Threshold-awareness in adaptive cancer therapy.

Although adaptive cancer therapy shows promise in integrating evolutionary dynamics into treatment scheduling, the stochastic nature of cancer evolution has seldom been taken into account. Various sources of random perturbations can impact the evolution of heterogeneous tumors, making performance metrics of any treatment policy random as well. In this paper, we propose an efficient method for selecting optimal adaptive treatment policies under randomly evolving tumor dynamics. The goal is to improve the cumulative "cost" of treatment, a combination of the total amount of drugs used and the total treatment time. As this cost also becomes random in any stochastic setting, we maximize the probability of reaching the treatment goals (tumor stabilization or eradication) without exceeding a pre-specified cost threshold (or a "budget"). We use a novel Stochastic Optimal Control formulation and Dynamic Programming to find such "threshold-aware" optimal treatment policies. Our approach enables an efficient algorithm to compute these policies for a range of threshold values simultaneously. Compared to treatment plans shown to be optimal in a deterministic setting, the new "threshold-aware" policies significantly improve the chances of the therapy succeeding under the budget, which is correlated with a lower general drug usage. We illustrate this method using two specific examples, but our approach is far more general and provides a new tool for optimizing adaptive therapies based on a broad range of stochastic cancer models.

Ottowia cancrivicina sp. nov., isolated from human stomach.

A Gram-negative, facultative anaerobic, non-motile and rod-shaped bacterium, designated 10c7w1T, was isolated from a human gastrointestinal tract. Colonies on agar plates were small, circular, smooth and beige. The optimal growth conditions were determined to be 37 °C, pH 7.0-7.5 and 0 % (w/v) NaCl. Comparative analysis of complete 16S rRNA gene sequences revealed that strain 10c7w1T showed the highest sequence similarity of 95.8 % to Ottowia beijingensis MCCC 1A01410T, followed by Ottowia thiooxydans (95.2 %) JCM 11629T. The average amino acid identity values between 10c7w1T and O. beijingensis MCCC 1A01410T and O. thiooxydans JCM 11629T were above 60 % (71.4 and 69.5 %). The average nucleotide identity values between strain 10c7w1T and O. beijingensis MCCC 1A01410T and O. thiooxydans JCM 11629T were 76.9 and 72.5 %, respectively. The dominant fatty acids (≥10 %) were straight chain ones, with summed feature 3 (C16 : 1 ω7c/C16 : 1 ω6c), summed feature 8 (C18 : 1 ω7c/C18 : 1 ω6c) and C16 : 00 being the most abundant. Q-8 was the only respiratory quinone. The major polar lipids of strain 10c7w1T were phosphatidylethanolamine, diphosphatidylglycerol and unknown lipids. The DNA G+C content of strain 10c7w1T was 63.6 mol%. On the basis of phylogenetic, phenotypic and chemotaxonomic data, strain 10c7w1T is considered to represent a novel species within the genus Ottowia, for which the name Ottowia cancrivicina sp. nov. is proposed. The type strain is 10c7w1T (=MCCC 1H01399T=KCTC 92200T).

The Senescent Heart-"Age Doth Wither Its Infinite Variety".

Cardiovascular diseases are a leading cause of morbidity and mortality world-wide. While many factors like smoking, hypertension, diabetes, dyslipidaemia, a sedentary lifestyle, and genetic factors can predispose to cardiovascular diseases, the natural process of aging is by itself a major determinant of the risk. Cardiac aging is marked by a conglomerate of cellular and molecular changes, exacerbated by age-driven decline in cardiac regeneration capacity. Although the phenotypes of cardiac aging are well characterised, the underlying molecular mechanisms are far less explored. Recent advances unequivocally link cardiovascular aging to the dysregulation of critical signalling pathways in cardiac fibroblasts, which compromises the critical role of these cells in maintaining the structural and functional integrity of the myocardium. Clearly, the identification of cardiac fibroblast-specific factors and mechanisms that regulate cardiac fibroblast function in the senescent myocardium is of immense importance. In this regard, recent studies show that Discoidin domain receptor 2 (DDR2), a collagen-activated receptor tyrosine kinase predominantly located in cardiac fibroblasts, has an obligate role in cardiac fibroblast function and cardiovascular fibrosis. Incisive studies on the molecular basis of cardiovascular aging and dysregulated fibroblast function in the senescent heart would pave the way for effective strategies to mitigate cardiovascular diseases in a rapidly growing elderly population.

