The ZMYND8-regulated mevalonate pathway endows YAP-high intestinal cancer with metabolic vulnerability.

Cholesterol metabolism is tightly associated with colorectal cancer (CRC). Nevertheless, the clinical benefit of statins, the inhibitor of cholesterol biogenesis mevalonate (MVA) pathway, is inconclusive, possibly because of a lack of patient stratification criteria. Here, we describe that YAP-mediated zinc finger MYND-type containing 8 (ZMYND8) expression sensitizes intestinal tumors to the inhibition of the MVA pathway. We show that the oncogenic activity of YAP relies largely on ZMYND8 to enhance intracellular de novo cholesterol biogenesis. Disruption of the ZMYND8-dependent MVA pathway greatly restricts the self-renewal capacity of Lgr5+ intestinal stem cells (ISCs) and intestinal tumorigenesis. Mechanistically, ZMYND8 and SREBP2 drive the enhancer-promoter interaction to facilitate the recruitment of Mediator complex, thus upregulating MVA pathway genes. Together, our results establish that the epigenetic reader ZMYND8 endows YAP-high intestinal cancer with metabolic vulnerability.

Isoalantolactone exerts anti-melanoma effects via inhibiting PI3K/AKT/mTOR and STAT3 signaling in cell and mouse models.

BACKGROUND AND AIM: Although the anti-cancer activity of isoalantolactone (IATL) has been extensively studied, the anti-melanoma effects of IATL are still unknown. Here, we have investigated the anti-melanoma effects and mechanism of action of IATL. MTT and crystal violet staining assays were performed to detect the inhibitory effect of IATL on melanoma cell viability. Apoptosis and cell cycle arrest induced by IATL were examined using flow cytometry. The molecular mechanism of IATL was explored by Western blotting, confocal microscope analysis, molecular docking, and cellular thermal shift assay (CETSA). A B16F10 allograft mouse model was constructed to determine the anti-melanoma effects of IATL in vivo. The results showed that IATL exerted anti-melanoma effects in vitro and in vivo. IATL induced cytoprotective autophagy in melanoma cells by inhibiting the PI3K/AKT/mTOR signaling. Moreover, IATL inhibited STAT3 activation both in melanoma cells and allograft tumors not only by binding to the SH2 domain of STAT3 but also by suppressing the activity of its upstream kinase Src. These findings demonstrate that IATL exerts anti-melanoma effects via inhibiting the STAT3 and PI3K/AKT/mTOR signaling pathways, and provides a pharmacological basis for developing IATL as a novel phytotherapeutic agent for treating melanoma clinically.

A Polyzwitterionic@MOF Hydrogel with Exceptionally High Water Vapor Uptake for Efficient Atmospheric Water Harvesting.

Atmospheric water harvesting (AWH) is considered a promising strategy for sustainable freshwater production in landlocked and arid regions. Hygroscopic salt-based composite sorbents have attracted widespread attention for their water harvesting performance, but suffer from aggregation and leakage issues due to the salting-out effect. In this study, we synthesized a PML hydrogel composite by incorporating zwitterionic hydrogel (PDMAPS) and MIL-101(Cr) as a host for LiCl. The PML hydrogel was characterized using various techniques including X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier transform infrared (FTIR), and thermogravimetric analysis (TGA). The swelling properties and water vapor adsorption-desorption properties of the PML hydrogel were also assessed. The results demonstrate that the MIL-101(Cr) was uniformly embedded into PDMAP hydrogel, and the PML hydrogel exhibits a swelling ratio of 2.29 due to the salting-in behavior. The PML hydrogel exhibited exceptional water vapor sorption capacity of 0.614 g/g at 298 K, RH = 40% and 1.827 g/g at 298 K, RH = 90%. It reached 80% of its saturated adsorption capacity within 117 and 149 min at 298 K, RH = 30% and 90%, respectively. Additionally, the PML hydrogel showed excellent reversibility in terms of water vapor adsorption after ten consecutive cycles of adsorption-desorption. The remarkable adsorption capacity, favorable adsorption-desorption rate, and regeneration stability make the PML hydrogel a potential candidate for AWH. This polymer-MOF synergistic strategy for immobilization of LiCl in this work offers new insights into designing advanced materials for AWH.

