Constitutive Modeling of Mouse Arteries Suggests Changes in Directional Coupling and Extracellular Matrix Remodeling That Depend on Artery Type, Age, Sex, and Elastin Amounts.

Arterial stiffening occurs during natural aging, is associated with an increased risk of adverse cardiovascular events, and can follow different timelines in males and females. One mechanism of arterial stiffening includes remodeling of the extracellular matrix (ECM), which alters the wall material properties. We used elastin haploinsufficient (Eln+/-) and wildtype (Eln+/+) mice to investigate how material properties of two different arteries (ascending aorta and carotid artery) change with age, sex, and ECM composition. We used a constitutive model by Dong and Sun that is based on the Holzapfel-Gasser-Ogden (HGO) type, but does not require a discrete number of fibrous ECM families and allows varied deformation coupling. We find that the amount of deformation coupling for the best fit model depends on the artery type. We also find that remodeling to maintain homeostatic (i.e., young, wildtype) values of biomechanical parameters with age, sex, and ECM composition depends on the artery type, with ascending aorta being more adaptable than carotid artery. Fitted material constants indicate sex-dependent remodeling that may be important for determining the time course of arterial stiffening in males and females. We correlated fitted material constants with ECM composition measured by biochemical (ascending aorta) or histological (carotid artery) methods. We show significant correlations between ECM composition and material parameters for the mean values for each group, with biochemical measurements correlating more strongly than histological measurements. Understanding how arterial stiffening depends on age, sex, ECM composition, and artery type may help design effective, personalized clinical treatment strategies.

[Adherence to adjuvant with therapy imatinib in patients with gastrointestinal stromal tumor: a national multi-center cross-sectional study].

Objective: To analyze the current adherence to imatinib in patients with gastrointestinal stromal tumors (GIST) in China and its influencing factors. Methods: A cross-sectional survey was conducted. Study period: from October 1, 2020 to November 31, 2020. Study subjects: GIST patients taking imatinib who were diagnosed and treated in public tertiary level A general hospitals or oncology hospitals; those who had not been pathologically diagnosed, those who never received imatinib, or those who had taken imatinib in the past but stopped afterwards were excluded. The Questionnaire Star online surgery platform was used to design a questionnaire about the adherence to adjuvant imatinib therapy of Chinese GIST patients. The link of questionnaire was sent through WeChat. The questionnaire contained basic information of patients, medication status and Morisky Medication Adherence Scale. Results: A total of 2162 questionnaires from 31 provinces, autonomous regions, and municipalities were collected, of which 2005 were valid questionnaires, with an effective rate of 92.7%. The survey subjects included 1104 males and 901 females, with a median age of 56 (22-91) years old. Working status: 609 cases (30.4%) in the work unit, 729 cases (36.4%) of retirement, 667 cases of flexible employment or unemployment (33.3%). Education level: 477 cases (23.8%) with bachelor degree or above, 658 cases (32.8%) of high school, 782 cases (39.0%) of elementary or junior high school, 88 cases (4.4%) without education. Marital status: 1789 cases (89.2%) were married, 179 cases (8.9%) divorced or widowed, 37 cases (1.8%) unmarried. Two hundred and ninety-four patients (14.7%) had metastasis when they were first diagnosed, including 203 liver metastases, 52 peritoneal metastases, and 39 other metastases. One thousand eight hundred and sixty-nine patients underwent surgical treatment, of whom 1642 (81.9%) achieved complete resection. The median time of taking imatinib was 25 (1-200) months. Common adverse reactions of imatinib included 1701 cases (84.8%) of periorbital edema, 1031 cases (51.4%) of leukopenia, 948 cases (47.3%) of fatigue, 781 cases (39.0%) of nausea and vomiting, 709 cases (35.4%) of rash, and 670 cases (33.4%) of lower extremity edema. The score of the Morisky Medication Adherence Scale showed that 392 cases (19.6%) had poor adherence, 1023 cases (51.0%) had moderate adherence, and 590 cases (29.4%) had good adherence. Univariate analysis showed that gender, age, work status, economic income, residence, education level, marriage, the duration of taking medication and adverse reactions were associated with adherence to adjuvant imatinib therapy (all P<0.05). Multivariate analysis showed that female (OR=1.264, P=0.009), non-retirement (OR=1.454, P=0.001), monthly income ≤4000 yuan (OR=1.280, P=0.036), township residents (OR=1.332, P=0.005), unmarried or divorced or widowed (OR=1.362, P=0.026), the duration of imatinib medication >36 months (OR=1.478, P<0.001) and adverse reactions (OR=1.719, P=0.048) were independent risk factors for poor adherence to adjuvant imatinib. Among patients undergoing complete resection, 324 (19.7%) had poor adherence, 836 (50.9%) had moderate adherence, and 482 (29.4%) had good adherence. Meanwhile, 55 patients with good adherence (11.4%) developed recurrence after surgery, 121 patients with moderate adherence (14.5%) developed recurrence, 61 patients with poor adherence (18.8%) developed recurrence, and the difference was statistically significant (P=0.017). Conclusions: The adherence to adjuvant therapy with imatinib in Chinese GIST patients is relatively poor. Females, non-retirement, monthly income ≤4000 yuan, township residents, unmarried or divorced or widowed, the duration of imatinib medication >36 months, and adverse reactions are independently associated with poor adherence of GIST patients. Those with poor adherence have a higher risk of recurrence after surgery. Positive interventions based on the above risk factors are advocated to improve the prognosis of patients with GIST.