A novel hypergraph model for identifying and prioritizing personalized drivers in cancer.

Cancer development is driven by an accumulation of a small number of driver genetic mutations that confer the selective growth advantage to the cell, while most passenger mutations do not contribute to tumor progression. The identification of these driver genes responsible for tumorigenesis is a crucial step in designing effective cancer treatments. Although many computational methods have been developed with this purpose, the majority of existing methods solely provided a single driver gene list for the entire cohort of patients, ignoring the high heterogeneity of driver events across patients. It remains challenging to identify the personalized driver genes. Here, we propose a novel method (PDRWH), which aims to prioritize the mutated genes of a single patient based on their impact on the abnormal expression of downstream genes across a group of patients who share the co-mutation genes and similar gene expression profiles. The wide experimental results on 16 cancer datasets from TCGA showed that PDRWH excels in identifying known general driver genes and tumor-specific drivers. In the comparative testing across five cancer types, PDRWH outperformed existing individual-level methods as well as cohort-level methods. Our results also demonstrated that PDRWH could identify both common and rare drivers. The personalized driver profiles could improve tumor stratification, providing new insights into understanding tumor heterogeneity and taking a further step toward personalized treatment. We also validated one of our predicted novel personalized driver genes on tumor cell proliferation by vitro cell-based assays, the promoting effect of the high expression of Low-density lipoprotein receptor-related protein 1 (LRP1) on tumor cell proliferation.

Dietary antarctic krill improves antioxidant capacity, immunity and reduces lipid accumulation, insights from physiological and transcriptomic analysis of Plectropomus leopardus.

BACKGROUND: Due to its enormous biomass, Antarctic krill (Euphausia superba) plays a crucial role in the Antarctic Ocean ecosystem. In recent years, Antarctic krill has found extensive application in aquaculture, emerging as a sustainable source of aquafeed with ideal nutritional profiles. However, a comprehensive study focused on the detailed effects of dietary Antarctic krill on aquaculture animals, especially farmed marine fishes, is yet to be demonstrated. RESULTS: In this study, a comparative experiment was performed using juvenile P. leopardus, fed with diets supplemented with Antarctic krill (the krill group) or without Antarctic krill (the control group). Histological observation revealed that dietary Antarctic krill could reduce lipid accumulation in the liver while the intestine exhibited no obvious changes. Enzyme activity measurements demonstrated that dietary Antarctic krill had an inhibitory effect on oxidative stress in both the intestine and the liver. By comparative transcriptome analysis, a total of 1,597 and 1,161 differentially expressed genes (DEGs) were identified in the intestine and liver, respectively. Functional analysis of the DEGs showed multiple enriched terms significantly related to cholesterol metabolism, antioxidants, and immunity. Furthermore, the expression profiles of representative DEGs, such as dhcr7, apoa4, sc5d, and scarf1, were validated by qRT-PCR and fluorescence in situ hybridization. Finally, a comparative transcriptome analysis was performed to demonstrate the biased effects of dietary Antarctic krill and astaxanthin on the liver of P. leopardus. CONCLUSIONS: Our study demonstrated that dietary Antarctic krill could reduce lipid accumulation in the liver of P. leopardus, enhance antioxidant capacities in both the intestine and liver, and exhibit molecular-level improvements in lipid metabolism, immunity, and antioxidants. It will contribute to understanding the protective effects of Antarctic krill in P. leopardus and provide insights into aquaculture nutritional strategies.

MaxCLK: discovery of cancer driver genes via maximal clique and information entropy of modules.

