Synthesis and Identification of decarbamoyloxySaxitoxins in Toxic Microalgae and their Reactions with the Oxygenase, SxtT, Reveal Saxitoxin Biosynthesis.

Saxitoxin (STX, 1) is a representative compound of paralytic shellfish toxins (PSTs) that are produced by marine dinoflagellates and freshwater cyanobacteria. Although several pathways have been proposed for the biosynthesis of STX, the order of ring and side chain hydroxylation, and formation of the tricyclic skeleton have not been well established. In this study, 12,12-dideoxy-decarbamoyloxySTX (dd-doSTX, 2), the most reduced STX analogue having the tricyclic skeleton, and its analogues, 12ß-deoxy-doSTX (12ß-d-doSTX, 3), 12α-deoxy-doSTX (12α-d-doSTX, 4), and doSTX (5), were synthesized, and these compounds were screened in the toxic microalgae using high-resolution LCMSMS. dd-doSTX (2) and 12ß-d-doSTX (3) were identified in the PSTs-producing dinoflagellates (Alexandrium catenella, A. pacificum, and/or Gymnodinium catenatum) and in the cyanobacterium Dolichospermum circinale (TA04). doSTX (5), previously isolated from the dinoflagellate G. catenatum, was also identified in D. circinale (TA04). Furthermore, the conversion of 2 to 3, and 4 to 5, by SxtT with VanB, a reported Rieske oxygenase and its redox partner in STX biosynthesis, was confirmed. These results support that 2 is a possible biosynthetic precursor of STX, and that ring and side-chain hydroxylations proceed after cyclization.

Approaches to Construction of the Medium-Sized Ring Structure in Zetekitoxin AB by Ring-Closing Metathesis.

Zetekitoxin AB (ZTX), a member of the saxitoxin (STX) family isolated from the Panamanian golden frog Atelopus zeteki, shows extremely potent NaV-inhibitory activity. Here, we investigate the synthesis of 12-membered ring structure with the C11 tertiary hydroxyl group in ZTX by means of the Mislow-Evans rearrangement reaction and subsequent ring-closing metathesis reaction. Although this approach did not provide access to the 12-membered macrocycle, we obtained a new STX analog with an 18-membered macrolactam structure as a synthetic mimic of ZTX.

Rapid transformation of branched pancreatic duct-derived intraductal tubulopapillary neoplasm into an invasive carcinoma: A case report.

BACKGROUND: Intraductal tubulopapillary neoplasm (ITPN) is a rare disease accounting for approximately 3% of all intraductal pancreatic tumors, with intraductal papillary mucinous neoplasm (IPMN) being one of the most common differential diagnoses. Both ITPN and IPMN display slow growth. A branched pancreatic duct type is commonly observed in IPMN, whereas ITPN derived from the branched pancreatic duct has been reported in a limited number of cases; hence, its pathogenesis remains unclear. CASE SUMMARY: Here, we present the case of a patient with ITPN localized in a branched pancreatic duct, with poorly controlled irritable bowel syndrome. A contrast-enhanced computed tomography scan of the abdomen incidentally revealed a 5-mm oligemic nodule-like change in the body of the pancreas. Endoscopic ultrasound (EUS) indicated a 10-mm hypoechoic mass without any cystic structures that had grown within 2 mo. EUS-guided fine needle aspiration was performed for definitive diagnosis, and the findings suggested ductal papillary carcinoma. Distal pancreatectomy was performed, and the tumor was pathologically diagnosed as ITPN with an invasive cancerous component, pT3N1aM0, pStage IIB (International Cancer Control, 8th edition). The patient underwent treatment with postoperative adjuvant chemotherapy (S-1 monotherapy); however, relapse was observed 1 year and 10 mo after surgical resection, and subsequent treatment involving a combination of chemotherapy and radiotherapy was administered. Maintenance therapy has since facilitated a stable disease state. CONCLUSION: Regardless of the microscopic size of the neoplasm, early diagnosis of ITPN with EUS-guided fine needle aspiration and surgical resection are crucial.

