Objective To compare the efficacy, safety, and survivability of TCbHP versus AC-THP in the neoadjuvant therapy of HER2-positive breast cancer in real-world. Methods Clinical data of patients with HER2 positive breast cancer, who have received TCbHP or AC-THP as neoadjuvant therapy and completed surgery in 11 third-class hospitals in various cities of Hebei Province, were retrospectively collected.The total pathological complete remission (tpCR) rate, the incidence of grade 3 or higher adverse reactions and the completion rate of the given approaches were compared. Results A total of 110 cases were collected, including 78 cases in the TCbHP group and 32 cases in the AC-THP group.The tpCR rate of the TCbHP group was higher than that of the AC-THP group, but the difference was not statistically significant (64.10% vs. 56.25%, P=0.441).No significant difference was found in the breast pathologic complete response (bpCR) and axillary pathologic complete response (apCR) rates between the TCbHP group and the AC-THP group (70.51% vs. 56.25%, P=0.150;78.21% vs. 84.38%, P=0.462).Exploratory analysis revealed that the tpCR rate of the TCbHP group was significantly higher than that of the AC-THP group in patients with HR-positive breast cancer (51.11% vs. 22.22%, P=0.036).As for the patients with HR-negative breast cancer, the tpCR rate of the AC-THP group tended to be higher than that of the TCbHP group (100% vs. 81.82%, P=0.088).The incidence of grade 3 or higher adverse reactions in the TCbHP group was slightly higher than that in the AC-THP group (12.82% vs. 9.38%, P=0.753).No deaths occurred in the whole group.Moreover, no significant difference was observed in the completion rate of the given approaches between the TCbHP group and the AC-THP group (92.31% vs. 90.63%, P=0.718). Conclusion In real-world clinical practice, the neoadjuvant therapy of TCbHP and AC-THP are effective, safe, and well tolerated among patients with HER2-positive breast cancer.The tpCR rate between the two approaches was not significantly different.The AC-THP regimen could also be considered as one of the optimal regimens for HER2-positive breast cancer in neoadjuvant therapy.

Objective: To investigate the anti-tumor effect of CTL cells on colon cancer xenograft in nude mice after knocking out the immune check point CTLA-4 by CRISPR/Cas9 technology. Methods: A specific small guide RNA (sgRNA) for CTLA-4 was designed to construct sgRNA/Cas9 plasmid, which was then transfected into CTL using a lentiviral vector to obtain CTL cells with CTLA-4 deletion (CTLA-4 KO CTL). The transfection efficiency of the plasmid and the deletion efficiency of CTLA-4 were verified. BALB/c nude mice were randomly divided into two groups to prophylactically inoculate CTLA-4 KO CTL (experimental group) or CTL (control group); 3 days later, the animals of two groups were inoculated with colon cancer cell line LS174-T to observe the tumor formation rate and tumor formation time. After constructing colon cancer xenograft model in nude mice, the animals were randomly divided into two groups, respectively treated with CTLA-4 KO CTL (experimental group) and CTL (control group) cells to observe the tumor growth volume and survival time of mice. The serum levels of TNF-α and IFN-γ in nude mice were detected. Results: sgRNAwas designed and CRSIPR/Cas9 system with lentivirus as vector was successfully constructed. CTL cells were transfected with the established CRSIPR/ Cas9 system, and the highest transfection efficiency was up to (28.80±0.62)%. After transfection, the deletion efficiency of CTLA-4 was detected by Flow cytometry. The CTLA-4 expression of CTLA-4 KO CTL group was significantly lower than that of CTL group [(0.91±0.25)% vs (42.70±2.72)%, P<0.05]. In prophylactic assay, the formation rate of colon cancer xenografts in the experimental group was significantly lower than that in the control group(33.33%vs100%,P<0.05). In treatment assay, the tumor volume in the experimental group was significantly inhibited compared with the control group ([503±23.9] vs [911.2±51.4] mm3, P<0.05), and the survivaltimeoftheexperimentalgroupwassignificantlyprolonged (mediansurvivaltime:78dvs42d,P<0.05); Moreover, the secretion levels of serumTNF-α([268.93±17.04]pg/mlvs[148.26±20.07]pg/ml,P<0.05) and IFN-γ(315.38±18.67 pg/ml vs 202.92±29.32 pg/ml, P<0.05) in the experimental group were significantly higher than those in the control group. Conclusions: The lentiviral vector CRSIPR/Cas9 system is an effective gene editing method; its successful deletion of CTLA-4 in CTL cells can significantly inhibit the tumor formation rate of colon cancer xenografts in nude mice and enhance the anti-tumor effect of CTLon colon cancer xenografts.