MOTIVATION: Cancer is caused by the accumulation of somatic mutations in multiple pathways, in which driver mutations are typically of the properties of high coverage and high exclusivity in patients. Identifying cancer driver genes has a pivotal role in understanding the mechanisms of oncogenesis and treatment. RESULTS: Here, we introduced MaxCLK, an algorithm for identifying cancer driver genes, which was developed by an integrated analysis of somatic mutation data and protein-protein interaction (PPI) networks and further improved by an information entropy index. Tested on pancancer and single cancers, MaxCLK outperformed other existing methods with higher accuracy. About pancancer, we predicted 154 driver genes and 787 driver modules. The analysis of co-occurrence and exclusivity between modules and pathways reveals the correlation of their combinations. Overall, our study has deepened the understanding of driver mechanism in PPI topology and found novel driver genes. AVAILABILITY AND IMPLEMENTATION: The source codes for MaxCLK are freely available at https://github.com/ShandongUniversityMasterMa/MaxCLK-main.

Marinicella marina sp. nov. and Marinicella gelatinilytica sp. nov., isolated from coastal sediment, and genome analysis and habitat distribution of the genus Marinicella.

Three Marinicella strains, X102, S1101T and S6413T, were isolated from sediment samples from different coasts of Weihai, PR China. All strains were Gram-stain-negative, rod-shaped and non-motile. The predominant fatty acids of all strains were iso-C15 : 0 and summed feature 3 (C16 : 1 ω7c/C16 : 1 ω6c) and the major polar lipids comprised phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. Strains X102 and S1101T shared 100 % 16S rRNA gene sequence similarity, and strains S1101T/X102 and S6413T had 95.4 % similarity. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between strains S1101T and X102 were 99.9 and 99.2 %, respectively. Strain S1101T had ANI values of 69.1-72.9% and dDDH values of 17.9-20.5 % to members of the genus Marinicella. Strain S6413T had ANI values of 69.1-77.5% and dDDH values of 17.6-21.5 % to members of the genus Marinicella. The results of phylogenetic and comparative genomic analysis showed that the three strains belong to two novel species in the genus Marinicella, and strains X102 and S1101T represented one novel species, and strain S6413T represented another novel species. The result of BOX-PCR and genomic analysis showed that X102 and S1101T were not the same strain. The phylogenetic analyses and genomic comparisons, combined with phylogenetic, phenotypic and chemotaxonomic features, strongly supported that the three strains should be classified as representing two novel species of the genus Marinicella, for which the names Marinicella marina sp. nov. and Marinicella gelatinilytica sp. nov. are proposed, respectively. The type strains of the two novel species are S1101T (=KCTC 92642T=MCCC 1H01359T) and S6413T (=KCTC 92641T=MCCC 1H01362T), respectively. In addition, all previously described isolates of Marinicella were isolated from marine environments, but our study showed that Marinicella is also distributed in non-/low-saline habitats (e.g. animal gut, soil and indoor surface), which broadened our perception of the environmental distribution of Marinicella.

Tumebacillus lacus sp. nov., isolated from lake water.

A Gram-stain-positive, aerobic, rod-shaped, endospore-forming and motile, by means of peritrichous flagella, bacterium, designated DT12T, was isolated from a lake water sample from Datun Lake of Yunnan Province, PR China. The results of phylogenetic analysis based on 16S rRNA gene sequence and the concatenated alignment of 120 ubiquitous single-copy proteins indicated that the novel strain represented a member of the genus Tumebacillus. The sole quinone was menaquinone-7 and the cell-wall peptidoglycan was type-A1γ. The major fatty acids (>10 %) of the novel strain were iso-C15 : 0 and anteiso-C15 : 0, while the major polar lipids were phosphatidylmonomethylethanolamine, phosphatidylethanolamine and phosphatidylglycerol. The results of phylogenetic analyses combined with phylogenetic, phenotypic and chemotaxonomic features, strongly supported the hypothesis that the strain should be classified as representing a novel species of the genus Tumebacillus, for which the name Tumebacillus lacus sp. nov. is proposed. The type strain is DT12T (=KCTC 33958T= MCCC 1H00320T). The genomic analysis revealed that DT12T has various biosynthetic gene clusters for secondary metabolites, and members of the genus Tumebacillus may represent a promising source of new natural products. Our study also showed that members of the genus Tumebacillus are widely distributed in a variety of habitats throughout the globe, particularly in soils, human-, animal- and plant-associated environments. Members of the genus Tumebacillus may have an important role in the growth and health of humans, plants and animals.

Incidence and risk factors of surgical site infection in patients with head and neck cancer: A meta-analysis.

