In Vitro Evaluation of the Reductase Activities of Human AKR1C3 Allelic Variants.

Aldo-keto reductase 1C3 (AKR1C3) plays a role in the detoxification and activation of clinical drugs by catalyzing reduction reactions. There are approximately 400 single-nucleotide polymorphisms (SNPs) in the AKR1C3 gene, but their impact on the enzyme activity is still unclear. This study aimed to clarify the effects of SNPs of AKR1C3 with more than 0.5% global minor allele frequency on the reductase activities for its typical substrates. Recombinant AKR1C3 wild-type and R66Q, E77G, C145Y, P180S, or R258C variants were constructed using insect Sf21 cells, and reductase activities for acetohexamide, doxorubicin, and loxoprofen by recombinant AKR1C3s were measured by liquid chromatography-tandem mass spectrometry. Among the variants tested, the C145Y variant showed remarkably low (6%-14% of wild type) intrinsic clearances of reductase activities for all three drugs. Reductase activities of these three drugs were measured using 34 individual Japanese liver cytosols, revealing that heterozygotes of the SNP g.55101G>A tended to show lower reductase activities for three drugs than homozygotes of the wild type. Furthermore, genotyping of the SNP g.55101G>A causing C145Y in 96 Caucasians, 166 African Americans, 192 Koreans, and 183 Japanese individuals was performed by polymerase chain reaction-restriction fragment length polymorphism. This allelic variant was specifically detected in Asians, with allele frequencies of 6.8% and 3.6% in Koreans and Japanese, respectively. To conclude, an AKR1C3 allele with the SNP g.55101G>A causing C145Y would be one of the causal factors for interindividual variabilities in the efficacy and toxicity of drugs reduced by AKR1C3. SIGNIFICANCE STATEMENT: This is the first study to clarify that the AKR1C3 allele with the SNP g.55101G>A causing C145Y results in a decrease in reductase activity. Since the allele was specifically observed in Asians, the allele would be a factor causing an interindividual variability in sensitivity of drug efficacy or toxicity of drugs reduced by AKR1C3 in Asians.

Quantitative Evaluation of the Contribution of Each Aldo-Keto Reductase and Short-Chain Dehydrogenase/Reductase Isoform to Reduction Reactions of Compounds Containing a Ketone Group in the Human Liver.

Enzymes of the aldo-keto reductase (AKR) and short-chain dehydrogenase/reductase superfamilies are involved in the reduction of compounds containing a ketone group. In most cases, multiple isoforms appear to be involved in the reduction of a compound, and the enzyme(s) that are responsible for the reaction in the human liver have not been elucidated. The purpose of this study was to quantitatively evaluate the contribution of each isoform to reduction reactions in the human liver. Recombinant cytosolic isoforms were constructed, i.e., AKR1C1, AKR1C2, AKR1C3, AKR1C4, and carbonyl reductase 1 (CBR1), and a microsomal isoform, 11ß-hydroxysteroid dehydrogenase type 1 (HSD11B1), and their contributions to the reduction of 10 compounds were examined by extrapolating the relative expression of each reductase protein in human liver preparations to recombinant systems quantified by liquid chromatography-mass spectrometry. The reductase activities for acetohexamide, doxorubicin, haloperidol, loxoprofen, naloxone, oxcarbazepine, and pentoxifylline were predominantly catalyzed by cytosolic isoforms, and the sum of the contributions of individual cytosolic reductases was almost 100%. Interestingly, AKR1C3 showed the highest contribution to acetohexamide and loxoprofen reduction, although previous studies have revealed that CBR1 mainly metabolizes them. The reductase activities of bupropion, ketoprofen, and tolperisone were catalyzed by microsomal isoform(s), and the contributions of HSD11B1 were calculated to be 41%, 32%, and 104%, respectively. To our knowledge, this is the first study to quantitatively evaluate the contribution of each reductase to the reduction of drugs in the human liver. SIGNIFICANCE STATEMENT: To our knowledge, this is the first study to determine the contribution of aldo-keto reductase (AKR)-1C1, AKR1C2, AKR1C3, AKR1C4, carbonyl reductase 1, and 11ß-hydroxysteroid dehydrogenase type 1 to drug reductions in the human liver by utilizing the relative expression factor approach. This study found that AKR1C3 contributes to the reduction of compounds at higher-than-expected rates.

