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RAS mutations occur in approximately 30% of tumors worldwide and have a poor prognosis due to limited therapies. Covalent targeting of KRAS G12C has achieved significant success in recent years, but there is still a lack of efficient therapeutic approaches for tumors with non-G12C KRAS mutations. A highly promising approach is to target the MAPK pathway downstream of RAS, with a particular focus on RAF kinases. First-generation RAF inhibitors have been authorized to treat BRAF mutant tumors for over a decade. However, their use in RAS-mutated tumors is not recommended due to the paradoxical ERK activation mainly caused by RAF dimerization. To address the issue of RAF dimerization, type II RAF inhibitors have emerged as leading candidates. Recent clinical studies have shown the initial effectiveness of these agents against RAS mutant tumors. Promisingly, type II RAF inhibitors in combination with MEK or ERK inhibitors have demonstrated impressive efficacy in RAS mutant tumors. This review aims to clarify the importance of RAF dimerization in cellular signaling and resistance to treatment in tumors with RAS mutations, as well as recent progress in therapeutic approaches to address the problem of RAF dimerization in RAS mutant tumors.

Abstract A high-fat diet (HFD) may be linked to an increased colorectal cancer (CRC) risk. Stem cell proliferation and adipokine release under inflammatory and obese conditions are the main factors regulating CRC progression. Furthermore, alterations in intestinal flora have been linked to tumorigenesis and tumour progression. However, whether a HFD can promote CRC occurrence by altering intestinal flora remains unclear. The objective of this study was to identify bacterial strains enriched by a HFD and investigate the association and mechanism by which a HFD and bacterial enrichment promote CRC occurrence and development. In this study, the intestinal microbiota of mice was assessed using 16S rRNA and metagenomic sequencing. Serum metabolites of HFD-fed mice were assessed using tandem liquid chromatography-mass spectrometry. CRC cell lines and organoids were co-cultured with Coriobacteriaceae to evaluate the effect of these bacteria on the CPT1A-ERK signalling pathway. We found that Coriobacteriaceae were enriched in the colons of HFD-fed mice. An endogenous Coriobacteriaceae strain, designated as Cori.ST1911, was successfully isolated and cultured from the stools of HFD-fed mice, and the tumorigenic potential of Cori.ST1911 in CRC was validated in several CRC mouse models. Furthermore, Cori.ST1911 increased acylcarnitine levels by activating CPT1A, demonstrating the involvement of the CPT1A-ERK axis. We also found that the endogenous Lactobacillus strain La.mu730 can interfere with Cori.ST1911 colonisation and restore gut barrier function. In conclusion, we identified a novel endogenous intestinal Coriobacteriaceae, Cori.ST1911, which might lead to a new gut microbiota intervention strategy for the prevention and treatment of CRC.

Abstract The 2023 update of the Chinese Society of Clinical Oncology (CSCO) Clinical Guidelines for Gastric Cancer focuses on standardizing cancer diagnosis and treatment in China, reflecting the latest advancements in evidence‐based medicine, healthcare resource availability, and precision medicine. These updates address the differences in epidemiological characteristics, clinicopathological features, tumor biology, treatment patterns, and drug selections between Eastern and Western gastric cancer patients. Key revisions include a structured template for imaging diagnosis reports, updated standards for molecular marker testing in pathological diagnosis, and an elevated recommendation for neoadjuvant chemotherapy in stage III gastric cancer. For advanced metastatic gastric cancer, the guidelines introduce new recommendations for immunotherapy, anti‐angiogenic therapy and targeted drugs, along with updated management strategies for human epidermal growth factor receptor 2 (HER2)‐positive and deficient DNA mismatch repair (dMMR)/microsatellite instability‐high (MSI‐H) patients. Additionally, the guidelines offer detailed screening recommendations for hereditary gastric cancer and an appendix listing drug treatment regimens for various stages of gastric cancer. The 2023 CSCO Clinical Guidelines for Gastric Cancer updates are based on both Chinese and international clinical research and expert consensus to enhance their applicability and relevance in clinical practice, particularly in the heterogeneous healthcare landscape of China, while maintaining a commitment to scientific rigor, impartiality, and timely revisions.

ObjectiveProgrammed cell death protein-1 (PD-1) inhibitor-based therapy has demonstrated promising results in metastatic gastric cancer (MGC). However, the previous researches are mostly clinical trials and have reached various conclusions. Our objective is to investigate the efficacy of PD-1 inhibitor-based treatment as first-line therapy for MGC, utilizing real-world data from China, and further analyze predictive biomarkers for efficacy.MethodsThis retrospective study comprised 105 patients diagnosed with MGC who underwent various PD-1 inhibitor-based treatments as first-line therapy at West China Hospital of Sichuan University from January 2018 to December 2022. Patient characteristics, treatment regimens, and tumor responses were extracted. We also conducted univariate and multivariate analyses to assess the relationship between clinical features and treatment outcomes. Additionally, we evaluated the predictive efficacy of several commonly used biomarkers for PD-1 inhibitor treatments.ResultsOverall, after 28.0 months of follow-up among the 105 patients included in our study, the objective response rate (ORR) was 30.5%, and the disease control rate (DCR) was 89.5% post-treatment, with two individuals (1.9%) achieving complete response (CR). The median progression-free survival (mPFS) was 9.0 months, and the median overall survival (mOS) was 22.0 months. According to both univariate and multivariate analyses, favorable OS was associated with patients having Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1. Additionally, normal baseline levels of carcinoembryonic antigen (CEA), as well as the combination of PD-1 inhibitors with chemotherapy and trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive MGC, independently predicted longer PFS and OS. However, microsatellite instability/mismatch repair (MSI/MMR) status and Epstein-Barr virus (EBV) infection status were not significantly correlated with PFS or OS extension.ConclusionAs the first-line treatment, PD-1 inhibitors, either as monotherapy or in combination therapy, are promising to prolong survival for patients with metastatic gastric cancer. Additionally, baseline level of CEA is a potential predictive biomarker for identifying patients mostly responsive to PD-1 inhibitors.

