Hepatic arterial infusion therapy for advanced hepatocellular carcinoma after systemic treatment failure: Multicenter, real-world study.

AIM: The study was conducted to evaluate the feasibility and safety profile of hepatic arterial infusion chemotherapy with oxaliplatin, 5-fluorouracil, and leucovorin (HAIC-FOLFOX) as an alternative therapeutic choice for patients with advanced hepatocellular carcinoma (HCC) that is refractory to systemic treatment including immune checkpoint blockades or molecular targeting agents. METHODS: Two hundred and forty five consecutive patients with advanced HCC who received HAIC-FOLFOX treatment after systemic treatment failure were retrospectively reviewed in six institutions and their survival, tumor response, and tolerance were assessed. RESULTS: The median overall survival (OS) and progression-free survival of the 209 included participants were 10.5 months (95% confidence interval [CI], 8.1-12.9) and 6.0 months (95% CI, 5.1-6.9), respectively. According to Response Evaluation Criteria in Solid Tumors 1.1 criteria, the objective response rate was 21.1%, and the disease control rate was 64.6%. Multivariate analysis of risk factors of OS were albumin-bilirubin grade (2 and 3 vs. 1, hazard ratio [HR] 1.57; 95% CI, 1.05-2.34; p = 0.028), tumor number (>3 vs. 1-3, HR 2.18; 95% CI, 1.10-4.34; p = 0.026), extrahepatic spread (present vs. absent, HR 1.61, 95% CI, 1.06-2.45; p = 0.027), synchronous systemic treatment (present vs. absent, HR 0.55, 95% CI, 0.37-0.83; p = 0.004) and treatment response (responder vs. nonresponder, HR 0.30, 95% CI, 0.17-0.53; p < 0.001). Grade 3-4 adverse events (AEs) occurred in 59 (28.2%) HCC patients. All AEs were manageable, and deaths related to hepatic artery infusion chemotherapy treatment were not observed. CONCLUSIONS: Our findings support the effectiveness and safety of HAIC-FOLFOX treatment for patients with advanced HCC who have failed systemic treatment.

Structural insights into substrate recognition and translocation of human peroxisomal ABC transporter ALDP.

Dysfunctions of ATP-binding cassette, subfamily D, member 1 (ABCD1) cause X-linked adrenoleukodystrophy, a rare neurodegenerative disease that affects all human tissues. Residing in the peroxisome membrane, ABCD1 plays a role in the translocation of very long-chain fatty acids for their ß-oxidation. Here, the six cryo-electron microscopy structures of ABCD1 in four distinct conformational states were presented. In the transporter dimer, two transmembrane domains form the substrate translocation pathway, and two nucleotide-binding domains form the ATP-binding site that binds and hydrolyzes ATP. The ABCD1 structures provide a starting point for elucidating the substrate recognition and translocation mechanism of ABCD1. Each of the four inward-facing structures of ABCD1 has a vestibule that opens to the cytosol with variable sizes. Hexacosanoic acid (C26:0)-CoA substrate binds to the transmembrane domains (TMDs) and stimulates the ATPase activity of the nucleotide-binding domains (NBDs). W339 from the transmembrane helix 5 (TM5) is essential for binding substrate and stimulating ATP hydrolysis by substrate. ABCD1 has a unique C-terminal coiled-coil domain that negatively modulates the ATPase activity of the NBDs. Furthermore, the structure of ABCD1 in the outward-facing state indicates that ATP molecules pull the two NBDs together and open the TMDs to the peroxisomal lumen for substrate release. The five structures provide a view of the substrate transport cycle and mechanistic implication for disease-causing mutations.

Clinical Predictive Models for Delayed Cerebral Infarction After Ruptured Intracranial Aneurysm Clipping for Patients: A Retrospective Study.

