A prediction nomogram for perineural invasion in colorectal cancer patients: a retrospective study.

BACKGROUND: Perineural invasion (PNI), as the fifth recognized pathway for the spread and metastasis of colorectal cancer (CRC), has increasingly garnered widespread attention. The preoperative identification of whether colorectal cancer (CRC) patients exhibit PNI can assist clinical practitioners in enhancing preoperative decision-making, including determining the necessity of neoadjuvant therapy and the appropriateness of surgical resection. The primary objective of this study is to construct and validate a preoperative predictive model for assessing the risk of perineural invasion (PNI) in patients diagnosed with colorectal cancer (CRC). MATERIALS AND METHODS: A total of 335 patients diagnosed with colorectal cancer (CRC) at a single medical center were subject to random allocation, with 221 individuals assigned to a training dataset and 114 to a validation dataset, maintaining a ratio of 2:1. Comprehensive preoperative clinical and pathological data were meticulously gathered for analysis. Initial exploration involved conducting univariate logistic regression analysis, with subsequent inclusion of variables demonstrating a significance level of p < 0.05 into the multivariate logistic regression analysis, aiming to ascertain independent predictive factors, all while maintaining a p-value threshold of less than 0.05. From the culmination of these factors, a nomogram was meticulously devised. Rigorous evaluation of this nomogram's precision and reliability encompassed Receiver Operating Characteristic (ROC) curve analysis, calibration curve assessment, and Decision Curve Analysis (DCA). The robustness and accuracy were further fortified through application of the bootstrap method, which entailed 1000 independent dataset samplings to perform discrimination and calibration procedures. RESULTS: The results of multivariate logistic regression analysis unveiled independent risk factors for perineural invasion (PNI) in patients diagnosed with colorectal cancer (CRC). These factors included tumor histological differentiation (grade) (OR = 0.15, 95% CI = 0.03-0.74, p = 0.02), primary tumor location (OR = 2.49, 95% CI = 1.21-5.12, p = 0.013), gross tumor type (OR = 0.42, 95% CI = 0.22-0.81, p = 0.01), N staging in CT (OR = 3.44, 95% CI = 1.74-6.80, p < 0.001), carcinoembryonic antigen (CEA) level (OR = 3.13, 95% CI = 1.60-6.13, p = 0.001), and platelet-to-lymphocyte ratio (PLR) (OR = 2.07, 95% CI = 1.08-3.96, p = 0.028).These findings formed the basis for constructing a predictive nomogram, which exhibited an impressive area under the receiver operating characteristic (ROC) curve (AUC) of 0.772 (95% CI, 0.712-0.833). The Hosmer-Lemeshow test confirmed the model's excellent fit (p = 0.47), and the calibration curve demonstrated consistent performance. Furthermore, decision curve analysis (DCA) underscored a substantial net benefit across the risk range of 13% to 85%, reaffirming the nomogram's reliability through rigorous internal validation. CONCLUSION: We have formulated a highly reliable nomogram that provides valuable assistance to clinical practitioners in preoperatively assessing the likelihood of perineural invasion (PNI) among colorectal cancer (CRC) patients. This tool holds significant potential in offering guidance for treatment strategy formulation.

The dual-targeting mechanism of an anti-inflammatory diarylheptanoid from Curcuma zedoaria (Christm.) Roscoe with the capacity for ß2-adrenoreceptor agonism and NLRP3 inhibition.

