PALI1 promotes tumor growth through competitive recruitment of PRC2 to G9A-target chromatin for dual epigenetic silencing.

PALI1 is a newly identified accessory protein of the Polycomb repressive complex 2 (PRC2) that catalyzes H3K27 methylation. However, the roles of PALI1 in cancer are yet to be defined. Here, we report that PALI1 is upregulated in advanced prostate cancer (PCa) and competes with JARID2 for binding to the PRC2 core subunit SUZ12. PALI1 further interacts with the H3K9 methyltransferase G9A, bridging the formation of a unique G9A-PALI1-PRC2 super-complex that occupies a subset of G9A-target genes to mediate dual H3K9/K27 methylation and gene repression. Many of these genes are developmental regulators required for cell differentiation, and their loss in PCa predicts poor prognosis. Accordingly, PALI1 and G9A drive PCa cell proliferation and invasion in vitro and xenograft tumor growth in vivo. Collectively, our study shows that PALI1 harnesses two central epigenetic mechanisms to suppress cellular differentiation and promote tumorigenesis, which can be targeted by dual EZH2 and G9A inhibition.

Genotypic and phenotypic features of 39 Chinese patients with glycogen storage diseases type I, VI, and IX.

Glycogen storage diseases (GSDs) are abnormally inherited glycogen metabolism mainly affecting the liver, muscles, and heart. Deficiency of proteins involved in glycogen metabolism caused by genetic mutations are responsible for different subtype of GSDs. However, there are still some challenges in diagnosing GSD. This study includes 39 suspected GSDs patients from unrelated families in China. Next-generation sequencing (NGS) was used to investigate the reason for their diseases at the genetic level. Finally, all 39 patients were diagnosed with GSDs, including 20 GSD-Ia, 4 GSD-VI, and 15 GSD IX (12 GSD-IXa patients and 3 GSD-IXb patients). Thirty-two mutations in G6PC1, PYGL, PHKA2, and PHKB genes were identified, with 14 of them being novel variants. The pathogenicity of novel variants was classified according to ACMG guildlines and predicted by in slico algorithms. Mutations p.L216L and p.R83H in G6PC1 gene may be the hot spot mutation in Chinese. Hearing impairment is a rare clinical feature of GSD Ia, which has also been observed in our cohort. The severity of GSD VI and IX was indicated by our patients. Close follow-up should be applied to GSD VI and IX patients. Our findings provided evidence for building the phenotype-genotype of GSDs and expanded the mutation spectrum of related genes.

Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer.

The evolution of prostate cancer from an androgen-dependent state to one that is androgen-independent marks its lethal progression. The androgen receptor (AR) is essential in both, though its function in androgen-independent cancers is poorly understood. We have defined the direct AR-dependent target genes in both androgen-dependent and -independent cancer cells by generating AR-dependent gene expression profiles and AR cistromes. In contrast to what is found in androgen-dependent cells, AR selectively upregulates M-phase cell-cycle genes in androgen-independent cells, including UBE2C, a gene that inactivates the M-phase checkpoint. We find that epigenetic marks at the UBE2C enhancer, notably histone H3K4 methylation and FoxA1 transcription factor binding, are present in androgen-independent cells and direct AR-enhancer binding and UBE2C activation. Thus, the role of AR in androgen-independent cancer cells is not to direct the androgen-dependent gene expression program without androgen, but rather to execute a distinct program resulting in androgen-independent growth.

The role of NSD1, NSD2, and NSD3 histone methyltransferases in solid tumors.

