The crucial role of SETDB1 in structural and functional transformation of epithelial cells during regeneration after intestinal ischemia reperfusion injury.

Su (var) 3-9, enhancer of seste, trithorax (SET)-domain bifurcated histone lysine methyltransferase (SETDB1) plays a crucial role in maintaining intestinal stem cell homeostasis; however, its physiological function in epithelial injury is largely unknown. In this study, we investigated the role of SETDB1 in epithelial regeneration using an intestinal ischemia/reperfusion injury (IRI) mouse model. Jejunum tissues were sampled after 75 min of ischemia followed by 3, 24, and 48 h of reperfusion. Morphological evaluations were performed using light microscopy and electron microscopy, and the involvement of SETDB1 in epithelial remodeling was investigated by immunohistochemistry. Expression of SETDB1 was increased following 24 h of reperfusion and localized in not only the crypt bottom but also in the transit amplifying zone and part of the villi. Changes in cell lineage, repression of cell adhesion molecule expression, and decreased histone H3 methylation status were detected in the crypts at the same time. Electron microscopy also revealed aberrant alignment of crypt nuclei and fusion of adjacent villi. Furthermore, increased SETDB1 expression and epithelial remodeling were confirmed with loss of stem cells, suggesting SETDB1 affects epithelial cell plasticity. In addition, crypt elongation and increased numbers of Ki-67 positive cells indicated active cell proliferation after IRI; however, the expression of PCNA was decreased compared to sham mouse jejunum. These morphological changes and the aberrant expression of proliferation markers were prevented by sinefungin, a histone methyltransferase inhibitor. In summary, SETDB1 plays a crucial role in changes in the epithelial structure after IRI-induced stem cell loss.

Nasogastric administration of lenvatinib solution in a mechanically ventilated patient with rapidly growing anaplastic thyroid cancer.

SUMMARY: A 54-year-old woman was referred to our hospital with a cervical tumor. CT revealed a cervical tumor extending to the upper mediastinum, tracheal deviation and tumor infiltration in the cervical vessels. She was followed-up because no diagnosis of malignancy was made by cytology. However, 2 months later, a CT scan showed enlargement of the tumor and tracheal stenosis, and a surgical biopsy was performed and she was diagnosed with anaplastic thyroid cancer (ATC). The tracheal tube with tracheal stenosis could not be removed due to the rapid growth of the tumor, necessitating management by mechanical ventilation. Due to the difficulty of surgical resection, she was treated with lenvatinib. A lenvatinib solution was made and administered via a nasogastric tube. After lenvatinib treatment, the tumor volume decreased and the tracheal stenosis improved. The tracheal tube was removed and oral intake became possible. She was discharged and received ambulatory lenvatinib therapy. The tumor was significantly reduced in size, but gradually grew and was exposed through the cervical wound 6 months later. Esophageal perforation occurred 10 months after the start of treatment. Lenvatinib was re-administered via a nasogastric tube. Eleven months later, the patient died of massive bleeding from the exposed cervical tumor. Patients with advanced ATC may require management with mechanical ventilation for airway stenosis or with a nasogastric tube for esophageal stenosis and perforation. We experienced a case in which lenvatinib was safely administered via a nasogastric tube while performing mechanical ventilation. LEARNING POINTS: An anaplastic thyroid cancer patient under mechanical ventilator management was treated with lenvatinib via a nasogastric tube. The lenvatinib solution can easily be prepared and administered via a nasogastric tube. The lenvatinib solution was effective for a patient with difficulty in oral intake. Lenvatinib could also improve the prognosis of an anaplastic thyroid cancer patient with severe airway and esophageal trouble.

Left Subclavian Artery Revascularization for Delayed Paralysis after Thoracic Endovascular Aortic Repair.

Spinal cord ischemia (SCI) is a devastating complication following thoracic endovascular aortic repair (TEVAR). A man with a ruptured thoracic aortic aneurysm (TAA) was transferred to our hospital. Emergency TEVAR, with left subclavian artery (LSA) coverage, was performed for the ruptured TAA. On postoperative day two, the patient had incomplete paralysis in his legs, presumably caused by SCI. We performed LSA revascularization (LSAR) to provide blood supply to the spinal cord; his paralysis improved and almost resolved after surgery. To our knowledge, this is the first report on LSAR's efficacy for delayed paraplegia due to SCI.