Special issue "The advance of solid tumor research in China": Prognosis prediction for stage II colorectal cancer by fusing computed tomography radiomics and deep-learning features of primary lesions and peripheral lymph nodes.

Currently, the prognosis assessment of stage II colorectal cancer (CRC) remains a difficult clinical problem; therefore, more accurate prognostic predictors must be developed. In our study, we developed a prognostic prediction model for stage II CRC by fusing radiomics and deep-learning (DL) features of primary lesions and peripheral lymph nodes (LNs) in computed tomography (CT) scans. First, two CT radiomics models were built using primary lesion and LN image features. Subsequently, an information fusion method was used to build a fusion radiomics model by combining the tumor and LN image features. Furthermore, a transfer learning method was applied to build a deep convolutional neural network (CNN) model. Finally, the prediction scores generated by the radiomics and CNN models were fused to improve the prognosis prediction performance. The disease-free survival (DFS) and overall survival (OS) prediction areas under the curves (AUCs) generated by the fusion model improved to 0.76 ± 0.08 and 0.91 ± 0.05, respectively. These were significantly higher than the AUCs generated by the models using the individual CT radiomics and deep image features. Applying the survival analysis method, the DFS and OS fusion models yielded concordance index (C-index) values of 0.73 and 0.9, respectively. Hence, the combined model exhibited good predictive efficacy; therefore, it could be used for the accurate assessment of the prognosis of stage II CRC patients. Moreover, it could be used to screen out high-risk patients with poor prognoses, and assist in the formulation of clinical treatment decisions in a timely manner to achieve precision medicine.

Systemic lupus erythematosus patients have unique changes in serum metabolic profiles across age associated with cardiometabolic risk.

OBJECTIVES: Cardiovascular disease through accelerated atherosclerosis is a leading cause of mortality for patients with systemic lupus erythematosus (SLE), likely due to increased chronic inflammation and cardiometabolic defects over age. We investigated age-associated changes in metabolomic profiles of SLE patients and healthy controls (HCs). METHODS: Serum NMR metabolomic profiles from female SLE patients (n = 164, age = 14-76) and HCs (n = 123, age = 13-72) were assessed across age by linear regression and by age group between patients/HCs (Group-1, age ≤ 25, n = 62/46; Group-2, age = 26-49, n = 50/46; Group-3, age ≥ 50, n = 52/31) using multiple t-tests. The impact of inflammation, disease activity and treatments were assessed, and UK Biobank disease-wide association analysis of metabolites was performed. RESULTS: Age-specific metabolomic profiles were identified in SLE patients vs HCs, including reduced amino acids (Group-1), increased very-low-density lipoproteins (Group-2), and increased low-density lipoproteins (Group-3). Twenty-five metabolites were significantly altered in all SLE age groups, dominated by decreased atheroprotective high-density lipoprotein (HDL) subsets, HDL-bound apolipoprotein(Apo)A1 and increased glycoprotein acetyls (GlycA). Furthermore, ApoA1 and GlycA were differentially associated with disease activity and serological measures, as well as atherosclerosis incidence and myocardial infarction mortality risk through disease-wide association. Separately, glycolysis pathway metabolites (acetone/citrate/creatinine/glycerol/lactate/pyruvate) uniquely increased with age in SLE, significantly influenced by prednisolone (increased pyruvate/lactate) and hydroxychloroquine (decreased citrate/creatinine) treatment and associated with type-1 and type-2 diabetes by disease-wide association. CONCLUSIONS: Increasing HDL (ApoA1) levels through therapeutic/nutritional intervention, whilst maintaining low disease activity, in SLE patients from a young age could improve cardiometabolic disease outcomes. Biomarkers from the glycolytic pathway could indicate adverse metabolic effects of current therapies.

Size and number of lymph nodes were risk factors of recurrence in stage II colorectal cancer.

