Clonal Hematopoiesis of Indeterminate Potential in Chronic Thromboembolic Pulmonary Hypertension: A Multicenter Study.

BACKGROUND: The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) is multifactorial and growing evidence has indicated that hematological disorders are involved. Clonal hematopoiesis of indeterminate potential (CHIP) has recently been associated with an increased risk of both hematological malignancies and cardiovascular diseases. However, the prevalence and clinical relevance of CHIP in patients with CTEPH remains unclear. METHODS: Using stepwise calling on next-generation sequencing data from 499 patients with CTEPH referred to 3 centers between October 2006 and December 2021, CHIP mutations were identified. We associated CHIP with all-cause mortality in patients with CTEPH. To provide insights into potential mechanisms, the associations between CHIP and inflammatory markers were also determined. RESULTS: In total, 47 (9.4%) patients with CTEPH carried at least 1 CHIP mutation at a variant allele frequency of ≥2%. The most common mutations were in DNMT3A, TET2, RUNX1, and ASXL1. During follow-up (mean, 55 months), deaths occurred in 22 (46.8%) and 104 (23.0%) patients in the CHIP and non-CHIP groups, respectively (P<0.001, log-rank test). The association of CHIP with mortality remained robust in the fully adjusted model (hazard ratio, 2.190 [95% CI, 1.257-3.816]; P=0.006). Moreover, patients with CHIP mutations showed higher circulating interleukin-1ß and interleukin-6 and lower interleukin-4 and IgG galactosylation levels. CONCLUSIONS: This is the first study to show that CHIP mutations occurred in 9.4% of patients with CTEPH are associated with a severe inflammatory state and confer a poorer prognosis in long-term follow-up.

DNA topoisomerase II alpha promotes the metastatic characteristics of glioma cells by transcriptionally activating ß-catenin.

DNA topoisomerase II alpha (TOP2A) reportedly plays a crucial role in several cancers, however, the precise regulatory role of TOP2A in metastatic characteristics of glioma is still poorly understood. Herein, we sought to elucidate the mechanisms by which TOP2A affects the metastatic phenotypes of glioma. We observed that a high level of TOP2A expression was dramatically linked with inferior survival in glioma patients while silencing of TOP2A impaired glioma cell proliferation and aggressiveness. TOP2A was found to directly interact with ß-catenin and facilitated its translocation into the nucleus. Mechanistically, TOP2A effectively induced glioma cell growth and invasion in a ß-catenin-dependent manner. Overall, we pinpoint TOP2A as a critical activator of the Wnt/ß-catenin pathway in glioma, promoting cell growth, migration, and invasion.

Subendocardial Involvement as an Underrecognized Cardiac MRI Phenotype in Myocarditis.

Background Subendocardial late gadolinium enhancement (LGE) detected with cardiac MRI in myocarditis represents a diagnostic dilemma, since it may resemble myocardial ischemia. Purpose To explore and compare the histopathologic characteristics and clinical features and outcomes in patients with myocarditis with and without subendocardial involvement at cardiac MRI. Materials and Methods This retrospective study evaluated 39 patients with myocarditis pathologically proven by means of either endomyocardial biopsy or explant pathologic findings between 2015 and 2020. Patients were divided into two groups according to cardiac MRI phenotype: 18 with subendocardial involvement (mean age ± standard deviation, 40 years ± 17; 10 women) and 21 with no subendocardial involvement (mean age, 35 years ± 11; six women). The median follow-up period was 784 days (interquartile range [IQR], 90-1123 days). The Student t test, Mann-Whitney U test, and univariable Cox regression were used for statistical analyses. Results In the 18 patients with subendocardial involvement, 12 (67%) had lymphocytic myocarditis and six (33%) had giant cell myocarditis. Patients with subendocardial involvement compared with those without subendocardial involvement had lower left ventricular ejection fraction (mean ± standard deviation, 27% ± 11 vs 41% ± 19; P = .004), larger LGE extent (median, 13% [IQR, 10%-22%] vs 5% [IQR, 2%-17%]; P < .001), higher rates of cardiac death or transplant (eight of 18 patients [44%] vs one of 21 patients [4.8%]; P = .006), higher probability of giant cell myocarditis (six of 18 [33%] vs one of 21 [4.8%]; P = .02), and more major adverse cardiovascular events (MACE) (15 of 18 [83%] vs seven of 21 [33%]; P = .002). In a subgroup of patients with comparable LGE extent (median, 15% vs 16%; P = .40) and left ventricular ejection fraction (median, 27% vs 31%; P = .26), the prognostic difference in terms of MACE remained (15 of 17 patients [88%] vs five of 10 [50%]; P = .02). Conclusion Subendocardial involvement detected with cardiac MRI in myocarditis indicated more severe clinical features, including a higher frequency of severe lymphocytic myocarditis or giant cell myocarditis and worse prognosis. © RSNA, 2021 See also the editorial by de Roos in this issue.

