[Strategies of chemotherapy for peritoneal metastasis of gastrointestinal cancer].

Peritoneal metastasis of gastrointestinal cancer is an independent factor that seriously affects the prognosis of patients. The "seed-soil" theory is considered to be the main theory to explain peritoneal metastasis. Because of the small size of peritoneal metastatic nodules at the initial stage, early diagnosis is particularly difficult, therefore, the risk assessment of peritoneal metastasis is very important. Recently, the diagnosis methods have gradually developed from clinicopathological factors to cytology and molecular level. In addition, the integrated assessment of multiple groups including radiomics further enriches the accurate diagnosis of peritoneal metastasis. Peritoneal metastasis is a big challenge in the treatment of gastrointestinal cancer which may also lead to refractory malignant ascites, intestinal obstruction, cachexia and other related complications. At present, the treatment is based on systemic chemotherapy. The combination of surgery, intraperitoneal chemotherapy and HIPEC is an effective treatment for peritoneal metastasis of gastrointestinal cancer. How to enrich peritoneal metastasis patients with potential benefits, how to determine the timing of conversion surgery, how to further optimize the existing treatment plan, especially how to formulate treatment plan for patients after conversion surgery, call for improved study design and prospective randomized controlled trials. The goal of continuous efforts is to effectively prolong the survival of gastrointestinal cancer trials patients with peritoneal metastasis.

Anti-epidermal growth factor receptor (EGFR) monoclonal antibody combined with cisplatin and 5-fluorouracil in patients with metastatic nasopharyngeal carcinoma after radical radiotherapy: a multicentre, open-label, phase II clinical trial.

BACKGROUND: We conducted a single-arm phase II trial to evaluate the efficacy and adverse effects (AEs) of an anti-epidermal growth factor receptor monoclonal antibody, nimotuzumab, combined with cisplatin and 5-fluorouracil (PF) as first-line treatment in recurrent metastatic nasopharyngeal carcinoma after radical radiotherapy. METHODS: Patients who met the eligibility criteria were recruited from ten institutions (ClinicalTrials.gov; NCT01616849). A Simon optimal two-stage design was used to calculate the sample size. All patients received weekly nimotuzumab (200 mg) added to cisplatin (100 mg/m2 D1) and 5-fluorouracil (4 g/m2 continuous infusion D1-4) every 3-weekly for a maximum of six cycles. Primary end point was objective response rate (ORR). Secondary end points included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and AEs. RESULTS: A total of 35 patients were enrolled (13 in stage 1 and 22 in stage 2). Overall ORR and DCR were 71.4% (25/35) and 85.7% (30/35), respectively. Median PFS and OS were 7.0 (95% CI 5.8-8.2) months and 16.3 (95% CI 11.4-21.3) months, respectively. Unplanned exploratory analyses suggest that patients who received ≥2400 mg nimotuzumab and ≥4 cycles of PF had superior ORR, PFS and OS than those who did not (88.9% versus 12.5%, P < 0.001; 7.4 versus 2.7 months, P = 0.081; 17.0 versus 8.0 months, P = 0.202). Favourable subgroups included patients with lung metastasis [HROS 0.324 (95% CI 0.146-0.717), P = 0.008] and disease-free interval of >12 months [HROS 0.307 (95% CI 0.131-0.724), P = 0.004], but no difference was observed for metastatic burden. The only major grade 3/4 AE was leukopenia (62.9%). CONCLUSION: Combination nimotuzumab-PF chemotherapy demonstrates potential efficacy, and is well tolerated as first-line chemotherapy regimen in recurrent metastatic nasopharyngeal carcinoma.

Protective effects of fraction 4a of polysaccharides isolated from Lycium barbarum against KBrO3-induced renal damage in rats.

