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Abstract A spontaneously occurring temperature increase in solid tumors has been reported sporadically, but is largely overlooked in terms of cancer biology. Here we show that temperature is increased in tumors of patients with pancreatic ductal adenocarcinoma (PDAC) and explore how this could affect therapy response. By mimicking this observation in PDAC cell lines, we demonstrate that through adaptive changes in lipid metabolism, the temperature increase found in human PDAC confers protection to lipid peroxidation and contributes to gemcitabine resistance. Consistent with the recently uncovered role of p38 MAPK in ferroptotic cell death, we find that the reduction in lipid peroxidation potential following adaptation to tumoral temperature allows for p38 MAPK inhibition, conferring chemoresistance. As an increase in tumoral temperature is observed in several other tumor types, our findings warrant taking tumoral temperature into account in subsequent studies related to ferroptosis and therapy resistance. More broadly, our findings indicate that tumoral temperature affects cancer biology.

A novel reactive P-N intumescent flame retardant tetroxo (3-triethylphosphine-5-chlorine-1-triazine) neopentane (TTCTN) was prepared, and its structure was determined by Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR). The flame retardance and physiological comfort properties of TTCTN-treated cotton fabrics (TTCTN-CF) was researched. The CF treated with 20 wt% TTCTN (TTCTN(20)-CF) showed the limiting oxygen index (LOI) was up to 28.6%, and the flame retardancy reached the class B1 of national standard of flame retardant fabrics, and its peak heat release rate and total heat release were reduced by 55.7% and 37.4% comparing with untreated CF, respectively. The FTIR proved the TTCTN was grafted on the CF matrix. Thermogravimetric (TG) showed TTCTN could reduce the decomposition speed of the cotton fabric and formed the stable char residue at high temperature to protect the remaining CF from complete dehydration. After 50 washing cycles, the LOI of TTCTN(20)-CF was 26.2%, still reaching class B1 of national standard of flame retardant fabrics. Scanning electron microscope showed the TTCTN was still bounded to the matrix of CF after 50 washing cycles which further proved TTCTN(20)-CF had excellent durable flame retardancy.

Abstract Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, lacking effective therapy. Many TNBCs show remarkable response to carboplatin-based chemotherapy, but often develop resistance over time. With increasing use of carboplatin in the clinic, there is a pressing need to identify vulnerabilities of carboplatin-resistant tumors. In this study, we generated carboplatin-resistant TNBC MDA-MB-468 cell line and patient derived TNBC xenograft models. Mass spectrometry-based proteome profiling demonstrated that carboplatin resistance in TNBC is linked to drastic metabolism rewiring and upregulation of anti-oxidative response that supports cell replication by maintaining low levels of DNA damage in the presence of carboplatin. Carboplatin-resistant cells also exhibited dysregulation of the mitotic checkpoint. A kinome shRNA screen revealed that carboplatin-resistant cells are vulnerable to the depletion of the mitotic checkpoint regulators, whereas the checkpoint kinases CHEK1 and WEE1 are indispensable for the survival of carboplatin-resistant cells in the presence of carboplatin. We confirmed that pharmacological inhibition of CHEK1 by prexasertib in the presence of carboplatin is well tolerated by mice and suppresses the growth of carboplatin-resistant TNBC xenografts. Thus, abrogation of the mitotic checkpoint by CHEK1 inhibition re-sensitizes carboplatin-resistant TNBCs to carboplatin and represents a potential strategy for the treatment of carboplatin-resistant TNBCs.

A total of 30% of lung adenocarcinoma are driven by activating KRAS mutations. The treatment options for KRAS-mutant lung cancer are still limited as a challenge for therapy is the high heterogeneity within KRAS mutant tumors. Co-existing genetic events alter RAS signaling, such as the genetic alteration of the ubiquitin ligase leucine zipper-like transcriptional regulator 1 (LZTR1). LZTR1 is an adaptor of CUL3 E3 ligase that controls the localization and expression levels of RAS proteins by regulating their ubiquitination. Recent studies demonstrated that the loss of LZTR1 leads to resistance to the tyrosine kinase inhibitor and the multi-kinase inhibitor, suggesting that LZTR1 loss might be associated with the drug resistance of KRAS-mutated lung tumors. TCGA analysis indicated that LZTR1 loss affected progression survival in KRAS mutant LUAD patients, with a significant co-occurrence of LZTR1 loss and KRAS mutations. While LZTR1 depletion in LUAD cell lines did not affect proliferation in the cell culture, the knock-out (KO) of Lztr1 in a mouse model with Kras G12D oncogenic mutations caused a clear and significant acceleration of tumor progression in the Lztr1 loss groups, indicating that Lztr1 can affect tumor onset and progression. To study the alterations of the RAS pathway triggered by LZTR1 loss, we performed a global OMICS analysis on both in vitro and in vivo systems, identifying potential therapeutic targets. The characterization of immune populations in the tumors of flow cytometry also revealed changes in immune infiltrate in the KO mouse. We are now investigating how the changes caused by Lztr1 deletion on KRAS signaling heterogeneity within tumor cells can affect the tumor microenvironment composition. Our results suggest that the dysregulation of KRAS function by Lztr1 deletion contributes to cancer progression by affecting tumor cell communication with the microenvironment. Our work could explain how Lztr1 loss can affect drug response and lead to therapy resistance.

