, the effect on survival of having a spouse is unknown. Objective: To determine the effect of marital status on event-free survival in patients with heart failure who did or did not have depressive symptoms. Methods: Depressive symptoms were assessed by using the Back Depression Inventory-II in patients with heart failure who were followed-up for up to 4 years to collect data on mortality and hospitalizations. Patients were grouped according to the presence and absence of depressive symptoms by using the standard cutoff score of 14 on the Beck Depression Inventory-II. Kaplan-Meier and Cox regression analyses were used to compare event-free survival for married and nonmarried patients who were stratified according to the presence or absence of depressive symptoms. Results: Of 166 patients, 56% were married, and 33% had depressive symptoms. Levels of depressive symptoms were similar between married and nonmarried patients (10.9 vs 12.1; P=.39). Married patients experienced longer event-free survival than did nonmarried patients (P=.01). Conclusions: Patients with a spouse had longer event-free survival than nonmarried patients did, even in the context of depressive symptoms

Evaluation of Silk Biomaterials in Combination with Extracellular Matrix Coatings for Bladder Tissue Engineering with Primary and Pluripotent Cells

Silk-based biomaterials in combination with extracellular matrix (ECM) coatings were assessed as templates for cell-seeded bladder tissue engineering approaches. Two structurally diverse groups of silk scaffolds were produced by a gel spinning process and consisted of either smooth, compact multi-laminates (Group 1) or rough, porous lamellar-like sheets (Group 2). Scaffolds alone or coated with collagen types I or IV or fibronectin were assessed independently for their ability to support attachment, proliferation, and differentiation of primary cell lines including human bladder smooth muscle cells (SMC) and urothelial cells as well as pluripotent cell populations, such as murine embryonic stem cells (ESC) and induced pluripotent stem (iPS) cells. AlamarBlue evaluations revealed that fibronectin-coated Group 2 scaffolds promoted the highest degree of primary SMC and urothelial cell attachment in comparison to uncoated Group 2 controls and all Group 1 scaffold variants. Real time RT-PCR and immunohistochemical (IHC) analyses demonstrated that both fibronectin-coated silk groups were permissive for SMC contractile differentiation as determined by significant upregulation of α-actin and SM22α mRNA and protein expression levels following TGFβ1 stimulation. Prominent expression of epithelial differentiation markers, cytokeratins, was observed in urothelial cells cultured on both control and fibronectin-coated groups following IHC analysis. Evaluation of silk matrices for ESC and iPS cell attachment by alamarBlue showed that fibronectin-coated Group 2 scaffolds promoted the highest levels in comparison to all other scaffold formulations. In addition, real time RT-PCR and IHC analyses showed that fibronectin-coated Group 2 scaffolds facilitated ESC and iPS cell differentiation toward both urothelial and smooth muscle lineages in response to all trans retinoic acid as assessed by induction of uroplakin and contractile gene and protein expression. These results demonstrate that silk scaffolds support primary and pluripotent cell responses pertinent to bladder tissue engineering and that scaffold morphology and fibronectin coatings influence these processes

Defining an Evidence-Based Cutpoint for Medication Adherence in Heart Failure

BACKGROUND: Despite the importance of medication adherence in heart failure, clinically relevant cutpoints for distinguishing the level of adherence associated with outcomes are unknown. OBJECTIVE: The purpose of this study is to determine the cutpoint above which there is a positive relationship between level of medication adherence and event-free survival. METHODS: This was a longitudinal study of 135 patients with heart failure. Medication adherence was measured using a valid and objective measure, the Medication Event Monitoring System. Two indicators of adherence were assessed by the Medication Event Monitoring System (AARDEX, Union City, CA): (1) dose count, percentage of prescribed doses taken, and (2) dose days, percentage of days the correct number of doses was taken. Patients were followed up to 3.5 years to collect data on outcomes. A series of Kaplan-Meier plots with log-rank tests, Cox survival analyses, and receiver operating characteristic curves were assessed comparing event-free survival in patients divided at one-point incremental cutpoints. RESULTS: Event-free survival was significantly better when the prescribed number of doses taken (dose count) or the correct dose (dose day) was \u3e or =88%. This level was confirmed in a Cox regression model controlling for age, gender, ejection fraction, New York Heart Association, comorbidity, angiotensin-converting enzyme inhibitor use, and beta-blocker use. Receiver operating characteristic curves showed that adherence rates above 88% produced the optimal combination of sensitivity and specificity with respect to predicting better event-free survival. With 88% as the adherence cutpoint, the hazard ratio for time to first event for the nonadherent group was 2.2 by dose count (P = .021) and 3.2 by dose day (P = .002). CONCLUSION: The results of this study provide clinicians and researchers with an evidence-based recommendation about the level of adherence needed to achieve optimal clinical outcomes

Rurality and Event-Free Survival in Patients With Heart Failure

Background Evidence of health disparities between urban and rural populations usually favors urban dwellers. The impact of rurality on heart failure (HF) outcomes is unknown. Objective We compared event-free survival between HF patients living in urban and rural areas. Methods In this longitudinal study, 136 patients with HF (male, 70%; age, mean ± SD 61 ± 11 years; New York Heart Association class III/IV, 60%) were enrolled. Patients\u27 emergency department visits for HF exacerbation and rehospitalization during follow-up were identified. Rural status was determined by rural-urban commuting area code. Survival analysis was used to determine the effect of rurality on outcomes while controlling for relevant demographic, clinical, and psychosocial variables. Results Rural patients (64%) had longer event-free survival than urban patients (P = .015). Rurality (P = .04) predicted event-free survival after controlling for age, marital status, New York Heart Association class, medications, adherence to medications, depressive symptoms, and social support. Conclusions Rural patients were less likely than their urban counterparts to experience an event. Further research is needed to identify protective factors that may be unique to rural settings