Potassium bromate (KBrO3) is widely used as a food additive and is a major by-product of water disinfection. The aim of this study was to investigate the protective effects of fraction 4a of polysaccharides isolated from Lycium barbarum (LBP-4a) against renal damage induced by KBrO3 in rats and to determine the relevant mechanisms behind these effects. Male Wistar rats were divided into a normal control group, a KBrO3 control group, and LBP-4a(L) and LBP-4a(H) groups. With the exception of the normal control group, the rats in the other three groups were administered KBrO3 by intraperitoneal injection to induce renal damage. Before the induction of renal damage, rats in the LBP-4a(L) and LBP-4a(H) groups were pretreated with 50 mg per kg b.w. or 100 mg per kg b.w. LBP-4a, respectively, by intragastric administration. Clinical biochemical parameters and markers of oxidative damage were also determined. Treatment by administration of LBP-4a prior to challenge with KBrO3 prevented increases in the levels of nitrite, creatinine, urea nitrogen and uric acid in serum and increased the activities of antioxidant enzymes in kidney tissues. A comet assay and FCS results showed that pretreatment with LBP-4a also alleviated DNA damage and decreases in mitochondrial membrane potentials in renal cells. Histological studies further supported the above results and showed extensive renal damage in animals treated with KBrO3 and greatly reduced tissue injury in groups pretreated with LBP-4a. In conclusion, LBP-4a exhibited protective effects against renal damage induced by KBrO3, and the mechanism was closely correlated with a reduction in levels of lipid peroxidation and an increase in the activities of antioxidant enzymes in kidney tissues, which alleviated DNA damage and increased mitochondrial membrane potentials in renal cells. These observations provide the background for the further development of LBP-4a as a protective agent for use in the treatment of renal damage.

Effects of goal-directed fluid therapy with different lactated Ringer's: hydroxyethyl starch ratios in hemorrhagic shock dogs.

The effects of goal-directed fluid therapy, with lactated Ringer's (LR) and 6% hydroxyethyl starch (HES) solution, on hemorrhagic shock dogs are unknown. We aimed to determine the optimal LR: HES ratio for the resuscitation of hemorrhagic shock dogs. Hemorrhagic shock was induced in 40 ventilated dogs by drawing an estimated 60% blood volume. The animals were randomly divided into five groups (N = 8) according to the LR: HES ratio of the resuscitation fluid (3:1, 2:1, 1:1, 1:2, and 1:3), and were then resuscitated for 24 h to reach the stroke volume variation (SVV) and hemoglobin (Hb) goals by fluid infusion and autologous blood perfusion. The extravascular lung water index (EVLWI), pH, partial pressure of oxygen (PaO2), base excess (BE), sodium, chloride, Hb and creatinine clearance (Clearcrea) were checked after 24 h (R24). The EVLWI of the 3:1 group at R24 were higher than that of the 1:3 group and the baseline value (P < 0.05), whereas the PaO2 was lower (P < 0.05). In contrast to the 3:1 group at R24 and baseline, plasma chloride and sodium in the 1:3 and 1:2 groups increased; however, pH, BE, and Clearcrea decreased (P < 0.05). No significant differences were found in the 1:1 and 2:1 groups at R24 compared with baseline (P > 0.05). Resuscitation with LR and HES at 2:1 and 1:1 ratios are superior in maintaining the acid-base, electrolyte, and lung water balances as well as renal function in hemorrhagic shock dogs than at ratios of 3:l, 1:2, and1:3.

Ginsenoside Rd attenuates mitochondrial dysfunction and sequential apoptosis after transient focal ischemia.

