Our innate immune system distinguishes microbes from self by detecting conserved pathogen-associated molecular patterns. However, these are produced by all microbes, regardless of their pathogenic ...potential. To distinguish virulent microbes from those with lower disease-causing potential the innate immune system detects conserved pathogen-induced processes, such as the presence of microbial products in the host cytosol, by mechanisms that are not fully resolved. Here we show that NOD1 senses cytosolic microbial products by monitoring the activation state of small Rho GTPases. Activation of RAC1 and CDC42 by bacterial delivery or ectopic expression of SopE, a virulence factor of the enteric pathogen Salmonella, triggered the NOD1 signalling pathway, with consequent RIP2 (also known as RIPK2)-mediated induction of NF-κB-dependent inflammatory responses. Similarly, activation of the NOD1 signalling pathway by peptidoglycan required RAC1 activity. Furthermore, constitutively active forms of RAC1, CDC42 and RHOA activated the NOD1 signalling pathway. Our data identify the activation of small Rho GTPases as a pathogen-induced process sensed through the NOD1 signalling pathway.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Circulating tumor cell (CTC) enumeration promises to be an important predictor of clinical outcome for a range of cancers. Established CTC enumeration methods primarily rely on affinity capture of ...cell surface antigens, and have been criticized for underestimation of CTC numbers due to antigenic bias. Emerging CTC capture strategies typically distinguish these cells based on their assumed biomechanical characteristics, which are often validated using cultured cancer cells. In this study, we developed a software tool to investigate the morphological properties of CTCs from patients with castrate resistant prostate cancer and cultured prostate cancer cells in order to establish whether the latter is an appropriate model for the former. We isolated both CTCs and cultured cancer cells from whole blood using the CellSearch® system and examined various cytomorphological characteristics. In contrast with cultured cancer cells, CTCs enriched by CellSearch® system were found to have significantly smaller size, larger nuclear-cytoplasmic ratio, and more elongated shape. These CTCs were also found to exhibit significantly more variability than cultured cancer cells in nuclear-cytoplasmic ratio and shape profile.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Context Due to high recurrence rates, intensive surveillance strategies, and expensive treatment costs, the management of bladder cancer contributes significantly to medical costs. Objective ...To provide a concise evaluation of contemporary cost-related challenges in the care of patients with bladder cancer. An emphasis is placed on the initial diagnosis of bladder cancer and therapy considerations for both non–muscle-invasive bladder cancer (NMIBC) and more advanced disease. Evidence acquisition A systematic review of the literature was performed using Medline (1966 to February 2011). Medical Subject Headings (MeSH) terms for search criteria included “bladder cancer, neoplasms” OR “carcinoma, transitional cell” AND all cost-related MeSH search terms. Studies evaluating the costs associated with of various diagnostic or treatment approaches were reviewed. Evidence synthesis Routine use of perioperative chemotherapy following complete transurethral resection of bladder tumor has been estimated to provide a cost savings. Routine office-based fulguration of small low-grade recurrences could decrease costs. Another potential important target for decreasing variation and cost lies in risk-modified surveillance strategies after initial bladder tumor removal to reduce the cost associated with frequent cystoscopic and radiographic procedures. Optimizing postoperative care after radical cystectomy has the potential to decrease length of stay and perioperative morbidity with substantial decreases in perioperative care expenses. The gemcitabine-cisplatin regimen has been estimated to result in a modest increase in cost effectiveness over methotrexate, vinblastine, doxorubicin, and cisplatin. Additional costs of therapies need to be balanced with effectiveness, and there are significant gaps in knowledge regarding optimal surveillance and treatment of both early and advanced bladder cancer. Conclusions Regardless of disease severity, improvements in the efficiency of bladder cancer care to limit unnecessary interventions and optimize effective cancer treatment can reduce overall health care costs. Two scenarios where economic and comparative-effectiveness research is limited but would be most beneficial are (1) the management of NMIBC patients where excessive costs are due to vigilant surveillance strategies and (2) in patients with metastatic disease due to the enormous cost associated with late-stage and end-of-life care.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
ABSTRACT We combine wide and deep galaxy number-count data from the Galaxy And Mass Assembly, COSMOS/G10, Hubble Space Telescope (HST) Early Release Science, HST UVUDF, and various near-, mid-, and ...far-IR data sets from ESO, Spitzer, and Herschel. The combined data range from the far UV (0.15 m) to far-IR (500 m), and in all cases the contribution to the integrated galaxy light (IGL) of successively fainter galaxies converges. Using a simple spline fit, we derive the IGL and the extrapolated IGL in all bands. We argue that undetected low-surface-brightness galaxies and intracluster/group light are modest, and that our extrapolated-IGL measurements are an accurate representation of the extragalactic background light (EBL). Our data agree with most earlier IGL estimates and with direct measurements in the far IR, but disagree strongly with direct estimates in the optical. Close agreement between our results and recent very high-energy experiments (H.E.S.S. and MAGIC) suggests that there may be an additional foreground affecting the direct estimates. The most likely culprit could be the adopted model of zodiacal light. Finally we use a modified version of the two-component model to integrate the EBL and obtain measurements of the cosmic optical background (COB) and cosmic infrared background of nW m−2 sr−1 and nW m−2 sr−1 respectively (48%:52%). Over the next decade, upcoming space missions such as Euclid and the Wide Field Infrared Space Telescope will have the capacity to reduce the COB error to <1%, at which point comparisons to the very high-energy data could have the potential to provide a direct detection and measurement of the reionization field.