ObjectiveTo compare computed tomography (CT)- and magnetic resonance imaging (MRI)-based multiparametric radiomics models and validate a multi-modality, multiparametric clinical-radiomics nomogram for individual preoperative prediction of lymph node metastasis (LNM) in rectal cancer (RC) patients.Methods234 rectal adenocarcinoma patients from our retrospective study cohort were randomly selected as the training (n = 164) and testing (n = 70) cohorts. The radiomics features of the primary tumor were extracted from the non-contrast enhanced computed tomography (NCE-CT), the enhanced computed tomography (CE-CT), the T2-weighted imaging (T2WI) and the gadolinium contrast-enhanced T1-weighted imaging (CE-TIWI) of each patient. Three kinds of models were constructed based on training cohort, including the Clinical model (based on the clinical features), the radiomics models (based on NCE-CT, CE-CT, T2WI, CE-T1WI, CT, MRI, CT combing with MRI) and the clinical-radiomics models (based on CT or MRI radiomics model combing with clinical data) and Clinical-IMG model (based on CT and MRI radiomics model combing with clinical data). The performances of the 11 models were evaluated via the area under the receiver operator characteristic curve (AUC), accuracy, sensitivity, and specificity in the training and validation cohort. Differences in the AUCs among the 11 models were compared using DeLong’s test. Finally, the optimal model (Clinical-IMG model) was selected to create a radiomics nomogram. The performance of the nomogram to evaluate clinical efficacy was verified by ROC curves and decision curve analysis (DCA).ResultsThe MRI radiomics model in the validation cohort significantly outperformed than CT radiomics model (AUC, 0.785 vs. 0.721, p

Circadian rhythms are natural rhythms that widely exist in all creatures, and regulate the processes and physiological functions of various biochemical reactions. The circadian clock is critical for cancer occurrence and progression. Its function is regulated by metabolic activities, and the expression and transcription of various genes. This review summarizes the composition of the circadian clock; the biological basis for its function; its relationship with, and mechanisms in, cancer; its various functions in different cancers; the effects of anti-tumor treatment; and potential therapeutic targets. Research in this area is expected to advance understanding of circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like protein 1 (BMAL1) in tumor diseases, and contribute to the development of new anti-tumor treatment strategies.

Follicular dendritic cell sarcoma (FDCS) is an uncommon low-grade malignant sarcoma. For localized FDCS, surgery is the most commonly recommended therapy option. However, there is no standard treatment protocol for metastatic FDCS. Here, we present a 68-year-old female with primary spleen FDCS who had multiple peritoneal metastases. She was treated with sintilimab (PD-1 inhibitor) plus chemotherapy (epirubicin plus ifosfamide) as first-line treatment achieving partial response (PR) and a relatively long progression-free survival (PFS) of 17 months. This case suggests that PD-1 inhibitor plus chemotherapy as first-line therapy seem to be a promising treatment option for metastatic FDCS.

Pancreatic cancer is one of the leading causes of cancer-related mortality in both developed and developing countries. The incidence of pancreatic cancer in China accounts for about a quater of the global incidence, and the epidemiological characteristics and therapeutic strategies differ due to social, economic, cultural, environmental, and public health factors. Non-domestic guidelines do not reflect the clinicopathologic characteristics and treatment patterns of Chinese patients. Thus, in 2018, the Chinese Society of Clinical Oncology (CSCO) organized a panel of senior experts from all sub-specialties within the field of pancreatic oncology to compile the Chinese guidelines for the diagnosis and treatment of pancreatic cancer. The guidelines were made based on both the Western and Eastern clinical evidence and updated every one or two years. The experts made consensus judgments and classified evidence-based recommendations into various grades according to the regional differences, the accessibility of diagnostic and treatment resources, and health economic indexes in China. Here we present the latest version of the guidelines, which covers the diagnosis, treatment, and follow-up of pancreatic cancer. The guidelines might standardize the diagnosis and treatment of pancreatic cancer in China and will encourage oncologists to design and conduct more clinical trials about pancreatic cancer.

Abstract Aggresome formation is a protective cellular response to counteract proteasome dysfunction by sequestering misfolded proteins and reducing proteotoxic stress. Autophagic degradation of the protein aggregates is considered to be a key compensating mechanism for balancing proteostasis. However, the precise role of autophagy in proteasome inhibition-induced aggresome biogenesis remains unclear. Herein, we demonstrate that in the early stage of proteasome inhibition, the maturation of the autophagosome is suppressed, which facilitates aggresome formation of misfolded proteins. Proteasome inhibition-induced phosphorylation of SQSTM1 T269/S272 inhibits its autophagic receptor activity and promotes aggresome formation of misfolded proteins. Inhibiting SQSTM1 T269/S272 phosphorylation using Doramapimod aggravates proteasome inhibitor-mediated cell damage and tumor suppression. Taken together, our data reveal a negative effect of autophagy on aggresome biogenesis and cell damage upon proteasome inhibition. Our study suggests a novel therapeutic intervention for proteasome inhibitor-mediated tumor treatment.

BackgroundImmune checkpoint blockade (ICB) and anti-angiogenic drug combination has prolonged the survival of patients with advanced renal cell carcinoma (RCC). However, not all patients receive clinical benefits from this intervention. In this study, we aimed to establish a promising immune-related prognostic model to stratify the patients responding to ICB and anti-angiogenic drug combination and facilitate the development of personalized therapies for patients with RCC.Materials and methodsBased on clinical annotations and RNA-sequencing (RNA-seq) data of 407 patients with advanced RCC from the IMmotion151 cohort, nine immune-associated differentially expressed genes (DEGs) between responders and non-responders to atezolizumab (anti-programmed death-ligand 1 antibody) plus bevacizumab (anti-vascular endothelial growth factor antibody) treatment were identified via weighted gene co-expression network analysis. We also conducted single-sample gene set enrichment analysis to develop a novel immune-related risk score (IRS) model and further estimate the prognosis of patients with RCC by predicting their sensitivity to chemotherapy and responsiveness to immunotherapy. IRS model was further validated using the JAVELIN Renal 101 cohort, the E-MTAB-3218 cohort, the IMvigor210 and GSE78220 cohort. Predictive significance of the IRS model for advanced RCC was assessed using receiver operating characteristic curves.ResultsThe IRS model was constructed using nine immune-associated DEGs: SPINK5, SEMA3E, ROBO2, BMP5, ORM1, CRP, CTSE, PMCH and CCL3L1. Advanced RCC patients with high IRS had a high risk of undesirable clinical outcomes (hazard ratio = 1.91; 95% confidence interval = 1.43–2.55; P < 0.0001). Transcriptome analysis revealed that the IRS-low group exhibited significantly high expression levels of CD8+ T effectors, antigen-processing machinery, and immune checkpoints, whereas the epithelial–mesenchymal transition pathway was enriched in the IRS-high group. IRS model effectively differentiated the responders from non-responders to ICB combined with angiogenesis blockade therapy or immunotherapy alone, with area under the curve values of 0.822 in the IMmotion151 cohort, 0.751 in the JAVELIN Renal 101 cohort, and 0.776 in the E-MTAB-3218 cohort.ConclusionIRS model is a reliable and robust immune signature that can be used for patient selection to optimize the efficacy of ICB plus anti-angiogenic drug therapies in patients with advanced RCC.

