Objectives:This study aimed to assess the efficacy and safety of bendamustine in combination with rituximab (BR regimen) for the treatment of newly diagnosed indolent B-cell non-Hodgkin's lymphoma (B-iNHL) and elderly mantle cell lymphoma (eMCL) .Methods:From December 1, 2020 to September 10, 2022, a multi-center prospective study was conducted across ten Grade A tertiary hospitals in Shandong Province, China. The BR regimen was administered to evaluate its efficacy and safety in newly diagnosed B-iNHL and eMCL patients, and all completed at least four cycles of induction therapy.Results:The 72 enrolled patients with B-iNHL or MCL were aged 24-74 years, with a median age of 55 years. Eastern Cooperative Oncology Group (ECOG) performance status scores of 0-1 were observed in 76.4% of patients, while 23.6% had scores of 2. Disease distribution included follicular lymphoma (FL) (51.4% ), marginal zone lymphoma (MZL) (33.3% ), eMCL (11.1% ), and the unknown subtype (4.2% ). According to the Ann Arbor staging system, 16.7% and 65.3% of patients were diagnosed with stage Ⅲ and stage Ⅳ lymphomas, respectively. Following four cycles of BR induction therapy, the overall response rate was 98.6%, with a complete response (CR) rate of 83.3% and a partial response (PR) rate of 15.3%. Only one eMCL patient experienced disease progression during treatment, and only one FL patient experienced a relapse. Even when evaluated using CT alone, the CR rate was 63.9%, considering the differences between PET/CT and CT assessments. The median follow-up duration was 11 months (range: 4-22), with a PFS rate of 96.8% and an OS rate of 100.0%. The main hematologic adverse reactions included grade 3-4 leukopenia (27.8%, with febrile neutropenia observed in 8.3% of patients), grade 3-4 lymphopenia (23.6% ), grade 3-4 anemia (5.6% ), and grade 3-4 thrombocytopenia (4.2% ). The main non-hematologic adverse reactions such as fatigue, nausea/vomiting, rash, and infections occurred in less than 20.0% of patients.Conclusion:Within the scope of this clinical trial conducted in China, the BR regimen demonstrated efficacy and safety in treating newly diagnosed B-iNHL and eMCL patients.

Objective:To evaluate the relationship between the second messenger cyclic GMP-AMP (cGAS)-cyclic GMP-AMP receptor stimulator of interferon genes (STING) signaling pathway and ferritinophagy in the early stage of cerebral ischemia-reperfusion (I/R) in mice.Methods:Twenty-four clean-grade healthy male C57BL/6 mice, aged 6-8 weeks, weighing 21-25 g, were divided into 4 groups ( n=6 each) using a random number table method: sham group, cerebral I/R injury group (CIRI group), cerebral I/R injury + cGAS inhibitor group (CIRI + RU group), and cerebral I/R injury + cGAS inhibitor + overexpressed nuclear receptor coactivator 4 (NCOA4) group (MCAO + RU + LV-NCOA4 group). The model of cerebral I/R injury was developed using the middle cerebral artery occlusion (MCAO) in anesthetized animals.In CIRI+ RU group, cGAS inhibitor 5 mg/kg was intraperitoneally injected at 10 min before reperfusion.In CIRI+ RU+ LV-NCOA4 group, NCOA4-overexpressing lentivirus (1×10 9 TU/ml) 2 μl was injected into the ventricle at 7 days before MCAO, and the other operations were the same as those previously described in CIRI+ RU group.After 6 h of reperfusion, the neurological function deficits were assessed and scored, then the mice were sacrificed, and brains were removed for determination of the cerebral infarct size (by TTC method), MDA content (by TBA method), activity of SOD (by WST-1 method), and expression of cGAS, STING, NCOA4, ferritin, and microtubule-associated protein 1 light chain 3B (LC3B) (by Western blot). Results:Compared with Sham group, the neurological function deficit score and cerebral infarct size were significantly increased, SOD activity was decreased, MDA content was increased, the expression of cGAS, STING, NCOA4 and LC3B was up-regulated, and the expression of ferritin was down-regulated in CIRI group ( P<0.05). Compared with CIRI group, the neurological function deficit score and cerebral infarct size were significantly decreased, SOD activity was increased, MDA content was decreased, the expression of cGAS, STING, NCOA4 and LC3B was down-regulated, and the expression of ferritin was up-regulated in CIRI+ RU group ( P<0.05). Compared with CIRI+ RU group, the neurological function deficit score and cerebral infarct size were significantly increased, SOD activity was decreased, MDA content was increased, the expression of cGAS, STING, NCOA4 and LC3B was up-regulated, and the expression of ferritin was down-regulated in CIRI group ( P<0.05), and no significant change was found in the expression of cGAS and STING in CIRI+ RU+ LV-NCOA4 group ( P>0.05). Conclusions:The cGAS-STING signaling pathway can promote the over-activation of ferritinophagy, enhance oxidative stress, and thus induce early CIRI in mice.