Objective To evaluate the effect of resuscitation with hypertonic sodium chloride hydroxyethyl starch 40 injection (HSH40) mixed with suberoylanilide hydroxamic acid (SAHA) on oxidative stress responses of lung tissues and histone acetylation in a rat model of lethal hemorrhagic shock after entering high altitude for the first time.Methods Forty-five healthy male Wistar rats,aged 3-4 months,weighing 250-300 g,were transported from the breeding area at altitude 1500 m to the experimental area at altitude 3 780 m.The rats were divided into 3 groups (n=15 each) using a random number table:sham operation group (group Sham),hemorrhagic shock group (group HS),and resuscitation with HSH40 mixed with SAHA group (group HSH/SAHA).Lethal hemorrhagic shock was induced by removing 40％ of blood volume from the left femoral artery at a constant speed within 10 min,followed by removing 15％ of blood volume from the right femoral vein at a constant speed within 50 min.Only cannulation was performed,and the rats received no blood letting or resuscitation in group Sham.The animals were resuscitated via the right femoral artery after successful establishment of the model,SAHA 7.5/Kg dissolved in HSH40 4 ml/kg was infused within 5 min in group HSH+SAHA.Immediately before blood letting,immediately after blood letting and at 3 h after resuscitation (at the time of death for the rats survived less than 3 h),arterial blood samples were obtained for blood gas analysis,and pH value,partial pressure of arterial carbon dioxide (PaCO2),partial pressure of arterial oxygen (PaO2) and arterial oxygen saturation (SaO2) were recorded.The rats were sacrificed after blood samples were collected from the abdominal aorta at 3 h after resuscitation (at the time of death for the rats died within 3 h after resuscitation),and lungs were removed for examination of the pathologic changes which were scored (with a light microscope) and for determination of wet to dry weight ratio (W/D ratio),activity of superoxide dismutase (SOD) and content of malondialdehyde (MDA) and expression of histone H3 acetylation at lysine 9 (Ac-H3K9) in lung tissues (by Western blot).Results Compared with group Sham,the lung injury score,W/D ratio and content of MDA were significantly increased,and the activity of SOD was decreased in HS and HSH+SAHA groups,pH value and PaCO2 were significantly decreased and PaO2 and SaO2 were increased immediately after blood letting and at 3 h after resuscitation in group HS,and PaO2 and SaO2 were significantly increased immediately after blood letting and at 3 h after resuscitation,pH value and PaCO2 were decreased immediately after blood letting,and the expression of Ac-H3K9 was up-regulated in group HSH+SAHA (P＜0.05).Compared with group HS,pH value,PaCO2,PaO2 and SaO2 were significantly increased at 3 h after resuscitation,the lung injury score,W/D ratio and content of MDA were decreased,the activity of SOD was increased,and the expression of Ac-H3K9 was up-regulated in group HSH+SAHA (P＜0.05).Conclusion The mechanism by which resuscitation with HSH40 mixed with SAHA exerts lung protection may be related to inhibiting oxidative stress responses and histone acetylation in lung tissues in a rat model of lethal hemorrhagic shock after entering high altitude for the first time.

Objective To investigate the analgesic efficacy of ultrasound?guided adductor canal blockade (ACB)after minor arthroscopic knee surgery. Methods Sixty patients undergone minor arthroscopic knee surgery were randomly divided into group ACB(n=20)and group Control(n=20). All patients received spinal anesthesia. The patients in group ACB received ultrasound?gGuided ACB with 20 ml 0.5% ropivacaine,and patients in group Control received 20 ml saline after the surgery. In addition ,all patients have a basic analgesic regimen with etoricoxib. Visual analogue scales(VAS) during rest and passive movement ,additional analgesic dose and side effects were recorded at 4,8,12,24 h Post?operation. At 24 h post?operation,the numbers of patients who can walk for 5 meters were recorded. Results VAS during rest and movement at 4 h,8 h and 12 h post?operation in group ACB were significantly lower than those in group Control. And all patients could walk 5m at 24 h post?operation. No headache,nausea and vomiting,urinary retention and other adverse reactions were observed in group ACB. There were four patients who received additional analgesic and one patient vomitted. Conclusions Significant analgesic effect of the ACB could be detected after minor arthroscopic knee surgery ,with less reduction in requirements for supplemental opioids.

