Glu1022.53-Mediated Early Conformational Changes in the Process of Light-Induced Green Cone Pigment Activation.

Ligand-triggered activation of G protein-coupled receptors (GPCRs) relies on the phenomenon of loose allosteric coupling, which involves conformational alterations spanning from the extracellular ligand-binding domain to the cytoplasmic region, where interactions with G proteins occur. During the GPCR activation process, several intermediate and equilibrium states orchestrate the movement of the flexible and rigid transmembrane (TM) segments of the GPCR. Monitoring early conformational changes is important in unraveling the structural intricacies of the loose allosteric coupling. Here, we focus on the lumi intermediate formed by thermal relaxation from the initial photointermediate, batho in primate green cone pigment (MG), a light-sensitive GPCR responsible for color vision. Our findings from light-induced Fourier transform infrared difference spectroscopy reveal its similarity with rhodopsin, which mediates twilight vision, specifically involving the flip motion of the ß-ionone ring, the relaxation of the torsional structure of the retinal, and local perturbations in the α-helix upon lumi intermediate formation. Conversely, we observe a hydrogen bond modification specific to MG's protonated carboxylic acid, identifying its origin as Glu1022.53 situated in TM2. The weakening of the hydrogen bond strength at Glu1022.53 during the transition from the batho to the lumi intermediates corresponds to a slight outward movement of TM2. Additionally, within the X-ray crystal structure of the rhodopsin lumi intermediate, we note the relocation of the Met862.53 side chain in TM2, expanding the volume of the retinal binding pocket. Consequently, the position of 2.53 emerges as the early step in the conformational shift toward light-induced activation. Moreover, given the prevalence of IR-insensitive hydrophobic amino acids at position 2.53 in many rhodopsin-like GPCRs, including rhodopsin, the hydrogen bond alteration in the C═O stretching band at Glu1022.53 of MG can be used as a probe for tracing conformational changes during the GPCR activation process.

Long-term effect of pulmonary rehabilitation in idiopathic pulmonary fibrosis: a randomised controlled trial.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterised by worsening dyspnoea and exercise intolerance. RESEARCH QUESTION: Does a long-term pulmonary rehabilitation improve exercise tolerance in patients with IPF treated with standard antifibrotic drugs, which are expected to reduce disease progression? METHODS: This open-label randomised controlled trial was performed at 19 institutions. Stable patients receiving nintedanib were randomised into pulmonary rehabilitation and control groups (1:1). The pulmonary rehabilitation group underwent initial rehabilitation which included twice-weekly sessions of monitored exercise training for 12 weeks, followed by an at-home rehabilitation programme for 40 weeks. The control group received usual care only, without pulmonary rehabilitation. Both groups continued to receive nintedanib. The primary and main secondary outcomes were change in 6 min walking distance (6MWD) and change in endurance time (using cycle ergometry) at week 52. RESULTS: Eighty-eight patients were randomised into pulmonary rehabilitation (n=45) and control (n=43) groups. Changes in 6MWD were -33 m (95% CI -65 to -1) and -53 m (95% CI -86 to -21) in the pulmonary rehabilitation and control groups, respectively, with no statistically significant difference (mean difference, 21 m (95% CI -25 to 66), p=0.38). Changes in endurance time were significantly better in the pulmonary rehabilitation (64 s, 95% CI -42.3 to 171)) than in the control (-123 s (95% CI -232 to -13)) group (mean difference, 187 s (95% CI 34 to 153), p=0.019). INTERPRETATION: Although pulmonary rehabilitation in patients taking nintedanib did not improve 6MWD in the long term, it led to prolonged improvement in endurance time. TRIAL REGISTRATION NUMBER: UMIN000026376.

