A proposed new Japanese classification of synchronous peritoneal metastases from colorectal cancer: A multi-institutional, prospective, observational study conducted by the Japanese Society for Cancer of the Colon and Rectum.

Aim: To establish a new Japanese classification of synchronous peritoneal metastases from colorectal cancer. Methods: This multi-institutional, prospective, observational study enrolled patients who underwent surgery for colorectal cancer with synchronous peritoneal metastases. Overall survival rates were compared according to the various models using objective indicators. Each model was evaluated by Akaike's information criterion (AIC). The region of peritoneal metastases was evaluated by the peritoneal cancer index (PCI). Results: Between October 2012 and December 2016, 150 patients were enrolled. The AIC of the present Japanese classification was 1020.7. P1 metastasis was defined as confined to two regions. The minimum AIC was obtained with the cutoff number of 10 or less for P2 metastasis and 11 or more for P3 metastasis. As for size, the best discrimination ability between P2 and P3 metastasis was obtained with a cutoff value of 3 cm. The AIC of the proposed classification was 1014.7. The classification was as follows: P0, no peritoneal metastases; P1, metastases localized to adjacent peritoneum (within two regions of PCI); P2, metastases to distant peritoneum, number ≤10 and size ≤3 cm; P3, metastases to distant peritoneum, number ≥11 or size >3 cm; P3a, metastases to distant peritoneum, number ≥11 and size ≤3 cm, or number ≤10 and size >3 cm; P3b, metastases to distant peritoneum, number ≥11 and size >3 cm. Conclusion: This objective classification could improve the ability to discriminate prognosis in patients with synchronous peritoneal metastases from colorectal cancer.

Comprehensive data of 4502 patients newly diagnosed with colorectal liver metastasis between 2015 and 2017, and prognostic data of 2427 patients newly diagnosed with colorectal liver metastasis in 2013 and 2014: Third report of a nationwide survey in Japan.

To improve treatment outcomes in patients with colorectal liver metastasis (CRLM), the Joint Committee for Nationwide Survey on CRLM was established by the Japanese Society for Cancer of the Colon and Rectum and the Japanese Society of Hepato-Biliary-Pancreatic Surgery. The aim of the study was to evaluate transition in the characteristics and treatment strategy in CRLM patients and analyze prognostic factors using large-scale data. The present study summarizes the data of patients newly diagnosed between 2015 and 2017 and presents prognostic data of patients newly diagnosed in 2013 and 2014. Survival curves were generated by the Kaplan-Meier method and compared by log-rank test. Multivariate analyses were carried out using Cox proportional hazard modeling. The data of 4502 patients newly diagnosed with CRLM between 2015 and 2017 and the prognostic data of 2427 patients diagnosed in 2013 and 2014 are included. Regarding the 2013 and 2014 prognostic data, the 5-year overall survival (OS) rates of patients who underwent hepatectomy alone was 59.8%. Multivariate analyses identified age at diagnosis of CRLM ≥70 years, concomitant extrahepatic metastasis at diagnosis of CRLM, tumor depth of primary lesion ≥subserosa/pericolic or perirectal tissue, mutant KRAS status, number of CRLM ≥5, maximum diameter of CRLM >5 cm, and surgical curability R1/R2 as independent predictors of OS. Analysis of the latest nationwide database of patients diagnosed with CRLM revealed changes in patients and oncological characteristics, a transition in treatment strategy, and different independent prognosticators to those reported previously.

Validation study of the JSHBPS nomogram for patients with colorectal liver metastases who underwent hepatic resection in the recent era - a nationwide survey in Japan.