We previously found that ginsenoside Rd (Rd), one of the major active ingredients in Panax ginseng, protects neuronal cells from hydrogen peroxide and oxygen-glucose deprivation, an in vitro model of cerebral ischemia. In this study, we examined the protective effects of Rd in an animal model of focal cerebral ischemia. Rats administered with Rd or vehicle were subjected to transient middle cerebral artery occlusion (MCAO). Rd (50 mg/kg) significantly reduced the infarct volume by 52.8%. This reduction of injury volume was associated with an improvement in neurological function and was sustained for at least 2 weeks after the induction of ischemia. To evaluate the underlying mechanisms of Rd against stroke, brain tissues were assayed for mitochondrial enzyme activities, mitochondrial membrane potential (MMP), production of reactive oxygen species (ROS), energy metabolites, and apoptosis. Rd markedly protected mitochondria as indicated by preserved respiratory chain complex activities and aconitase activity, lowered mitochondrial hydrogen peroxide production, and hyperpolarized MMP. Microdialysis results illustrated that Rd significantly decreased the accumulation of lactate, the end product of anaerobic glycolysis, and increased pyruvate, the end product of aerobic glycolysis, hence inducing a lower lactate/pyruvate ratio. Additionally, in vitro studies further exhibited that Rd protected isolated mitochondria from calcium-induced damage by attenuating mitochondrial swelling, preserving MMP and decreasing ROS production. Moreover, Rd treatment reduced mitochondrial release of cytochrome c (CytoC) and apoptosis-inducing factor (AIF), thereby minimizing mitochondria-mediated apoptosis following ischemia. In conclusion, these findings demonstrated that Rd exerts neuroprotective effects in transient focal ischemia, which may involve an integrated process of the mitochondrial protection, energy restoration and inhibition of apoptosis.

Involvement of microglial cells in infrasonic noise-induced stress via upregulated expression of corticotrophin releasing hormone type 1 receptor.

Infrasound is a kind of environmental noise and threatens the public health as a nonspecific biological stressor. Upregulated expression of corticotrophin releasing hormone (CRH) and its receptor CRH-R1 in the neurons of hypothalamic paraventricular nucleus (PVN) was reported to be responsible for infrasonic noise-induced stress and injuries. Recent studies revealed that CRH-R1 is expressed in activated microglial cells, lending support to the hypothesis that microglial cells may be also responsible for infrasonic noise-induced stress. In this work, we exposed Sprague-Dawley rats and in vitro cultured microglial cells to infrasound with a main frequency of 16 Hz and a sound pressure level of 130 dB for 2 h, and examined the changes in the expression of CRH-R1 at different time points after infrasound exposure by immunohistochemistry and semi-quantitative RT-PCR. We found that infrasound exposure resulted in a significant activation of microglia cells and upregulated their expression of CRH-R1 in the PVN in vivo. Upregulated expression of CRH-R1 can be blocked by antalarmin, a selective CRH-R1 antagonist. Our in vitro data further revealed that in the absence of neurons, infrasound can directly induce microglial activation and upregulate their CRH-R1 expression. These findings suggest that in addition to the PVN neurons, microglial cells are the effector cells for infrasound as well, and involve in the infrasound-induced stress through upregulated expression of CRH-R1.

Comparison of genome screens for two independent cohorts provides replication of suggestive linkage of bone mineral density to 3p21 and 1p36.

Low bone mineral density (BMD) is a major risk factor for osteoporotic fracture. Studies of BMD in families and twins have shown that this trait is under strong genetic control. To identify regions of the genome that contain quantitative trait loci (QTL) for BMD, we performed independent genomewide screens, using two complementary study designs. We analyzed unselected nonidentical twin pairs (1,094 pedigrees) and highly selected, extremely discordant or concordant (EDAC) sib pairs (254 pedigrees). Nonparametric multipoint linkage (NPL) analyses were undertaken for lumbar spine and total-hip BMD in both cohorts and for whole-body BMD in the unselected twin pairs. The maximum evidence of linkage in the unselected twins (spine BMD, LOD 2.7) and the EDAC pedigrees (spine BMD, LOD 2.1) was observed at chromosome 3p21 (76 cM and 69 cM, respectively). These combined data indicate the presence, in this region, of a gene that regulates BMD. Furthermore, evidence of linkage in the twin cohort (whole-body BMD; LOD 2.4) at chromosome 1p36 (17 cM) supports previous findings of suggestive linkage to BMD in the region. Weaker evidence of linkage (LOD 1.0-2.3) in either cohort, but not both, indicates the locality of additional QTLs. These studies validate the use, in linkage analysis, of large cohorts of unselected twins phenotyped for multiple traits, and they highlight the importance of conducting genome scans in replicate populations as a prelude to positional cloning and gene discovery.

