Inhibition of Notch4 Using Novel Neutralizing Antibodies Reduces Tumor Growth in Murine Cancer Models by Targeting the Tumor Endothelium.

Endothelial Notch signaling is critical for tumor angiogenesis. Notch1 blockade can interfere with tumor vessel function but causes tissue hypoxia and gastrointestinal toxicity. Notch4 is primarily expressed in endothelial cells, where it may promote angiogenesis; however, effective therapeutic targeting of Notch4 has not been successful. We developed highly specific Notch4-blocking antibodies, 6-3-A6 and humanized E7011, allowing therapeutic targeting of Notch4 to be assessed in tumor models. Notch4 was expressed in tumor endothelial cells in multiple cancer models, and endothelial expression was associated with response to E7011/6-3-A6. Anti-Notch4 treatment significantly delayed tumor growth in mouse models of breast, skin, and lung cancers. Enhanced tumor inhibition occurred when anti-Notch4 treatment was used in combination with chemotherapeutics. Endothelial transcriptomic analysis of murine breast tumors treated with 6-3-A6 identified significant changes in pathways of vascular function but caused only modest change in canonical Notch signaling. Analysis of early and late treatment timepoints revealed significant differences in vessel area and perfusion in response to anti-Notch4 treatment. We conclude that targeting Notch4 improves tumor growth control through endothelial intrinsic mechanisms. SIGNIFICANCE: A first-in-class anti-Notch4 agent, E7011, demonstrates strong antitumor effects in murine tumor models including breast carcinoma. Endothelial Notch4 blockade reduces perfusion and vessel area.

High-intensity interval training versus moderate-intensity continuous training in patients with heart failure: a systematic review and meta-analysis.

The effects of high-intensity interval training (HIIT) in patients with heart failure (HF) remain controversial. This systematic review and meta-analysis aimed to examine the efficacy of HIIT versus moderate-intensity continuous aerobic training (MCT) on exercise tolerance in patients with HF. We searched for studies published up to 4 March 2022 in Embase, MEDLINE, PubMed, and the Cochrane Library with no limitations on data, language, or publication status. We included randomized controlled trials comparing the efficacy of HIIT and MCT on peak oxygen uptake (VO2), as a measure of exercise tolerance. We pooled the data on peak VO2, compared HIIT to MCT, and conducted a sub-analysis if there was heterogeneity in the result. We identified 15 randomized controlled trials with 557 patients. Our meta-analysis showed that participants who underwent HIIT achieved a significantly higher peak VO2 than those who underwent MCT (mean difference 1.46 ml/kg/min, 95% confidence interval 0.39 to 2.53; participants = 557; studies = 15; I2 = 65.7%; very low-quality evidence). The meta-regression analysis, conducted as a sub-analysis to explore possible causes of heterogeneity, revealed that the difference in peak VO2 between HIIT and MCT was inversely associated with body mass index (r = - 0.508, p = 0.028, 95% confidence interval - 0.95 to - 0.07). Our systematic review showed that HIIT achieved a higher peak VO2 than MCT in patients with HF. In addition, HIIT may be more effective in improving exercise tolerance in patients with low body mass index.

Pharmacological Profile of GPD-1116, an Inhibitor of Phosphodiesterase 4.

We have previously reported that GPD-1116, an inhibitor of phosphodiesterase (PDE) 4, exhibits anti-inflammatory effects in a model of cigarette smoke-induced emphysema in senescence-accelerated P1 mice. In the present study, we further characterized the pharmacological profile of GPD-1116 in several experiments in vitro and in vivo. GPD-1116 and its metabolite GPD-1133 predominantly inhibited not only human PDE4, but also human PDE1 in vitro. Moreover, GPD-1116 was effective in several disease models in animals, including acute lung injury, chronic obstructive pulmonary disease (COPD), asthma and pulmonary hypertension; the effective doses of GPD-1116 were estimated to be 0.3-2 mg/kg in these models. With regard to undesirable effects known as class effects of PDE4 inhibitors, GPD-1116 showed suppression of gastric emptying in rats and induction of emesis in dogs, but showed no such suppression of rectal temperature in rats, and these side effects of GPD-1116 seemed to be less potent than those of roflumilast. These results suggested that GPD-1116 could be a promising therapeutic agent for the treatment of inflammatory pulmonary diseases. Furthermore, the inhibitory effects of GPD-1116 for PDE1 might be associated with its excellent pharmacological profile. However, the mechanisms through which PDE1 inhibition contributes to these effects should be determined in future studies.