NSD1, NSD2, and NSD3 constitute the nuclear receptor-binding SET Domain (NSD) family of histone 3 lysine 36 (H3K36) methyltransferases. These structurally similar enzymes mono- and di-methylate H3K36, which contribute to the maintenance of chromatin integrity and regulate the expression of genes that control cell division, apoptosis, DNA repair, and epithelial-mesenchymal transition (EMT). Aberrant expression or mutation of members of the NSD family is associated with developmental defects and the occurrence of some types of cancer. In this review, we discuss the effect of alterations in NSDs on cancer patient's prognosis and response to treatment. We summarize the current understanding of the biological functions of NSD proteins, focusing on their activities and the role in the formation and progression in solid tumors biology, as well as how it depends on tumor etiologies. This review also discusses ongoing efforts to develop NSD inhibitors as a promising new class of cancer therapeutic agents.

[Clinical analysis of endoscopic esophageal dilation for the treatment of corrosive esophageal strictures in children]. / å† é•œä¸‹é£Ÿç®¡æ‰©å¼ æ²»ç–—å„¿ç«¥è èš€æ€§é£Ÿç®¡ç‹­çª„çš„ä¸´åºŠåˆ†æž.

OBJECTIVES: To investigate the clinical application of endoscopic esophageal dilation in the treatment of corrosive esophageal strictures in children. METHODS: A retrospective analysis was performed on the clinical data of 15 children with corrosive esophageal strictures who underwent endoscopic esophageal dilation in Children's Hospital, Zhejiang University School of Medicine. The clinical features, treatment modality of endoscopic esophageal dilation, number of dilations, complications, and prognosis were reviewed. RESULTS: A total of 96 esophageal dilations were performed in the 15 children with corrosive esophageal strictures, with a median of 6 dilations per child. Among them, 9 children (60%) underwent 6 or more dilations. The children with a stricture length of >3 cm had a significantly higher number of dilations than those with a stricture length of ≤3 cm (P<0.05). The children with strictures in a single segment had a significantly better treatment outcome than those with strictures in multiple segments (P=0.005). No complication was observed during all sessions of dilation. The overall effective rate (including significant improvement and improvement) of endoscopic esophageal dilation treatment was 87%, with 2 cases of failure. CONCLUSIONS: Endoscopic esophageal dilation is an effective and relatively safe treatment method for corrosive esophageal strictures in children, and children with strictures in a single segment tend to have a better treatment outcome than those with strictures in multiple segments.

[Effectiveness of induction therapy with exclusive enteral nutrition in pediatric Crohn's disease]. / å ¨è‚ å† è¥å »å¯¹å„¿ç«¥å ‹ç½—æ©ç— è¯±å¯¼ç¼“è§£ç–—æ•ˆç ”ç©¶.

OBJECTIVES: To evaluate the effectiveness of induction therapy with exclusive enteral nutrition (EEN) in pediatric Crohn's disease (CD). METHODS: A retrospective analysis was performed on the medical data of 62 children with CD who received EEN in Children's Hospital, Zhejiang University School of Medicine, from March 2013 to August 2021. The medical data included general information and height, weight, Pediatric Crohn's Disease Activity Index (PCDAI), Crohn's Disease Endoscopic Index of Severity, C-reactive protein, erythrocyte sedimentation rate, and serum albumin level before treatment and after 8 weeks of treatment. The changes in the above indicators were compared before and after treatment. RESULTS: Among the 62 children with CD, there were 39 boys (63%) and 23 girls (37%), with a mean age of (11.9±3.0) years at diagnosis. Among the 55 children who completed EEN treatment for at least 8 weeks, 48 (87%) achieved clinical remission at week 8. PCDAI at week 8 was significantly lower than that before treatment (P<0.001). Except for 17 children with involvement of the small intestine alone and 3 children with involvement of the colon who did not receive colonoscopy reexamination, the remaining 35 children with involvement of the colon received colonoscopy reexamination after the 8-week EEN treatment. Of the 35 children, 29 (83%) achieved mucosal healing. As for the 48 children who achieved clinical remission at week 8, there were significant improvements in height-for-age Z-score and body mass index-for-age Z-score at week 8 (P<0.01). As for the 7 children who did not achieve clinical remission at week 8, there were no significant changes in height-for-age Z-score and body mass index-for-age Z-score at week 8 (P>0.05). CONCLUSIONS: The 8-week EEN treatment has a good effect on clinical remission and mucosal healing in children with CD. For the children with CD achieving clinical remission, EEN can improve their height and body mass index.