BACKGROUND: Size and number of lymph nodes (LNs) were reported to be associated with the prognosis of stage II colorectal cancer (CRC). The purpose of this study was to determine the prognostic role of the size of LNs (SLNs) measured by computer tomography (CT) and the number of retrieved LNs (NLNs) in the relapse-free survival (RFS) and overall survival (OS) among stage II CRC patients. METHODS: Consecutive patients diagnosed with stage II CRC at Fudan University Shanghai Cancer Center (FUSCC) from January 2011 to December 2015 were reviewed, and 351 patients were randomly divided into two cohorts for cross-validation. The optimal cut-off values were obtained using X-tile program. Kaplan-Meier curves and Cox regression analyses were conducted for the two cohorts. RESULTS: Data from 351 stage II CRC patients were analyzed. The cut-off values for SLNs and NLNs were 5.8 mm and 22, respectively, determined by the X-tile in the training cohort. In the validation cohort, Kaplan-Meier curves demonstrated SLNs (P = 0.0034) and NLNs (P = 0.0451) were positively correlated with RFS but not with OS. The median follow-up time in the training cohort and the validation cohort were 60.8 months and 61.0 months respectively. Univariate and multivariate analysis revealed that both SLNs (training cohort: Hazard Ratio (HR) = 2.361, 95% Confidence interval (CI): 1.044-5.338, P = 0.039; validation cohort: HR = 2.979, 95%CI: 1.435-5.184, P = 0.003) and NLNs (training cohort: HR = 0.335, 95%CI: 0.113-0.994, P = 0.049; validation cohort: HR = 0.375, 95%CI: 0.156-0.900, P = 0.021) were independent prognostic factors for RFS whereas not for OS. CONCLUSION: SLNs and NLNs are independent prognostic factors for patients with stage II CRC. Patients with SLNs > 5.8 mm and NLNs ≤ 22 are apt to have higher risk of recurrence.

A procedure in mice to obtain intact pituitary-infundibulum-hypothalamus preparations: a method to evaluate the reconstruction of hypothalamohypophyseal system.

PURPOSE: The histopathological study of brain tissue is a common method in neuroscience. However, efficient procedures to preserve the intact hypothalamic-pituitary brain specimens are not available in mice for histopathological study. METHOD: We describe a detailed procedure for obtaining mouse brain with pituitary-hypothalamus continuity. Unlike the traditional methods, we collect the brain via a ventral approach. We cut the intraoccipital synchondrosis, transection the endocranium of pituitary, broke the spheno-occipital synchondrosis, expose the posterior edge of pituitary, separate the trigeminal nerve, then the intact pituitary gland was preserved. RESULT: We report an more effective and practical method to obtain continuous hypothalamus -pituitary preparations based on the preserve of leptomeninges. COMPARED WITH THE EXISTING METHODS: Our procedure effectively protects the integrity of the fragile infundibulum preventing the pituitary from separating from the hypothalamus. This procedure is more convenient and efficient. CONCLUSION: We present a convenient and practical procedure to obtain intact hypothalamic-pituitary brain specimens for subsequent histopathological evaluation in mice.

Adult neurogenesis of the median eminence contributes to structural reconstruction and recovery of body fluid metabolism in hypothalamic self-repair after pituitary stalk lesion.

Body fluid homeostasis is critical to survival. The integrity of the hypothalamo-neurohypophysial system (HNS) is an important basis of the precise regulation of body fluid metabolism and arginine vasopressin (AVP) hormone release. Clinically, some patients with central diabetes insipidus (CDI) due to HNS lesions can experience recovery compensation of body fluid metabolism. However, whether the hypothalamus has the potential for structural plasticity and self-repair under pathological conditions remains unclear. Here, we report the repair and reconstruction of a new neurohypophysis-like structure in the hypothalamic median eminence (ME) after pituitary stalk electrical lesion (PEL). We show that activated and proliferating adult neural progenitor cells differentiate into new mature neurons, which then integrate with remodeled AVP fibers to reconstruct the local AVP hormone release neural circuit in the ME after PEL. We found that the transcription factor of NK2 homeobox 1 (NKX2.1) and the sonic hedgehog signaling pathway, mediated by NKX2.1, are the key regulators of adult hypothalamic neurogenesis. Taken together, our study provides evidence that adult ME neurogenesis is involved in the structural reconstruction of the AVP release circuit and eventually restores body fluid metabolic homeostasis during hypothalamic self-repair.

Academic cheating interferes with learning among middle school children.