Molecular immuno-imaging improves tumor detection in head and neck cancer.

Detection and accurate delineation of tumor is important for the management of head and neck squamous cell carcinoma (HNSCC) but is challenging with current imaging techniques. In this study, we evaluated whether molecular immuno-imaging targeting myeloperoxidase (MPO) activity, an oxidative enzyme secreted by many myeloid innate immune cells, would be superior in detecting tumor extent compared to conventional contrast agent (DTPA-Gd) in a carcinogen-induced immunocompetent HNSCC murine model and corroborated in human surgical specimens. In C57BL/6 mice given 4-nitroquinoline-N-oxide (4-NQO), there was increased MPO activity in the head and neck region as detected by luminol bioluminescence compared to that of the control group. On magnetic resonance imaging, the mean enhancing volume detected by the MPO-targeting agent (MPO-Gd) was higher than that by the conventional agent DTPA-Gd. The tumor volume detected by MPO-Gd strongly correlated with tumor size on histology, and higher MPO-Gd signal corresponded to larger tumor size found by imaging and histology. On the contrary, the tumor volume detected by DTPA-Gd did not correlate as well with tumor size on histology. Importantly, MPO-Gd imaging detected areas not visualized with DTPA-Gd imaging that were confirmed histopathologically to represent early tumor. In human specimens, MPO was similarly associated with tumors, especially at the tumor margins. Thus, molecular immuno-imaging targeting MPO not only detects oxidative immune response in HNSCC, but can better detect and delineate tumor extent than nonselective imaging agents. Thus, our findings revealed that MPO imaging could improve tumor resection as well as be a useful imaging biomarker for tumor progression, and potentially improve clinical management of HNSCC once translated.

Potential roles of oxidative distress on neurodegeneration in Parkinson's disease with neuropsychiatric symptoms.

Background: Neuropsychiatric symptoms (NPSs) belong to a category of non-motor symptoms of Parkinson's disease (PD), which seriously compromise the quality of life and prognosis of PD. This study focused on the correlations between NPSs, free radicals, neuroinflammatory factors, and neuropathological proteins in cerebrospinal fluid (CSF) in patients with PD, aiming to provide insights into the potential mechanisms and therapeutic target for PD with NPSs (PD-NPSs). Methods: In total, 129 patients with PD were enrolled and assessed by the Neuropsychiatric Symptoms Inventory (NPI); they were divided into the PD-NPSs group (75 patients) and PD with no NPSs (PD-nNPSs) group (54 patients). The levels of hydrogen peroxide (H2O2) and nitric oxide (NO), and hydroxyl radical (·OH), anti-oxidative enzyme, neuroinflammatory factors, and neuropathological proteins in CSF from patients with PD were measured. The levels of the above variables were compared between PD-NPSs and PD-nNPSs groups, and correlation analyses among the above variables were conducted. Results: (1) The levels of H2O2 and NO in CSF from the PD-NPSs group were significantly elevated compared with the PD-nNPSs group (p = 0.001), and NPI score positively correlated with the levels of H2O2 and NO (r = 0.283, P = 0.001; r = 0.231, P = 0.008). Reversely, total superoxide dismutase (tSOD) activity in CSF from the PD-NPSs group was significantly reduced compared with the PD-nNPSs group (p = 0.011), and negatively correlated with NPI score (r = -0.185, p = 0.036). (2) The tumor necrosis factor (TNF)-α level in CSF from the PD-NPSs group was significantly decreased compared with the PD-nNPSs group (p = 0.002) and negatively correlated with NPI score (r = -0.211, p = 0.016). (3) The total tau (T-tau) level in CSF from the PD-NPSs group was significantly higher than in the PD-nNPSs group (p = 0.014) and positively correlated with the NPI score (r = 0.167, p = 0.060). (4) The levels of H2O2 and NO positively correlated with the T-tau level in CSF from the PD-NPSs group (r = 0.183, p = 0.039; r = 0.251, P = 0.004), and the levels of TNF-α and T-tau showed a negative correlation (r = -0.163, p = 0.067). Conclusion: Oxidative distress characterized by the elevations of H2O2 and NO levels may closely correlate with the neurodegeneration in brain regions related to PD-NPSs. Thus, therapeutic antioxidants may become an important target for PD-NPSs therapy.

