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The distributed optimization problem is set up in a collection of nodes interconnected via a communication network. The goal is to find the minimizer of a global objective function formed by the addition of partial functions locally known at each node. A number of methods are available for addressing this problem, having different advantages. The goal of this work is to achieve the maximum possible convergence rate. As the first step towards this end, we propose a new method which we show converges faster than other available options. As with most distributed optimization methods, convergence rate depends on a step size parameter. As the second step towards our goal we complement the proposed method with a fully distributed method for estimating the optimal step size that maximizes convergence speed. We provide theoretical guarantees for the convergence of the resulting method in a neighborhood of the solution. Also, for the case in which the global objective function has a single local minimum, we provide a different step size selection criterion together with theoretical guarantees for convergence. We present numerical experiments showing that, when using the same step size, our method converges significantly faster than its rivals. Experiments also show that the distributed step size estimation method achieves an asymptotic convergence rate very close to the theoretical maximum.

Overexpression of ATP-binding cassette subfamily B member 1 (ABCB1)–encoded multidrug resistance protein 1 (MDR1) constitutes a major mechanism of cancer drug resistance including docetaxel (DTX) and cabazitaxel (CTX) resistance in castration-resistant prostate cancer (CRPC). However, no therapeutics that targets MDR1 is available at clinic for taxane sensitization. We report here that retinoic acid receptor-related orphan receptor γ (RORγ), a nuclear receptor family member, unexpectedly mediates MDR1/ABCB1 overexpression. RORγ plays an important role in controlling the functions of subsets of immune cells and has been an attractive target for autoimmune diseases. We found that its small-molecule antagonists are efficacious in resensitizing DTX and CTX cross-resistant CRPC cells and tumors to taxanes in both androgen receptor–positive and –negative models. Our mechanistic analyses revealed that combined treatment with RORγ antagonists and taxane elicited a robust synergy in killing the resistant cells, which involves a coordinated alteration of p53, Myc, and E2F-controlled programs critical for both intrinsic and extrinsic apoptosis, survival, and cell growth. Our results suggest that targeting RORγ with small-molecule inhibitors is a novel strategy for chemotherapy resensitization in tumors with MDR1 overexpression.