There has been extensive research on the causes of academic cheating, but little is known about its consequences. The current research sought to fill this gap in the literature by examining how cheating by middle school children (total N = 198) affects their learning outcomes. In a naturalistic paradigm, children scored a math test they had taken previously, which gave them an opportunity to cheat by falsely scoring incorrect answers to be correct. Results from this phase showed that 54 % of the children cheated on at least one question. One week later, the children took the same test again, but this time without being given an opportunity to cheat. Among children who cheated, items they had answered incorrectly on the first round showed significantly less improvement on the second round if they had dishonestly scored them as correct rather than honestly scoring them as incorrect. This finding provides the first experimental evidence that academic cheating can interfere with children's learning.

Efficient Selective Capture of Carbon Dioxide from Nitrogen and Methane Using a Metal-Organic Framework-Based Nanotrap.

Selective carbon capture from exhaust gas and biogas, which mainly involves the separation of CO2/N2 and CO2/CH4 mixtures, is of paramount importance for environmental and industrial requirements. Herein, we propose an interesting metal-organic framework-based nanotrap, namely ZnAtzCO3 (Atz- = 3-amino-1,2,4-triazolate, CO32- = carbonate), with a favorable ultramicroporous structure and electrostatic interactions that facilitate efficient capture of CO2. The structural composition and stability were verified by FTIR, TGA, and PXRD techniques. Particularly, ZnAtzCO3 demonstrated high CO2 capacity in a wide range of pressures, with values of 44.8 cm3/g at the typical CO2 fraction of the flue gas (15 kPa) and 56.0 cm3/g at the CO2 fraction of the biogas (50 kPa). Moreover, ultrahigh selectivities over CO2/N2 (15:85, v:v) and CO2/CH4 (50:50, v:v) of 3538 and 151 were achieved, respectively. Molecular simulations suggest that the carbon atom of CO2 can form strong electrostatic Cδ+···Î´-O-C interactions with four oxygen atoms in the carbonate ligands, while the oxygen atom of CO2 can interact with the hydrogen atoms in the triazolate ligands through Oδ-···Î´+H-C interactions, which makes ZnAtzCO3 an optimal nanotrap for CO2 fixation. Furthermore, breakthrough experiments confirmed excellent real-world separation toward CO2/N2 and CO2/CH4 mixtures on ZnAtzCO3, demonstrating its great potential for selective CO2 capture.

A Microporous Zn(bdc)(ted)0.5 with Super High Ethane Uptake for Efficient Selective Adsorption and Separation of Light Hydrocarbons.

Separating light hydrocarbons (C2H6, C3H8, and C4H10) from CH4 is challenging but important for natural gas upgrading. A microporous metal-organic framework, Zn(bdc)(ted)0.5, based on terephthalic acid (bdc) and 1,4-diazabicyclo[2.2.2]octane (ted) ligands, is synthesized and characterized through various techniques, including powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and porosity analysis. The adsorption isotherms of light hydrocarbons on the material are measured and the isosteric adsorption heats of CH4, C2H6, C3H8, and C4H10 are calculated. The prediction of C2-4/C1 adsorption selectivities is accomplished using ideal adsorbed solution theory (IAST). The results indicate that the material exhibits exceptional characteristics, including a Brunauer-Emmett-Teller (BET) surface area of 1904 m2/g and a pore volume of 0.73 cm3/g. Notably, the material demonstrates remarkable C2H6 adsorption capacities (4.9 mmol/g), while CH4 uptake remains minimal at 0.4 mmol/g at 298 K and 100 kPa. These findings surpass those of most reported MOFs, highlighting the material's outstanding performance. The isosteric adsorption heats of C2H6, C3H8, and C4H10 on the Zn(bdc)(ted)0.5 are higher than CH4, suggesting a stronger interaction between C2H6, C3H8, and C4H10 molecules and Zn(bdc)(ted)0.5. The molecular simulation reveals that Zn(bdc)(ted)0.5 prefers to adsorb hydrocarbon molecules with richer C-H bonds and larger polarizability, which results in a stronger dispersion force generated by an adsorbent-adsorbate induced polarization effect. Therefore, the selectivity of C4H10/CH4 is up to 180 at 100 kPa, C3H8/CH4 selectivity is 67, and the selectivity of C2H6/CH4 is 13, showing a great potential for separating C2-4 over methane.

