Plasma proteomic and polygenic profiling improve risk stratification and personalized screening for colorectal cancer.

This study aims to identify colorectal cancer (CRC)-related proteomic profiles and develop a prediction model for CRC onset by integrating proteomic profiles with genetic and non-genetic factors (QCancer-15) to improve the risk stratification and estimate of personalized initial screening age. Here, using a two-stage strategy, we prioritize 15 protein biomarkers as predictors to construct a protein risk score (ProS). The risk prediction model integrating proteomic profiles with polygenic risk score (PRS) and QCancer-15 risk score (QCancer-S) shows improved performance (C-statistic: 0.79 vs. 0.71, P = 4.94E-03 in training cohort; 0.75 vs 0.69, P = 5.49E-04 in validation cohort) and net benefit than QCancer-S alone. The combined model markedly stratifies the risk of CRC onset. Participants with high ProS, PRS, or combined risk score are proposed to start screening at age 46, 41, or before 40 years old. In this work, the integration of blood proteomics with PRS and QCancer-15 demonstrates improved performance for risk stratification and clinical implication for the derivation of risk-adapted starting ages of CRC screening, which may contribute to the decision-making process for CRC screening.

Organoid-Based Assessment of Metal-Organic Framework (MOF) Nanomedicines for Ex Vivo Cancer Therapy.

Nanomaterials have been extensively exploited in tumor treatment, leading to numerous innovative strategies for cancer therapy. While nanomedicines present immense potential, their application in cancer therapy is characterized by significant complexity and unpredictability, especially regarding biocompatibility and anticancer efficiency. These considerations underscore the essential need for the development of ex vivo research models, which provide invaluable insights and understanding into the biosafety and efficacy of nanomedicines in oncology. Fortunately, the emergence of organoid technology offers a novel approach to the preclinical evaluation of the anticancer efficacy of nanomedicines in vitro. Hence, in this study, we constructed intestine and hepatocyte organoid models (Intestine-orgs and Hep-orgs) for assessing intestinal and hepatic toxicity at the microtissue level. We utilized three typical metal-organic frameworks (MOFs), ZIF-8, ZIF-67, and MIL-125, as nanomedicines to further detect their interactions with organoids. Subsequently, the MIL-125 with biocompatibility loaded methotrexate (MTX), forming the nanomedicine (MIL-125-PEG-MTX), indicated a high loading efficiency (82%) and a well-release capability in an acid microenvironment. More importantly, the anticancer effect of the nanomedicine was investigated using an in vitro patient-derived organoids (PDOs) model, achieving inhibition rates of 48% and 78% for PDO-1 and PDO-2, respectively, demonstrating that PDOs could predict clinical response and facilitate prospective therapeutic selection. These achievements presented great potential for organoid-based ex vivo models for nano theragnostic evaluation in biosafety and function.

Circulation immune cell landscape in canonical pathogenesis of colorectal adenocarcinoma by CyTOF analysis.

Current studies on the immune microenvironment of colorectal cancer (CRC) were mostly limited to the tissue level, lacking relevant studies in the peripheral blood, and failed to describe its alterations in the whole process of adenocarcinoma formation, especially of adenoma carcinogenesis. Here, we constructed a large-scale population cohort and used the CyTOF to explore the changes of various immune cell subsets in peripheral blood of CRC. We found monocytes and basophils cells were significantly higher in adenocarcinoma patients. Compared with early-stage CRC, effector CD4+T cells and naive B cells were higher in patients with lymph node metastasis, whereas the basophils were lower. We also performed random forest algorithm and found monocytes play the key role in carcinogenesis. Our study draws a peripheral blood immune cell landscape of the occurrence and development of CRC at the single-cell level and provides a reference for other researchers.

Spike structure of gold nanobranches induces hepatotoxicity in mouse hepatocyte organoid models.