Abstract Colorectal cancer (CRC) is a heterogeneous disease at the cellular and molecular levels. Kirsten rat sarcoma (KRAS) is a commonly mutated oncogene in CRC, with mutations in approximately 40% of all CRC cases; its mutations result in constitutive activation of the KRAS protein, which acts as a molecular switch to persistently stimulate downstream signaling pathways, including cell proliferation and survival, thereby leading to tumorigenesis. Patients whose CRC harbors KRAS mutations have a dismal prognosis. Currently, KRAS mutation testing is a routine clinical practice before treating metastatic cases, and the approaches developed to detect KRAS mutations have exhibited favorable sensitivity and accuracy. Due to the presence of KRAS mutations, this group of CRC patients requires more precise therapies. However, KRAS was historically thought to be an undruggable target until the development of KRASG12C allele-specific inhibitors. These promising inhibitors may provide novel strategies to treat KRAS-mutant CRC. Here, we provide an overview of the role of KRAS in the prognosis, diagnosis and treatment of CRC.

Abstract The Hippo/YAP pathway plays an important role in the development of cancers. Previous studies have reported that bile acids can activate YAP (Yes Associated Protein) to promote tumorigenesis and tumor progression. Ursodeoxycholic acid (UDCA) is a long-established old drug used for cholestasis treatment. So far, the effect of UDCA on YAP signaling in colorectal cancer (CRC) is not well defined. This study means to explore relationship of UDCA and YAP in CRC. UDCA suppressed YAP signaling by activating the membrane G-protein-coupled bile acid receptor (TGR5). TGR5 mainly regulated cAMP/PKA signaling pathway to inhibit RhoA activity, thereby suppressing YAP signaling. Moreover, the restoration of YAP expression alleviated the inhibitory effect of UDCA on CRC cell proliferation. In AOM/DSS-induced CRC model, UDCA inhibited tumor growth in a concentration-dependent manner and decreased expression of YAP and Ki67. UDCA plays a distinguished role in regulating YAP signaling and CRC growth from the primary bile acids and partial secondary bile acids, demonstrating the importance of maintaining normal intestinal bile acid metabolism in cancer patients. It also presents a potential therapeutic intervention for CRC.

Abstract There exist differences in the epidemiological characteristics, clinicopathological features, tumor biological characteristics, treatment patterns, and drug selections between gastric cancer patients from the Eastern and Western countries. The Chinese Society of Clinical Oncology (CSCO) has organized a panel of senior experts specializing in all sub‐specialties of gastric cancer to compile a clinical guideline for the diagnosis and treatment of gastric cancer since 2016 and renews it annually. Taking into account regional differences, giving full consideration to the accessibility of diagnosis and treatment resources, these experts have conducted expert consensus judgment on relevant evidence and made various grades of recommendations for the clinical diagnosis and treatment of gastric cancer to reflect the value of cancer treatment and meeting health economic indexes in China. The 2021 CSCO Clinical Practice Guidelines for Gastric Cancer covers the diagnosis, treatment, follow‐up, and screening of gastric cancer. Based on the 2020 version of the CSCO Chinese Gastric Cancer guidelines, this updated guideline integrates the results of major clinical studies from China and overseas for the past year, focused on the inclusion of research data from the Chinese population for more personalized and clinically relevant recommendations. For the comprehensive treatment of non‐metastatic gastric cancer, attentions were paid to neoadjuvant treatment. The value of perioperative chemotherapy is gradually becoming clearer and its recommendation level has been updated. For the comprehensive treatment of metastatic gastric cancer, recommendations for immunotherapy were included, and immune checkpoint inhibitors from third‐line to the first‐line of treatment for different patient groups with detailed notes are provided.

Cholesterol metabolism is often dysregulated in cancer. Squalene monooxygenase (SQLE) is the second rate-limiting enzyme involved in cholesterol synthesis. Since the discovery of SQLE dysregulation in cancer, compelling evidence has indicated that SQLE plays a vital role in cancer initiation and progression and is a promising therapeutic target for cancer treatment. In this review, we provide an overview of the role and regulation of SQLE in cancer and summarize the updates of antitumor therapy targeting SQLE.

Abstract Background To compare the efficacy of first‐line bevacizumab plus chemotherapy with cetuximab plus chemotherapy based on the stratification of metastatic colorectal cancer (mCRC) patients with mucinous adenocarcinoma (MA) or mucinous component (MC). Methods A retrospective study involving all mCRC patients receiving first‐line bevacizumab‐based or cetuximab‐based chemotherapy at our hospital from September 2013 to January 2020 was conducted. Overall survival (OS), progression‐free survival (PFS), and objective response rate (ORR) were compared between the cetuximab‐chemotherapy group and the bevacizumab‐chemotherapy group on the basis of the conventional pathological classification of MA or MC. Results A total of 620 patients with mCRC were included in our study, consisting of 141 (22.7%) patients with MA/MC and 479 (77.3%) patients with non‐mucinous adenocarcinoma (NMA). In the MA/MC cohort, patients who were treated with bevacizumab‐based chemotherapy were associated with significantly better OS than those treated with cetuximab‐base chemotherapy (30.0 vs. 26.3 months, p = 0.002), irrespective of tumor sites. The efficacy of bevacizumab‐based chemotherapy was higher in nearly all subgroups as shown in the subgroup analysis. In the NMA cohort, median OS was better in the cetuximab plus chemotherapy group than that in the bevacizumab plus chemotherapy group (32.2 vs. 27.0 months, p = 0.005) for left‐side mCRC patients, whereas OS was significantly longer in the bevacizumab plus chemotherapy group for right‐side mCRC patients (26.0 vs. 20.9 months, p = 0.013). Conclusion Conventional pathological classification (e.g. MA/MC) should be considered when tailoring the individualized optimal treatment for mCRC. Bevacizumab plus chemotherapy as first‐line therapy may be the optimal option for patients with MA/MC.