Letter to the Editor: An ultra-sensitive assay using cell-free DNA fragmentomics for multi-cancer early detection.

Early detection can benefit cancer patients with more effective treatments and better prognosis, but existing early screening tests are limited, especially for multi-cancer detection. This study investigated the most prevalent and lethal cancer types, including primary liver cancer (PLC), colorectal adenocarcinoma (CRC), and lung adenocarcinoma (LUAD). Leveraging the emerging cell-free DNA (cfDNA) fragmentomics, we developed a robust machine learning model for multi-cancer early detection. 1,214 participants, including 381 PLC, 298 CRC, 292 LUAD patients, and 243 healthy volunteers, were enrolled. The majority of patients (N = 971) were at early stages (stage 0, N = 34; stage I, N = 799). The participants were randomly divided into a training cohort and a test cohort in a 1:1 ratio while maintaining the ratio for the major histology subtypes. An ensemble stacked machine learning approach was developed using multiple plasma cfDNA fragmentomic features. The model was trained solely in the training cohort and then evaluated in the test cohort. Our model showed an Area Under the Curve (AUC) of 0.983 for differentiating cancer patients from healthy individuals. At 95.0% specificity, the sensitivity of detecting all cancer reached 95.5%, while 100%, 94.6%, and 90.4% for PLC, CRC, and LUAD, individually. The cancer origin model demonstrated an overall 93.1% accuracy for predicting cancer origin in the test cohort (97.4%, 94.3%, and 85.6% for PLC, CRC, and LUAD, respectively). Our model sensitivity is consistently high for early-stage and small-size tumors. Furthermore, its detection and origin classification power remained superior when reducing sequencing depth to 1× (cancer detection: ≥ 91.5% sensitivity at 95.0% specificity; cancer origin: ≥ 91.6% accuracy). In conclusion, we have incorporated plasma cfDNA fragmentomics into the ensemble stacked model and established an ultrasensitive assay for multi-cancer early detection, shedding light on developing cancer early screening in clinical practice.

The pattern and treatment outcomes for rectal cancer with concurrent locoregional recurrence and distant metastases after total mesorectal excision.

BACKGROUND: To study the pattern and treatment outcome of rectal cancer (RC) with concurrent locoregional recurrence (LR) and distant metastasis (DM) after total mesorectal excision (TME) and to identify patient-, disease-, and treatment-related factors associated with differences in prognosis after concurrent LR and DM. METHODS: RC patients who were diagnosed with concurrent LR and DM after TME from May 2015 to June 2019 were included in our study. All patients received single or multiple treatment modalities under the guidance of multidisciplinary team (MDT) of colorectal cancer in Fudan University Shanghai Cancer Center. The prognostic value of various clinicopathological factors for survival were calculated by Kaplan-Meier curves and Cox regression analyses. RESULTS: A total of 74 RC patients with concurrent LR and DM who had undergone TME with a median follow-up of 27 months were eligible for analysis. The median survival of the included patients was 34 months, and 30 patients (41%) died. Fifty-nine patients (80%) underwent comprehensive treatments. Patients with oligometastatic disease (OMD) achieved no evidence of disease (NED) status more frequently than those with multiple metastases (P = 0.003). In the univariate analysis, patients achieving NED, diagnosed with OMD and five or less peritoneal metastases tended to have longer survival after LR and DM diagnosis (P < 0.05). In the multivariate analysis, attaining NED status was the only independent factor for survival (hazard ratio (HR), 2.419; P = 0.032). Survival after concurrent LR and DM in the non-NED group was significantly shorter than that in the NED group (median survival, 32 vs. 46 months; HR, 2.7; P = 0.014). CONCLUSIONS: The pattern and treatment outcome of RC with concurrent LR and DM after TME has changed with the development of multiple treatment modalities. Although the prognosis remains poor, pursuing NED status through comprehensive treatments may improve the survival of RC patients with concurrent LR and DM after TME.

Transcriptomic Analysis Reveals that Activating Transcription Factor 3/c-Jun/Lgals3 Axis Is Associated with Central Diabetes Insipidus after Hypothalamic Injury.