A CASE OF ADVANCED NON-SEMINOMATOUS TESTICULAR GERM CELL TUMOR ACCOMPANIED PANIC DISORDER.

We report a 33-year-old male with a left advanced non-seminomatous testicular germ cell tumor (NSGCT) accompanied panic disorder. He had experienced palpitation and hyperpnea in crowds in his twenties. He was admitted to the Department of Otorhinolaryngology with the chief complaint of left neck swelling. 18F-fluorodeoxy glucose positron emission tomography/computed tomography (FDG-PET/CT) demonstrated left neck, left supraclavicular, left axillary, and paraaortic lymph node (LN) swelling and left testicular swelling. He was referred to our department. The left testis had enlarged to the size of a fist. He rejected admission at that time, but next day, he was taken to our hospital by an ambulance because he lost consciousness at home. No abnormalities were found in the brain CT and electrocardiogram. He was admitted and left high orchiectomy was performed. The human chorionic gonadotropin (HCG) level had elevated to 9,717 IU/L and alpha fetoprotein level (AFP) had elevated to 427 ng/ml. The histopathological diagnosis was tumors of more than one histological type, mixed forms: seminoma and embryonal carcinoma.He had palpitation and hyperpnea after admission and was diagnosed with panic disorder by a psychiatrist. Psychotropic drugs (fluvoxamine maleate 50 mg/day, alprazolam 0.8 mg/day) were prescribed and the panic attacks disappeared afterwards. The psychiatric social worker supported his mind side. Bleomycin, etoposide, and cisplatin (BEP) therapy was performed for 4 courses. He put on a blanket to his face and came to avoid a conversation with other people during the chemotherapy. He was diagnosed with depression and psychotropic drugs were increased (fluvoxamine maleate 50→75 mg/day, alprazolam 0.8→1.2 mg/day) in quantity.Lymphadenectomies for LN metastases were performed and their histopathological examination revealed the existence of viable embryonal carcinoma in the supraclavicular LN. Etoposide, ifosfamide, and cisplatin (VIP) therapy was performed for 2 courses.The pateint has remained alive without tumor recurrence. Psychotropic drugs were reduced and the recent drug is fluvoxamine maleate 25 mg/day.

[Construction and usefulness of the dose management system using DICOM radiation dose structured report (Dose SR) in angiography].

The International Commission on Radiological Protection recommends diagnostic reference levels (DRL) in each radiological examination for justification and optimization of patients' dose in medicine. The aim of our study was to propose the dose management system by utilizing dose information in diagnostic X-ray radiation dose structured report (Dose SR) in The Digital Imaging and Communications in Medicine to optimize radiation dose in institutions. Our dose management system is able to organize dose information obtained from various angiography systems and CTs. It is possible to provide this information to operators for justification and optimization of patient dose. Our system would be useful for the estimation of organ dose and could be used for the determination of local DRL (LDRL) for each radiological practice. In addition, the optimization became possible to compare LDRL with national DRL.

α-1,6-Fucosyltransferase (FUT8) inhibits hemoglobin production during differentiation of murine and K562 human erythroleukemia cells.

Erythropoiesis results from a complex combination of the expression of several transcription factor genes and cytokine signaling. However, the overall view of erythroid differentiation remains unclear. First, we screened for erythroid differentiation-related genes by comparing the expression profiles of high differentiation-inducible and low differentiation-inducible murine erythroleukemia cells. We identified that overexpression of α-1,6-fucosyltransferase (Fut8) inhibits hemoglobin production. FUT8 catalyzes the transfer of a fucose residue to N-linked oligosaccharides on glycoproteins via an α-1,6 linkage, leading to core fucosylation in mammals. Expression of Fut8 was down-regulated during chemically induced differentiation of murine erythroleukemia cells. Additionally, expression of Fut8 was positively regulated by c-Myc and c-Myb, which are known as suppressors of erythroid differentiation. Second, we found that FUT8 is the only fucosyltransferase family member that inhibits hemoglobin production. Functional analysis of FUT8 revealed that the donor substrate-binding domain and a flexible loop play essential roles in inhibition of hemoglobin production. This result clearly demonstrates that core fucosylation inhibits hemoglobin production. Third, FUT8 also inhibited hemoglobin production of human erythroleukemia K562 cells. Finally, a short hairpin RNA study showed that FUT8 down-regulation induced hemoglobin production and increase of transferrin receptor/glycophorin A-positive cells in human erythroleukemia K562 cells. Our findings define FUT8 as a novel factor for hemoglobin production and demonstrate that core fucosylation plays an important role in erythroid differentiation.