Objectives To develop a model of in-hospital mortality using medical record front page (MRFP) data and assess its validity in case-mix standardisation by comparison with a model developed using the complete medical record data.Design A nationally representative retrospective study.Setting Representative hospitals in China, covering 161 hospitals in modelling cohort and 156 hospitals in validation cohort.Participants Representative patients admitted for acute myocardial infarction. 8370 patients in modelling cohort and 9704 patients in validation cohort.Primary outcome measures In-hospital mortality, which was defined explicitly as death that occurred during hospitalisation, and the hospital-level risk standardised mortality rate (RSMR).Results A total of 14 variables were included in the model predicting in-hospital mortality based on MRFP data, with the area under receiver operating characteristic curve of 0.78 among modelling cohort and 0.79 among validation cohort. The median of absolute difference between the hospital RSMR predicted by hierarchical generalised linear models established based on MRFP data and complete medical record data, which was built as ‘reference model’, was 0.08% (10th and 90th percentiles: −1.8% and 1.6%). In the regression model comparing the RSMR between two models, the slope and intercept of the regression equation is 0.90 and 0.007 in modelling cohort, while 0.85 and 0.010 in validation cohort, which indicated that the evaluation capability from two models were very similar.Conclusions The models based on MRFP data showed good discrimination and calibration capability, as well as similar risk prediction effect in comparison with the model based on complete medical record data, which proved that MRFP data could be suitable for risk adjustment in hospital performance measurement.

The title complex, [Fe2(C8H12S3)(CO)6] or [{Fe(CO)3}2(μ-L)] [L = 3,3-dimethyl-4-(propan-2-ylidene)thietane-2,2-bis(thiolato)], consists of two Fe(CO)3 moieties double-bridged by a dithiolate ligand. Each of the two FeI atoms has a distorted anti-prismatic coordination environment consisting of three carbonyl groups, two S atoms of the dithiolate ligand and the neighboring FeI atom [Fe—Fe = 2.4921 (4) Å]. Weak C—H...O intermolecular interactions result in the formation of dimers. This is the second crystal structure reported with the 3,3-dimethyl-4-(propan-2-ylidene)thietane-2,2-bis(thiolate) ligand and the first in which it bridges two metal atoms.

Hirschsprung-associated enterocolitis (HAEC) is a life-threatening complication of Hirschsprung's disease (HD). Although the pathological mechanisms are still unclear, studies have shown that HAEC has a close relationship with the disturbance of intestinal microbiota. This study aimed to investigate the characteristics of the intestinal microbiome of HD patients with or without enterocolitis. During routine or emergency surgery, we collected 35 intestinal content samples from five patients with HAEC and eight HD patients, including three HD patients with a history of enterocolitis who were in a HAEC remission (HAEC-R) phase. Using Illumina-MiSeq high-throughput sequencing, we sequenced the V4 region of bacterial 16S rRNA, and operational taxonomic units (OTUs) were defined by 97% sequence similarity. Principal coordinate analysis (PCoA) of weighted UniFrac distances was performed to evaluate the diversity of each intestinal microbiome sample. The microbiota differed significantly between the HD patients (characterized by the prevalence of Bacteroidetes) and HAEC patients (characterized by the prevalence of Proteobacteria), while the microbiota of the HAEC-R patients was more similar to that of the HAEC patients. We also observed that the specimens from different intestinal sites of each HD patient differed significantly, while the specimens from different intestinal sites of each HAEC and HAEC-R patient were more similar. In conclusion, the microbiome pattern of the HAEC-R patients was more similar to that of the HAEC patients than to that of the HD patients. The HD patients had a relatively distinct, more stable community than the HAEC and HAEC-R patients, suggesting that enterocolitis may either be caused by or result in a disruption of the patient's uniquely adapted intestinal flora. The intestinal microbiota associated with enterocolitis may persist following symptom resolution and can be implicated in the symptom recurrence.