Abstract Background Serotonin signaling has been associated with tumorigenesis and tumor progression. Targeting the serotonin transporter to block serotonin cellular uptake confers antineoplastic effects in various tumors, including colon cancer. However, the antineoplastic mechanism of serotonin transporter inhibition and serotonin metabolism alterations in the absence of serotonin transporter have not been elucidated, especially in colon cancer, which might limit anti-tumor effects associating with targeting serotonin transporter. Methods The promotion in the uptake and catabolism of extracellular tryptophan and targeting serotonin transporter was detected by using quantitative reverse-transcription polymerase chain reaction, western blotting and liquid chromatography tandem mass spectrometry. Western blotting Immunoprecipitation and immunofluorescence was utilized to research the serotonylation of mTOR by serotonin and serotonin transporter inhibition. The primary mouse model, homograft model and tissue microarry was used to explore the tryptophan pathway in colon cancer. The cell viability assay, western blotting, xenograft and primary colon cancer mouse model were used to identify whether the combination of sertraline and tryptophan restriction had a synergistic effect. Results Targeting serotonin transporter through genetic ablation or pharmacological inhibition in vitro and in vivo induced a compensatory effect by promoting the uptake and catabolism of extracellular tryptophan in colon cancer. Mechanistically, targeting serotonin transporter suppressed mTOR serotonylation, leading to mTOR inactivation and increased tryptophan uptake. In turn, this process promoted serotonin biosynthesis and oncogenic metabolite kynurenine production through enhanced tryptophan catabolism. Tryptophan deprivation, or blocking its uptake by using trametinib, a MEK inhibitor, can sensitize colon cancer to selective serotonin reuptake inhibitors. Conclusions The present study elucidated a novel feedback mechanism involved in the regulation of serotonin homeostasis and suggested innovative strategies for selective serotonin reuptake inhibitors-based treatment of colon cancer.

Abstract Lipid homeostasis plays a fundamental role in the development of hepatocellular carcinoma (HCC). However, the mechanisms that regulate lipid homeostasis to avoid lipotoxicity in HCC remain elusive. Here, we found high-fat diet (HFD) improved the expression of sterol o-acyltransferase1 (SOAT1) and carnitine palmitoyltransferase 1A (CPT1A) in diethylnitrosamine-induced HCC. Bioinformatic analysis showed that SOAT1-mediated fatty acid storage and CPT1A-mediated fatty acids oxidation (FAO) formed a double-negative feedback loop in HCC. We verified that SOAT1 inhibition enhanced CPT1A protein, which shuttled the released fatty acids into the mitochondria for oxidation in vivo and in vitro. Besides, we further confirmed that CPT1A inhibition converted excess fatty acids into lipid drops by SOAT1 in vitro. Simultaneously targeting SOAT1 and CPT1A by the small-molecule inhibitors avasimibe and etomoxir had synergistic anticancer efficacy in HCC in vitro and in vivo. Our study provides new mechanistic insights into the regulation of lipid homeostasis and suggests the combination of avasimibe and etomoxir is a novel strategy for HCC treatment.

Abstract Background Tumor metastasis is one of the leading reasons of the dismal prognosis of hepatocellular carcinoma (HCC). Epithelial-mesenchymal transition (EMT) is closely associated with tumor metastasis including HCC. The purpose of this study is to construct and validate an EMT-related gene signature for predicting the prognosis of HCC patients. Methods Gene expression data of HCC patients was downloaded from The Cancer Genome Atlas (TCGA) database. Gene set enrichment analysis (GSEA) was performed to found the EMT-related gene sets which were obviously distinct between normal samples and paired HCC samples. Cox regression analysis was used to develop an EMT-related prognostic signature, and the performance of the signature was evaluated by Kaplan–Meier curves and time-dependent receiver operating characteristic (ROC) curves. A nomogram incorporating the independent predictors was established. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression levels of the hub genes in HCC cell lines, and the role of PDCD6 in the metastasis of HCC was determined by functional experiments. Results An EMT-related 5-gene signature (PDCD6, TCOF1, TRIM28, EZH2 and FAM83D) was constructed using univariate and multivariate Cox regression analysis. Based on the signature, the HCC patients were classified into high- and low-risk groups, and patients in high-risk group had a poor prognosis. Time-dependent ROC and Cox regression analyses suggested that the signature could predict HCC prognosis exactly and independently. The predictive capacity of the signature was also validated in two external cohorts. GSEA results showed that many cancer-related signaling pathways such as PI3K/Akt/mTOR pathway and TGF-β/SMAD pathway were enriched in high-risk group. The result of qRT-PCR revealed that PDCD6, TCOF1 and FAM83D were highly expressed in HCC cancer cells. Among them, PDCD6 were found to promote cell migration and invasion. Conclusion The EMT-related 5-gene signature can serve as a promising prognostic biomarker for HCC patients and may provide a novel mechanism of HCC metastasis.

Abstract Intracellular free cholesterol can be converted to cholesteryl ester and stored as lipid droplets through SOAT1-mediated esterification. Compelling evidence implicate targeting SOAT1 as a promising therapeutic strategy for cancer management. Herein, we demonstrate how targeting SOAT1 promotes YAP expression by elevating cellular cholesterol content in colon cancer cells. Results revealed that cholesterol alleviates the inhibitory effect of LRP6 on the Wnt/PCP pathway by impeding the interaction of LRP6 with FZD7. Subsequently, FZD7-mediated PCP signaling directly elevated YAP expression by activating RhoA. Nystatin-mediated cholesterol sequestration significantly inhibited YAP expression under SOAT1 inhibition. Moreover, nystatin synergized with the SOAT1 inhibitor avasimibe in suppressing the viability of colon cancer cells in vitro and in vivo. The present study provides new mechanistic insights into the functions of cholesterol metabolism on growth signaling pathways and implicates a novel strategy for cholesterol metabolic-targeted treatment of colon cancers.

Background: Hepatocellular carcinoma (HCC) is the most common type of liver cancer and causes many cancer-related deaths worldwide; in China it is the second most prevalent cause of cancer deaths. Most patients are diagnosed clinically with advanced stage disease. Summary: For more than a decade, sorafenib, a small molecular weight tyrosine kinase-inhibitor (SMW TKI) was the only molecular targeted drug available with a survival benefit for the treatment of advanced HCC. With the development of novel TKIs and immune checkpoint inhibitors (ICIs) for advanced HCC, the management of patients has been greatly improved. However, though angiogenic-based targeted therapy remains the backbone for the systemic treatment of HCC, to date no Chinese guidelines for novel molecular targeted therapies to treat advanced HCC have been established. Our interdisciplinary panel on the treatment of advanced HCC comprising hepatologists, hepatobiliary surgeons, oncologists，radiologists，pathologists, orthopedic surgeons, traditional Chinese medicine physicians and interventional radiologists have reviewed the literature in order to develop updated treatment regimens. Key Messages: Panel consensus statements for the appropriate use of new molecular targeted drugs including doses, combination therapies, adverse reaction management as well as efficacy evaluation and predictions for treatment of advanced HCC with evidence levels based on published data are presented, thereby providing an overview of molecular targeted therapies for healthcare professionals.