Objective To explore the pathogenesis of acute lung injury in rats suffering hemorrhagic shock at plateau.Methods Seventy-two male Wistar rats, weighing 280-320 g, were randomized into 6 groups (n=12): sham group (group Sham), hemorrhagic shock for 15 min (group HS15), hemorrhagic shock for 30 min group (group HS30), hemorrhagic shock for 45 min group (group HS45), hemorrhagic shock for 60 min group (group HS60) and 90 min group (group HS90).Hemorrhagic shock model of Wistar rats was reproduced at plateau.The rats were only anesthetized, no shock and were sacrificed after 90 min in group Sham.The other groups were different in bleeding time and then were respectively sacrificed at 15, 30, 45, 60 and 90 min after shock.The pathological changes in the lungs were observed with light microscope.Wet to dry weight ratio (W/D), lung permeability index (LPI), myeloperoxidase (MPO) activity, malondialdehyde (MDA) and superoxide dismutase (SOD) in lung were measured.Enzyme-linked immunosorbent assay was used to detect the TNF-α and IL-10 in lung tissue, the expression and distribution of claudin-3 and claudin-4 in lung tissue was verified by immunohistochemistry method.Results Compared with group Sham, shock causes acute lung injury at different degree, and was positively correlated with the duration of shock, during the period of 15 to 30 min, it merely rendered a slight change in lung W/D, LPI, MPO, MDA, TNF-α, T-SOD and IL-10.Subsequently, along with time prolonged, lung W/D, neutrophils in BALF, LPI, MPO, MDA, TNF-α were significantly elevated, while T-SOD and IL-10 were notably reduced (P<0.05).Immunohistochemical results showed that claudin-3 and claudin-4 expression in lung epithelial cells and endothelial cells expressed at low levels and dislocated (P<0.05).Conclusion After a short time compensatory lesions, the change of rats' hemodynamic stability suffering severe hemorrhagic shock showed a spiral downward.Along with the extension of the shock, hemorrhagic shock at plateau results into the disturbance of inflammatory response and oxidative stress, the loss of claudin-3 and claudin-4 in lung epithelial cells, which triggers the acute lung injury.

Objective To investigate the effect of aloe polysaccharides (AP) pre-emptive treatment on the expression of nuclear factor kappa B (NF-κB),ntercellulor adhesion molecule-1 (ICAM-1) and cell apoptosis in hippocampal brain tissue in rats with severely hemorrhagic shock for the first time of entering high altitude.Methods Forty healthy male SD rats weighing 250-300 g were randomly (random number) divided into 5 groups (n =8 each):sham group,shock group and AP group which was further divided into 3 subgroups as per different dosages of AP administered (AP1:0.75 mg/kg; AP2:1.50 mg/kg; AP3:3.00 mg/kg).Rats in sham group were treated with surgical procedure without exsanguination.Rats in shock group were exsanguinated until hemorrhagic shock emerged without resuscitation.Rats in AP subgroups were intravenously infused with given doses of AP in different AP subgroups at 30 min before hemorrhagic shock.MAP was dropped to (35 ±5) mmHg (1 mmHg =0.133 kPa) in 15 min by bleeding from femoral artery,the mean arterial pressure (MAP) was maintained at (35 ±5) mmHg for 60 min with bleeding or re-transfusing.At 3 h after resuscitation,rats were sacrificed immediately by bleeding,and the hippocampus of brain was harvested on the ice.The expressions of NF-κB and ICAM-1 in the hippocampus of rats were determined by immuno-histochemical method,and number of cell apoptosis in the hippocampus of rats was determined by TUNEL.The means were compared with analysis of variance and Student-NewmanKeuls test,and statistical significance was established at a P value of less than 0.05.Results Compared with sham group,the expressions of NF-κB (5.03 ±0.42),ICAM-1 (4.14 ±0.29) and number of cell apoptosis (44.3 ± 7.2) in hippocampal tissue were significantly increased in shock group (P ＜ 0.05).There were no significant differences in these three variables between shock group and AP1 group.Compared with shock group,the expressions of NF-κB (3.12 ±0.34),ICAM-1 (2.93 ±0.21) and number of cell apoptosis (24.8 ± 3.6) in hippocampal tissue were significantly decreased in AP2 group (P ＜ 0.05).There were no significant differences in these three variables between AP2 and AP3 groups.Conclusion AP pre-emptive treatment can significantly attenuate the expressions of NF-κB,ICAM-1 and number of cell apoptosis in hippocampal tissue in hemorrhagic shock rats.