Clinicopathologic analysis of pineal parenchymal tumors of intermediate differentiation: a multi-institutional cohort study by the Kyushu Neuro-Oncology Study Group.

PURPOSE: Pineal parenchymal tumors of intermediate differentiation (PPTIDs), which were recognized in the 2007 World Health Organization (WHO) classification, are rare, accounting for less than 1% of all central nervous system tumors. This rarity and novelty complicate the diagnosis and treatments of PPTID. We therefore aimed to evaluate the clinicopathological significance of this tumor. METHODS: At 11 institutions participating in the Kyushu Neuro-Oncology Study Group, data for patients diagnosed with PPTID were collected. Central pathology review and KBTBD4 mutation analysis were applied to attain the diagnostically accurate cohort. RESULTS: PPTID was officially diagnosed in 28 patients: 11 (39%) with WHO grade 2 and 17 (61%) with WHO grade 3 tumors. Median age was 49 years, and the male:female ratio was 1:2.1. Surgery was attempted in all 28 patients, and gross total resection (GTR) was achieved in 46% (13/28). Adjuvant radiotherapy and chemotherapy were administered to, respectively, 82% (23/28) and 46% (13/28). The 5-year progression-free survival (PFS) and overall survival rates were 64.9% and 70.4% respectively. Female sex (p = 0.018) and GTR (p < 0.01) were found to be independent prognostic factors for PFS and female sex (p = 0.019) was that for OS. Initial and second recurrences were most often leptomeningeal (67% and 100% respectively). 80% (20/25) of patients harbored a KBTBD4 mutation. CONCLUSIONS: Female sex and GTR were independent prognostic factors in our patients with PPTID. Leptomeningeal recurrence was observed to be particularly characteristic of this tumor. The rate of KBTBD4 mutation observed in our cohort was acceptable and this could prove the accuracy of our PPTID cohort.

Activation of Inflammation by MCF-7 Cells-Derived Small Extracellular Vesicles (sEV): Comparison of Three Different Isolation Methods of sEV.

PURPOSE: Small extracellular vesicles (sEV) containing proteins and RNAs play important roles as intercellular signal mediators. A critical issue is that there are multiple methods to prepare sEV fractions. The purpose of this study was to examine whether cancer cell-derived sEV fractions prepared by different isolation methods show similar responses for the induction of inflammatory cytokines in macrophages. METHODS: sEV fractions from the conditioned medium of MCF-7 cells were prepared by ultracentrifugation (UC), the MagCapture Exosome Isolation Kit PS (PS), or the ExoQuick-TC kit (EQ). The mRNA levels of inflammatory cytokines in differentiated THP-1 cells treated with the sEV fractions were evaluated. RESULTS: The yields of sEV fractions obtained from 1 mL conditioned medium by UC, PS, or EQ were 3.2×108 particles (0.27 µg protein), 12.8×108 particles (0.87 µg protein) and 23.5 ×108 particles (4.50 µg protein), respectively. The average particle sizes in the UC, PS, and EQ fractions were 184.8 ± 1.8 nm, 157.8 ± 1.3 nm and 165.8 ± 1.1 nm, respectively. CD9 and CD81, markers of sEV, were most highly detected in the PS fraction, followed by the EQ and UC fractions. These results suggest that PS gave sEV with relatively high purity, and many protein contaminants appear to be included in the EQ fraction. The mRNA levels of inflammatory cytokines in THP-1 macrophages were most prominently increased by treatment with the UC fraction, followed by the EQ and PS fractions, suggesting that contaminants rather than sEV may largely induce an inflammatory response. CONCLUSION: The isolation method affects the evaluation of sEV function.

Development and Validation of a Deep Neural Network for Accurate Evaluation of Endoscopic Images From Patients With Ulcerative Colitis.

