Anal metastasis from carcinoma of the lung: Report of a case

We report herein the case of a 75-year-old man who developed anal canal metastasis from squamous cell carcinoma of the lung. Initially, he underwent a right middle and lower lobectomy combined with left atrial wall resection under cardiopulmonary bypass. He presented 3 months later with an anal polyp which had prolapsed and bled, for which he underwent a transanal polypectomy. Histologically, the polyp was classified as squamous cell carcinoma and considered to be a metastasis from the primary lung cancer. He is presently well with no signs of recurrence 9 months after his initial operation. To our knowledge, there has been no other case of anal metastasis from lung cancer ever reported.     

Intraoperative packing of a pancreatic pseudocyst complicated with bleeding pseudoaneurysm

Hemosuccus pancreaticus (HP) is a rare cause of gastrointestinal bleeding, usually due to rupture of a visceral artery aneurysm in chronic pancreatitis. Other causes of HP are rare. We present a case of HP which occurred in a patient with chronic calcifying pancreatitis and a pancreatic pseudocyst documented by ultrasonography and computed tomography. With detectable fresh blood in the descending duodenum, an aneurysm in the pancreatic head was revealed by superior mesenteric angiography as the suspected origin of intermittent bleeding from the pancreatic duct. Because an artery feeding the pseudocyst could not be identified, angiographic embolization was not possible. Surgical resection or ligation was difficult by laparotomy; therefore, intraoperative packing of the pseudocyst with absorbable gelatin sponges was achieved via a cannula through a directly punctured site in the pseudocyst wall. The patient has been followed for 4.25 years with no further episodes of HP. It is possible that the packing of a pancreatic pseudocyst with gelatin sponges is a method that can be used in similar cases, where control of hemostasis is the primary concern. The packing of a pancreatic pseudocyst with gelatin sponges is a technique that can be performed not only via laparotomy but also via laparoscopy or concomitant angiography and ultrasonography.     

Idiopathic hypertrophic cranial pachymeningitis with perifocal brain edema--case report

A 51-year-old female presented with an extremely rare case of idiopathic hypertrophic cranial pachymeningitis manifesting as markedly thickened frontotemporal meninges with expanding perifocal edema. Magnetic resonance imaging with gadolinium revealed enhancement of the thickened dura mater protruding into the brain parenchyma accompanied by focal edema causing a mass effect. Histological examination of a biopsy specimen revealed thickened dura with infiltrating lymphocytes. Serological and immunological tests were normal. No inflammatory response or evidence of malignant tumors was observed. The patient was treated with predonisolone, resulting in marked improvement of the mass effect. High-dose steroid therapy appears to be effective for intracranial pachymeningitis associated with expanding perifocal brain edema.     

Streamlined human antibody generation and optimization by exploiting designed immunoglobulin loci in a B cell line

Monoclonal antibodies (mAbs) are widely utilized as therapeutic drugs for various diseases, such as cancer, autoimmune diseases, and infectious diseases. Using the avian-derived B cell line DT40, we previously developed an antibody display technology, namely, the ADLib system, which rapidly generates antigen-specific mAbs. Here, we report the development of a human version of the ADLib system and showcase the streamlined generation and optimization of functional human mAbs. Tailored libraries were first constructed by replacing endogenous immunoglobulin genes with designed human counterparts. From these libraries, clones producing full-length human IgGs against distinct antigens can be isolated, as exemplified by the selection of antagonistic mAbs. Taking advantage of avian biology, effective affinity maturation was achieved in a straightforward manner by seamless diversification of the parental clones into secondary libraries followed by single-cell sorting, quickly affording mAbs with improved affinities and functionalities. Collectively, we demonstrate that the human ADLib system could serve as an integrative platform with unique diversity for rapid de novo generation and optimization of therapeutic or diagnostic antibody leads. Furthermore, our results suggest that libraries can be constructed by introducing exogenous genes into DT40 cells, indicating that the ADLib system has the potential to be applied for the rapid and effective directed evolution and optimization of proteins in various fields beyond biomedicine.     

ClpB chaperone passively threads soluble denatured proteins through its central pore

ClpB disaggregase forms a ring‐shaped hexamer that threads substrate proteins through the central pore using energy from ATP. The ClpB protomer consists of an N‐terminal domain, a middle domain, and two AAA+ modules. These two AAA+ modules bind and hydrolyze ATP and construct the core of the hexameric ring. Here, we investigated the roles of the two AAA+ modules in substrate threading. BAP is an engineered ClpB that can bind ClpP proteolytic chamber; substrates threaded by BAP are degraded by ClpP. We combined BAP with conserved motif mutations in two AAA+ modules and measured the steady‐state rates of threading of soluble denatured proteins by these mutants over a range of substrate concentrations. By fitting the data to the Michaelis‐Menten equation, k_cat and K_m values were determined. We found that the kinetic parameters of the substrate threading correlate with the type of mutation introduced rather than the ATPase activity of the mutant. Moreover, some mutants having no or marginal ATPase activity could thread denatured proteins significantly. These results indicate that ClpB can passively thread soluble denatured proteins.     

cAMP-activated protein kinase-independent potentiation of insulin secretion by cAMP is impaired in SUR1 null islets

Whereas the loss of ATP-sensitive K(+) channel (K(ATP) channel) activity in human pancreatic beta-cells causes severe hypoglycemia in certain forms of hyperinsulinemic hypoglycemia, similar channel loss in sulfonylurea receptor-1 (SUR1) and Kir6.2 null mice yields a milder phenotype that is characterized by normoglycemia, unless the animals are stressed. While investigating potential compensatory mechanisms, we found that incretins, specifically glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), can increase the cAMP content of Sur1KO islets but do not potentiate glucose-stimulated insulin release. This impairment is secondary to a restriction in the ability of Sur1KO beta-cells to sense cAMP correctly. Potentiation does not appear to require cAMP-activated protein kinase (PKA) because H-89 (N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide) and KT5720, inhibitors of PKA, do not affect stimulation by GLP-1, GIP, or exendin-4 in wild-type islets, although they block phosphorylation of cAMP-response element-binding protein. The impaired incretin response in Sur1KO islets is specific; the stimulation of insulin release by other modulators, including mastoparan and activators of protein kinase C, is conserved. The results suggest that the defect responsible for the loss of cAMP-induced potentiation of insulin secretion is PKA independent. We hypothesize that a reduced release of insulin in response to incretins may contribute to the unexpected normoglycemic phenotype of Sur1KO mice versus the pronounced hypoglycemia seen in neonates with loss of K(ATP) channel activity.     

Expression of tissue factor is associated with clinical features and angiogenesis in prostate cancer

BACKGROUND: Tissue factor (TF), the main initiator of blood coagulation, is involved in cancer metastasis and progression. We examined the role of TF on prostate cancer. MATERIALS AND METHODS: Immunohistochemical analysis was performed using the anti-TF antibody. Intra-tumoral blood vessels were visualized by staining endothelial cells with CD34 antibody. We examined the expression of TF and the microvessel density (MVD) in 66 biopsy specimens of prostate cancer, in order to investigate the relationship between the expression of TF and the clinicopathology of prostate cancer. RESULTS: TF antigen was positive in 41 (62%) of the specimens. There were significant differences in TF expression according to the pretreatment prostate specific antigen (PSA) level (p = 0.0193) and bone metastasis (p = 0.0029). MVD was significantly related to bone metastasis (p = 0.0175). TF-positive carcinomas more frequently presented high MVD expressions (p = 0.017) than TF-negative tumors. CONCLUSION: These results suggest that increased angiogenesis associated with TF expression might cause the metastasis and progression of prostate cancer.