Infliximab Therapy in Very Early Onset Crohn's Disease: Real-World Experience in China.

BACKGROUND: Data concerning of the effectiveness of infliximab in very early onset Crohn's disease patients are rare. AIM: To assess the effectiveness and safety issues of infliximab treatment for this rare cohort. METHODS: The pediatric Crohn's disease activity index, Crohn's disease endoscopic index score, height, and weight were retrospectively recorded at baseline, week 14, and week 54. The rates of clinical remission and mucosal healing and growth of patients were compared between patients younger and older than 6 years of age. Loss of response or non-response to infliximab and adverse events were assessed during the entire treatment period. RESULTS: Sixty-five patients were enrolled in the study. Sixty-four percent and 40.0% of very early onset Crohn's disease patients achieved clinical remission and mucosal healing after induction therapy. Adjusted for the covariances, very early disease onset had no association with primary non-response (p = 0.360) or mucosal healing (p = 0.361). Early disease onset was associated with discontinuation of infliximab due to adverse events (hazard ratio [HR] 7.15, 95% CI 1.73-29.51, p = 0.006). Patients < 6 years had lower body mass index for age z score improvement during the induction phase (p = 0.04). CONCLUSIONS: Very early onset Crohn's disease patients had similar non-response rates and mucosal healing rates as those who were 6 years or older during induction therapy. Greater discontinuation of infliximab due to adverse events was observed in very early onset Crohn's disease patients.

USP22 deficiency leads to myeloid leukemia upon oncogenic Kras activation through a PU.1-dependent mechanism.

Ras mutations are commonly observed in juvenile myelomonocytic leukemia (JMML) and chronic myelomonocytic leukemia (CMML). JMML and CMML transform into acute myeloid leukemia (AML) in about 10% and 50% of patients, respectively. However, how additional events cooperate with Ras to promote this transformation are largely unknown. We show that absence of the ubiquitin-specific peptidase 22 (USP22), a component of the Spt-Ada-GCN5-acetyltransferase chromatin-remodeling complex that is linked to cancer progression, unexpectedly promotes AML transformation in mice expressing oncogenic KrasG12D/+ USP22 deficiency in KrasG12D/+ mice resulted in shorter survival compared with control mice. This was due to a block in myeloid cell differentiation leading to the generation of AML. This effect was cell autonomous because mice transplanted with USP22-deficient KrasG12D/+ cells developed an aggressive disease and died rapidly. The transcriptome profile of USP22-deficient KrasG12D/+ progenitors resembled leukemic stem cells and was highly correlated with genes associated with poor prognosis in AML. We show that USP22 functions as a PU.1 deubiquitylase by positively regulating its protein stability and promoting the expression of PU.1 target genes. Reconstitution of PU.1 overexpression in USP22-deficient KrasG12D/+ progenitors rescued their differentiation. Our findings uncovered an unexpected role for USP22 in Ras-induced leukemogenesis and provide further insights into the function of USP22 in carcinogenesis.

PRDM4 mediates YAP-induced cell invasion by activating leukocyte-specific integrin ß2 expression.

Yes-associated protein (YAP) is a transcriptional co-activator and a major effector of the Hippo pathway that promotes cell proliferation and stemness, while inhibiting apoptosis. YAP plays a central role in organ size control, and its deregulation strongly promotes cancer initiation and progression. However, the mechanisms by which YAP promotes cell invasion and metastasis are not fully understood. Here, we report that YAP induces leukocyte-specific integrin ß2 (ITGB2) expression in cancer cells, thereby promoting cell invasion through the endothelium in a manner mimicking leukocytes. Through independent biochemical purification and a functional screen, we further identified PR/SET domain 4 (PRDM4) as a transcription factor interacting with the WW domains of YAP to mediate ITGB2 expression and cell invasion. Consistently, ITGB2 and PRDM4 mRNA levels are significantly increased in metastatic prostate cancer. In addition, PRDM4 contributes to YAP-induced tumorigenesis possibly via mediating the expression of other YAP target genes. Our results demonstrate that YAP promotes cell invasion by inducing leukocyte-specific integrin expression, and identify PRDM4 as a novel transcription factor for YAP targets.