Objective: A nomogram was developed in this work to predict the probability of delayed cerebral infarction (DCI) after ruptured intracranial aneurysms (RIA) clipping. Methods: Clinical data of patients with intracranial aneurysm were obtained from the neurosurgery department of the First Affiliated Hospital of Chongqing Medical University from January 2016 to December 2020. A total of 419 patients receiving surgery of ruptured intracranial aneurysm clipping were included and a total of 37 patients with DCI were set as the observation group. The control group consisted of 382 patients without DCI. Risk factors of DCI were screened by univariate and multivariate logistic regression analysis and included in the nomogram. Results: Univariate analysis showed that female (P = 0.009), small aneurysm (P = 0.031), intraoperative aneurysm rupture (P = 0.007) and cerebral vasospasm (P < 0.001) were risk factors for postoperative DCI while smoking history (P = 0.044) were protective factors for postoperative DCI. Multivariate Logistic regression analysis showed that small aneurysm (P = 0.002, OR = 3.332, 95%-7.104), intraoperative aneurysm rupture (P = 0.004, OR = 0.122, 95%-CI, 0.029-0.504)and cerebral vasospasm (P < 0.001, OR = 0.153, 95%-CI, 0.070-0.333) were independent risk factors of postoperative DCI. The calibration curve of the probability of occurrence showed that the nomogram was in good correspondence with the observed results with a C-index of 0.766 (95% CI, 0.684-0.848). Meanwhile, the Decision curve analysis (DCA) showed that the established predictive model had a good clinical net benefit. Conclusion: The well-established nomogram is expected to be an effective tool to predict the occurrence of DCI after intracranial ruptured aneurysm and can be used to assist clinicians to develop more effective treatment strategies and improve the prognosis of patients.

Spontaneous cellular vibratory motions of osteocytes are regulated by ATP and spectrin network.

Vibration at high frequency has been demonstrated to be anabolic for bone and embedded osteocytes. The response of osteocytes to vibration is frequency-dependent, but the mechanism remains unclear. Our previous computational study using an osteocyte finite element model has predicted a resonance effect involving in the frequency-dependent response of osteocytes to vibration. However, the cellular spontaneous vibratory motion of osteocytes has not been confirmed. In the present study, the cellular vibratory motions (CVM) of osteocytes were recorded by a custom-built digital holographic microscopy and quantitatively analyzed. The roles of ATP and spectrin network in the CVM of osteocytes were studied. Results showed the MLO-Y4 osteocytes displayed dynamic vibratory motions with an amplitude of ~80 nm, which is relied both on the ATP content and spectrin network. Spectrum analysis showed several frequency peaks in CVM of MLO-Y4 osteocytes at 30 Hz, 39 Hz, 83 Hz and 89 Hz. These peak frequencies are close to the commonly used effective frequencies in animal training and in-vitro cell experiments, and show a correlation with the computational predictions of the osteocyte finite element model. These results implicate that osteocytes are dynamic and the cellular dynamic motion is involved in the cellular mechanotransduction of vibration.

Visfatin Plays a Significant Role in Alleviating Lipopolysaccharide-Induced Apoptosis and Autophagy Through PI3K/AKT Signaling Pathway During Acute Lung Injury in Mice.

Visfatin is involved in the body's inflammation and immune response. Inflammation could promote, while visfatin may directly or indirectly mitigate the effects of apoptosis and autophagy. Whether visfatin lessens the detrimental effects of lipopolysaccharide (LPS)-induced mouse acute lung injury (ALI) is poorly understood yet. Therefore, in the current study, the regulation mechanism of visfatin on apoptosis and autophagy was explored in Kunming mice by replicating LPS-induced inflammatory ALI model. Based on the mouse model of ALI, HE staining, TUNEL, transmission electron microscopy, immunohistochemical staining, real-time fluorescence quantitative PCR and western blot were used and the results showed that the alveolar septum was thinner than that of the LPS group, slight lung interstitial and alveolar exudation appeared, and a small number of inflammatory cell infiltration was found in the visfatin intervention group, indicating reduced tissue damage in lungs. After visfatin treatment, the expression of pro-apoptotic genes Bax, Bik, and p53 decreased and the expression of anti-apoptotic genes Bcl-2 and Bcl-xl increased, and expression of autophagy factors LC3 and Beclin1 decreased, indicating that visfatin inhibits apoptosis and reduces autophagy. The expression of PI3K and p-AKT was upregulated in the visfatin intervention group, the expression of AKT was downregulated, and the PI3K/AKT signaling pathway was activated. Hence, visfatin could activate the PI3K/AKT signaling pathway, reduce the apoptotic rate in alveolar epithelial cells and the level of autophagy in ALI by regulating the expression of autophagy factors, ultimately causing a protective effect on lung tissue.

Visfatin regulates the production of lipopolysaccharide-induced inflammatory cytokines through p38 signaling in murine macrophages.