Micropursuit and the control of attention and eye movements in dynamic environments.

It is more challenging to plan eye movements during perceptual tasks performed in dynamic displays than in static displays. Decisions about the timing of saccades become more critical, and decisions must also involve smooth eye movements, as well as saccades. The present study examined eye movements when judging which of two moving discs would arrive first, or collide, at a common meeting point. Perceptual discrimination after training was precise (Weber fractions < 6%). Strategies reflected a combined contribution of saccades and smooth eye movements. The preferred strategy was to look near the meeting point when strategies were freely chosen. When strategies were assigned, looking near the meeting point produced better performance than switching between the discs. Smooth eye movements were engaged in two ways: (a) low-velocity smooth eye movements correlated with the motion of each disc (micropursuit) were found while the line of sight remained between the discs; and (b) spontaneous smooth pursuit of the pair of discs occurred after the perceptual report, when the discs moved as a pair along a common path. The results show clear preferences and advantages for those eye movement strategies during dynamic perceptual tasks that require minimal management or effort. In addition, smooth eye movements, whose involvement during perceptual tasks within dynamic displays may have previously escaped notice, provide useful indictors of the strategies used to select information and distribute attention during the performance of dynamic perceptual tasks.

[A multi-center retrospective study of perioperative chemotherapy for gastric cancer based on real-world data].