Overexpression of agouti protein and stress responsiveness in mice.

Ectopic overexpression of agouti protein, an endogenous antagonist of melanocortin receptors' linked to the beta-actin promoter (BAPa) in mice, produces a phenotype of yellow coat color, Type II diabetes, obesity and increased somatic growth. Spontaneous overexpression of agouti increases stress-induced weight loss. In these experiments, other aspects of stress responsiveness were tested in 12-week-old male wild-type mice and BAPa mice. Two hours of restraint on three consecutive days produced greater increases in corticosterone and post-stress weight loss in BAPa than wild-type mice. In Experiment 2, anxiety-type behavior was measured immediately after 12 min of restraint. This mild stress did not produce many changes indicative of anxiety, but BAPa mice spent more time in the dark side of a light-dark box and less time in the open arms of an elevated plus maze than restrained wild-type mice. In a defensive withdrawal test, grooming was increased by restraint in all mice, but the duration of each event was substantially shorter in BAPa mice, possibly due to direct antagonism of the MC4-R by agouti protein. Thus, BAPa mice showed exaggerated endocrine and energetic responses to restraint stress with small differences in anxiety-type behavior compared with wild-type mice. These results are consistent with observations in other transgenic mice in which the melanocortin system is disrupted, but contrast with reports that acute blockade of central melanocortin receptors inhibits stress-induced hypophagia. Thus, the increased stress responsiveness in BAPa mice may be a developmental compensation for chronic inhibition of melanocortin receptors.

[Determination of protocatechualdehyde in yu xue bi granula].

The content of Protocatechualdehyde in YuXueBi granula was determined by HPLC. The chromatographic column was packed with ODS-2 (particle size 5 microns). The mobile phase was MeOH-H2O-H3PO4(17:83:0.003) adjusted to pH 3 with N(C2H5)3. The detection wavelength was 280 nm. The velocity of flow was 1.0 ml/min. The average recovery rate was 96.14%, RSD was 1.16%. The method was simple and stable.

Molecular cloning and characterization of DEFCAP-L and -S, two isoforms of a novel member of the mammalian Ced-4 family of apoptosis proteins.

We report the deduced amino acid sequences of two alternately spliced isoforms, designated DEFCAP-L and -S, that differ in 44 amino acids and encode a novel member of the mammalian Ced-4 family of apoptosis proteins. Similar to the other mammalian Ced-4 proteins (Apaf-1 and Nod1), DEFCAP contains a caspase recruitment domain (CARD) and a putative nucleotide binding domain, signified by a consensus Walker's A box (P-loop) and B box (Mg(2+)-binding site). Like Nod1, but different from Apaf-1, DEFCAP contains a putative regulatory domain containing multiple leucine-rich repeats (LRR). However, a distinguishing feature of the primary sequence of DEFCAP is that DEFCAP contains at its NH(2) terminus a pyrin-like motif and a proline-rich sequence, possibly involved in protein-protein interactions with Src homology domain 3-containing proteins. By using in vitro coimmunoprecipitation experiments, both long and short isoforms were capable of strongly interacting with caspase-2 and exhibited a weaker interaction with caspase-9. Transient overexpression of full-length DEFCAP-L, but not DEFCAP-S, in breast adenocarcinoma cells MCF7 resulted in significant levels of apoptosis. In vitro death assays with transient overexpression of deletion constructs of both isoforms using beta-galactosidase as a reporter gene in MCF7 cells suggest the following: 1) the nucleotide binding domain may act as a negative regulator of the killing activity of DEFCAP; 2) the LRR/CARD represents a putative constitutively active inducer of apoptosis; 3) the killing activity of LRR/CARD is inhibitable by benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethyl ketone and to a lesser extent by Asp-Glu-Val-Asp (OMe)-fluoromethyl ketone; and 4) the CARD is critical for killing activity of DEFCAP. These results suggest that DEFCAP is a novel member of the mammalian Ced-4 family of proteins capable of inducing apoptosis, and understanding its regulation may elucidate the complex nature of the mammalian apoptosis-promoting machinery.

