Breast cancer cell debris diminishes therapeutic efficacy through heme oxygenase-1-mediated inactivation of M1-like tumor-associated macrophages

Chemotherapy is commonly used as a major therapeutic option for breast cancer treatment, but its efficacy is often diminished by disruption of patient's anti-tumor immunity. Chemotherapy-generated tumor cell debris could hijack accumulated tumor-associated macrophages (TAMs), provoking tumor recurrence. Therefore, reprogramming TAMs to acquire an immunocompetent phenotype is a promising strategy to potentiate therapeutic efficacy. In this study, we analyzed the proportion of immune cells in the breast cancer patients who received chemotherapy. To validate our findings in vivo, we used a syngeneic murine breast cancer (4T1) model. Chemotherapy generates an immunosuppressive tumor microenvironment in breast cancer. Here, we show that phagocytic engulfment of tumor cell debris by TAMs reduces chemotherapeutic efficacy in a 4T1 breast cancer model. Specifically, the engulfment of tumor cell debris by macrophages reduced M1-like polarization through heme oxygenase-1 (HO-1) upregulation. Conversely, genetic or pharmacologic inhibition of HO-1 in TAMs restored the M1-like polarization. Our results demonstrate that tumor cell debris-induced HO-1 expression in macrophages regulates their polarization. Inhibition of HO-1 overexpression in TAMs may provoke a robust anti-tumor immune response, thereby potentiating the efficacy of chemotherapy.

Transarterial chemoembolization versus resection for intermediate-stage (BCLC B) hepatocellular carcinoma

Background/Aims: Several studies have suggested that surgical resection (SR) can provide a survival benefit over transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) at the intermediate stage according to the Barcelona Clinic Liver Cancer (BCLC) staging system. However, the criteria for SR remain to be determined. This study compared the long-term outcome of intermediate-stage HCC patients treated by either TACE or SR as a primary treatment modality, with the aim of identifying the patient subgroup that gained a survival benefit by either modality. Methods: In total, 277 BCLC intermediate-stage HCC patients treated by either TACE (N=225) or SR (N=52) were analyzed. Results: The overall median survival time was significantly better for SR than TACE (61 vs. 30 months, P=0.002). Decision-tree analysis divided patients into seven nodes based on tumor size and number, serum alpha-fetoprotein (AFP) level, and Child-Pugh score, and these were then simplified into four subgroups (B1–B4) based on similarities in the overall hazard rate. SR provided a significant survival benefit in subgroup B2, characterized by ‘oligo’ (2–4) nodules of intermediate size (5–10 cm) when the AFP levels was <400 ng/ml, or ‘oligo’ (2–4) nodules of small to intermediate size (<10 cm) plus a Child-Pugh score of 5 when the AFP level was ≥400 ng/mL (median survival 73 vs. 28 months for SR vs. TACE respectively; P=0.014). The survival rate did not differ significantly between SR and TACE in the other subgroups (B1 and B3). Conclusion: SR provided a survival benefit over TACE in intermediate-stage HCC, especially for patients meeting certain criteria. Re-establishing the criteria for optimal treatment modalities in this stage of HCC is needed to improve survival rates

Stochastic carbon emission estimation method for construction operation

Low carbon construction is an important operation management goal because greenhouse gas (GHG) reduc­tion has become a global concern. Major construction resources that contribute GHG, such as equipment and labour, are being targeted to achieve this goal. The GHG emissions produced by the resources vary with their operating conditions. It is commendable to provide a statistical GHG emission estimation method that models the transitory nature of resource states at micro-scale of construction operations. This paper proposes a computational method called Stochastic Carbon Emission Estimation (SCE2) that measures the variability of GHG emissions. It creates construction operation models consisting of atomic work tasks, utilizes hourly equipment fuel consumption and hourly labourer respiratory rates that change according to their operating conditions classified into five categories, and identifies an optimal resource combi­nation by trading off eco-economic performance metrics such as the amount of GHG emissions, operation completion time, operation completion cost, and productivity. The study is of value to researchers because SCE2 fill in a gap to eco-economic operation modelling and analysis tool which considers operating conditions at micro-scale of construction operation having many stochastic work tasks. This study is also relevance to practitioners because it allows project man­agers to achieve eco-economic goals while honouring predefined constraints associated with time and cost. First published online: 13 Jul 201

