JAK2 inhibitor protects the septic heart through enhancing mitophagy in cardiomyocytes.

Sepsis-induced myocardial dysfunction (SIMD) is a severe complication in sepsis, manifested as myocardial systolic dysfunction, which is associated with poor prognosis and higher mortality. Mitophagy, a self-protective mechanism maintaining cellular homeostasis, plays an indispensable role in cardioprotection. This study aimed to unveil the cardioprotective effects of Baricitinib on LPS-induced myocardial dysfunction and its effect on mitophagy. Herein, we demonstrated that LPS induced severe myocardial dysfunction and initiated mitophagy in septic mice hearts. Despite the initiation of mitophagy, a significant number of apoptotic cells and damaged mitochondria persisted in the myocardium, and myocardial energy metabolism remained impaired, indicating that the limited mitophagy was insufficient to mitigate LPS-induced damage. The JAK2-AKT-mTOR signaling pathway is activated in LPS-induced cardiomyocytes and in the hearts of septic mice. Baricitinib administration remarkably improved cardiac function, suppressed systemic inflammatory response, attenuated histopathological changes, inhibited cardiac cell apoptosis and alleviated myocardial damage in septic mice. Furthermore, Baricitinib treatment significantly enhanced PINK1-Parkin-mediated mitophagy, increased autophagosomes, decreased impaired mitochondria, and restored myocardial energy metabolism. Mechanically, the limited mitophagy in septic myocardium was associated with increased p-ULK1 (Ser757), which was regulated by p-mTOR. Baricitinib reduced p-ULK1 (Ser757) and enhanced mitophagy by inhibiting the JAK2-AKT-mTOR signaling pathway. Inhibition of mitophagy with Mdivi-1 reversed the cardiac protective and anti-inflammatory effects of Baricitinib in septic mice. These findings suggest that Baricitinib attenuates SIMD by enhancing mitophagy in cardiomyocytes via the JAK2-AKT-mTOR signaling pathway, providing a novel mechanistic and therapeutic insight into the SIMD.

Postoperative brainstem cavernous malformations complicated with LGI1 encephalitis and hypertrophic olivary degeneration: A case report and literature review.

We presented a case of a 34-year-old male with postoperative brainstem cavernous malformations complicated with LGI1 encephalitis and secondary hypertrophic olivary degeneration (HOD). Due to recurrent dizziness and headache, the patient was diagnosed as brainstem cavernous malformations with recurrent hemorrhage and underwent resection. He subsequently developed unexplained abnormal mental behavior 1 month after the surgery, and diagnosed with LGI1 encephalitis. Six months later, cranial MRI showed HOD. This condition is rare in clinical practice,and a complex mechanism underlies the occurrence.

Luteolin regulating synthesis and catabolism of osteoarthritis chondrocytes via activating autophagy.

Osteoarthritis (OA) is a prevalent bone and joint disease characterized by degeneration. The dysregulation between chondrocyte synthesis and breakdown is a key factor in OA development. Targeting the degenerative changes in cartilage tissue degradation could be a potential treatment approach for OA. Previous research has established a strong link between autophagy and the regulation of chondrocyte functions. Activating autophagy has shown promise in mitigating cartilage tissue degeneration. Currently, osteoarthritis treatment primarily focuses on symptom management, as there is no definitive medication to stop disease progression. Previous studies have demonstrated that luteolin, a flavonoid present in Chinese herbal medicine, can activate autophagy and reduce the expression of MMP1 and ADAMTS-5. This study utilized an in vitro osteoarthritis model with chondrocytes stimulated by IL-1ß, treated with varying concentrations of luteolin. Treatment with luteolin notably increased the levels of synthesis factors Aggrecan and Collagen II, while decreasing the levels of decomposition factors MMP-1 and ADAMTS-5. Moreover, inhibition of autophagy by Chloroquine reversed the imbalances in chondrocyte activities induced by IL-1ß. In an in vivo model of knee osteoarthritis induced by medial meniscal instability (DMM), luteolin was administered as a therapeutic regimen. After 12 weeks, knee cartilage tissues from mice were analyzed. Immunofluorescence and immunohistochemical staining revealed a decrease in P62 expression and an increase in Beclin-1 in the cartilage tissues. Additionally, cartilage wear in the knee joints of mice was alleviated by safranin O and fast green staining. Our study findings underscore the significant role of luteolin in effectively rebalancing chondrocyte activities disrupted by IL-1ß. Our results strongly indicate that luteolin has the potential to be developed as a novel therapeutic agent for the treatment of osteoarthritis, offering promising prospects for future drug development.