Identification of urocortin mRNA antisense transcripts in rat tissue.

Urocortin (UCN) has 45% sequence homology with corticotropin releasing factor (CRF) and binds to CRF receptors. We used reverse-transcriptase-polymerase chain reaction to demonstrate the presence of UCN RNA in various brain regions and in peripheral tissues. Ribonuclease protection assay (RPA) using sense and antisense riboprobes demonstrated the presence of a naturally occurring antisense UCN RNA transcript in a number of tissues. Northern blot indicated that the antisense transcript was the same size as sense UCN. RPA, using probes that covered bases 1 to 560 of 579 bp sequence of rat UCN, indicated that the antisense sequence was complementary to sense UCN but did not contain an open reading frame. Sense and antisense UCN RNA were co-expressed in all tissues that contained levels of either transcript detectable by RPA. Sense RNA expression was greater than antisense in the midbrain, the two transcripts were expressed equally in the hypothalamus and antisense was expressed at higher levels than sense in the liver, heart, and skeletal muscle. Antisense RNA expression was stress responsive, suggesting that it may play a role in regulating transcription or translation of UCN mRNA.

[Effects of total flavones of metasequosia on left ventricular hypertrophy due to pressure overload in rats].

OBJECTIVE: To determine the preventive and regressive effects of total flavones of metasequosia (TFM) on left ventricular hypertrophy in rats. METHOD: Left ventricular hypertrophy was inducedin by partial ligation of abdominal aorta. The rats were given ig TFM(4, 40, 400 mg.kg-1.d-1) for six weeks. RESULT: TFM markedly reduced the HW/BW, LVW/BW, myofibril diameter and Ca2+ content in left ventricles but the systolic blood pressure (SBP) in rats wasn't obviously influenced. CONCLUSION: TFM can prevent and reverse the left ventricular hypertrophy due to pressure overload in rats. The mechanism may be related to its calcium antagonistic properties.

[Kidney reinforcing and yang supporting action of cistanche deserticola Y. C. Ma before and after preparation].

The weights of seminal vesicle and prostate gland of castrated young rats were significantly increased by administration of alcoholsoluble extract from decoction of Cistanche deserticola. The weights of testes, seminal vesicle and prostate gland in mice and rats were also increased by the extract. The phagocytic function of intra-abdominal macrophage in mice was activated by decoction of Cistanche deserticola. The results showed no statistical differences between crude and prepared drugs. The maximum oral tolerance for mouse was 40 g/kg.

[Comparison between Cistanche deserticola Y. C. Ma and C, tubulosa (Shenk) Wight on some pharmacological actions].

The weights of seminal vesicle and prostate gland of castrated young rats were significantly increased by administration of alcohol soluble extract from the decoction of Cintanche deserticola, C. tubulosa and soaked C. deserticola. The phagocytic function of intra-abdominal macrophage in mice was activated by the decoction of C. deserticola and C. tubulosa.

[Stimulating action of Carthamus tinctorius L., Angelica sinensis (Oliv.) Diels and Leonurus sibiricus L. on the uterus].

The experimental results indicate that the decoction of Chinese drugs Carthamus tinctorius, Angelica sinensis and Leonurus sibiricus has stimulating action on the uterus of mouse in vitro. The stimulating action of Carthamus tinctorius and Leomurus sibiricus has been found related to stimulating H1-receptor and alpha-adrenergic receptor of uterus, but the action of Angelica sinensis to stimulating H1-receptor of uterus only.

[Effect of Chinese herbal preparation on major constituents of bile of gallstones patients].