Parkinson's Disease With Depression: The Correlations Between Neuroinflammatory Factors and Neurotransmitters in Cerebrospinal Fluid.

Background: To explore the changes of neuroinflammatory factors in cerebrospinal fluid (CSF) and their correlation with monoamine neurotransmitters in Parkinson's disease (PD) with depression (PD-D) patients. Methods: Neuroinflammatory factors and neurotransmitters in CSF were measured and compared between PD with no depression (PD-ND) and PD-D groups. The relationship between PD-D and neuroinflammatory factors was studied by binary logistic regression equation, and the related factors of PD-D were adjusted. The correlations of the levels of neuroinflammatory factors and neurotransmitters in PD-D group were analyzed. Results: The levels of tumor necrosis factor (TNF)-α in CSF from PD-D group were significantly higher and there were no significant differences in the levels of interleukin-1ß, prostaglandin (PG) E2, hydrogen peroxide (H2O2), and nitric oxide (NO). The 24-item Hamilton Depression Scale (HAMD-24) score was positively correlated with the level of TNF-α in CSF. Binary logistic regression showed that the OR of CSF TNF-α level was 1.035 (95% CI 1.002-1.069). The level of dopamine (DA) in CSF of PD-D group was significantly lower than that in PD-ND group. TNF-α level was negatively correlated with DA level in CSF from PD patients (r = -0.320, P = 0.003). Conclusions: Neuroinflammatory factors, especially TNF-α, may play an important role in PD-D. It may cause damage to DA neurons and lead to the depletion of DA, which is related to the occurrence and development of PD-D.

Dexmedetomidine-mediated protection against septic liver injury depends on TLR4/MyD88/NF-κB signaling downregulation partly via cholinergic anti-inflammatory mechanisms.

BACKGROUND: Uncontrolled inflammatory responses exacerbate the pathogenesis of septic acute liver injury (ALI), posing a lethal threat to the host. Dexmedetomidine (DEX) has been reported to possess protective properties in inflammatory conditions. This study aimed to investigate whether DEX pretreatment exhibits hepatoprotection against ALI induced by lipopolysaccharide (LPS) in rats and determine its possible molecular mechanism. METHODS: Septic ALI was induced by intravenous injection of LPS. The rats received DEX intraperitoneally 30 min before LPS administration. α-Bungarotoxin (α-BGT), a specific α7 nicotinic acetylcholine receptor (α7nAChR) antagonist, was administered intraperitoneally 1 h before LPS exposure. The role of the vagus nerve was verified by performing unilateral cervical vagotomy or sham surgery before sepsis. RESULTS: The expression of α7nAChR, toll-like receptor 4 (TLR4), high mobility group box 1 (HMGB1), and cleaved caspase-3 increased, peaking 24 h during sepsis. DEX enhanced α7nAChR activation and reduced TLR4 expression upon challenge with LPS. DEX significantly prevented LPS-induced ALI, which was associated with increased survival, the mitigation of pathological changes, the attenuation of inflammatory cytokine expression and apoptosis, and the downregulation of TLR4/MyD88/NF-κB pathway. Moreover, the hepatoprotective effect of DEX was abolished by α-BGT. Further investigation established that vagotomy, compared to sham surgery, triggered more severe pathogenic manifestations and higher proinflammatory cytokine levels. The inhibitory effects of DEX were shown in sham-operated rats but not in vagotomized rats. CONCLUSIONS: Our data highlight the pivotal function of α7nAChR and intact vagus nerves in protecting against LPS-induced ALI through inhibiting the TLR4/MyD88/NF-κB signaling pathway upon pretreatment with DEX.

Impact of Pituitary-Gonadal Axis Hormones on Pulmonary Arterial Hypertension in Men.

The association of sex hormone (estradiol, testosterone, and progesterone) with cardiopulmonary disease has already attracted great attention, especially in pulmonary arterial hypertension (PAH). However, the impact of sex hormones and their pituitary stimulators (follicle-stimulating hormone and luteinizing hormone) on PAH in men remains unclear. We conducted a prospective cohort study recruiting 95 patients with idiopathic PAH from 2008 to 2014 and following up for a median of 65 months for death. Compared with control, abnormal plasma levels of sex hormones were more common in patients with PAH. Higher estradiol and estradiol/testosterone levels were associated with risk of PAH diagnosis (odds ratio per ln estradiol, 3.55; P<0.001; odds ratio per ln estradiol/testosterone, 4.30; P<0.001), whereas higher testosterone and progesterone were associated with a reduced risk (odds ratio per ln testosterone, 0.48; P=0.003; odds ratio per ln progesterone, 0.09; P<0.001). Fifty patients died during follow-up. Men with higher estradiol had increased mortality (hazard ratio per ln estradiol, 2.02; P=0.007), even after adjustment for baseline characteristics and PAH treatment. According to receiver operating characteristic analysis, patients with PAH with higher estradiol level (≥145.55 pmol/L) had worse 5-year survival rate compared with those with lower estradiol (38.6% versus 68.2%; log-rank test P=0.001). Therefore, our data show higher estradiol, estradiol/testosterone ratio, lower testosterone, and progesterone were associated with increased risk of PAH. Meanwhile, higher estradiol was independently associated with higher mortality in men with PAH. Further studies are needed to explain the origin of these hormonal derangements and their potential pathophysiological implications in PAH.