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Background The local recurrence of rectal cancer has been improved by total mesorectal excision following neoadjuvant chemoradiotherapy. However, in patients with low locally advanced rectal cancer, lateral pelvic recurrence remains to be addressed. Objective This study aimed to determine the efficiency of neoadjuvant radiotherapy in addressing lateral pelvic recurrence and which subgroup of patients might be optimal to receive lateral lymph node dissection. Design The MRI/CT images were reassessed for lateral lymph node status. The lateral lymph nodes with short axis ≥5 mm and ≥4 mm were considered positive in pretreatment and restaging MRI/CT. Setting This was a post hoc analysis of a prospective randomized controlled trial (FOWARC, NCT01211210). Patients A total of 495 patients with stage II or III rectal adenocarcinoma were included in the original trial. According to the excluding criteria, the finally included population consists of 253 patients; of these, 195 patients received neoadjuvant chemoradiotherapy and 94 received chemotherapy alone. Main outcomes and measures The primary outcome was the 5-year lateral pelvic recurrence rate. Results Compared with patients receiving chemotherapy alone, patients receiving additional radiotherapy had a marginal significance of lower lateral pelvic recurrence rate (6.6% vs 13.0%; p = 0.051). In the subset with pretreatment positive lateral lymph nodes, patients had a lateral pelvic recurrence rate of 22.6% and 45.1% after neoadjuvant chemoradiotherapy and chemotherapy alone. Of note, 34.9% of the pretreatment positive lateral lymph nodes were persistent after neoadjuvant chemoradiotherapy, culminating in a lateral pelvic recurrence rate of 63.3%. Limitations This is a post hoc analysis, and only the patients from the leading center were included, which limited the sample size. In addition, the lateral lymph node dissection was not performed in this cohort. Conclusions The addition of radiotherapy in neoadjuvant regimens could not address lateral pelvic recurrence adequately. Some subgroups of patients might need additional dissection. See Video Abstract at http://links.lww.com/DCR/B613. La inclusion de la radioterapia preoperatoria es insuficiiente en el control plvico lateral en un subgrupo de pacientes con cncer de recto inferior localmente avanzado un estudio posthoc controlado y randomizado ANTECEDENTES:La recurrencia local del cancer de recto ha disminuido al efectuar una excision mesorrectal total seguida de quimioradioterapia neoadyuvante. No obstante, en pacientes con cancer de tercio inferior de recto avanzado localmente, aun esta por controlarse la recurrencia pelvicaOBJETIVOS:Determinar la eficacia de la radioterapia neoadyuvante en el control de la recurrencia pelvica lateral y en que subgrupo de pacientes seria conveniente efecutar una excision lateral de las cadenas ganglionares.DISENO:Se reevaluaron las imagenes tomograficas y de resonancia magnetica del status de las cadenas ganglionares linfaticas laterales. Los ganglios linfaticos laterales con un eje-corto > 5 mm y ≥ 4 mm se consideraron como positivos previo al tratamiento y reestadificados con RM y TAC respectivamente.ESCENARIO:Es un analisis post hoc de un studio prospectivo randomizado controlado (FOWARC, NCT01211210).PACIENTESSe incluyeron un total de 495 pacientes en estdio II o III con adenomcarcinoma rectal en el estudio original. De acuerdo a los criterios de exclusion, la poblacion final incluida consistio en 253 pacientes; de estos, 195 recibieron quimioradioterapia neoadyuvante y 94 quimioterapia sola.EVALUACION DE LOS RESULTADOS PRINCIPALES:El parametro mas importante fue la tasa de recurrencia pelvica lateral a cinco anos.RESULTADOS:En comparacion con los pacientes que recibieron quimioterapia sola, aquellos que ademas fueron sometidos a radioterapia adicional presentaron un margen significativo de menor tasa de recurrencia pelvica lateral (6.6% vs. 13.0%; p=0.051). En el grupo de pacientes con ganglios linfaticos laterales positivos, los enfermos presentaron una tasa de recurrencia pelvica lateral de 22.6% y 45.1% despues de quimioradiaterapia neoadyuvante en comparacion con quimioterapia sola respectivamente. Cabe mencionar que el 34.9% de los pacientes con ganglios linfaticos laterales positivos antes del tratamiento persistieron despues de la quimioradioterapia neoadyuvante, reportandose finalmente una recurrencia pelvica lateral de un 63.3%.LIMITACIONES:Se trata de un analisis posthoc y solo los pacientes del hospital fueron incluidos, lo que limita el tamano de la muestra. Ademas, no se efectuo la diseccion de los ganglios linfaticos laterales en este grupo.CONCLUSIONES:La radioterapia en los esquemas de neoadyuvancia no logran controlar la recurrencia pelvica lateral en forma adecuada. Algunos subgrupos de pacientes podria requerir de diseccion adicional. Consulte Video Resumen en http://links.lww.com/DCR/B613.