Chronic obstructive pulmonary disease (COPD) is a common respiratory disease characterized by symptoms of shortness of breath and chronic inflammation. Curcuma zedoaria (Christm.) Roscoe is a well-documented traditional medical herb that is frequently used in the treatment of COPD. Previously, we identified a diarylheptanoid compound (1-(4-hydroxy-5-methoxyphenyl)-7-(4,5-dihydroxyphenyl)-3,5-dihydroxyheptane; abbreviated as HMDD) from this herb that exhibited potent agonistic activity on ß2-adrenergic receptors (ß2 adrenoreceptor) that are present on airway smooth muscle cells. In this work, we used chemically synthesized HMDD compound, and confirmed its bioactivity on ß2 adrenoreceptors. Then by a proteomics study and anti-inflammatory evaluation detections, we found that HMDD downregulated the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) signaling pathway and suppressed the NLRP3 receptor expression in RAW264.7 macrophages and in a COPD model in A549 lung carcinoma cells. HMDD also decreased nitric oxide production levels, and impacted other interleukins and the phosphorylation of NF-κB and ERK pathways. We performed molecular docking of HMDD on ß2 adrenoreceptor and NLRP3 protein models. This work reports the anti-inflammatory effects of HMDD and suggests a dual-targeting mechanism of ß2-adrenoreceptor agonism and NLRP3 inhibition. Such a mechanism scientifically supports the clinical uses of Curcuma zedoaria (Christm.) Roscoe in treating COPD, as it can simultaneously relieve persistent breathlessness and inflammation. HMDD can be considered as a potential non-steroidal anti-inflammatory drug in novel therapy design for the treatment of COPD and other inflammatory diseases.

Latest advances in the regulatory genes of adipocyte thermogenesis.

An energy imbalance cause obesity: more energy intake or less energy expenditure, or both. Obesity could be the origin of many metabolic disorders, such as type 2 diabetes and cardiovascular disease. UCP1 (uncoupling protein1), which is highly and exclusively expressed in the thermogenic adipocytes, including beige and brown adipocytes, can dissipate proton motive force into heat without producing ATP to increase energy expenditure. It is an attractive strategy to combat obesity and its related metabolic disorders by increasing non-shivering adipocyte thermogenesis. Adipocyte thermogenesis has recently been reported to be regulated by several new genes. This work provided novel and potential targets to activate adipocyte thermogenesis and resist obesity, such as secreted proteins ADISSP and EMC10, enzyme SSU72, etc. In this review, we have summarized the latest research on adipocyte thermogenesis regulation to shed more light on this topic.

FXYD6 Regulates Chemosensitivity by Mediating the Expression of Na+/K+-ATPase α1 and Affecting Cell Autophagy and Apoptosis in Colorectal Cancer.

PURPOSE: Chemoresistance is a challenge of improving chemotherapeutic efficacy and prolonging survival time for patients with colorectal cancer (CRC); it is the major cause of frequent recurrence, rapid metastasis, and poor prognosis for CRC patients. FXYD6 is a regulator of Na+/K+-ATPase which is depressed in chemoresistant CRC patients. However, the biological roles of FXYD6 on regulating chemoresistance in CRC are still unclear. METHODS: GSE3964 and GSE69657 from GEO DataSets were used to analyze the relationship of genes and chemoresistance. The FXYD6 expression level was detected by western blotting and real-time PCR and also analyzed from TCGA DataSet. To investigate the functional role of FXYD6 and ATP-α1, FXYD6 and ATP-α1 functional cell models were constructed. Drug sensitivity and cell proliferation were performed by MTT assay. Autophagy and apoptosis were conducted by autophagy fluorescence analysis and flow cytometric analysis, respectively. Autophagy and apoptosis markers were tested by western blotting. RESULTS: FXYD6 was downregulated in CRC resistant patients and irinotecan- (Iri-) resistant SW620 cells (SW620/Iri). FXYD6 silence inhibited cell apoptosis and enhanced prosurvival autophagy, whereas FXYD6 overexpression produced the opposite effect which alleviated the drug resistance to irinotecan and oxaliplatin of CRC cells. FXYD6 regulates chemosensitivity by mediating the expression of Na+/K+-ATPase α1 and affecting cell autophagy and apoptosis in colorectal cancer. CONCLUSION: FXYD6 functions as a chemosensitivity regulator which may predict the curative effect of chemotherapy in colorectal cancer.

Pyrroloquinoline quinone promotes mitochondrial biogenesis in rotenone-induced Parkinson's disease model via AMPK activation.