Smoking and hOGG1 Ser326Cys polymorphism contribute to lung cancer risk: evidence from a meta-analysis.

The human 8-oxoguanine DNA glycosylase (hOGG1) gene plays an important role in the repair of oxidatively damaged DNA base lesions and its functional single nucleotide polymorphisms (SNPs) may alter DNA repair capacity and thus contributes to cancer susceptibility. Numerous studies have investigated the association between hOGG1 Ser326Cys polymorphism and lung cancer susceptibility; however, the conclusions are still inconclusive. We searched eligible publications from MEDLINE, EMBASE, and CBM and performed a meta-analysis to assess the associations between hOGG1 Ser326Cys polymorphism and lung cancer risk. Pooled odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated to estimate risk associations, and false-positive report probability (FPRP) analysis was also carried out to evaluate significant findings. A total of 31 investigations with 10,220 cases and 12,284 controls were identified. When all studies were pooled, a significantly increased overall lung cancer risk was found (Cys/Cys vs. Ser/Ser: OR = 1.24, 95 % CI = 1.05-1.47, P = 0.013; recessive model: OR = 1.22, 95 % CI = 1.05-1.41, P = 0.008, and Cys vs. Ser: OR = 1.11, 95 % CI = 1.02-1.21, P = 0.022), and further stratification analysis showed that the association was stronger in Asians, never smokers, and more-cigarette takers. These results were confirmed by FPRP analysis. Despite some limitations, this meta-analysis provides solid evidence that hOGG1 Ser326Cys polymorphism may contribute to lung cancer risk, particularly for Asian populations, never smokers, and more-cigarette takers. Nevertheless, these findings warrant further validation in single large investigations.

Expression of angiotensin II and its receptors in activated microglia in experimentally induced cerebral ischemia in the adult rats.

Expression of angiotensin II (Ang II) and its receptors (AT1/AT2) is undetected in the mature microglia in normal brain. We report here that the immunoexpression of Ang II and AT1/AT2 was altered in activated microglia notably at 1 week in rats subjected to middle cerebral artery occlusion (MCAO). Immunolabeled activated microglia were widely distributed in the infarcted cerebral tissue after MCAO. By enzyme immunoassay, Ang II protein expression levels of the ischemic tissues were decreased drastically at 12 h after ischemia, then rose rapidly at 3 days and 1 week after MCAO when compared with the control. On the other hand, AT1 and AT2 receptor mRNA and protein levels were up-regulated after MCAO, peaking at 12 h, but declined thereafter. Expression of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) mRNA and protein levels was concomitantly increased. Edaravone significantly suppressed Ang II and AT1/AT2 receptor expression as well as that of TNF-α and IL-1ß suggesting that microglia-derived Ang II can act through an autocrine manner via its receptor that may be linked partly to the production of proinflammatory cytokines. We conclude that neuroinflammation in MCAO may be attenuated by Edaravone which acts through suppression of expression of Ang II and its receptors and proinflammatory cytokines in activated microglia.

Review of clinical investigation on recurrence of gastric cancer following curative resection.

OBJECTIVE: To discuss the present status and progress of clinical research on recurrence of gastric cancer after surgery, including patterns, clinicopathologic factors, prognosis, detection, diagnosis, prevention, and treatment strategies. DATA SOURCES: The data used in this review were mainly from PubMed articles published in English from 2000 to August 2011. The search terms were "gastric cancer" and "recurrence". STUDY SELECTION: Articles were selected if they involved clinicopathologic factors, detection methods, and treatment strategies of recurrence of gastric cancer. RESULTS: Peritoneal recurrence is the most common pattern in recurrence of gastric cancer. The main risk factors for recurrence of gastric cancer are tumor stage, including depth of tumor invasion and lymph node metastasis, and Borrmann classification. The prognosis of patients with recurrence is very poor, especially patients with peritoneal recurrence. Systemic chemotherapy is still the main treatment method for patients with recurrent cancer. If complete resection can be accomplished, some benefits may be obtained from surgery for recurrence. However, standard treatment for patients with recurrence has not yet been established. CONCLUSIONS: Early detection and diagnosis of recurrence is quite crucial for treatment and prognosis. The optimal therapeutic strategy for recurrence should be based on a multidisciplinary assessment and the patient's individual state and should involve combined therapy.