We systematically review the incidence and risk factors of surgical site infection (SSI) in patients with head and neck cancer. PubMed, Embase, Cochrane Library, and Web of Science databases were searched to obtain studies on the risk factors for SSI in patients with HNC. The retrieval time was from the establishment of the database to February 2023. Two reviewers independently screened the literature, extracted data, and assessed the risk of bias in included studies. Meta-analysis was performed by using Stata 15.1 software. A total of 32 articles including 128 919 patients with head and neck cancer and 2949 cases of SSI were included in this meta-analysis. The incidence rate of SSI in head and neck cancer ranges from 19% to 29%, and the overall infection rate was 24%. Meta-analysis indicated that BMI < 20 kg/m2 (OR, 2.64; 95% CI, 1.74-4.00; I2 , 0%), diabetes (OR, 3.00; 95% CI, 2.12-4.16; I2 , 60.6%), ASA score (OR, 1.51; 95% CI, 1.29-1.77; I2 , 0%), radiotherapy (OR, 2.27; 95% CI, 1.87-2.77; I2 , 44.8%), chemotherapy (OR, 2.36; 95% CI, 1.64-3.40; I2 , 0%), clindamycin antibiotic (OR, 2.99; 95% CI, 1.82-2.93; I2 , 36.5%), deficit repair (OR, 3.76; 95% CI, 1.22-11.59; I2 , 91.4%), neck dissection (OR, 2.13; 95% CI, 1.63-2.79; I2 , 16.4%), blood transfusion (OR, 2.29; 95% CI, 1.52-3.45; I2 , 66.2%), mandibular (OR, 3.17; 95% CI, 1.85-5.42; I2 , 73%), tracheostomy (OR, 2.51; 95% CI, 1.74-3.62; I2 , 86.4%), operation time (OR, 1.42; 95% CI, 1.16-1.74; I2 , 86.4%), ALB (OR, 2.48; 95% CI, 1.95-3.15; I2 , 5.3%) were risk factors of surgical site infection in patients with head and neck cancer (p < 0.05). The results of the sensitivity analysis showed good agreement in all risk factors and the results had stability. The present meta-analysis suggests that BMI < 20 kg/m2 , diabetes, ASA score, radiotherapy, chemotherapy, clindamycin antibiotic, deficit repair, neck dissection, blood transfusion, mandibular, tracheostomy, operation time, and ALB were significant risk factors for SSI.

Autologous Fat Grafting for Functional and Aesthetic Improvement in Patients with Head and Neck Cancer: A Systematic Review.

INTRODUCTION: The efficacy and safety of autologous fat grafting for use in oncology patients are controversial. Patients with head and neck cancer have complex anatomy and require reconstructive repair of the head and neck after comprehensive treatment. The limited additional aesthetic and functional studies on the use of autologous fat fillers in patients with head and neck cancer are unclear. This study systematically evaluates the additional function of autologous fat fillers in the head and neck and systematically reviews issues related to autologous fat grafting after comprehensive head and neck cancer treatment, including current indications, techniques, potential complications, graft survival, and patient satisfaction. METHODS: A systematic literature review was performed using PubMed, The Cochrane Library, EMBASE, and Web of Science (last accessed on January 9, 2023). RESULTS: A total of 249 cases of autologous fat fillers in patients with head and neck cancer were reported in 10 clinical publications. Observations were based mainly on subjective physician and patient evaluation indicators, and all studies reported the beneficial effects of autologous fat fillers on aesthetics and function after treatment for head and neck cancer. CONCLUSIONS: Autologous fat fillers are effective in improving the aesthetics and function of head and neck cancer, and due to the limitations of the original study, future studies with large samples are needed to support this. PROSPERO registration number is CRD42020222870. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Downregulation of miR­7 and miR­153 is involved in Helicobacter pylori CagA induced gastric carcinogenesis and progression.