Mitochondrial dysfunction is considered to be one of the important pathogenesis in Parkinson's disease (PD). We previously showed that pyrroloquinoline quinone (PQQ) could protect SH-SY5Y cells and dopaminergic neurons from cytotoxicity and prevent mitochondrial dysfunction in rotenone-induced PD models. In the present study we investigated the mechanisms underlying the protective effects of PQQ in a mouse PD model, which was established by intraperitoneal injection of rotenone (3 mg·kg-1·d-1, ip) for 3 weeks. Meanwhile the mice were treated with PQQ (0.8, 4, 20 mg·kg-1·d-1, ip) right after rotenone injection for 3 weeks. We showed that PQQ treatment dose-dependently alleviated the locomotor deficits and nigral dopaminergic neuron loss in PD mice. Furthermore, PQQ treatment significantly diminished the reduction of mitochondria number and their pathological change in the midbrain. PQQ dose-dependently blocked rotenone-caused reduction in the expression of PGC-1α and TFAM, two key activators of mitochondrial gene transcription, in the midbrain. In rotenone-injured human neuroblastoma SH-SY5Y cells, PTMScan Direct analysis revealed that treatment with PQQ (100 µM) differentially regulated protein phosphorylation; the differentially expressed phosphorylated proteins included the signaling pathways related with adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) pathway. We conducted Western blot analysis and confirmed that AMPK was activated by PQQ both in PD mice and in rotenone-injured SH-SY5Y cells. Pretreatment with AMPK inhibitor dorsomorphin (4 µM) significantly attenuated the protective effect and mitochondrial biogenesis by PQQ treatment in rotenone-injured SH-SY5Y cells. Taken together, PQQ promotes mitochondrial biogenesis in rotenone-injured mice and SH-SY5Y cells via activation of AMPK signaling pathway.

Outcomes for Hyperthermia Combined with Concurrent Radiochemotherapy for Patients with Cervical Cancer.

PURPOSE: To evaluate the effect of hyperthermia combined with concurrent radiochemotherapy (RCT) and treatment-related toxicity in patients with cervical cancer (CC) stage IB-IV. METHODS AND MATERIALS: This study was conducted between 2009 and 2013 in patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB-IV CC. The patients were randomly assigned into 2 treatment groups: RCT and RCT plus hyperthermia (RCHT). Five-year survival, treatment-related toxicity, and other prognostic factors were evaluated. RESULTS: Three hundred seventy-three patients completed treatment and were analyzed by per-protocol (PP) analysis. The 5-year overall survival (OS) in the RCHT group (81.9%) was better than that in RCT group (72.3%), and the log-rank test showed a statistically significant difference between the 2 groups (P = .040). Univariate and multivariate Cox regression analysis for 5-year OS showed a statistically significant difference (P = .043, P = .045, respectively). The 5-year local relapse-free survival in RCHT (86.8%) was also better than that in RCT (82.7%), but the difference was not significant. Acute or late toxicity was not significantly different between the 2 groups. Advanced clinical stage (FIGO) and larger tumor size showed higher risk of death and a relatively poor prognosis in univariate and multivariate analysis. CONCLUSIONS: The study confirmed that hyperthermia combined with RCT yielded a better 5-year OS in CC. Acute and late toxicity was similar between the RCT and RCHT groups. Clinical stage (FIGO) and tumor size were independent prognostic factors in CC.

Involvement of Akt/mTOR in the Neurotoxicity of Rotenone-Induced Parkinson's Disease Models.