BACKGROUND: The Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) nomogram was developed to predict disease-free survival in patients with colorectal liver metastases (CRLM) undergoing upfront hepatectomy. However, the utility of the nomogram in patients with resected CRLM remains unknown in the current situation in which treatment strategies are changing with advances in drugs. METHODS: Patients in the initial nomogram cohort (n = 727) and validation cohort (n = 2225) were divided into the upfront hepatectomy and preoperative chemotherapy groups. The nomogram was validated by measuring calibration and discrimination in the two cohorts. Calibration curves were plotted, and survival probabilities were compared. Finally, to quantify the discrimination power, we estimated the concordance index (C-index). RESULTS: In the upfront hepatectomy group, the C-index was 0.63, the suitable cutoff value of the Beppu score was 7, and adjuvant chemotherapy was significantly effective limited to high-risk patients (Beppu score ≥7). The C-index was 0.56 in the preoperative chemotherapy group. CONCLUSIONS: The JSHBPS nomogram remains beneficial for patients undergoing upfront hepatectomy in the recent era but is less effective for patients undergoing hepatectomy after chemotherapy. Patients with a Beppu score ≥7 showed high-risk recurrence, and adjuvant chemotherapy should be recommended for these patients.

Factors Affecting Positive Peritoneal Lavage Cytology in Patients with Stage II and III Colorectal Cancer with R0 Resection: A Multi-institutional, Prospective Study.

OBJECTIVES: This study aimed to explore the risk factors associated with cancer cell exfoliation in Stage II and III colorectal cancer (CRC). METHODS: This multicenter, prospective, observational study targeted 1,698 patients with cStage II and III CRC who underwent R0 resection between 2013 and 2017. Clinicopathological variables were analyzed for correlations with positive peritoneal lavage cytology (PLC). RESULTS: The positive PLC rate was 2.7% (46/1,694 cases) at laparotomy and 1.6% (25/1,590 cases) after tumor resection. Logistic regression analyses identified that undifferentiated histologies diagnosed by preoperative biopsy specimen, cT4, and pN+ were independent factors that affected the positive PLC at laparotomy. The positive PLC rate at laparotomy was 4.5% (33/736 cases) among the patients with undifferentiated histology and/or cT4. Logistic regression analyses revealed that the presence of ascites and undifferentiated histology by biopsy independently affected positive PLC after tumor resection. CONCLUSIONS: The undifferentiated histology and/or T4 indicated by preoperative diagnosis were identified as factors affecting PLC at laparotomy. Furthermore, ascites and preoperative histological type were identified as factors affecting positive PLC after tumor resection. As factors affecting positive PLC, these preoperative findings were found to be equivalent to pathological findings.

Impact of R0 resection for synchronous peritoneal metastasis from colorectal cancer: A propensity score-matched analysis of a multi-institutional database.

AIM: To investigate the usefulness of resection for synchronous peritoneal metastasis from colorectal cancer. METHODS: The patients who underwent surgery for stage IV colorectal cancer at 16 hospitals between 1991 and 2007 were enrolled in this study. The overall survival rates of patients with synchronous peritoneal metastasis from colorectal cancer with and without R0 resection were compared using a propensity score-matched analysis. RESULTS: Among the 3965 patients with stage IV colorectal cancer, 1169 had synchronous peritoneal metastasis (28.5%). No patients received hyperthermic intraperitoneal chemotherapy (HIPEC) in this study. Among the 1169 patients, 783 had enough clinicopathologic information and went through further analysis. Out of 783 patients, 204 underwent R0 resection. A multivariate analysis revealed that severity of peritoneal metastasis according to the Japanese classification (P < .0001) and distant metastases (P < .0001) were independently associated with non-R0 resection. In a propensity score-matched analysis, 118 patients who underwent R0 resection were matched with 118 patients who did not undergo R0 resection. There was no significant difference in each parameter between patients with and without R0 resection. After matching, the overall survival in patients with R0 resection was better than that without R0 resection (median survival time: 28.8 months and 15.6 months, P < .0001). CONCLUSION: The overall survival of patients with R0 resection for synchronous peritoneal metastasis from colorectal cancer was better than that without R0 resection even without HIPEC.