BACKGROUND:Studies have shown that suberoylanilide hydroxamic acid (SAHA) has protective effects in some vital organs in animals after hemorrhagic shock, and 7.5% hypertonic saline (HS) exerts significant effects on stabilizing the hemodynamics of hemorrhagic shock animals. OBJECTIVE:To evaluate the effect of SAHA combined with HS on the hemodynamics of hemorrhagic shock rats. METHODS: Fifty rats were randomly and equaly divided into five groups: sham, shock non-resuscitation, SAHA, 7.5% HS, and 7.5% HS + SAHA. Each group contained 10 rats. Except the sham group, rats in the remaining four groups were applied to establish hemorrhagic shock models. In the sham group, rats were given anesthesia catheter, not bleeding; in the shock non-resuscitation group, the bleeding was found, but rats were not resuscitated and were kiled after 60 minutes of observations; in the other three groups, rats were respectively resuscitated at 60 minutes after bleeding, through intravenous administration of SAHA within 5 minutes, 7.5% HS and SAHA + 7.5% HS within 20 minutes. Heart rate, mean arterial pressure and left ventricular systolic pressure were monitored through the femoral artery and the right common carotid artery catheter in each group. RESULTS AND CONCLUSION:At 3 hours after resuscitation, the heart rate was the highest in the 7.5% HS + SAHA group, compared with the SAHA and 7.5% HS groups (P < 0.05). After resuscitation, the mean arterial pressure and left ventricular systolic pressure were increased, with long-lasting effect and less fluctuation (P < 0.05). Experimental results show that 7.5% HS combined with SAHA has a superiority than traditional HS and simple drugs for resuscitation after hemorrhagic shock.

BACKGROUNDA proinflammatory milieu emerging in the lung due to neutrophil accumulation and activation is a key in the pathogenesis of acute lung injury (ALI). 15-deoxy-Δ(12, 14)-prostaglandin J2 (15d-PGJ2), one of the terminal products of the cyclooxygenase-2 pathway, is known to be the endogenous ligand of peroxisome proliferator-activated receptor γ (PPAR-γ) with multiple physiological properties. Growing evidence indicates that 15d-PGJ2 has anti-inflammatory, antiproliferative, cytoprotective and pro-resolving effects. We investigated whether 15d-PGJ2 has a protective effect against endotoxin-induced acute lung injury in rats.

METHODSTwenty-four male Wistar rats were randomly assigned into four groups (n = 6 per group): sham+vehicle group, sham+15d-PGJ2 group, LPS+vehicle group, and LPS+15d-PGJ2 group. The rats were given either lipopolysaccharide (LPS, 6 mg/kg intravenously) or saline, and pretreated with 15d-PGJ2 (0.3 mg/kg intravenously) or its vehicle (dimethyl sulphoxide) 30 minutes before LPS. Histological alterations, wet/dry weight (W/D) ratio and myeloperoxidase (MPO) activity as well as tumor necrosis factor (TNF)-α and cytokine-induced neutrophil chemoattractant-1 (CINC-1) levels were determined in lung tissues four hours after LPS injection. Immunohistochemical analysis for intercellular adhesion molecule-1 (ICAM-1) expression and Western blotting analysis for nuclear factor (NF)-κB p65 translocation and IκBα protein levels were also studied.

RESULTS15d-PGJ2 pretreatment significantly attenuated LPS-induced lung injury, and reduced the increased W/D ratio, MPO activity, TNF-α, CINC-1 levels, and ICAM-1 expression in the lung. 15d-PGJ2 also suppressed the nuclear NF-κB p65 translocation and increased cytosolic IκBα levels.

CONCLUSIONS15d-PGJ2 protects against endotoxin-induced acute lung injury, most likely through the reduction of proinflammatory protein levels during endotoxemia subsequent to the inhibition of NF-κB activation.