Rotenone has recently been widely used to establish Parkinson's disease (PD) models to replicate the features of PD. However, the mechanisms involved in rotenone neurotoxicity have not been elucidated. The aim of the present study was to identify the neurotoxicity of rotenone through intraperitoneal injection in mice and to investigate the global changes of phosphorylation proteomic profiles in rotenone-injured SH-SY5Y cells through a label-free proteomic analysis using a PTMScan with LC-MS/MS. ICR (Institute of Cancer Research) mice were intraperitoneally injected with different dosages of rotenone (1 mg/kg/d or 3 mg/kg/d) daily for 21 consecutive days. Rotenone caused a dose-dependent decrease in locomotor activities and a decrease in the number of Nissl-positive and tyrosine hydroxylase (TH)-immunoreactive neurons in the substantia nigra pars compacta (SNpc). Here, 194 phosphopeptides on 174 proteins were detected in SH-SY5Y cells, and 37 phosphosites on 33 proteins displayed statistically significant changes in expression after rotenone injury. The downregulation of phosphorylated Akt and mTOR was further confirmed by western blot analysis. A specific Akt activator, SC79, could protect cell viability and induce autophagy in rotenone-injured SH-SY5Y cells. This study indicates the involvement of the Akt/mTOR (mammalian target of rapamycin) signaling pathway in rotenone-injured SH-SY5Y cells and provides molecular information for the neurotoxicity of rotenone.

Mitochondrial regulation by pyrroloquinoline quinone prevents rotenone-induced neurotoxicity in Parkinson's disease models.

Pyrroloquinoline quinone (PQQ), a redox cofactor in the mitochondrial respiratory chain, has been reported to protect SH-SY5Y cells from cytotoxicity induced by rotenone, a mitochondrial complex I inhibitor. In this study, we aimed to investigate the mitochondrial mechanisms involved in the neuroprotection of PQQ both in vitro and in vivo. The cultured human SH-SY5Y neuroblastoma cells were exposed to different concentrations of PQQ after which the cells were treated with rotenone. Electron microscopy images showed that PQQ could prevent the mitochondrial morphology damage. The down-regulation of mitochondrial biogenesis related genes (PGC-1alpha and TFAM) and mitochondrial fission and fusion related genes (Drp1and Mfn2) in rotenone-injured SH-SY5Y cells could be inhibited by PQQ. PQQ could also promote the transposition of Drp1 and Mfn2 from cytosol to mitochondria. In addition, rotenone was injected into the left medial forebrain bundle of SD rats to establish a Parkinson's disease (PD) model in vivo, after which different doses of PQQ or Edaravone were given intraperitoneally once daily for 8 weeks. PQQ could up-regulate the mRNA levels of PGC-1alpha, TFAM, Drp-1 and Mfn2 in the midbrain of PD rats. Our findings indicated that PQQ could prevent mitochondrial dysfunction by promoting mitochondrial biogenesis and regulating mitochondrial fission and fusion, which might contribute to its neuroprotective effect in PD models.

Analysis of soluble components in coals and interpretations for the complex mass spectra.

RATIONALE: The deduction of useful information from the mass spectra of a complex mixture like coals remains difficult, which limits the clean and efficient utilization of coals. It is necessary to explore the data interpretation methods for mass spectra and visualize the analytical data of coals for industrial utilization such as feedstock selection. METHODS: Coal sample and methanol were mixed and heated to 310 °C and kept at that temperature for 2 h. The solvent was under supercritical state at 310 °C and the solubility for the solid mixture increased. Soluble products from thermal dissolution of two Chinese coals were analyzed by high-performance liquid chromatography/atmospheric pressure chemical ionization orbitrap mass spectrometry. RESULTS: The iso-abundance plot for molecules in coals was upgraded to display the distributions of isomers which are indicated as concentric circles or triangles with the same carbon number and value of double-bond equivalent. The concentration ratio was introduced from economics to describe the content inequality of organic species within the same class of coal molecules. CONCLUSIONS: Interpretation methods for mass spectra visualize and simplify the understanding of complex components in coals for industrial utilization. Coals with a high concentration ratio for a specific class should take priority as a feedstock for chemicals and receive more attention. Copyright © 2016 John Wiley & Sons, Ltd.

Randomized phase III trial of radiotherapy or chemoradiotherapy with topotecan and cisplatin in intermediate-risk cervical cancer patients after radical hysterectomy.

