A widespread family of heat-resistant obscure (Hero) proteins protect against protein instability and aggregation.

Proteins are typically denatured and aggregated by heating at near-boiling temperature. Exceptions to this principle include highly disordered and heat-resistant proteins found in extremophiles, which help these organisms tolerate extreme conditions such as drying, freezing, and high salinity. In contrast, the functions of heat-soluble proteins in non-extremophilic organisms including humans remain largely unexplored. Here, we report that heat-resistant obscure (Hero) proteins, which remain soluble after boiling at 95°C, are widespread in Drosophila and humans. Hero proteins are hydrophilic and highly charged, and function to stabilize various "client" proteins, protecting them from denaturation even under stress conditions such as heat shock, desiccation, and exposure to organic solvents. Hero proteins can also block several different types of pathological protein aggregations in cells and in Drosophila strains that model neurodegenerative diseases. Moreover, Hero proteins can extend life span of Drosophila. Our study reveals that organisms naturally use Hero proteins as molecular shields to stabilize protein functions, highlighting their biotechnological and therapeutic potential.

Identification of aminobenzoic acids as selective inhibitors of the N-terminal phosphatase of soluble epoxide hydrolase.

Soluble epoxide hydrolase (EC 3.3.2.10) is a key enzyme in the regulation of inflammation and metabolism, whereas, the role of its N-terminal phosphatase activity (N-phos) has been poorly understood because of a lack of selective inhibitors. Here we report 4-aminobenzoic (Ki 15.3 µm) and 3-amino-4-hydroxy benzoic acid (Ki 11.7 µm) as selective competitive inhibitors of N-phos.

A quantitative method to detect non-antithrombin-binding 3-O-sulfated units in heparan sulfate.

Heparan sulfate is synthesized by most animal cells and interacts with numerous proteins via specific sulfation motifs to regulate various physiological processes. Various 3-O-sulfated motifs are considered to be key in controlling the binding specificities to the functional proteins. One such motif synthesized by 3-O-sulfotransferase-1 (3OST-1) serves as a binding site for antithrombin (AT) and has been thoroughly studied because of its pharmacological importance. However, the physiological roles of 3-O-sulfates produced by other 3OST isoforms, which do not bind AT, remain obscure, in part due to the lack of a standard method to analyze this rare modification. This study aims to establish a method for quantifying 3-O-sulfated components of heparan sulfate, focusing on non-AT-binding units. We previously examined the reaction products of human 3OST isoforms and identified five 3-O-sulfated components, including three non-AT-binding disaccharides and two AT-binding tetrasaccharides, as digestion products of heparin lyases. In this study, we prepared these five components as a standard saccharide for HPLC analysis. Together with eight non-3-O-sulfated disaccharides, a standard mixture of 13 units was prepared. Using reverse-phase ion-pair HPLC with a postcolumn fluorescent labeling system, the separation conditions were optimized to quantify the 13 units. Finally, we analyzed the compositional changes of 3-O-sulfated units in heparan sulfate from P19 cells before and after neuronal differentiation. We successfully detected the 3-O-sulfated units specifically expressed in the differentiated neurons. This is the first report that shows the quantification of three non-AT-binding 3-O-sulfated units and establishes a new approach to explore the physiological functions of 3-O-sulfate.

Direct cell-cell interaction regulates division of stem cells from PC-3 human prostate cancer cell line.

