GET4 is a novel driver gene in colorectal cancer that regulates the localization of BAG6, a nucleocytoplasmic shuttling protein

Colorectal cancer (CRC) is one of the most common types of cancer and a significant cause of cancer mortality worldwide. Further improvements of CRC therapeutic approaches are needed. BCL2‐associated athanogene 6 (BAG6), a multifunctional scaffold protein, plays an important role in tumor progression. However, regulation of BAG6 in malignancies remains unclear. This study showed that guided entry of tail‐anchored proteins factor 4 (GET4), a component of the BAG6 complex, regulates the intercellular localization of BAG6 in CRC. Furthermore, GET4 was identified as a candidate driver gene on the short arm of chromosome 7, which is often amplified in CRC, by our bioinformatics approach using the CRC dataset from The Cancer Genome Atlas. Clinicopathologic and prognostic analyses using CRC datasets showed that GET4 was overexpressed in tumor cells due to an increased DNA copy number. High GET4 expression was an independent poor prognostic factor in CRC, whereas BAG6 was mainly overexpressed in the cytoplasm of tumor cells without gene alteration. The biological significance of GET4 was examined using GET4 KO CRC cells generated with CRISPR‐Cas9 technology or transfected CRC cells. In vitro and in vivo analyses showed that GET4 promoted tumor growth. It appears to facilitate cell cycle progression by cytoplasmic enrichment of BAG6‐mediated p53 acetylation followed by reduced p21 expression. In conclusion, we showed that GET4 is a novel driver gene and a prognostic biomarker that promotes CRC progression by inducing the cytoplasmic transport of BAG6. GET4 could be a promising therapeutic molecular target in CRC.     

Anterior cingulate pathology and social cognition in schizophrenia: a study of gray matter, white matter and sulcal morphometry

The anterior cingulate gyrus (ACG) is a critical structure for social cognitive processing; the pathology of this structure might be a major source of social dysfunction in schizophrenia. Multiple structural abnormalities of the ACG have been demonstrated in schizophrenia including changes in gray matter volume, white matter microstructures and macroscopic sulcal morphology. However, the interrelationships among these different abnormalities have not been investigated. Thus, the relationship between structural abnormalities in the ACG and social cognition in schizophrenia remains to be elucidated. Magnetic resonance imaging data were acquired at 3.0 T from 26 schizophrenic patients and 20 healthy participants. We performed anterior cingulate cortex (ACC) volumetry, evaluated diffusion tensor imaging of the anterior cingulum, analyzed paracingulate/cingulate sulcus (PCS/CS) morphology and investigated the interrelationships among these measures. We also investigated the association between ACG structural abnormalities and psychopathology, and the social cognition ability of schizophrenic patients as estimated by emotion attribution tasks. Compared with healthy subjects, schizophrenic patients exhibited reduced ACC volume, decreased fractional anisotropy in the anterior cingulum bilaterally and a poorly developed PCS/CS in the left hemisphere. No interrelationship was identified among these measures in the schizophrenic group. Schizophrenic patients performed poorly on emotion attribution tasks. Importantly, clinical symptoms and performance on emotion attribution subtasks were associated with ACC volumes and left PCS/CS variation in different ways. These results suggested that pathology of the ACC, anterior cingulum and PCS/CS is, at least partially, independent and has differential impacts on psychopathology and social cognitive impairment in schizophrenia.     

Pathogenesis of idiopathic scoliosis. Experimental study in rats.

STUDY DESIGN: A radiographic examination of pinealectomized rats to observe the development of scoliosis and halt the condition by administration of melatonin. OBJECTIVES: To discover whether pinealectomy has the same effect in mammals as shown in the chicken, and to determine whether the bipedal condition is important for development of scoliosis. SUMMARY OF BACKGROUND DATA: Pinealectomizing chickens shortly after hatching consistently resulted in scoliosis closely resembling human idiopathic scoliosis. It has not been determined whether this phenomenon is restricted solely to chickens, or if this experimental model is applicable to other animals, especially those more closely related to humans. METHODS: A sham operation in five bipedal rats served as the control in this study. Pinealectomy was performed in 10 quadrupedal rats, pinealectomy in 20 bipedal rats, and pinealectomy with implantation of melatonin pellet in 10 bipedal rats. Spinal radiographs were used to measure the degree of scoliosis at 3 months after surgery. RESULTS: Scoliosis developed only in pinealectomized bipedal rats and not in quadrupedal rats. It developed in none of the sham operation group and in only 1 of 10 pinealectomized bipedal rats with melatonin treatment. CONCLUSIONS: Melatonin deficiency secondary to pinealectomy alone does not produce scoliosis if the quadrupedal condition is maintained. The bipedal condition, such as that in chickens or humans, plays an important role in the development of scoliosis. The findings suggest a critical influence of a postural mechanism for the development of scoliosis.     

Percutaneous stenting for malignant biliary stenosis

Summary Percutaneous stenting for malignant biliary stenosis is quite beneficial to patients with unresectable or recurrent disease, tremendously improving the quality of their lives. Percutaneous transhepatic biliary drainage (PTBD) was attempted in 92 patients with obstructive jaundice during the period between January 1986 and July 1989. Implantation of an endoprosthesis was performed in 14 cases (15.2%) and succeeded in 12 (85.7%). When a guide wire could not be passed distally across the stricture site, percutaneous transhepatic cholangioscopy (PTCS) through the dilated PTBD fistula was carried out to enable its passage. PTCS is also valuable in the preoperative diagnosis of obstructive jaundice. The patients who are not candidates for surgery are suitable for this procedure. A Miller double-mushroom stent is used as the endoprosthesis in the majority of cases. One patient with recurrent hepatoma has lived at home with this stent for >3 years due to repeated transarterial embolization and chemotherapy and does not need to wash or change the stent.     

