Objective:The study aimed to study the efficacy and safety of combined dual therapy using anti-programmed death (PD)-1 and tyrosine kinase inhibitor (TKI) with combined triple therapy using anti-PD-1, TKI and locoregional intervention triple therapy in patients with postoperative refractory recurrent liver cancer.Methods:Patients with postoperative refractory recurrent liver cancer who had undergone either anti-PD-1 and TKI dual therapy or anti-PD-1, TKI and locoregional intervention triple therapy between July 2016 and March 2019 at the First Medical Center, Chinese PLA General Hospital were retrospectively studied. Tumor responses were assessed by the modified response evaluation criteria in solid tumors and overall survival and progression free survival were compared. Adverse events were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events.Results:Of 63 patients who were included in this study, there were 25 patients in the dual therapy group (16 males and 9 females, aged 54.3±8.8 years) and 38 patients in the triple therapy group (31 males and 7 females, aged 55.5±8.4 years). The 1-year survival rate of the triple therapy group was significantly higher than the dual therapy group (94.5%vs 54.9%) ( P<0.01). The disease control rate was 64.0% (16/25) in the dual therapy group and 84.2% (32/38) in the triple therapy group, and the difference was not significant ( P>0.05). The incidence of treatment-related adverse events in the triple therapy group and the dual therapy group were 78.9% (30/38) and 80% (20/25), respectively. There was no treatment-related death in the 2 groups. Conclusions:Anti-PD-1 and TKI dual therapy and anti-PD-1, TKI and locoregional intervention triple therapy were effective and tolerable treatments for postoperative refractory recurrent liver cancer. The latter treatment had a significantly better clinical benefit on survival outcomes.

Objective: To examine whether presepsin level can serve as a distinguishing marker between G- bacteria and G+ bacteria, fungal infection in sepsis patients. Methods: A prospective observation study was conducted on the consecutive patients with positive bacterial cultures in intensive care unit (ICU) from June 2017 to November 2018. The patients were divided into the G- group, G+ group and fungal group. Blood samples were collected upon admission to measure the levels of presepsin and procalcitonin (PCT). Results: (1) Of the 156 patients met the inclusion criteria. 96 (62% G- rods, 25 (16%) G+ microbes, and 35 (22%) fungi were detected. (2) Presepsin concentrations were significantly higher in the G- group compared with the G+ and fungal groups (P = 0.000). (3) Presepsin level has a higher accuracy in differentiating G- sepsis from Gram+ and fungal sepsis than PCT level [area under the curve (AUC): 0.809 vs 0.712]. The AUC value of a combination of presepsin and PCT level was significantly larger than that of presepsin level alone in differentiating G- sepsis from Gram+ and fungal sepsis (AUC: 0.866 vs 0.809). Conclusions In contrast to PCT, presepsin is a good discriminative biomarker in different infections.

Objective To evaluate the effect of lovastatin on shedding of heparan sulfate proteoglycan (HSPG) and syndecan-1 (SDC-1) in the lung tissues of rats with sepsis-induced acute lung injury.Methods One-hundred and twenty male Wistar rats aged 8-12 weeks,weighing 325-425 g,were randomly divided into 3 groups (n =40 each) using a random number table:sham operation group (group S),cecal ligation and puncture (CLP) group and lovastatin group (group L).Lovastatin 4 mg/kg was injected once a day for 5 consecutive days in S and L groups,while the equal volume of 0.5％ CMC (the solvent) was given in CLP group.Sepsis was produced by CLP on 5th day of administration in CLP and L groups.The left lung was lavaged at 24 h after operation.The broncho-alveolar lavage fluid (BALF) was collected for determination of protein concentrations,white blood cell (WBC) count and percentage of neutrophils.Blood samples were collected for determination of the concentrations of HSPG and SDC-1 in serum (by ELISA).Evans blue was injected at 24 h after operation in the remaining 20 rats of each group.The lungs were removed for examination of the pathological changes and for measurement of HSPG and SDC-1 mRNA and protein expression (using Western blot and PCR),and Evans blue content (reflecting pulmonary capillary permeability) in the lung tissue.Results Compared with group S,the protein concentrations,WBC count and percentage of neutrophils in BALF,Evans blue content in lung tissues and the concentrations of HSPG and SDC-1 in serum were significantly increased,and HSPG and SDC-1 mRNA and protein expression was down-regulated in CLP and L groups.Compared with group CLP,the protein concentrations,WBC count and percentage of neutrophils in BALF,Evans blue content in lung tissues and the concentrations of HSPG and SDC-1 in serum were significantly decreased,and HSPG and SDC-1 mRNA and protein expression was up-regulated in group L.The pathological changes of lungs were significantly attenuated in group L as compared with group CLP.Conclusion The mechanism by which lovastatin attenuates acute lung injury induced by sepsis may be related to reduced shedding of HSPG and SDC-1 in lung tissues and improved function of pulmonary vascular endothelium in rats.