Chaoshan businessmen were widely involved in internal group cooperation. Based on historical and comparative institutional analysis, it is found that the cooperative behavior of Chaoshan businessmen in the Ming and Qing Dynasties is not simply an economic behavior. It reflects the historical evolution of the interaction between the regional cultures concerning the sea, clan and Confucianism, the governance of merchant groups with blood and geographical characteristics, and the beliefs of merchants in Mazu and Guan Yu. The evolutionary game theory is used to investigate the evolutionary process and the evolutionary stable strategy of the internal cooperative behavior of Chaoshan businessmen. It shows that due to the joint influence of regional culture, governance of merchant groups and beliefs of merchants, a multilateral collective punishment mechanism for untrustworthy merchants and a loss compensation mechanism for trustworthy merchants are established through channels such as chambers of commerce and ancestral temples. Thus, it reinforces the group cooperation institutions of integrity within Chaoshan merchant groups in the Ming and Qing Dynasties. [ABSTRACT FROM AUTHOR]

This paper uses evolutionary game theory to analyse regional tourism cooperation. Asymmetric evolutionary game model is established to explore the intrinsic motivation of regional tourism cooperation, and we via rigorous mathematical reasoning to prove a series of proposition. At the same time, through numerical simulation on each proposition by the MATLAB software, it vividly reflects the evolution process of the regional tourism cooperation. The results show that, first, it is necessary to cooperate, which is the inevitable trend in the development; Second, we shall specify the necessary condition to maintain cooperation, when the no-cooperative party can obtain additional benefit of freeriding from the cooperation party, and the additional benefit is greater than the benefit from bilateral cooperation, cooperation will ultimately fail; third, we must focus on the sufficient conditions to guarantee cooperation, which mainly reflected on the utilization of shared resources, cooperation cost, the benefit of "free-riding" etc. In view of the results, we propose some suggestions to promote regional tourism cooperation from the regulations of regional tourism cooperation, government and the utilization of shared resources. [ABSTRACT FROM AUTHOR]

The problem of MNCs' technology transfer is virtually the dynamic game problem between MNCs and host country enterprises. The paper introduces evolutionary game theory to the field of technology transfer. For the problem of technology transfer between MNCs and host country enterprises, Evolutionary game theory sets up the model of an evolutionary game according to host country enterprises whether they have research and development capability or not, and comparatively analyzes the equilibrium results. Finally, the paper draws a useful and enlightening conclusion. [ABSTRACT FROM AUTHOR]

Mitochondrial DNA (mtDNA) mutations are frequent in cancer, yet their precise role in cancer progression remains debated. To functionally evaluate the impact of mtDNA variants on tumor growth and metastasis, we developed an enhanced cytoplasmic hybrid (cybrid) generation protocol and established isogenic human melanoma cybrid lines with wild-type mtDNA or pathogenic mtDNA mutations with partial or complete loss of mitochondrial oxidative function. Cybrids with homoplasmic levels of pathogenic mtDNA reliably established tumors despite dysfunctional oxidative phosphorylation. However, these mtDNA variants disrupted spontaneous metastasis from primary tumors and reduced the abundance of circulating tumor cells. Migration and invasion of tumor cells were reduced, indicating that entry into circulation is a bottleneck for metastasis amid mtDNA dysfunction. Pathogenic mtDNA did not inhibit organ colonization following intravenous injection. In heteroplasmic cybrid tumors, single-cell analyses revealed selection against pathogenic mtDNA during melanoma growth. Collectively, these findings experimentally demonstrate that functional mtDNA is favored during melanoma growth and supports metastatic entry into the blood. [ABSTRACT FROM AUTHOR]

The article discusses a study by Massimiliano Mazzone and his team, published in the journal "Science Advance," which shows that breast tumors hinder endothelial TRAIL, preventing its signaling and preserving a quiescent vascular phenotype. The study reveals an intracrine mechanism where TRAIL blocks DR5 signaling in quiescent endothelia, serving as a gatekeeper of the vascular barrier that is corrupted by the tumor during cancer cell dissemination.