An anti-alcoholism drug, disulfiram and copper complex improves radio-resistance of tumor-initiating cells in esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a malignant cancer with a poor prognosis. Chemoradiotherapy is one of the most important strategies for patients with locally advanced unresectable ESCC; however, its therapeutic effect is unsatisfactory. Tumor-initiating cells (TICs) have been reported to be resistant to conventional chemotherapy and radiotherapy so far. Therefore, we aimed to develop a treatment strategy targeting TICs in ESCC to improve radiosensitivity. METHODS: First, we validated aldehyde dehydrogenase 1 (ALDH1) as a TIC marker and investigated its ability to mediate resistance in human ESCC cell lines using flow cytometry, Western blotting, and functional analyses. Then, we focused on disulfiram (DSF), an aldehyde dehydrogenase inhibitor, used to treat alcohol use disorder. We investigated the effect of DSF and copper (II) D-gluconate (Cu) on the radiosensitivity of ESCC in xenograft mouse models. RESULTS: ALDH1-positive cells showed an upregulation of SOX2 and Nanog, exhibiting much stronger tumor-initiating properties than ALDH1-negative cells. Furthermore, inhibition of ALDH1 attenuated the tumor-initiating properties of ESCC cell lines. Our results also showed that ALDH1-positive cells were resistant to chemotherapy and radiotherapy, and the inhibition of ALDH1 led to the mitigation of therapeutic resistance. Our in vitro and in vivo studies revealed that the DSF/Cu complex could radiosensitize ALDH1-positive ESCC cells and downregulate the phosphoinositide 3-kinase/Akt pathway. CONCLUSION: ALDH1 inhibition by the DSF/Cu complex enhances the radiosensitivity of TICs in ESCC. The drug repositioning approach using disulfiram is a potential treatment option to overcome radioresistance in patients with locally advanced ESCC.

Gut microbiome can predict chemoradiotherapy efficacy in patients with esophageal squamous cell carcinoma.

PURPOSE: The gut microbiome plays an important role in cancer pathogenesis and therapy. Some studies have reported that specific bacteria in tumor tissues may contribute to the prognosis and treatment of esophageal squamous cell carcinoma (ESCC). However, there is limited evidence that the gut microbiome is associated with ESCC. This study assessed the utility of the gut microbiome as a predictive marker of the therapeutic effect in patients with ESCC undergoing chemo-radiotherapy (CRT). PATIENTS AND METHODS: Fecal samples were collected from 51 patients with ESCC who had never undergone treatment between April 2021 and May 2022 in the Department of Frontier Surgery, Chiba University. The gut microbiome was analyzed using 16S metagenomics sequencing. The association between the gut microbiome composition and stage according to the TNM classification (American Joint Committee on Cancer 7.0) and CRT response according to the RECIST criteria was evaluated. RESULTS: The relative abundance of Fusobacteriaceae was enriched in cStage III-IVb group. Among the 27 patients who received CRT, the relative abundance of Lactobacillaceae was enriched in those with a partial and complete response. Lactobacillaceae also did not correlate with any clinical data, but the high Lactobacillales group had a higher LMR (P = 0.032) and lower PLR (P = 0.045) than in the low Lactobacillales group. CONCLUSIONS: In conclusion, we found that the relative abundance of Lactobacillaceae was enriched in patients with a partial or complete response among CRT those with ESCC, thus suggesting that the relative abundance of Lactobacillaceae can predict the effect of CRT.

Metformin-Induced Heat Shock Protein Family A Member 6 Is a Promising Biomarker of Esophageal Squamous Cell Carcinoma.