From 1991 to 1993, 51 patients in 3 groups who had received biliary operation with T tube drainage were selected for observation of dynamic change in bile acid, bilirubin, cholesterol and mucin in the bile within 3 days after taking the Danyihewei granule (DYHW) and Rongshisan (RSS). Result showed that in DYHW group the bile acid increased significantly on the 2nd and 3rd day (P < 0.01), along with significant lowering of bilirubin (P < 0.01) and mucin (P < 0.05, P < 0.01) in 1st through 3rd day. In the RSS group the bile acid remarkably increased on the 3rd day (P < 0.05) with significant reduction of bilirubin (P < 0.01) on 2nd and 3rd day. The control group showed no remarkable change. The bile acid/bilirubin and bile acid/cholesterol ratios all had a dynamic increase with 3 days in treated group. Whereas the control group remained unchanged. Therefore the DYHW and RSS were able to produce a strong inhibitory effect on stone-forming bile through regulation of liver and discharge of bile.

[Comparison between actions of shiquandabu pills and shiquandabu liquor on immunological parameters in mice].

The comparison shows that both Shiquandabu pills and Shiquandabu liquor are efficacious in strengthening the immunological functions of mice. No significant difference has been found between the two forms of preparation. There exists a good dose-efficacy relationship for the pills in immunological functions.

[Effect of insulin therapy on abnormal bone and mineral metabolism in chronic streptozotocin-induced diabetic rat].

By use of histomorphometry and photon and physical, calcium homeostasis, bone morphology, bone mass and bone growth were studied in freely fed control, streptozotocin-induced diabetic, long-term and short-term insulin treated diabetic rats 14 weeks after the induction of diabetes. We conclude that untreated chronic streptozotocin-induced diabetic rat could result in abnormal bone and mineral metabolism, which is characterized by hypercalciuria, hyperphosphaturia and hyperphosphatemia, significant bone loss and growth arrest. The extent of bone loss correlated with the duration of the disease process. The anatomical basis of bone mass reduction is the diminution of osteoblasts activity which results in reduction of bone formation and insufficient bone calcification and relative increment of osteoclasts activity. Thus, bone resorption overweight bone formation leading to a negative balance of bone remodeling. The effect of PTH and CT on bone changes in diabetic rats can't be affirmed in our experiments. It is probable that metabolic disorder and/or insulin deficiency has a direct effect on bone changes. Insulin therapy started earlier in the course can prevent and somewhat later can completely normalize the altered skeletal morphology of diabetic rats. Whether this result is due to direct effect of insulin on skeletal tissue or through the correction of metabolic disorder remains to be resolved.

[Determination of multiple chemical elements in CSF in Parkinson disease after intracerebral autotransplantation of the adrenal medulla].

The contents of indispensable major elements sodium (Na), phosphorus (P), calcium (Ca), magnesium (Mg), trace elements iron (Fe), copper (Cu), nickel (Ni), zinc (Zn), strontium (Sr), vanadium (V), chromium (Cr), manganese (Mn), molybdenum (Mo), and other elements lead (Pb), silicon (Si), aluminium (Al), titanium (Ti), barium (Ba), lanthanum (La), cadmium (Yb), cerium (Ce), scandium (Sc), silver (Ag), in cerebrospinal fluid (CSF) were measured in 13 patients suffering from Parkinson disease before and after autotransplantation of adrenal medulla. It was found that while the patients' objective symptoms were relieved and the contents of monoamine transmitters were changed, the contents of P, V, Co, Cr, in CSF increased significantly (P less than 0.05 or 0.01) at the first, 2nd, 4th, 6th, and 8th week, the contents of Mn in CSF also increased significantly at the first 4th week (P less than 0.05) but decreased significantly at the 8th week the contents of Zn in CSF increased significantly (P less than 0.05) at the 2nd week; Mo increased significantly (P less than 0.05 or 0.01) at the 4th and 8th week B increased significantly (P less than 0.05) at the first week; the contents of Ca, Na, Sr, Ba, Al, Ti, La, Ce, Yb, Sc, Ag in CSF increased significantly (P less than 0.05 or 0.01) at the 8th week, Mg, Fe, Cu Ni, Pb, Si, Cd remained unchanged after operation. The results suggest that the contents of these chemical elements can be affected by this kind of operation, indicating that these elements are involved in the pathogenesis of Parkinsonism.