A case of severe malnutrition infant with neonatal onset intractable diarrhea.

BACKGROUND: Congenital tufting enteropathy (CTE) is a rare disease that manifests as intractable diarrhea during the neonatal period which is associated with mutations of the epithelial cell adhesion molecule (EpCAM) gene. CASE PRESENTATION: A male infant who presented with vomiting, diarrhea, abdominal distention, malnutrition and growth failure was admitted to our department when he was 2 months old. His parents were healthy and nonconsanguineous. Etiologic examinations of stool, inflammatory markers, blood gas and electrolytes levels, serum albumin level, serum immunoglobin levels were all normal. And there was no indication for metabolic diseases. Additionally, gastrointestinal contrast did not reveal abnormality of gastrointestinal. The patient was diagnosed with intestinal malabsorptive syndrome and severe malnutrition without definite cause. He was on supportive treatment and nutritional therapy for 13 months. However, he did not gain weight obviously. He was discharged at the age of 15 months and was fed with partial hydrolyzed formula and rice paste at home. Three months later he developed hypoglycemia and severe respiratory infection. Finally, he died due to sepsis and multiple organs failure. The next generation sequencing revealed one homozygous mutation of EpCAM gene and one complex heterozygous mutation of TTC7A gene. He was diagnosed CTE according to the genetic results and clinical manifestations. CONCLUSIONS: CTE is rarely reported in Asia. Patients present with congenital diarrhea, poor weight gain and growth failure are recommended to perform endoscopy examination with proper immunohistochemistry study as early as possible, and genetic testing is necessary when suspecting congenital diarrhea and enteropathy.

Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis.

Cell attachment to the extracellular matrix (ECM) is crucial to cell physiology such as polarity, motility, and proliferation. In normal cells, loss of attachment to the ECM induces a specific type of apoptosis, termed anoikis. Resistance to anoikis in cancer cells promotes their survival in circulation and dispersion to distant anatomic sites, leading to tumor metastasis. The Yes-associated protein (YAP) transcription coactivator is a human oncogene and a key regulator of organ size. The Hippo tumor suppressor pathway phosphorylates and inhibits YAP. However, little is known about the signals that regulate the Hippo pathway. Here we report that through cytoskeleton reorganization, cell detachment activates the Hippo pathway kinases Lats1/2 and leads to YAP phosphorylation and inhibition. The detachment-induced YAP inactivation is required for anoikis in nontransformed cells, whereas in cancer cells with deregulation of the Hippo pathway, knockdown of YAP and TAZ restores anoikis. Furthermore, we provided evidence that Lats1/2 expression level is indeed significantly down-regulated in metastatic prostate cancer. Our findings provide a novel connection between cell attachment and anoikis through the Hippo pathway and have important implications in cancer therapeutics.

In Inflamed Intestinal Tissues and Epithelial Cells, Interleukin 22 Signaling Increases Expression of H19 Long Noncoding RNA, Which Promotes Mucosal Regeneration.