INTRODUCTION: Antidiabetic drug metformin exerts various antitumor effects on different cancers. Esophageal squamous cell carcinoma (ESCC) is an intractable digestive organ cancer and new treatment strategy is required. In this study, we performed a comprehensive gene expression analysis of ESCC cell lines treated with metformin, which provided helpful information on the antitumor effects of metformin in ESCC. Next, we selected a promising gene among them and examined its effects on ESCC properties. METHODS: We examined metformin-induced mRNA expression changes in two human ESCC cell lines by performing next-generation sequencing (NGS) and pathway analysis. Heat shock protein family A (Hsp70) member 6 (HSPA6) expression in surgical specimens obtained from 83 ESCC patients who underwent curative operations was evaluated immunohistochemically and analyzed. RESULTS: Metformin upregulated mRNA expression of the many genes, including HSPA6, a cancer immune-related gene, and inhibited mRNA expression of the other many genes. Pathway analysis indicated major canonical pathways and upstream regulators related to metformin. The result indicated HSPA6 as a promising biomarker. HSPA6 expression correlated with disease-free survival (DFS) of the patients with all stage ESCC (p = 0.021), especially with stage I/II ESCC (p < 0.001). With stage III, low HSPA6 expression was not associated with poor DFS (p = 0.918). Multivariate analysis indicated that independent low HSPA6 expression was an independent poor prognostic factor of stage I/II ESCC (p < 0.001). However, HSPA6 expression did not correlate with the clinicopathological characteristics, including age, sex, tumor depth, lymph node metastasis, tumor stage, and tumor markers of the patients with stage I/II ESCC. CONCLUSIONS: This NGS analysis detected prospective candidate genes, including HSPA6. Our results indicate that HSPA6 is a promising biomarker of the recurrence risk of stage I/II ESCC. Further studies on HSPA6 would lead to better treatment.

Role of Gln114 in Spectral Tuning of a Long-Wavelength Sensitive Visual Pigment.

Visual pigments of the long-wavelength sensitive opsin group (L group) are anion sensitive in nature. Their highly conserved amino acid residues, H197 and K200, exclusively interact with a chloride ion (Cl-) in the chromophore-binding pocket. Substitution of H197 completely abolishes Cl- binding and results in an ∼30 nm spectral blue-shift. Recent attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy studies of monkey green sensitive pigment have provided insights into the role of Cl- binding in stabilizing the antiparallel ß-sheet at extracellular loop 2 (ECL2). In addition to maintaining the dark state of L opsins, Cl- binding is also believed to play a crucial role in spectral tuning. Here, we used a combination of site-directed mutagenesis in combination with UV-visible spectroscopy to show that Q1142.65 that is positioned far from ECL2 is also a crucial residue for the Cl- effect in L opsins. Comprehensive FTIR spectroscopic analyses on both ion-binding-induced and light-induced structural changes revealed that Q1142.65 contributes to the stability of ß-sheet structure indirectly even though Q1142.65 is not located in ECL2. Overall, these structure-function studies are important for understanding the functional role of Cl- binding in L opsins.

Common-signal-induced synchronization in photonic integrated circuits and its application to secure key distribution.

We experimentally achieve common-signal-induced synchronization in two photonic integrated circuits with short external cavities driven by a constant-amplitude random-phase light. The degree of synchronization can be controlled by changing the optical feedback phase of the two photonic integrated circuits. The change in the optical feedback phase leads to a significant redistribution of the spectral energy of optical and RF spectra, which is a unique characteristic of PICs with the short external cavity. The matching of the RF and optical spectra is necessary to achieve synchronization between the two PICs, and stable synchronization can be obtained over an hour in the presence of optical feedback. We succeed in generating information-theoretic secure keys and achieving the final key generation rate of 184 kb/s using the PICs.

Nucleotide excision repair-dependent DNA double-strand break formation and ATM signaling activation in mammalian quiescent cells.

Histone H2A variant H2AX is phosphorylated at Ser(139) in response to DNA double-strand break (DSB) and single-stranded DNA (ssDNA) formation. UV light dominantly induces pyrimidine photodimers, which are removed from the mammalian genome by nucleotide excision repair (NER). We previously reported that in quiescent G0 phase cells, UV induces ATR-mediated H2AX phosphorylation plausibly caused by persistent ssDNA gap intermediates during NER. In this study, we have found that DSB is also generated following UV irradiation in an NER-dependent manner and contributes to an earlier fraction of UV-induced H2AX phosphorylation. The NER-dependent DSB formation activates ATM kinase and triggers the accumulation of its downstream factors, MRE11, NBS1, and MDC1, at UV-damaged sites. Importantly, ATM-deficient cells exhibited enhanced UV sensitivity under quiescent conditions compared with asynchronously growing conditions. Finally, we show that the NER-dependent H2AX phosphorylation is also observed in murine peripheral T lymphocytes, typical nonproliferating quiescent cells in vivo. These results suggest that in vivo quiescent cells may suffer from NER-mediated secondary DNA damage including ssDNA and DSB.