Background: Colorectal cancer (CRC) is one of the most common causes of cancer-related death in the world. More comprehensive studies of key molecular alterations in CRC progression were urgent. DNA methylation promotes tumor progression. However, the mechanism of the ANKRD13 gene methylation that drives colorectal cancer evolution remains largely unknown. This was the first study focused on the role of ANKRD13 and the hypermethylated mechanisms in colorectal cancer. Methods: Chi-Square tests were utilized to the comparison of the baseline characteristics of patients with hypomethylation ANKRD13B and hypermethylated ANKRD13B. Kaplan-Meier analysis were used to estimate the difference of overall survival between the two groups patients. The methylation level of ANKRD13B was quantified by qMSP in colorectal cancer, normal colon epitheliums and colorectal adenoma tissues. CRISPR/dCas9-DNMT3A and CRISPR/dCas9-TET1-CD methylation editing tools were applied to enable targeted and specific CpG methylation at the CpG loci near stop codon of ANKRD13B. Transwell-migrated assay, wound scratch assay and colony formation assay were preformed to ascertain the abilities of viability, migration and invasion in the editing CRC cell lines. The methylated RNA immunoprecipitation (MeRIP) assays, chromatin immunoprecipitation (ChIP) assays and 5-AZA treatment assays were performed combined with qPCR to quantify the m6A levels of ANKRD13B mRNA following hypermethylated-editing. Results: Here, we identified a novel oncogenic gene, ANKRD13B, encoding ankyrin repeat domain 13B. This gene was frequently hypermethylated in CpG islands surrounding the stop codon region of colorectal cancer. This hypermethylation was associated with poor clinical outcomes in patients diagnosed with colorectal cancer. Compared with normal tissue (4.2%), this type of epigenetic alteration upregulated ANKRD13B expression in both adenoma (73.0%) and adenoma cancer tissues (83.3%) (P< 0.0001), and it also promoted colorectal cancer cell growth, invasion, and migration. Demethylation treatment can reduce the ANKRD13B expression and the growth, migration, and invasion of the cancer cell. Moreover, we found that the aberrant ANKRD13B methylated surrounding the stop codon, and it can promote RNA N6-methyladenosine methylation modification, suggesting that aberrant DNA 5mC methylation promotes ANKRD13B expression and tumor progression in an RNA m6A-dependent manner. Conclusions: In summary, our findings illustrated that ANKRD13B is an oncogenic gene of colorectal cancer that is commonly methylated and overexpressed in colorectal cancer whose function in the pathogenesis of colorectal cancer depends on RNA m6A-dependent manner. Aberrant DNA 5mC methylation promotes ANKRD13B expression and tumor progression in an RNA m6A-dependent Manner. Key words: ANKRD13B, DNA methylation, Epigenetic regulation, Colorectal cancer Citation Format: JingRong Weng, JinXin Lin, YuMo Xie, GuanNan Tang, LiangLiang Bai, JinHua Chen, ZengHong Huang, ZhuoKai Zhuang, ShaoYong Peng, Heng Wang, GaoPo Xu, Yu Zhang, XiaoXia Liu, MeiJin Huang, YanXin Luo, XiaoLin Wang, Huichuan Yu. RNA m6A methylation relay the oncogenic flow from DNA methylationto gene expression of ANKRD13B [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6006.

Overexpression of ATP-binding cassette subfamily B member 1 (ABCB1)–encoded multidrug resistance protein 1 (MDR1) constitutes a major mechanism of cancer drug resistance including docetaxel (DTX) and cabazitaxel (CTX) resistance in castration-resistant prostate cancer (CRPC). However, no therapeutics that targets MDR1 is available at clinic for taxane sensitization. We report here that retinoic acid receptor-related orphan receptor γ (RORγ), a nuclear receptor family member, unexpectedly mediates MDR1/ABCB1 overexpression. RORγ plays an important role in controlling the functions of subsets of immune cells and has been an attractive target for autoimmune diseases. We found that its small-molecule antagonists are efficacious in resensitizing DTX and CTX cross-resistant CRPC cells and tumors to taxanes in both androgen receptor–positive and –negative models. Our mechanistic analyses revealed that combined treatment with RORγ antagonists and taxane elicited a robust synergy in killing the resistant cells, which involves a coordinated alteration of p53, Myc, and E2F-controlled programs critical for both intrinsic and extrinsic apoptosis, survival, and cell growth. Our results suggest that targeting RORγ with small-molecule inhibitors is a novel strategy for chemotherapy resensitization in tumors with MDR1 overexpression.