Cancer stem cells (CSCs) are a subpopulation that can drive recurrence and metastasis. Therefore, therapies targeting CSCs are required. Although previous findings have suggested that non-CSCs regulate the proliferation and differentiation of CSCs in the tumor microenvironment, the precise molecular mechanism is largely unknown. In this study, we found that a direct interaction between CSCs and non-CSCs downregulated CSC division in the PC-3 human prostate cancer cell line. We found that the proliferation of PC-3-derived CSCs (PrSCs) was significantly decreased (∼47%) in the presence of non-CSC-rich parental PC-3 cells compared with that in a culture in which they were absent. We observed no differences in PrSC proliferation when we indirectly cocultured them with PC-3 cells across a Transwell insert, and PrSCs that were transiently bound to immobilized PC-3 cells proliferated more slowly than those bound to PrSCs. The frequency of cell division with prior PrSC-PrSC contact was 2.8 times higher in the PrSC monoculture compared with that in the coculture with PC-3 cells. We found that the PrSCs were approximately 1.3 times more closely associated in the monoculture compared with the coculture with PC-3 cells, as determined by a cell proximity assay. The frequency of asymmetric PrSC division was 6.5% in the monoculture compared with 1.0% in the coculture with PC-3 cells (P < 0.045). By analyzing our data, we determined the importance of PrSC-non-CSC contact in regulating the frequency and mode of PrSC division. This regulation might be a valuable target for treating cancer.

Impact of SMTP Targeting Plasminogen and Soluble Epoxide Hydrolase on Thrombolysis, Inflammation, and Ischemic Stroke.

Stachybotrys microspora triprenyl phenol (SMTP) is a large family of small molecules derived from the fungus S. microspora. SMTP acts as a zymogen modulator (specifically, plasminogen modulator) that alters plasminogen conformation to enhance its binding to fibrin and subsequent fibrinolysis. Certain SMTP congeners exert anti-inflammatory effects by targeting soluble epoxide hydrolase. SMTP congeners with both plasminogen modulation activity and anti-inflammatory activity ameliorate various aspects of ischemic stroke in rodents and primates. A remarkable feature of SMTP efficacy is the suppression of hemorrhagic transformation, which is exacerbated by conventional thrombolytic treatments. No drug with such properties has been developed yet, and SMTP would be the first to promote thrombolysis but suppress disease-associated bleeding. On the basis of these findings, one SMTP congener is under clinical study and development. This review summarizes the discovery, mechanism of action, pharmacological activities, and development of SMTP.

[Surgical Treatment and Outcomes for Synchronous Multiple Lung Cancer].

OBJECTIVES: With the advent of high-resolution chest imaging systems and lung cancer screening programs, the number of patients diagnosed with multiple primary lung cancers is increasing. For the treatment of multiple lung cancers, a surgical procedure that preserves the lung function while ensuring curability is required. We herein report the surgical strategy and outcomes of synchronous multiple lung cancer. SUBJECTS: The subjects were 83 patients with synchronous multiple lung cancer who received surgical resection between January 2010 and March 2020. Cases within the same lobe were excluded, and only cases with two or more lobes involved were included in this study. RESULTS: The study enrolled 39 male and 44 female patients, and the mean age was 67.8 years old. Sixty-five patients had cancers within a unilateral lobe, and all had undergone surgery for one term. Eighteen patients had cancers in bilateral lobes, and 17 of them received secondary surgery for more advanced cancer. Bilobectomy was performed in 9 patients( 10.8%), consisting of 5 upper-middle lobectomies, 3 middle-lower lobectomies, and 1 right middle lobectomy with left lower lobectomy. Seventy-four patients (89.2%) underwent combination surgery with sublobar resection, such as segmentectomy and partial resection. Pneumonectomy was not performed in any patients. The histologic type was adenocarcinoma in 78 patients (94.0%), and 37 patients (47.4%) had adenocarcinoma in situ. Regarding the most advanced pathological stage, 57 patients( 68.7%) were stage≤Ⅰ, and 26( 31.3%) were stage≥Ⅱ. Postoperative complications were observed in 29 patients( 34.9%), and persistent pulmonary fistula of ≥7 days after the surgery was the most common, being observed in 16 patients. Operative death within 30 days after surgery occurred in 2 patients( 2.4%)[ due to pneumonia in 1 and cerebral infarction in 1]. None of the patients required home oxygen therapy after surgery. Recurrence occurred in 20 patients;14 of these had pathological stage ≥Ⅱ, 11 had lymph node metastases, and 2 had pleural dissemination. The recurrence patterns were metastasis to other organs, pleural dissemination, or lymph node metastasis;no local recurrence was observed. The mean recurrence-free survival was 32.4 months, and the five-year survival rate was 84.8%. On comparing outcomes according to the most advanced pathological stage, the five-year survival rate for stage ≤Ⅰdisease was 94.9%, and that for stage ≥Ⅱ disease was 61.7%, showing a significantly better prognosis for stage ≤Ⅰdisease (p<0.001). CONCLUSIONS: Selecting an appropriate operative procedure for synchronous multiple lung cancer renders the prognosis equivalent to that of single cancer. Surgical treatments, including sublobar resection, are thus deemed important.