Improvement of the antitumor activity of poorly soluble sapacitabine (CS-682) by using Soluplus® as a surfactant.

Sapacitabine (CS-682 or CYC682; 1-[2-C-cyano-2-deoxy-ß-D-arabino-pentfuranosyl]N4-palmitoyl cytosine), a novel antitumor 2'-deoxycytidine analogue, shows a marked reduction in the water solubility because of the fatty acid side chain on the N4 group of the cytosine moiety. Poor water solubility is one of the important reasons why sapacitabine does not exert maximum antitumor activity. Therefore, we attempted to improve the water solubility of sapacitabine using a novel surfactant, Soluplus®, which consisted of a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In this study, we examined whether Soluplus® increased the water solubility and an antitumor activity of sapacitabine. The cytotoxicity of Soluplus® alone was lower than that of Tween 80 and Kolliphor® D-α-tocopherylpolyethylene glycol 1000 succinate (TPGS). The water solubility and the chemosensitivity of sapacitabine against several tumor cell lines to sapacitabine markedly increased upon using Soluplus®. In addition, the potential of Soluplus® including sapacitabine in increasing the antitumor activity was compared with sapacitabine alone in vivo. Although the total dose in the experimental period was considerably lower than the effective dose of sapacitabine alone, the life span of mice treated with sapacitabine containing 40 mg/mL Soluplus® increased by 150%. If Soluplus® was used as the solubilizing agent in clinical trials of sapacitabine, a low administration dose was appeared to require, and thus side effects might be prevented.

Small bowel adenocarcinomas with favorable prognoses by radical resection and adjuvant chemotherapy: a case series of five cases.

BACKGROUND: Small bowel cancer is very rare, accounting for less than 5% of all gastrointestinal cancers, and small bowel adenocarcinoma accounts for approximately 40% of all small bowel cancers. Small bowel adenocarcinoma is often found in advanced stages, with only 40-65% of cases being curatively resectable. The prognosis is poor, with a 5-year survival rate of 14-33% for all patients and 40-60% for those who are curatively resectable. In Japan, practice guidelines for duodenal cancer were instituted in 2021. However, evidence-based standard treatments have not been established for jejunal and ileal cancers. In particular, chemotherapeutic options are limited, and there are only a few reports on multidisciplinary treatments, including adjuvant chemotherapy. CASE PRESENTATION: We report five cases of jejunal or ileal lesions that were treated with adjuvant chemotherapy after radical resection. Three patients were male and two were female, with a median age of 67 years. Tumor localization was observed in the jejunum in all cases. Clinical staging was as follows: stage IIIA in two cases and stage IIIB in three cases. Laparotomy was then performed in all cases, employing partial resection with lymph node dissection. Pathological staging in all cases was as follows: stage IIB in two cases, stage IIIA in one case, and stage IIIB in two cases. In all cases, the regimen for adjuvant chemotherapy was selected based on the colorectal cancer guidelines. No serious complications arose from adjuvant therapy; however, adverse events occurred in patients receiving multi-agent chemotherapy. No recurrence was observed in any of the cases, and all the patients survived, with a median survival time of 32 months. As a representative case, we present a case of adjuvant chemotherapy for jejunal adenocarcinoma staged as pT3N2M0, pStage IIIB, with no recurrence at 32 months postoperatively. CONCLUSIONS: In general, favorable outcomes were achieved with adjuvant therapy applied in accordance with the criteria for colorectal cancer. These favorable outcomes suggest that it is necessary to identify the risk factors and indications for adjuvant therapy, specifically for small bowel adenocarcinoma.

Serum Versus Tissue SIRT1 as Potentially Valuable Biomarkers in Gastric Cancer.