BACKGROUND: Hypothalamic injury causes several complicated neuroendocrine-associated disorders, such as water-electrolyte imbalance, obesity, and hypopituitarism. Among these, central diabetes insipidus (CDI), characterized by polyuria, polydipsia, low urine specific gravity, and deficiency of arginine vasopressin contents, is a typical complication after hypothalamic injury. METHODS: CDI was induced by hypothalamic pituitary stalk injury in male animals. Behavioral parameters and blood sample were collected to evaluate the characteristics of body fluid metabolism imbalance. The brains were harvested for high-throughput RNA sequencing and immunostaining to identify pathophysiological changes in corresponding hypothalamic nuclei. RESULTS: Based on transcriptomic analysis, we demonstrated the upregulation of the activating transcription factor 3 (Atf3)/c-Jun axis and identified Lgals3, a microglial activation-related gene, as the most significant target gene in response to the body fluid imbalance in CDI. Furthermore, we found that the microglia possessed elevated phagocytic ability, which could promote the elimination of arginine vasopressin neurons after hypothalamic injury. CONCLUSION: Our findings suggested that the Atf3/c-Jun/Lgals3 axis was associated with the microglial activation, and might participate in the loss of functional arginine vasopressin neurons in CDI after hypothalamic injury.

Serum Metabolomic Signatures Can Predict Subclinical Atherosclerosis in Patients With Systemic Lupus Erythematosus.

[Figure: see text].

Circulating tumor DNA as a prognostic indicator of colorectal cancer recurrence-a systematic review and meta-analysis.

PURPOSE: Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. After resection, patients need extensive follow-up to detect asymptomatic recurrences as early as possible to obtain optimal treatment. This study evaluated the prognostic value of circulating tumor DNA (ctDNA) for CRC recurrence. METHODS: Two investigators independently conducted a systematic literature search of peer-reviewed studies that investigated the prognostic value of ctDNA in CRC. Fixed effects or random effects models were applied for all analyses based on the assessment of heterogeneity. RESULTS: A total of 189 studies were initially retrieved from all databases; ultimately, eight studies with 879 CRC patients were included in this analysis. The pooled median recurrence-free survival was 11.36 months for ctDNA-positive patients. Meta-analysis of hazard ratio (HR) suggested that postoperative ctDNA-positive patients were more likely to experience cancer recurrence than ctDNA-negative patients (pooled HR: 5.41; 95% confidence interval (CI): 2.37-8.45). CONCLUSIONS: Successive monitoring of ctDNA status and follow-up with postoperative computed tomography (CT)/magnetic resonance imaging (MRI) are useful tools to detect early recurrence in postoperative ctDNA-positive patients.

Effects of test difficulty messaging on academic cheating among middle school children.

Academic cheating is a serious worldwide problem that begins during childhood. However, to date there has been little research on academic cheating with children before high school age. The current study used a naturalistic experimental paradigm to evaluate the possibility that systematically manipulating messages about the difficulty of a test can affect whether middle school children (N = 201) would cheat by reporting a falsely inflated test score. We found that test difficulty messaging significantly affected children's cheating behavior. Specifically, telling children that a test was either easy or hard produced higher rates of cheating than telling them that the difficulty level was on par with their current skills. In addition, among the children who chose to cheat, telling them that the test was easy led to a greater degree of cheating. These findings are consistent with theories of academic cheating that point to the importance of approach and avoidance motives in achievement motivation. The findings also suggest that simple messaging can have a significant impact on children's moral behavior and that seemingly innocuous messages such as describing the difficulty of a test can influence children's decisions about whether and how much to cheat.

Performance of common genetic variants in risk prediction for colorectal cancer in Chinese: A two-stage and multicenter study.

The efficacy of susceptible variants derived from genome-wide association studies (GWAs) optimizing discriminatory accuracy of colorectal cancer (CRC) in Chinese remains unclear. In the present validation study, we assessed 75 recently identified variants from GWAs. A risk predictive model combining 19 variants using the least absolute shrinkage and selection operator (LASSO) statistics offered certain clinical advantages. This model demonstrated an area under the receiver operating characteristic (AUC) of 0.61 during training analysis and yielded robust AUCs from 0.59 to 0.61 during validation analysis in three independent centers. The individuals carrying the highest quartile of risk score revealed over 2-fold risks of CRC (ranging from 2.12 to 2.90) compared with those who presented the lowest quartile of risk score. This genetic model offered the possibility of partitioning risk within the average risk population, which might serve as a first step toward developing individualized CRC prevention strategies in China.