Visfatin plays an important role in regulation of inflammatory cytokines. However, the role of visfatin under bacterial stress condition is not fully explored yet. Therefore, the present study was conducted for the better understanding of the regulation mechanism of visfatin on the production of inflammatory cytokines under lipopolysaccharide (LPS) stress in RAW264.7 murine macrophages. Enzyme Linked Immuno-sorbent Assay (ELISA) results showed that, as compared to the control group, visfatin significantly up-regulated the levels of interleukin (IL)-1ß, IL-6, IL-10, tumor necrosis factor (TNF)-α (P < 0.05). Compared to the LPS group, the levels of IL-1ß, IL-10, TNF-α was down-regulated in visfatin + LPS group (P < 0.05). After adding p38 inhibitor, SB203580 to culture, the production of IL-1ß, IL-6, IL-10, TNF-α was significantly reduced as compared to visfatin only (P < 0.01). The results showed that visfatin may regulate the production of IL-1ß, IL-6, IL-10, TNF-α through the p38 signaling pathway. As compared to the PBS group, phosphorylayed p38 (P-p38) level in visfatin group was significantly decreased (P < 0.05). Compared with LPS group, P-p38 level was significantly decreased in visfatin + LPS group (P < 0.05). Hence, it is concluded that visfatin can significantly increase the levels of IL-1ß, IL-10 and TNF-α in normal conditions, while their levels significantly decrease during inflammation. Moreover, visfatin participates in the inflammatory response through the p38 mitogen-activated protein kinase (MAPK) signal pathway by the up-regulation of p38 and down-regulation of P-p38 levels.

Effects of visfatin on the apoptosis of intestinal mucosal cells in immunological stressed rats.

This study was undertaken to determine if visfatin is involved in the inflammation or apoptosis introduced by LPS in rats. Forty 8-week old Wistar rats were divided into four groups (n=10 in each group) and injected with saline, visfatin, LPS and visfatin+LPS co-stimulated via caudal vein. The duodenum, jejunum and ileum were harvested from all the rats. Compared to the saline treated group, visfatin significantly increased the number of TUNEL-positive apoptotic cells and the expression of caspase-3 protein in intestinal mucosa. Similarly, ELISA and western blot analysis also showed the up-regulation of pro-caspase-3 and cleaved caspase-3 expression in the visfatin group compared to the control group. In contrast to LPS, visfatin down-regulated the expression of cleaved-caspase-3 in the visfatin+LPS co-stimulated group, resulting in a significant decrease in apoptosis in intestinal mucosal cells. We observed more pro-caspase-3 positive cells in the visfatin+LPS co-stimulated group. The results indicate that, in the presence of LPS, visfatin plays an important role in the regulation of cell apoptosis and inflammation.

Effects of supplemental boron on intestinal proliferation and apoptosis in African ostrich chicks / Efectos del boro suplementario sobre la proliferación intestinal y apoptosis en polluelos de avestruz africana

Boron is an essential trace element which plays an important role in process of metabolism and the function of the tissues. However, the effects of boron on the intestinal cells in African ostrich chicks are poorly reported. Therefore, this study was designed to investigate the role of boron on proliferation and apoptosis of the intestinal cells. A total of 36, ten day-old ostrich chicks were randomly divided into six groups and fed on the same basal diet supplemented with 0, 40, 80, 160, 320 and 640 mg/L boric acid in drinking water for 80 days. Proliferatingcell nuclearantigen (PCNA) wasused to test the proliferation indexof intestine in different group byimmunohistochemicalstaining (IHC). Apoptoticcellsofintestinewere detectedbyDutp-biotin nick end labeling (TUNEL) reaction and evaluated by integral optical density (IOD). Results showed that proliferationof intestinal cells significantly increased in groups of 80, 160, 320 and 640 mg/L. TUNEL reaction showed that apoptosis significantly decreased in 80 mg/L groups, while significantly increased in high dose of boron groups (320 and 640 mg/L), especially inepithelium. In conclusion, low dose of boron-supplemented water could promote cell proliferation and depress apoptosis, while high dose of boron could cause intestinal apoptosis and thus we found increased proliferation of intestine cell as a compensatory adaption. These findings may support optimal dosage of boron that could protect the development of ostrich intestine, while high dosage of boron could suppress it, or even has toxic effects on it.