BACKGROUND/AIM: We lack reports on the clinicopathological characteristics and prognostic value of serum sirtuin 1 (SIRT1) levels and their association with SIRT1 expression in tissues of patients with gastric cancer (GC). Thus, we investigated the pathological characteristics and prognostic values of SIRT1 tissue expression and its serum concentration in GC. Moreover, we investigated the correlation between these two factors. MATERIALS AND METHODS: A total of 78 patients with GC who underwent curative gastrectomy were evaluated in this study. The expression of SIRT1 in the surgical specimens was assessed using immunohistochemistry. Serum levels of SIRT1 were measured using an enzyme-linked immunosorbent assay. The association of tissue and serum SIRT1 with the clinicopathological features and prognosis were evaluated. RESULTS: Positive SIRT1 tissue expression was significantly related to an advanced cancer stage (p=0.017). Furthermore, a significant relationship existed between a positive SIRT1 tissue expression and poorer overall survival (OS) and relapse-free survival (RFS) (p=0.033 and p=0.033, respectively). In contrast, serum SIRT1 levels showed no significant association with clinicopathological characteristics besides age. In addition, no significant correlation was observed between tissue SIRT1 expression and serum SIRT1 concentration. CONCLUSION: Tissue SIRT1 expression may be a valuable novel prognostic biomarker; nonetheless, further studies are required to clarify the relationship between tissue SIRT1 expression and serum SIRT1 levels in GC.

Soluble PD­L1 reflects cachexia status in patients with gastric cancer and is an independent prognostic marker for relapse­free survival after radical surgery.

Soluble programmed death-ligand 1 (sPD-L1) levels can be used as a biomarker for gastric cancer (GC). However, comprehensive information regarding the sPD-L1 expression profiles and their association with cachexia in GC is lacking. Therefore, the present study evaluated the association between clinicopathological findings and sPD-L1 levels in patients with GC. Serum samples were collected from patients with GC during their first visit to Department of Esophageal-Gastro-Intestinal Surgery, Chiba University Hospital, Chiba, Japan (January 2012-December 2017; n=173), and sPD-L1 levels were measured using an enzyme-linked immunosorbent assay. Survival rates among 116 patients, excluding cases with preoperative chemotherapy or no radical procedures, were analyzed. sPD-L1 levels were associated with factors such as neutrophil-to-lymphocyte ratio, hemoglobin (Hb) and albumin (Alb) levels, total cholesterol and C-reactive protein (CRP) levels, and related to inflammation and nutrition in patients. Notably, the higher the number of applicable indicators related to cachexia (Hb <12 g/dl, Alb <3.2 g/dl, CRP >0.5 mg/dl and low body mass index) was, the higher the sPD-L1 value was. However, the pathological stage did not significantly differ between the groups. Clinicopathologically, there was no association with tumor depth, lymph node metastasis or vascular invasion; however, patients with the intestinal type had significantly higher sPD-L1 levels than patients with the diffuse type (P=0.032; Wilcoxon test). The overall survival did not significantly differ between the groups with low and high sPD-L1 levels; however, among patients who received radical treatment, the relapse-free survival was significantly worse in the high-sPD-L1-level group than in the low-sPD-L1-level group (P=0.025; log-rank test). Multivariate Cox regression analysis revealed that a high sPD-L1 concentration was a sign of poor prognosis, independent of pathological stage and cancer antigen CA19-9 (P=0.0029). Therefore, the present findings suggest that sPD-L1 can reflect cachexia status in patients with GC and may serve as a prognostic marker for relapse-free survival after radical GC surgery.

Apparent diffusion coefficient by magnetic resonance cholangiopancreatography is useful for grading cholecystitis and surgery planning.