Cabozantinib, mainly targeting cMet and vascular endothelial growth factor receptor 2, is the second-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, the lower response rate and resistance limit its enduring clinical benefit. In this study, we found that cMet-low HCC cells showed primary resistance to cMet inhibitors, and the combination of cabozantinib and mammalian target of rapamycin (mTOR) inhibitor, rapamycin, exhibited a synergistic inhibitory effect on the in vitro cell proliferation and in vivo tumor growth of these cells. Mechanically, the combination of rapamycin with cabozantinib resulted in the remarkable inhibition of AKT, extracellular signal-regulated protein kinases, mTOR, and common downstream signal molecules of receptor tyrosine kinases; decreased cyclin D1 expression; and induced cell cycle arrest. Meanwhile, rapamycin enhanced the inhibitory effects of cabozantinib on the migration and tubule formation of human umbilical vascular endothelial cells and human growth factor-induced invasion of cMet inhibitor-resistant HCC cells under hypoxia condition. These effects were further validated in xenograft models. In conclusion, our findings uncover a potential combination therapy of cabozantinib and rapamycin to combat cabozantinib-resistant HCC.
Anilides/pharmacology* ; Animals ; Carcinoma, Hepatocellular/drug therapy* ; Cell Line, Tumor ; Cell Proliferation ; Endothelial Cells/metabolism* ; Humans ; Liver Neoplasms/drug therapy* ; Pyridines/pharmacology* ; Sirolimus/pharmacology* ; Xenograft Model Antitumor Assays

Objective:To evaluate the role of B/glycogen synthase kinase-3β (Akt/GSK-3β) signaling pathway in interleukin-4 (IL-4)-induced reduction of cerebral ischemia-reperfusion (I/R) injury in mice and the relationship with autophagy.Methods:Forty clean-grade healthy male Balb/c mice, aged 10-12 weeks, weighing 20-25 g, were divided into 4 groups ( n=10 each) using a random number table method: sham operation group (group S), cerebral I/R group (group IR), IR plus IL-4 group, and IR plus IL-4 plus Akt inhibitor LY294002 group (IR+ IL-4+ LY group). Cerebral I/R was induced by 60 min middle cerebral artery occlusion followed by 24 reperfusion in anesthetized mice.IL-4 compound solution 0.2 ml was intraperitoneally given at 30 min before establishing the model in group IL-4.IL-4 compound solution 0.2 ml was intraperitoneally given at 30 min before establishing the model, and LY294002 15 nmol/kg was simultaneously injected via the tail vein in group IR+ IL-4+ LY.Neurological function was assessed and scored at 24 h of reperfusion, and then animals were sacrificed and brains removed for determination of cerebral infarct size (by TTC assay), cell apoptosis, autophagosome count (with transmission electron microscope), levels of superoxide dismutase (SOD), malondialdehyde (MDA) and reactive oxygen species (ROS) (using colorimetric assay), phosphorylation of Akt and GSK-3β, expression of LC3 and Beclin-1 (by Western blot). The apoptosis index and LC3Ⅱ/LC3Ⅰ ratio were calculated. Results:Compared with Sham group, the neurological scores, cerebral infarct size and apoptosis index were significantly increased, the SOD activity in brain tissues was decreased, levels of MDA and ROS were increased, phosphorylation of Akt and GSK-3β was decreased, and LC3Ⅱ/LC3Ⅰ ratio, Beclin-1 expression and autophagosome count were increased in the other three groups ( P<0.05). Compared with IR group, the neurological scores, cerebral infarct size and apoptosis index were significantly decreased, the SOD activity in brain tissues was increased, levels of MDA and ROS were decreased, phosphorylation of Akt and GSK-3β was increased, and LC3Ⅱ/LC3Ⅰ ratio, Beclin-1 expression and autophagosome count were decreased in IR+ IL-4 group ( P<0.05), and no significant change was found in the parameters mentioned above in IR+ IL-4+ LY group ( P>0.05). Compared with IR+ IL-4 group, the neurological scores, cerebral infarct size and apoptosis index were significantly increased, the SOD activity in brain tissues was decreased, levels of MDA and ROS were increased, phosphorylation of Akt and GSK-3β was decreased, and LC3Ⅱ/LC3Ⅰ ratio, Beclin-1 expression and autophagosome count were increased in IR+ IL-4+ LY group ( P<0.05). Conclusion:IL-4 can inhibit cell autophagy through activating Akt/GSK-3β signaling pathway and thus reduces cerebral I/R injury in mice.