BACKGROUND: Gold nanoparticles (GNPs) have been extensively recognized as an active candidate for a large variety of biomedical applications. However, the clinical conversion of specific types of GNPs has been hindered due to their potential liver toxicity. The origin of their hepatotoxicity and the underlying key factors are still ambiguous. Because the size, shape, and surfactant of GNPs all affect their properties and cytotoxicity. An effective and sensitive platform that can provide deep insights into the cause of GNPs' hepatotoxicity in vitro is therefore highly desired. METHODS: Here, hepatocyte organoid models (Hep-orgs) were constructed to evaluate the shape-dependent hepatotoxicity of GNPs. Two types of GNPs with different nanomorphology, gold nanospheres (GNSs) and spiny gold nanobranches (GNBs), were synthesized as the representative samples. Their shape-dependent effects on mice Hep-orgs' morphology, cellular cytoskeletal structure, mitochondrial structure, oxidative stress, and metabolism were carefully investigated. RESULTS: The results showed that GNBs with higher spikiness and tip curvature exhibited more significant cytotoxicity compared to the rounded GNSs. The spike structure of GNBs leads to a mitochondrial damage, oxidative stress, and metabolic disorder in Hep-orgs. Meanwhile, similar trends can be observed in HepG2 cells and mice models, demonstrating the reliability of the Hep-orgs. CONCLUSIONS: Hep-orgs can serve as an effective platform for exploring the interactions between GNPs and liver cells in a 3D perspective, filling the gap between 2D cell models and animal models. This work further revealed that organoids can be used as an indispensable tool to rapidly screen and explore the toxic mechanism of nanomaterials before considering their biomedical functionalities.

Primary Surgery Followed by Selective Chemoradiotherapy Versus Preoperative Chemoradiotherapy Followed by Surgery for Locally Advanced Rectal Cancer: A Randomized Clinical Trial.

PURPOSE: The aim of this work was to determine whether locally advanced rectal cancer (LARC) with negative mesorectal fascia (MRF) predicted by magnetic resonance imaging (MRI) can be excluded from preoperative radiation therapy treatment. METHODS AND MATERIALS: This multicenter, open-label, non-inferiority, randomized clinical trial enrolled patients with LARC within 6 to 12 cm from the anal verge and with negative MRI-predicted MRF. Participants were randomized to the intervention group (primary surgery, in which the patients with positive pathologic [CRM] circumferential margins were subjected to chemoradiotherapy [CRT] and those with negative CRM underwent adjuvant chemotherapy according to pathologic staging) or the control group (preoperative CRT, in which all patients underwent subsequent surgery and adjuvant chemotherapy). The primary endpoint was 3-year disease-free survival (DFS). RESULTS: A total of 275 patients were randomly assigned to the intervention (n = 140) and control (n = 135) groups, in which 33.57% and 28.15% patients were at clinical T4 stage and 85.92% and 80.45% patients were at "bad" or "ugly" risk in the intervention and control groups, respectively. There were 2 patients (1.52%) and 1 patient (0.77%) with positive CRM in the intervention and control groups, respectively (P > .05). The non-adherence rates for the intervention and control groups were 3.6% and 23.7%, respectively. After a median follow-up of 34.6 months (IQR, 18.2-45.7), 43 patients had positive events (28 patients and 15 patients in the intervention and control groups, respectively). There were 6 patients (4.4%) with local recurrence in the intervention group and none in the control group, which led to the termination of the trial. The 3-year DFS rate was 81.82% in the intervention group (95% CI, 78.18%-85.46%) and 85.37% in the control group (95% CI, 81.75%-88.99%), with a difference of -3.55% (95% CI, -3.71% to -3.39%; hazard ratio, 1.76; 95% CI, 0.94-3.30). In the per-protocol data set, the difference between 3-year DFS rates was -5.44% (95% CI, -5.63% to -5.25%; hazard ratio, 2.02; 95% CI, 1.01-4.06). CONCLUSIONS: Based on the outcomes of this trial, in patients with LARC and MRI-negative MRF, primary surgery could negatively influence their DFS rates. Therefore, primary surgery was an inferior strategy compared with preoperative CRT followed by surgery and cannot be recommended for patients with LARC.