Electroacupuncture Downregulating Neuronal Ferroptosis in MCAO/R Rats by Activating Nrf2/SLC7A11/GPX4 Axis.

Ischemic stroke involves various pathological processes, among which ferroptosis is crucial. Previous studies by our group have indicated that electroacupuncture (EA) mitigates ferroptosis after ischemic stroke; however, the precise mechanism underlying this effect remains unclear. In the present study, we developed a rat model of middle cerebral artery occlusion/reperfusion. We chose the main acupoint of the treatment methods of the "Awakening and Opening of the Brain". Rats' neurological function and motor coordination were evaluated by neurological function score and the rotarod test, respectively, and the volume of cerebral infarction was analyzed by 2,3,5-triphenyltetrazolium chloride Staining. The cerebrovascular conditions were visualized by time-of-flight magentic resonance angiography. In addition, we detected changes in lipid peroxidation and endogenous antioxidant activity by measuring the malondialdehyde, glutathione, superoxide dismutase activities, glutathione/oxidized glutathione and reduced nicotinamide adenine dinucleotide phosphate/oxidized nicotinamide adenine dinucleotide phosphate ratios. Inductively coupled plasma-mass spectrometry, western blot, reverse transcription-polymerase chain reaction, fluoro-jade B staining, immunofluorescence analysis, and transmission electron microscopy were utilized to examine the influence of EA. The results indicate that EA treatment was effective in reversing neurological impairment, neuronal damage, and protecting mitochondrial morphology and decreasing the cerebral infarct volume in the middle cerebral artery occlusion/reperfusion rat model. EA reduced iron levels, inhibited lipid peroxidation, increased endogenous antioxidant activity, modulated the expression of several ferroptosis-related proteins, and promoted nuclear factor-E2-related factor 2 (Nrf2) nuclear translocation. However, the protective effect of EA was hindered by the Nrf2 inhibitor ML385. These findings suggest that EA can suppress ferroptosis and decrease damage caused by cerebral ischemia/reperfusion by activating Nrf2 and increasing the protein expression of solute carrier family 7 member 11 and glutathione peroxidase 4.

Soluble ST2 as a possible biomarker for inflammation in patients with acute heart failure.

AIM: The aim of this study was to explore the relationship between peripheral circulating serum soluble suppression of tumorigenicity-2 (sST2) levels and inflammatory biomarkers in patients with acute heart failure (AHF). METHODS: One hundred and eleven consecutive AHF patients with NYHA class II-IV were enrolled, and peripheral blood was collected within 24 h of admission for the detection of NT-ProBNP, sST2, hypersensitive troponin I, cytokines, precalcitoninogen, C-reactive protein, in addition to routine standard of care blood tests. RESULTS: The median sST2 of 111 patients was 47.50 ng/ml (24.25-86.15 IQR), of whom 43 patients (38.7%) had sST2 35 ng/ml or less; linear correlation analysis showed that serum sST2 correlated with NT-ProBNP ( r2  = 0.32), NEU% ( r2  = 0.41), NLR ( r2  = 0.36), CRP ( r2  = 0.50), IL-18 ( r2  = 0.43) ( P  < 0.001), and correlated with Hs-cTnI ( r2  = 0.19), NUE ( r2  = 0.25), LYM ( r2  = -0.23), IL-2RA ( r2  = 0.29) ( P  < 0.05). Multiple linear regression analysis depicted that CRP (ß = 0.318), IL-18 (ß = 0.368), NEU% (ß = 0.346), NLR (ß = -0.304), and NT-ProBNP (ß = 0.324) significantly correlated with sST2 values, respectively ( P  < 0.05). ST2 levels have a linear association with length of hospitalization. CONCLUSION: Peripheral blood inflammatory markers (CRP, IL-18, NEU%, NLR) in patients with AHF had a close relationship with sST2 levels, and the mechanism of action of sST2 may be related to the inflammatory response.