Objective: To explore the effect of perioperative chemotherapy on the prognosis of gastric cancer patients under real-world condition. Methods: A retrospective cohort study was carried out. Real world data of gastric cancer patients receiving perioperative chemotherapy and surgery + adjuvant chemotherapy in 33 domestic hospitals from January 1, 2014 to January 31, 2016 were collected. Inclusion criteria: (1) gastric adenocarcinoma was confirmed by histopathology, and clinical stage was cT2-4aN0-3M0 (AJCC 8th edition); (2) D2 radical gastric cancer surgery was performed; (3) at least one cycle of neoadjuvant chemotherapy (NAC) was completed; (4) at least 4 cycles of adjuvant chemotherapy (AC) [SOX (S-1+oxaliplatin) or CapeOX (capecitabine + oxaliplatin)] were completed. Exclusion criteria: (1) complicated with other malignant tumors; (2) radiotherapy received; (3) patients with incomplete data. The enrolled patients who received neoadjuvant chemotherapy and adjuvant chemotherapy were included in the perioperative chemotherapy group, and those who received only postoperative adjuvant chemotherapy were included in the surgery + adjuvant chemotherapy group. Propensity score matching (PSM) method was used to control selection bias. The primary outcome were overall survival (OS) and progression-free survival (PFS) after PSM. OS was defined as the time from the first neoadjuvant chemotherapy (operation + adjuvant chemotherapy group: from the date of operation) to the last effective follow-up or death. PFS was defined as the time from the first neoadjuvant chemotherapy (operation + adjuvant chemotherapy group: from the date of operation) to the first imaging diagnosis of tumor progression or death. The Kaplan-Meier method was used to estimate the survival rate, and the Cox proportional hazards model was used to evaluate the independent effect of perioperative chemo therapy on OS and PFS. Results: 2 045 cases were included, including 1 293 cases in the surgery+adjuvant chemotherapy group and 752 cases in the perioperative chemotherapy group. After PSM, 492 pairs were included in the analysis. There were no statistically significant differences in gender, age, body mass index, tumor stage before treatment, and tumor location between the two groups (all P>0.05). Compared with the surgery + adjuvant chemotherapy group, patients in the perioperative chemotherapy group had higher proportion of total gastrectomy (χ(2)=40.526, P<0.001), smaller maximum tumor diameter (t=3.969, P<0.001), less number of metastatic lymph nodes (t=1.343, P<0.001), lower ratio of vessel invasion (χ(2)=11.897, P=0.001) and nerve invasion (χ(2)=12.338, P<0.001). In the perioperative chemotherapy group and surgery + adjuvant chemotherapy group, 24 cases (4.9%) and 17 cases (3.4%) developed postoperative complications, respectively, and no significant difference was found between two groups (χ(2)=0.815, P=0.367). The median OS of the perioperative chemotherapy group was longer than that of the surgery + adjuvant chemotherapy group (65 months vs. 45 months, HR: 0.74, 95% CI: 0.62-0.89, P=0.001); the median PFS of the perioperative chemotherapy group was also longer than that of the surgery+adjuvant chemotherapy group (56 months vs. 36 months, HR=0.72, 95% CI:0.61-0.85, P<0.001). The forest plot results of subgroup analysis showed that both men and women could benefit from perioperative chemotherapy (all P<0.05); patients over 45 years of age (P<0.05) and with normal body mass (P<0.01) could benefit significantly; patients with cTNM stage II and III presented a trend of benefit or could benefit significantly (P<0.05); patients with signet ring cell carcinoma benefited little (P>0.05); tumors in the gastric body and gastric antrum benefited more significantly (P<0.05). Conclusion: Perioperative chemotherapy can improve the prognosis of gastric cancer patients.

Elastin haploinsufficiency in mice has divergent effects on arterial remodeling with aging depending on sex.

Elastin is a primary structural protein in the arterial wall that contributes to vascular mechanical properties and degrades with aging. Aging is associated with arterial stiffening and an increase in blood pressure. There is evidence that arterial aging follows different timelines with sex. Our objective was to investigate how elastin content affects arterial remodeling in male and female mice with aging. We used male and female wild-type (Eln+/+) and elastin heterozygous (Eln+/-) mice at 6, 12, and 24 mo of age and measured their blood pressure and arterial morphology, wall structure, protein content, circumferential stress, stretch ratio, and stiffness. Two arteries were used with varying contents of elastin: the left common carotid and ascending aorta. We show that Eln+/- arteries start at a different homeostatic set point for circumferential wall stress, stretch, and material stiffness but show similar increases with aging to Eln+/+ mice. With aging, structural stiffness is greatly increased, while material stiffness and circumferential stress are only slightly increased, highlighting the importance of maintaining these homeostatic values. Circumferential stretch shows the smallest change with age and may be important for controlling cellular phenotype. Independent sex differences are mostly associated with males being larger than females; however, many of the measured factors show age × sex and/or genotype × sex interactions, indicating that males and females follow different cardiovascular remodeling timelines with aging and are differentially affected by reduced elastin content.NEW & NOTEWORTHY A comprehensive study on arterial mechanical behavior as a function of elastin content, aging, and sex in mice. Elastin haploinsufficient arteries start at a different homeostatic set point for mechanical parameters such as circumferential stress, stretch, and material stiffness. Structural stiffness of the arterial wall greatly increases with aging, as expected, but there are interactions between sex and aging for most of the mechanical parameters that are important to consider in future work.

Long non-coding RNA AFAP1-AS1 promotes proliferation and migration of gastric cancer by downregulating KLF2.

