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Motile bacteria can overcome diffusion resistances that substantially reduce the efficacy of standard cancer therapies. Many reports have also recently described the ability of Salmonella to deliver therapeutic molecules to tumors. Despite this potential, little is known about the spatiotemporal dynamics of bacterial accumulation in solid tumors. Ultimately this timing will affect how these microbes are used therapeutically. To determine how bacteria localize, we intravenously injected Salmonella typhimurium into BALB/c mice with 4T1 mammary carcinoma and measured the average bacterial content as a function of time. Immunohistochemistry was used to measure the extent of apoptosis, the average distance of bacteria from tumor vasculature and the location of bacteria in four different regions: the core, transition, body and edge. Bacteria accumulation was also measured in pulmonary and hepatic metastases. The doubling time of bacterial colonies in tumors was measured to be 16.8 h, and colonization was determined to delay tumor growth by 48 h. From 12 and 48 h after injection, the average distance between bacterial colonies and functional vasculature significantly increased from 130 to 310 μm. After 48 h, bacteria migrated away from the tumor edge toward the central core and induced apoptosis. After 96 h, bacteria began to marginate to the tumor transition zone. All observed metastases contained Salmonella and the extent of bacterial colocalization with metastatic tissue was 44% compared with 0.5% with normal liver parenchyma. These results demonstrate that Salmonella can penetrate tumor tissue and can selectively target metastases, two critical characteristics of a targeted cancer therapeutic. [ABSTRACT FROM AUTHOR]

Background: An effective cancer therapeutic must selectively target tumours with minimal systemic toxicity. Expression of a cytotoxic protein using Salmonella typhimurium would enable spatial and temporal control of delivery because these bacteria preferentially target tumours over normal tissue.Methods: We engineered non-pathogenic S. typhimurium to secrete murine TNF-related apoptosis-inducing ligand (TRAIL) under the control of the prokaryotic radiation-inducible RecA promoter. The response of the RecA promoter to radiation was measured using fluorometry and immunoblotting. TRAIL toxicity was determined using flow cytometry and by measuring caspase-3 activation. A syngeneic murine tumour model was used to determine bacterial accumulation and the response to expressed TRAIL.Results: After irradiation, engineered S. typhimurium secreted TRAIL, which caused caspase-3-mediated apoptosis and death in 4T1 mammary carcinoma cells in culture. Systemic injection of Salmonella and induction of TRAIL expression using 2 Gy gamma-irradiation caused a significant delay in mammary tumour growth and reduced the risk of death by 76% when compared with irradiated controls. Repeated dosing with TRAIL-bearing Salmonella in conjunction with radiation improved the 30-day survival from 0 to 100%.Conclusion: These results show the pre-clinical utility of S. typhimurium as a TRAIL expression vector that effectively reduces tumour growth and extends host survival. [ABSTRACT FROM AUTHOR]

Background. The present study aimed to examine the long-term impact of CS on Executive Function (EF) and memory among older adults living in the community. Methods. Clock Drawing Test (CDT) and Delayed Word Recall Test (DWRT) were used to examine EF and memory, respectively, using four waves of National Health and Aging Trend Study. The respondents were asked whether they have ever smoked, length of smoking, and age of start and quit smoking. Results. CS can have a long-term impact on both EF and memory. However, current smoking can increase the risk of EF impairment compared to former smokers. Lung disease and current smoking can have a synergic effect of impairment in EF. Conclusion. In the long-term, smoking can negatively affect cognitive. Lung diseases and smoking can synergize their impacts on EF. The impact of smoking on cognition varies across ethnic groups; hence, educational programs targeting minorities can reduce discrepancies. [ABSTRACT FROM AUTHOR]

Obesity has been variously associated with reduced or similar rates of postoperative complications compared to normal weight patients undergoing esophagectomy for cancer. In contrast, little is known about esophagectomy risks in the underweight population. The relationship between the extremes of body mass index (BMI) and postoperative complications after esophagectomy was evaluated. Consecutive esophagectomy patients (2000-2013) were reviewed. The patients were stratified based on BMI at the time of diagnosis: underweight (<18.5), normal (18.5-24.9), overweight (25-29.9), obese I (30-34.9), and obese II or III (≥35). Hospital length of stay as well as postoperative complications and their accordion severity grading were evaluated according to the BMI category. Of 388 patients, 78.6% were male with a median age of 62 years at the time of operation. Pathologic cancer stage was 0 to I in 53%. BMI distribution was as follows: 5.6% underweight, 28.7% normal, 31.4% overweight, 22.8% obese I, and 11.5% obese II or III. Performance status was 0 or 1 in 99.2%. Compared to normal BMI patients, underweight patients had increased pulmonary complications (odds ratio (OR) 3.32, P = 0.014) and increased other postoperative complications (OR 3.00, P = 0.043). Patients who were overweight did not have increased complications compared to normal BMI patients. BMI groups did not differ in mortality rates or complication accordion severity grading. Hospital length of stay trended toward a longer duration in the underweight population (P = 0.06). Underweight patients are at increased risk for postoperative pulmonary and other complications. Underweight patients may benefit from preoperative nutritional repletion and mitigation for sarcopenia. Aggressive postoperative pulmonary care may help reduce complications in these patients. In contrast, the operative risk in overweight and obese patients is similar to normal BMI patients. [ABSTRACT FROM AUTHOR]

Background:The CXCL10/CXCR3 signalling mediates paracrine interactions between tumour and stromal cells that govern leukocyte trafficking and angiogenesis. Emerging data implicate noncanonical CXCL10/CXCR3 signalling in tumourigenesis and metastasis. However, little is known regarding the role for autocrine CXCL10/CXCR3 signalling in regulating the metastatic potential of individual tumour clones.Methods:We performed transcriptomic and cytokine profiling to characterise the functions of CXCL10 and CXCR3 in tumour cells with different metastatic abilities. We modulated the expression of the CXCL10/CXCR3 pathway using shRNA-mediated silencing in both in vitro and in vivo models of B16F1 melanoma. In addition, we examined the expression of CXCL10 and CXCR3 and their associations with clinical outcomes in clinical data sets derived from over 670 patients with melanoma and colon and renal cell carcinomas.Results:We identified a critical role for autocrine CXCL10/CXCR3 signalling in promoting tumour cell growth, motility and metastasis. Analysis of publicly available clinical data sets demonstrated that coexpression of CXCL10 and CXCR3 predicted an increased metastatic potential and was associated with early metastatic disease progression and poor overall survival.Conclusion:These findings support the potential for CXCL10/CXCR3 coexpression as a predictor of metastatic recurrence and point towards a role for targeting of this oncogenic axis in the treatment of metastatic disease. [ABSTRACT FROM AUTHOR]