Abstract Background The aim was to evaluate the changes of 16S rDNA sequencing and LC-MS metabolomics in breast cancer and explore the growth inhibition of breast cancer cells by Faecalibacterium prausnitzii. Results Total 49 significantly different flora and 26 different metabolites were screened between two groups, and the correlation was calculated. Relative abudance of Firmicutes and Bacteroidetes were decreased, while relative abundance of verrucomicrobla, proteobacteria and actinobacteria was increased in breast cancer group. Differentially expressed metabolites were mainly enriched in pathways such as linoleic acid metabolism, retrograde endocannabinoid signaling, biosynthesis of unsaturated fatty acids, choline metabolism in cancer and arachidonic acid metabolism. Lipid upregulation was found in breast cancer patients, especially phosphorocholine. The abundance of Faecalibacterium was reduced in breast cancer patients, which was negatively correlated with various phosphorylcholines. Moreover, Faecalibacterium prausnitzii, the most well-known species in Faecalibacterium genus, could inhibit the secretion of interleukin-6 (IL-6) and the phosphorylation of Janus kinases 2 (JAK2)/signal transducers and activators of transcription 3 (STAT3) in breast cancer cells. Faecalibacterium prausnitzii also suppressed the proliferation and invasion and promoted the apoptosis of breast cancer cells, while these effects disappeared after adding recombinant human IL-6. Conclusions Flora-metabolites combined with the flora-bacteria (such as Faecalibacterium combined with phosphorocholine) might a new detection method for breast cancer. Faecalibacterium may be helpful for prevention of breast cancer. Faecalibacterium prausnitzii suppresses the growth of breast cancer cells through inhibition of IL-6/STAT3 pathway.

ObjectivesAccurate prediction of prognosis will help adjust or optimize the treatment of cervical cancer and benefit the patients. We aimed to investigate the incremental value of radiomics when added to the FIGO stage in predicting overall survival (OS) in patients with cervical cancer.MethodsThis retrospective study included 106 patients with cervical cancer (FIGO stage IB1–IVa) between October 2017 and May 2019. Patients were randomly divided into a training cohort (n = 74) and validation cohort (n = 32). All patients underwent contrast-enhanced computed tomography (CT) prior to treatment. The ITK-SNAP software was used to delineate the region of interest on pre-treatment standard-of-care CT scans. We extracted 792 two-dimensional radiomic features by the Analysis Kit (AK) software. Pearson correlation coefficient analysis and Relief were used to detect the most discriminatory features. The radiomic signature (i.e., Radscore) was constructed via Adaboost with Leave-one-out cross-validation. Prognostic models were built by Cox regression model using Akaike information criterion (AIC) as the stopping rule. A nomogram was established to individually predict the OS of patients. Patients were then stratified into high- and low-risk groups according to the Youden index. Kaplan–Meier curves were used to compare the survival difference between the high- and low-risk groups.ResultsSix textural features were identified, including one gray-level co-occurrence matrix feature and five gray-level run-length matrix features. Only the FIGO stage and Radscore were independent risk factors associated with OS (p < 0.05). The C-index of the FIGO stage in the training and validation cohorts was 0.703 (95% CI: 0.572–0.834) and 0.700 (95% CI: 0.526–0.874), respectively. Correspondingly, the C-index of Radscore was 0.794 (95% CI: 0.707–0.880) and 0.754 (95% CI: 0.623–0.885). The incorporation of the FIGO stage and Radscore achieved better performance, with a C-index of 0.830 (95% CI: 0.738–0.922) and 0.772 (95% CI: 0.615–0.929), respectively. The nomogram based on the FIGO stage and Radscore could individually predict the OS probability with good discrimination and calibration. The high-risk patients had shorter OS compared with the low-risk patients (p < 0.05).ConclusionRadiomics has the potential for noninvasive risk stratification and may improve the prediction of OS in patients with cervical cancer when added to the FIGO stage.

PurposeThe aim of this retrospective study was to probe into clinicopathological features and prognosis of early-onset gastric cancer (EOGC) patients aged ≤ 45 years old.MethodsThis study selected 154 young gastric cancer patients aged ≤ 45 years old and 158 elderly gastric cancer patients aged > 50 years old admitted to West China Hospital of Sichuan University in 2009-2019 as the research object. These patients were further divided into two groups according to whether tumor can be resected radically. The following parameters were analyzed: age, gender, helicobacter pylori (HP) infection status, Her-2 status, pathological type and stage, chemotherapy, tumor differentiation degree, overall survival (OS).ResultsMore than 3,000 patients with gastric carcinoma were screened, and 154 young gastric cancer patients aged ≤ 45 years old were identified as EOGC. Among them, the number of female patients in EOGC group was significantly higher than that of males, accounting for 63.6%. In addition, EOGC were associated with diffuse Laur´en type and poorly differentiated tumors. Interestingly, the Kaplan–Meier method showed that the OS of unresectable EOGC group was significantly lower than that of unresectable LOGC group (P = 0.0005) and chemotherapy containing paclitaxel tended to be more effective in the young people (P = 0.0511). Nevertheless, there was no significant difference in OS between young and elderly patients with gastric cancer in the radical resection group (P = 0.3881).ConclusionEOGC patients have a worse prognosis than late-onset gastric cancer (LOGC) patients with advanced unresectable gastric cancer. Palliative surgery or chemotherapy containing paclitaxel may improve the OS of unresectable young individuals with gastric cancer. Additional randomized controlled trials are required for guiding clinical practice.