Predictive factors improving survival after gastric and hepatic surgical treatment in gastric cancer patients with synchronous liver metastases.

BACKGROUND: The prognosis for patients with gastric cancer and synchronous liver metastases is very poor. However, a standard therapeutic strategy has not been well established. The clinical benefit and prognostic factors after hepatic surgical treatment for liver metastases from gastric cancer remain controversial. METHODS: Records of 105 patients who underwent gastrectomy regardless of hepatic surgical treatment for gastric cancer with synchronous liver-only metastases in our center between 1995 and 2010 were retrospectively reviewed. RESULTS: The overall survival rate for the 105 patients was 42.1%, 17.2%, and 10.6% at 1, 2, and 3 years, respectively, with a median survival time of 11 months. Multivariate survival analysis revealed that the extent of lymphadenectomy (D) (P < 0.001), lymph node metastases (P < 0.001), extent of liver metastases (H) (P = 0.008), and lymphovascular invasion (P = 0.002) were significant independent prognostic factors for survival. Among patients who underwent D2 lymphadenectomy, those who underwent hepatic surgical treatment had a significantly improved survival compared with those who underwent gastrectomy alone (median survival, 24 vs. 12 months; P < 0.001). However, hepatic surgical treatment was not a prognostic factor for patients who underwent D1 lymphadenectomy (median survival, 8 vs. 8 months; P = 0.495). For the 35 patients who underwent gastrectomy plus hepatic surgical treatment, D2 lymphadenectomy (P < 0.001), lymph node metastases (P = 0.015), and extent of liver metastases (H1 vs. H2 and H3) (P = 0.017) were independent significant prognostic factors for survival. CONCLUSIONS: D2 lymphadenectomy plus hepatic surgical treatment may provide hope for long-term survival of judiciously selected patients with hepatic metastases from gastric cancer. Patients with a low degree of lymph node metastases and H1 liver metastases would make the most appropriate candidates. However, if D2 dissection cannot be achieved, hepatic surgical treatment is not recommended.

[Effects of fentanyl administrated nasally and intravenously in post-operative analgesia in pediatric children: a comparative study of 36 cases].

OBJECTIVE: To observe the effectiveness and adverse reactions of fentanyl used by nasal infusion or intravenous injection in post-operative analgesia in pediatric patients. METHODS: Forty children, underwent selective lower abdomen surgery under intravenous anesthesia. At the end of operation, 36 patients with the scores > 6 according to the Objective Pain Scale (OPS) were randomly divided into 2 groups, Group A (n = 17) undergoing nasal administration of fentanyl 0.5 microg/kg, then intravenous injection of 1 ml 0.9% sodium chloride, Group B group (n = 19) undergoing nasal administration of 1 ml 0.9% sodium chloride and then intravenous injection of fentanyl 0.5 microg/kg. Five min later pain scoring was conducted. Those with the OPS score > or = 2 received the same protocol once, and then scoring was conducted every 1 min. Another 5 min later the same protocol was used to those still with the OPS score > or = 2 once again. Such a protocol was continued till the OPS score < or = 2. Sixty min after the first administration, the primary scheme was carried out once per hour until 24 h later. RESULTS: The time needed to achieve the OPS score < or = 2 of Group A was (16 +/- 5) min, not significantly different from that of Group B [(14 +/- 5) min, P > 0.05]. The amount of fentanyl used in Group A was (21 +/- 5) microg, significantly higher than that of Group B [(15 +/- 7) microg, P < 0.05]. When the OPS score < or = 2 was achieved the dizziness rate of Group B was 31.58%, and the nausea /vomiting rate of Group B was 21.05%, both significantly higher than those of Group A (11.76% and 31.58% respectively, both P < 0.05), however, there were significant differences in the adverse reaction rates since 12 h after the first administration. There were no significant differences in the OPS score 4 h after the first administration. CONCLUSION: There are not significant differences in the time needed to achieve the analgesic effect in the pediatric children who undergo lower abdomen surgery. Nasal administration of fentanyl needs a higher dose with a higher comfort and lower adverse reaction rate.