El boro es un elemento esencial que desempeña un importante rol en el proceso del metabolismo y en la función de los tejidos. Sin embargo, existe poca información de los efectos del boro en las células intestinales de polluelos de avestruz Africana. Por lo tanto, este estudio fue diseñado para investigar el papel del boro sobre la proliferación y la apoptosis de las células intestinales. Un total de 36 polluelos de avestruz de diez días se dividieron, aleatoriamente, en seis grupos y se alimentaron con una misma dieta basal suplementada con 0, 40, 80, 160, 320 y 640 mg/L de ácido bórico en agua potable durante 80 días. Se utilizó el antígeno nuclear celular de células en proliferación (PCNA) para probar el índice de proliferación de intestino en diferentes grupos por tinción inmunohistoquímica. Las células apoptóticas del intestino fueron detectadas por dUTP-biotina nick etiquetado para reacción (TUNEL) y evaluadas por la densidad óptica integrada (DOI). Los resultados mostraron que la proliferación de las células intestinales aumentó significativamente en los grupos de 80, 160, 320 y 640 mg /L. La reacción TUNEL mostró que la apoptosis se redujo significativamente en los grupos de 80 mg/L, mientras que el aumento fue significativo en grupos tratados con dosis alta de boro (320 y 640 mg/L), especialmente en el epitelio. En conclusión, la baja dosis de boro en agua suplementada podría promover la proliferación celular y deprimir la apoptosis, mientras que altas dosis de boro podrían provocar apoptosis intestinal y, por lo tanto, se halló una mayor proliferación de las células del intestino como una adaptación compensatoria. Estos hallazgos indican que una dosis óptima de boro podría proteger el desarrollo del intestino del avestruz, mientras que altas dosis de boro podrían suprimirla, o incluso tener efectos tóxicos sobre ella.

Complementary use of video-electroencephalography and magnetoencephalography in frontal lobe epilepsy.

PURPOSE: The aim of this study was to compare magnetoencephalography (MEG) and video-electroencephalography (VEEG) source localization in frontal lobe epilepsy (FLE) and determine if these methods can be complementary to each other in clinical practice. METHOD: Thirty patients with pharmaco-resistant FLE who underwent epilepsy surgery were retrospectively enrolled. Video EEG was recorded using an IT-med system using 10/20 system. Regional localization of spikes in VEEG was defined as spikes discharged from adjacent electrodes and no further propagation to a large and/or contralateral area. Magnetoencephalography was recorded for the purpose of focus assessment. Magnetoencephalography spikes were detected for dipole localization of the epileptogenic cortex and the epileptogenic area was classified as mono- or multi-focal. RESULTS: Regional spike discharges were identified in the interictal VEEG of 20 patients and in the ictal VEEG of 17 patients. Thirteen patients had regional spikes in both interictal and ictal VEEG. Mono-focal localization was identified in the MEG of 20 patients. Fourteen of these patients had regional spike discharges in VEEG. In the remaining six patients, sources localization was only identified by MEG and there were no regional spike discharges either interictal or ictal VEEG. CONCLUSION: In clinical practice, VEEG is the routine procedure in the presurgical evaluation of FLE. However, we found six cases in which VEEG failed to locate the epileptogenic area that was identified by MEG. We therefore propose that combining VEEG and MEG will optimize the noninvasive presurgical evaluation of epileptiform activities in FLE.

How to effectively constrain the cost of presurgical evaluation for resective surgery in low-income population: clinically oriented opinions.

Epilepsy surgery plays a pivotal role in the successful treatments of intractable epilepsy. In China, economic burden for epileptic patients is heavy. Because of limited economic resources, appropriate utilization of presurgical evaluation technologies is especially important for low-income patients, who could benefit from surgery. This study proposed the strategies for restricting the cost of presurgical evaluation for resective surgery in low-income population with refractory epilepsy. A retrospective study was performed on the database of patients with resective surgery from January 2007 to June 2009 in West China Hospital of Sichuan University. Presurgical evaluation technologies and outcome were analyzed. As a result, 143 patients underwent resective operation were included in this study. Seizure free can be reached at 63.8% patients with (ATL) and 61.1% with focal lesionectomy (FLE). Magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), positron emission tomography (PET), routine electroencephalography (REEG), video-EEG (VEEG) and invasive-EEG (IEEG) were used for investigation. The cost of those technologies was listed for consultation. Based on these findings, how to make the proper choice for surgery candidates was suggested according to different types of epilepsy.