Acute Lung Injury ; chemically induced ; drug therapy ; immunology ; Animals ; Chemokine CXCL1 ; metabolism ; I-kappa B Proteins ; metabolism ; Intercellular Adhesion Molecule-1 ; metabolism ; Lipopolysaccharides ; toxicity ; Male ; NF-KappaB Inhibitor alpha ; NF-kappa B ; metabolism ; Prostaglandin D2 ; analogs & derivatives ; therapeutic use ; Rats ; Rats, Wistar ; Tumor Necrosis Factor-alpha ; metabolism

Objective To evaluate the role of haeme oxygenase-1 (HO-1) in remote limb ischemic preconditioning (RLIP)-induced attenuation of lung ischemia-reperfusion (I/R) injury in rabbits.Methods Twenty-four Japanese White Rabbits,aged 4-5 months,weighing 2.0-2.5 kg,were randomly divided into 4 groups (n =6 each) using a random number table:sham operation group (S group),I/R group,RLIP group and zinc protoporphyrin (ZnPP,an inhibitor of HO-1) plus RLIP group (ZnPP + RLIP group).Lung I/R was produced by 60 min occlusion of the left lung hilum followed by 180 min of reperfusion in I/R,RLIP and ZnPP + RLIP groups.RLIP and ZnPP + RLIP groups received 3 cycles of 10 min ischemia followed by 10 min reperfusion in the bilateral hind limbs immediately before occlusion of the left lung hilum.In ZnPP + RLIP group,ZnPP 10 μmol/kg was injected intravenously 10 min prior to hind limb ischemia and the rest of the procedures were similar to those previously described in RLIP group.At the end of reperfusion,arterial blood samples were collected for blood gas analysis.The animals were then sacrificed and pulmonary specimens were obtained for microscopic examination of the pathological changes which were scored (lung injury score,LIS) and for determination of wet/dry lung weight ratio (W/D ratio),myleoperoxidase (MPO) activity,malondialdehyde (MDA) content and expression and activity of HO-1 in the lung tissues.Results Compared with group S,PaO2 was significantly decreased,and LIS,W/D ratio,MPO activity,MDA content,and HO-1 expression and activity were increased in I/R group (P ＜ 0.01).Compared with I/R group,PaO2 and HO-1 expression and activity were significantly increased,and LIS,W/D ratio,MPO activity and MDA content were decreased in RLIP group (P ＜ 0.01).Compared with RLIP group,PaO2 and HO-1 expression and activity were significantly decreased,and LIS,W/D ratio,MPO activity and MDA content were increased in ZnPP + RLIP group (P ＜ 0.01).Conclusion RLIP up-regulates HO-1 expression and enhances HO-1 activity,thus reducing lung I/R injury in rabbits.

Objective To evaluate the effect of suberoylanilide hydroxamic acid (SAHA) on liver injury induced by lethal hemorrhagic shock in rats first entering high altitude.Methods Forty healthy male SpragueDawley rats,aged 2-3 months,weighing 240-280 g,transported from breeding grounds at an altitude of 1520 meters to the experimental station at an altitude of 3780 meters,were randomly divided into 4 groups (n =10each):sham operation group (group S),lethal hemorrhagic shock group (group LHS),normal saline group (group NS),and SAHA group.Anesthesia was induced with inhalation of 3% isoflurane and maintained with inhalation of 0.5%-1.0% isoflurane.Lethal hemorrhagic shock was induced by withdrawing blood from the femoral artery in groups LHS,NS and SAHA.Normal saline 0.25 ml and SAHA 7.5 mg/kg (0.25 ml) were injected intravenously over 2 min after completion of blood-letting in groups NS and SAHA,respectively.The survival rates with 3 h were recorded.Blood samples from femoral veins were taken before blood-letting,immediately after completion of blood-letting and at 3 h after completion of blood-letting (immediately after death if the survival time was less than 3 h) for determination of serum aspartate aminotransferase (AST),alanine aminotransferase (ALT) and lactic dehydrogenase (LDH) activities by the colorimetric method.Liver specimens were taken at 3 h after completion of blood-letting or immediately after death for examination of the pathological changes of the liver and for determination of c-Jun N-terminal kinase (JNK),phosphorylated-JNK (p-JNK) and caspase-3 expression and acetylation of H3K9 in liver tissues by Western blot.Results Compared with group S,the activities of serum AST,ALT and LDH were significantly increased in the other three groups (P ＜ 0.01).Compared with LHS and NS groups,the activities of serum AST,ALT and LDH were significantly decreased,the survival rate within 3 h and acetylation of H3K9 were increased,caspase-3 expression was down-regulated,and p-JNK/JNK ratio was decreased in group SAHA (P ＜ 0.05 or 0.01).The pathological changes of the liver were severe in LHS and NS groups and attenuated in SAHA group.Conclusion Administration of SAHA in early shock can significantly protect the liver after lethal hemorrhage in rats first entering high altitude,and increased acetylation of H3K9 and inhibition of the JNK/caspase-3 apoptotic pathway in liver tissues are involved in the mechanism.