Background Colorectal cancer (CRC) patients with different molecular phenotypes, including microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and somatic mutations in BRAF and KRAS gene, vary in treatment response and prognosis. However, molecular phenotyping under adequate quality control in a community-based setting may be difficult. We aimed to build the nomograms based on easily accessible clinicopathological characteristics to predict molecular phenotypes. Methods Three hundred and six patients with pathologically confirmed stage I-IV CRC were included in the cohort. The assays for MSI, CIMP, and mutations in BRAF and KRAS gene were performed using resected tumor samples. The candidate predictors were identified from clinicopathological variables using multivariate Logistic regression analyses to construct the nomograms that could predict each molecular phenotype. Results The incidences of MSI, CIMP, BRAF mutation and KRAS mutation were 25.3% (72/285), 2.5% (7/270), 3.4% (10/293), and 34.8% (96/276) respectively. In the multivariate Logistic analysis, poor differentiation and high neutrophil/lymphocyte ratio (NLR) were independently associated with MSI; poor differentiation, high NLR and high carcinoembryonic antigen/tumor size ratio (CSR) were independently associated with CIMP; poor differentiation, lymphovascular invasion and high CSR were independently associated with BRAF mutation; poor differentiation, proximal tumor, mucinous tumor and high NLR were independently associated with KRAS mutation. Four nomograms for MSI, CIMP, BRAF mutation and KRAS mutation were developed based on these independent predictors, the C-indexes of which were 61.22% (95% CI: 60.28-62.16%), 95.57% (95% CI: 95.20-95.94%), 83.56% (95% CI: 81.54-85.58%), and 69.12% (95% CI: 68.30-69.94%) respectively. Conclusion We established four nomograms using easily accessible variables that could well predict the presence of MSI, CIMP, BRAF mutation and KRAS mutation in CRC patients.

BACKGROUND Carcinoembryonic antigen (CEA) is a commonly used biomarker in colorectal cancer. However, controversy exists regarding the insufficient prognostic value of preoperative serum CEA alone in rectal cancer. Here, we combined preoperative serum CEA and the maximum tumor diameter to correct the CEA level, which may better reflect the malignancy of rectal cancer. AIM To assess the prognostic impact of preoperative CEA/tumor size in rectal cancer. METHODS We retrospectively reviewed 696 stage I to III rectal cancer patients who underwent curative tumor resection from 2007 to 2012. These patients were randomly divided into two cohorts for cross-validation: training cohort and validation cohort. The training cohort was used to generate an optimal cutoff point and the validation cohort was used to further validate the model. Maximally selected rank statistics were used to identify the optimum cutoff for CEA/tumor size. The Kaplan-Meier method and log-rank test were used to plot the survival curve and to compare the survival data. Univariate and multivariate Cox regression analyses were used to determine the prognostic value of CEA/tumor size. The primary and secondary outcomes were overall survival (OS) and disease-free survival (DFS), respectively. RESULTS In all, 556 patients who satisfied both the inclusion and exclusion criteria were included and randomly divided into the training cohort (2/3 of 556, n = 371) and the validation cohort (1/3 of 556, n = 185). The cutoff was 2.429 ng/mL per cm. Comparison of the baseline data showed that high CEA/tumor size was correlated with older age, high TNM stage, the presence of perineural invasion, high CEA, and high carbohydrate antigen 19-9 (CA 19-9). Kaplan-Meier curves showed a manifest reduction in 5-year OS (training cohort: 56.7% vs 81.1%, P < 0.001; validation cohort: 58.8% vs 85.6%, P < 0.001) and DFS (training cohort: 52.5% vs 71.9%, P = 0.02; validation cohort: 50.3% vs 79.3%, P = 0.002) in the high CEA/tumor size group compared with the low CEA/tumor size group. Univariate and multivariate analyses identified CEA/tumor size as an independent prognostic factor for OS (training cohort: hazard ratio (HR) = 2.18, 95% confidence interval (CI): 1.28-3.73, P = 0.004; validation cohort: HR = 4.83, 95%CI: 2.21-10.52, P < 0.001) as well as DFS (training cohort: HR = 1.47, 95%CI: 0.93-2.33, P = 0.096; validation cohort: HR = 2.61, 95%CI: 1.38-4.95, P = 0.003). CONCLUSION Preoperative CEA/tumor size is an independent prognostic factor for patients with stage I-III rectal cancer. Higher CEA/tumor size is associated with worse OS and DFS.