In vitro reconstitution of chaperone-mediated human RISC assembly.

To silence target mRNAs, small RNAs and Argonaute (Ago) proteins need to be assembled into RNA-induced silencing complexes (RISCs). Although the assembly of Drosophila melanogaster RISC was recently reconstituted by Ago2, the Dicer-2/R2D2 heterodimer, and five chaperone proteins, the absence of a reconstitution system for mammalian RISC assembly has posed analytical challenges. Here we describe reconstitution of human RISC assembly using Ago2 and five recombinant chaperone proteins: Hsp90ß, Hsc70, Hop, Dnaja2, and p23. Our data show that ATP hydrolysis by both Hsp90ß and Hsc70 is required for RISC assembly of small RNA duplexes but not for that of single-stranded RNAs. The reconstitution system lays the groundwork for further studies of small RNA-mediated gene silencing in mammals.

Epigenetic silencing of core histone genes by HERS in Drosophila.

Cell cycle-dependent expression of canonical histone proteins enables newly synthesized DNA to be integrated into chromatin in replicating cells. However, the molecular basis of cell cycle-dependency in the switching of histone gene regulation remains to be uncovered. Here, we report the identification and biochemical characterization of a molecular switcher, HERS (histone gene-specific epigenetic repressor in late S phase), for nucleosomal core histone gene inactivation in Drosophila. HERS protein is phosphorylated by a cyclin-dependent kinase (Cdk) at the end of S-phase. Phosphorylated HERS binds to histone gene regulatory regions and anchors HP1 and Su(var)3-9 to induce chromatin inactivation through histone H3 lysine 9 methylation. These findings illustrate a salient molecular switch linking epigenetic gene silencing to cell cycle-dependent histone production.

N-Substituted amino acid inhibitors of the phosphatase domain of the soluble epoxide hydrolase.

The soluble epoxide hydrolase (sEH) is a bifunctional enzyme implicated in the regulation of inflammation. The N-terminal domain harbors a phosphatase activity (N-phos) with an affinity to lipid phosphomonoesters, and the C-terminal domain has an activity to hydrolyze anti-inflammatory lipid epoxides (C-EH). Although many potent inhibitors of C-EH have been discovered, little is known about inhibitors of N-phos. Here, we identify N-substituted amino acids as selective inhibitors of N-phos. Many of the N-substituted amino acids inhibited differently mouse and human N-phos; phenylalanine derivatives are relatively selective for mouse N-phos, whereas tyrosine derivatives are more selective for human N-phos. The best inhibitors, Fmoc-l-Phe(4-CN) (67) and Boc-l-Tyr(Bzl) (23), inhibited mouse and human N-phos competitively with KI in the low micromolar range. These compounds inhibit the N-phos activity 37- (67) and 137-folds (23) more potently than the C-EH. The differences in inhibitor structure activity suggest different active site structure between species, and thus, probably a divergent substrate preference between mouse and human N-phos.

Neuroprotective effects of SMTP-44D in mice stroke model in relation to neurovascular unit and trophic coupling.

