Characteristics of the magnetic resonance imaging findings of cervical gastric-type adenocarcinoma.

AIMS: This study identified the distinct magnetic resonance imaging findings of cervical gastric-type adenocarcinoma (GAS) that can help differentiate it from squamous cell carcinoma (SCC) and usual-type endocervical adenocarcinoma (UEA) and reveal the radiologic-pathologic correlation. MATERIALS AND METHODS: All consecutive patients with cervical GAS treated at our hospital from November 2009 to August 2021 were included. The SCC and UEA cases were considered controls. Tumor location, tumor shape, presence and size of cysts, presence of uterine fluid, and apparent diffusion coefficient (ADC) were evaluated. RESULTS: Overall, 18 GAS, 55 SCC, and 23 UEA cases were evaluated. The tumor was located in the entire cervix in 13/18 GAS cases, whereas it was predominantly located in the lower cervix in 38/55 SCC cases and 14/23 UEA cases. Most GAS cases exhibited a diffuse infiltration growth pattern (17/18), whereas most SCC and UEA cases exhibited a mass-forming pattern (39/55 and 20/23, respectively). Moreover, the percentages of cases presenting microcysts or macrocysts and undergoing uterine fluid collection were significantly higher in the GAS group (14/18 and 13/18) than in the SCC and UEA groups. ADC was significantly higher in the GAS group than in the SCC group (1.092 × 10-3 vs. 0.819 × 10-3 mm2/s). CONCLUSION: This study revealed that GAS is characterized by tumor presence in the entire cervix, infiltrative growth pattern, intrauterine fluid collection, and frequent microcyst or macrocyst formation. Moreover, ADC was significantly higher in the GAS group than in the SCC group.

A pleiotropy scan to discover new susceptibility loci for pancreatic ductal adenocarcinoma.

Pleiotropic variants (i.e., genetic polymorphisms influencing more than one phenotype) are often associated with cancer risk. A scan of pleiotropic variants was successfully conducted ten years ago in relation to pancreatic ductal adenocarcinoma susceptibility. However, in the last decade, genetic association studies performed on several human traits have greatly increased the number of known pleiotropic variants. Based on the hypothesis that variants already associated with a least one trait have a higher probability of association with other traits, 61,052 variants reported to be associated by at least one genome wide association study (GWAS) with at least one human trait were tested in the present study consisting of two phases (discovery and validation), comprising a total of 16,055 pancreatic ductal adenocarcinoma (PDAC) cases and 212,149 controls. The meta-analysis of the two phases showed two loci (10q21.1-rs4948550 (P=6.52×10-5) and 7q36.3-rs288762 (P=3.03×10-5) potentially associated with PDAC risk. 10q21.1-rs4948550 shows a high degree of pleiotropy and it is also associated with colorectal cancer risk while 7q36.3-rs288762 is situated 28,558 base pairs upstream of the Sonic Hedgehog (SHH) gene, which is involved in the cell differentiation process and PDAC etiopathogenesis. In conclusion, none of the single nucleotide polymorphisms (SNPs) showed a formally statistically significant association after correction for multiple testing. However, given their pleiotropic nature and association with various human traits including colorectal cancer, the two SNPs showing the best associations with PDAC risk merit further investigation through fine mapping and ad hoc functional studies.

Clinical Features of Cytotoxic Lesions of the Corpus Callosum Associated with Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND AND PURPOSE: Patients with SAH due to a ruptured intracranial aneurysm occasionally show reversible high-signal lesions in the splenium of the corpus callosum on DWI. These lesions are called cytotoxic lesions of the corpus callosum. This study retrospectively reviewed cases of aneurysmal SAH and investigated clinical features of cytotoxic lesions of the corpus callosum associated with SAH. MATERIALS AND METHODS: Participants comprised 259 patients with aneurysmal SAH who had undergone curative treatment at our hospital. We examined the following items related to cytotoxic lesions of the corpus callosum: occurrence rate, timing of appearance and disappearance of the lesions, lesion size, aneurysm location, severity of SAH, treatment method, clinical course, and outcome. RESULTS: Among the 259 cases, DWI detected cytotoxic lesions of the corpus callosum in 33 patients (12.7%). The mean periods from the onset of SAH to detection and disappearance of cytotoxic lesions of the corpus callosum were 6.3 days (range, 0-25 days) and 35.7 days (range, 9-78 days), respectively. Cytotoxic lesions of the corpus callosum were classified into 2 types: a small type localized in the splenium in 26 cases (78.9%) and a large type spread along the ventricle in 7 cases (21.2%). The severity of SAH, coiling, hydrocephalus, and poor mRS score at discharge were significantly higher in the group with cytotoxic lesions of the corpus callosum. However, multivariate analysis did not identify cytotoxic lesions of the corpus callosum as a risk factor for poor outcome. CONCLUSIONS: Cytotoxic lesions of the corpus callosum appear at a frequency of 12.7% in patients with aneurysmal SAH. Cytotoxic lesions of the corpus callosum associated with SAH take several days to appear and subsequently resolve within about a month. Cytotoxic lesions of the corpus callosum were likely to occur in patients with high-grade SAH but did not represent a predictor of poor outcome.

A20 targets caspase-8 and FADD to protect HTLV-I-infected cells.