Circulating tumor cells (CTCs) offer tremendous potential for the detection and characterization of cancer. A key challenge for their isolation and subsequent analysis is the extreme rarity of these ...cells in circulation. Here, a novel label‐free method is described to enrich viable CTCs directly from whole blood based on their distinct deformability relative to hematological cells. This mechanism leverages the deformation of single cells through tapered micrometer scale constrictions using oscillatory flow in order to generate a ratcheting effect that produces distinct flow paths for CTCs, leukocytes, and erythrocytes. A label‐free separation of circulating tumor cells from whole blood is demonstrated, where target cells can be separated from background cells based on deformability despite their nearly identical size. In doping experiments, this microfluidic device is able to capture >90% of cancer cells from unprocessed whole blood to achieve 104‐fold enrichment of target cells relative to leukocytes. In patients with metastatic castration‐resistant prostate cancer, where CTCs are not significantly larger than leukocytes, CTCs can be captured based on deformability at 25× greater yield than with the conventional CellSearch system. Finally, the CTCs separated using this approach are collected in suspension and are available for downstream molecular characterization.
Deformability‐based separation of circulating tumor cells (CTCs) from similarly sized leukocytes using microfluidic ratchets formed by oscillatory flow through asymmetrical constrictions is demonstrated. This mechanism can process whole blood directly to provide divergent paths for CTCs, leukocytes, and erythrocytes depending on cell deformability. In concurrent tests against conventional methods, this system is able to isolate ≈25× more CTCs from patients with castrate resistant prostate cancer.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Objective
To assess the safety and feasibility of robot‐assisted retroperitoneal lymph node dissection (R‐RPLND) and to compare the perioperative outcomes of R‐RPLND with open RPLND (O‐RPLND), as ...RPLND forms an integral part of the management of testis cancer and R‐RPLND is a minimally invasive treatment option for this disease.
Materials and Methods
The PubMed®, Scopus®, Cochrane Central Register of Controlled Trials, and Web of Science™ databases were searched for studies reporting perioperative outcomes of primary and post‐chemotherapy R‐RPLND and studies comparing R‐RPLND with O‐RPLND.
Results
The search yielded 42 articles describing R‐RPLND, including five comparative studies. The systematic review included 4222 patients (single‐arm studies, n = 459; comparative studies, n = 3763). Of 459 patients in the single‐arm studies, 271 underwent primary R‐RPLND and 188 underwent post‐chemotherapy R‐RPLND. For primary R‐RPLND, the operative time ranged from 175 to 540 min and the major complication rate was 4.1%. For post‐chemotherapy R‐RPLND, the operative time ranged from 134 to 550 min and the major complication rate was 8.5%. The conversion rate to open surgery was 2.2% in primary R‐RPLND and 9.0% in post‐chemotherapy R‐RPLND. In comparison with O‐RPLND, R‐RPLND was associated with a lower transfusion rate (14.5% vs 0.9%, P < 0.001) and a lower complication rate (18.5% vs 7.8%, P = 0.002).
Conclusion
Robot‐assisted RPLND has acceptable perioperative outcomes in both the primary and post‐chemotherapy settings but a notable rate of conversion to open surgery in the post‐chemotherapy setting. Compared with O‐RPLND, R‐RPLND is associated with a lower transfusion rate and fewer overall complications. Given the potential impact of selection bias, the optimal patient selection criteria for R‐RPLND remain to be elucidated.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Given the lack of randomized trials comparing robot-assisted radical prostatectomy (RARP) and open radical prostatectomy (ORP), we sought to re-examine the outcomes of these techniques using a cohort ...of patients treated in the postdissemination era.