Prophylactic hyperthermic intraperitoneal chemotherapy in T4 colorectal cancer: Can it improve the oncologic prognosis? - A propensity score matching study.

BACKGROUND: Some studies show that cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) may improve overall survival and is a possible curative treatment for selected colorectal cancer (CRC) patients with restricted peritoneal metastasis (PM). The value of HIPEC in preventing PM of CRC is still controversial. MATERIALS AND METHODS: In this retrospective propensity score matching (PSM) cohort study, all patients with cT4N0-2M0 undergoing treatment at a single institution in China (2014-2018) were reviewed. The 3-year disease-free survival (DFS) was set as the primary outcome, and the 3-year PM rate was also analyzed. RESULTS: 220 patients were included in this study for analysis. After 1:3 PSM: HIPEC (n = 45) and No HIPEC (n = 135). Through analysis, it was found that prophylactic HIPEC correlated to better DFS [hazard ratio (HR) 0.43, 95 % confidence interval (CI) 0.19-0.95; p = 0.037], and N2 stage correlated to worse DFS [HR 1.97, 95 % CI 1.09-3.56; p = 0.025]. For laparoscopic surgery subgroup analyses, 3-year PM rate of patients with laparoscopic surgery was 13.8 % in No HIPEC group, and 2.6 % in HIPEC group (p = 0.070). Besides, no post-operative death occurred, the anastomotic leakage rate was 2.2 % in HIPEC group and 0.7 % in the control group (p = 0.439). CONCLUSIONS: Prophylactic HIPEC may improve the prognosis in patients with cT4N0-1M0 CRC, but not in cT4N2M0 CRC, and it does not significantly increase surgery-related complications. Laparoscopic surgery followed by HIPEC for T4 stage CRC may not increase risk of PM.

Metformin Hydrochloride Significantly Inhibits Rotavirus Infection in Caco2 Cell Line, Intestinal Organoids, and Mice.

Rotavirus is one of the main pathogens that causes severe diarrhea in children under the age of 5, primarily infecting the enterocytes of the small intestine. Currently, there are no specific drugs available for oral rehydration and antiviral therapy targeting rotavirus. However, metformin hydrochloride, a drug known for its antiviral properties, shows promise as it accumulates in the small intestine and modulates the intestinal microbiota. Therefore, we formulated a hypothesis that metformin hydrochloride could inhibit rotavirus replication in the intestine. To validate the anti-rotavirus effect of metformin hydrochloride, we conducted infection experiments using different models, ranging from in vitro cells and organoids to small intestines in vivo. The findings indicate that a concentration of 0.5 mM metformin hydrochloride significantly inhibits the expression of rotavirus mRNA and protein in Caco-2 cells, small intestinal organoids, and suckling mice models. Rotavirus infections lead to noticeable pathological changes, but treatment with metformin has been observed to mitigate the lesions caused by rotavirus infection in the treated group. Our study establishes that metformin hydrochloride can inhibit rotavirus replication, while also affirming the reliability of organoids as a virus model for in vitro research.

Clinical evaluation of a multitarget fecal immunochemical test-sDNA test for colorectal cancer screening in a high-risk population: a prospective, multicenter clinical study.

Colorectal cancer (CRC) is a major malignancy threatening the health of people in China and screening could be effective for preventing the occurrence and reducing the mortality of CRC. We conducted a multicenter, prospective clinical study which recruited 4,245 high-risk CRC individuals defined as having positive risk-adapted scores or fecal immunochemical test (FIT) results, to evaluate the clinical performance of the multitarget fecal immunochemical and stool DNA (FIT-sDNA) test for CRC screening. Each participant was asked to provide a stool sample prior to bowel preparation, and FIT-sDNA test and FIT were performed independently of colonoscopy. We found that 186 (4.4%) were confirmed to have CRC, and 375 (8.8%) had advanced precancerous neoplasia among the high CRC risk individuals. The sensitivity of detecting CRC for FIT-sDNA test was 91.9% (95% CI, 86.8-95.3), compared with 62.4% (95% CI, 54.9-69.3) for FIT (P < 0.001). The sensitivity for detecting advanced precancerous neoplasia was 63.5% (95% CI, 58.3-68.3) for FIT-sDNA test, compared with 30.9% (95% CI, 26.3-35.6) for FIT (P < 0.001). Multitarget FIT-sDNA test detected more colorectal advanced neoplasia than FIT. Overall, these findings indicated that in areas with limited colonoscopy resources, FIT-sDNA test could be a promising further risk triaging modality to select patients for colonoscopy in CRC screening.