Stachybotrys microspora triprenyl phenol (SMTP)-44D has both anti-oxidative and anti-inflammatory activities, but its efficacy has not been proved in relation to the pathological changes of neurovascular unit (NVU) and neurovascular trophic coupling (NVTC) in ischemic stroke. Here, the present study was designed to assess the efficacies of SMTP-44D, moreover, compared with the standard neuroprotective reagent edaravone in ischemic brains. ICR mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 60 min, SMTP-44D (10 mg/kg) or edaravone (3 mg/kg) was intravenously administrated through subclavian vein just after the reperfusion, and these mice were examined at 1, 3, and 7 d after reperfusion. Compared with the vehicle group, SMTP-44D treatment revealed obvious ameliorations in clinical scores and infarct volume, meanwhile, markedly suppressed the accumulations of 4-HNE, 8-OHdG, nitrotyrosine, RAGE, TNF-α, Iba-1, and cleaved caspase-3 after tMCAO. In addition, SMTP-44D significantly prevented the dissociation of NVU and improved the intensity of NAGO/BDNF and the number of BDNF/TrkB and BDNF/NeuN double positive cells. These effects of SMTP-44D in reducing oxidative and inflammatory stresses were similar to or stronger than those of edaravone. The present study demonstrated that SMTP-44D showed strong anti-oxidative, anti-inflammatory, and anti-apoptotic effects, moreover, the drug also significantly improved the NVU damage and NVTC in the ischemic brain.

Correction to: Radiopharmaceutical tracers for cardiac imaging.

Regrettably the original version of the above article contained errors in the three chemical structures presented in the 'Atherosclerosis imaging' section of Table 5, namely: 99mTc annexin V, 68Ga DOTATATE, and 64Cu DOTATATE; the chemical structures have been corrected in Table presented here. In addition, the radiopharmaceutical for isotope 67Ga has been corrected to 67Ga citrate, and many of the radiopharmaceuticals presented at the end of the table have been corrected.

Radiopharmaceutical tracers for cardiac imaging.

Cardiovascular disease (CVD) is the leading cause of death and disease burden worldwide. Nuclear myocardial perfusion imaging with either single-photon emission computed tomography or positron emission tomography has been used extensively to perform diagnosis, monitor therapies, and predict cardiovascular events. Several radiopharmaceutical tracers have recently been developed to evaluate CVD by targeting myocardial perfusion, metabolism, innervation, and inflammation. This article reviews old and newer used in nuclear cardiac imaging.

A histone chaperone, DEK, transcriptionally coactivates a nuclear receptor.

Chromatin reorganization is essential for transcriptional control by sequence-specific transcription factors. However, the molecular link between transcriptional control and chromatin reconfiguration remains unclear. By colocalization of the nuclear ecdysone receptor (EcR) on the ecdysone-induced puff in the salivary gland, Drosophila DEK (dDEK) was genetically identified as a coactivator of EcR in both insect cells and intact flies. Biochemical purification and characterization of the complexes containing fly and human DEKs revealed that DEKs serve as histone chaperones via phosphorylation by forming complexes with casein kinase 2. Consistent with the preferential association of the DEK complex with histones enriched in active epigenetic marks, dDEK facilitated H3.3 assembly during puff formation. In some human myeloid leukemia patients, DEK was fused to CAN by chromosomal translocation. This mutation significantly reduced formation of the DEK complex, which is required for histone chaperone activity. Thus, the present study suggests that at least one histone chaperone can be categorized as a type of transcriptional coactivator for nuclear receptors.

Reduction of Ischemia Reperfusion-Related Brain Hemorrhage by Stachybotrys Microspora Triprenyl Phenol-7 in Mice With Antioxidant Effects.

