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IntroductionHeart failure occasionally develops after transcatheter aortic valve implantation (TAVI) for severe aortic stenosis (AS), despite procedural success. Most cases present with mildly reduced or preserved left ventricular ejection fraction (LVEF), underscoring the role of diastolic dysfunction. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown benefits across the heart failure spectrum, independent of LVEF. The purpose of this randomised controlled trial is to determine whether adding a SGLT2 inhibitor to conventional medications improves LV diastolic function in patients with preserved LVEF after TAVI.Methods and analysisThis study is a prospective, single-centre, open-label, randomised, parallel-group, two-arm trial enrolling patients with mildly reduced or preserved LVEF (≥40%) undergoing TAVI for severe AS. Participants will be randomised in a 1:1 ratio to receive either conventional medications plus empagliflozin or conventional medications alone. In the empagliflozin group, participants will receive conventional medical therapy plus empagliflozin 10 mg orally once daily, initiated 4 weeks after TAVI. Empagliflozin treatment will continue throughout the study period. Participants in the control group will receive conventional medications without empagliflozin. The primary endpoint is the change in E/e’, assessed by echocardiography from treatment initiation at 4 weeks post TAVI (day 1) to day 168 (week 24). Each group will include 50 patients, totalling 100 patients.Ethics and disseminationEthical approval for this study has been obtained from the Chiba University Hospital Certified Clinical Research Review Board (CRB0111-25).Trial registration numberjRCT1031250190.

IntroductionThere are a substantial number of patients developing heart failure after transcatheter aortic valve implantation (TAVI) for severe aortic stenosis (AS), even though AS has been successfully treated. The purpose of this randomised controlled trial was to determine whether the addition of an angiotensin receptor–neprilysin inhibitor (ARNI), sacubitril/valsartan, is superior to conventional medications in lowering N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in patients undergoing TAVI for AS.Methods and analysisThe study design is a prospective, single-centre, open-label, randomised, parallel-group, two-arm study, in which participants will be randomised in a 1:1 ratio to receive either conventional medications plus ARNI or conventional medications only. In the ARNI group, if a patient was on an ACE inhibitor or angiotensin II receptor blocker before TAVI, it will be switched to ARNI 100 mg/day (50 mg two times per day) on the first postoperative day. If not, candesartan 4 mg/day will be started 1–2 days before TAVI, and switched to ARNI 100 mg/day on the first postoperative day. As the patient has tolerability to ARNI, dosage will be increased stepwise to 400 mg/day 2–4 weeks apart. ARNI will be continued until at least 6-month follow-up. In the control group, the patient will receive conventional medications. The primary endpoint is the serum NT-proBNP value at 6-month follow-up after TAVI. Each group includes 42 patients (84 total patients).Ethics and disseminationEthical approval for this study has been obtained from the Chiba University Hospital Certified Clinical Research Review Board (CRB3180015). The study is ongoing. Findings from this study will be disseminated through peer-reviewed publications and conference presentations.Trial registration numberThis trial has been registered on the Japan Registry of Clinical Trials: jRCT1031220344.

Although the in-hospital prognosis after acute myocardial infarction (AMI) has considerably improved to date, ischemic, bleeding, and heart failure (HF) events after discharge remain clinical challenges. However, the pattern of such events is not fully understood in contemporary clinical practice. This study aimed to evaluate the timing and prognostic impact of cardiovascular and bleeding events after AMI. This multicenter, retrospective registry included 2,059 patients with AMI who underwent percutaneous coronary intervention. Patients were grouped according to their first events after discharge, consisting of ischemic events (recurrent AMI or ischemic stroke), major bleeding, and HF hospitalization, whereas those without such events were classified as the no cardiovascular event group. All-cause mortality after discharge and the ischemic, bleeding, and HF events were evaluated. Ischemic events, major bleedings, and HF hospitalization as their first clinical outcome measures after discharge occurred in 99 (4.8%), 57 (2.8%), and 75 (3.6%) patients, respectively, during the median follow-up period of 538 days. Postdischarge mortality was highest in the major bleeding group, followed by the ischemic events, HF hospitalization, and no cardiovascular event groups. HF hospitalization occurred earlier than major bleeding and ischemic events after discharge. The mortality impact after the first events was greater in the major bleeding rather than ischemic events and HF hospitalization. In conclusion, patterns and prognostic impact of postdischarge outcomes differed significantly among ischemic, bleeding, and HF events, suggesting that timely and tailored follow-up may be needed after AMI.