Tissue factor (TF) has been confirmed to be specifically expressed by vascular endothelial cells (VECs) in solid tumors and certain types of malignant tumor cells. Coagulation factor VII (FVII) can specifically bind to TF with high affinity, so the FVII-TF interaction provides an ideal target for tumor therapy. Expression of proteins in skeletal muscles is a simple and economical avenue for continuous production of therapeutic molecules. However, it is difficult to treat solid tumors till now due to the limited number of therapeutic proteins produced by the intramuscular gene expression system. Herein, we strived to explore whether anti-tumor effects can be achieved via intramuscular delivery of a plasmid encoding a FVII-guided immunoconjugate (Icon) molecule by a previously established Pluronic L64/electropulse (L/E) technique. Our study exhibited several interesting outcomes. 1) The mouse light chain of FVII (mLFVII) molecule could guide red fluorescent protein (RFP) to accumulate predominantly at tumor sites in a TF-dependent manner. 2) Intramuscular expression of mLFVII-hFc (human IgG1 Fc) Icon could significantly inhibit the growth of both liver and lung cancers in nude mice, and the inhibition extent was proportional to the level of tumor-expressed TF. 3) The number of blood vessels and the amount of blood flow in tumors were significantly decreased in mLFVII-hFc Icon-treated mice. 4) This immunotherapy system did not display obvious side effects. Our study provided an efficient and economical system for tumor immunotherapy by targeting both blood vessels and tumor cells. It is also an open system for synergistic therapy by conveniently integrating other anticancer regimens.

Abstract Background The 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX) regimen is the standard first-line treatment for metastatic colorectal cancer (mCRC), however, the optimal second-line regimen for KRAS wild-type mCRC patients is still investigational. In this study, we aimed to determine the clinical efficacy and safety of CMAB009 plus irinotecan compared to irinotecan-only as a second-line regimen for treating KRAS wild-type mCRC patients. Methods Patients with KRAS wild-type mCRC who had previously failed to respond to FOLFOX treatment were randomly assigned in a 2:1 ratio, to receive CMAB009 plus irinotecan or irinotecan-only. Patients receiving irinotecan-only were permitted to switch to CMAB009 therapy on disease progression and were grouped as the sequential-CMAB009 arm. The primary endpoints were overall response rate (ORR) and median progression-free survival (PFS). The secondary endpoints were median overall survival (OS), disease control rate (DCR), clinical benefit rate (CBR), and duration of response (DOR). Results The CMAB009 plus irinotecan arm demonstrated significantly improved ORR (33.2% vs. 12.8%; P

Abstract The lungs are the second most common site of metastasis for colorectal cancer (CRC) after the liver. Rectal cancer is associated with a higher incidence of lung metastases compared to colon cancer. In China, the proportion of rectal cancer cases is around 50%, much higher than that in Western countries (nearly 30%). However, there is no available consensus or guideline focusing on CRC with lung metastases. We conducted an extensive discussion and reached a consensus of management for lung metastases in CRC based on current research reports and the experts’ clinical experiences and knowledge. This consensus provided detailed approaches of diagnosis and differential diagnosis and provided general guidelines for multidisciplinary therapy (MDT) of lung metastases. We also focused on recommendations of MDT management of synchronous lung metastases and initial metachronous lung metastases. This consensus might improve clinical practice of CRC with lung metastases in China and will encourage oncologists to conduct more clinical trials to obtain high-level evidences about managing lung metastases.

Abstract. Objectives:. The aim of this multicenter, prospective, registry study was to summarize the epidemiology of Chinese patients with locally advanced and end-stage gastroenteropancreatic neuroendocrine tumors (GEP-NETs) as well as the diagnostic methods and treatment strategies used for these patients. Methods:. GEP-NET patients from 11 departments of 8 hospitals in China were prospectively enrolled for a pre-defined period (June 30, 2011 to May 29, 2012). The patients’ demographic, pathological, and treatment data were recorded, analyzed, and released on June 29, 2015. Results:. Seventy-nine eligible patients were enrolled, and most of these patients were classified according to the World Health Organization 2010 classifications. The most common primary tumor site was the pancreas. The liver was the most common site of metastases, followed by the lymph nodes. The majority of the patients underwent surgical interventions. Patients also received local treatment, medication, or chemotherapy. Conclusion:. The pancreas was the most common primary tumor site of locally advanced and end-stage GEP-NETs. Surgical interventions are currently the most common treatment strategy.

BackgroundSignet ring cell containing gastric cancer (SRCGC) is a rare subtype of gastric cancer, and its adjuvant therapy is based on general gastric cancer. However, the effectiveness of radiotherapy for those SRCGC patients remains unknown.PurposeThe purpose of the study was to analyze whether the addition of radiotherapy to adjuvant chemotherapy (CT) can benefit survival in resected SRCGC patients.MethodsPatients with SRCGC, who underwent D2 gastrectomy followed by adjuvant chemotherapy or chemoradiotherapy (CRT), were retrospectively collected. According to the proportion of signet ring cells, patients were histologically classified as pure SRCGC (pSRCGC) containing 100% of signet ring cells, mixed SRCGC (mSRCGC) containing >50% of signet ring cells, and contaminated SRCGC (cSRCGC) containing

Abstract Background ERRα, a constitutive transcription factor that regulates energy metabolism, plays an important role in the progression of various tumours. However, its role in cell survival and proliferation and its implication in targeted therapy in colon cancer remains elusive. Methods The expression of ERRα in colon cancer tissues and cell lines was detected by using western blotting and immunohistochemistry. A wound healing assay and a transwell assay were performed to examine the migration and invasion of the colon cancer cells. A cell viability assay, clonogenic assay, western blot assay and the dual-luciferase reporter assay were employed to study the interaction between trametinib (inhibitor of MEK) and EGF treatment. Flow cytometry, western blotting, quantitative reverse-transcription polymerase chain reaction and xenograft studies were used to identify whether the combination of trametinib and simvastatin had a synergistic effect. Results ERRα positively regulated the cell proliferation, migration and invasion of colon cancer cells, and the suppression of ERRα completely reduced the EGF treatment-induced proliferation of colon cancer cells. Further investigation showed that trametinib partially restrained the up-regulation of ERRα induced by the EGF treatment, and ERRα inhibition increased the sensitivity of colon cancer cells to trametinib. At last, we combined trametinib with simvastatin, a common clinically used drug with a new reported function of transcriptional activity inhibition of ERRα, and found that this combination produced a synergistic effect in inhibiting the proliferation and survival of colon cancer cells in vitro as well as in vivo. Conclusions The present data indicated that ERRα acted as an oncogene in colon cancer cells, and the combined targeting of ERRα and MEK might be a promising therapeutic strategy for colon cancer treatment.