We report the design, optimization, and biological evaluation of nuclear receptor RORγ inverse agonists as therapeutic agents for prostate cancer treatment. The most potent compound 27 (designated as XY101) exhibited cellular activity with an IC50 value of 30 nM in a cell-based reporter gene assay with good selectivity against other nuclear receptor subtypes. The cocrystal structure of 27 in complex with the RORγ ligand binding domain provided a solid structural basis for its antagonistic mechanism. 27 potently inhibited cell growth, colony formation, and the expression of AR, AR-V7, and PSA. 27 also exhibited good metabolic stability and a pharmacokinetic profile with oral bioavailability of 59% and a half-life of 7.3 h. Notably, 27 demonstrated promising therapeutic effects with significant tumor growth inhibition in a prostate cancer xenograft model in mice. The potent, selective, metabolically stable, and orally available RORγ inverse agonists represent a new class of compounds as potential therapeutics against prostate cancer.

This paper studies the distributed state estimation over sensor networks based on receding horizon estimation (RHE). Firstly, a new scheme of centralized RHE is introduced, which gathers the decomposition terms instead of collecting the measurements of each node. Then, we present a distributed estimate algorithm based on the centralized RHE. To avoid the quadratic programming (QP) problem, the proposed algorithm takes advantage of the analytical solution of the centralized RHE and performs consensus steps to generalize the distributed estimation for each node, which greatly reduces each node’s computation. Under the assumption of collective observability over networks, the proposed algorithm can guarantee the stability of estimation error in the case of enough consensus steps. Finally, the simulation results verify the effectiveness of the proposed method.

Simple Summary Prostate cancer is one of the most frequently diagnosed cancers in men and is the second leading cause of cancer death in developed countries. Current therapeutics that target the androgen receptor (AR) are only transiently effective. Anti-AR therapy-resistant tumors often emerge with vast cellular and molecular alterations and present themselves at the clinic in more deadly forms including metastatic castration-resistant prostate cancer (mCRPC) or neuroendocrine prostate cancer (NEPC). One emerging strategy in effective treatment of the advanced forms of prostate cancer is to target drivers other than AR. The present study shows that the nuclear receptor RORγ and the serine/threonine kinase PBK form a regulatory loop in hyperactive AR signaling. It also demonstrates that orally administered, small-molecule antagonists/inverse agonists of RORγ are effective in blocking the growth of the mCRPC tumors. Our findings provide a rationale for therapeutic targeting of RORγ alone or in combination with PBK inhibitors for the advanced forms of prostate cancer. Abstract Metastatic castration-resistant prostate cancer (mCRPC) is a highly aggressive disease with few therapeutic options. Hyperactive androgen receptor (AR) signaling plays a key role in CRPC progression. Previously, we identified RAR-related orphan receptor gamma (RORγ) as a novel key driver of AR gene overexpression and increased AR signaling. We report here that several RORγ antagonists/inverse agonists including XY018 and compound 31 were orally effective in potent inhibition of the growth of tumor models including patient-derived xenograft (PDX) tumors. RORγ controls the expression of multiple aggressive-tumor gene programs including those of epithelial-mesenchymal transition (EMT) and invasion. We found that PDZ binding kinase (PBK), a serine/threonine kinase, is a downstream target of RORγ that exerts the cellular effects. Alterations of RORγ expression or function significantly downregulated the mRNA and protein level of PBK. Our further analyses demonstrated that elevated PBK associates with and stabilizes RORγ and AR proteins, thus constituting novel, interlocked feed-forward loops in hyperactive AR and RORγ signaling. Indeed, dual inhibition of RORγ and PBK synergistically inhibited the expression and function of RORγ, AR, and AR-V7, and the growth and survival of CRPC cells. Therefore, our study provided a promising, new strategy for treatment of advanced forms of prostate cancer.