BACKGROUND: In cervical cancer patients with intermediate-risk factors, the optimal adjuvant therapy is still controversial. We undertook a randomized trial (ClinicalTrials.gov Identifier: NCT01418859) to compare the efficacy and toxicity of concurrent chemoradiotherapy with topotecan and cisplatin with radiotherapy alone in intermediate-risk cervical cancer patients. METHODS: Eligible patients were randomly assigned to one of three treatment arms including arm A (radiotherapy only,RT), arm B(concurrent chemoradiotherapy only, CCRT), and arm C (concurrent chemoradiotherapy with following consolidation chemotherapy, CCRT + CT). All eligible patients completed external RT (IMRT or 3D-CRT), receiving 45-50 Gy /25 f uniformly to the pelvis. Concurrent chemotherapy regimen was topotecan 0.75 mg/m(2) for days 1, 2 and 3, followed by cisplatin 25 mg/m(2) for days 1, 2 and 3. Three cycles of consolidation chemotherapy regimen was topotecan 1.5 mg/m(2) for days 1 and 2, and 0.75 mg/m(2) for day 3; followed by cisplatin 25 mg/m(2) for days 1, 2 and 3, repeated every 21 days. Adverse events of each group were investigated and compared. RESULTS: Thirty-nine patients enrolled onto the remaining regimens: 14 to RT, 15 to CCRT and 10 to CCRT + CT. Six patients (15.4%) did not complete the protocol treatment. Hematologic toxicity was more frequent and more severe in the CCRT and CCRT + CT arms compared with the RT arm. The incidence of grade 3-4 neutropenia was significantly different statistically between the RT, CCRT and CCRT + RT groups (15.4%, 46.7% and 100%, respectively; P = 0.002). Specially, three patients in CCRT + CT arm of all six patients who did not complete the protocol treatment discontinued planned therapy because of persistent grade 4 neutropenia. However, there were no significant differences in grade 3-4 non-hematologic toxicities between the three groups(all P > 0.05). Recurrence-free survival and overall survival of each group were not analyzed on account of a median follow-up of only 16 months. CONCLUSIONS: Concurrent chemoradiotherapy with topotecan and cisplatin showed severe hematologic toxicity in intermediate-risk cervical cancer patients after radical hysterectomy. Thus, the study was closed ahead of schedule. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01418859 .

[Concurrent chemoradiotherapy followed by consolidation chemotherapy and sequential chemoradiotherapy for stage III non-small cell lung cancer: comparison in 93 patients].

OBJECTIVE: To compare the efficacy and toxicity of concurrent chemoradiotherapy followed by consolidation chemotherapy (CCRT-CT) and sequential chemoradiotherapy (SCRT) in the treatment of stage III non-small cell lung cancer. METHODS: From February, 2007 to June, 2010, 93 patients with unresectable stage III non-small cell lung cancer were treated with SCRT or CCRT-CT. SCRT group (50 cases) received radiotherapy after 2-6 cycles of chemotherapy (median 2 cycles) followed by 0-4 cycles (median 2 cycles) of chemotherapy. CCRT-CT group (43 cases) received 2 cycles of chemotherapy every 3 weeks with concurrent radiotherapy followed by 2-4 cycles (median 2 cycles) of chemotherapy with the same drugs. The chemotherapy consisted of cisplatin plus gemcitabine, docetaxel or vinorelbine. Radiotherapy was administered using two-dimensional conformal irradiation (36-40 Gy/18-20f) followed by three-dimensional conformal boost to 56-70 Gy/28-35f (median DT64Gy) or using three-dimensional conformal irradiation 50-74 Gy/25-37f (median DT62Gy). RESULTS: The response rates were 76.7% and 54.0% in CCRT-CT and SCRT group, respectively (P<0.05). The median progression-free time in the two groups was 16.0 and 10.0 months, with the overall survival time of 18.0 and 12.5 months, respectively. The 1-, 2- and 3-year overall survival rates were 83.7%, 48.8% and 20.9% in CCRT-CT group and 52.0%, 20.0%, and 2.0% in SCRT group, respectively (P<0.05). CCRT-CT group showed a significantly lower rate of distant metastasis than SCRT group (P<0.05), but the local recurrence rate was similar between the two groups. The main side effects included radiation pneumonitis, radiation esophagitis, nausea/vomiting and anemia/leucopenia/thrombocytopenia. CCRT-CT group had a significantly higher rate of III-IV grade nausea/vomiting and anemia/leucopenia/thrombocytopenia than SCRT group. CONCLUSION: Compared to SCRT, CCRT-CT can improve the response rate, progression free survival and overall survival and decrease the rate of distant metastasis, but is associated with a higher toxicity.