Objective:To study the orthopedic treatment strategy for hemophilia complicated with musculoskeletal disorders as well as the peri-operative consumption of clotting factor.Methods:Total 338 orthopedic surgeries were performed for 261 patients, average age of 30.6 y (6-65 y) , with hemophilia between January 1996 and December 2019 at our institute. Two hundred and twenty-six patients presented with bleeds within the joints. Sixty-one patients presented with intramuscular bleeds, 45 presented with hemophilic pseudotumors, and six presented with miscellaneous complaints. Strategy of clotting factor replacement therapy was designed as per differences in the level of the operation procedure. Information regarding clinical manifestation, operative strategy, clotting factor consumption, and re-operation for complications was retrospectively recorded. The costs for multiple joint procedure and single joint procedure were studied.Results:We found that 270 of the 338 surgical procedures were major surgical procedures (79.9%) . There were 203 procedures of joint arthroplasty (60%) . Fourteen patients underwent reoperations for local recurrence (4.2%) . The average factor Ⅷ consumption before the surgery was 44.4 ± 8.1 IU/kg. The average FⅧ consumption within postoperative 2 weeks was 40 962 IU (647±177 IU/kg) . Seven type A hemophilic patients developed F Ⅷ inhibitor following the surgical procedure, with an average level of 13.7±11.2 BU/mL. Sixty-eight patients underwent multiple joint procedures under one anesthesia session (26%) . There was no significant difference in the factor consumption between the multiple joint procedure and single joint procedure.Conclusions:Surgical treatment was found to be effective for hemophilic arthropathy and lesion of the musculoskeletal apparatus, with the clotting factor replacement therapy. Multiple joint procedures under one anesthesia were more cost effective for patients with hemophilia, with less factor consumption than staged single joint procedure.

OBJECTIVE： To investigate and analyze the current status and existing problems of Chinese patent medicine instructions in outpatient department of our hospital， and to provide suggestions for the improvement of Chinese patent medicine instructions. METHODS： A total of 435 copies of Chinese patent medicines instructions using in the outpatient pharmacy of our hospital were collected in 2018. The labeling of usage and dosage of the instructions and other items were not clear and missing items were analyzed statistically. RESULTS： In 435 copies of drug instructions， unclear usage and dosage included usage and dosage were marked only in grams or milliliters （54 kinds， 12.4％）； daily dosage was not clear （165 kinds， 37.9％）； the words “or follow the doctor’s advice” were involved in drug instructions （86 kinds， 19.8％）； the labeling of usage and dosage for special population were not clear （34 kinds， 7.8％）； medication time was not labeled （365 kinds， 83.9％）. Unclear labeling of other items included unclear drug interaction （121 kinds， 27.8％）， unclear matters needing attention （12 kinds， 2.8％）， unclear ADR （307 kinds， 70.6％）， unclear contraindications （257 kinds， 59.1％） and unclear indications （1 kind， 0.2％）. The missing items included that drug dosage for special population （41 kinds， 94.5％）， pharmacological and toxicological items （305 kinds， 70.1％）， clinical trial data （395 kinds， 90.8％）， storage temperature label （377 kinds， 86.7％）. CONCLUSIONS： Missing items and unclear information on safe medication are common in Chinese patent medicine instructions， which need to be standardized and perfected in order to provide reference for rational drug use and guarantee the safety of drug use in patients.

Whether habit stimulation is effective in DOC patient arousal has not been reported. In this paper, we analyzed the responses of DOC patients to habit stimulation. Nineteen DOC patients with alcohol consumption or smoking habits were recruited and 64-channel EEG signals were acquired both at the resting state and at three stimulation states. Wavelet transformation and nonlinear dynamics were used to extract the features of EEG signals and four brain lobes were selected to investigate the degree of EEG response to habit stimulation. Results showed that the highest degree of EEG response was from the call-name stimulation, followed by habit and music stimulations. Significant differences in EEG wavelet energy and response coefficient were found both between habit and music stimulation, and between habit and call-name stimulation. These findings prove that habit stimulation induces relatively more intense EEG responses in DOC patients than music stimulation, suggesting that it may be a relevant additional method for eliciting patient arousal.
Adult ; Alcohol Drinking ; physiopathology ; Brain ; physiopathology ; Consciousness Disorders ; physiopathology ; therapy ; Electroencephalography ; Female ; Habits ; Humans ; Male ; Middle Aged ; Music ; Names ; Nonlinear Dynamics ; Physical Stimulation ; Rest ; Smoking ; physiopathology ; Speech ; Treatment Outcome ; Wavelet Analysis