[Cystoid macular edema secondary to albumin-bound paclitaxel therapy for pancreatic cancer].

Cystoid macular edema (CME) is a rare adverse event induced by taxane-based chemotherapy. Here, we describe the case of a 71-year-old man who developed bilateral CME during treatment with nab-paclitaxel (nab-PTX) for unresectable pancreatic cancer. Two months after drug discontinuation, his vision improved, and there was significant reduction in the CME on optical coherence tomography. CME is an adverse event that can be treated with the early withdrawal of nab-PTX. Oncologists who use nab-PTX should be aware of this adverse event for timely patient referral to an ophthalmologist and appropriate treatment that would enable the preservation of the patient's visual acuity.

An Autopsy Case of Anaplastic Carcinoma of the Pancreas in a 39-Year-Old Woman that Developed from Hereditary Pancreatitis.

BACKGROUND Anaplastic carcinoma of the pancreas (ACP) is a rare type of cancer with an extremely poor prognosis. Hereditary pancreatitis is a rare autosomal-dominant disease. It progresses to chronic pancreatitis at a young age, increasing the risk of pancreatic cancer. CASE REPORT A 39-year-old woman was diagnosed with chronic pancreatitis at the age of 18 years. The patient was referred to our hospital for epigastralgia and jaundice. We identified a tumor mass at the head of the pancreas using contrast computed tomography (CT) and endoscopic ultrasound (EUS) of the abdomen. Tissue biopsy revealed ACP of the spindle cell type. We started the patient on combination chemotherapy using gemcitabine and nanoparticle albumin-bound (nab) -paclitaxel, but she died 1 month after her first visit. An autopsy revealed a mixture of tubular adenocarcinoma and anaplastic carcinoma. We performed genetic analysis using DNA samples from the biopsy tissues but did not find mutations in the PRSS1 and SPINK1 genes associated with hereditary pancreatitis. CONCLUSIONS The risk of pancreatic cancer generally increases in patients with hereditary pancreatitis after 50 years of age. However, in this case, the development of pancreatic cancer occurred at a younger age, suggesting the importance of early detection in such cases. Furthermore, this case suggests that EUS is a useful method for monitoring patients with hereditary pancreatitis and the diagnosis of ACP.

Synthesis of C12-Keto Saxitoxin Derivatives with Unusual Inhibitory Activity Against Voltage-Gated Sodium Channels.

A novel series of C12-keto-type saxitoxin (STX) derivatives bearing an unusual nonhydrated form of the ketone at C12 has been synthesized, and their NaV -inhibitory activity has been evaluated in a cell-based assay as well as whole-cell patch-clamp recording. Among these compounds, 11-benzylidene STX (3 a) showed potent inhibitory activity against neuroblastoma Neuro 2A in both cell-based and electrophysiological analyses, with EC50 and IC50 values of 8.5 and 30.7 nm, respectively. Interestingly, the compound showed potent inhibitory activity against tetrodotoxin-resistant subtype of NaV 1.5, with an IC50 value of 94.1 nm. Derivatives 3 a-d and 3 f showed low recovery rates from NaV 1.2 subtype (ca 45-79 %) compared to natural dcSTX (2), strongly suggesting an irreversible mode of interaction. We propose an interaction model for the C12-keto derivatives with NaV in which the enone moiety in the STX derivatives 3 works as Michael acceptor for the carboxylate of Asp1717 .

An autopsy case of granulocyte colony-stimulating factor-producing pancreatic adenosquamous carcinoma.