Sexual dysfunction in Wilson disease: Prevalence and influencing factors.

Wilson disease is a rare neurogenetic disorder that receives significant attention due to its manifestations, such as jaundice, cirrhosis, tremor, dystonia, and others. However, the impact of Wilson disease on sexual function has been overlooked. In this study, we aimed to investigate current status of sexual dysfunction in Wilson disease. In this study, we investigated the sexual function status and possible influencing factors of 245 Wilson disease patients by questionnaire. Our study identified sexual dysfunction as a prevalent issue in Wilson disease patients, with an overall prevalence of 49.0 %, of which 33.9 % in males and 63.7 % in females, both higher than the prevalence of sexual dysfunction in the normal Chinese population. Compared with non-sexual dysfunction patients, sexual dysfunction was more common in the older age group, females, less educated, rural residence, no occupation, lower income, taking sedatives/antipsychotics, and high SIS scores (P < 0.05). Our binary logistic regression analysis revealed that older age (OR: 1.103, 95 %CI: 1.058-1.151, P < 0.001), being female (OR: 5.900,95 %CI: 2.966-11.736, P < 0.001), and the use of antipsychotics or sedatives (OR: 3.277,95 %CI: 1.065-10.077, P < 0.05) were all positively linked with an increased risk of sexual dysfunction. Despite the well-known symptoms of Wilson disease, sexual dysfunction is also a frequent issue in Wilson disease patients, necessitating further attention.

A weighted cranial diffusion-weighted imaging scale for Wilson's disease.

Objectives: Cranial magnetic resonance imaging (MRI) could be a crucial tool for the assessment for neurological symptoms in patients with Wilson's disease (WD). Diffusion-weighted imaging (DWI) hyperintensity reflects the acute brain injuries, which mainly occur in specific brain regions. Therefore, this study aimed to develop a weighted cranial DWI scale for patients with WD, with special focus on specific brain regions. Materials and methods: In total, 123 patients with WD were enrolled, 118 of whom underwent 1.5 T-MRI on admission. The imaging score was calculated as described previously and depended on the following sequences: one point was acquired when abnormal intensity occurred in the T1, T2, and fluid-attenuation inversion recovery sequences, and two points were acquired when DWI hyperintensity were found. Consensus weighting was conducted based on the symptoms and response to treatment. Results: Intra-rater agreement were good (r = 0.855 [0.798-0.897], p < 0.0001). DWI hyperintensity in the putamen was a high-risk factor for deterioration during de-copper therapy (OR = 8.656, p < 0.05). The high-risk factors for readmission for intravenous de-copper therapies were DWI hyperintensity in the midbrain (OR = 3.818, p < 0.05) and the corpus callosum (OR = 2.654, p < 0.05). Both scoring systems had positive correlation with UWDRS scale (original semi-quantitative scoring system, r = 0.35, p < 0.001; consensus semi-quantitative scoring system, r = 0.351, p < 0.001.). Compared to the original scoring system, the consensus scoring system had higher correlations with the occurrence of deterioration (OR = 1.052, 95%CI [1.003, 1.0103], p < 0.05) and readmission for intravenous de-copper therapy (OR = 1.043, 95%CI [1.001, 1.086], p < 0.05). Conclusion: The predictive performance of the consensus semi-quantitative scoring system for cranial MRI was improved to guide medication, healthcare management, and prognosis prediction in patients with WD. For every point increase in the neuroimaging score, the risk of exacerbations during treatment increased by 5.2%, and the risk of readmission to the hospital within 6 months increased by 4.3%.