This work addresses quasisynchronization (QS) of the master-slave (MS) neural networks (NNs) with mismatched parameters. The logarithmic quantizer and the round-robin protocol (RRP) are used to deal with the limited communication channel (CC) capacity, then the intermittent control strategy is employed to improve the efficiency of CC and the controller. A transmission-dependent controller is designed, and the synchronization error system (SES) is established. The QS with a boundary is ensured for the MS NNs by a developed sufficient condition, and the controller design method is given. A numerical simulation is given to show the effectiveness of the obtained method.

Background Neurotrophic tropomyosin receptor kinases (NTRKs) are a gene family function as oncogene or tumor suppressor gene in distinct cancers. We aimed to investigate the methylation and expression profiles and prognostic value of NTRKs gene in colorectal cancer (CRC). Methods An analysis of DNA methylation and expression profiles in CRC patients was performed to explore the critical methylations within NTRKs genes. The methylation marker was validated in a retrospectively collected cohort of 229 CRC patients and tested in other tumor types from TCGA. DNA methylation status was determined by quantitative methylation-specific PCR (QMSP). Results The profiles in six CRC cohorts showed that NTRKs gene promoter was more frequently methylated in CRC compared to normal mucosa, which was associated with suppressed gene expression. We identified a specific methylated region within NTRK3 promoter targeted by cg27034819 and cg11525479 that best predicted survival outcome in CRC. NTRK3 promoter methylation showed independently predictive value for survival outcome in the validation cohort (P = 0.004, HR 2.688, 95% CI [1.355, 5.333]). Based on this, a nomogram predicting survival outcome was developed with a C-index of 0.705. Furthermore, the addition of NTRK3 promoter methylation improved the performance of currently-used prognostic model (AIC: 516.49 vs 513.91; LR: 39.06 vs 43.64, P = 0.032). Finally, NTRK3 promoter methylation also predicted survival in other tumors, including pancreatic cancer, glioblastoma and stomach adenocarcinoma. Conclusions This study highlights the essential value of NTRK3 methylation in prognostic evaluation and the potential to improve current prognostic models in CRC and other tumors.

Additional file 1. Table S1. Primer and Probe Sequences. Table S2. The mean methylation of NTRKs promoter in CRC samples and matched normal mucosae in FHCRC cohort. Table S3. Univariate Cox analysis of probes targeting NTRKs gene in TCGA-COADREAD cohort. Table S4. Sensitivity analysis excluding patients with CIMP-positive status. Table S5. Sensitivity analysis excluding patients with MSI. Table S6. Sensitivity analysis excluding patients with BRAF mutation. Table S7. Sensitivity analysis excluding patients with KRAS mutation.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to block tumor-associated inflammation in rectal cancer. However, the perioperative use of NSAIDs remains controversial. This study was designed to investigate whether the perioperative use of NSAIDs influences outcomes and to provide a predictive marker to identify patients who would benefit from NSAIDs. We enrolled 515 patients with stage I to III rectal cancer in this retrospective study. Patients were classified into the NSAID and non-NSAID groups according to their perioperative use of NSAIDs. The whole cohort was stratified by platelet-to-lymphocyte ratio (PLR). The primary endpoints were disease-free survival (DFS) and overall survival (OS). The NSAID group had a 12.6% lower risk of recurrence than the non-NSAID group (P = 0.015), while the association with survival was nonsignificant. In the high-PLR subset, the NSAID group had a 17.3% lower risk of recurrence (P = 0.003) and a better DFS (P = 0.033) outcome than the non-NSAID group. Multivariate analysis confirmed this independent significant association with DFS (P = 0.023). In the low-PLR subset, the association of NSAID use with survival was nonsignificant. Perioperative use of NSAIDs was associated with improved survival outcomes in rectal cancer patients with high PLR.

