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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

Biophysics in drug discovery : impact, challenges and opportunities

Over the past 25 years, biophysical technologies such as X-ray crystallography, nuclear magnetic resonance spectroscopy, surface plasmon resonance spectroscopy and isothermal titration calorimetry have become key components of drug discovery platforms in many pharmaceutical companies and academic laboratories. There have been great improvements in the speed, sensitivity and range of possible measurements, providing high-resolution mechanistic, kinetic, thermodynamic and structural information on compound-target interactions. This Review provides a framework to understand this evolution by describing the key biophysical methods, the information they can provide and the ways in which they can be applied at different stages of the drug discovery process. We also discuss the challenges for current technologies and future opportunities to use biophysical methods to solve drug discovery problems

Proteomic-Based Biosignatures in Breast Cancer Classification and Prediction of Therapeutic Response

Protein-based markers that classify tumor subtypes and predict therapeutic response would be clinically useful in guiding patient treatment. We investigated the LC-MS/MS-identified protein biosignatures in 39 baseline breast cancer specimens including 28 HER2-positive and 11 triple-negative (TNBC) tumors. Twenty proteins were found to correctly classify all HER2 positive and 7 of the 11 TNBC tumors. Among them, galectin-3-binding protein and ALDH1A1 were found preferentially elevated in TNBC, whereas CK19, transferrin, transketolase, and thymosin β4 and β10 were elevated in HER2-positive cancers. In addition, several proteins such as enolase, vimentin, peroxiredoxin 5, Hsp 70, periostin precursor, RhoA, cathepsin D preproprotein, and annexin 1 were found to be associated with the tumor responses to treatment within each subtype. The MS-based proteomic findings appear promising in guiding tumor classification and predicting response. When sufficiently validated, some of these candidate protein markers could have great potential in improving breast cancer treatment

Humor Therapy: Relieving Chronic Pain and Enhancing Happiness for Older Adults

The present study examined the effectiveness of a humor therapy program in relieving chronic pain, enhancing happiness and life satisfaction, and reducing loneliness among older persons with chronic pain. It was a quasiexperimental pretest-posttest controlled design. Older persons in a nursing home were invited to join an 8-week humor therapy program (experimental group), while those in another nursing home were treated as a control group and were not offered the program. There were 36 older people in the experimental group and 34 in the control group. Upon completion of the humor therapy program, there were significant decreases in pain and perception of loneliness, and significant increases in happiness and life satisfaction for the experimental group, but not for the control group. The use of humor therapy appears to be an effective nonpharmacological intervention. Nurses and other healthcare professionals could incorporate humor in caring for their patients

Assessment of Water Quality in a Subtropical Alpine Lake Using Multivariate Statistical Techniques and Geostatistical Mapping: A Case Study

Concerns about the water quality in Yuan-Yang Lake (YYL), a shallow, subtropical alpine lake located in north-central Taiwan, has been rapidly increasing recently due to the natural and anthropogenic pollution. In order to understand the underlying physical and chemical processes as well as their associated spatial distribution in YYL, this study analyzes fourteen physico-chemical water quality parameters recorded at the eight sampling stations during 2008–2010 by using multivariate statistical techniques and a geostatistical method. Hierarchical clustering analysis (CA) is first applied to distinguish the three general water quality patterns among the stations, followed by the use of principle component analysis (PCA) and factor analysis (FA) to extract and recognize the major underlying factors contributing to the variations among the water quality measures. The spatial distribution of the identified major contributing factors is obtained by using a kriging method. Results show that four principal components i.e., nitrogen nutrients, meteorological factor, turbidity and nitrate factors, account for 65.52% of the total variance among the water quality parameters. The spatial distribution of principal components further confirms that nitrogen sources constitute an important pollutant contribution in the YYL

Influence of the peritoneal lavage with bupivacaine on the survival and resistance of colonic anastomoses performed under fecal peritonitis in rats

PURPOSE: To evaluate the effects of peritoneal lavage with bupivacaine on survival and initial resistance of anastomosis on distal colon, performed under peritonitis or not. METHODS: Forty rats, weighing from 300 to 350g (321.29±11.31g), were randomly divided in four groups and underwent laparotomy and anastomosis on the distal colon six hours after induction of peritonitis by intraperitoneal injection of autologous fecal material or not. Group 1: No peritonitis and lavage with 3ml NS; Group 2: No peritonitis and lavage with 8 mg.kg-1 (± 0.5 mL) of 0.5% bupivacaine added to 2.5 mL of NS; Group 3: Peritonitis and lavage with 3ml NS; Group 4: Peritonitis and lavage with 8 mg.kg-1 (± 0.5 mL) of 0.5% bupivacaine added to 2.5 mL of NS. Necropsies were performed on the animals that died and the time of death was recorded. Surviving animals were submitted to euthanasia on the fifth post-operative day and Total Energy of Rupture biomechanical test (TER) was applied. RESULTS: Group 4 showed survival increase compared to Group 3, without statistical significance. Group 3 presented the smallest average TER, with statistical significance. CONCLUSION: Peritonitis increased mortality and influenced negatively the resistance of colic anastomosis in rats. Peritoneal lavage with bupivacaine increased anastomotic resistance.78378