OBJECTIVETo study the relationship between fibrotic focus (FF) and carbonic anhydrase (CA) IX in invasive ductal carcinomas (IDC) of the breast.

METHODSIn 167 cases of IDC, the FF was assessed morphologically, and expression of ER, PR and CA IX was evaluated using MaxVision immunohistochemistry.

RESULTSThe expression of CA IX in IDC with and without FF was 56.3% (45/80) and 28.7% (25/87) respectively, with significant difference (P=0.001). In IDC with FF, the CA IX expression of tumor cells in tumors with CA IX-positive fibroblasts (35/40, 87.5%) was significantly (P<0.001) higher than that in tumors with CA IX-negative fibroblasts (10/40, 25.0%). In IDC with FF, the CA IX expression of fibroblasts of FF in grade 3 IDC (23/33, 69.7%) was significantly (P=0.006) higher than that in grade 1+2 tumors (17/47, 36.2%). The ER and PR expression of tumor cells in tumors containing CA IX-negative fibroblasts was 72.5% (29/40) and 65.0% (26/40) respectively, whereas the ER and PR expression of tumor cells in tumors containing CA IX-positive fibroblasts was 50.0% (20/40) and 42.5% (17/40) respectively; the difference was statistically significant (for both ER and PR, P=0.04). The age of patients with tumors containing CA IX-negative fibroblasts was significantly (P=0.002) older than those containing CA IX-positive fibroblasts. The FF diameter/tumor diameter in tumors containing CA IX-positive fibroblasts was significantly larger than those containing CA IX-negative fibroblasts. (3) For the groups of tumor size≤2 cm and tumor size between 2 cm to 5 cm, the diameter of the fibrotic focus was significantly (P<0.01) smaller than the fibrotic focus size of tumors>5 cm in size.

CONCLUSIONSCA IX expression is correlated with FF, and that in fibroblasts of FF correlated with patients' age, tumor grade, hormone receptors and FF diameter/tumor diameter. CA IX expression in FF might be a marker for poor prognosis in patients with breast cancer.

Age Factors ; Antigens, Neoplasm ; Breast Neoplasms ; metabolism ; pathology ; Carbonic Anhydrase IX ; Carbonic Anhydrases ; Carcinoma, Ductal, Breast ; enzymology ; pathology ; Female ; Fibroblasts ; metabolism ; Humans ; Immunohistochemistry ; Neoplasm Grading ; Neoplasm Proteins ; Receptors, Estrogen ; metabolism ; Receptors, Progesterone ; metabolism