Overall, data from 5,915 patients with prostate cancer treated with RARP or ORP within the SEER-Medicare linked database diagnosed between October 2008 and December 2009 were abstracted. Postoperative complications, blood transfusions, prolonged length of stay (pLOS), readmission, additional cancer therapies, and costs of care within the first year after surgery were compared between the two surgical approaches. To decrease the effect of unmeasured confounders, instrumental variable analysis was performed. Multivariable logistic regression analyses were then performed.
Overall, 2,439 patients (41.2%) and 3,476 patients (58.8%) underwent ORP and RARP, respectively. In multivariable analyses, patients undergoing RARP had similar odds of overall complications, readmission, and additional cancer therapies compared with patients undergoing ORP. However, RARP was associated with a higher probability of experiencing 30- and 90-day genitourinary and miscellaneous medical complications (all P ≤ .02). Additionally, RARP led to a lower risk of experiencing blood transfusion and of having a pLOS (all P < .001). Finally, first-year reimbursements were greater for patients undergoing RARP compared with ORP (P < .001).
RARP and ORP have comparable rates of complications and additional cancer therapies, even in the postdissemination era. Although RARP was associated with lower risk of blood transfusions and a slightly shorter length of stay, these benefits do not translate to a decrease in expenditures.
Purpose The relative effectiveness of partial vs radical nephrectomy remains unclear in light of the recent phase 3 European Organization for the Research and Treatment of Cancer trial. We performed ...a systematic review and meta-analysis of partial vs radical nephrectomy for localized renal tumors, considering all cause and cancer specific mortality, and severe chronic kidney disease. Materials and Methods Cochrane Central Register of Controlled Trials, MEDLINE®, EMBASE®, Scopus and Web of Science® were searched for sporadic renal tumors that were surgically treated with partial or radical nephrectomy. Generic inverse variance with fixed effects models were used to determine the pooled HR for each outcome. Results Data from 21, 21 and 9 studies were pooled for all cause and cancer specific mortality, and severe chronic kidney disease, respectively. Overall 31,729 (77%) and 9,281 patients (23%) underwent radical and partial nephrectomy, respectively. According to pooled estimates partial nephrectomy correlated with a 19% risk reduction in all cause mortality (HR 0.81, p <0.0001), a 29% risk reduction in cancer specific mortality (HR 0.71, p = 0.0002) and a 61% risk reduction in severe chronic kidney disease (HR 0.39, p <0.0001). However, the pooled estimate of cancer specific mortality for partial nephrectomy was limited by the lack of robustness in consistent findings on sensitivity and subgroup analyses. Conclusions Our findings suggest that partial nephrectomy confers a survival advantage and a lower risk of severe chronic kidney disease after surgery for localized renal tumors. However, the results should be evaluated in the context of the low quality of the existing evidence and the significant heterogeneity across studies. Future research should use higher quality evidence to clearly demonstrate that partial nephrectomy confers superior survival and renal function.
African American men are more likely to be diagnosed with, die of and experience decisional regret about their prostate cancer than nonAfrican American men. Although some clinical discrepancies may ...be attributed to genetic risk and/or access to care, explanations for racial discrepancies in decisional regret remain largely speculative. We aim to identify sources of prostate cancer decisional regret with a focus on racial disparities.
A cohort of 1,112 patients with localized prostate cancer treated at the Cleveland Clinic between 2010 and 2016 were matched by race, Gleason score, treatment (external beam radiation, brachytherapy, prostatectomy, active surveillance), prostate specific antigen at diagnosis, age at treatment and time since treatment. All patients received 4 surveys, including the Expanded Prostate Cancer Index Composite (EPIC) 26, the Decisional Regret Scale, our novel Prostate Cancer Beliefs Questionnaire and a modified EPIC demographics form. Descriptive and comparative statistics and multivariable logistic regression were used to compare survey outcomes by race and treatment method.
Of 1,048 deliverable surveys 378 (36.07%) were returned. African American men had worse decisional regret than nonAfrican American men even after adjusting for relevant covariates (OR 2.46, p <0.0001). African American men also had higher Prostate Cancer Beliefs Questionnaire medical mistrust and masculinity scores, both of which predicted worse decisional regret independent of race (1.415 and 1.350, p=0.0001, respectively).
African American men suffer worse decisional regret than nonAfrican American men, which may be partially explained by higher medical mistrust and concerns about masculinity as captured by the Prostate Cancer Beliefs Questionnaire. This novel survey may facilitate identifying targets to reduce racial disparities in prostate cancer.
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