BACKGROUND & AIMS: There are intra- and interobserver variations in endoscopic assessment of ulcerative colitis (UC) and biopsies are often collected for histologic evaluation. We sought to develop a deep neural network system for consistent, objective, and real-time analysis of endoscopic images from patients with UC. METHODS: We constructed the deep neural network for evaluation of UC (DNUC) algorithm using 40,758 images of colonoscopies and 6885 biopsy results from 2012 patients with UC who underwent colonoscopy from January 2014 through March 2018 at a single center in Japan (the training set). We validated the accuracy of the DNUC algorithm in a prospective study of 875 patients with UC who underwent colonoscopy from April 2018 through April 2019, with 4187 endoscopic images and 4104 biopsy specimens. Endoscopic remission was defined as a UC endoscopic index of severity score of 0; histologic remission was defined as a Geboes score of 3 points or less. RESULTS: In the prospective study, the DNUC identified patients with endoscopic remission with 90.1% accuracy (95% confidence interval [CI] 89.2%-90.9%) and a kappa coefficient of 0.798 (95% CI 0.780-0.814), using findings reported by endoscopists as the reference standard. The intraclass correlation coefficient between the DNUC and the endoscopists for UC endoscopic index of severity scoring was 0.917 (95% CI 0.911-0.921). The DNUC identified patients in histologic remission with 92.9% accuracy (95% CI 92.1%-93.7%); the kappa coefficient between the DNUC and the biopsy result was 0.859 (95% CI 0.841-0.875). CONCLUSIONS: We developed a deep neural network for evaluation of endoscopic images from patients with UC that identified those in endoscopic remission with 90.1% accuracy and histologic remission with 92.9% accuracy. The DNUC can therefore identify patients in remission without the need for mucosal biopsy collection and analysis. Trial number: UMIN000031430.

Functional analysis of isoflavones using patient-derived human colonic organoids.

Inflammatory bowel disease (IBD) comprises two major subtypes, ulcerative colitis (UC) and Crohn's disease, which are multifactorial diseases that may develop due to genetic susceptibility, dysbiosis, or environmental factors. Environmental triggers of IBD include food-borne factors, and a previous nationwide survey in Japan identified pre-illness consumption of isoflavones as a risk factor for UC. However, the precise mechanisms involved in the detrimental effects of isoflavones on the intestinal mucosa remain unclear. The present study employed human colonic organoids (hCOs) to investigate the functional effect of two representative isoflavones, genistein and daidzein, on human colonic epithelial cells. The addition of genistein to organoid reformation assays significantly decreased the number and size of reformed hCOs compared with control and daidzein treatment, indicating an inhibitory effect of genistein on colonic cell/progenitor cell function. Evaluation of the phosphorylation status of 49 different receptor tyrosine kinases showed that genistein selectively inhibited phosphorylation of epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (HGFR). We established a two-dimensional wound-repair model using hCOs and showed that genistein significantly delayed the overall wound-repair response. Our results collectively show that genistein may exert its detrimental effects on the intestinal mucosa via negative regulation of stem/progenitor cell function, possibly leading to sustained mucosal injury and the development of UC.

Posterior fossa subdural hematoma in a neonate with cleidocranial dysostosis after a spontaneous vaginal delivery: a case report.

BACKGROUND: Cleidocranial dysostosis (CCD) is an anomaly characterized by delayed closure of the cranial sutures, midface hypoplasia, moderately short stature, hypoplastic or aplastic clavicles, dental abnormalities, and other complications. CASE PRESENTATION: We report a case of posterior fossa subdural hematoma (PFSDH) after vaginal delivery in a neonate with CCD, which presented with several clinical symptoms such as apnea, vomiting, and bradycardia. Our patient, who had a family history of CCD, developed apnea and vomiting shortly after birth; PFSDH was detected by head computed tomography, and the patient recovered well following standard medical treatment. CONCLUSION: The prognosis of intracranial hemorrhage in neonates with CCD is generally poor. In neonates, PFSDH occurs by the following mechanism: the distortion of the infant's cranium during delivery, by the strong force, causes elongation of the falx and angulation of the tentorium that leads to tears in the posterior fossa venous structures, which then cause bleeding into the subdural space. In CCD, the forces occurring during vaginal delivery may causeexcessive distortion of the fragile skull. An awareness of CCD is hence important to avoid vaginal delivery in prenatally diagnosed CCD cases with a family history of CCD.

Atypical and Fibrous Meningioma with Differential Cerebral Blood Volume on Magnetic Resonance Imaging: A Case Report.

Magnetic resonance imaging (MRI) features of meningiomas typically reveal a well-circumscribed and contrast-enhancing dural mass. Here we discuss the differences in MRI findings between typically benign and atypical meningioma, and their clinical implications. An MRI of a 67-year-old man revealed a substantial homogeneous enhancing tumor nodule. The MRI also showed two components in the tumor, and the regional cerebral blood volume (rCBV) was higher in the lateral than in the medial mass. A pathological examination also revealed features of both benign and atypical meningiomas. The Ki-67 labeling index was 1% on the medial side and 5% on the lateral side. There were clearly two components within the tumor mass, and the MRI revealed differential rCBV in the tumor. The results indicated a nontypical MRI of meningiomas, allowing for predictability of atypical meningiomas using MRI before surgical resection.