Chronic ß-adrenergic stress contributes to cardiomyopathy in rodents with collagen-induced arthritis.

Patients with rheumatoid arthritis (RA) have a much higher incidence of cardiac dysfunction, which contributes to the high mortality rate of RA despite anti-arthritic drug therapy. In this study, we investigated dynamic changes in cardiac function in classic animal models of RA and examined the potential effectors of RA-induced heart failure (HF). Collagen-induced arthritis (CIA) models were established in rats and mice. The cardiac function of CIA animals was dynamically monitored using echocardiography and haemodynamics. We showed that cardiac diastolic and systolic dysfunction occurred in CIA animals and persisted after joint inflammation and that serum proinflammatory cytokine (IL-1ß, TNF-α) levels were decreased. We did not find evidence of atherosclerosis (AS) in arthritic animals even though cardiomyopathy was significant. We observed that an impaired cardiac ß1AR-excitation contraction coupling signal was accompanied by sustained increases in blood epinephrine levels in CIA rats. Furthermore, serum epinephrine concentrations were positively correlated with the heart failure biomarker NT-proBNP in RA patients (r2 = +0.53, P < 0.0001). In CIA mice, treatment with the nonselective ßAR blocker carvedilol (2.5 mg·kg-1·d-1, for 4 weeks) or the specific GRK2 inhibitor paroxetine (2.5 mg·kg-1·d-1, for 4 weeks) effectively rescued heart function. We conclude that chronic and persistent ß-adrenergic stress in CIA animals is a significant contributor to cardiomyopathy, which may be a potential target for protecting RA patients against HF.

Effects of vitamin A on intramuscular fat development in beef cattle: A meta-analysis.

Vitamin A, a fat-soluble vitamin, is the basic substance required to maintain healthy vision and the main physiological functions of cattle. The results from previous studies regarding the effect of vitamin A on intramuscular fat varied. This meta-analysis aimed to generate a more comprehensive understanding of the relationship between vitamin A and intramuscular fat content and to provide potential clues for future research and commercial practice. Electronic databases such as MEDLINE and Ovid were systematically searched, and studies investigating the relationship between vitamin A and intramuscular fat content were included. Standardized mean differences (SMDs) in intramuscular fat percentage and intramuscular fat score, with their respective 95% confidence intervals (CIs), were calculated. The heterogeneity and publication bias were evaluated. A total of 152 articles were identified through searches of databases. Seven articles were confirmed for inclusion in this meta-analysis. The SMD of IMF percentage derived from the analysis was-0.78 (-2.68, 1.12) (Q = 246.84, p < 0.01). The SMD of the IMF score was 1.25 (-2.75, 5.25) (Q = 87.20, p < 0.01). Our meta-analysis indicates that the addition of vitamin A could decrease intramuscular fat in cattle steers.

Dynamics of Peripheral Blood Immune Cells during the Perioperative Period after Digestive System Resections: A Systematic Analysis of the Literature.

An operation in itself is a kind of trauma and may lead to immunosuppression followed by a bounce back. Not many studies exist that describe dynamics of the distribution of peripheral blood (PB) immune cells during the perioperative period. Considering this scarcity, we aggregated the data on the dynamics of immune cells in patients with digestive system resections during the perioperative period and the relationship with short- and long-term prognoses. By the systematic retrieval of documents, we collected perioperative period data on white blood cells (WBC), lymphocytes, neutrophil-lymphocyte ratio (NLR), CD4+ T cells, CD8+ T cells, helper T cells (Th), B cells, natural killer cells (NK), dendritic cells (DCs), regulatory T cells (Tregs), regulatory B cells (Bregs), and Myeloid derived suppressor cells (MDSC). The frequency and distribution of these immune cells and the relationship with the patient's prognosis were summarized. A total of 1916 patients' data were included. Compared with before surgery, WBC, lymphocytes, CD4+ cells, CD8+ T cells, MDSC, and NK cells decreased after surgery, and then returned to preoperative levels. After operation DCs increased, then gradually recovered to the preoperative level. No significant changes were found in B cell levels during the perioperative period. Compared with the preoperative time-point, Tregs and Bregs both increased postoperatively. Only high levels of the preoperative and/or postoperative NLR were found to be related to the patient's prognosis. In summary, the surgery itself can cause changes in peripheral blood immune cells, which might change the immunogenicity. Therefore, the immunosuppression caused by the surgical trauma should be minimized. In oncological patients this might even influence long-term results.