Development of intrahepatic biliary stones after excision of choledochal cysts

Background: The incidence of intrahepatic cholelithiasis and cholangitis has not yet been well studied postoperatively in patients with choledochal cysts. Methods: One hundred three patients with choledochal cysts had operative cholangiography, underwent standard excision of a choledochal cyst with Roux-en-Y hepatico-jejunal anastomosis, and were at a mean follow-up of 12[frac12] years. The incidence of intrahepatic bile duct stones was analyzed according to the 3 morphologic types of intrahepatic bile duct observed at initial operative cholangiography: type 1, no dilatation of the intrahepatic bile ducts; type 2, dilatation of the intrahepatic bile ducts but without any downstream stenosis; and type 3, dilatation of the intrahepatic bile ducts associated with downstream stenosis. Initially, there was no evidence of intrahepatic bile duct stones in any of the 103 patients. Results: Among 50 type 1 patients, intrahepatic cholelithiasis developed in only 1 patient (2%). Among 43 type 2 patients, 1 patient (2%) had intrahepatic cholelithiasis, and 2 (5%) had postoperative cholangitis. Among 10 type 3 patients, 4 (40%) had intrahepatic cholelithiasis (P [lt ] .01), and 3 (30%) had postoperative cholangitis. Time intervals between the initial surgery and the first identification of intrahepatic stones ranged from 3 to 22 years. Conclusions: One of the major causes of formation of intrahepatic cholelithiasis has been clarified; patients with intrahepatic biliary dilatation with downstream stenosis can get intrahepatic bile duct stones long after excision of a choledochal cyst.     

Bortezomib induces thrombocytopenia by the inhibition of proplatelet formation of megakaryocytes

Bortezomib is a potent proteasome inhibitor that has been extensively used to treat multiple myeloma. One of the most common grade 3 adverse events is cyclic thrombocytopenia. In this study, we studied the mechanism by which bortezomib induces thrombocytopenia in a mouse model. After the intravenous administration of bortezomib (2.5 mg/kg) via tail vein, platelet counts significantly decreased on days 2–4 and recovered to the normal range on day 6. Bortezomib (2.5 mg/kg) injected into mice in vivo did not affect colony‐forming unit‐megakaryocytes (CFU‐Mk) or megakaryocytes in the bone marrow. However, proplatelet formation (PPF) significantly decreased on days 2 and 4, after bortezomib administration to mice. Meanwhile, CFU‐Mk formation and the ploidy distribution of cultured megakaryocytes in vitro were not affected by bortezomib used at concentrations of ≤1 ng/mL. The PPF of megakaryocytes in vitro significantly decreased with 0.1, 1, 10, and 100 ng/mL bortezomib. Considering the bortezomib concentration in clinical studies, these data strongly suggest that decreased PPF activity induces thrombocytopenia. To elucidate the mechanism behind decreased PPF, Western blot was performed. Activated Rho expression increased after the incubation of murine platelets with bortezomib. Decreased PPF activity was eliminated by the addition of Y27632, a Rho kinase inhibitor, in vitro. Given that the Rho/Rho kinase pathway is a negative regulator of PPF, bortezomib increases activated Rho, inducing decreased PPF, which results in decreased platelet count.     

A study on auditory disturbances after microvascular decompression for hemifacial spasm

After establishing an operation of microvascular decompression by Jannetta in 1975, an improvement rate of hemifacial spasm have increased. However, postoperative hearing deficits, equilibrium disturbances and facial paresis have been described in some publications. Fifty-seven of 119 patients with hemifacial spasm operated from 1982 to 1989, were examined by audiometry before and after operation. In patients with tinnitus at the time of facial spasm and closing eyelids, tinnitus improved almost in many cases. Of 57 patients, 8 (5 with sensorineural hearing loss, 3 with conductive hearing loss) had postoperative hearing impairments in operated ears, and 7 (7 with sensorineural hearing loss) had in the other ears, too. Of 7 patients having sensorineural hearing loss observed for several months, 4 having slight sensorineural hearing loss recovered at the same hearing level before operation. In 2 patients having profound sensorineural hearing loss, however, hearing improvement did not observed in each case.     

The Endotoxin 10,000 Reference Standard of the National Institute of Health Sciences (the Japanese Pharmacopoeia Endotoxin 10,000 Reference Standard) (Control 0001)

To establish the fourth lot (Control 0001) of the Endotoxin 10,000 Reference Standard of the National Institute of Health Sciences (the Japanese Pharmacopoeia Endotoxin 10,000 Reference Standard), a candidate standard (CS) was prepared and then evaluated. The potency of the CS was assayed against USP Endotoxin Reference Standard (Lot G-1) and defined as containing approximately 20,000 endotoxin units (EU) per vial by a collaborative study in which 5 laboratories participated. Based on the results, the CS was authorized to be the fourth lot of the Endotoxin 10,000 Reference Standard containing 20,000 EU per vial.