Anti-VEGF therapy as adjuvant therapy: clouds on the horizon?

Anti-angiogenic therapies have demonstrated their value in the setting of advanced cancer, and are being explored for use in micrometastatic disease. Recent preclinical studies suggest that adjuvant anti-vascular endothelial growth factor (VEGF) therapies may increase the risk of metastasis. How concerning are these preclinical studies, and should they affect our willingness to explore anti-VEGF therapy in the adjuvant setting

Small-Molecule Binding Sites to Explore New Targets in the Cancer Proteome

The Cancer Genome Atlas (TCGA) offers an unprecedented opportunity to identify small-molecule binding sites on proteins with overexpressed mRNA levels that correlate with poor survival. Here, we analyze RNA-seq and clinical data for 10 tumor types to identify genes that are both overexpressed and correlate with patient survival. Protein products of these genes were scanned for binding sites that possess shape and physicochemical properties that can accommodate small-molecule probes or therapeutic agents (druggable). These binding sites were classified as enzyme active sites (ENZ), protein-protein interaction sites (PPI), or other sites whose function is unknown (OTH). Interestingly, the overwhelming majority of binding sites were classified as OTH. We find that ENZ, PPI, and OTH binding sites often occurred on the same structure suggesting that many of these OTH cavities can be used for allosteric modulation of enzyme activity or protein-protein interactions with small molecules. We discovered several ENZ (PYCR1, QPRT, and HSPA6) and PPI (CASC5, ZBTB32, and CSAD) binding sites on proteins that have been seldom explored in cancer. We also found proteins that have been extensively studied in cancer that have not been previously explored with small molecules that harbor ENZ (PKMYT1, STEAP3, and NNMT) and PPI (HNF4A, MEF2B, and CBX2) binding sites. All binding sites were classified by the signaling pathways to which the protein that harbors them belongs using KEGG. In addition, binding sites were mapped onto structural protein-protein interaction networks to identify promising sites for drug discovery. Finally, we identify pockets that harbor missense mutations previously identified from analysis of the TCGA data. The occurrence of mutations in these binding sites provides new opportunities to develop small-molecule probes to explore their function in cancer.

Quality of Life in Younger versus Older Breast Cancer Survivors

poster abstractBackground: Breast cancer is one of the most frequently occurring cancers in the developing world, but with earlier detection and better treatment, the majority of breast cancer survivors will live many years after diagnosis. Breast cancer survivors may experience many symptoms that impact their quality of life, and these symptoms may vary by age. The purpose of this study is to compare breast cancer survivors who were diagnosed at 45 and under (n=469) with survivors diagnosed at 55 to 70 (n=584) years of age. Materials and methods: Participants were identified through a large cooperative group (Eastern Cancer Cooperative Group). Eligibility criteria included use of chemotherapy at initial diagnosis, being 3 to 8 years from diagnosis, and not having a recurrence of breast cancer. The mean current age of younger survivors was 45.2 and for older survivors was 66.7. Women who agreed to participate were sent a survey and informed consent which was completed and returned via mail. Overall, 80% of eligible women contacted by researchers agreed to participate. Measures included physical, psychological, social, spiritual, and overall quality of life constructs. All measurements had good reported validity and reliability. A total of 469 younger and 584 older breast cancer survivors are included. Linear regression was used to compare the two groups on continuous outcomes while adjusting for the following potentially confounding covariates: marital status (married versus not), years of education, and total household income, and years since diagnosis. Results: Younger survivors scored significantly worse than older survivors on gynecological problems, sexual enjoyment, attention function, and overall reported symptoms. Psychologically, younger survivors demonstrated greater symptom distress, greater depression, and greater state and trait anxiety than older survivors. Younger survivors had lower marital satisfaction scores. Younger survivors reported greater fear of recurrence and less favorable body image. Younger survivors reported lower perceived social support from their partners and greater social constraint. Older survivors held higher spiritual beliefs and behaviors as compared to younger survivors. Perceived self efficacy for dealing with problems related to cancer survivorship was lower in younger survivors as compared to older survivors. For overall quality of life measures, younger survivors reported lower index of well being scores than older survivors and reported that breast cancer had a greater impact on their life. Health care service use was greater for younger as opposed to older survivors both during and after treatment. Conclusions: Younger survivors reported significantly more problems on several, physical, psychological, social and generic quality of life issues as compared to older survivors. Results indicate a need to proactively assess quality of life issues in younger women at time of diagnosis

Impact of social distancing during COVID-19 pandemic on crime in Los Angeles and Indianapolis

Governments have implemented social distancing measures to address the ongoing COVID-19 pandemic. The measures include instructions that individuals maintain social distance when in public, school closures, limitations on gatherings and business operations, and instructions to remain at home. Social distancing may have an impact on the volume and distribution of crime. Crimes such as residential burglary may decrease as a byproduct of increased guardianship over personal space and property. Crimes such as domestic violence may increase because of extended periods of contact between potential offenders and victims. Understanding the impact of social distancing on crime is critical for ensuring the safety of police and government capacity to deal with the evolving crisis. Understanding how social distancing policies impact crime may also provide insights into whether people are complying with public health measures. Examination of the most recently available data from both Los Angeles, CA, and Indianapolis, IN, shows that social distancing has had a statistically significant impact on a few specific crime types. However, the overall effect is notably less than might be expected given the scale of the disruption to social and economic life