Botulinum toxin type A treatment of four cases of Wilson disease with lower limb dystonia: A prospective study.

Botulinum toxin type A (BoNT-A) has been recommended in various neurological disorders as a useful tool for alleviating dystonia. In Wilson disease (WD) patients with dystonia, BoNT-A injection can be used as a treatment modality when conventional treatment is ineffective for alleviating symptoms. The purpose of this study was to thoroughly evaluate the efficacy of BoNT-A injection in treating WD complicated by lower extremity dystonia. The efficacy of these injections was assessed by clinical scales, surface electromyography (EMG), and gait analysis. A comparative analysis of all gait parameters, EMG parameters, and clinical scales revealed a significant increase in velocity, decrease in integrated EMG (iEMG), and improvement in modified Ashworth scale (MAS), Burke Fahn Marsden (BFM), and activities of daily living (ADL) scores (all P < 0.05). Overall, our findings indicated that BoNT-A injection led to marked relief of symptoms in patients with WD with lower extremity dystonia.

Attention impairment in patients with cervical dystonia: An attention network test study.

Objective: The purpose of this study was to investigate attentional network functional characteristics in patients with cervical dystonia (CD). Methods: A total of 29 patients with CD and 26 healthy controls (HCs) were recruited. All subjects participated in the study and underwent the Attention Network Test (ANT), which evaluated the efficiencies of three independent attention networks (alerting, orienting, and executive control), as well as reaction time (RT) and accuracy. Results: Significant differences between CD patients (9.86 ± 27.95 ms) and HCs (33.62 ± 23.41 ms) were observed in the alerting network (t = -3.40, p < 0.05). In contrast, the orienting network (t = 0.26, p = 0.79), executive control network (Z = -0.55, p = 0.58), total mean reaction time (t = -2.6, p = 0.79), and total accuracy rate (Z = -1.67, p = 0.09) showed no significant differences between the two groups. Conclusion: Patients with CD showed a significant deficit in the alerting network. However, they did not show any deficits in the orienting or executive control network. In addition, the alerting, orienting, and executive control network functions of CD patients were all affected by the severity of torticollis, especially the alerting network function.

Integration of H2V3O8 nanowires and a GaN thin film for self-powered UV photodetectors.

H2V3O8/GaN n-n heterojunction ultraviolet photodetectors are fabricated via a facile dip-coating method. The Schottky junction between the GaN and H2V3O8 builds a built-in electric field to achieve the self-powered phenomenon. The photodetector presents a high photocurrent (0.23 µA) and a fast response speed (less than 0.3 s) at 0 V bias and under 365 nm light illumination (24.50 mW cm-2). Furthermore, the photocurrent increases steadily as the light intensity increases from 0.53 to 24.50 mW cm-2. The H2V3O8/GaN heterojunction holds great potential to realize high-performance hybrid PDs.

A novel fluorescent digitonin derivative for non-invasive skin cholesterol detection: potential application in atherosclerosis screening.

There is a great demand for the rapid and non-invasive atherosclerosis screening method. Cholesterol content in the epidermis of the skin is an early biomarker for atherosclerosis. Risk assessment of atherosclerosis can be achieved by measuring cholesterol in the epidermis. Here, we synthesised a new fluorescent digitonin derivative (FDD) for the non-invasive detection of skin cholesterol. The results of fluorescence spectroscopy studies indicated that the probe exhibited desirable selectivity for cholesterol. The proof-of-concept preclinical study confirmed that FDD can detect different concentrations of skin cholesterol; patients diagnosed with atherosclerotic cardiovascular disease and the at-risk atherosclerosis group exhibited higher skin cholesterol content than the normal group. The area under the ROC curve for distinguishing the normal/disease group was 0.9228 (95% confidence interval, 0.8938 to 0.9518), and the area under the ROC curve for distinguishing the normal/risk group was 0.9422 (95% confidence interval, 0.9178 to 0.9665). We anticipate that this non-invasive skin cholesterol test may be used as a risk assessment tool for atherosclerosis screening in a large population for further examination and intervention in high-risk populations.