A rare case of simultaneous rectal and gastric carcinomas accompanied with inferior mesenteric arterioportal fistula: case report.

BACKGROUND: Inferior mesenteric arterioportal fistula (APF) is rare as only 35 case reports in the literature. We herein presented a case of simultaneously double cancer in the rectum and stomach with inferior mesenteric APF, which is the first case report by searching using PubMed. Combination of interventional embolization and surgical operation seemed to be optimal treatment for avoiding postoperative complications and the curability. CASE PRESENTATION: A 66-year-old male with epigastric pain was admitted to a practitioner. He underwent a gastroscopy with biopsy, and cancer located in the lesser curvature of the gastric cardia was found. Enhanced CT did not reveal wall thickening of the stomach and distant metastases, but several swollen lymph nodes were observed in the right cardia. In the arterial phase, dilation of inferior mesenteric vein (IMV) and superior rectal artery (SRA) were noted, which raised suspicions of an arterioportal communication. Colonoscopy revealed a type 2 rectal tumor located 12 cm from the anal verge. The histological diagnosis of well-differentiated tubular adenocarcinoma was confirmed by biopsy. At a first step, we planned to perform a radiological embolization of inflow vessels to APFs except for SRA. Additionally, we determined the interval time of 1 month between the first low anterior rectal resection and the sequential gastrectomy for the purpose of decreasing portal pressure. The postoperative course was uneventful without hemorrhagic complications, and S-1 was taken internally 1 year as adjuvant chemotherapy for gastric cancer. The patient still lives without recurrence of this cancer with APF and portal vein thrombosis 2.5 years after the aforementioned surgeries. CONCLUSION: Inferior mesenteric APF and/or arteriovenous fistula (AVF) would be consisted of the several inflow arteries as superior rectal, internal iliac, and median sacral arteries, and outflow veins as inferior mesenteric, internal iliac, and median sacral veins. To determine the therapeutic strategy for left-sided colorectal cancers with abnormal vessel communications of the pelvis, it is significant to comprehend distribution and component vessels of APF and/or AVF.

Resected Intrahepatic Cholangiocarcinoma with Anaphylactic Shock from a Preoperative Liver Function Test before Hepatectomy.

The indocyanine green test is a reliable liver function examination before major hepatectomy, and anaphylaxis is rarely a concern. A 65-year-old male patient without epigastralgia was diagnosed with a 2.2-cm intrahepatic cholangiocarcinoma. He had no history of allergic reactions. Some liver dysfunction was indicated by the laboratory data; however, there was no marked obstructive jaundice and the liver functional reserve was maintained by technetium-99m galactosyl serum albumin. The indocyanine green test was routinely performed, but the patient immediately demonstrated severe anaphylaxis due to indocyanine green administration. He had cardiorespiratory arrest, but recovered after immediate resuscitation. Although acute renal and respiratory failure was significant, the patient recovered at day 10 after the event, and his liver function and other organ functions were improved. Then, the scheduled left hepatectomy with caudate and extrahepatic duct resection was successfully performed without issues. The patient exhibited no allergic response against the administration of antibiotics or other drugs and the postoperative course was uneventful. The patient was discharged on day 17. The tumor was diagnosed as stage III intrahepatic cholangiocarcinoma and R0 resection was accomplished. Preoperative management, including the liver functional loading test, should be carefully carried out before major hepatectomy.

Port-site implantation of Type A Masaoka Stage I thymoma after video-assisted thoracic surgery: a case report.