Although the mammalian intestinal epithelium manifests robust regenerative capacity after various cytotoxic injuries, the underlying mechanism has remained unclear. Here we identify the cyclin-dependent kinase inhibitor p57 as a specific marker for a quiescent cell population located around the +4 position of intestinal crypts. Lineage tracing reveals that the p57 + cells serve as enteroendocrine/tuft cell precursors under normal conditions but dedifferentiate and act as facultative stem cells to support regeneration after injury. Single-cell transcriptomics analysis shows that the p57 + cells undergo a dynamic reprogramming process after injury that is characterized by fetal-like conversion and metaplasia-like transformation. Population-level analysis also detects such spatiotemporal reprogramming widely in other differentiated cell types. In intestinal adenoma, p57 + cells manifest homeostatic stem cell activity, in the context of constitutively activated spatiotemporal reprogramming. Our results highlight a pronounced plasticity of the intestinal epithelium that supports maintenance of tissue integrity in normal and neoplastic contexts. Rapid turnover and regeneration of intestinal epithelium requires distinct intestinal stem cell (ISC) populations. Here the authors show p57 marks quiescent ISCs, and that differentiated cells revert to stem cell state after injury, through dynamic reprogramming characterized by fetal- and metaplastic-like changes.

Copy number alterations detected by comparative genomic hybridization (CGH) can lead to the identification of novel cancer‐related genes. We analyzed chromosomal aberrations in a set of 100 human primary colorectal cancers (CRCs) using CGH and found a solute carrier (SLC) 7A1 gene, which encodes cationic amino acid transporter 1 (CAT1) with 14 putative transmembrane domains, in a chromosome region (13q12.3) with a high frequency of gene amplifications. SLC7A1/CAT1 is a transporter responsible for the uptake of cationic amino acids (arginine, lysine, and ornithine) essential for cellular growth. Microarray and PCR analyses have revealed that mRNA transcribed from CAT1 is overexpressed in more than 70% of human CRC samples, and RNA interference–mediated knockdown of CAT1 inhibited the cell growth of CRCs. Rats were immunized with rat hepatoma cells expressing CAT1 tagged with green fluorescent protein (GFP), and rat splenocytes were fused with mouse myeloma cells. Five rat monoclonal antibodies (mAbs) (CA1 ~ CA5) reacting with HEK293 cells expressing CAT1‐GFP in a GFP expression–dependent manner were selected from established hybridoma clones. Novel anti‐CAT1 mAbs selectively reacted with human CRC tumor tissues compared with adjacent normal tissues according to immuno‐histochemical staining and bound strongly to numerous human cancer cell lines by flow cytometry. Anti‐CAT1 mAbs exhibited internalization activity, antibody‐dependent cellular cytotoxicity, and migration inhibition activity against CRC cell lines. Furthermore, CA2 inhibited the in vivo growth of human HT29 and SW‐C4 CRC tumors in nude mice. This study suggested CAT1 to be a promising target for mAb therapy against CRCs. Frequent gene amplification of SLC7A1/CAT1 and increased CAT1 mRNA expression in colorectal cancers (CRC) were demonstrated. Novel anti‐CAT1 monoclonal antibodies (mAbs) were developed, and higher expression of CAT1 protein in CRC and in vivo antitumor effects of mAbs on xenografted CRC cells in nude mice were confirmed. CAT1 may be a promising target for anti‐CRC therapy.