Analyzing the Impacts of Public Policy on COVID-19 Transmission: A Case Study of the Role of Model and Dataset Selection Using Data from Indiana

Dynamic estimation of the reproduction number of COVID-19 is important for assessing the impact of public health measures on virus transmission. State and local decisions about whether to relax or strengthen mitigation measures are being made in part based on whether the reproduction number, Rt , falls below the self-sustaining value of 1. Employing branching point process models and COVID-19 data from Indiana as a case study, we show that estimates of the current value of Rt , and whether it is above or below 1, depend critically on choices about data selection and model specification and estimation. In particular, we find a range of Rt values from 0.47 to 1.20 as we vary the type of estimator and input dataset. We present methods for model comparison and evaluation and then discuss the policy implications of our findings

Predicting fear of breast cancer recurrence and self-efficacy in survivors by age at diagnosis

PURPOSE/OBJECTIVES: To determine the effect that age at diagnosis has on fear of breast cancer recurrence and to identify the predictors of fear of recurrence using self-efficacy as a mediator. DESIGN: Cross-sectional survey. SETTING: Two university cancer centers and one cooperative group in the midwestern United States. SAMPLE: 1,128 long-term survivors. METHODS: Survivors were eligible if they were aged 18-45 years (younger group) or 55-70 years (older group) at cancer diagnosis, had received chemotherapy, and were three to eight years postdiagnosis. Fear of recurrence was compared between younger and older groups. Multiple regression analyses were used to test variables' prediction of fear of recurrence and breast cancer survivor self-efficacy, as well as breast cancer survivor self-efficacy mediation effects. MAIN RESEARCH VARIABLES: Fear of recurrence, breast cancer survivor self-efficacy, and age at diagnosis. FINDINGS: Survivors diagnosed at a younger age had significantly higher fear of recurrence, as well as health, role, womanhood, death, and parenting worries. Perceived risk of recurrence, trait anxiety, and breast cancer reminders explained significant variance in fear of recurrence and breast cancer survivor self-efficacy. Breast cancer survivor self-efficacy partially mediated the effects of variables on fear of recurrence. CONCLUSIONS: The findings suggest that breast cancer survivor self-efficacy may have a protective effect for survivors who are younger at diagnosis and have higher perceived risk of recurrence, higher trait anxiety, and more breast cancer reminders. Oncology nurses already use the skills required to support self-efficacy. Additional research is needed to define and test breast cancer survivor self-efficacy interventions. IMPLICATIONS FOR NURSING: Oncology nurses are in a key role to assess fear of recurrence and provide self-efficacy interventions to reduce it in breast cancer survivors. Strategies to efficiently address fear of recurrence to reduce psychological distress in survivorship follow-up care are warranted

Inhibition of breast cancer regrowth and pulmonary metastasis in nude mice by anti-gastric ulcer agent, irsogladine.

金沢大学医学部附属病院Irsogladine is a commonly used anti-gastric ulcer agent in Japan, and recent in vivo studies have shown it to have anti-angiogenic properties. The exact role of irsogladine as an inhibitor of angiogenesis remains uncertain. In this study, we show that irsogladine inhibited breast cancer regrowth and pulmonary metastasis but had no anti-angiogenic function against HUVEC cells. Irsogladine failed to inhibit proliferation, tubular formation, and the uPA/MMP-1 mRNA expression of HUVEC cells. We also examined the effect of irsogladine in an orthotopic transplant model of human breast cancer metastasis in athymic mice. Human MDA-MB-435 cells were injected into the mammary fat pads. After 9 weeks, the tumors were resected under general anesthesia. Irsogladine or vehicle was given p.o. daily thereafter. Daily administration of irsogladine at 120 mg/kg per day over a 5-week period had no effect on the body weight of the mice. Tumor regrowth, average volume of pulmonary metastases, and the number of metastases were inhibited by 40, 48 and 64%, respectively. These results suggest that irsogladine may be useful in the breast cancer adjuvant setting

Classification of large circulating tumor cells isolated with ultra-high throughput microfluidic Vortex technology.

Circulating tumor cells (CTCs) are emerging as rare but clinically significant non-invasive cellular biomarkers for cancer patient prognosis, treatment selection, and treatment monitoring. Current CTC isolation approaches, such as immunoaffinity, filtration, or size-based techniques, are often limited by throughput, purity, large output volumes, or inability to obtain viable cells for downstream analysis. For all technologies, traditional immunofluorescent staining alone has been employed to distinguish and confirm the presence of isolated CTCs among contaminating blood cells, although cells isolated by size may express vastly different phenotypes. Consequently, CTC definitions have been non-trivial, researcher-dependent, and evolving. Here we describe a complete set of objective criteria, leveraging well-established cytomorphological features of malignancy, by which we identify large CTCs. We apply the criteria to CTCs enriched from stage IV lung and breast cancer patient blood samples using the High Throughput Vortex Chip (Vortex HT), an improved microfluidic technology for the label-free, size-based enrichment and concentration of rare cells. We achieve improved capture efficiency (up to 83%), high speed of processing (8 mL/min of 10x diluted blood, or 800 μL/min of whole blood), and high purity (avg. background of 28.8±23.6 white blood cells per mL of whole blood). We show markedly improved performance of CTC capture (84% positive test rate) in comparison to previous Vortex designs and the current FDA-approved gold standard CellSearch assay. The results demonstrate the ability to quickly collect viable and pure populations of abnormal large circulating cells unbiased by molecular characteristics, which helps uncover further heterogeneity in these cells