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Background The “watch-and-wait” approach is a common treatment option amongst patients with locally advanced rectal cancer (LARC). However, the diagnostic sensitivity of clinical modalities, such as colonoscopy and magnetic resonance imaging to determine pathological response, is not high. We analysed the clinical utility of circulating tumour DNA (ctDNA) of patients with LARC to predict response to preoperative therapy and postoperative recurrence. Methods A serial ctDNA analysis of 222 plasma samples from 85 patients with LARC was performed using amplicon-based deep sequencing on a cell-free DNA panel covering 14 genes with over 240 hotspots. Results ctDNA was detected in 57.6% and 22.3% of samples at baseline and after preoperative treatment, respectively, which was significantly different ( P  = 0.0003). Change in ctDNA was an independent predictor of complete response to preoperative therapy ( P  = 0.0276). In addition, postoperative ctDNA and carcinoembryonic antigen (CEA) were independent prognostic markers for risk of recurrence after surgery (ctDNA, P  = 0.0127 and CEA, P  = 0.0105), with a combined analysis having cumulative effects on recurrence-free survival ( P  = 1.0 × 10 –16 ). Conclusions Serial ctDNA analysis may offer clinically useful predictive and prognostic markers for response to preoperative therapy and postoperative recurrence in patients with LARC.

Gastric cancer in young adults has been pointed out to comprise a subgroup associated with distinctive clinicopathological features, including an equal gender distribution, advanced disease, and diffuse‐type histology. Comprehensive molecular analyses of gastric cancers have led to molecular‐based classifications and to specific and effective treatment options. The molecular traits of gastric cancers in young adults await investigations, which should provide a clue to explore therapeutic strategies. Here, we studied 146 gastric cancer patients diagnosed at the age of 40 years or younger at the Cancer Institute Hospital (Tokyo, Japan). Tumor specimens were examined for Helicobacter pylori infection, Epstein‐Barr virus positivity, and for the expression of mismatch repair genes to indicate microsatellite instability. Overexpression, gene amplifications, and rearrangements of 18 candidate driver genes were examined by immunohistochemistry and FISH. Although only a small number of cases were positive for Epstein‐Barr virus and microsatellite instability (n = 2 each), we repeatedly found tumors with gene fusion between a tight‐junction protein claudin, CLDN18, and a regulator of small G proteins, ARHGAP, in as many as 22 cases (15.1%), and RNA sequencing identified 2 novel types of the fusion. Notably, patients with the CLDN18‐ARHGAP fusion revealed associations between aggressive disease and poor prognosis, even when grouped by their clinical stage. These observations indicate that a fusion gene between CLDN18 and ARHGAP is enriched in younger age‐onset gastric cancers, and its presence could contribute to their aggressive characteristics. In our gastric cancer in young adult cohort, we found enrichment of fusion genes between CLDN18 and ARHGAP. The positivity of the CLDN18‐ARHGAP fusion relates to advanced disease and poor prognosis, indicating its clinical relevance.

Carcinosarcoma (CS) of the uterus or ovary is a rare, aggressive and biphasic neoplasm composed of carcinoma and sarcoma elements. Previous genomic studies have identified the driver genes and genomic properties associated with CS. However, there is still no molecular subtyping scheme with clinical relevance for this disease. Here, we sequence 109 CS samples, focusing on 596 genes. We identify four molecular subtypes that resemble those observed in endometrial carcinoma: POLE -mutated, microsatellite instability, copy number high, and copy number low subtypes. These molecular subtypes are linked with DNA repair deficiencies, potential therapeutic strategies, and multiple clinicopathological features, including patient outcomes. Multi-regional comparative sequencing reveals genomic alteration-independent CS cell differentiation. Transcriptome and DNA methylome analyses confirm epithelial-mesenchymal transition as a mechanism of sarcoma differentiation. The current study thus provides therapeutic possibilities for CS as well as clues to understanding the molecular histogenic mechanism of its development. Carcinosarcoma of the ovary or uterus comprises both carcinoma and sarcoma elements. Here, the authors perform a multi -omics study of the disease revealing therapeutic possibilities for this rare and aggressive disease.