OBJECTIVE: To clarify the function of actin filament associated protein 1-antisense RNA1 (AFAP1-AS1) to promote the proliferation and migration of gastric cancer (GC) cells by downregulating Krüppel-like factor 2 (KLF2). MATERIALS AND METHODS: Expression level of AFAP1-AS1 in GC tissues and matched paracancerous tissues was determined by quantitative real-time polymerase chain reaction (qRT-PCR). Besides, its level in GC either with lymphatic metastasis or not, and those in different tumor stages were determined as well. Regulatory roles of AFAP1-AS1 in cellular behaviors of GC cells were evaluated by functional experiments. The ability of AFAP1-AS1 to recruit EZH2 was evaluated through chromatin immunoprecipitation (ChIP) assay. The expression level of KLF2 in GC cells influenced by AFAP1-AS1 and EZH2 was detected by Western blot. Finally, a series of rescue experiments were conducted to clarify the role of AFAP-AS1/KLF2 in GC cell performances. RESULTS: AFAP1-AS1 was upregulated in GC tissues, and its expression in lymph node metastasis and progressive gastric cancer tissues were much higher. Knockdown of AFAP1-AS1 reduced the viability, proliferative and migratory abilities, but induced apoptosis of GC cells. AFAP1-AS1 was verified to bind to EZH2. After knockdown of AFAP1-AS1, the ability of AFAP1-AS1 to recruit EZH2 was remarkably attenuated. Knockdown of AFAP1-AS1 or EZH2 upregulated KLF2 expression in GC cells. Notably, knockdown of KLF2 partially reversed the effect of AFAP1-AS1 on GC cell performances. CONCLUSIONS: LncRNA AFAP1-AS1 accelerates the proliferative and migratory abilities of GC cells by downregulating the expression of KLF2, thus promoting the progression of GC.

Heterogeneous Cellular Contributions to Elastic Laminae Formation in Arterial Wall Development.

RATIONALE: Elastin is an important ECM (extracellular matrix) protein in large and small arteries. Vascular smooth muscle cells (SMCs) produce the layered elastic laminae found in elastic arteries but synthesize little elastin in muscular arteries. However, muscular arteries have a well-defined internal elastic lamina (IEL) that separates endothelial cells (ECs) from SMCs. The extent to which ECs contribute elastin to the IEL is unknown. OBJECTIVE: To use targeted elastin (Eln) deletion in mice to explore the relative contributions of SMCs and ECs to elastic laminae formation in different arteries. METHODS AND RESULTS: We used SMC- and EC-specific Cre recombinase transgenes with a novel floxed Eln allele to focus gene inactivation in mice. Inactivation of Eln in SMCs using Sm22aCre resulted in depletion of elastic laminae in the arterial wall with the exception of the IEL and SMC clusters in the outer media near the adventitia. Inactivation of elastin in ECs using Tie2Cre or Cdh5Cre resulted in normal medial elastin and a typical IEL in elastic arteries. In contrast, the IEL was absent or severely disrupted in muscular arteries. Interruptions in the IEL resulted in neointimal formation in the ascending aorta but not in muscular arteries. CONCLUSIONS: Combined with lineage-specific fate mapping systems, our knockout results document an unexpected heterogeneity in vascular cells that produce the elastic laminae. SMCs and ECs can independently form an IEL in most elastic arteries, whereas ECs are the major source of elastin for the IEL in muscular and resistance arteries. Neointimal formation at IEL disruptions in the ascending aorta confirms that the IEL is a critical physical barrier between SMCs and ECs in the large elastic arteries. Our studies provide new information about how SMCs and ECs contribute elastin to the arterial wall and how local elastic laminae defects may contribute to cardiovascular disease.

[Current status of diagnosis and treatment of community-acquired pneumonia in Shanghai revealed by a questionnaire analysis].