BACKGROUND: Stachybotrys microspora triprenyl phenol-7 (SMTP-7) has both thrombolytic and anti-inflammatory effects, but its neuroprotective effects on cerebral ischemia are still unclear. The present study assessed the antioxidative and neurovascular unit (NVU) protective effects of SMTP-7 using transient middle cerebral artery occlusion (tMCAO) mice. METHODS: After 60 minutes tMCAO, 0.9% NaCl, tissue-type plasminogen activator (tPA), SMTP-7 or tPA + SMTP-7 was intravenously administrated through subclavian vein just before the reperfusion, and these mice were examined at 24 hours after reperfusion. We histologically assessed the hemorrhage and expressive changes of antioxidative markers in brains. RESULTS: SMTP-7 treatment showed a similar antithrombotic effect to tPA, but significantly decreased the hemorrhage volumes and the number of 4-HNE, 3-NT and 8-OHdG positive cells, meanwhile, ameliorated the decrease of collagen IV in the ischemic brains. However, tPA + SMTP-7 treatment did not decrease hemorrhage volumes nor showed NVU protective effect. CONCLUSIONS: The present study suggested that SMTP-7 provided therapeutic benefits for ischemic stroke through antioxidative and NVU protective effects unlike tPA alone or tPA + SMTP-7.

Antineuroinflammatory Effect of SMTP-7 in Ischemic Mice.

BACKGROUND: Stachybotrys microspora triprenyl phenol-7 (SMTP-7) has both potentials of thrombolytic and neuroprotective effects, but its detailed neuroprotective mechanisms in ischemic stroke are still unclear. Here, we assessed the neuroprotective effects of SMTP-7 for anti-inflammatory and antiapoptosis mechanisms after 60 minutes of transient middle cerebral artery occlusion (tMCAO) in mice. METHODS: After 60minutes of tMCAO, 0.9% NaCl, tissue-type plasminogen activator (tPA), SMTP-7 or tPA+SMTP-7 was intravenously administrated through subclavian vein just before the reperfusion, and these mice were examined at 24hours after reperfusion. We histologically assessed the antineuroinflammatory effect of SMTP-7 on the expressive changes of inflammatory markers in ischemic mouse brains. RESULTS: Compared with the vehicle and tPA groups, SMTP-7 treatment significantly improved clinical scores and decreased the infarct volume and the numbers of TNF-α, nuclear factor-κB (NF-κB), nucleotide oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3), and cleaved caspase-3-positive cells in the brain of mice at 24hours after tMCAO but not p62-positive cells. However, tPA+SMTP-7 treatment did not show such effects. CONCLUSIONS: The present study suggested that SMTP-7 provides a therapeutic benefit for ischemic stroke mice through anti-inflammatory and antiapoptotic effects but not antiautophagic effect.

[Outcome of Surgical Treatment of Locally Advanced Lung Cancer after Induction Chemoradiotherapy].

OBJECTIVE: The outcome of surgical treatment of non-small-cell lung cancer after induction chemoradiotherapy was investigated. SUBJECTS: The subjects were 74 patients with non-small-cell lung cancer who received induction chemoradiotherapy( ICRT) between 1998 and 2016. ICRT was administered to pT3 lung cancer invading the chest wall(20 patients), pT4 lung cancer invading the adjacent organ(22 patients), and cN2 lung cancer(32 patients). cN2 was confirmed by mediastinoscopy(13 patients) and endobronchial ultrasound-guided transbronchial needle aspiration(EBUS-TBNA)(19 patients). RESULTS: Sixty-eight and 6 patients were male and female, respectively, and the mean age was 59.6 years old. The histologic type was adenocarcinoma in 43 patients, squamous cell carcinoma in 24, adenosquamous carcinoma in 5, and others in 2. In chemotherapy, 2 or more anticancer drugs including platinum agent were administered. The radiation dosage was 36 Gy in 1 patient, 40 Gy in 43, 50 Gy in 28, and 60 Gy in 2. The effect of ICRT was complete response( CR) in 1 patient, partial response( PR) in 40, and stable disease (SD) in 33 (CR+PR:55.4%). The surgical procedure was lobectomy in 60 patients, pneumonectomy in 10, bilobectomy in 3, and segmentectomy in 1. Tracheobronchoplasty was performed in 9 patients, and combined resection of the vertebral body, left atrium, carina, superior vena cava, aorta, and brachiocephalic subclavian artery was performed in 7, 5, 4, 3, 3, and 3 patients, respectively. Regarding postoperative complications, empyema developed in 5 patients, acute respiratory distress syndrome(ARDS)in 3, pneumonia in 3, tracheobronchial dehiscence in 2, postoperative hemorrhage in 1, atrial fibrillation in 1, and others in 5. Postoperative complication rate was 27.0%, and operative death occurred due to postoperative hemorrhage in 1 patient. Complete resection was achieved in 69 patients(93.2%). Regarding the histological effect of ICRT, Ef.1/2/3 = 32/28/14(Ef.2-3:56.7%), and down stage was achieved in 24 patients (32.4%). The 5-year survival rate of all 74 patients was 51.0%, median survival time (MST)was 62.7 months, and the recurrence-free survival rate was 47.3%. Recurrence occurred in 28 patients (40.6%)with complete resection and the recurrence was distant metastasis in 20 of them. Regarding the outcome by the effect of ICRT, the 5-year survival rates of patients who achieved CR+PR/SD, Ef.2-3/Ef.0-1, and down stage/non-down stage were 66.0%/34.3%(p=0.009), 73.2%/20.1%(p=0.001), and 83.7%/44.0%(p=0.02), respectively, showing that the outcomes of patients who achieved CR/PR, Ef.2-3, and down stage were significantly favorable. CONCLUSION: The morbidity and mortality rates of patients who underwent surgery after ICRT were 27 and 1.4%, respectively. More than half of the patients achieved CR-PR and Ef.2-3, 1/3 of the cases were down staged, and the outcomes of these patients were significantly favorable. Surgery after ICRT may improve the treatment outcome of patients with locally advanced lung cancer.