Objective To study the relationship between fibrotic focus ( FF ) and carbonic anhydrase ( CA) Ⅸin invasive ductal carcinomas ( IDC) of the breast.Methods In 167 cases of IDC, the FF was assessed morphologically, and expression of ER, PR and CA Ⅸ was evaluated using MaxVision immunohistochemistry.Results The expression of CAⅨin IDC with and without FF was 56.3%(45/80) and 28.7%(25/87) respectively, with significant difference (P=0.001).In IDC with FF, the CA Ⅸexpression of tumor cells in tumors with CAⅨ-positive fibroblasts (35/40, 87.5%) was significantly (P<0.001) higher than that in tumors with CAⅨ-negative fibroblasts (10/40, 25.0%).In IDC with FF, the CAⅨexpression of fibroblasts of FF in grade 3 IDC ( 23/33, 69.7%) was significantly ( P =0.006 ) higher than that in grade 1 +2 tumors (17/47, 36.2%).The ER and PR expression of tumor cells in tumors containing CA Ⅸ-negative fibroblasts was 72.5% ( 29/40 ) and 65.0% ( 26/40 ) respectively, whereas the ER and PR expression of tumor cells in tumors containing CAⅨ-positive fibroblasts was 50.0%(20/40) and 42.5% (17/40) respectively; the difference was statistically significant (for both ER and PR, P=0.04 ) .The age of patients with tumors containing CA Ⅸ-negative fibroblasts was significantly ( P=0.002) older than those containing CA Ⅸ-positive fibroblasts.The FF diameter/tumor diameter in tumors containing CA Ⅸ-positive fibroblasts was significantly larger than those containing CA Ⅸ-negative fibroblasts.(3) For the groups of tumor size≤2 cm and tumor size between 2 cm to 5 cm, the diameter of the fibrotic focus was significantly (P<0.01) smaller than the fibrotic focus size of tumors >5 cm in size. Conclusions CA IX expression is correlated with FF, and that in fibroblasts of FF correlated with patients′age, tumor grade, hormone receptors and FF diameter/tumor diameter.CAⅨexpression in FF might be a marker for poor prognosis in patients with breast cancer.

Objective To observe the protective effects of lovastatin against lung injury and the expression changes of adiponectin in the septic rats.Methods Fifty four male Wistar rats weighting 250-300g were randomly divided into the three groups:sham operation group ( group Sham) ,sepsis group ( group CLP) and lovastatin interven tion group (group LOV).Rats were injected with lovastatin (4mg/kg) or 0.5%CMC (vehicle) for five days and then subjected to CLP.At 4h,12h and 24h after operation.BALF was collected to determine the levels of TNF-αand IL-6,lung tissue was obtained to observe histopathological changes,and to detect the content of MPO and MDA,the blood sample was obtained to detect the level of adiponectin.Results In the group Sham,at 4h,12h and 24h time points,the levels of TNF-αwere (1.80 ±0.13)pg/mL,(2.04 ±0.15)pg/mL and (1.930.19)pg/mL;the levels of IL-6 were (20.56 ±0.23)pg/mL,(18.35 ±0.15) pg/mL and (21.23 ±0.20) pg/mL;the contents of MPO were (2.82 ±0.14) U/g tissue,(2.88 ±0.07) U/g tissue and (2.76 ±0.18) U/g tissue;and the levels of MDA were (3.32 ±0.12)nmol/mg,(3.09 ±0.11)nmol/mg and (3.21 ±0.08)nmol/mg;the concentrations of adiponectin were (2.68 ±0.14)μg/mL,(2.80 ±0.07)μg/mL and (2.86 ±0.18)μg/mL.Compared with group Sham,both LOV group and CLP group had increased pulmonary damage:(1)the levels of TNF-α[4h,12h and 24h were (4.23 ± 0.18)pg/mL,(5.62 ±0.24)pg/mL and (5.14 ±0.10)pg/mL,t=28.41,30.98 and 36.62]and IL-6[4h,12h and 24h were (39.12 ±0.17) pg/mL,(47.25 ±0.21) pg/mL and (44.690.27) pg/mL,t =158.90,273.40 and 127.28] of the CLP group in BALF were both increased,and MPO[4h,12h and 24h were (4.85 ±0.13) U/g tissue, (6.17 ±0.08)U/g tissue and (7.84 ±0.10)U/g tissue,t=26.39,79.40 and 60.43]and MDA[4h,12h and 24h were (6.24 ±0.06)nmol/mg,(7.56 ±0.15)nmol/mg and (8.43 ±0.10)nmol/mg,t=53.31,58.86 and 90.06] concentrations in lung homogenate were raised with the decreased expression of serum adiponectin[4h,12h and 24h were (1.35 ±0.10)μg/mL,(1.17 ±0.07)μg/mL and (1.24 ±0.11)μg/mL,t=19.86,12.75 and 18.81](all P<0.05);(2) meanwhile the levels of TNF-α[4h,12h and 24h were (2.85 ±0.17) pg/mL,(3.720.13) pg/mL and (3.240.09)pg/mL,t=12.02、20.73 and 16.68]and IL-6[4h,12h and 24h were (30.75 ±0.22)pg/mL, (37.52 ±0.29)pg/mL and (32.43 ±0.26)pg/mL,t=78.42,68.29 and 83.67]in BALF of the LOV group were all increased,the contents of MPO[4h,12h and 24h were(3.59 ±0.05)U/g tissue,(4.67 ±0.11)U/g tissue and (5.33 ± 0.05)U/g tissue,t=12.03,33.63 and 33.70]and MDA[4h,12h and 24h were (4.45 ±0.10)nmol/mg,(5.01 ± 0.11)nmol/mg and (5.83 ±0.04) nmol/mg,t =17.72,30.23 and 71.75] were also increased with the serum adiponectin concentrations[4h,12h and 24h were (2.09 ±0.08)μg/mL,(2.07 ±0.05)μg/mL and (2.03 ± 0.10)μg/mL,t=8.96,20.79 and 6.30]dicreased(all P<0.05).There were less histopathological changes in the LOV group,and the levels of TNF-α(t=13.46,17.05 and 15.43),IL-6(t=73.70,64.10 and 80.12),MPO(t=22.16,27.01and 32.86) and MDA(t=37.59,42.72 and 59.13) were lower than those in CLP group,also the level of adiponectin(t=14.15,8.10 and 3.19) increased siginificantly(all P<0.05).Conclusion Administration of lovastatin could attenuate lung injury of the sepsis by down-regulate the level of TNF-αand IL-6,with reduced inflam-matory response and oxidative stress,and could upregulate the level of adiponectin in serums of rats with sepsis.