BACKGROUND & AIMS: Inflammation affects regeneration of the intestinal epithelia; long noncoding RNAs (lncRNAs) regulate cell functions, such as proliferation, differentiation, and migration. We investigated the mechanisms by which the lncRNA H19, imprinted maternally expressed transcript (H19) regulates regeneration of intestinal epithelium using cell cultures and mouse models of inflammation. METHODS: We performed RNA-sequencing transcriptome analyses of intestinal tissues from mice with lipopolysaccharide (LPS)-induced sepsis to identify lncRNAs associated with inflammation; findings were confirmed by quantitative real-time polymerase chain reaction and in situ hybridization analyses of intestinal tissues from mice with sepsis or dextran sulfate sodium (DSS)-induced mucosal wound healing and patients with ulcerative colitis compared to healthy individuals (controls). We screened cytokines for their ability to induce expression of H19 in HT-29 cells and intestinal epithelial cells (IECs), and confirmed findings in crypt epithelial organoids derived from mouse small intestine. IECs were incubated with different signal transduction inhibitors and effects on H19 lncRNA levels were measured. We assessed intestinal epithelial proliferation or regeneration in H19ΔEx1/+ mice given LPS or DSS vs wild-type littermates (control mice). H19 was overexpressed in IECs using lentiviral vectors and cell proliferation was measured. We performed RNA antisense purification, RNA immunoprecipitation, and luciferase reporter assays to study functions of H19 in IECs. RESULTS: In RNA-sequencing transcriptome analysis of lncRNA expression in intestinal tissues from mice, we found that levels of H19 lncRNA changed significantly with LPS exposure. Levels of H19 lncRNA increased in intestinal tissues of patients with ulcerative colitis, mice with LPS-induced and polymicrobial sepsis, or mice with DSS-induced colitis, compared with controls. Increased H19 lncRNA localized to epithelial cells in the intestine, regardless of Lgr5 messenger RNA expression. Exposure of IECs to interleukin 22 (IL22) increased levels of H19 lncRNA with time and dose, which required STAT3 and protein kinase A activity. IL22 induced expression of H19 in mouse intestinal epithelial organoids within 6 hours. Exposure to IL22 increased growth of intestinal epithelial organoids derived from control mice, but not H19ΔEx1/+ mice. Overexpression of H19 in HT-29 cells increased their proliferation. Intestinal mucosa healed more slowly after withdrawal of DSS from H19ΔEx1/+ mice vs control mice. Crypt epithelial cells from H19ΔEx1/+ mice proliferated more slowly than those from control mice after exposure to LPS. H19 lncRNA bound to p53 and microRNAs that inhibit cell proliferation, including microRNA 34a and let-7; H19 lncRNA binding blocked their function, leading to increased expression of genes that promote regeneration of the epithelium. CONCLUSIONS: The level of lncRNA H19 is increased in inflamed intestinal tissues from mice and patients. The inflammatory cytokine IL22 induces expression of H19 in IECs, which is required for intestinal epithelial proliferation and mucosal healing. H19 lncRNA appears to inhibit p53 protein and microRNA 34a and let-7 to promote proliferation of IECs and epithelial regeneration.

The DEK oncoprotein is a Su(var) that is essential to heterochromatin integrity.

Heterochromatin integrity is crucial for genome stability and regulation of gene expression, but the factors involved in mammalian heterochromatin biology are only incompletely understood. Here we identify the oncoprotein DEK, an abundant nuclear protein with a previously enigmatic in vivo function, as a Suppressor of Variegation [Su(var)] that is crucial to global heterochromatin integrity. We show that DEK interacts directly with Heterochromatin Protein 1 α (HP1α) and markedly enhances its binding to trimethylated H3K9 (H3K9me3), which is key for maintaining heterochromatic regions. Loss of Dek in Drosophila leads to a Su(var) phenotype and global reduction in heterochromatin. Thus, these findings show that DEK is a key factor in maintaining the balance between heterochromatin and euchromatin in vivo.

[Inflammatory bowel disease with growth hormone deficiency in adolescents: an analysis of 4 cases and literature review].