Small Bowel Healing Detected by Endoscopy in Patients With Crohn's Disease After Treatment With Antibodies Against Tumor Necrosis Factor.

BACKGROUND & AIMS: It is important to objectively assess Crohn's disease (CD) activity in patients treated with antibodies against tumor necrosis factor (anti-TNF). Detection of healing by endoscopy (endoscopic healing) associates with patient outcome, based on evidence from studies of ileocolonoscopy. We assessed endoscopic healing after treatment, based on findings from balloon-assisted enteroscopy (BAE), in patients with CD. METHODS: We performed a post-hoc analysis of data from a clinical trial from 116 patients with CD (46 with ileal and 70 with ileocolonic type) who received induction and then maintenance therapy with anti-TNF agents from January 2013 through March 2018 at a single center in Japan. We compared findings from BAE before induction therapy and then again during maintenance therapy (median 13 months later). Endoscopic healing was defined as the modified simple endoscopic score for CD below 5. We also collected data on previous treatments, makers of inflammation, and disease type. RESULTS: Before treatment, small bowel ulcerations were present in 114 patients (98%); 42 patients (60%) with ileocolonic disease had colon ulcerations. During maintenance therapy, 41/114 patients (36%) had small bowel endoscopic healing; all the patients with small bowel endoscopic healing also had colonic endoscopic healing. Colonic endoscopic healing was observed in 33/42 patients (79%). The proportion of patients with small bowel endoscopic healing was significantly lower than that of colonic endoscopic healing (P < .001). Among all patients, failure to achieve small bowel endoscopic healing was significantly associated with structuring or penetrating disease (P = .014), lack of concomitant treatment with immunomodulators (P = .015), and having received previous treatment with an anti-TNF agents (P = .018). CONCLUSIONS: In a post-hoc analysis of patients with CD treated with anti-TNF agents, we found small bowel ulcerations, detected by BAE, to be more difficult to heal than colon ulcerations.

TGF-ß promotes fetal gene expression and cell migration velocity in a wound repair model of untransformed intestinal epithelial cells.

The early-phase wound repair response of the intestinal epithelium is characterized by rapid and organized cell migration. This response is regulated by several humoral factors, including TGF-ß. However, due to a lack of appropriate models, the precise response of untransformed intestinal epithelial cells (IECs) to those factors is unclear. In this study, we established an in vitro wound repair model of untransformed IECs, based on native type-I collagen. In our system, IECs formed a uniform monolayer in a two-chamber culture insert and displayed a stable wound repair response. Gene expression analysis revealed significant induction of Apoa1, Apoa4, and Wnt4 during the collagen-guided wound repair response. The wound repair response was enhanced significantly by the addition of TGF-ß. Surprisingly, addition of TGF-ß induced a set of genes, including Slc28a2, Tubb2a, and Cpe, that were expressed preferentially in fetal IECs. Moreover, TGF-ß significantly increased the peak velocity of migrating IECs and, conversely, reduced the time required to reach the peak velocity, as confirmed by the motion vector prediction (MVP) method. Our current in vitro system could be employed to assess other humoral factors involved in IEC migration and could contribute to a deeper understanding of the wound repair potentials of untransformed IECs.

1000-volume/s high-speed volumetric display for high-speed HMD.

In this paper, we propose a high-speed volumetric display principle that can solve two problems faced by three-dimensional displays using the parallax stereo principle (namely, the vergence-accommodation conflict and display latency) and we report evaluation results. The proposed display method can update a set of images at different depths at 1000 Hz and is consistent with accommodation. The method selects the depth position in microseconds by combining a high-speed variable-focus lens that vibrates at about 69 kHz and sub-microsecond control of illumination light using an LED. By turning on the LED for only a few hundred nanoseconds when the refractive power of the lens is at a certain value, an image can be presented with this specific refractive power. The optical system is combined with a DMD to form an image at each depth. 3D information consisting of multiple planes in the depth direction can be presented at a high refresh rate by switching the images and changing the refractive power at high speed. A proof-of-concept system was developed to show the validity of the proposed display principle. The system successfully displayed 3D information consisting of six binary images at an update rate of 1000 volume/s.