Response to intra-arterial cisplatin and concurrent radiotherapy in a patient with primary mucosal malignant melanoma of the nasal cavity.

BACKGROUND: The prognosis for patients with mucosal malignant melanoma (MMM) of the nasal cavity is very poor because of the radioresistance of melanoma cells. METHODS: We present the first case report of the efficacy of superselective intra-arterial cisplatin (CDDP) infusion concurrent with hypofractionated radiotherapy (RT) for MMM of the nasal cavity. RESULTS: A pink, polypoid mass, histopathologically diagnosed as an amelanostic melanoma, occupied the right nasal cavity. After the treatment, a nasal tumor disappeared, leaving only a small bulge in the medial wall of the middle turbinate. Histopathologic examination revealed scattered degenerated melanoma cells, remaining only in the small restricted area in the medial surface of the excised middle turbinate. Twelve months after the treatment, the patient has not experienced any local recurrence or regional and distant metastasis. CONCLUSIONS: The superselective intra-arterial CDDP infusion concurrent with hypofractionated RT might be useful for the management of nasal MMM.

[Case of antiamphiphysin antibody-positive stiff-person syndrome with breast cancer diagnosed by FDG-PET].

We report a case of antiamphiphysin antiboddy-positive stiff-person syndrome associated with breast cancer, which was detected only by FDG-PET. A 46-year-old woman was admitted to our hospital because of painful muscle cramp and stiffness of both legs. Laboratory results were negative for anti-GAD antibody, but highly positive for antiamphiphysin antibody (1: 61,440). She had been diagnosed as having paraneoplastic stiff-person syndrome. However, mammogram, thoracic CT, breast MRI and ultrasonic echography showed no abnormal findings. A whole-body fluorodeoxyglucose (FDG) PET was performed, showing an increased uptake in the left axillary lymph nodes. Then, the left axillary lymph nodes were resected and immunohistochemically diagnosed as breast adenocarcinoma. Treatment of stiff-person syndrome was initiated with corticosteroids followed by chemotherapy against breast cancer, which led to a remarkable improvement of her neurological symptoms. If there is possibility of paraneoplastic syndromes like stiff-person syndrome, FDG-PET is very useful for detecting the occult carcinoma.

Positron emission tomography for predicting malignancy of sinonasal inverted papilloma.

BACKGROUND: Sinonasal inverted papilloma (IP) is an uncommon nasal tumor. It is known for being locally invasive and recurrent, with a high probability of malignant transformation. Accurate initial staging and close surveillance are critical in the management of the disease. METHODS AND RESULTS: Fluorine-18 fluorodeoxyglucose positron emission tomography (FDG PET) was performed in 5 patients with IP. High FDG uptake (maximum standardized uptake (SUVmax) value >3.0) was observed in all patients, and 2 patients with IP associated with squamous cell carcinoma (SCC) exhibited higher SUVmax values. CONCLUSION: The SUVmax value of a sinonasal tumor can warn the surgeon of the probability of an associated malignancy, even when preoperative biopsy demonstrates a purely benign papilloma.

Significance of intraoperative monitoring of arterial blood flow velocity and hepatic venous oxygen saturation for performing minimally invasive surgery in a patient with multiple calcified pancreaticoduodenal aneurysms with celiac artery occlusion.

Even for patients with multiple pancreaticoduodenal aneurysms, successful treatment with noninvasive operative procedures can be employed, if intraoperative devices are considered. A 73-year-old man, without any symptoms, was admitted to our hospital and had computed tomography (CT) scanning to examine his liver for hepatitis C virus (HCV). Selective superior mesenteric artery (SMA) angiography confirmed multiple aneurysms in the anterior inferior pancreaticoduodenal artery (AIPDA), one aneurysm in the posterior inferior mesenteric artery (PIPDA), and another in the occluded celiac trunk, all with severe calcification. All of the aneurysms were thought to communicate with each other. With the celiac artery occlusion, the right hepatic artery (RHA) was revealed to be supplied by collateral arteries from the aneurysms in the AIPDA, and the left hepatic artery was shown to be supplied by collaterals from the left gastric artery. Intraoperative Doppler echography, at the time of the clamping of both IPDAs, demonstrated a marked decrease of blood velocity in all aneurysms (before clamping, >50 cm/s; after, <10 cm/s), although loss of pulsation and a marked decrease of flow in the RHA were inevitable. Therefore, each of these two IPDAs were ligated on the proximal side to the aneurysm, thus preserving the blood flow of the pancreas head fed by the PIPDA; bypass grafting from the AIPDA to the RHA, using the great saphenous vein, was done at the same time. After the creation of an anastomosis, the hepatic venous oxygen saturation (ShvO2) increased from 38% (at the time of ligation of the IPDAs) to 57% under ventilation. The patient's postoperative clinical course was uneventful. We describe and discuss our successful noninvasive operative management of multiple pancreaticoduodenal aneurysms, done while monitoring the blood flow and ShvO2, with some consideration of the literature.