Helicobacter pylori (H. pylori) infection plays a pivotal role in the development of gastric cancer (GC). However, the association between aberrant microRNAs (miRNAs/miRs) expression and H. pylori­induced GC remains poorly understood. The present study reported that repeated infection of H. pylori caused the oncogenicity of GES­1 cells in BALB/c Nude mice. miRNA sequencing revealed that both miR­7 and miR­153 were significantly decreased in the cytotoxin­associated gene A (CagA) positive GC tissues and this was further confirmed in a chronic infection model of GES­1/HP cells. Further biological function experiments and in vivo experiments validated that miR­7 and miR­153 can promote apoptosis and autophagy, inhibit proliferation and inflammatory response in GES­1/HP cells. All the associations between miR­7/miR­153 and their potential targets were revealed via bioinformatics prediction and dual­luciferase reporter assay. Particularly, downregulation of both miR­7 and miR­153 obtained an improved sensitivity and specificity in diagnosing H. pylori (CagA+)­induced GC. The present study identified that the combination of miR­7 and miR­153 may be regarded as novel therapeutic targets in H. pylori CagA (+)­associated GC.

DPP4 inhibition impairs senohemostasis to improve plaque stability in atherosclerotic mice.

Senescent vascular smooth muscle cells (VSMCs) accumulate in the vasculature with age and tissue damage and secrete factors that promote atherosclerotic plaque vulnerability and disease. Here, we report increased levels and activity of dipeptidyl peptidase 4 (DPP4), a serine protease, in senescent VSMCs. Analysis of the conditioned media from senescent VSMCs revealed a unique senescence-associated secretory phenotype (SASP) signature comprising many complement and coagulation factors; silencing or inhibiting DPP4 reduced these factors and increased cell death. Serum samples from persons with high risk for cardiovascular disease contained high levels of DPP4-regulated complement and coagulation factors. Importantly, DPP4 inhibition reduced senescent cell burden and coagulation and improved plaque stability, while single-cell resolution of senescent VSMCs reflected the senomorphic and senolytic effects of DPP4 inhibition in murine atherosclerosis. We propose that DPP4-regulated factors could be exploited therapeutically to reduce senescent cell function, reverse senohemostasis, and improve vascular disease.

Helicobacter pylori and gastric microbiota homeostasis: progress and prospects.

Helicobacter pylori, a Gram-negative microaerobic bacteria belonging to the phylum Proteobacteria, can colonize in the stomach and duodenum, and cause a series of gastrointestinal diseases such as gastritis, gastric ulcer and even gastric cancer. At present, the high diversity of the microorganisms in the stomach has been confirmed with culture-independent methods; some researchers have also studied the stomach microbiota composition at different stages of H. pylori carcinogenesis. Here, we mainly review the possible role of H. pylori-mediated microbiota changes in the occurrence and development of gastric cancer to provide new ideas for preventing H. pylori infection and regulating microecological imbalance.

Milk Fat Globule Epidermal Growth Factor VIII Fragment Medin in Age-Associated Arterial Adverse Remodeling and Arterial Disease.

Medin, a small 50-amino acid peptide, is an internal cleaved product from the second discoidin domain of milk fat globule epidermal growth factor VIII (MFG-E8) protein. Medin has been reported as the most common amylogenic protein in the upper part of the arterial system, including aortic, temporal, and cerebral arterial walls in the elderly. Medin has a high affinity to elastic fibers and is closely associated with arterial degenerative inflammation, elastic fiber fragmentation, calcification, and amyloidosis. In vitro, treating with the medin peptide promotes the inflammatory phenotypic shift of both endothelial cells and vascular smooth muscle cells. In vitro, ex vivo, and in vivo studies demonstrate that medin enhances the abundance of reactive oxygen species and reactive nitrogen species produced by both endothelial cells and vascular smooth muscle cells and promotes vascular endothelial dysfunction and arterial stiffening. Immunostaining and immunoblotting analyses of human samples indicate that the levels of medin are increased in the pathogenesis of aortic aneurysm/dissection, temporal arteritis, and cerebrovascular dementia. Thus, medin peptide could be targeted as a biomarker diagnostic tool or as a potential molecular approach to curbing the arterial degenerative inflammatory remodeling that accompanies aging and disease.

Huntingtin-associated protein 1 is a potential tumor suppressor for gastric cancer.