Direct C3-Selective Arylation of N-Unsubstituted Indoles with Aryl Chlorides, Triflates, and Nonaflates Using a Palladium-Dihydroxyterphenylphosphine Catalyst.

A palladium-dihydroxyterphenylphosphine (DHTP) catalyst was successfully applied to the direct C3-arylation of N-unsubstituted indoles with aryl chlorides, triflates, and nonaflates. This catalyst showed C3-selectivity, whereas catalysts with other structurally related ligands exhibited N1-selectivity. Complex formation between the lithium salts of the ligand and the indole is assumed to accelerate the arylation at the C3 position. Reactions using 3-alkylindoles afforded 3,3-disubstituted indolenines, which can be further converted to the corresponding indoline derivatives.

5-Aminolevulinic Acid: Pitfalls of Fluorescence-guided Resection for Malignant Gliomas and Application for Malignant Glioma Therapy.

5-Aminolevulinic acid (ALA) has been widely used as an intravital fluorescence marker in the fluorescence-guided resection of malignant gliomas. Although not a photosensitizer itself, 5-ALA is a prodrug that accumulates protoporphyrin IX (PpIX) in the mitochondria of glioma cells; PpIX acts as a photosensitizer. Fluorescence-guided resection for malignant gliomas has some pitfalls. Moreover, 5-ALA is not merely a fluorescence marker but has potential as a mitochondria-targeting drug for malignant glioma therapy. In this article, we review the literature related to 5-ALA, discuss the pitfalls of fluorescence-guided resection using 5-ALA for malignant gliomas, and describe the application of 5-ALA for malignant glioma therapy with personal opinions.

Recurrent Shoulder Tip Pain After Ventriculoperitoneal Shunt Placement Associated with Infectious Peritonitis with Propionibacterium acnes; A Case Report and Review of the Literature.

Ventriculoperitoneal (VP) shunt placement is commonly performed for the treatment of hydrocephalus, and several complications of this procedure are well known. Radiating shoulder tip pain after VP shunt placement has been reported as an unusual complication in a few cases, associated with dislocation of the peritoneal catheter. We described the case of a 9-year-old girl who presented with recurrent radiating shoulder tip pain after VP shunt placement. The pain recurred after peritoneal catheter repositioning because of peritoneal inflammation and adhesion due to peritonitis with Propionibacterium acnes (P. acnes). This bacterium was isolated using 16S ribosomal RNA gene polymerase chain reaction (16S rRNA gene PCR), and anaerobic and prolonged culture tests. After antibacterial treatment, ventriculoarterial (VA) shunt placement was successfully performed. Hemidiaphragm irritation by the peritoneal catheter leads to radiating shoulder tip pain, and peritoneal inflammation and adhesion caused by infectious peritonitis may cause recurrence of this despite catheter repositioning. Clinicians should be aware of shoulder pain as a complication of VP shunt placement, and should consider VA shunt placement as an alternative treatment if this symptom recurs after catheter repositioning. Furthermore, 16S rRNA gene PCR and anaerobic and prolonged culture tests should be considered to detect P. acnes infection.

Long-term effect of NUDT15 R139C on hematologic indices in inflammatory bowel disease patients treated with thiopurine.

BACKGROUND AND AIM: A missense variant of the nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene (R139C) predisposes Asian patients with inflammatory bowel disease (IBD) to thiopurine-induced leukopenia. This study evaluates the long-term effect of NUDT15 R139C heterozygosity on hematological parameters during thiopurine administration. METHODS: We enrolled 83 Japanese IBD patients who were on anti-tumor necrosis factor-α agents and had used thiopurine. NUDT15 R139C was genotyped by polymerase chain reaction. We retrospectively reviewed patient clinical charts to collect data on white blood cell (WBC) count, mean corpuscular volume (MCV), hemoglobin, and platelet count during the 24 months following thiopurine initiation. RESULTS: The included patients had either Crohn's disease (54; 65.1%) or ulcerative colitis (29; 34.9%). Genotyping of NUDT15 R139C identified 62 patients (74.7%) of genotype C/C and 21 (25.3%) of genotype C/T. The median dose of thiopurine was lower in the C/T group than in the C/C group after starting thiopurine. At 6 months, the mean WBC count of the C/T group became significantly lower than that of the C/C group (P = 0.008) and remained lower through the 24 months. The C/T group developed grade 2-4 leukopenia by 6 months, which persisted through 12-24 months. The mean MCV in the C/T group became higher than that of the C/C group after 3 months. CONCLUSIONS: NUDT15 R139C heterozygosity affected the WBC count and MCV for 24 months after thiopurine administration. Our results indicate that careful monitoring of leukopenia and dose adjustment are necessary throughout treatment in IBD patients heterozygous for the NUDT15 R139C.

