Ischemic stroke is a common cerebrovascular disease， characterized by hypoxia and nutritional deficiency in local brain tissue due to insufficient blood supply. Angiogenesis， the formation of new vascular networks on the basis of existing blood vessels， is of great significance for increasing blood flow in the ischemic area of brain tissue， restoring blood and oxygen supply， and improving disease prognosis. This complex process is regulated by various factors， including cytokines， growth factors， and signaling pathways. Among these， the phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt） signaling pathway is considered a key regulatory pathway. It not only plays an important role in anti-apoptosis and promoting cell survival， but also regulates cell growth， differentiation， migration， and survival， while deeply participating in the regulation of angiogenesis. Chinese medicine offers unique advantages with its multi-component， multi-target， and multi-pathway approach in the treatment of stroke， showing significant potential in treating ischemic stroke. In recent years， it has been found that Chinese medicine can promote angiogenesis after ischemic stroke through the PI3K/Akt signaling pathway. This paper focuses on the PI3K/Akt signaling pathway as the research entry point， and explores in-depth the mechanisms by which Chinese medicine monomers， active components， extracts， derivatives， drug pairs， and Chinese medicine compounds promote angiogenesis after ischemic stroke. The research discusses the regulation of microRNAs （miRNA）， endothelial progenitor cells （EPCs）， apoptosis， upstream pro-angiogenic factors， and downstream target molecules. The paper also elaborates on related research progress， aiming to reveal how Chinese medicine can exert its potential utility in ischemic stroke treatment through this key signaling pathway， providing a theoretical basis for clinical treatment.

Ischemic stroke is a common cerebrovascular disease， characterized by hypoxia and nutritional deficiency in local brain tissue due to insufficient blood supply. Angiogenesis， the formation of new vascular networks on the basis of existing blood vessels， is of great significance for increasing blood flow in the ischemic area of brain tissue， restoring blood and oxygen supply， and improving disease prognosis. This complex process is regulated by various factors， including cytokines， growth factors， and signaling pathways. Among these， the phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt） signaling pathway is considered a key regulatory pathway. It not only plays an important role in anti-apoptosis and promoting cell survival， but also regulates cell growth， differentiation， migration， and survival， while deeply participating in the regulation of angiogenesis. Chinese medicine offers unique advantages with its multi-component， multi-target， and multi-pathway approach in the treatment of stroke， showing significant potential in treating ischemic stroke. In recent years， it has been found that Chinese medicine can promote angiogenesis after ischemic stroke through the PI3K/Akt signaling pathway. This paper focuses on the PI3K/Akt signaling pathway as the research entry point， and explores in-depth the mechanisms by which Chinese medicine monomers， active components， extracts， derivatives， drug pairs， and Chinese medicine compounds promote angiogenesis after ischemic stroke. The research discusses the regulation of microRNAs （miRNA）， endothelial progenitor cells （EPCs）， apoptosis， upstream pro-angiogenic factors， and downstream target molecules. The paper also elaborates on related research progress， aiming to reveal how Chinese medicine can exert its potential utility in ischemic stroke treatment through this key signaling pathway， providing a theoretical basis for clinical treatment.

Objective To investigate the effect of electroacupuncture preconditioning on microglia polarization in rats after cerebral ischemia reperfusion(IR)injury and explore the role of tyrosine kinase 2(J AK2)/signal transducer and activator of transcription 3(STAT3)pathway in the process.Methods Forty-five clean-grade healthy male Sprague-Dawley rats were randomly and equally divided into sham operation group,IR group and electroacupuncture preconditioning group.Rat model of IR injury was induced with thread occlusion of the internal carotid artery.Before modeling,electroacupuncture preconditioning was applied to Baihui acupoint for 5 consec-utive days in the preconditioning group,and exposure of the cervical blood vessels were inflicted in the sham-operation group.At 24 h after reperfusion,the severity of neurological deficit was observed by modified neurological deficit score(mNSS),and the cerebral infarct volume was observed by TTC staining.Western blotting was used to detect the protein levels of classical acti-vated type(M1)marker inducible nitric oxide synthase(iNOS),alternative activated type(M2)marker arginase 1(Arg-1),JAK2 and p-JAK2,and STAT3 and p-STAT3,and q-PCR was applied to detect the mRNA expression of iNOS and Arg-1.The expression of TNF-α and IL-10 was measured by ELISA.Results Compared with the sham operation group,the mNSS,infarct vol-ume,protein levels of p-JAK2/JAK2,p-STAT3/STAT3,protein and mRNA levels of iNOS and Arg-1,and expression of TNF-α and IL-10 were significantly increased in the IR and electroacu-puncture preconditioning groups(P＜0.01).The preconditioning group had obviously lower mNSS,smaller infarct volume,decreased protein levels of p-JAK2/JAK2,p-STAT3/STAT3,re-duced protein and mRNA levels of iNOS,and declined TNF-α expression,but elevated expression of Arg-1 at protein(2.0±0.2 vs 1.5±0.1)and mRNA(4.2±0.8 vs 3.1±0.3)levels and increased IL-10 expression(49.1±7.1 pg/mg vs 27.9±5.9 pg/mg)when compared with the IR group(P＜0.01).Conclusion Electroacupuncture preconditioning can promote the polarization of microglia to M2 and inhibit the polarization of microglia to M1 after cerebral IR injury,which may be relat-ed to the inhibition of JAK2/STAT3 pathway.