BACKGROUND: Gastric cancer is heterogeneous cancer and the causes of this disease are complex. New diagnostic and therapeutic targets are urgently needed to explore. Huntingtin-associated protein 1 (HAP1) is directly related to Huntington's disease (HD). However, patients with Huntington's disease have a lower incidence of cancer. Therefore, we are committed to studying the correlation between HAP1 and gastric carcinogenesis and development. METHODS AND RESULTS: Immunohistochemical staining, western blot analysis, and RT-qPCR were conducted to explore the localization and expression of HAP1 in gastric cancer. To study the biological significance of HAP1, we overexpressed HAP1 in both MKN28 and AGS cell lines by lentivirus infection. To explore the role of HAP1 in cell proliferation, the cells counting assay, EdU incorporation assay, and colony formation assay were carried out. We performed the wound healing assay and transwell assay to study the cell migration and invasion. To further investigate whether HAP1 could regulate gastric cancer cell death during glucose deprivation, Annexin V-FITC/PI staining was performed. In our study, we elucidated that HAP1 was downregulated in gastric cancer. What's more, overexpressing HAP1 inhibited cell proliferation, cell migration and invasion, and triggered apoptosis during glucose deprivation. More importantly, the antitumor properties and mechanisms of HAP1 have been elucidated further in gastric cancer. CONCLUSIONS: Taken together, the available evidence implies that HAP1 may serve as a potential tumor suppressor, making it a significant target in preventing and treating gastric cancer. This research provides a theoretical basis for the early diagnosis, clinical targeted therapy, and prognosis evaluation of gastric cancer.

The gas-phase formation mechanism of iodic acid as an atmospheric aerosol source.

Iodine is a reactive trace element in atmospheric chemistry that destroys ozone and nucleates particles. Iodine emissions have tripled since 1950 and are projected to keep increasing with rising O3 surface concentrations. Although iodic acid (HIO3) is widespread and forms particles more efficiently than sulfuric acid, its gas-phase formation mechanism remains unresolved. Here, in CLOUD atmospheric simulation chamber experiments that generate iodine radicals at atmospherically relevant rates, we show that iodooxy hypoiodite, IOIO, is efficiently converted into HIO3 via reactions (R1) IOIO + O3 → IOIO4 and (R2) IOIO4 + H2O → HIO3 + HOI + (1)O2. The laboratory-derived reaction rate coefficients are corroborated by theory and shown to explain field observations of daytime HIO3 in the remote lower free troposphere. The mechanism provides a missing link between iodine sources and particle formation. Because particulate iodate is readily reduced, recycling iodine back into the gas phase, our results suggest a catalytic role of iodine in aerosol formation.

Locoregional therapy for oligometastatic cervical cancer: a single-center retrospective study.

BACKGROUND: Oligometastases are limited in number and extent, and therefore, are amenable to locoregional therapy. OBJECTIVE: To analyze recurrence patterns, survival outcomes, and prognostic factors in patients with cervical cancer receiving locoregional therapy for oligometastases. METHODS: The included patients had 1-3 extracranial oligometastases and received definitive radiotherapy, surgery, or ablation at a single institution between January 2007 and May 2022. Outcomes were evaluated using the Kaplan-Meier method. Prognostic factors were examined using the Cox proportional hazards model, and tumor growth rates were predicted by non-linear regression. RESULTS: We identified 56 patients who presented with an oligometastatic disease to the supraclavicular fossa (n=19), lung (n=33), or other sites (n=4). Totals of 30 (53.6%), 41 (73.2%), 47 (83.9%), and 52 (92.9%) patients were diagnosed 1, 2, 3, and 4 years after cervical cancer diagnosis, respectively. Seven patients were simultaneously treated for para-aortic or pelvic recurrences. After a median follow-up of 24 months (range 1-86), the 3-year local recurrence-free rate in patients with supraclavicular versus non-supraclavicular oligometastases was 100% vs 93.5%. The 3-year overall survival rate was 40.1% vs 55.2% (p=0.04). Ten (17.9%) patients experienced new oligometastatic progression in a median of 8 months (range 4-14). Multivariate analysis showed that tumor size was the only prognostic factor for overall survival, with a 3-year overall survival rate of 91.7% vs 21.6% (≤15 mm vs >15 mm, p<0.001). Nineteen (86.4%) of 22 lesions diagnosed within 6 months of the last negative CT scan had a maximum diameter of ≤15 mm, and the predicted interval of tumor growth to 15 mm was 5.8 months. CONCLUSION: Locoregional therapy for cervical cancer oligometastases can achieve long-term survival, especially in patients with small lesions (≤15 mm). Better follow-up mode after cervical cancer treatment and system therapy for oligometastases should be further explored.