Objective To evaluate the effects of adiponectin on the mitochondrial damage in septic rats with lung injury .Methods Sixty male Wistar rats ,aged 7-8 weeks ,weighing 180-220 g ,were randomly divided into 3 groups (n=20 each) using a random number table :sham operation group (S group) ,sepsis group (SEP group) and adiponectin group (APN group) .The animals were anesthetized with intraperitoneal 2% pentobarbital sodium 50 mg/kg .Sepsis was produced by cecum ligation and puncture (CLP) .In APN groups ,gene recombinant adiponectin 6 mg/kg was injected intraperitoneally at 12 h after CLP .At 24 h after the operation ,10 rats from each group were chosen and sacrificed ,and lungs were removed for detection of interleukin-6 (IL-6 ) and high-mobility group box-1 (HMGB1 ) contents . The mitochondria of lung samples were isolated for measurement of the malondialdehyde (MDA ) content and degree of mitochondrial swelling and mitochondrial activity . The survival rates within 7 days after operation were recorded in the left 10 rats in each group .Results Compared with S group , IL-6 and HMGB1 contents in lung tissues and MDA content in the mitochondria were significantly increased ,the degree of mitochondrial swelling was increased , and the mitochondrial activity and survival rates within 7 days after operation were decreased in SEP group ( P<0.05 ) . Compared with SEP group , IL-6 and HMGB1 contents in lung tissues and MDA content in the mitochondria were significantly decreased ,the degree of mitochondrial swelling was reduced ,and the mitochondrial activity and survival rates within 7 days after operation were increased in APN groups ( P< 0.05 ) .Conclusion Adiponectin can attenuate lung injury and raise the survival rates in septic rats ,and reduction of mitochondrial damage in lung tissues is involved in the mechanism .

Adenocarcinoma, Clear Cell ; metabolism ; pathology ; surgery ; Alkaline Phosphatase ; metabolism ; Carcinoma, Endometrioid ; metabolism ; pathology ; Diagnosis, Differential ; Endodermal Sinus Tumor ; metabolism ; pathology ; surgery ; Female ; GPI-Linked Proteins ; metabolism ; Glypicans ; metabolism ; Humans ; Isoenzymes ; metabolism ; Keratin-7 ; metabolism ; Liver Neoplasms ; metabolism ; pathology ; secondary ; Middle Aged ; Mucin-1 ; metabolism ; Ovarian Neoplasms ; metabolism ; pathology ; surgery ; alpha-Fetoproteins ; metabolism