Quantitative Analysis on Molecular Characteristics Evolution of Gastric Cancer Progression and Prognosis.

The dynamic changes of key biological characteristics from gastric low-grade intraepithelial neoplasia (LGIN) to high-grade intraepithelial neoplasia (HGIN) to early gastric cancer (EGC) are still unclear, which greatly affect the accurate diagnosis and treatment of EGC and prognosis evaluation of gastric cancer (GC). In this study, bioinformatics methods/tools are applied to quantitatively analyze molecular characteristics evolution of GC progression, and a prognosis model is constructed. This study finds that some dysregulated differentially expressed mRNAs (DEmRNAs) in the LGIN stage may continue to promote the occurrence and development of EGC. Among the LGIN, HGIN, and EGC stages, there are differences and relevance in the transcription expression patterns of DEmRNAs, and the activation related to immune cells is very different. The biological functions continuously changed during the progression from LGIN to HGIN to EGC. The COX model constructed based on the three EGC-related DEmRNAs has GC prognostic risk prediction ability. The evolution of biological characteristics during the development of EGC mined by the authors provides new insight into understanding the molecular mechanism of EGC occurrence and development. The three-gene prognostic risk model provides a new method for assisting GC clinical treatment decisions.

N6-methyladenosine related gene expression signatures for predicting the overall survival and immune responses of patients with colorectal cancer.

N6-methyladenosine (m6A) modification has been demonstrated to exhibit a crucial prognostic effect on colorectal cancer (CRC). Nonetheless, potential mechanism of m6A in survival rate and immunotherapeutic response remains unknown. Here we investigated the genes associated with m6A regulators and developed a risk score for predicting the overall survival (OS) of CRC patients. RNA-seq transcriptomic profiling data of COAD/READ samples were obtained from The Cancer Genome Atlas (TCGA) database. Absolute Shrinkage and Selection Operator (LASSO)- Cox regression analysis was conducted to identify the m6A-related gene expression signatures and the selected genes were inputted into stepwise regression to develop a prognostic risk score in TCGA, and its predictive performance of CRC survival was further validated in Gene Expression Omnibus (GEO) datasets. According to our results, the risk score comprising 18 m6A-related mRNAs was significantly associated with CRC survival in both TCGA and GEO datasets. And the stratified analysis also confirmed that high-risk score acted as a poor factor in different age, sex, T stage, and tumour, node, metastasis (TNM) stages. The m6A-related prognostic score in combination with clinical characteristics yielded time-dependent area under the receiver operating characteristic curve (AUCs) of 0.85 (95%CI: 0.79-0.91), 0.84 (95%CI: 0.79-0.90) and 0.80 (95%CI: 0.71-0.88) for the prediction of the 1-, 3-, 5-year OS of CRC in TCGA cohort. Furthermore, mutation of oncogenes occurred more frequently in the high-risk group and the composition of immune cells in tumour microenvironment (TME) was significantly distinct between the low- and high-risk groups. The low-risk group had a lower microsatellite instability (MSI) score, T-cell exclusion score and dysfunction score, implying that low-risk patients may have a better immunotherapy response than high-risk patients. In summary, a prognostic risk score derived from m6A-related gene expression signatures could serve as a potential prognostic predictor for CRC survival and indicator for predicting immunotherapy response in CRC patients.

Risk assessment for colorectal cancer via polygenic risk score and lifestyle exposure: a large-scale association study of East Asian and European populations.