A 60-year-old female was admitted to hospital with a continuous fever, a decreased appetite, and abdominal pain. Laboratory tests showed an elevated peripheral leukocyte count (13,800/µl) and increased C-reactive protein (19.1 mg/dl) and carbohydrate antigen 19-9 (4057 U/ml) levels. Abdominal contrast-enhanced computed tomography showed multiple bulky hypovascular nodules in the liver, swelling of the paraaortic lymph nodes, and a hypovascular mass (diameter 3.0 cm) in the pancreatic body. The serum concentrations of granulocyte colony-stimulating factor (G-CSF) and interleukin-6 were 172 pg/µl and 541 pg/µl, respectively. Liver biopsy specimens revealed an adenosquamous carcinoma, which was positively immunostained for G-CSF. We diagnosed the patient with G-CSF-producing pancreatic cancer with multiple metastases. Four courses of gemcitabine with dexamethasone and one course of nab-paclitaxel and gemcitabine were administered. Although the pancreatic tumor and paraaortic lymph node metastases decreased in size, the liver metastases continued to grow. The patient died 4 months after the diagnosis of pancreatic cancer. An autopsy resulted in the tumor being diagnosed as poorly differentiated adenosquamous pancreatic carcinoma, which was histopathologically G-CSF-positive. Although G-CSF-producing pancreatic adenosquamous carcinomas are extremely rare, they have been encountered more frequently in recent years. In such cases, chemotherapy combined with dexamethasone might be effective at temporarily improving the patient's condition.

Synthetic Approaches to Zetekitoxin AB, a Potent Voltage-Gated Sodium Channel Inhibitor.

Voltage-gated sodium channels (NaVs) are membrane proteins that are involved in the generation and propagation of action potentials in neurons. Recently, the structure of a complex made of a tetrodotoxin-sensitive (TTX-s) NaV subtype with saxitoxin (STX), a shellfish toxin, was determined. STX potently inhibits TTX-s NaV, and is used as a biological tool to investigate the function of NaVs. More than 50 analogs of STX have been isolated from nature. Among them, zetekitoxin AB (ZTX) has a distinctive chemical structure, and is the most potent inhibitor of NaVs, including tetrodotoxin-resistant (TTX-r) NaV. Despite intensive synthetic studies, total synthesis of ZTX has not yet been achieved. Here, we review recent efforts directed toward the total synthesis of ZTX, including syntheses of 11-saxitoxinethanoic acid (SEA), which is considered a useful synthetic model for ZTX, since it contains a key carbon-carbon bond at the C11 position.

Listeria Monocytogenes Septicemia and Meningitis Caused by Listeria Enteritis Complicating Ulcerative Colitis.

An 80-year-old man, who had been diagnosed with ulcerative colitis, was admitted due to a fever and bloody diarrhea and was treated with a glucocorticoid and azathioprine. After 5 days, he developed an impaired consciousness, headache, and neck stiffness. A sample of the colonic mucosa, blood cultures, and cerebrospinal fluid revealed Listeria monocytogenes infection. Intravenous ampicillin improved the symptoms of fever, bloody diarrhea, and headache without any neurological sequelae. Physicians should consider that Listeria enteritis complicating ulcerative colitis can cause septicemia and meningitis in immunosuppressed patients. A patient's central nervous system can avoid the effects of Listeria meningitis by an early diagnosis and appropriate treatment.

[A case report of primary small cell esophageal carcinoma responding successfully to radiochemotherapy].

Primary small cell esophageal carcinoma is a rare cancer with a poor prognosis, for which to date there is no recommended standard treatment. We present a 60-year-old male with this disease who was successfully managed by the combination of radiation and chemotherapy. The patient was referred to our hospital for liver dysfunction of unknown cause. On admission, he was diagnosed as having a primary small cell esophageal carcinoma and multifocal metastasis in the liver. He received cisplatin and 5-fluorouracil(CDDP 40mg/m2-days 1, 8, 5-FU 400 mg/m2-days 1-5, 8-12)and local radiation of 50 Gy for the esophagus, followed by 4 courses of chemotherapy the same as listed above. At the end of therapy, radiological findings showed that both primary and metastatic lesions completely disappeared. Unfortunately, he died of liver failure due to the recurrence of metastatic small cell carcinoma in the liver 13 months after the end of initial therapy. However, the primary cancer lesion had not recurred by that time. These findings suggest the beneficial effect of the combination of radiotherapy and chemotherapy for advanced-stage small cell esophageal carcinoma.