Objective To calculate the pre-stretching of the microscopic components of the aortic wall under physiological homeostasis by considering a three-dimensional(3D)residual stress field.Methods The aortic wall was simplified into a double-layer ideal circular tube,and the 3D residual stress field of the vascular wall was calculated based on a 3D expansion angle experiment.Then,the in vivo stress distribution characteristics under mean blood pressure and the pre-stretching of each microscopic constituent of the vascular wall under a physiologically steady state were obtained.The inverse problem was constructed according to the internal pressure-radius relationship measured in vivo.Physiological homeostasis of the aorta was considered the reference state,and inversion identification of the material parameters of the aorta in vivo was realized while integrating the three residual stress fields.Results When residual stress was not considered,the mean stress of the middle membrane was greater than that of the outer membrane.When residual stress was considered,the outer membrane bore more stress than the middle membrane,and the outer membrane protected the middle membrane.The pre-stretching of the middle film with residual stress was lower than that without residual stress,whereas the pre-stretching of the outer film was higher than that without residual stress.Moreover,the pre-stretching of the outer membrane collagen fibers was greater than that of the middle membrane collagen fibers.The in vivo calculations of the material parameters of the aorta were performed using physiological homeostasis as the reference configuration,and the proportion of each component was consistent with the experimental results.However,the proportion of elastin in the outer membrane was significantly overestimated when the non-stress configuration was used as the initial configuration,which was inconsistent with the experimental results.Conclusions Residual stress significantly influences the pre-stretching and physiologically steady mechanical states of the microscopic components of the aortic wall.Therefore,it is necessary to fully consider the influence of residual stress to establish the physiologically steady state of the aortic wall accurately.Furthermore,it is also necessary to fully consider the 3D characteristics and layer specificity of residual stress in the in vivo identification of material parameters.

Effectiveness of tumor immunotherapy is largely evaluated based on mouse models.Due to species differences,traditional mouse models cannot mirror condition of immune response in human body,resulting in vast majority of mouse-based achievements are not applicable to humans.In recent years,with emergence of immunodeficient mice and its improvement,humanized immune system mouse models based on immunodeficient mice are expected to help us overcome this barrier.We highlight the latest advances and barriers in generation of immunodeficient mice and humanized mouse models,as well as application of humanized mouse models on tumor immune,with aim of providing a guide for their application to tumor immunotherapy studies with potential for clinical translation.

Objective:To investigate the effects of mild hypothermia on microglia polarization and janus kinase 2/signal transduction and transcriptional activation factor 3 (JAK2/STAT3) signaling pathway during cerebral ischemia-reperfusion (I/R) in rats.Methods:Forty-five clean-grade healthy male Sprague-Dawley rats, aged 8 weeks, weighing 260-280 g, were divided into 3 groups ( n=15 each) by the random number table method: sham operation group (S group), cerebral I/R group (I/R) and mild hypothermia group (H group). In I/R group and H group, cerebral I/R was induced by middle cerebral artery occlusion using a nylon thread in anesthetized animals, the nylon thread was removed to restore the perfusion after 2 h of occlusion, and the rectal temperature was maintained at 36-37 ℃ during the period. Group H was wiped with 75% alcohol for 3 h starting from the time point immediately after reperfusion, and the rectal temperature was maintained at 32-33℃. Modified neurological severity score (mNSS) was evaluated at 24 h of reperfusion. Animals were then sacrificed for determination of the cerebral infarct size (using TTC staining), expression of M1 marker inducible nitric oxide synthase (iNOS), M2 marker arginase 1(Arg-1), phosphorylated JAK2(p-JAK2)and phosphorylated STAT3(p-STAT3)(by Western blot), expression of iNOS mRNA and Arg-1 mRNA (by quantitative polymerase chain reaction), and contents of interleukin-6 (IL-6) and IL-10 (by enzyme-linked immunosorbent assay). Results:Compared with group S, mNSS and cerebral infarct size were significantly increased, the expression of iNOS, Arg-1 protein and mRNA in cerebral ischemic penumbral zone was up-regulated, and the p-JAK2/JAK2 ratio, p-STAT3/STAT3 ratio, and contents of IL-6 and IL-10 were increased in the other two groups ( P<0.05). Compared with I/R group, mNSS and cerebral infarct size were significantly decreased, the expression of iNOS protein and mRNA in cerebral ischemic penumbral zone was down-regulated, the expression of Arg-1 and mRNA was up-regulated, and the p-JAK2/JAK2 ratio, p-STAT3/STAT3 ratio and IL-6 content were decreased, and the IL-10 content was increased in group H ( P<0.05). Conclusions:Mild hypothermia can promote the polarization shift of microglia from M1 to M2 phenotype during cerebral I/R and inhibit the central inflammatory responses, and the mechanism may be related to inhibition of JAK2/STAT3 signaling pathway in rats.