BACKGROUND: The genetic architectures of colorectal cancer are distinct across different populations. To date, the majority of polygenic risk scores (PRSs) are derived from European (EUR) populations, which limits their accurate extrapolation to other populations. Here, we aimed to generate a PRS by incorporating East Asian (EAS) and EUR ancestry groups and validate its utility for colorectal cancer risk assessment among different populations. METHODS: A large-scale colorectal cancer genome-wide association study (GWAS), harboring 35,145 cases and 288,934 controls from EAS and EUR populations, was used for the EAS-EUR GWAS meta-analysis and the construction of candidate EAS-EUR PRSs via different approaches. The performance of each PRS was then validated in external GWAS datasets of EAS (727 cases and 1452 controls) and EUR (1289 cases and 1284 controls) ancestries, respectively. The optimal PRS was further tested using the UK Biobank longitudinal cohort of 355,543 individuals and ultimately applied to stratify individual risk attached by healthy lifestyle. RESULTS: In the meta-analysis across EAS and EUR populations, we identified 48 independent variants beyond genome-wide significance (P < 5 × 10-8) at previously reported loci. Among 26 candidate EAS-EUR PRSs, the PRS-CSx approach-derived PRS (defined as PRSCSx) that harbored genome-wide variants achieved the optimal discriminatory ability in both validation datasets, as well as better performance in the EAS population compared to the PRS derived from known variants. Using the UK Biobank cohort, we further validated a significant dose-response effect of PRSCSx on incident colorectal cancer, in which the risk was 2.11- and 3.88-fold higher in individuals with intermediate and high PRSCSx than in the low score subgroup (Ptrend = 8.15 × 10-53). Notably, the detrimental effect of being at a high genetic risk could be largely attenuated by adherence to a favorable lifestyle, with a 0.53% reduction in 5-year absolute risk. CONCLUSIONS: In summary, we systemically constructed an EAS-EUR PRS to effectively stratify colorectal cancer risk, which highlighted its clinical implication among diverse ancestries. Importantly, these findings also supported that a healthy lifestyle could reduce the genetic impact on incident colorectal cancer.

DOX-loaded hydroxyapatite nanoclusters for colorectal cancer (CRC) chemotherapy: Evaluation based on the cancer cells and organoids.

It is meaningful to find suitable in vitro models for preclinical toxicology and efficacy evaluation of nanodrugs and nanocarriers or drug screening and promoting clinical transformation of nanocarriers. The emergence and development of organoids technology provide a great possibility to achieve this goal. Herein, we constructed an in vitro 3D organoid model to study the inhibitory effect of nanocarriers on colorectal cancer. And designed hydroxyapatite nanoclusters (c-HAP) mediated by polydopamine (PDA) formed under alkaline conditions (pH 9.0), then used c-HAP to load DOX (c-HAP/DOX) as nanocarrier for improved chemotherapy. In vitro, drug release experiments show that c-HAP/DOX has suitable responsive to pH, can be triggered to the facile release of DOX in a slightly acidic environment (pH 6.0), and maintain specific stability in a neutral pH value (7.4) environment. c-HAP/DOX showed an excellent antitumor effect in the two-dimensional (2D) cell model and three-dimensional (3D) patient-derived colon cancer organoids (PDCCOs) model. In addition, c-HAP/DOX can release a sufficient amount of DOX to produce cytotoxicity in a slightly acidic environment, entering efficiently into the colorectal cancer cells caused endocytosis and induced apoptosis. Therefore, organoids can serve as an effective in vitro model to present the structure and function of colorectal cancer tissues and be used to evaluate the efficacy of nanocarriers for tumors.

Long-term risk of colorectal cancer after removal of adenomas during screening colonoscopies in a large community-based population in China.

