Derivation and validation of a nomogram incorporating modifiable lifestyle factors to predict development of colorectal adenomas after negative index colonoscopy.

This retrospective cohort study aimed to identify baseline patient characteristics involving modifiable lifestyle factors that are associated with the development of colorectal adenomas, and establish and validate a nomogram for risk predictions among high-risk populations with negative index colonoscopy. A total of 83,076 participants who underwent an index colonoscopy at the Tianjin Union Medical Center between 2004 and 2019 were collected. According to meticulous inclusion and exclusion criteria, 249 subjects were enrolled and categorized into the primary and validation cohorts. Based on the primary cohort, we utilized the LASSO-Cox regression and the univariate/multivariate Cox proportional hazards (Cox-PH) regression parallelly to select variables, and incorporated selected variables into two nomogram models established using the multivariate Cox-PH regression. Comparison of the Akaike information criterion and the area under the receiver operating characteristic curve of the two models demonstrated that the nomogram model constituted by four covariates retained by the LASSO-Cox regression, including baseline age, body mass index, physical activity and family history of colorectal cancer (CRC) in first-degree relatives, performed better at predicting adenoma-free survival probabilities. Further validation including the concordance index, calibration plots, decision curve analysis and Kaplan-Meier survival curves also revealed good predictive accuracy, discriminating ability, clinical utility and risk stratification capacity of the nomogram model. Our nomogram will assist high-risk individuals with negative index colonoscopy to prevent colorectal adenoma occurrence and CRC morbidity with improved cost-effectiveness.

Malignant triton tumor of uterus: A case report and literature review.

Malignant triton tumor (MTT) is a highly aggressive malignant neoplasm, classified as a variant of malignant peripheral nerve sheath tumor with rhabdomyoblastic differentiation. There are few reports that MTT occurred in urogenital system. In the present study, we report the first MTT occurring in the uterus. A 57-year-old woman came to the emergency department due to persistent vaginal bleeding for 2 months. The gynecological palpation found that a club-shaped excrescence existed in the vagina about 7 cm × 3 cm × 3 cm. The mass located in the lower segment of the uterus and the cervix was confirmed by gynecological vaginal ultrasound and magnetic resonance imaging, which was preliminarily diagnosed as cervical carcinoma. After neoplasm punch biopsy, the pathological diagnosis was malignant triton tumor. The patient finally lost follow-up. This is the first report about MTT in the uterus and suggests that pathological biopsy combined with imaging examination is necessary for the diagnosis of rarely MTT.

PTPN2 in the Immunity and Tumor Immunotherapy: A Concise Review.

PTPN2 (protein tyrosine phosphatase non-receptor 2), also called TCPTP (T cell protein tyrosine phosphatase), is a member of the PTP family signaling proteins. Phosphotyrosine-based signaling of this non-transmembrane protein is essential for regulating cell growth, development, differentiation, survival, and migration. In particular, PTPN2 received researchers' attention when Manguso et al. identified PTPN2 as a cancer immunotherapy target using in vivo CRISPR library screening. In this review, we attempt to summarize the important functions of PTPN2 in terms of its structural and functional properties, inflammatory reactions, immunomodulatory properties, and tumor immunity. PTPN2 exerts synergistic anti-inflammatory effects in various inflammatory cells and regulates the developmental differentiation of immune cells. The diversity of PTPN2 effects in different types of tumors makes it a potential target for tumor immunotherapy.

Intra-heterogeneity in transcription and chemoresistant property of leukemia-initiating cells in murine Setd2-/- acute myeloid leukemia.