Discovery of a Vitamin D Receptor-Silent Vitamin D Derivative That Impairs Sterol Regulatory Element-Binding Protein In Vivo.

Vitamin D3 metabolites inhibit the expression of lipogenic genes by impairing sterol regulatory element-binding protein (SREBP), a master transcription factor of lipogenesis, independent of their canonical activity through a vitamin D receptor (VDR). Herein, we designed and synthesized a series of vitamin D derivatives to search for a drug-like small molecule that suppresses the SREBP-induced lipogenesis without affecting the VDR-controlled calcium homeostasis in vivo. Evaluation of the derivatives in cultured cells and mice led to the discovery of VDR-silent SREBP inhibitors and to the development of KK-052 (50), the first vitamin D-based SREBP inhibitor that has been demonstrated to mitigate hepatic lipid accumulation without calcemic action in mice. KK-052 maintained the ability of 25-hydroxyvitamin D3 to induce the degradation of SREBP but lacked in the VDR-mediated activity. KK-052 serves as a valuable compound for interrogating SREBP/SCAP in vivo and may represent an unprecedented translational opportunity of synthetic vitamin D analogues.

Proposal of a novel H category-based classification of colorectal liver metastases based on a Japanese nationwide survey.

BACKGROUND: The conventional H category-based classification for colorectal liver metastases (CRLM) was created by equal weighting of tumor number and tumor size; however, our previous nomogram to predict postoperative disease-free survival demonstrated that CRLM ≥5 as a parameter provided 4.5 times greater impact compared with a largest CRLM size >5 cm. METHODS: A total of 3815 patients newly diagnosed with CRLM between 2005 and 2007, including 2220 resectable cases, were investigated. Six groups were created based on largest lesion size (≤ 5 vs >5 cm) and lesion number (1, 2-4, and ≥5). RESULTS: The novel (n) H1, nH2, and nH3 categories were defined as solitary lesions with a size ≤5 cm; lesions other than nH1 or nH3; and ≥5 lesions with any lesion size, respectively. In the resectable cohort, the 5-year cumulative overall survival rates were 64.0%, 53.5%, and 42.6% in the nH1, nH2, and nH3 groups, respectively (P < .001), and no significant differences were observed between the conventional H2 and H3 categories. In the overall cohort, the discrimination ability of the two classifications were comparable. CONCLUSION: The novel H category-based classification might be beneficial in predicting overall survival in patients with CRLM independent of their resectability.

Investigation of the Japanese Classification of Peritoneal Metastasis from Colorectal Cancer Referring to the Correlation with PCI.

OBJECTIVES: In Japan, there are three grades of peritoneal metastasis from colorectal cancer. The grade depends on the extent and number of lesions (P classification). The P classification is useful for its simplicity but lacks objectivity. On the other hand, the peritoneal cancer index (PCI) objectively indicates the peritoneal metastasis grade. However, the evaluation process is complicated clinically. In this study, we compared these two methods and investigated how to improve the P classification's objectivity by referring to PCI. METHODS: We investigated 150 cases of synchronous peritoneal metastasis from colorectal cancer. We inspected the correlation between the P classification and the PCI and pointed out the problems which prevented objective evaluation when using the P classification. We also estimated new criteria for extent and number in the P classification. RESULTS: We found the ideal definition for the best alignment between the P classification and the PCI was: ・P1 is metastases confined to one peritoneal region, ・P2 is 19 or fewer peritoneal metastases in two or more regions, and ・P3 is 20 or more metastases in two or more regions. This revision improved the P classification's objectivity and correlated with the PCI. CONCLUSIONS: Grading using the P classification was both imprecise and subjective. We propose a new standard value of extent and number in the P classification based on the PCI. This improvement would provide an objective, simple method of grading for peritoneal metastasis from colorectal cancer.

Long-term outcome of liver resection for colorectal metastases in the presence of extrahepatic disease: A multi-institutional Japanese study.