Patients with conventional adenoma removal are recommended to undergo colonoscopy surveillance to prevent colorectal cancer (CRC). However, evidence supporting the guidelines of colonoscopy surveillance is limited, especially among the Chinese population. We investigated the association between colonoscopy adenoma findings and CRC risk among individuals aged 40 to 74 years who underwent baseline colonoscopy from 2007 to 2016 in Jiashan and Haining, Zhejiang, China; 34 382 participants were categorized into advanced adenoma, nonadvanced adenoma and no adenoma based on adenoma findings. A multivariable Cox regression model was used to estimate the hazard ratio (HR) of CRC incidence with adjustment for potential confounding factors. After a median follow-up time of 7.7 years, 113 incident cases of CRC were identified (18 occurred in 1632 participants with advanced adenoma, 16 in 3973 participants with nonadvanced adenoma and 79 in 28 777 participants with no adenoma). Compared to no adenoma group, the adjusted HR for CRC in advanced adenoma group was 4.01 (95% CI, 2.37-6.77). For nonadvanced adenomas, individuals with ≥3 adenomas showed an increased risk of CRC (HR, 3.65; 95% CI, 1.43-9.31), but no significantly increased risk of CRC was found for 1 to 2 nonadvanced adenomas, compared to those with no adenoma. Our study suggested that the risk of subsequent CRC increased in individuals with high-risk adenoma (at least one advanced adenoma or ≥3 nonadvanced adenomas), but not in those with 1 to 2 nonadvanced adenomas. These results provide the first evidence from the Chinese population for the current surveillance guidelines.

Cohort profile: The National Colorectal Cancer Cohort (NCRCC) study in China.

PURPOSE: The National Colorectal Cancer Cohort (NCRCC) study aims to specifically assess risk factors and biomarkers related to endpoints across the colorectal cancer continuum from the aetiology through survivorship. PARTICIPANTS: The NCRCC study includes the Colorectal Cancer Screening Cohort (CRCSC), which recruited individuals who were at high risk of CRC between 2016 and 2020 and Colorectal Cancer Patients Cohort (CRCPC), which recruited newly diagnosed patients with CRC between 2015 and 2020. Data collection was based on questionnaires and abstraction from electronic medical record. Items included demographic and lifestyle factors, clinical information, survivorship endpoints and other information. Multiple biospecimens including blood, tissue and urine samples were collected. Participants in CRCSC were followed by a combination of periodic survey every 5 years and annual linkage with regional or national cancer and death registries for at least 10 years. In CRCPC, follow-up was conducted with both active and passive approaches at 6, 12, 18, 24, 36, 48 and 60 months after surgery. FINDINGS TO DATE: A total of 19 377 participants and 15 551 patients with CRC were recruited in CRCSC and in CRCPC, respectively. In CRCSC, 48.0% were men, and the average age of participants at enrolment was 58.7±8.3 years. In CRCPC, 61.4% were men, and the average age was 60.3±12.3 years with 18.9% of participants under 50 years of age. FUTURE PLANS: Longitudinal data and biospecimens will continue to be collected. Based on the cohorts, several studies to assess risk factors and biomarkers for CRC or its survivorship will be conducted, ultimately providing research evidence from Chinese population and optimising evidence-based guidelines across the CRC continuum.

The Disulfiram/Copper Complex Induces Autophagic Cell Death in Colorectal Cancer by Targeting ULK1.

Colorectal cancer (CRC) is highly prevalent worldwide, but there has been limited development of efficient and affordable treatment. Induced autophagy has recently been recognized as a novel therapeutic strategy in cancer treatment, and disulfiram (DSF), a well-known antialcohol drug, is also found to inhibit tumor growth in various malignancies. Recently, DSF has been reported to induce excessive autophagy in oral squamous cells; however, little is known about whether it can induce autophagy and suppress proliferation in CRC. In this study, we investigate the effect of DSF with copper (DSF/Cu) on CRC both in vitro and in vivo and find that the combination significantly inhibits CRC cell viability and mainly induces autophagy instead of apoptosis. Furthermore, we use whole genome CRISPR library screening and identify a new mechanism by which DSF triggers autophagy by ULK1. Overall, these findings provide a potential CRC treatment.

Efficacy of rigosertib, a small molecular RAS signaling disrupter for the treatment of KRAS-mutant colorectal cancer.