Epithelial‐mesenchymal transition (EMT) is a reversible and dynamic process hypothesized to be co‐opted by carcinoma during invasion and metastasis. Yet, there is still no quantitative measure to assess the interplay between EMT and cancer progression. Here, we derived a method for universal EMT scoring from cancer‐specific transcriptomic EMT signatures of ovarian, breast, bladder, lung, colorectal and gastric cancers. We show that EMT scoring exhibits good correlation with previously published, cancer‐specific EMT signatures. This universal and quantitative EMT scoring was used to establish an EMT spectrum across various cancers, with good correlation noted between cell lines and tumours. We show correlations between EMT and poorer disease‐free survival in ovarian and colorectal, but not breast, carcinomas, despite previous notions. Importantly, we found distinct responses between epithelial‐ and mesenchymal‐like ovarian cancers to therapeutic regimes administered with or without paclitaxel in vivo and demonstrated that mesenchymal‐like tumours do not always show resistance to chemotherapy. EMT scoring is thus a promising, versatile tool for the objective and systematic investigation of EMT roles and dynamics in cancer progression, treatment response and survival. Synopsis A novel EMT scoring method reveals that EMT status does not unanimously correlate with poorer overall and disease‐free survival. Different EMTed tumours show distinct responses to certain chemotherapeutics, with the potential to stratify patients by EMT status. A novel scoring method was developed based on transcriptomics to universally estimate and compare the Epithelial‐Mesenchymal Transition (EMT) phenotype across cancer types. A spectrum of EMT was established across more than 15 cancers using this EMT scoring method. Correlations of EMT status with poorer overall‐ and disease‐free survival were not unanimously observed in all cancers. Differential and preferential responses of EMTed tumours to certain chemotherapeutics were observed, suggesting the potential to stratify patients by EMT status. Graphical Abstract A novel EMT scoring method reveals that EMT status does not unanimously correlate with poorer overall and disease‐free survival. Different EMTed tumours show distinct responses to certain chemotherapeutics, with the potential to stratify patients by EMT status.

Aging is considered to be accelerated by insulin signaling in lower organisms, but it remained unclear whether this could hold true for mammals. Here we show that mice with skeletal muscle-specific double knockout of Akt1 / 2 , key downstream molecules of insulin signaling, serve as a model of premature sarcopenia with insulin resistance. The knockout mice exhibit a progressive reduction in skeletal muscle mass, impairment of motor function and systemic insulin sensitivity. They also show osteopenia, and reduced lifespan largely due to death from debilitation on normal chow and death from tumor on high-fat diet. These phenotypes are almost reversed by additional knocking out of Foxo1 / 4 , but only partially by additional knocking out of Tsc2 to activate the mTOR pathway. Overall, our data suggest that, unlike in lower organisms, suppression of Akt activity in skeletal muscle of mammals associated with insulin resistance and aging could accelerate osteosarcopenia and consequently reduce lifespan. Sasako et al. show that disruption of the insulin/IGF-1 signaling by suppressing Akt activity in mouse skeletal muscle can accelerate osteosarcopenia and shortens lifespan, which is reversed by inactivation of FoxOs rather than activation of mTOR, suggesting FoxOs as therapeutic targets.

Colorectal cancer (CRC) is a heterogenous disease, and patients have differences in therapeutic response. However, the mechanisms underlying interpatient heterogeneity in the response to chemotherapeutic agents remain to be elucidated, and molecular tumor characteristics are required to select patients for specific therapies. Patient‐derived organoids (PDOs) established from CRCs recapitulate various biological characteristics of tumor tissues, including cellular heterogeneity and the response to chemotherapy. Patient‐derived organoids established from CRCs show various morphologies, but there are no criteria for defining these morphologies, which hampers the analysis of their biological significance. Here, we developed an artificial intelligence (AI)‐based classifier to categorize PDOs based on microscopic images according to their similarity in appearance and classified tubular adenocarcinoma‐derived PDOs into six types. Transcriptome analysis identified differential expression of genes related to cell adhesion in some of the morphological types. Genes involved in ribosome biogenesis were also differentially expressed and were most highly expressed in morphological types showing CRC stem cell properties. We identified an RNA polymerase I inhibitor, CX‐5641, to be an upstream regulator of these type‐specific gene sets. Notably, PDO types with increased expression of genes involved in ribosome biogenesis were resistant to CX‐5461 treatment. Taken together, these results uncover the biological significance of the morphology of PDOs and provide novel indicators by which to categorize CRCs. Therefore, the AI‐based classifier is a useful tool to support PDO‐based cancer research. We developed an artificial intelligence (AI)‐based classifier to categorize Patient‐derived organods(PDOs). Transcriptome analysis identified differential expression of genes related to cell adhesion and ribosome biogenesis and an RNA polymerase I inhibitor, CX‐5641, exhibeted type‐specific response. These results uncover the biological significance of the morphology of PDOs and the AI‐based classifier is a useful tool to support PDO‐based cancer research.

Background Multiple factors, including hypertension, affect left ventricular remodeling in hemodialysis (HD) patients. Therefore, this retrospective study used left ventricular global longitudinal strain (GLS), an excellent method for detecting mild left ventricular systolic dysfunction, to compare left ventricular systolic function in HD patients with preserved left ventricular ejection fraction (LVEF) and patients with hypertensive left ventricular hypertrophy (HLVH). Methods Participants were aged 60 years or older and had an LVEF of 60% or higher. We compared 20 HD patients (HD group) with 20 HLVH patients matched for age and sex (HLVH group) and 20 healthy control individuals (C group). GLS decline was defined as a GLS value greater than the GLS reference value, which was the mean value of + 2×standard deviation in the C group. Results LVEF was not significantly different between the 3 groups, but GLS was significantly worse in the HD group (-15.8%±1.4%) than in the C group (-19.3%±1.1%, p  < 0.01) and HLVH group (-17.0%±1.4%, p  < 0.05). Relative wall thickness (RWT) and left ventricular mass index (LVMI) were significantly higher in the HLVH and HD groups than in the C group ( p  < 0.01), and hemoglobin (Hb) levels were significantly lower in the HD group than in the C and HLVH groups ( p  < 0.01). The frequency of GLS decline (i.e., GLS > -17.0%) was significantly higher in the HD group than in the HLVH group ( p  < 0.01). Multiple regression analysis of the 3 groups showed that increased RWT and LVMI and decreased Hb were significantly associated with GLS decline ( p  < 0.01). Conclusions HD patients with preserved LVEF have a significantly greater decline in GLS than HLVH patients. Increased RWT and LVMI with renal anemia may contribute to GLS decline in HD patients with LVEF. Clinical trial number 2023-01-02.