INTRODUCTION: Laparoscopic cholecystectomy is a standard procedure for treating cholescytitis, but severe inflammation may cause complications. Our previous study showed that the apparent diffusion coefficient (ADC) values could predict difficult surgery. In the present study, relevance of ADC values in grading the severity of cholecystitis was pathologically investigated. METHODS: We retrospectively analyzed a total of 50 patients who underwent laparoscopic cholecystectomy or laparotomic cholecystectomy/choledocholithotomy. The degree of inflammation in the neck of the gall bladder was pathologically graded into three tiers (grade 1, mild; grade 2, moderate; grade 3, severe), and ulceration, lymphoid follicle formation, and wall thickness of the gallbladder neck were recorded. All factors were statistically compared with the measured ADC values. RESULTS: The ADC value was significantly lower in the severe inflammation group ( grade 3) than in the weak inflammation group (grades 1 and 2) (1.93 ± 0.22 vs 2.38 ± 0.67, respectively; P = .02). Ulceration and wall thickness in the gallbladder neck were significantly correlated with ADC values (P = .04 and .006, respectively), and lymphoid follicle formation was marginally correlated with ADC values (P = .06). The diagnostic utility of the ADC values decreased as the interval between imaging and cholecystectomy increased. [Correction added on 19 October 2022, after first online publication: [On the first sentence of the Results section, (grades 2 and 3) for weak inflammation group has been changed to (grades 1 and 2).] CONCLUSION: ADC values were inversely associated with the pathologic intensity of cholecystitis. We recommend that the ADC value be measured before surgery, so that the procedure can be accordingly planned.

SIRT1 Expression Is a Promising Prognostic Biomarker in Esophageal Squamous Cell Carcinoma: A Systematic Review and Meta-analysis.

Background/Aim: Several articles have assessed the prognostic significance of the expression of sirtuin 1 (SIRT1) in esophageal squamous cell carcinoma (ESCC). However, evidence in this field is insufficient. Thus, we conducted a meta-analysis to investigate the prognostic and clinical impact of SIRT1 expression in ESCC. Materials and Methods: We searched the PubMed, Cochrane Library, and Web of Science databases for articles on the expression of SIRT1 and clinicopathological features in patients with ESCC. A meta-analysis was conducted. Results: Four studies with 429 patients were included. The meta-analysis revealed a significant relationship between the high expression of SIRT1 and higher T-stage (odds ratio=2.39. 95% confidence interval=1.12-5.13, p=0.02), more advanced TNM stage (odds ratio=2.35. 95% confidence interval=1.20-4.60, p=0.01), and a poor overall survival (hazard ratio=1.90, 95% confidence interval=1.45-2.47, p<0.00001). Conclusion: SIRT1 expression may be a promising prognostic biomarker for patients with ESCC.

Preoperative prediction of difficult laparoscopic cholecystectomy based on diffusion-weighted magnetic resonance imaging.

INTRODUCTION: Laparoscopic cholecystectomy is a common surgery with a varying difficulty level. Difficult laparoscopic cholecystectomy may be experienced by many surgeons. If difficult procedures are predicted preoperatively, surgeons may be able to plan the surgical approach and treatment accordingly. Studies have reported using blood and clinical imaging data to predict difficult cholecystectomy. However, to our knowledge, no studies have reported using MRI. The purpose of this study was to evaluate the usefulness of MRI as a predictor of difficult laparoscopic cholecystectomy. METHODS: We retrospectively evaluated 25 patients with cholecystitis or biliary colic who had undergone diffusion-weighted whole-body imaging before laparoscopic cholecystectomy. The apparent diffusion coefficient value of the cystic duct was measured and its relationship with operative time and blood loss was examined to assess the capacity of diffuse-weighted whole-body imaging to predict difficult cholecystectomy. Further, we collected blood data and compared its usefulness as a predictor. RESULTS: The apparent diffusion coefficient value of the cystic duct was significantly lower in patients with difficult laparoscopic cholecystectomy than in those with non-difficult procedures (P = .00007). White blood cell count and serum C-reactive protein level were significantly higher in patients with difficult cholecystectomy than in those with non-difficult procedures (P = .035, .030). In the receiver operating characteristic analysis, the apparent diffusion coefficient value was the best predictor. CONCLUSION: Our results suggest that the apparent diffusion coefficient value of the cystic duct is a predictor of difficult laparoscopic cholecystectomy. In the future, it may be useful to study changes in coefficient values over time to determine optimal surgical timing.