[A Patient with Lung Adenocarcinoma, Lymphangitis Carcinomatosa, and Multiple Bone Metastases Who Achieved Long-Term Survival after Successful Treatment with Carboplatin, Paclitaxel, and Bevacizumab].

BACKGROUND: Lymphangitis carcinomatosa of the lung is intractable and associated with a poor prognosis. CASE: A 53-year-old woman was admitted to our hospital due to an uncomfortable feeling on deep inspiration. She was diagnosed with left lung adenocarcinoma with lymphangitis carcinomatosa and bone metastases to the frontal bone of the skull and thoracic vertebrae. The lung carcinoma was positive for an EGFR mutation. Because the patient's performance status (PS) was 0, carboplatin plus paclitaxel plus bevacizumab therapy was initiated and she received zoledronic acid and concurrent radiation therapy of 40 Gy for the metastasis to the thoracic vertebrae. After 2 courses of treatment, the respiratory symptoms had improved. After 6 courses of treatment, a chest CT indicated that the lymphangitis carcinomatosa had disappeared. The serum CEA level, which was 126.2 ng/mL (normal<5.0) before treatment, reduced to 5.0 ng/mL. She was administered 10 courses of bevacizumab as a maintenance therapy; however, the CEA level rose again to 11.7 ng/mL, the lung tumor volume increased, and the metastasis of the frontal bone deteriorated. As second-line chemotherapy, EGFR-TKI was started. However, after 11 months, because of grade 4 liver dysfunction, EGFR-TKI was stopped. She then received fourth-line chemotherapy in our outpatient hospital. This patient has survived 52 months since the initial diagnosis. CONCLUSION: Chemotherapy including bevacizumab facilitated long-term survival (52 months) of a patient with lung adenocarcinoma accompanied by lymphangitis carcinomatosa and multiple bone metastases.

Soluble epoxide hydrolase as an anti-inflammatory target of the thrombolytic stroke drug SMTP-7.