Characterization of 9-nitrocamptothecin liposomes: anticancer properties and mechanisms on hepatocellular carcinoma in vitro and in vivo.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third most common cause of cancer related mortality worldwide. 9-Nitrocamptothecin (9NC) is a potent topoisomerase-I inhibitor with strong anticancer effect. To increase the solubility and stability, we synthesized a novel 9NC loaded liposomes (9NC-LP) via incorporating 9NC into liposomes. In the present study, we determined the effects of 9NC and 9NC-LP on in vitro and in vivo, and the underlying mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: We first analyzed the characteristics of 9NC-LP. Then we compared the effects of 9NC and 9NC-LP on the proliferation and apoptosis of HepG2, Bel-7402, Hep3B and L02 cells in vitro. We also investigated their anticancer properties in nude mice bearing HCC xenograft in vivo. 9NC-LP has a uniform size (around 190 nm) and zeta potential (∼-11 mV), and exhibited a steady sustained-release pattern profile in vitro. Both 9NC and 9NC-LP could cause cell cycle arrest and apoptosis in a dose-dependent and p53-dependent manner. However, this effect was not ubiquitous in all cell lines. Exposure to 9NC-LP led to increased expression of p53, p21, p27, Bax, caspase-3, caspase-8, caspase-9 and apoptosis-inducing factor, mitochondrion-associated 1 and decreased expression of Bcl-2, cyclin E, cyclin A, Cdk2 and cyclin D1. Furthermore, 9NC-LP exhibited a more potent antiproliferative effect and less side effects in vivo. Western blot analysis of the xenograft tumors in nude mice showed similar changes in protein expression in vivo. CONCLUSIONS/SIGNIFICANCE: In conclusion, 9NC and 9NC-LP can inhibit HCC growth via cell cycle arrest and induction of apoptosis. 9NC-LP has a more potent anti-tumor effect and fewer side effects in vivo, which means it is a promising reagent for cancer therapy via intravenous administration.

[Study on esterified modification of anthocyanins by FTIR].

Anthocyanins are relatively abundant in vegetables and fruits, which have potential positive health effects. The role of anthocyanins as food coloring agents becomes very important because they can provide attractive bright color of many food products. Nevertheless, the instability of natural anthocyanins was a big obstacle for its usage in food as colorants. The stability of the red radish anthocyanins is significantly improved by modified esterification of the colorant. Usually, the red radish anthocyanins was composed of several components of similar structures. The major methods for determining the structures of anthocyanin colorants involve chromatographic techniques such as TLC, HPLC and HPLC-MS, which are very useful in separation and identification of the components of anthocyanins However, compared to the spectroscopic method, the chromatographic methods are usually complicated and time-consuming during separation and analysis. In the present paper, the authors seek to establish a new, rapid and economic method for the analysis of structural change before and after esterified modification of anthcyanins in view of unique macro-fingerprint characteristics of infrared spectroscopy, which could reflect the whole change of complicated mixture system. The anthocyanins from red radish was esterification-modified by reacting with succinic anhydride, and the natural and modified anthocyanins were detected by FTIR The results showed that carbonyl of succinic anhydride was connected with the hydroxyl in glucosyl rings of anthocyanins to form new esterified anthocyanins, which are more stable than the natural one and present attractive bright color as usual.