Association study of lamotrigine-induced cutaneous adverse reactions and HLA-B*1502 in a Han Chinese population.

Antiepileptic drugs including lamotrigine (LTG) and carbamazepine (CBZ) are among the most common causes of cutaneous adverse reactions (cADRs). Human leukocyte antigen (HLA)-B*1502 has been strongly associated with CBZ-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). To investigate this relationship, we performed high-resolution HLA genotyping on LTG-tolerant controls, healthy volunteers, and patients affected by LTG-induced cADRs, ranging from maculopapular exanthema (MPE) to SJS/TEN. Patients with LTG-induced cADRs (n=25, including three with SJS/TEN and 22 with MPE), 21 LTG-tolerant controls, and 71 healthy volunteers were enrolled. The differences in the starting dosage of LTG among the SJS/TEN, MPE, and LTG-tolerant control groups were not statistically significant. HLA-B*1502 frequency was 33.3% (1/3; LTG-induced SJS/TEN group), 9.1% (2/22; LTG-induced MPE group), 4.8% (1/21; LTG-tolerant group), and 8.5% (6/71; healthy volunteers). There was no significant difference in the frequency of subjects with the HLA-B*1502 allele between the SJS/TEN group and LTG-tolerant group (p=0.239, OR=10.0, 95% CI 0.44-228.7), and healthy volunteers (p=0.26, OR=5.42, 95% CI 0.43-68.8), MPE and LTG-tolerant groups (p=1.0, OR=1.08, 95% CI 0.20-5.8), and healthy volunteers (p=1.0, OR=2.0, 95% CI 0.17-23.9). None of the HLA alleles detected were associated with LTG-induced cADRs. In conclusion, HLA-B*1502 and other HLA alleles are not directly associated with LTG-induced MPE. The possibility that HLA-B*1502 is associated with an increased risk of LTG-induced SJS/TEN could not be excluded.

[Effect of geniposide on vascular dementia in rats].

OBJECTIVE: To investigate the effect of geniposide on vascular dementia (VaD) in rats. METHODS: VaD rat model was established by permanent ligation of bilateral common carotid arteries. Morris water maze performance was assessed after 4 weeks of treatment with geniposide, followed by pathological examinations of hippocampus and cerebral cortex. RESULTS: The VaD rats had significantly longer escape latency and lower percentage of activities in platform quadrant than the rats in the sham surgery group (P<0.05). The VaD rats treated with geniposide [50 mg/(kg x d), 75 mg/(kg x d)] had significantly shorter escape latency (except the first day of the test) and significantly higher percentage of activities in platform quadrant than the VaD rats without treatment (P<0.05). No significant differences were found between the geniposide treated group and the Donepezil treated group and the sham surgery control group. Geniposide significantly alleviated neurons,apoptosis and necrosis induced by chronic cerebral hypoperfusion of cortex and hippocampus. CONCLUSION: Chronic cerebral hypoperfusion can induce cognitive impairment. Geniposide can improve cognitive ability of Vascular Dementia in rats. This may represent a potential treatment strategy for vascular dementia.

Economic burden of epilepsy in a developing country: a retrospective cost analysis in China.

PURPOSE: To study the cost of epilepsy in China, and, therefore, provide essential information on the burden of the disease to individuals and society. METHODS: A cost-of-illness study was performed on a retrospective cohort of medically treated patients. Data on clinical characteristics, utilization of sources, and costs were collected from 289 patients in a standardized format. RESULTS: Direct medical care costs was Chinese yuan, renminbi (RMB) 2,529 (USD 372) per year per patient, of which antiepileptic drugs (RMB 1,651 or USD 243) accounted for the major cost component. Nonmedical direct costs were much less than direct health care costs, averaging approximately RMB 756 (USD 111). Costs due to loss of productivity averaged approximately RMB 1,968 (USD 289) per patient per year. Taken together, the overall mean annual cost for epilepsy per patient in our series was approximately RMB 5,253 (USD 773), and these costs accounted for more than half of the mean annual income. Total cost was significantly associated with disease severity and different responses to drug treatment. In addition, new antiepileptic drugs and the number of drugs taken were closely related with the drug cost. CONCLUSION: The results indicate that the economic burden of epilepsy to both Chinese patients and the nation is heavy, and the composition proportions of the costs in China have many similar features and some noteworthy differences with that of other countries.