BACKGROUND/PURPOSE: The purpose of the present study was to assess long-term outcomes following liver resection for colorectal liver metastases (CRLM) with concurrent extrahepatic disease and to identify the preoperative prognostic factors for selection of operative candidates. METHODS: In this retrospective, multi-institutional study, 3820 patients diagnosed with CRLM during 2005-2007 were identified using nationwide survey data. Data of identified patients with concurrent extrahepatic lesions were analyzed to estimate the impact of liver resection on overall survival (OS) and to identify preoperative, prognostic indicators. RESULTS: Three- and 5-year OS rates after liver resection in 251 CRLM patients with extrahepatic disease (lung, n = 116; lymph node, n = 51; peritoneal, n = 37; multiple sites, n = 23) were 50.2% and 32.0%, respectively. Multivariate analysis revealed that a primary tumor in the right colon, lymph node metastasis from the primary tumor, serum carbohydrate antigen (CA) 19-9 level >37 UI/mL, the site of extrahepatic disease, and residual liver tumor after hepatectomy were associated with higher mortality. We proposed a preoperative risk scoring system based on these factors that adequately discriminated 5-year OS after liver resection in training and validation datasets. CONCLUSIONS: Performing R0 liver resection for colorectal liver metastases with treatable extrahepatic disease may prolong survival. Our proposed scoring system may help select appropriate candidates for liver resection.

Impact of adherence to board-certified surgeon systems and clinical practice guidelines on colon cancer surgical outcomes in Japan: A questionnaire survey of the National Clinical Database.

AIM: To investigate the effectiveness of the institutional medical structure and of the implemented clinical practice guidelines for improving colon cancer surgical outcomes. METHODS: We conducted a web-based questionnaire survey among departments registered at the National Clinical Database in Japan from October 2014 to January 2015 to assess the association between quality indicators (QIs), including structure and process indicators (clinical practice guideline adherence), and the risk-adjusted odds ratio for operative mortality (AOR) after right hemicolectomy for colorectal cancer during the study period. RESULTS: Among the 2064 departments registering at least one colorectal surgery during the study period, we obtained responses from 814 departments (39.4%). Our analysis on data from 22 816 patients with right hemicolectomy demonstrated that three structural QIs (certification of training hospitals by the Japanese Society of Gastroenterological Surgery and the presences of board-certified gastroenterological and colorectal surgeons) were associated with significantly lower AOR (P < .001, P = .02, and P = .05, respectively). The "performed at the doctor's discretion" answer was associated with poorer short-term outcomes in six process QIs than other answers. CONCLUSION: The board certification system for gastroenterological and colorectal surgeons and the adherence to the clinical guidelines improve the operative mortality after right hemicolectomy. It is desired to clarify the most suitable QIs to reduce the operative mortality after colorectal surgery.

Prognostic Impact of the Length of the Distal Resection Margin in Rectosigmoid Cancer: An Analysis of the JSCCR Database between 1995 and 2004.

OBJECTIVES: The necessary and sufficient length of the distal resection margin (l-DRM) for rectosigmoid cancer remains controversial. This study evaluated the validity of the 3-cm l-DRM rule for rectosigmoid cancer in the Japanese classification of colorectal cancer. METHODS: We retrospectively reviewed 1,443 patients with cT3 and cT4 rectosigmoid cancer who underwent R0 resection in Japanese institutions between 1995 and 2004. We identified the optimal cutoff point of the l-DRM affecting overall survival (OS) rate using a multivariate Cox regression analysis model. Using this cutoff point, the patients were divided into two groups after balancing the potential confounding factors of the l-DRM using propensity score matching, and the OS rates of the two groups were compared. RESULTS: A multivariate Cox regression analysis model revealed that the l-DRM of 4 cm was the best cutoff point with the greatest impact on OS rate (hazard ratio [HR], 1.37; 95% confidence interval [CI], 1.00-1.84; P = 0.0452) and with the lowest Akaike information criterion value. In the matched cohort study, the OS rate of patients who had l-DRM of 4 cm or more was significantly higher than that of patients who had l-DRM < 4 cm (n = 402; 5-year OS rates, 87.6% vs. 80.3%, respectively; HR, 1.60; 95% CI, 1.09-2.31; P = 0.0136). CONCLUSIONS: For cT3 and cT4 rectosigmoid cancer, l-DRM of 4 cm may be an appropriate landmark for a curative intent surgery, and we were unable to definitively confirm the validity of the Japanese 3-cm l-DRM rule.