Stress-based topology optimization of continuum structures for the elastic contact problems with friction.

Structural problems have various nonlinearities in the real world and these nonlinearities should be accommodated in structural topology optimization. This work proposes a topology optimization method for minimizing the maximum von Mises stress of elastic continuum structures with frictional contact under material usage constraint, using an extended Bi-directional Evolutionary Structural Optimization (BESO) method. Stresses are treated as global performance (objective) function, the global von Mises stress is measured by the p-norm stress aggregation approach, and the friction behavior is governed by the Coulomb friction law regularized in analogy with the perfect elasto-plastic theory. BESO method based on discrete variables which can avoid the well-known stress singularity and the numerical instability issue in frictional contact problems. The adjoint sensitivity analysis method is adopted to derive the sensitivity numbers. The effectiveness of the proposed method is validated through a series of comparison studies including elastic-rigid and elastic-elastic contact problems. The influence of varying friction coefficient on the optimized results and the stress distributions are investigated in comparison with the maximum stiffness design. The effect of different parameters including p-norm, volume fraction and mesh density on the optimized results are discussed. The optimized results, for elastic-rigid contact, indicate that the maximum stress can be reduced compared with elastic-elastic contact. The optimized stress decreases as the friction coefficient increases because the friction behavior resists the tangential deformation at the contact interface. The results also show that the proposed approach can achieve a reasonable design that effectively controls the stress level and reduces the stress concentration effect at the critical stress areas.

Standard-Intensity Induction and Intermediate/High-Dose Cytarabine Consolidation Can Improve Survival for Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia: A Retrospective Cohort Study.

BACKGROUND: There is great uncertainty in the treatment of elderly patients with acute myeloid leukemia (AML), which leads to great challenges in treatment decision. The aim of this study is to find more suitable induction therapy and consolidation therapy for elderly AML patients. METHODS: A total of 149 consecutive newly diagnosed elderly AML patients (aged ≥60 years) who received induction chemotherapy in our medical center from January 2015 to December 2019 were retrospectively analyzed. RESULTS: After the first induction treatment, the complete remission/or complete remission with incomplete hematologic recovery (CR/CRi) rates in the standard-intensity chemotherapy group was significantly higher than that in the low-intensity chemotherapy group (58.2% vs 32.9%, p = 0.003). Compared with the low-intensity chemotherapy, the incidence of severe infection in the standard-intensity chemotherapy was significantly increased (p < 0.001), but the early mortality was comparable. One hundred and seven patients received minimal residual disease (MRD) examination after the first induction treatment; and MRD was negative accounting for 51.9% in the standard-intensity chemotherapy group, while only 32.7% in the low-intensity group (p = 0.05). The 2-year-overall survival (OS) of patients in standard-intensity induction chemotherapy group (37.2%) was slightly higher than that in low-intensity induction chemotherapy group (23.4%) (p = 0.075). Eighty-one CR/CRi patients received intermediate or high dose cytarabine (n = 35) or sequential chemotherapy regimens (n = 46) as consolidation treatment. The 2-year OS and event-free survival (EFS) of patients in the intermediate or high-dose cytarabine group were significantly higher than those in the sequential chemotherapy regimens group (73.0% vs 38.5%, p = 0.002; 54.8% vs 35.0%, p = 0.035). CONCLUSION: Our results showed that standard-intensity induction chemotherapy can significantly improve the CR rate for elderly AML patients, and does not increase the early mortality; consolidation therapy with intermediate or high-dose cytarabine can significantly improve EFS and OS for elderly AML patients achieved CR.