Effective therapies have yet to be established for pancreatic ductal adenocarcinomas (PDAC) even though it is the most aggressive cancer. In the present study, PDAC was analyzed using novel rat mAbs against membrane proteins in conjunction with flow cytometry and immunohistochemistry. Human epidermal growth receptor (HER)1–4, mesenchymal to epithelial transition factor (MET), sphingosine‐1‐phospahate receptor 1 (S1PR1), l‐type amino acid transporter 1 (LAT1), system x−c transporter (xCT), alanine‐serine‐cysteine transporter (ASCT2), cationic amino acid transporter 1 (CAT1) and variant CD44 (CD44v) were expressed at high frequencies in both in vitro and in vivo PDAC. Internalization of membrane proteins by mAbs and growth inhibition by toxin‐linked mAbs were demonstrated in many PDAC cell lines, and mAbs against S1PR1, ASCT2, HER3 and CD44v inhibited the growth of xenografted MIA PaCa‐2 PDAC cells. Furthermore, CD44v‐high PDAC showed high mRNA expression of HER1–3, MET and CD44v, and was correlated with poor prognosis. Taken together, our results suggest that CD44v, S1PR1, HER3, MET and the above‐mentioned cancer‐associated amino acid transporters might be promising targets for the diagnosis and treatment of PDAC. Novel mAbs could detect cancer‐associated membrane proteins on various type of pancreatic ductal adenocarcinomas (PDAC) by flow cytometry with viable PDAC cells and by immunohistochemistry with PDAC tissues. Results of protein expression were substantiated by mRNA expression by The Cancer Genome Atlas. PDAC will be handled by targeting mAb‐defined single or combinations of multiple molecules such as variant CD44 (CD44v), sphingosine‐1‐phospahate receptor 1 (S1PR1), human epidermal growth receptor (HER)1–4, mesenchymal to epithelial transition factor (MET), l‐type amino acid transporter 1 (LAT1), system x−c transporter (xCT), alanine‐serine‐cysteine transporter (ASCT2) and cationic amino acid transporter 1 (CAT1).

Neuroendocrine carcinoma (NEC) of the gallbladder origin is particularly rare, accounting for only 0.38% of primary malignancies of the gallbladder, and standard therapies are limited. The MET gene encodes the tyrosine kinase receptor, c-Met. Pathogenic variants of MET , such as MET exon 14 skipping and MET amplification, result in excessive downstream signaling that promotes tumor progression. A MET inhibitor, capmatinib, blocks signaling of c-Met and has been approved by the Food and Drug Administration for non-small cell lung cancer with MET exon 14 skipping. The effectiveness of capmatinib has been reported in other cancers with MET amplification, but NEC with MET variants has not been reported. Here, we present a case of a 72-year-old woman with NEC of the gallbladder with multiple liver and lymph node metastases, who was resistant to conventional chemotherapy including carboplatin plus etoposide as first-line treatment and irinotecan as second-line treatment, but she responded to capmatinib. After 6 weeks of treatment, CT scan showed a partial response (80% reduction in size), but after 13 weeks, regrowth of liver metastasis was observed. Herein, we report a meaningful efficacy of capmatinib to the patient of NEC of the gallbladder origin with MET amplification.

Background Colorectal cancer (CRC) is the most common malignancy in the world, and novel molecular targeted therapies for CRC have been vigorously pursued. We searched for novel combination therapies based on the expression patterns of membrane proteins in CRC cell lines. Results A positive correlation was observed between the expression of human pidermal growth factor receptor (HER) 3 and mesenchymal‐to‐epithelial transition factor (MET) on the cell surface of CRC cell lines. The brief stimulation of HER3/MET‐high SW1116 CRC cells with both neuregulin‐1 (NRG1) and hepatocyte growth factor enhanced ERK phosphorylation and cell proliferation more than each stimulation alone. In addition, a prolonged NRG1 stimulation resulted in the tyrosine phosphorylation of MET. In this context, the Forkhead Box protein M1 (FOXM1)‐regulated tyrosine phosphorylation of MET by NRG1 was demonstrated, suggesting the existence of a signaling pathway mediated by FOXM1 upon the NRG1 stimulation. Since the co‐expression of HER3 and MET was also demonstrated in in vivo CRC tissues by immunohistochemistry, we investigated whether the co‐inhibition of HER3 and MET could be an effective therapy for CRC. We established HER3‐and/or MET‐KO SW1116 cell lines, and HER3/MET‐double KO resulted in the inhibition of in vitro cell proliferation and in vivo tumor growth in nude mice by SW1116 cells. Furthermore, the combination of patritumab, an anti‐HER3 fully human mAb, and PHA665752, a MET inhibitor, markedly inhibited in vitro cell proliferation, 3D‐colony formation, and in vivo tumor growth in nude mice by SW1116 cells Conclusion The dual targeting of HER3/MET has potential as CRC therapy. The present study demonstrated that HER3 and MET were not directly associated with each other in CRC but cooperated for the cellular and tumor growth of CRC. In this context, the combination of anti‐HER3 (patritumab) and anti‐MET (PHA665752) drugs was definitely effective against HER3/MET‐high SW1116 CRC cells, indicating the potential of the dual inhibition of HER3 and MET as targeting therapy in human CRC.