A novel human colon signet-ring cell carcinoma organoid line: establishment, characterization and application.

Colon signet-ring cell carcinoma (SRCC) is a rare type of malignant dedifferentiated adenocarcinomas, and is associated with poor survival. However, an in-depth study of the biological features of SRCC is hindered by the lack of a reliable in vitro model of colon SRCC. Thus, the establishment of cell cultures from SRCC has become the most challenging task. Here, by harnessing the power of the organoid culture system, we describe the establishment of a human colon SRCC organoid line from a surgical sample from one patient with colon SRCC. The colon SRCC organoid line, YQ-173, was characterized for morphology, histology, ultrastructure and chromosome stability levels, showing that it resembles the histological and growth characteristics of the original tumor cells; xenografts were used to show that it also has a high tumor formation rate. RNA sequencing of YQ-173 compared with the normal tissue verified its mucinous nature. Capture-based targeted DNA sequencing combined with drug screening based on a bespoke 88 compound library identified that JAK2 might be a treatment target. An in vitro drug screening found that AT9283 and Pacritinib could be effective JAK2 inhibitors, which was consistent with the in vivo xenograft response. We report, for the first time, the establishment of an SRCC organoid line allowing in-depth study of SRCC biology, as well as a strategy to assess in vitro drug testing in a personalized fashion.

Immunohistochemistry-Based Consensus Molecular Subtypes as a Prognostic and Predictive Biomarker for Adjuvant Chemotherapy in Patients with Stage II Colorectal Cancer.

BACKGROUND: For stage II colorectal cancer (CRC), the efficacy of adjuvant chemotherapy remains controversial. Consensus molecular subtype (CMS) has been validated to be a prognostic tool for CRCs. In this study, CMS status was investigated as a prognostic biomarker for the efficacy of adjuvant chemotherapy for stage II colorectal cancer. MATERIALS AND METHODS: The tissue microarray was retrospectively constructed of 165 nonconsecutive, primary, and sporadic stage II CRCs. CMS status was determined by immunohistochemistry staining of CDX2, HTR2B, FRMD6, and ZEB1, combining with microsatellite instability testing. The prognostic for adjuvant chemotherapy efficacy of CMS status was calculated by Kaplan-Meier curves and Cox regression analysis. Subgroup analyses were conducted according to tumor location. RESULTS: Kaplan-Meier curves indicated that CMS was associated with overall survival (OS) and disease-free survival for stage II CRCs. Cox regression analysis showed that CMS was an independent risk factor for OS. Among high-risk clinicopathological factors, patients with CMS2/3 (hazard ratio [HR]: 0.445, 95% confidence interval [CI]: 0.227-0.875), left-sided tumors (HR: 0.488, 95% CI: 0.247-0.968), or fewer than 12 lymph nodes examined (HR: 0.307, 95% CI: 0.097-0.974) had survival benefit from adjuvant chemotherapy. Subgroup analysis showed that adjuvant chemotherapy only improved OS for patients with left-sided tumors of CMS2/3 subtype. Regardless of CMS, right-sided tumors had no benefit from adjuvant chemotherapy. CONCLUSION: CMS is a better prognostic factor for adjuvant chemotherapy for stage II CRCs. Together with tumor location, CMS classification will aid in personalized treatment for stage II CRCs. IMPLICATIONS FOR PRACTICE: For stage II colorectal cancer (CRC), the efficacy of adjuvant chemotherapy remains controversial, in that its minimal benefit (no more than 5% on average) is considered not worth the toxic effects of the drugs. There are still no effective prognostic and predictive biomarkers. This study showed that consensus molecular subtype (CMS) status is a predictive marker for adjuvant chemotherapy efficacy. Patients with left-sided tumors of CMS2/3 subtype have survival benefit by receiving adjuvant chemotherapy, which will aid in personalized treatment for stage II CRCs. Moreover, this test of CMS based on immunohistochemistry is cheap, not time consuming, and easily conducted in the laboratories of most hospitals.