Objective To evaluate the role of protein kinase B∕glycogen synthase kinase-3 beta (Akt∕GSK-3β) signaling pathway in trichostatin-A (TSA)-induced reduction of cerebral ischemia-reperfu-sion ( I∕R) injury in mice. Methods Forty pathogen-free healthy male Balb∕c mice, weighing 18-22 g, were divided into 4 groups ( n=10 each) using a random number table method: sham operation group ( S group), I∕R group, TSA group and TSA plus Akt inhibitor LY294002 group (TL group). Cerebral I∕R was induced by middle cerebral artery occlusion ( 1-h ischemia followed by 24-h reperfusion) . TSA 5 mg∕kg was intraperitoneally injected for 3 consecutive days before establishing the model in TSA group. TSA 5 mg∕kg was intraperitoneally injected for 3 consecutive days before establishing the model, and LY29400215 nmol∕kg was injected via the caudal vein at 30 min before establishing the model. Brain tissues were ob-tained at 24 h of reperfusion for determination of cerebral infarct size ( by TTC ) , activities of superoxidedismutase ( SOD) and reactive oxygen species ( ROS) and malondialdehyde ( MDA) content ( by colorimet-ric assay), cell apoptosis (by TUNEL) and expression of Akt, phosphorylated Akt (p-Akt), GSK-3βand phosphorylated GSK-3β ( p-GSK-3β) . The apoptosis index and ratios of p-Akt∕Akt and p-GSK-3β∕GSK-3β were calculated. Results Compared with S group, the cerebral infarct size was significantly in-creased, the activity of SOD in brain tissues was decreased, the MDA content and ROS activity in brain tissues and apoptosis index were increased, and the ratios of p-Akt∕Akt and p-GSK-3β∕GSK-3β were de-creased in I∕R group ( P<0. 05) . Compared with I∕R group, the cerebral infarct size was significantly de-creased, the activity of SOD in brain tissues was increased, the MDA content and ROS activity in brain tis-sues and apoptosis index were decreased, and the ratios of p-Akt∕Akt and p-GSK-3β∕GSK-3β were de-creased in TSA group ( P<0. 05) . Compared with TSA group, the cerebral infarct size was significantly in-creased, the activity of SOD in brain tissues was decreased, the MDA content and ROS activity in brain tissues and apoptosis index were increased, and the ratios of p-Akt∕Akt and p-GSK-3β∕GSK-3β were de-creased in TL group ( P<0. 05) . Conclusion The mechanism by which TSA attenuates cerebral I∕R injury is related to activating Akt∕GSK-3β signaling pathway in mice.

Objective To evaluate the imaging features and causes of cerebral cortical laminar necrosis(CLN) in children,to improve understanding this sign.Methods The imaging and clinical data of 33 children diagnosed with CLN were analyzed retrospectively.The imaging features of CT and MRI were summarized and compared according to their etiologies.Results Children cerebral CLN involved multiple lobes of bilateral hemicerebrum, including the cortical region, subcortical region and basal ganglia region, and linear or gyral shape,patchy shape and punctate shape abnormal density or signal were demonstrated.The typical imaging features were high-signal intensity over the lateral cortical surfaces or along the gyri on T1WI and FLAIR.Diffusion weighted imaging(DWI) showed high signal with restricted diffusion on acute-stage, and Gd-DTPA enhancement demonstrated linear or gyrate enhanced appearance on early-stage.The extent of CLN of cerebral infarction was relatively limited.Acute anoxic encephalopathy showed an early imaging change and extensive involvement.While chronic anoxic encephalopathy and inflammatory encephalopathy showed a late imaging change and a longer existence.Conclusion Children cerebral CLN may have various causes and imaging features,and show characteristic chronological signal changes on imaging studies.The different causes result in the different patterns for CLN in distribution and time distribution.

Objective To improve the diagnostic level of the holoprosencephaly (HPE) disease in children by imaging analysis. Methods From May 2007 to August 2015, 14 cases of HPE in children were collected (7 males and 7 females, aged 2 days to 8 years, mean 14 months). Two cases were showed as sucking difficulty and convulsions frequently after birth. Mental and motor development defects were showed in 12 cases, in which 4 cases were associated with cleft lip and palate deformities and 1 case with microcephaly. Of the 14 cases, CT scan was performed in 7 cases and MRI scan in 7 cases. Results All 14 cases were consistent with the diagnostic criteria of HPE according to the imaging findings of literatures reviewed. Four cases were showed as semilobar HPE, 8 cases were lober HPE, and 2 cases were middle interhemispheric fusion variant. There were thirteen cases were associated with corpus callosum agenesis, including 2 cases were with heterotopic gray matter. Putamen and caudate partia fusion were showed in 6 cases, and thalamus partia fusion in 3 cases. One case was associated with schizencephaly, 4 cases were palate malformation, one case was microcephaly, and one case was cerebellar hypoplasia. Conclusion CT and MRI scan could contribute to diagnosis and classification of holoprosencephaly, and determine whether HPE was associated with other neurological abnormalities. MRI scan should be the first choice for HPE diagnosis.