Comprehensive data of 3525 patients newly diagnosed with colorectal liver metastasis between 2013 and 2014: 2nd report of a nationwide survey in Japan.

BACKGROUND: To collect large-scale data for further research to improve treatment outcomes in patients with colorectal liver metastasis (CRLM), the Joint Committee for Nationwide Survey on CRLM was established by the Japanese Society for Cancer of the Colon and Rectum and the Japanese society of Hepato-Biliary-Pancreatic Surgery. The joint committee was initiated to collect data since 2014 and has already reported data including the prognostic data of 3820 patients newly diagnosed with CRLM between 2005 and 2007. METHODS: The data of patients newly diagnosed with CRLM after 2013 are continuously being registered prospectively, and herein, we report the data of the patients newly diagnosed with CRLM in 2013 and 2014. RESULTS: The data of 3839 patients newly diagnosed with CRLM in 2013 and 2014 were registered from 156 departments (75%) of 152 institutions among 209 departments (from 201 institutions) that agreed to participate in this database system at its initiation. Finally, 3525 patients were enrolled in this study after a quality management process conducted by the joint committee. We report the comprehensive data obtained from 3525 patients, including clinicopathological findings, treatment strategies, and implementation status of chemotherapy. CONCLUSION: The joint committee will provide these raw data while updating prognostic data to researchers who will conduct meaningful studies that meet the aim of the joint committee.

N 1-Methylpseudouridine substitution enhances the performance of synthetic mRNA switches in cells.

Synthetic messenger RNA (mRNA) tools often use pseudouridine and 5-methyl cytidine as substitutions for uridine and cytidine to avoid the immune response and cytotoxicity induced by introducing mRNA into cells. However, the influence of base modifications on the functionality of the RNA tools is poorly understood. Here we show that synthetic mRNA switches containing N1-methylpseudouridine (m1Ψ) as a substitution of uridine substantially out-performed all other modified bases studied, exhibiting enhanced microRNA and protein sensitivity, better cell-type separation ability, and comparably low immune stimulation. We found that the observed phenomena stem from the high protein expression from m1Ψ containing mRNA and efficient translational repression in the presence of target microRNAs or proteins. In addition, synthetic gene circuits with m1Ψ significantly improve performance in cells. These findings indicate that synthetic mRNAs with m1Ψ modification have enormous potentials in the research and application of biofunctional RNA tools.

S-1 and Oxaliplatin Versus Tegafur-uracil and Leucovorin as Postoperative Adjuvant Chemotherapy in Patients With High-risk Stage III Colon Cancer (ACTS-CC 02): A Randomized, Open-label, Multicenter, Phase III Superiority Trial.