Although ischemic stroke is a major cause of death and disability worldwide, only a small fraction of patients benefit from the current thrombolytic therapy due to a risk of cerebral hemorrhage caused by inflammation. Thus, the development of a new strategy to combat inflammation during thrombolysis is an urgent demand. The small molecule thrombolytic SMTP-7 effectively treats ischemic stroke in several animal models with reducing cerebral hemorrhage. Here we revealed that SMTP-7 targeted soluble epoxide hydrolase (sEH) to suppress inflammation. SMTP-7 inhibited both of the two sEH enzyme activities: epoxide hydrolase (which inactivates anti-inflammatory epoxy-fatty acids) and lipid phosphate phosphatase. SMTP-7 suppressed epoxy-fatty acid hydrolysis in HepG2 cells in culture, implicating the sEH inhibition in the anti-inflammatory mechanism. The sEH inhibition by SMTP-7 was independent of its thrombolytic activity. The simultaneous targeting of thrombolysis and sEH by a single molecule is a promising strategy to revolutionize the current stroke therapy.

Down-regulation of NF kappa B activation is an effective therapeutic modality in acquired platinum-resistant bladder cancer.

BACKGROUND: No previous study has addressed the efficacy of NF-κB blockade when bladder tumors develop acquired resistance toward CDDP-treatments. We investigated the changes in NF-κB activation and therapeutic impact of NF-κB blockade by the novel NF-κB inhibitor dehydroxymethyl derivative of epoxyquinomicin (DHMEQ) in CDDP-resistant bladder cancer cells. METHODS: Two human invasive bladder cancer cell lines, T24 and T24PR, were used. The T24PR cell line was newly established as an acquired platinum-resistant subline by culturing in CDDP-containing medium for 6 months. Expression of intranuclear p65 protein in the fractionated two cell lines was determined by Western blotting analysis. DNA-binding activity of NF-κB was detected by electrophoretic mobility shift assay. The cytotoxic effects and induction of apoptosis were analyzed in vivo and in vitro. RESULTS: Intranuclear expression and DNA-binding activity of p65 were strongly enhanced in T24PR cells compared with those of T24 cells, and both were significantly suppressed by DHMEQ. Lowered cell viability and strong induction of apoptosis were observed by treatment with DHMEQ alone in these chemo-resistant cells compared with parent cells. As T24PR cells did not show dramatic cross-resistance to paclitaxel in the in vitro study, we next examined whether the combination of DHMEQ with paclitaxel could enhance the therapeutic effect of the paclitaxel treatment in T24PR tumors. Using mouse xenograft models, the mean volume of tumors treated with the combination of DHMEQ (2 mg/kg) and paclitaxel (10 mg/kg) was significantly smaller than those treated with paclitaxel alone (p < 0.05), and the reduction of tumor volume in mice treated with DHMEQ in combination with paclitaxel and paclitaxel alone as compared to vehicle control was 66.9% and 17.0%, respectively. CONCLUSION: There was a distinct change in the activation level of NF-κB between T24 and T24PR cells, suggesting strong nuclear localization of NF-κB could be a promising target after developing acquired platinum-resistance in bladder cancer.

Ischaemic memory imaging using metabolic radiopharmaceuticals: overview of clinical settings and ongoing investigations.

"Ischaemic memory" is defined as a prolonged functional and/or biochemical alteration remaining after a particular episode of severe myocardial ischaemia. The biochemical alteration has been reported as metabolic stunning. Metabolic imaging has been used to detect the footprint left by previous ischaemic episodes evident due to delayed recovery of myocardial metabolism (persistent dominant glucose utilization with suppression of fatty acid oxidation). ß-Methyl-p-[(123)I]iodophenylpentadecanoic acid (BMIPP) is a single-photon emission computed tomography (SPECT) radiotracer widely used for metabolic imaging in clinical settings in Japan. In patients with suspected coronary artery disease but no previous myocardial infarction, BMIPP has shown acceptable diagnostic accuracy. In particular, BMIPP plays an important role in the identification of prior ischaemic insult in patients arriving at emergency departments with acute chest pain syndrome. Recent data also show the usefulness of (123)I-BMIPP SPECT for predicting cardiovascular events in patients undergoing haemodialysis. Similarly, SPECT or PET imaging with (18)F-FDG injected during peak exercise or after exercise under fasting conditions shows an increase in FDG uptake in postischaemic areas. This article will overview the roles of ischaemic memory imaging both under established indications and in ongoing investigations.