The novel drug candidate S2/IAPinh improves survival in models of pancreatic and ovarian cancer

Cancer selective apoptosis remains a therapeutic challenge and off-target toxicity has limited enthusiasm for this target clinically. Sigma-2 ligands (S2) have been shown to enhance the cancer selectivity of small molecule drug candidates by improving internalization. Here, we report the synthesis of a novel drug conjugate, which was created by linking a clinically underperforming SMAC mimetic (second mitochondria-derived activator of caspases; LCL161), an inhibitor (antagonist) of inhibitor of apoptosis proteins (IAPinh) with the sigma-2 ligand SW43, resulting in the new chemical entity S2/IAPinh. Drug potency was assessed via cell viability assays across several pancreatic and ovarian cancer cell lines in comparison with the individual components (S2 and IAPinh) as well as their equimolar mixtures (S2 + IAPinh) both in vitro and in preclinical models of pancreatic and ovarian cancer. Mechanistic studies of S2/IAPinh-mediated cell death were investigated in vitro and in vivo using syngeneic and xenograft mouse models of murine pancreatic and human ovarian cancer, respectively. S2/IAPinh demonstrated markedly improved pharmacological activity in cancer cell lines and primary organoid cultures when compared to the controls. In vivo testing demonstrated a marked reduction in tumor growth rates and increased survival rates when compared to the respective control groups. The predicted mechanism of action of S2/IAPinh was confirmed through assessment of apoptosis pathways and demonstrated strong target degradation (cellular inhibitor of apoptosis proteins-1 [cIAP-1]) and activation of caspases 3 and 8. Taken together, S2/IAPinh demonstrated efficacy in models of pancreatic and ovarian cancer, two challenging malignancies in need of novel treatment concepts. Our data support an in-depth investigation into utilizing S2/IAPinh for the treatment of cancer

Correspondence between otolith microstructual changes and early life history events in Anguilla marmorata leptocephali and glass eels

To determine the exact correspondence between otolith characteristics and early life history events such as metamorphosis, coastal migration and recruitment to estuaries, both otolith microstructure and microchemistry analyses were applied to a sequential developmental series of samples, e. g. leptocephali, a metamorphosing larva, oceanic glass eels, and coastal glass eels. Total length and age were 10.1-50.7 mm and 22-137 d in leptocephali, 46.3 mm and 147 d in a metamorphosing larva, 47.8, 48.6 mm and 159, 160 d in oceanic glass eels, and 47.9-54.8 mm and 119-168 d in coastal glass eels. Checks at hatching and first feeding were observed in all specimens, but metamorphosis and freshwater checks were observed only in some specimens. It was confirmed that the abrupt drop in otolith Sr : Ca ratios and drastic increases of otolith increment widths in the metamorphosing larval stage correspond to the onset of metamorphosis, and the decrease after the peaks suggested the completion of metamorphosis, because the metamorphosing larva had no decrease in incremental widths. The relatively conserved Sr : Ca ratios decreased sharply in synchrony with the increasing increment widths. This study provides the first direct evidence that these drastic changes in otolith microstructure and microchemistry actually occur during metamorphosis, which has been only hypothesized

Correspondence between otolith microstructual changes and early life history events in Anguilla marmorata leptocephali and glass eels

To determine the exact correspondence between otolith characteristics and early life history events such as metamorphosis, coastal migration and recruitment to estuaries, both otolith microstructure and microchemistry analyses were applied to a sequential developmental series of samples, e. g. leptocephali, a metamorphosing larva, oceanic glass eels, and coastal glass eels. Total length and age were 10.1-50.7 mm and 22-137 d in leptocephali, 46.3 mm and 147 d in a metamorphosing larva, 47.8, 48.6 mm and 159, 160 d in oceanic glass eels, and 47.9-54.8 mm and 119-168 d in coastal glass eels. Checks at hatching and first feeding were observed in all specimens, but metamorphosis and freshwater checks were observed only in some specimens. It was confirmed that the abrupt drop in otolith Sr : Ca ratios and drastic increases of otolith increment widths in the metamorphosing larval stage correspond to the onset of metamorphosis, and the decrease after the peaks suggested the completion of metamorphosis, because the metamorphosing larva had no decrease in incremental widths. The relatively conserved Sr : Ca ratios decreased sharply in synchrony with the increasing increment widths. This study provides the first direct evidence that these drastic changes in otolith microstructure and microchemistry actually occur during metamorphosis, which has been only hypothesized