Objective To evaluate the effects of rapamycin combined with rosiglitazone on lung injury in septic rats.Methods One hundred and twenty healthy male Wistar rats were randomly divided into 5 groups (n =6 each):sham operation group (group S); cecum ligation and punture (CLP) group; rapamycin group (group RPM) ; rosiglitazone group (group RGZ) ; rapamycin plus rosiglitazone group (group RPM + RGZ).The rats were anesthetized with intraperitoneal 10% chloral hydrate 100 mg/kg.Sepsis was induced by CLP in groups CLP,RPM,RGZ and RPM + RGZ.At 30 min before CLP,rapamycin 0.4 mg/kg was injected subcutaneously in RPM group,rosiglitazone 0.3 mg/kg was injected via the femoral vein in RGZ group,and rapamycin 0.4 mg/kg was injected subcutaneously and rosiglitazone 0.3 mg/kg was injected via the femoral vein in group RPM + RGZ.While the equal volume of normal saline was given instead in CLP group.Six rats were sacrificed at 2,6,24 and 48 h after CLP in each group,and lungs were removed and cut into sections which were stained with haematoxylin and eosin and examined under microscope.The pathological changes of lungs were scored.The myeloperoxidase (MPO) activity and signal transducer and activator of transcription 3 (STAT3)-DNA binding activity in lung tissues were measured.Results Compared with group S,the pathological scores,MPO activity and STAT3-DNA binding activity were significantly increased in groups CLP,RPM,RGZ,RPM + RGZ (P ＜ 0.05).The pathological scores,MPO activity and STAT3-DNA binding activity were significantly lower in groups RPM,RGZ and RPM +RGZ than in group CLP,and in group RPM + RGZ than in groups RPM and RGZ (P ＜ 0.05).Conclusion Rapamycin combined with rosiglitazone offers additional benefit to attenuating lung injury induced by sepsis over rapamycin or rosiglitazone alone,and inhibition of activation of STAT3 pathway is involved in the mechanism.

Objective To evaluate the effect of dexmedetomidine on the expression of 8-Oxoguanine DNA glycosylase 1 (OGG1) mRNA in rat hippocampal neurons subjected to oxygen-glucose deprivation/reoxygenation and restoration (OGD/R).Methods Hippocampal neurons isolated from pathogen-free neonatal Sprague-Dawley rats born within 3 days,were cultured primarily and seeded in 96-well plates (100 μl/well) or 6-well plates (2 ml/well) at the density of 1 × 106 cells/ml.The cells were randomly divided into 5 groups (n=30 each):control group (group C),group OGD/R,and different concentrations of dexmedetomidine groups (DEX1-3 groups).The cells were cultured in normal culture medium in group C and the cells were subjected to OGD/R in the other groups.In DEX1-3 groups,dexmedetomidine with the final concentrations of 0.1,1.0 and 10.0μmol/L were added,respetively,at 2h before OGD.At 24h of restoration,hippocampal neurons were stained with haematoxylin and eosin (H.E) for examination of pathological changes,the cell survival rate was detected by MTT method,the activity of superoxide dismutase (SOD) and content of malondialdehyde (MDA) were detected by colorimetric method,and the expression of OGG1 mRNA was detected by RT-PCR.Results The pathological changes of neurons were obvious in group OGD/R,and the pathological changes of neurons were significantly mitigated in DEX1,DEX2 and DEX3 groups.Compared with group C,the cell survival rate and SOD activity were significantly decreased,MDA content was increased,and the expression of OGG1 mRNA was down-regulated in OGD/R,DEX1,DEX2 and DEX3 groups (P ＜ 0.05).Compared with group OGD/R,the cell survival rate and SOD activity were significantly increased,MDA content was decreased,and the expression of OGG1 mRNA was up-regulated in DEX1,DEX2 and DEX3 groups (P ＜ 0.05).There was no significant difference in the indices mentioned above between DEX1,DEX2 and DEX3 groups (P ＞ 0.05).Conclusion Dexmedetomidine may protect hippocampal neurons against oxidative stress injury by up-regulating the expression of OGG1 mRNA in rat hippocampal neurons subjected to OGD/R.