Influence of cytidine deaminase on antitumor activity of 2'-deoxycytidine analogs in vitro and in vivo.

Antitumor 2'-deoxycytidine (dCyd) analogs such as gemcitabine (dFdC), cytarabine (Ara-C), and 2'-C-cyano-2'-deoxy-1-ß-d-arabinofuranosylcytosine (CNDAC) are activated by dCyd kinase, whereas cytidine deaminase (CDA) inactivates them by conversion to their uracil forms. To elucidate the relationship between the chemosensitivity to antitumor dCyd nucleosides and CDA expression, we established a stable line of human gastric carcinoma TMK-1 cells constitutively overexpressing CDA (TMK-1/CDA) and examined its chemosensitivity to antitumor dCyd analogs in vitro and in vivo. We observed comparable reactivity for dFdC and Ara-C, and the substrate reactivity of CNDAC to recombinant human CDA was more than 10 times less efficient than those of Ara-C and dFdC. Next, we examined the in vitro chemosensitivity of TMK-1/CDA and observed a marked decrease in the sensitivity of TMK-1/CDA to Ara-C, dFdC, and CNDAC compared with mock-transfected cells. In addition, we transplanted TMK-1/CDA cells into a nude mouse xenograft model and examined their in vivo chemosensitivity to CNDAC. The in vivo antitumor effect of CNDAC on TMK-1/CDA cells was substantially reduced compared with that of mice transplanted with mock-transfected cells. These results indicate that CDA could play an important role in regulating susceptibility to antitumor dCyd analogs in vitro and in vivo. In addition, the expression level of CDA was found to affect the antitumor activity of CNDAC, even though the substrate reactivity of CNDAC to CDA is relatively low.

1-(3-C-Ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd, TAS-106), a novel potent inhibitor of RNA polymerase, potentiates the cytotoxicity of CDDP in human cancer cells both in vitro and in vivo.

1-(3-C-Ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd, TAS-106) is a novel antitumor ribonucleoside that inhibits RNA polymerase. In the present study, we investigated the cellular and molecular interactions between TAS-106 and cisplatin (CDDP) in vitro using A549 human lung cancer cells and the in vivo antitumor effect of combined treatment using OCC-1 and LX-1 human tumor xenografts. The treatment effects were determined by evaluating cytotoxicity, the cell cycle distribution, apoptosis induction and the expression of checkpoint-associated proteins. In vitro, the combination of TAS-106 and CDDP synergistically inhibited the growth of A549 cells, as determined using isobologram analysis. TAS-106 potently inhibited the expression of Chk1 protein and the phosphorylation of Chk1 and Chk2. Moreover, based on the inhibition of checkpoint-associated protein, TAS-106 abrogated the CDDP-induced S- and G2M-checkpoints and induced apoptosis in A549 cells. In vivo, TAS-106 alone showed antitumor activity; however, its combination with CDDP significantly enhanced the growth inhibition of OCC-1 and LX-1 tumors. Moreover, combination therapy with TAS-106 and CDDP in the OCC-1 xenograft model resulted in significant life-prolongation. These findings provide a rationale for combination chemotherapy using TAS-106 and CDDP in clinical settings.

Safety and efficacy of bidirectional chemotherapy for treatment of patients with peritoneal dissemination from gastric cancer: Selection for cytoreductive surgery.