Space-Constrained Scheduling Optimization Method for Minimizing the Effects of Stacking of Trades

Existing SCS (space-constrained scheduling) studies fall short of minimizing the effect of the stacking of trades that decline productivity due to an increase in resources within a physically limited work area. This article presents a space-constrained scheduling optimization (i.e., SSO) method for minimizing the stacking of trades. It imports schedule information from the project database, extracts IFC files of construction site area from the BIM model, defines the occupation density function of each activity to track the level of stacking of trades, and identifies the optimal solution (i.e., the optimal set of pairs of execution pattern alternatives and start times of activities) by implementing genetic algorithm (GA) optimization analysis. The study is of value to practitioners because SSO provides an easy-to-use computerized tool that reduces the lengthy computations relative to data processing and GAs. Test cases verify the validity of the computational method

GA-Based Optimization Method for Mobile Crane Repositioning Route Planning

Mobile cranes have been used extensively as essential equipment at construction sites. The productivity improvement of the mobile crane affects the overall productivity of the construction project. Hence, various studies have been conducted regarding mobile crane operation planning. However, studies on solving RCP (the repositioning mobile crane problem) are insufficient. This article presents a mobile crane reposition route planning optimization method (RPOS) that minimizes the total operating time of mobile crane. It converts the construction site into a mathematical model, determines feasible locations of the mobile crane, and identifies near-global optimal solution (s) (i.e., the placement point sequences of mobile crane) by implementing genetic algorithm and dijkstra’s algorithm. The study is of value to practitioners because RPOS provides an easy-to-use computerized tool that reduces the lengthy computations relative to data processing and Genetic Algorithms (GAs). Test cases verify the validity of the computational method

Nonhypertensive White Matter Hyperintensities in Stroke: Risk Factors, Neuroimaging Characteristics, and Prognosis

Background This study explored the risk factors, neuroimaging features, and prognostic implications of nonhypertensive white matter hyperintensity (WMH) in patients with acute ischemic stroke and transient ischemic attack. Methods and Results We included 2283 patients with hypertension and 1003 without from a pool of 10 602. Associations of moderate‐to‐severe WMH with known risk factors, functional outcome, and a composite of recurrent stroke, myocardial infarction, and all‐cause mortality were evaluated. A subset of 351 patients without hypertension and age‐ and sex‐matched pairs with hypertension and moderate‐to‐severe WMH was created for a detailed topographic examination of WMH, lacunes, and microbleeds. Approximately 35% of patients without hypertension and 65% of patients with hypertensive stroke exhibited moderate‐to‐severe WMH. WMH was associated with age, female sex, and previous stroke, irrespective of hypertension. In patients without hypertension, WMH was associated with initial systolic blood pressure and was more common in the anterior temporal region. In patients with hypertension, WMH was associated with small vessel occlusion as a stroke mechanism and was more frequent in the periventricular region near the posterior horn of the lateral ventricle. The higher prevalence of occipital microbleeds in patients without hypertension and deep subcortical lacunes in patients with hypertension were also observed. Associations of moderate‐to‐severe WMH with 3‐month functional outcome and 1‐year cumulative incidence of the composite outcome were significant (both P<0.01), although the latter lost significance after adjustments. The associations between WMH and outcomes were consistent across hypertensive status. Conclusions One‐third of patients without hypertension with stroke have moderate‐to‐severe WMH. The pathogenesis of WMH may differ between patients without and with hypertension, but its impact on outcome appears similar