BACKGROUND: The efficacy of S-1 plus oxaliplatin (SOX) as postoperative adjuvant chemotherapy for colon cancer has not been established. This randomized phase III study was designed to verify the superiority of SOX over tegafur-uracil and leucovorin (UFT/LV) in patients with high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries). PATIENTS AND METHODS: Patients who underwent curative resection for pathologically confirmed high-risk stage III colon cancer were randomly assigned to receive either UFT/LV (300 mg/m2 of UFT and 75 mg/day of LV on days 1-28, every 35 days, 5 cycles) or SOX (100 mg/m2 of oxaliplatin on day 1 and 80 mg/m2 of S-1 on days 1-14, every 21 days, 8 cycles). The primary endpoint was disease-free survival (DFS). RESULTS: A total of 478 patients in the UFT/LV group and 477 patients in the SOX group were included in the primary analysis. The 3-year DFS was 60.6% (95% confidence interval [CI], 56.0%-64.9%) in the UFT/LV group and 62.7% (95% CI, 58.1%-66.9%) in the SOX group. The stratified hazard ratio for DFS was 0.90 (95% CI, 0.74-1.09; stratified log-rank test, P = .2780). In the N2b subgroup, the 3-year DFS was 46.0% (95% CI, 37.5%-54.0%) in the UFT/LV group and 54.7% (95% CI, 45.7%-62.7%) in the SOX group (hazard ratio, 0.76; 95% CI, 0.55-1.05). CONCLUSION: As postoperative adjuvant chemotherapy, SOX was not superior to UFT/LV in terms of DFS in patients with high-risk stage III colon cancer.

Survival Benefit of and Indications for Adjuvant Chemotherapy for Resected Colorectal Liver Metastases-a Japanese Nationwide Survey.

BACKGROUND: The survival benefit of and indications for adjuvant chemotherapy (AC) for colorectal liver metastases (CRLM) remain unclear. METHODS: Patients who were diagnosed with liver-limited CRLM between 2005 and 2007 and subsequently underwent R0 resection without preoperative chemotherapy were identified in a Japanese nationwide survey. This overall cohort was divided into synchronous and metachronous CRLM cohorts. In each of the three cohorts, the patients that were given AC were matched with those treated with surgery alone via 1:1 propensity score (PS) matching. Recurrence-free survival (RFS) and overall survival (OS) after the initial hepatectomy were compared. RESULTS: The median follow-up period was 79.4 months and the overall, synchronous, and metachronous cohorts included 1145, 498, and 647 patients, respectively. After the PS matching, the patients' demographics were well balanced. AC was effective in terms of both RFS and OS in the overall cohort (RFS hazard ratio [HR] 0.784, p = 0.045; OS HR 0.716, p = 0.028) and synchronous cohort (RFS HR 0.677, p = 0.027; OS HR 0.642, p = 0.036), whereas AC was not effective in the metachronous cohort (RFS HR 0.875, p = 0.378; OS HR 0.881, p = 0.496). However, in the metachronous cohort, AC was effective in terms of OS in the subgroup that exhibited disease-free intervals of ≤ 1 year after primary tumor resection (RFS HR 0.667, p = 0.068; OS HR 0.572, p = 0.042). CONCLUSION: Adjuvant chemotherapy has a survival benefit for patients with resected CRLM. Synchronous CRLM is a favorable indication for AC, whereas in metachronous CRLM, the use of AC should be individualized according to each patient's risk factors.

Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2019 for the treatment of colorectal cancer.

The number of deaths from colorectal cancer in Japan continues to increase. Colorectal cancer deaths exceeded 50,000 in 2016. In the 2019 edition, revision of all aspects of treatments was performed, with corrections and additions made based on knowledge acquired since the 2016 version (drug therapy) and the 2014 version (other treatments). The Japanese Society for Cancer of the Colon and Rectum guidelines 2019 for the treatment of colorectal cancer (JSCCR guidelines 2019) have been prepared to show standard treatment strategies for colorectal cancer, to eliminate disparities among institutions in terms of treatment, to eliminate unnecessary treatment and insufficient treatment and to deepen mutual understanding between healthcare professionals and patients by making these guidelines available to the general public. These guidelines have been prepared by consensuses reached by the JSCCR Guideline Committee, based on a careful review of the evidence retrieved by literature searches and in view of the medical health insurance system and actual clinical practice settings in Japan. Therefore, these guidelines can be used as a tool for treating colorectal cancer in actual clinical practice settings. More specifically, they can be used as a guide to obtaining informed consent from patients and choosing the method of treatment for each patient. Controversial issues were selected as clinical questions, and recommendations were made. Each recommendation is accompanied by a classification of the evidence and a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here, we present the English version of the JSCCR guidelines 2019.