FDG-PET imaging in duodenal cancer.

F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) imaging is a useful modality in the detection of various tumors, including colon cancer and gastric cancer. We evaluated a patient with duodenal cancer with multiple metastases including brain metastases using FDG-PET imaging. It revealed multiple tumor uptake in the brain, clavicular fossa, mediastinum, right adrenal gland and duodenum. These results suggest that FDG-PET imaging may be useful in detecting the primary and metastatic lesions of duodenal adenocarcinoma.

A case of renal pelvic tumor visualized by 18F-FDG-PET imaging.

18F fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging is a useful modality in detecting various tumors, including renal cell carcinoma. We evaluated a patient with renal pelvic tumor (transitional cell carcinoma) with multiple metastases using 18F-FDG PET imaging and detected abnormal increased uptake of a right renal pelvic tumor extending to the renal cortex with liver metastasis and paraaortic lymph node metastases. These results suggest that 18F-FDG PET imaging may be useful in detecting primary and metastatic lesions of renal pelvic tumor (transitional cell carcinoma).

The radiotoxicity of 131I therapy of thyroid cancer: assessment by micronucleus assay of B lymphocytes.

UNLABELLED: We investigated cytologic radiation damage in thyroid cancer after (131)I therapy using micronucleus assay (MNA) of B lymphocytes exclusively, as opposed to our previous study in which MNA of all lymphocyte subsets was used. METHODS: We studied 22 thyroid cancer patients treated with 3.7 GBq of (131)I. Peripheral lymphocytes were harvested, and B lymphocytes were isolated by an immunomagnetic method and assayed for the frequency of micronuclei. RESULTS: The frequency of micronuclei among B cells after (131)I therapy was significantly increased relative to that in untreated control subjects, and the (131)I-induced increase in micronuclei frequency among B cells was significantly greater than that among all lymphocytes. CONCLUSION: Compared with the MNA of all lymphocytes, the MNA among specifically B cells may more sensitively detect cytologic radiation damage associated with (131)I therapy of thyroid cancer.

DNA alterations during multi-step development of human hepatocellular carcinomas revealed by laser capture microdissection.

In order to clarify early molecular events involved in liver carcinogenesis, we analyzed 53 liver-cirrhosis nodules (LCNs) from five patients and 13 micro-hepatocellular carcinoma (HCC) nodules from one patient and looked for alterations of microsatellites in genomic DNA after carefully preparing the tissue samples by laser-capture microdissection (LCM). Allelotyping was done with 20 markers corresponding to anonymous microsatellites and 13 corresponding to tumor suppressor genes (TSGs) that had shown significant alterations in HCCs. We detected both loss of heterozygosity (LOH) and microsatellite shifts (MS). Overall, 24 of 53 (47%) of LCNs showed LOH with any of the informative markers used in the study, reflecting that proportion of LCNs with clonal growth. The fractional allelic loss (FAL) index, an indication of total genomic complexity, was not significantly different between LCN and micro-HCC nodules, but their profiles of alteration were different. These profiles were classified into three groups: (1) LCN profile-allelic loss at chromosomal arms 1q and 14q, TBP and BRCA1; (2) HCC profile-LOH at 4q, 6q, 7q, 17p, NF1, IGFIIr and p53 in micro-HCC nodules; these changes in early lesions were identical to those seen in mature HCCs; (3) Common profile-LOH at NF1 and 6q, including IGFIIr, common to both LCN and HCC. No LCN showed LOH at p53 and Rb, loci that are generally altered in HCCs. However, 12 intra-tumoral nodules examined had lost p53 in all informative cases, although the loss of Rb was a late event. These results suggest that early genomic profiles confined to LCNs, and additional profiles that can be observed when liver tissue undergoes malignant transformation, support a model of multi-step development of HCC.