Beta-tropomyosin (β-tropomyosin, TPM2) has been found to be downregulated in colorectal cancer (CRC) in previous studies. In this study, we aimed to investigate the mechanisms and potential biological consequences of the downregulation of TPM2 in colorectal cancer. TPM2 expression in colorectal cancer was assessed by qRT-PCR and immunostaining. The biological functions of TPM2 were assessed in cell lines either overexpressing or underexpressingTPM2. Aberrant DNA methylation in the promoter region is associated with suppression of TPM2 expression in primary colorectal cancer tissue samples. Treatment with the demethylation agent 5-AZA can induceTPM2 expression in colorectal cancer cell lines. Reconstitution of TPM2 suppresses cell proliferation and migration in colorectal cancer cell lines, whereas the loss of TPM2 expression is associated with increased tumor proliferation and migration in vitro, which was accompanied by RhoA activation. In summary, our findings indicate that TPM2 appears to be commonly silenced by aberrant DNA methylation in colon cancer. TPM2 loss is associated with RhoA activation and tumor proliferation.

Tumor subtype-specific metabolic reprogrammers could serve as targets of therapeutic intervention. Here we show that triple-negative breast cancer (TNBC) exhibits a hyper-activated cholesterol-biosynthesis program that is strongly linked to nuclear receptor RORγ, compared to estrogen receptor-positive breast cancer. Genetic and pharmacological inhibition of RORγ reduces tumor cholesterol content and synthesis rate while preserving host cholesterol homeostasis. We demonstrate that RORγ functions as an essential activator of the entire cholesterol-biosynthesis program, dominating SREBP2 via its binding to cholesterol-biosynthesis genes and its facilitation of the recruitment of SREBP2. RORγ inhibition disrupts its association with SREBP2 and reduces chromatin acetylation at cholesterol-biosynthesis gene loci. RORγ antagonists cause tumor regression in patient-derived xenografts and immune-intact models. Their combination with cholesterol-lowering statins elicits superior anti-tumor synergy selectively in TNBC. Together, our study uncovers a master regulator of the cholesterol-biosynthesis program and an attractive target for TNBC., Enhanced cholesterol biosynthesis is associated with cancer progression. Here the authors identify the nuclear receptor RORγ as a novel master regulator of cholesterol metabolism in triple negative breast cancer (TNBC) and find that RORγ small-molecule antagonists induce tumor regression in patient-derived xenografts and immunocompetent mouse models.

Purpose. To investigate the effects of sleeve gastrectomy (SG) on glucose metabolism and changes in glucagon-like peptide 1 (GLP-1) in Goto-Kakizaki (GK) rats. Methods. GK rats were randomly assigned to one of three groups: SG, SG pair-fed plus sham surgery (PF-sham), and ad libitum-fed no surgery (control). Food intake, body weight, blood glucose, GLP-1 and insulin levels, and GLP-1 expression in the jejunum and ileum were compared. Results. The SG rats exhibited lower postoperative food intake, body weight, and fasting glucose than did the control rats (P<0.05). SG significantly improved glucose and insulin tolerance (P<0.05). Plasma GLP-1 levels were higher in SG rats than in control or PF-sham rats in the oral glucose tolerance test (OGTT) (P<0.05). Blood glucose levels expressed as a percentage of baseline were higher in SG rats than in control rats after exendin (9-39) administration (P<0.05). The levels of GLP-1 expression in the jejunum and ileum were higher in SG rats than in PF-sham and control rats (P<0.05). Conclusions. Improvement of glucose metabolism by SG was associated with increased GLP-1 secretion. SG contributes to an increase in plasma GLP-1 levels via increased GLP-1 expression in the mucosa of the jejunum and/or ileum.