Summary: RHOA, a founding member of the Rho GTPase family, is critical for actomyosin dynamics, polarity, and morphogenesis in response to developmental cues, mechanical stress, and inflammation. In murine small intestinal epithelium, inducible RHOA deletion causes a loss of epithelial polarity, with disrupted villi and crypt organization. In the intestinal crypts, RHOA deficiency results in reduced cell proliferation, increased apoptosis, and a loss of intestinal stem cells (ISCs) that mimic effects of radiation damage. Mechanistically, RHOA loss reduces YAP signaling of the Hippo pathway and affects YAP effector epiregulin (EREG) expression in the crypts. Expression of an active YAP (S112A) mutant rescues ISC marker expression, ISC regeneration, and ISC-associated Wnt signaling, but not defective epithelial polarity, in RhoA knockout mice, implicating YAP in RHOA-regulated ISC function. EREG treatment or active β-catenin Catnblox(ex3) mutant expression rescues the RhoA KO ISC phenotypes. Thus, RHOA controls YAP-EREG signaling to regulate intestinal homeostasis and ISC regeneration. : In this article, Zheng and colleagues show that inducible RHOA deletion in mice causes defects in intestine epithelial polarity and deficiencies in intestinal stem cell proliferation, survival, and regeneration. They further demonstrate by genetic rescues that RHOA controls a YAP-EREG axis to mediate canonical Wnt signaling, intestinal stem cell function, and intestinal homeostasis. Keywords: mouse model, intestinal stem cell, regeneration, Rho GTPase, RhoA, Hippo signaling, YAP, Wnt signaling

Studies of posttraumatic stress disorder (PTSD) are complicated by wide variability in the intensity and duration of prior stressors in patient participants, secondary effects of chronic psychiatric illness, and a variable history of treatment with psychiatric medications. In magnetic resonance imaging (MRI) studies, patient samples have often been small, and they were not often compared to similarly stressed patients without PTSD in order to control for general stress effects. Findings from these studies have been inconsistent. The present study investigated whole-brain microstructural alterations of white matter in a large drug-naive population who survived a specific, severe traumatic event (a major 8.0-magnitude earthquake). Using diffusion tensor imaging (DTI), we explored group differences between 88 PTSD patients and 91 matched traumatized non-PTSD controls in fractional anisotropy (FA), as well as its component elements axial diffusivity (AD) and radial diffusivity (RD), and examined these findings in relation to findings from deterministic DTI tractography. Relations between white matter alterations and psychiatric symptom severity were examined. PTSD patients, relative to similarly stressed controls, showed an FA increase as well as AD and RD changes in the white matter beneath left dorsolateral prefrontal cortex and forceps major. The observation of increased FA in the PTSD group suggests that the pathophysiology of PTSD after a specific acute traumatic event is distinct from what has been reported in patients with several years duration of illness. Alterations in dorsolateral prefrontal cortex may be an important aspect of illness pathophysiology, possibly via the region's established role in fear extinction circuitry. Use-dependent myelination or other secondary compensatory changes in response to heightened demands for threat appraisal and emotion regulation may be involved.

Abstract The impact of maintenance therapy on progression-free survival and overall survival as well as quality of life of Chinese patients with metastatic colorectal cancer has long been under discussion. Recently, some phase III clinical trials have revealed that maintenance therapy can significantly prolong the progression-free survival while maintain an acceptable safety profile. Based on this evidence and common treatment practice in China, we now generated one Expert Consensus on Maintenance Treatment for Metastatic Colorectal Cancer in China to further specify the necessity of maintenance therapy, suitable candidates for such treatment, and appropriate regimens.

Background and Objective Rho family is closely related with the growth , differentiation and metastasis of tumer cells. The objective of this work is to investigate the expression of RhoE in lung and breast carcinoma and their corresponding adjacent tissues, as well as its relationship between the expression and clinical pathological grades. The results of this study provide evidences for exploring the biological functions and clinical significance of RhoE. Methods The expression of RhoE was detected by immunohistochemistry in 62 lung carcinoma samples and 34 breast carcinoma samples, and their corresponding adjacent tissues were taken as control.Results RhoE was generally expressed in normal tissues, but the expression level of RhoE in carcerous tissueswas decreased or absent. The stained value of breast carcinoma was 3.65+/-0.62, but the adjacent cancerous tissueswas 10.53+/-0.44, significantly higher than that of the adjacent cancerous tissues (t=12.402, P

We report the development and characterization of graphene/LaAlO3/SrTiO3 heterostructures. Complex-oxide heterostructures are created by pulsed laser deposition and are integrated with graphene using both mechanical exfoliation and transfer from chemical-vapor deposition on ultraflat copper substrates. Nanoscale control of the metal-insulator transition at the LaAlO3/SrTiO3 interface, achieved using conductive atomic force microscope lithography, is demonstrated to be possible through the graphene layer. LaAlO3/SrTiO3-based electric field effects using a graphene top gate are also demonstrated. The ability to create functional field-effect devices provides the potential of graphene-complex-oxide heterostructures for scientific and technological advancement.

The interface between LaAlO3 and TiO2-terminated SrTiO3 can be switched between metastable conductive and insulating states using a conductive atomic force microscope probe. Determination of the nanoscale dimensions has previously required a destructive readout (e.g., local restoration of an insulating state). Here it is shown that high-resolution non-destructive imaging of conductive nanostructures can be achieved using a specific piezoresponse force microscopy (PFM) technique. Images of conductive and insulating nanoscale features are achieved with feature sizes as small as 30 nm. The measured nanowire width from PFM is well correlated with those obtained from nanowire erasure.

Letter to the Editor

Penile Squamous Cell Carcinoma (SCC) is a rare cancer with poor prognosis and limited response to conventional chemotherapy. The genetic and epigenetic alterations of Epidermal Growth Factor Receptor (EGFR)-RAS-RAF signaling in penile SCC are unclear. This study aims to investigate four key members of this pathway in penile SCC. We examined the expression of EGFR and RAS-association domain family 1 A (RASSF1A) as well as the mutation status of K-RAS and BRAF in 150 cases of penile SCC. EGFR and RASSF1A expression was evaluated by immunohistochemistry. KRAS mutations at codons 12 and 13, and the BRAF mutation at codon 600 were analyzed on DNA isolated from formalin fixed paraffin embedded tissues by direct genomic sequencing. EGFR expression was positive in all specimens, and its over-expression rate was 92%. RASSF1A expression rate was only 3.42%. Significant correlation was not found between the expression of EGFR or RASSF1A and tumor grade, pT stage or lymph node metastases. The detection of KRAS and BRAF mutations analysis was performed in 94 and 83 tumor tissues, respectively. We found KRAS mutation in only one sample and found no BRAF V600E point mutation. In summary, we found over-expression of EGFR in the majority cases of penile SCC, but only rare expression of RASSF1A, rare KRAS mutation, and no BRAF mutation in penile SCC. These data suggest that anti-EGFR agents may be potentially considered as therapeutic options in penile SCC.