Objective:To evaluate the effect of selective cerebral mild hypothermia on small ubiquitin-like modifier 2/3 (SUMO2/3) modification of dynamin-related protein 1 (Drp1) in a rat model of cerebral ischemia-reperfusion (I/R).Methods:Sixty clean-grade healthy male Sprague-Dawley rats, aged 6-8 weeks, weighing 240-260 g, were divided into 4 groups ( n=15 each) using a random number table method: sham operation group (S group), cerebral I/R group (I/R group), selective cerebral mild hypothermia group (HT group) and normal temperature group (NT group). The operation was performed under the monitoring of cerebral temperature and rectal temperature.Only the cervical blood vessels were exposed in S group, while focal cerebral I/R was induced by 2 h middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion in anesthetized animals in the other three groups.In HT group and NT group, 4 and 37 ℃ normal saline was perfused through the left internal carotid artery at a rate of 80 ml·kg -1·h -1 for 15 min, respectively. Modified neurological severity score (mNSS) was assessed at 24 h of reperfusion. Then the rats were sacrificed under deep anesthesia, brains were removed, brain tissues were obtained for determination of the percentage of cerebral infarct size (by TTC staining), and the ischemic penumbra tissues in the cerebral cortex were removed for examination of the ultra-structural changes of mitochondria (with a transmission electron microscope) and for determination of the SUMO2/3 modification of Drp1 (by CO-IP), expression of total Drp1 (T-Drp1) and total cytochrome c (T-Cytc) (by Western blot), and expression of mitochondrial outer membrane Drp1 (M-Drp1) and cytoplasmic Cytc (C-Cytc) (by Western blot) after isolation of mitochondria and cytoplasm. Results:Compared with S group, the mNSS and percentage of cerebral infarct size were significantly increased, the expression of M-Drp1, T-Drp1, C-Cytc and T-Cytc was up-regulated, and SUMO2/3 modification of Drp1 in ischemic penumbra area was increased ( P<0.05), the fragmentation of mitochondria was aggravated, and cristae rupture and vacuolation were obvious in the other three groups. Compared with I/R group, the mNSS and percentage of cerebral infarct size were significantly decreased, the expression of M-Drp1, T-Drp1, C-Cytc and T-Cytc was down-regulated, SUMO2/3 modification of Drp1 was increased ( P<0.05), the fragmentation of mitochondria was significantly attenuated, and cristae rupture and vacuolation were weakened in HT group. There were no significant differences in these detection parameters between NT group and I/R group ( P>0.05). Conclusions:The mechanism by which selective cerebral mild hypothermia alleviates the cerebral I/R injury is related to increased SUMO2/3 modification of Drp1, decreased binding of Drp1 to mitochondrial outer membrane, and reduced mitochondrial excessive fission in rats.

Objective:To evaluate the effect of sodium bicarbonate Ringer′s solution on acute kidney injury(AKI) following laparoscopic hepatectomy in elderly patients.Methods:A total of 362 American Society of Anesthesiologists Physical Status classification Ⅱ or Ⅲ elderly patients, aged 65-79 yr, with body mass index of 18-28 kg/m 2, scheduled for elective laparoscopic hepatectomy, were divided into 2 groups( n=181 each) using a random number table method: bicarbonate Ringer′s solution group(BR group) and lactated Ringer′s solution group(LR group). Bicarbonate Ringer′s solution and lactated Ringer′s solution were intravenously infused in BR group and LR group, respectively. All operations were performed under general anesthesia combined with abdominal fascia block, and the methods of controlled low central venous pressure and intermittent hepatic inflow occlusion were applied to reduce intraoperative bleeding. Radial artery blood samples were collected for blood gas analysis at 5 min before anesthesia induction(T 0), 20 min after occluding liver hilus(T 1), 10 min after hepatectomy and hemostasis(T 2), at the end of surgery(T 3) and at postanesthesia care unit discharge(T 4), and lactate value(Lac) was recorded. Blood samples from cubital vein were collected on admission to hospital(T A) and at 24(T 24) and 48 h after operation(T 48) for determination of serum creatinine(Cr) concentrations. Doppler-based renal resistive index(RRI) was measured at T A, T 4, T 24 and T 48. The incidence of AKI was calculated within 48 h after operation according to the Kidney Disease: Improving Global Outcomes criteria in 2012 for Cr concentration. Adverse reactions(such as nausea and vomiting) and complications(such as incision infection) within 48 h after operation were recorded. Results:Compared with the baseline at T 0, Lac concentrations were significantly increased at T 1-4 in both groups( P<0.01). Cr concentrations were significantly increased at T 24 and T 48, and RRI was increased at T 4, T 24 and T 48 than at T A in both groups( P<0.01). Compared with group LR, the incidence of AKI within 48 h after operation, Lac concentrations at T 3, 4, Cr concentrations at T 24 and T 48, and RRI at T 4, T 24 and T 48 were significantly decreased in group BR( P<0.05 or 0.01). There was no significant difference in the incidence of nausea, vomiting, incision infection, delirium, bile leakage and pulmonary infection within 48 h after operation among the two groups( P>0.05). Conclusions:Sodium bicarbonate Ringer′s solution can decrease the development of AKI following laparoscopic hepatectomy in elderly patients.