High Gas-Phase Methanesulfonic Acid Production in the OH-Initiated Oxidation of Dimethyl Sulfide at Low Temperatures.

Dimethyl sulfide (DMS) influences climate via cloud condensation nuclei (CCN) formation resulting from its oxidation products (mainly methanesulfonic acid, MSA, and sulfuric acid, H2SO4). Despite their importance, accurate prediction of MSA and H2SO4 from DMS oxidation remains challenging. With comprehensive experiments carried out in the Cosmics Leaving Outdoor Droplets (CLOUD) chamber at CERN, we show that decreasing the temperature from +25 to -10 °C enhances the gas-phase MSA production by an order of magnitude from OH-initiated DMS oxidation, while H2SO4 production is modestly affected. This leads to a gas-phase H2SO4-to-MSA ratio (H2SO4/MSA) smaller than one at low temperatures, consistent with field observations in polar regions. With an updated DMS oxidation mechanism, we find that methanesulfinic acid, CH3S(O)OH, MSIA, forms large amounts of MSA. Overall, our results reveal that MSA yields are a factor of 2-10 higher than those predicted by the widely used Master Chemical Mechanism (MCMv3.3.1), and the NOx effect is less significant than that of temperature. Our updated mechanism explains the high MSA production rates observed in field observations, especially at low temperatures, thus, substantiating the greater importance of MSA in the natural sulfur cycle and natural CCN formation. Our mechanism will improve the interpretation of present-day and historical gas-phase H2SO4/MSA measurements.

Inflammatory Role of Milk Fat Globule-Epidermal Growth Factor VIII in Age-Associated Arterial Remodeling.

Background Age-associated aortic remodeling includes a marked increase in intimal medial thickness (IMT), associated with signs of inflammation. Although aortic wall milk fat globule-epidermal growth factor VIII (MFG-E8) increases with age, and is associated with aortic inflammation, it is not known whether MFG-E8 is required for the age-associated increase in aortic IMT. Here, we tested whether MFG-E8 is required for the age-associated increase in aortic IMT. Methods and Results To determine the role of MFG-E8 in the age-associated increase of IMT, we compared aortic remodeling in adult (20-week) and aged (96-week) MFG-E8 (-/-) knockout and age matched wild-type (WT) littermate mice. The average aortic IMT increased with age in the WT from 50±10 to 70±20 µm (P<0.0001) but did not significantly increase with age in MFG-E8 knockout mice. Because angiotensin II signaling is implicated as a driver of age-associated increase in IMT, we infused 30-week-old MFG-E8 knockout and age-matched littermate WT mice with angiotensin II or saline via osmotic mini-pumps to determine whether MFG-E8 is required for angiotensin II-induced aortic remodeling. (1) In WT mice, angiotensin II infusion substantially increased IMT, elastic lamina degradation, collagen deposition, and the proliferation of vascular smooth muscle cells; in contrast, these effects were significantly reduced in MFG-E8 KO mice; (2) On a molecular level, angiotensin II treatment significantly increased the activation and expression of matrix metalloproteinase type 2, transforming growth factor beta 1, and its downstream signaling molecule phosphorylated mother against decapentaplegic homolog 2, and collagen type I production in WT mice; however, in the MFG-E8 knockout mice, these molecular effects were significantly reduced; and (3) in WT mice, angiotensin II increased levels of aortic inflammatory markers phosphorylated nuclear factor-kappa beta p65, monocyte chemoattractant protein 1, tumor necrosis factor alpha, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 molecular expression, while in contrast, these inflammatory markers did not change in knockout mice. Conclusions Thus, MFG-E8 is required for both age-associated proinflammatory aortic remodeling and also for the angiotensin II-dependent induction in younger mice of an aortic inflammatory phenotype observed in advanced age. Targeting MFG-E8 would be a novel molecular approach to curb adverse arterial remodeling.