[Study of intra-operative radiotherapy in primary liver cancer].

OBJECTIVE: To study the feasibility of intraoperative radiotherapy (IORT) in primary liver cancer. METHODS: Based on the target of dose curves, the dose-volume histogram (DVH) and cost of radiation equipment and radiation therapy, IORT was compared with protonbeam therapy (PBT) and 3DCRT in 16 patients with primary liver cancer using the therapy plan system (TPS). RESULTS: IORT had significantly better performance than 3DCRT to allow a target region surrounded by 90% of the dose lines. IORT was similar to protonbeam therapy in terms of target region surroundings and absorbed dose in the normal organs, but the cost of IORT was significantly lower. CONCLUSION: The TPS of IORT is better than 3DCRT and similar to protonbeam therapy in the treatment of primary liver cancer with similar cost to 3DCRT. IORT can effectively protect the neighboring sensitive organs and improve the absorbed dose in the tumors and the local control rate.

Differential alteration of heat shock protein 90 in mice modifies glucocorticoid receptor function and susceptibility to trauma.

Heat shock protein 90 (Hsp90), encoded by the murine hsp84 and hsp86 genes in mice, is a pivotal regulator of glucocorticoid receptor (GR) function in the hypothalamus-pituitary-adrenal axis and affords stress protection. To explore the underlying molecular mechanisms of strain susceptibility to traumatic stress, we investigated the alteration by Hsp90 of the function of the glucocorticoid-glucocorticoid receptor (GC-GR) pathway in attenuating stress responses in C57BL/6 and BALB/c mice using the whole-body blast injury (WBBI) model. We found that C57BL/6 mice had a lower WBBI-induced mortality, higher nuclear GR level, and higher glucocorticoid-response element (GRE) binding activity than BALB/c mice. This study is the first report identifying four genetic variations of the murine hsp84 gene: 226A>C, 996G>C, 1483G>C, and 2000G>T. These nucleotide changes occur in the functional domains associated with the nuclear/cytosolic translocation of GR, GR-Hsp90 interaction, ATP binding, and self-dimerization of Hsp90, respectively. Further, we used a specific Hsp90 inhibitor, geldanamycin (GA), to assess the role of Hsp90 in the discriminative traumatic response in C57BL/6 mice. Pretreatment with GA reduced nuclear GR levels and GRE binding activity, and enhanced WBBI-induced mortality. These findings suggest that Hsp90 may underlie the strain-selective (C57BL/6 versus BALB/c) susceptibility to WBBI by mediating the nuclear translocation of GRs and GRE binding. Thus, pharmacological manipulation of Hsp90 may represent a therapeutic strategy to modify the function of the GC-GR pathway and traumatic stress response.

[Clinical pharmacokinetic study of cisplatin in enhancing cervical cancer radiosensitivity].

OBJECTIVE: To evaluate the pharmacokinetics of cisplatin in enhancing the radiosensitivity of stage IIa-IIb bulky cervical cancer. METHODS: Thirty-six patients with stage IIa-IIb bulky cervical cancer were treated intravenously with cisplatin (30 mg/m(2)) and cisplatin levels were measured in tumor tissues and serum of the patients at the random time points of 1, 2, 4, 6, 10, 18, and 24 h following the injection. Cisplatin levels were also measured in the tissues following administration of different radiation doses by flameless atomic absorption spectrometry. RESULTS: Cisplatin level in the tumor tissues was the highest at 4 h following the injection, and its serum level showed obvious reduction within 2 h following the injection. Radiation increased cisplatin level in the tumor tissue. CONCLUSION: Cisplatin level reaches the highest level in the cancer tissue at 4 h following intravenous injection, a time when cisplatin can best execute its effect in enhancing the radiosensitivity of cervical cancer, and cisplatin administration in later stage of radiotherapy may achieve better effect than early stage administration.