A 60-year-old woman was referred to our hospital with an anterior mediastinal tumor measuring 3.5 cm in diameter on computed tomography (CT). We performed tumor resection by video-assisted thoracic surgery (VATS) with three ports. The final diagnosis was Type A Masaoka Stage I thymoma. On follow-up CT performed 36 months after the operation, two pleural tumors were detected at the port sites through which the forceps and ultrasonic scalpel had passed repeatedly during the operation. We therefore performed a second operation and enucleated the tumors while preserving the ribs. However, other tumor tissue was detected along the surgical marginal line during the pathological diagnosis after the operation. Surgeons should thus be aware that port-site recurrence can occur after VATS resection of Type A thymoma, despite its mild biological behavior. Wide resection of the chest wall is therefore recommended for operations of port-site recurrence after VATS thymectomy.

Synthesis and ABCG2 inhibitory evaluation of 5-N-acetylardeemin derivatives.

An efficient and versatile synthesis of 5-N-acetylardeemin (1a) and sixteen 2-, 3- and 13-substituted derivatives 1b-q was achieved through Ugi three-component reaction of 3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole and cyclization/epimerization. Their inhibitory activity on the drug efflux of breast cancer resistance protein (ABCG2) was evaluated by flow cytometric analysis of accumulation of Hoechst 33342 stain in Flp-In-293/ABCG2 cells. Most of the derivatives exhibited a stronger ABCG2 inhibitory effect compared with natural product 1a. The derivative 1m with a 4-tolyl substituent at the C-13 position exhibited the most potent ABCG2 inhibition. This preliminary structure-activity relationship study indicates that an electron-rich aryl moiety as the 13-substituent is key to increasing the inhibitory activity.

Osteosarcoma in Sprague-Dawley rats after long-term treatment with teriparatide (human parathyroid hormone (1-34)).

Teriparatide, a therapeutic agent for osteoporosis, has been reported to increase the incidences of bone neoplasms such as osteosarcoma when administered subcutaneously to Fischer 344 (F344) rats for a long term, but its non-carcinogenic dose level following 2-year daily administration has not been established. Here we report detailed studies on the carcinogenicity of teriparatide following long-term administration. When teriparatide was administered subcutaneously to male and female Sprague-Dawley (SD) rats daily for 2 years, the incidence of osteosarcoma was increased at 13.6 µg/kg/day. The non-carcinogenic dose level was 4.5 µg/kg/day for both males and females. The development of osteosarcoma in SD rats depends on the dose level of, and treatment duration with, teriparatide. Responses of the bones to teriparatide were similar between F344 and SD rats in many aspects. These results suggested that the carcinogenic potential of teriparatide in SD rats is essentially the same as in F344 rats.

Asymmetric total synthesis of fredericamycin A: an intramolecular cycloaddition pathway.

The asymmetric total synthesis of the potent antitumor antibiotic fredericamycin A ((S)-1) was achieved by the intramolecular [4+2] cycloaddition of the silylene-protected styrene derivative (S)-7 followed by the aromatic Pummerer-type reaction of the sulfoxide (S)-5. Although we had already succeeded in the total synthesis of racemic 1 by the same approach, synthesis of its asymmetric version was more complicated than we had expected due to the difficulties involved in constructing the quaternary carbon center and the tendency of this center to undergo facile racemization. Racemization of this center during the installation of the acetylene moiety on the dione (R)-8 was the most serious aspect. Systematic studies of its DE-ring analogue (R)-25 revealed that racemization of the quaternary carbon center proceeded by a retro-aldol-aldol reaction of the initial adduct, (1R)-39 a-Li, and that the degree of racemization was dependent on the reaction temperature. The racemization process could be completely depressed by keeping the reaction temperature at -78 degrees C. The construction of the stereogenic quaternary carbon center was achieved by the lipase-catalyzed desymmetrization of the prochiral 1,3-diol 9 a bearing the DEF-ring moiety. These studies enabled us to attain the asymmetric total synthesis of (S)-1 while completely retaining the chiral integrity created by the enzymatic reactions.

Asymmetric Total Synthesis of Fredericamycin A.

Seventeen years after the isolation of the promising antitumor antibiotic fredericamycin A, the first asymmetric total synthesis of this compound has been accomplished and thereby its absolute configuration established. The key feature is the regiocontrolled [4+2] cycloaddition of 3 to 2, which was obtained by the stereospecific rearrangement of 1. Cp = (-)-camphanoyl.