A primary hepatic gastrinoma accompanied by hyperplasia of multi-nodular Brunner’s glands

Abstract Background Primary hepatic gastrinoma causing severe ulcerogenic syndrome is extremely rare. Herein, we report a case of primary hepatic gastrinoma accompanied by hyperplasia of multi-nodular Brunner’s glands in a patient who instead, preoperatively, was suspected of having multiple duodenal gastrinomas and hepatic metastasis. Case presentation A 57-year-old woman consulted a clinic complaining of melena, intermittent abdominal pain, diarrhea, and vomiting which had persisted for about 3 years. Six months before her presentation, she underwent segmental resection of the jejunum for acute peritonitis due to the spontaneous jejunal perforation. A blood test revealed that her serum immunoreactive gastrin (IRG) level was 12,037 pg/mL. Subsequently, she was transferred to our hospital. On computed tomography (CT), a hypervascular tumor of 23 mm in the segment 5 (S5) region of the liver was visualized. A selective arterial secretagogue injection test (SASI test) was performed twice. The first SASI test revealed that the hepatic tumor was a gastrinoma, and there was no gastrinoma in the duodeno-pancreatic region. Additionally, somatostatin receptor scintigraphy only visualized the tumor in the liver. However, the second SASI test, which was performed during the administration of a proton pump inhibitor and a somatostatin analog (octreotide acetate), revealed that there may have been gastrinomas existing not only in the liver but also in the upper part of the duodenum or the head of the pancreas. Duodenal endoscopy revealed multiple submucosal tumors in the first and the second portion of the duodenum, although a pathological examination of biopsied specimens obtained from the duodenal lesions was negative for malignant cells. Multiple endocrine neoplasia type 1 (MEN1) was excluded from her family history, and serum levels of both intact parathyroid hormone (iPTH) and calcium were within normal ranges. An anterior segmentectomy of the liver and pancreas-preserving total duodenectomy were performed on September 9, 2013. Postoperatively, her serum immunoreactive gastrin level decreased to less than 50 pg/mL. Pathological study of the resected specimens revealed a gastrinoma in the liver, but no gastrinoma in the duodenum. Interestingly, the duodenal submucosal tumor-like lesions were hyperplastic Brunner’s glands. Postoperatively, she has been well without recurrence of hypergastrinemia for 4 years. Conclusion We report a case of primary hepatic gastrinoma in a patient who has been cured for 4 years postoperatively. The diagnosis was somewhat difficult due to the coexisting, multiple hyperplastic Brunner’s glands of the duodenum mimicking the submucosal neuroendocrine tumors, which might have developed due to long-term hypergastrinemia

Correspondence between otolith microstructual changes and early life history events in Anguilla marmorata leptocephali and glass eels

To determine the exact correspondence between otolith characteristics and early life history events such as metamorphosis, coastal migration and recruitment to estuaries, both otolith microstructure and microchemistry analyses were applied to a sequential developmental series of samples, e. g. leptocephali, a metamorphosing larva, oceanic glass eels, and coastal glass eels. Total length and age were 10.1-50.7 mm and 22-137 d in leptocephali, 46.3 mm and 147 d in a metamorphosing larva, 47.8, 48.6 mm and 159, 160 d in oceanic glass eels, and 47.9-54.8 mm and 119-168 d in coastal glass eels. Checks at hatching and first feeding were observed in all specimens, but metamorphosis and freshwater checks were observed only in some specimens. It was confirmed that the abrupt drop in otolith Sr : Ca ratios and drastic increases of otolith increment widths in the metamorphosing larval stage correspond to the onset of metamorphosis, and the decrease after the peaks suggested the completion of metamorphosis, because the metamorphosing larva had no decrease in incremental widths. The relatively conserved Sr : Ca ratios decreased sharply in synchrony with the increasing increment widths. This study provides the first direct evidence that these drastic changes in otolith microstructure and microchemistry actually occur during metamorphosis, which has been only hypothesized