Inflammatory bowel disease (IBD) is a chronic recurrent non-specific inflammatory disease in the intestinal tract. About 10%-56% of children with Crohn's disease and about 10% of children with ulcerative colitis have growth retardation. This study reports four adolescents with IBD and growth hormone deficiency who were diagnosed with Crohn's disease. There were three boys and one girl, with an age of 11.0-13.9 years and a disease duration of 11-85 months at diagnosis. The four patients had the involvement of the small intestine only, the colon only, both the small intestine and the upper gastrointestinal tract, and both the small intestine and the colon respectively. The pediatric Crohn's disease activity index ranged from 27.5 to 45 points. All four patients had a height-for-age Z-score (HAZ) of <-2, and the growth hormone provocative test suggested growth hormone deficiency. Of all four patients, two received recombinant human growth hormone combined with infliximab, one received infliximab only, and one received recombinant human growth hormone combined with mercaptopurine. All four patients had an improvement in HAZ after treatment.

FOXA1 potentiates lineage-specific enhancer activation through modulating TET1 expression and function.

Forkhead box A1 (FOXA1) is an FKHD family protein that plays pioneering roles in lineage-specific enhancer activation and gene transcription. Through genome-wide location analyses, here we show that FOXA1 expression and occupancy are, in turn, required for the maintenance of these epigenetic signatures, namely DNA hypomethylation and histone 3 lysine 4 methylation. Mechanistically, this involves TET1, a 5-methylcytosine dioxygenase. We found that FOXA1 induces TET1 expression via direct binding to its cis-regulatory elements. Further, FOXA1 physically interacts with the TET1 protein through its CXXC domain. TET1 thus co-occupies FOXA1-dependent enhancers and mediates local DNA demethylation and concomitant histone 3 lysine 4 methylation, further potentiating FOXA1 recruitment. Consequently, FOXA1 binding events are markedly reduced following TET1 depletion. Together, our results suggest that FOXA1 is not only able to recognize but also remodel the epigenetic signatures at lineage-specific enhancers, which is mediated, at least in part, by a feed-forward regulatory loop between FOXA1 and TET1.

A case of Metaplastic atrophic gastritis in immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome.

BACKGROUND: Autoimmune metaplastic atrophic gastritis is a chronic progressive inflammatory condition. The clinical spectrum includes pernicious anemia, atrophic gastritis, antibodies to parietal cell antigens and intrinsic factor, achlorhydria, hypergastrinemia and carcinoma. It is rare in paediatric cohorts. CASE PRESENTATION: We present the case of a boy with metaplastic atrophic gastritis in whom immune dysregulation, polyendocrinopathy, enteropathy, X-linked(IPEX) syndrome was confirmed by FOXP3 gene mutation. The patient was referred to the hospital at the age of 3 years with recurrent emesis, diarrhoea and malnutrition. His elder brother died at 9 years of age from acute respiratory distress syndrome and renal tubular acidosis. The patient was allergic to cow milk formula and noodles. Oesophagegastroduodenoscopy revealed redness, erosion and edema throughout the stomach; whitish granules in the duodenal bulb; and edema in the second part of the duodenum. Biopsies showed extensive villous atrophy and goblet cell depletion in the duodenum. He was diagnosed with type-1 diabetes mellitus (T1DM) during the treatment of methylprednisolone. Serum antibodies against glutamic acid decarboxylase and pancreatic islets were detected. The patient's FOXP3 gene was sequenced; this identified that the patient was hemizygous for a pathogenic variant [NM_014009.3:c.748_750del (p.Lys250del)]. CONCLUSION: Metaplastic atrophic gastritis is rarely reported in patients with IPEX. Clinical gastroenterologists should be aware of IPEX syndrome when facing the complex syndromes of metaplastic atrophic gastritis and endocrinopathy.

The role of YAP transcription coactivator in regulating stem cell self-renewal and differentiation.