Cancer is one of the major fatal diseases that seriously threaten human health， and its burden needs to be solved urgently. Health technology assessment （HTA） can provide scientific evidence-based basis for cancer diagnosis， treatment， prevention and related policy formulation. Cost-utility analysis is the gold standard for economic evaluation in HTA， and the accurate measurement of its health utility is one of the key elements to determine the accuracy of its results. This article focuses on systematic introduction of direct measures， multi-attribute health utility scales， and mapping methods in the field of cancer measurement and reviews their applications in cancer patients. Among them， direct measures are complex， costly， and require a high level of subject knowledge； multi-attribute health utility measures are currently the preferred method for measuring health utility in cancer patients； with the continuous development and refinement of disease-specific utility measures in multi-attribute health utility instruments， the mapping method may gradually decrease in future applications. This paper can provide a reference for the selection of health utility measurement tools for HTA in the field of cancer， and provide evidence-based basis for optimizing resource allocation and policy formulation in the field of cancer.

Objective:To evaluate the role of glutathione S-transferase μ1 (GSTM1) expression in mild hypothermia-induced mitigation of cerebral ischemia-reperfusion (I/R) injury and the relationship with microglial polarization.Methods:Eighty clean-grade healthy male Sprague-Dawley rats, aged 8 weeks, weighing 260-280 g, were divided into 4 groups ( n=20 each) using a random number table method: sham operation group (S group), cerebral I/R group (I/R group), mild hypothermia group (H group), and GSTM1 inhibitor + mild hypothermia group (IH group). The rat model of cerebral I/R injury was prepared using the filament occlusion method. The filament was removed to restore blood flow after the left middle cerebral artery was blocked for 2 h, and the rats′ brain and rectal temperature were maintained at 36-37 ℃ during the period. The vessels were only isolated and ligated without occlusion in S group. In H group, the entire body was wiped with 75% ethanol immediately after removing the filament, and the brain and rectal temperatures were maintained at 32-33 ℃ for 3 h, and the other procedures were the same as those previously described in I/R group. In IH group, GSTM1 inhibitor itaconic acid 8.6 mg/kg was intraperitoneally injected at 24 and 1 h before developing the model, and the other procedures were the same as those previously described in H group. Neurological deficits were evaluated using a modified neurological severity score (mNSS) at 24 h of reperfusion, and then the animals were sacrificed and the brains were removed for observation of cerebral infarction (by TTC staining) and for determination of the expression of GSTM1, M1-type microglial marker inducible nitric oxide synthase (iNOS), and M2-type microglial marker arginase-1 (Arg-1) (by Western blot), expression of GSTM1, iNOS and Arg-1 mRNA (quantitative real-time polymerase chain reaction) and contents of interleukin-6 (IL-6), IL-10, tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-β) (by enzyme-linked immunosorbent assay). Results:Compared with S group, the mNSS and percentage of cerebral infarct size were significantly increased, and the expression of iNOS and Arg-1 protein and mRNA was up-regulated, the expression of GSTM1 and mRNA was down-regulated, and the contents of IL-6, TNF-α, IL-10 and TGF-β were increased in the other three groups ( P<0.05). Compared with I/R group and IH group, the mNSS and percentage of cerebral infarct size were significantly decreased, and the expression of iNOS protein and mRNA was down-regulated, the expression of Arg-1 protein and mRNA and GSTM1 was up-regulated, the contents of TNF-α and IL-6 were decreased, and the contents of TGF-β and IL-10 were increased in H group ( P<0.05). Conclusions:Up-regulated expression of GSTM1 is involved in mild hypothermia-induced mitigation of cerebral I/R injury, which is associated with inhibition of microglial polarization toward the M1 phenotype and promotion of polarization toward the M2 phenotype.