Constructing electrostatic self-assembled ultrathin porous red 2D g-C3N4/Fe2N Schottky catalyst for high-efficiency tetracycline removal in photo-Fenton-like processes.

The traditional heterogeneous photo-Fenton reaction was mainly restricted by the fewer surface-active sites, low Fe3+/Fe2+ transformation and H2O2 activation efficiency of catalyst. This work designed and fabricated the efficient photo-Fenton Schottky catalysts via a facile electrostatic self-assembly of metallic Fe2N nanoparticles scattering on the surface of red g-C3N4 (ultrathin porous oxygen-doped 2D g-C3N4 nanosheets). The porous morphology and exceptional electrical structure of red g-C3N4 endowed more active sites and facilitated the photoexcited charge separation. Benefitting from the Schottky effect and unique dimensional coupling structure, the strong visible light absorption and fast spatial charge transfer were realized in the Schottky junction system. More strikingly, Fe2N as an efficient co-catalyst was in favor of the trap and export of e-, leading to the Fe3+/Fe2+ transformation and H2O2 activation during the photo-Fenton process. Accordingly, the as-prepared catalysts revealed outstanding activity in photo-Fenton like degradation of tetracycline (TC) although under 5 W white LED light irradiation. Furthermore, the reasonable degradation pathway of TC and corresponding toxicity of the intermediates, as well as the photo-Fenton catalytic mechanism were interpreted and discussed in detail. This study would be a great aid in the development of various Schottky catalysts for heterogeneous photo-Fenton-based environmental remediation systems.

Highly differential count of circulating and tumor infiltrating immune cells in patients with non-HCV/non-HBV hepatocellular carcinoma.

BACKGROUND: Liver transplantation and liver resection are curative options for early hepatocellular carcinoma (HCC). The outcome is in part depended on the immunological response to the malignancy. In this study, we aimed to identify immunological profiles of non-HCV/non-HBV HCC patients. METHODS: Thirty-nine immune cell subsets were measured with multicolor flow cytometry. This immunophenotyping was performed in peripheral blood (PB) and tumor specimens of 10 HCC resection patients and 10 healthy donors. The signatures of the highly differential leukocyte count (hDIF) were analyzed using multidimensional techniques. Functional capability was measured using intracellular IFN-γ staining (Trial Registration DRKS00013567). RESULTS: The hDIF showed activation (subsets of T-, B-, NK- and dendritic cells) and suppression (subsets of myeloid-derived suppressor cells and T- and B-regulatory cells) of the antitumor response. Principal component analysis of PB and tumor infiltrating leukocytes (TIL) illustrated an antitumor activating gradient. TILs showed functional capability by secreting IFN-γ but did not kill HCC cells. CONCLUSIONS: In conclusion, the measurement of the hDIF shows distinct differences in immune reactions against non-HBV/non-HCV HCC and illustrates an immunosuppressive gradient toward peripheral blood. TRIAL REGISTRATION: DRKS00013567.

Triggers of Cardiovascular Diseases in Rheumatoid Arthritis.

The risk of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA) is higher than that in patients without RA, and it is even higher than that in patients with diabetes. Autoimmune-mediated inflammation is observed in patients with RA, resulting in endothelial dysfunction, oxidative stress and activation, and vascular migration of white blood cells. Traditionally, RA-associated CVD was assumed to be mediated by disease-related inflammation, resulting in atherosclerosis (AS). However, this concept has been challenged because treatment with anti-rheumatic drugs, such as methotrexate or proinflammatory cytokine antagonists, such as tumor necrosis factor-alpha (TNF-α) inhibitors, did not reduce the risk of CVD in patients with RA. Current cardiovascular guidelines recommend screening and treatment of CVD risk factors in patients with RA but without clear biomarkers and treatment goals. There is no scientific basis for establishing therapeutic targets for cardiovascular risk factors in RA. Numerous studies have shown that the mechanism of early cardiac dysfunction in patients with RA may occur prior to AS. Therefore, it is crucial to explore the related mechanisms to prevent early cardiac dysfunction in patients with RA.