NUCB2¹⁻⁸³ has been recently reported as an anorexigenic and anti-hyperglycemic peptide. Here we report that NUCB2¹⁻⁸³ promotes osteogenesis. It was found after two months of once-a-day intravenous injection of NUCB2¹⁻⁸³, bone mineral density of femora and lumbar vertebrae were increased in ovariectomized rats. NUCB2¹⁻⁸³ also increased the alkaline phosphatase activity and promoted mineralization in mouse MC3T3-E1 preosteoblastic cell line. When either both Arg⁶⁰ and Arg⁶³ or Ser⁷² were mutated to Ala, the pro-osteogenic activity was completely lost, indicating that these residues are structurally important for its biological function. Furthermore, it encumbered osteoclastic differentiation of RAW 264.7 macrophage. It also excluded any possibility of the effect caused by contaminants or experimental faults, and demonstrated that the pro-osteogenic activity observed was a specific effect of NUCB2¹⁻⁸³ itself. These findings warranted that further studies on NUCB2¹⁻⁸³ would be valuable for the treatment of bone metabolic diseases especially for osteoporosis.

Rho family GTPases are critical regulators of many important cellular processes and the dysregulation of their activities is implicated in a variety of human diseases including oncogenesis and propagation of malignancy. The traditional methods, such as "pull-down" or two-hybrid procedures, are poorly suited to dynamically evaluate the activity of Rho GTPases, especially in living mammalian cells. To provide a novel alternative approach to analyzing Rho GTPase-associated signaling pathways in vivo, we developed a series of bioluminescent biosensors based on the genetically engineered firefly luciferase. These split-luciferase-based biosensors enable non-invasive visualization and quantification of the activity of Rho GTPases in living subjects. The strategy is to reasonably split the gene of firefly luciferase protein into two inactive fragments and then respectively fuse the two fragments to Rho GTPase and the GTPase-binding domain (GBD) of the specific effector. Upon Rho GTPase interacting with the binding domain in a GTP-dependent manner, these two luciferase fragments are brought into close proximity, leading to luciferase reconstitution and photon production in the presence of the substrate. Using these bimolecular luminescence complementation (BiLC) biosensors, we successfully visualized and quantified the activities of the three best characterized Rho GTPases by measuring the luminescence in living cells. We also experimentally investigated the sensitivity of these Rho GTPase biosensors to upstream regulatory proteins and extracellular ligands without lysing cells and doing labor-intensive works. By virtue of the unique functional characteristics of bioluminescence imaging, the BiLC-based biosensors provide an enormous potential for in vivo imaging of Rho GTPase signaling pathways and high-throughput screening of therapeutic drugs targeted to Rho GTPases and (or) upstream molecules in the near future.

Angiogenesis is a well-established target in anti-cancer therapy. Although vascular endothelial growth factor (VEGF)-mediated angiogenesis apparently requires the Rho GTPases Rac1 and Cdc42, the relevant mechanisms are unclear. Here, we determined that activated Rac1/Cdc42 in MCF-7 breast cancer cells could decrease p53 protein levels and increase VEGF secretion to promote proliferation and tube formation of human umbilical vein endothelial cells (HUVECs). However, these effects are reversed after ubiquitin-proteasome breakage. In exploring potential mechanisms for this relationship, we confirmed that activated Rac1/Cdc42 could enhance p53 protein ubiquitination and weaken p53 protein stability to increase VEGF expression. Furthermore, in a xenograft model using nude mice that stably express active Rac1/Cdc42 protein, active Rac1/Cdc42 decreased p53 levels and increased VEGF expression. Additionally, tumor angiogenesis was inhibited, and p53 protein levels were augmented, by intratumoral injection of the ubiquitin-proteasome inhibitor MG132. Finally in 339 human breast cancer tissues, our analyses indicated that Rac1/Cdc42 expression was related to advanced TNM staging, high proliferation index, ER status, and positive invasive features. In particular, our data suggests that high Rac1/Cdc42 expression is correlated with low wt-p53 and high VEGF expression. We conclude that activated Rac1/Cdc42 is a vascular regulator of tumor angiogenesis and that it may reduce stability of the p53 protein to promote VEGF expression by enhancing p53 protein ubiquitin.

To enrich our understanding of the mechanism of tumor lymphatic metastasis, we developed a model system for tracking metastatic tumor cells in the lymphatic system with cellular magnetic resonance imaging (MRI) in live mice to observe the interaction between tumor cells and the lymphatic system. Nude mice were inoculated subcutaneously with superparamagnetic iron oxide (SPIO)-labeled and unlabeled LOVO cells in the foot pad, groin, or axillary area. Serial 7 T MRI of the tumors and surrounding regions was performed in the following 2 weeks. After imaging, tumor tissues and regional lymph nodes were collected and subjected to immunohistologic analysis. T 2 /T 2 *-weighted MRIs showed the primary tumor growth and the draining lymphatic architecture, as well as the SPIO-labeled tumor cells metastasized into the regional lymph node at 8 days. MRIs also revealed information on sentinel lymph node mapping with high-resolution anatomic information. Histologic findings confirmed the in vivo MRI results and revealed lymphangiogenesis, angiogenesis, infiltration of macrophages, and expression of vascular endothelial growth factor C in tumor and draining lymph nodes as well. This technology provides a powerful tool for tracking SPIO-labeled cancer cells in the lymphatics by cellular MRI. There was a close relationship between tumor lymphatic metastasis and lymphangiogenesis.

The oxide heterostructure LaAlO_{3}/SrTiO_{3} supports a two-dimensional electron liquid with a variety of competing phases, including magnetism, superconductivity, and weak antilocalization because of Rashba spin-orbit coupling. Further confinement of this two-dimensional electron liquid to the quasi-one-dimensional regime can provide insight into the underlying physics of this system and reveal new behavior. Here, we describe magnetotransport experiments on narrow LaAlO_{3}/SrTiO_{3} structures created by a conductive atomic force microscope lithography technique. Four-terminal local-transport measurements on Hall bar structures about 10 nm wide yield longitudinal resistances that are comparable to the resistance quantum h/e^{2} and independent of the channel length. Large nonlocal resistances (as large as 10^{4} Ω) are observed in some but not all structures with separations between current and voltage that are large compared to the two-dimensional mean-free path. The nonlocal transport is strongly suppressed by the onset of superconductivity below about 200 mK. The origin of these anomalous transport signatures is not understood, but may arise from coherent transport defined by strong spin-orbit coupling and/or magnetic interactions.