OBJECTIVE: Mutant KRAS, the principal isoform of RAS, plays a pivotal role in the oncogenesis of colorectal cancer by constitutively activating the RAF/MEK/ERK and PI3K/AKT pathways. Effective targeted therapies are urgently needed. We investigated whether rigosertib, a benzyl styryl sulfone RAS signaling disruptor, could selectively kill KRAS-mutant colorectal cancer cells. METHODS: CCK-8 was used to determine the cell viability. Patient-derived tumor and cancer cell xenograft models were used to detect the inhibitory efficacy of rigosertib. Flow cytometry was used to evaluate the apoptosis and cell cycle progression. Apoptosis and cell cycle arrest markers were detected by Western blot. DCFH-DA was used to determine the reactive oxygen species. Immunohistochemistry staining and Western blot were performed to characterize RAS signaling markers in colorectal cancer tissues and cells. RESULTS: Rigosertib (RGS) exhibited a cytotoxic effect against colorectal cancer cells, which was greater in KRAS-mutant cells. Furthermore, RGS induced mitotic arrest and oxidative stress-dependent apoptosis in KRAS-mutant DLD1 and HCT116 cells. Besides, RGS disrupted RAS signaling, and the inhibition of RAS/MEK/ERK was independent of cellular oxidative stress. Using patient-derived xenograft models, the response and tumor inhibition of RGS were significantly higher in the KRAS-mutant subgroup, while p-MEK, p-ERK, and p-AKT levels of RGS-treated tumors were significantly decreased. Finally, in a KRAS-mutant, chemotherapy-resistant patient-derived xenograft model, RGS showed a stronger therapeutic effect than the combination standard therapy involving fluoropyrimidine + oxaliplatin/irinotecan + bevacizumab. CONCLUSIONS: These data showed that targeting RAS signaling using RGS could be a therapeutic treatment for KRAS-mutant colorectal cancer patients.

Hierarchically Microstructure-Bioinspired Flexible Piezoresistive Bioelectronics.

The naturally microstructure-bioinspired piezoresistive sensor for human-machine interaction and human health monitoring represents an attractive opportunity for wearable bioelectronics. However, due to the trade-off between sensitivity and linear detection range, obtaining piezoresistive sensors with both a wide pressure monitoring range and a high sensitivity is still a great challenge. Herein, we design a hierarchically microstructure-bioinspired flexible piezoresistive sensor consisting of a hierarchical polyaniline/polyvinylidene fluoride nanofiber (HPPNF) film sandwiched between two interlocking electrodes with microdome structure. Ascribed to the substantially enlarged 3D deformation rates, these bioelectronics exhibit an ultrahigh sensitivity of 53 kPa-1, a pressure detection range from 58.4 to 960 Pa, a fast response time of 38 ms, and excellent cycle stability over 50 000 cycles. Furthermore, this conformally skin-adhered sensor successfully demonstrates the monitoring of human physiological signals and movement states, such as wrist pulse, throat activity, spinal posture, and gait recognition. Evidently, this hierarchically microstructure-bioinspired and amplified sensitivity piezoresistive sensor provides a promising strategy for the rapid development of next-generation wearable bioelectronics.

Dicer1 Promotes Colon Cancer Cell Invasion and Migration Through Modulation of tRF-20-MEJB5Y13 Expression Under Hypoxia.

Hypoxia plays a key role in colorectal cancer (CRC) metastasis, but its underlying mechanism remains largely unknown. Dicer1, an RNase, has been considered as a tumor regulator in many tumors. However, whether Dicer1 affects CRC progression under hypoxia remains uncertain. In this study, we found that Dicer1 expression was induced by hypoxia in CRC cells and it mediates hypoxia-induced CRC cell progression. Furthermore, we found that the expression of tRF-20-MEJB5Y13, a small non-coding RNA derived from tRNA, was increased under hypoxic conditions, and its upregulation by Dicer1 resulted in hypoxia-induced CRC cell invasion and migration. These results advance the current understanding of the role of Dicer1 in regulating hypoxia signals and provide a new pathway for the development of therapeutic interventions for inhibiting cancer progression.