Hepatic insulin signalling involves insulin receptor substrates (Irs) 1/2, and is normally associated with the inhibition of gluconeogenesis and activation of lipogenesis. In diabetes and obesity, insulin no longer suppresses hepatic gluconeogenesis, while continuing to activate lipogenesis, a state referred to as ‘selective insulin resistance’. Here, we show that ‘selective insulin resistance’ is caused by the differential expression of Irs1 and Irs2 in different zones of the liver. We demonstrate that hepatic Irs2-knockout mice develop ‘selective insulin resistance’, whereas mice lacking in Irs1, or both Irs1 and Irs2, develop ‘total insulin resistance’. In obese diabetic mice, Irs1/2-mediated insulin signalling is impaired in the periportal zone, which is the primary site of gluconeogenesis, but enhanced in the perivenous zone, which is the primary site of lipogenesis. While hyperinsulinaemia reduces Irs2 expression in both the periportal and perivenous zones, Irs1 expression, which is predominantly in the perivenous zone, remains mostly unaffected. These data suggest that ‘selective insulin resistance’ is induced by the differential distribution, and alterations of hepatic Irs1 and Irs2 expression. Type 2 diabetes and obesity are associated with increased hepatic gluconeogenesis and lipogenesis, known as selective insulin resistance. Here Kubota et al . explain selective insulin resistance in the liver with the zonal distribution and selective insulin-mediated regulation of Irs1 and Irs2.

Background The intratumor heterogeneity (ITH) of cancer cells plays an important role in breast cancer resistance and recurrence. To develop better therapeutic strategies, it is necessary to understand the molecular mechanisms underlying ITH and their functional significance. Patient-derived organoids (PDOs) have recently been utilized in cancer research. They can also be used to study ITH as cancer cell diversity is thought to be maintained within the organoid line. However, no reports investigated intratumor transcriptomic heterogeneity in organoids derived from patients with breast cancer. This study aimed to investigate transcriptomic ITH in breast cancer PDOs. Methods We established PDO lines from ten patients with breast cancer and performed single-cell transcriptomic analysis. First, we clustered cancer cells for each PDO using the Seurat package. Then, we defined and compared the cluster-specific gene signature (ClustGS) corresponding to each cell cluster in each PDO. Results Cancer cells were clustered into 3–6 cell populations with distinct cellular states in each PDO line. We identified 38 clusters with ClustGS in 10 PDO lines and used Jaccard similarity index to compare the similarity of these signatures. We found that 29 signatures could be categorized into 7 shared meta-ClustGSs, such as those related to the cell cycle or epithelial–mesenchymal transition, and 9 signatures were unique to single PDO lines. These unique cell populations appeared to represent the characteristics of the original tumors derived from patients. Conclusions We confirmed the existence of transcriptomic ITH in breast cancer PDOs. Some cellular states were commonly observed in multiple PDOs, whereas others were specific to single PDO lines. The combination of these shared and unique cellular states formed the ITH of each PDO.

Esophageal squamous cell carcinoma (ESCC) is a malignant disease. At present, the genomic profiles of ESCC are known to a considerable extent, and DNA methylation and gene expression profiles have been mainly used for the classification of ESCC subtypes, but integrative genomic, transcriptomic, and epigenomic analyses remain insufficient. Therefore, we performed integrative analyses using whole‐exome sequencing, DNA methylation, and RNA sequencing (RNA‐seq) analyses of Japanese patients with ESCC. In cancer‐related genes, such as NOTCH family genes, RTK/PI3K pathway genes, and NFE2L2 pathway genes, variants and copy number amplification were detected frequently. Japanese ESCC cases were clustered into two mutational signatures: an APOBEC‐associated signature and an age‐related signature. In imprinted genes, DNA methylation was aberrant in gene promoter regions and correlated well with gene expression profiles. Nonsynonymous single‐nucleotide variants and allelic expression imbalance were detected frequently in FAT family genes. Our integrative genome‐wide analyses, including DNA methylation and allele‐specific gene expression profiles, revealed altered gene regulation of imprinted genes and FAT family genes in ESCC. In this study, we examined what functions or which pathways have been involved in aberrations through DNA methylation status. Furthermore, we revealed allelic expression imbalance (AEI) using RNA‐seq data. Our data suggest possible involvement of AEI and aberrant expression of imprinted genes in the pathogenesis of esophageal squamous cell carcinoma (ESCC), providing a new concept for the development of therapeutic modalities for patients with ESCC.