There is no standard treatment for peritoneal carcinomatosis (PC) from gastric cancer. New bidirectional chemotherapy (neoadjuvant intraperitoneal-systemic chemotherapy protocol (NIPS)) was developed. The aim of the present study was to assess the safety and efficacy of NIPS and to show the selection for cytoreductive surgery on PC from gastric cancer. Seventy-nine patients with PC from gastric cancer were treated with NIPS. A peritoneal port system was introduced into the abdominal cavity. The peritoneal wash cytological examination through a port was done before and after NIPS. The patients were treated with oral TS-1 twice a daily for 21 days, followed by a 1-week rest. On day 1, 8, and 15 from the start of oral TS-1 administration, 30 mg/m(2) of Docetaxel and 30 mg/m(2) of cisplatinum with 500 ml of saline were introduced into the peritoneal cavity through the port. A median course of oral TS-1 was 2.1 course and a median time of IP chemoterapy was 5.8. Peritoneal free cancer cells (PFCCs) had been detected in 65 (82.2%) patients before NIPS, and the positive cytology changed to be negative in 41 (63.0%) patients after NIPS. After NIPS, 41 patients underwent laparotomy, and complete cytoreduction was done in 32 (78%) patients. Complete cytoreduction was done in 27 (51.9%) of 52 patients with negative cytology but in only 4 (14.8%) of 27 patients with positive cytology (P < 0.001). Patients with negative cytology after NIPS survived significantly longer than those with positive cytology. The adverse effects after NIPS were mild and there was no treatment-related deaths. The grade 3/4 hematological adverse effects were found in 2 (2.6%) patients. Grade 3 renal toxicity and port site infection was found in three patients, respectively. NIPS using a port system is a safe and effective treatment for PC. Peritoneal wash cytology through a port system is a good indicator to select the patients to perform cytoreductive surgery.

Synthesis, configurational stability and stereochemical biological evaluations of (S)- and (R)-5-hydroxythalidomides.

The first asymmetric synthesis of (S)- and (R)-5-hydroxythalidomides, one of thalidomide's major metabolites, was achieved using HMDS/ZnBr(2)-induced imidation as a key reaction. 5-Hydroxythalidomide was found to be configurationally more stable than thalidomide at physiological pH. Stereochemical biological effects of thalidomide and 5-hydroxythalidomide on anti-angiogenesis and antitumor activities were also investigated using racemic and pure enantiomers.

Efficacy and safety of controlled-release oxycodone for the management of moderate-to-severe chronic low back pain in Japan: results of an enriched enrollment randomized withdrawal study followed by an open-label extension study.

BACKGROUND: Oxycodone is one of the options for the management of CLBP in patients with an inadequate response to other analgesics. However, oxycodone is not yet approved for noncancer pain in Japan. Here, we assessed the efficacy and long-term safety of S-8117, a controlled-release oxycodone formulation, for the management of Japanese CLBP patients. PATIENTS AND METHODS: An initial enriched enrollment randomized withdrawal, double-blind, placebo-controlled, 5-week phase III trial was conducted across 54 centers in Japan to assess the efficacy of S-8117 vs placebo in moderate-to-severe CLBP patients. Subsequently, a 52-week, open-label, single-arm study was conducted across 53 centers in Japan to evaluate the long-term safety of S-8117. The primary endpoint was the time to inadequate analgesic response during 35 days of the double-blind period. Secondary endpoints were the percentages of patients with inadequate analgesic response, discontinuation rate due to inadequate analgesic effects or AEs, and changes in scores of BPI severity, BPI pain interference, SF-36, and Roland-Morris Disability Questionnaire. Safety was assessed as the incidence of AEs and ADRs. RESULTS: Of the 189 patients enrolled in the double-blind study, 130 patients who completed the initial titration period were randomized 1:1 to receive either S-8117 (n=62) or placebo (n=68). Baseline characteristics were comparable across the study groups. The time to inadequate analgesic response was significantly longer in patients treated with S-8117 than placebo (P=0.0095). Secondary endpoints corroborated the efficacy of S-8117 vs placebo. Overall, 478 AEs were reported in 73/75 patients in the long-term study. The most frequent ADRs were somnolence, constipation, and nausea. No case of drug dependence was reported in the long-term study. CONCLUSION: Short-term efficacy vs placebo and long-term safety of S-8117 were demonstrated for the management of Japanese patients with moderate-to-severe CLBP.