BACKGROUND: Heterogeneity of leukemia-initiating cells (LICs) is a major obstacle in acute myeloid leukemia (AML) therapy. Accumulated evidence indicates that the coexistence of multiple types of LICs with different pathogenicity in the same individual is a common feature in AML. However, the functional heterogeneity including the drug response of coexistent LICs remains unclear. Therefore, this study aimed to clarify the intra-heterogeneity in LICs that can help predict leukemia behavior and develop more effective treatments. METHODS: Spleen cells from the primary Setd2-/- -AML mouse were transplanted into C57BL/6 recipient mice to generate a transplantable model. Flow cytometry was used to analyze the immunophenotype of the leukemic mice. Whole-genome sequencing was conducted to detect secondary hits responsible for leukemia transformation. A serial transplantation assay was used to determine the self-renewal potential of Setd2-/- -AML cells. A limiting-dilution assay was performed to identify the LIC frequency in different subsets of leukemia cells. Bulk and single-cell RNA sequencing were performed to analyze the transcriptional heterogeneity of LICs. Small molecular inhibitor screening and in vivo drug treatment were employed to clarify the difference in drug response between the different subsets of LICs. RESULTS: In this study, we observed an aged Setd2-/- mouse developing AML with co-mutation of NrasG12S and BrafK520E . Further investigation identified two types of LICs residing in the c-Kit+ B220+ Mac-1- and c-Kit+ B220+ Mac-1+ subsets, respectively. In vivo transplantation assay disclosed the heterogeneity in differentiation between the coexistent LICs. Besides, an intrinsic doxorubicin-resistant transcriptional signature was uncovered in c-Kit+ B220+ Mac-1+ cells. Indeed, doxorubicin plus cytarabine (DA), the standard chemotherapeutic regimen used in AML treatment, could specifically kill c-Kit+ B220+ Mac-1- cells, but it hardly affected c-Kit+ B220+ Mac-1+ cells. Transcriptome analysis unveiled a higher activation of RAS downstream signaling pathways in c-Kit+ B220+ Mac-1+ cells than in c-Kit+ B220+ Mac-1- cells. Combined treatment with DA and RAS pathway inhibitors killed both c-Kit+ B220+ Mac-1- and c-Kit+ B220+ Mac-1+ cells and attenuated disease progression. CONCLUSIONS: This study identified two cell subsets enriched for LICs in murine Setd2-/- -AML and disclosed the transcriptional and functional heterogeneity of LICs, revealing that the coexistence of different types of LICs in this model brings about diverse drug response.

Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation.

The histone H3 lysine 36 methyltransferase SETD2 is frequently mutated in various cancers, including leukemia. However, there has not been any functional model to show the contribution of SETD2 in hematopoiesis or the causal role of SETD2 mutation in tumorigenesis. In this study, using a conditional Setd2 knockout mouse model, we show that Setd2 deficiency skews hematopoietic differentiation and reduces the number of multipotent progenitors; although the number of phenotypic hematopoietic stem cells (HSCs) in Setd2-deleted mice is unchanged, functional assays, including serial BM transplantation, reveal that the self-renewal and competitiveness of HSCs are impaired. Intriguingly, Setd2-deleted HSCs, through a latency period, can acquire abilities to overcome the growth disadvantage and eventually give rise to hematopoietic malignancy characteristic of myelodysplastic syndrome. Gene expression profile of Setd2-deleted hematopoietic stem/progenitor cells (HSPCs) partially resembles that of Dnmt3a/Tet2 double knockout HSPCs, showing activation of the erythroid transcription factor Klf1-related pathway, which plays an important role in hematopoietic malignant transformation. Setd2 deficiency also induces DNA replication stress in HSCs, as reflected by an activated E2F gene regulatory network and repressed expression of the ribonucleotide reductase subunit Rrm2b, which results in proliferation and cell cycle abnormalities and genomic instability, allowing accumulation of secondary mutation(s) that synergistically contributes to tumorigenesis. Thus, our results demonstrate that Setd2 is required for HSC self-renewal, and provide evidence supporting the causal role of Setd2 deficiency in tumorigenesis. The underlying mechanism shall advance our understanding of epigenetic regulation of cancer and provide potential new therapeutic targets.