Factors affecting R0 resection of colorectal cancer with synchronous peritoneal metastases: a multicenter prospective observational study by the Japanese Society for Cancer of the Colon and Rectum.

BACKGROUND: In Japan, R0 resection has been recommended for colorectal cancer patients with peritoneal metastases confined to the adjacent peritoneum and those with a few metastases to the distant peritoneum. R0 resection for M1c disease has drawn attention in Western countries and is currently considered an acceptable therapeutic option in the US National Comprehensive Cancer Network guidelines. However, clinical factors that affect the choice of R0 resection are unknown. METHODS: This multicenter, prospective, observational study was conducted by the Japanese Society for Cancer of the Colon and Rectum. Colorectal cancer patients with synchronous peritoneal metastases were enrolled at 28 institutions in Japan from October 2012 to December 2016. To determine factors affecting R0 resection and R1 resection with intended R0 resection, stepwise logistic regression analyses were performed on clinical factors including age, sex, performance status (PS), body mass index, peritoneal cancer index (PCI) score, presence of ascites, presence of distant metastases, and primary tumor site. RESULTS: R0/R1 resection was performed in 36 (31/5; 25%) of 146 patients. No distant metastases [odds ratio (OR) 52.9; 95% confidence interval (CI) 13.3-210.1; p < 0.0001], low PCI score (1-6) (OR 20.0; 95% CI 4.8-83.4; p < 0.0001), and high PS (0) (OR 2.40; 95% CI 0.66-8.68; p = 0.18) were independent factors affecting R0/R1 resection. PCI score and PS were also independent factors affecting R0/R1 resection in M1c patients without non-peritoneal distant metastases (n = 59). CONCLUSION: Distant metastases, PCI score, and PS are three factors which affect R0 resection for M1c disease.

Synthetic Chemical Probes That Dissect Vitamin D Activities.

Vitamin D3 metabolites are capable of controlling gene expression in mammalian cells through two independent pathways: vitamin D receptor (VDR) and sterol regulatory element-binding protein (SREBP) pathways. In the present study, we dissect the complex biological activity of vitamin D by designing synthetic vitamin D3 analogs specific for VDR or SREBP pathway, i.e., a VDR activator that lacks SREBP inhibitory activity, or an SREBP inhibitor devoid of VDR activity. These synthetic vitamin D probes permitted identification of one of the vitamin D-responsive genes, Soat1, as an SREBP-suppressed gene. The chemical probes developed in the present study may prove useful in dissecting the intricate interplay of vitamin D actions, thereby providing insights into how vitamin D target genes are regulated.

Nutrient-Based Chemical Library as a Source of Energy Metabolism Modulators.

Covalent conjugates of multiple nutrients often exhibit greater biological activities than each individual nutrient and more predictable safety profiles than completely unnatural chemical entities. Here, we report the construction and application of a focused chemical library of 308 covalent conjugates of a variety of small-molecule nutrients. Screening of the library with a reporter gene of sterol regulatory element-binding protein (SREBP), a master regulator of mammalian lipogenesis, led to the discovery of a conjugate of docosahexaenoic acid (DHA), glucosamine, and amino acids as an inhibitor of SREBP (molecule 1, DHG). Mechanistic analyses indicate that molecule 1 impairs the SREBP activity by inhibiting glucose transporters and thereby activating AMP-activated protein kinase (AMPK). Oral administration of molecule 1 suppressed the intestinal absorption of glucose in mice. These results suggest that such synthetic libraries of nutrient conjugates serve as a source of novel chemical tools and pharmaceutical seeds that modulate energy metabolism.