Effective therapies have yet to be established for pancreatic ductal adenocarcinomas (PDAC) even though it is the most aggressive cancer. In the present study, PDAC was analyzed using novel rat mAbs against membrane proteins in conjunction with flow cytometry and immunohistochemistry. Human epidermal growth receptor (HER)1–4, mesenchymal to epithelial transition factor (MET), sphingosine‐1‐phospahate receptor 1 (S1PR1), l ‐type amino acid transporter 1 (LAT1), system x − c transporter (xCT), alanine‐serine‐cysteine transporter (ASCT2), cationic amino acid transporter 1 (CAT1) and variant CD44 (CD44v) were expressed at high frequencies in both in vitro and in vivo PDAC. Internalization of membrane proteins by mAbs and growth inhibition by toxin‐linked mAbs were demonstrated in many PDAC cell lines, and mAbs against S1PR1, ASCT2, HER3 and CD44v inhibited the growth of xenografted MIA PaCa‐2 PDAC cells. Furthermore, CD44v‐high PDAC showed high mRNA expression of HER1–3, MET and CD44v, and was correlated with poor prognosis. Taken together, our results suggest that CD44v, S1PR1, HER3, MET and the above‐mentioned cancer‐associated amino acid transporters might be promising targets for the diagnosis and treatment of PDAC.

We report detections of new exoplanets from a radial velocity (RV) survey of metal-rich FGK stars by using three telescopes. By optimizing our RV analysis method to long time-baseline observations, we have succeeded in detecting five new Jovian-planets around three metal-rich stars HD 1605, HD 1666, and HD 67087 with the masses of \\(1.3 M_\\), \\(1.5 M_\\), and \\(1.4 M_\\), respectively. A K1 subgiant star HD 1605 hosts two planetary companions with the minimum masses of \\( M_p i = 0.96 M_JUP\\) and \\(3.5 M_JUP\\) in circular orbits with the planets' periods \\(P = 577.9\\) days and \\(2111\\) days, respectively. HD 1605 shows a significant linear trend in RVs. Such a system consisting of Jovian planets in circular orbits has rarely been found and thus HD 1605 should be an important example of a multi-planetary system that is likely unperturbed by planet-planet interactions. HD 1666 is a F7 main sequence star which hosts an eccentric and massive planet of \\( M_p i = 6.4 M_JUP\\) in the orbit with \\(a_ p = 0.94\\) AU and an eccentricity \\(e=0.63\\). Such an eccentric and massive planet can be explained as a result of planet-planet interactions among Jovian planets. While we have found the large residuals of \\(rms = 35.6\\ m\\ s^-1\\), the periodogram analysis does not support any additional periodicities. Finally, HD 67087 hosts two planets of \\( M_p i = 3.1 M_JUP\\) and \\(4.9 M_JUP\\) in orbits with \\(P=352.2\\) days and \\(2374\\) days, and \\(e=0.17\\) and \\(0.76\\), respectively. Although the current RVs do not lead to accurate determinations of its orbit and mass, HD 67087 c can be one of the most eccentric planets ever discovered in multiple systems.