Importance of Finding Embolic Sources for Patients with Embolic Stroke of Undetermined Source.

OBJECTIVE: The concept of embolic stroke of undetermined source refers to cryptogenic strokes caused by either major or minor risks. Although antiplatelet treatments are most often used for secondary prevention of embolic stroke of undetermined source, optimal strategies remain unclear. To determine the ideal treatment strategy for secondary prevention, we investigated embolic sources among patients with embolic stroke of undetermined source. METHODS: The study included 292 consecutive patients (135 men, 157 women; mean age: 74.3 ± 11.6 years) diagnosed with cerebral infarction, 27 of whom were diagnosed with embolic stroke of undetermined source (9.2%; 14 men, 13 women; mean age: 70.7 ± 11.5 years). These 27 patients were examined using contrast-enhanced whole-body computed tomography, transesophageal echocardiography, and Holter electrocardiography. We evaluated whether antiplatelet or anticoagulant treatment was preferred based on the embolic source. RESULTS: Embolic sources among patients with embolic stroke of undetermined source included valve calcification (11.1%), left ventricle diastolic dysfunction (18.5%), cancer-associated stroke (25.9%), covert atrial fibrillation (7.4%), aortic arch atherosclerotic plaques (11.1%), paradoxical embolism (3.7%), and sick sinus syndrome (3.7%). Embolic sources remained unidentified in 5 patients (18.5%). Our analysis revealed that 21 of the 27 patients (77.8%) with embolic stroke of undetermined source required anticoagulant therapy for secondary prevention. CONCLUSION: Although aspirin is the most commonly used antithrombotic drug for embolic stroke of undetermined source, our results suggest that some patients require anticoagulant therapy. Determining embolic sources is important for selecting the appropriate treatment options for this patient population.

Characteristics of Bone Destruction in Cranial Vault Lymphoma Compared with Other Skull Tumors.

Cranial vault lymphomas are rare and challenging to diagnose. We present herein two cases of cranial vault lymphoma. The first patient was a 72-year-old woman who presented with a large mass in the parietal bone found incidentally following a head injury. The second patient was a 63-year-old man who presented with an occipital subcutaneous mass associated with visual disturbance and occipital headaches. The diagnosis of a malignant tumor in the second patient was straightforward due to his symptoms and considerable bone destruction, but the first patient was more difficult to diagnose due to a lack of symptoms and only slight bone destruction detected by computed tomography (CT). Both were histophathologically diagnosed with diffuse large B cell lymphoma (DLBCL) in the cranial vault. We also investigated the clinical features, including initial symptoms and patterns of bone destruction, in 23 patients with other types of skull tumors. This comparison showed that cranial vault lymphomas cause large masses on the scalp and lead to characteristic incomplete bone destruction, indicating that cranial bone is destroyed very slowly despite the expanding subcutaneous mass. This feature is unique compared with other benign and malignant skull tumors. In addition, cranial vault lymphoma can be confirmed via bone window CT.

Indispensable role of Notch ligand-dependent signaling in the proliferation and stem cell niche maintenance of APC-deficient intestinal tumors.

Ligand-dependent activation of Notch signaling is required to maintain the stem-cell niche of normal intestinal epithelium. However, the precise role of Notch signaling in the maintenance of the intestinal tumor stem cell niche and the importance of the RBPJ-independent non-canonical pathway in intestinal tumors remains unknown. Here we show that Notch signaling was activated in LGR5+ve cells of APC-deficient mice intestinal tumors. Accordingly, Notch ligands, including Jag1, Dll1, and Dll4, were expressed in these tumors. In vitro studies using tumor-derived organoids confirmed the intrinsic Notch activity-dependent growth of tumor cells. Surprisingly, the targeted deletion of Jag1 but not RBPJ in LGR5+ve tumor-initiating cells resulted in the silencing of Hes1 expression, disruption of the tumor stem cell niche, and dramatic reduction in the proliferation activity of APC-deficient intestinal tumors in vivo. Thus, our results highlight the importance of ligand-dependent non-canonical Notch signaling in the proliferation and maintenance of the tumor stem cell niche in APC-deficient intestinal adenomas.