Objective: To understand the current status of diagnosis and treatment of community-acquired pneumonia (CAP) among doctors in various hospitals across Shanghai, for the purpose of promoting the 2016 clinical practice guidelines for adult CAP of China. Methods: A questionnaire was designed to address the common questions in CAP management. The responses were collected via WeChat and the data were analyzed. Results: A total of 1 254 valid questionnaires were received, 46.1% from tertiary , 26.4% from secondary and 27.5% from primary care hospitals. Of these valid respondents, 31.4% were respiratory physicians and 68.6% from non-respiratory physicians. When diagnosing CAP, 78.1% of the doctors would use chest CT in more than 50% of the patients. Regarding the tools for evaluating the severity of CAP, 60.3% of the respondents would prefer CURB-65. "Respiratory failure requiring mechanical ventilation and septic shock" were the most common criteria for admission to ICU. Blood culture was not widely used in severe CAP regardless of the level of hospitals (P>0.05). The results of this survey showed that the top 5 pathogenic microorganisms of CAP were Streptococcus pneumoniae, Mycoplasma pneumoniae, Klebsiella pneumoniae, Haemophilus influenza and Chlamydia pneumoniae. For non-severe CAP patients, all the doctors tended to select monotherapy. The most frequently used antimicrobial regimen for severe CAP was third- or fourth-generation cephalosporin monotherapy. As for combination therapy, the most frequently used regimen in tertiary hospitals was "carbapenem plus vancomycin" , while in primary and secondary hospitals it was "ß-lactams plus macrolides" . More doctors from primary hospitals and non-respiratory medicine would consider "complete resolution of pulmonary opacity" as the indication to discontinue antimicrobial therapy or to discharge patients, and "prolonged high fever" , "large area consolidation" , "multiple lobe-segment involvement " as the indication for corticosteroid therapy. A significantly lower proportion of doctors in secondary and tertiary hospitals would recommend patients to receive vaccination than in primary hospitals (P<0.05). Conclusions: This questionnaire study showed that there was a gap between the ideal and the real world practice in CAP management. Efforts should be made to popularize the 2016 CAP guideline in hospitals of any level of care, especially primary hospitals, for the purpose of further standardizing CAP management in China.

Elastin, arterial mechanics, and cardiovascular disease.

Large, elastic arteries are composed of cells and a specialized extracellular matrix that provides reversible elasticity and strength. Elastin is the matrix protein responsible for this reversible elasticity that reduces the workload on the heart and dampens pulsatile flow in distal arteries. Here, we summarize the elastin protein biochemistry, self-association behavior, cross-linking process, and multistep elastic fiber assembly that provide large arteries with their unique mechanical properties. We present measures of passive arterial mechanics that depend on elastic fiber amounts and integrity such as the Windkessel effect, structural and material stiffness, and energy storage. We discuss supravalvular aortic stenosis and autosomal dominant cutis laxa-1, which are genetic disorders caused by mutations in the elastin gene. We present mouse models of supravalvular aortic stenosis, autosomal dominant cutis laxa-1, and graded elastin amounts that have been invaluable for understanding the role of elastin in arterial mechanics and cardiovascular disease. We summarize acquired diseases associated with elastic fiber defects, including hypertension and arterial stiffness, diabetes, obesity, atherosclerosis, calcification, and aneurysms and dissections. We mention animal models that have helped delineate the role of elastic fiber defects in these acquired diseases. We briefly summarize challenges and recent advances in generating functional elastic fibers in tissue-engineered arteries. We conclude with suggestions for future research and opportunities for therapeutic intervention in genetic and acquired elastinopathies.

[Effect of comprehensive schistosomiasis control strategy with focus on cattle and sheep removal in Junshan District, Yueyang City].

Objective To evaluate the effect of comprehensive schistosomiasis control measures with focus on total removal of cattle and sheep in Junshan District, Yueyang City. Methods The retrospective review and field survey were implemented in the pilot villages in Junshan District. The data of Schistosoma japonicum infection status of human, cattle, sheep and Oncomelania hupensis snails, and density of snails were gathered and modeled in the period of 2006 to 2016. Results The prevalence of schistosome infection in residents in the pilot villages decreased from 3.44% in 2006 to 0.59% in 2012 (F = 14.501, P = 0.013). After removal of all the cattle and sheep in 2013, the prevalence of schistosome infection in the residents decreased to zero in 2016 (F = 14.148, P = 0.033). The density of living snails decreased from 0.883 3/0.1 m2 in 2006 to 0.308 8/0.1 m2 in 2012 (F = 76.250, P = 0.005). Conclusion The comprehensive schistosomiasis control strategy with focus on cattle and sheep removal is remarkably effective.