Yes-associated protein (YAP) is a potent transcription coactivator acting via binding to the TEAD transcription factor, and plays a critical role in organ size regulation. YAP is phosphorylated and inhibited by the Lats kinase, a key component of the Hippo tumor suppressor pathway. Elevated YAP protein levels and gene amplification have been implicated in human cancer. In this study, we report that YAP is inactivated during embryonic stem (ES) cell differentiation, as indicated by decreased protein levels and increased phosphorylation. Consistently, YAP is elevated during induced pluripotent stem (iPS) cell reprogramming. YAP knockdown leads to a loss of ES cell pluripotency, while ectopic expression of YAP prevents ES cell differentiation in vitro and maintains stem cell phenotypes even under differentiation conditions. Moreover, YAP binds directly to promoters of a large number of genes known to be important for stem cells and stimulates their expression. Our observations establish a critical role of YAP in maintaining stem cell pluripotency.

[Clinical features and prognosis of gastrointestinal injury due to foreign bodies in the upper gastrointestinal tract in children: a retrospective analysis of 217 cases].

OBJECTIVE: To study the clinical features and prognosis of gastrointestinal injury caused by foreign bodies in the upper gastrointestinal tract in children. METHODS: A retrospective analysis was performed for the clinical data of 217 children who were diagnosed with foreign bodies in the upper gastrointestinal tract complicated by gastrointestinal injury by gastroscopy from January 2011 to December 2016, including clinical features, gastroscopic findings, complications, and prognosis. RESULTS: Among the 217 children, 114 (52.5%) were aged 1-3 years. The most common foreign body was coin (99/217, 45.6%), followed by hard/sharp-edged food (45/217, 20.7%) and metal (35/217, 16.1%). The most common gastrointestinal mucosal injury was ulceration (43.8%), followed by erosion (33.2%). Compared with other foreign bodies, button cells were significantly more likely to cause esophageal perforation (P<0.01). The esophagus was the most commonly injured organ (207/217, 95.4%). Of all the 217 children, 24 (11.1%) experienced infection. The children with perforation caused by foreign bodies had a significantly higher incidence rate of infection than those with ulceration caused by foreign bodies (P=0.003). Of all the 217 children, 204 (94.0%) underwent successful endoscopic removal of foreign bodies. Among these children, 98 were hospitalized due to severe mucosal injury and were given anti-infective therapy, antacids, and supportive care including enteral nutrition through a nasogastric tube and/or parenteral nutrition. Of all the children, 10 left the hospital and were lost to follow-up, and all the other children were improved and discharged. CONCLUSIONS: Most cases of foreign bodies in the upper gastrointestinal tract occur at 1-3 years of age. Coin, hard/sharp-edged food, and metal are the most common foreign bodies. Button cells are more likely to cause esophageal perforation. The incidence rate of secondary infection increases with the increasing severity of gastrointestinal mucosal injury. Children undergoing endoscopic removal of foreign bodies and enteral nutrition through a nasogastric tube tend to have a good prognosis.

BRCA1 is a negative modulator of the PRC2 complex.

The Polycomb-repressive complex 2 (PRC2) is important for maintenance of stem cell pluripotency and suppression of cell differentiation by promoting histone H3 lysine 27 trimethylation (H3K27me3) and transcriptional repression of differentiation genes. Here we show that the tumour-suppressor protein BRCA1 interacts with the Polycomb protein EZH2 in mouse embryonic stem (ES) and human breast cancer cells. The BRCA1-binding region in EZH2 overlaps with the noncoding RNA (ncRNA)-binding domain, and BRCA1 expression inhibits the binding of EZH2 to the HOTAIR ncRNA. Decreased expression of BRCA1 causes genome-wide EZH2 re-targeting and elevates H3K27me3 levels at PRC2 target loci in both mouse ES and human breast cancer cells. BRCA1 deficiency blocks ES cell differentiation and enhances breast cancer migration and invasion in an EZH2-dependent manner. These results reveal that BRCA1 is a key negative modulator of PRC2 and that loss of BRCA1 inhibits ES cell differentiation and enhances an aggressive breast cancer phenotype by affecting PRC2 function.