Adult T-cell leukemia (ATL) arises from a human T-cell leukemia virus type I (HTLV-I)-infected cell and has few therapeutic options. Here, we have uncovered a previously unrecognized role for a ubiquitin-editing enzyme A20 in the survival of HTLV-I-infected cells. Unlike in lymphomas of the B-cell lineage, A20 is abundantly expressed in primary ATL cells without notable mutations. Depletion of A20 in HTLV-I-infected cells resulted in caspase activation, cell death induction and impaired tumorigenicity in mouse xenograft models. Mechanistically, A20 stably interacts with caspase-8 and Fas-associated via death domain (FADD) in HTLV-I-infected cells. Mutational studies revealed that A20 supports the growth of HTLV-I-infected cells independent of its catalytic functions and that the zinc-finger domains are required for the interaction with and regulation of caspases. These results indicate a pivotal role for A20 in the survival of HTLV-I-infected cells and implicate A20 as a potential therapeutic target in ATL.

Split-gate organic field-effect transistors for high-speed operation.

Split-gate organic field-effect transistors have been developed for high-speed operation. Owing to the combination of reduced contact resistance and minimized parasitic capacitance, the devices have fast switching characteristics. The cutoff frequencies for the vacuum-evaporated devices and the solution-processed devices are 20 and 10 MHz, respectively. A speed of 10 MHz is the fastest device reported so far among solution-processed organic transistors.

Mitochondrial DNA depletion and its correlation with TFAM, TFB1M, TFB2M and POLG in human diffusely infiltrating astrocytomas.

Mitochondrial DNA (mtDNA) alterations and their clinical and pathological implications have been analyzed in several human malignancies. A marked decrease in mtDNA copy number along with the increase in malignancy was observed in diffusely infiltrating astrocytomas (24 WHO grade II, 18 grade III, and 78 grade IV or GBM) compared to non-neoplastic brain tissues, being mostly depleted in GBM. Although high relative gene expression levels of mtDNA replication regulators (mitochondrial polymerase catalytic subunit (POLG), transcription factors A (TFAM), B1 (TFB1M) and B2 (TFB2M)) were detected, it cannot successfully revert the mtDNA depletion observed in our samples. On the other hand, a strong correlation among the expression levels of mitochondrial transcription factors corroborates with the TFAM role in the direct control of TFB1M and TFB2M during initiation of mtDNA replication. POLG expression was related to decreased mtDNA copy number, and its overexpression associated with TFAM expression levels also have an impact on long-term survival among GBM patients, interpreted as a potential predictive factor for better prognosis.

A human anti-CD40 monoclonal antibody, 4D11, for kidney transplantation in cynomolgus monkeys: induction and maintenance therapy.

Blockade of CD40-CD154 signaling pathway is an attractive strategy to induce potent immunosuppression and tolerance in organ transplantation. Due to its strong immunosuppressive effect shown in nonhuman primate experiments, anti-CD154 monoclonal antibodies (mAbs) have been tried in clinical settings, but it was interrupted by unexpected thromboembolic complications. Thus, inhibition of the counter molecule, CD40, has remained an alternative approach. In the previous preliminary study, we have shown that 4D11, a novel fully human anti-CD40 mAb, has a fairly potent immunosuppressive effect on kidney allograft in nonhuman primates. In this study, we aimed to confirm the efficacy and untoward events of the 2-week induction and 180-day maintenance 4D11 treatments. In both, 4D11 significantly suppressed T-cell-mediated alloimmune responses and prolonged allograft survival. Addition of weekly 4D11 administration after the induction treatment further enhanced graft survival. Complete inhibition of both donor-specific Ab and anti-4D11 Ab productions was obtained only with higher-dose maintenance therapy. No serious side effect including thromboembolic complications was noted except for a transient reduction of hematocrit in one animal, and decrease of peripheral B-cell counts in all. These results indicate that the 4D11 appears to be a promising candidate for immunosuppression in clinical organ transplantation.

Can ultrasonographic evaluation of subcutaneous fat predict pressure ulceration?

High-resolution ultrasound may be able to detect pressure ulcers before clinical signs emerge. This retrospective study found that one such early indicator is inflammatory oedema in the subcutaneous fat, which resolves as healing occurs.

Association of EGFR c.2073A>T polymorphism with decreased risk of diffusely infiltrating astrocytoma in a Brazilian case-control study.

Epidermal growth factor receptor (EGFR) gene overexpression has been implicated in the development of many types of tumors, including glioblastomas, the most frequent diffusely infiltrating astrocytomas. However, little is known about the influence of the polymorphisms of EGFR on EGFR production and/or activity, possibly modulating the susceptibility to astrocytomas. This study aimed to examine the association of two EGFR promoter polymorphisms (c.-191C>A and c.-216G>T) and the c.2073A>T polymorphism located in exon 16 with susceptibility to astrocytomas, EGFR gene expression and survival in a case-control study of 193 astrocytoma patients and 200 cancer-free controls. We found that the variant TT genotype of the EGFR c.2073A>T polymorphism was associated with a significantly decreased risk of astrocytoma when compared with the AA genotype [sex- and age-adjusted odds ratio 0.51, 95% confidence interval 0.26-0.98]. No association of the two promoter EGFR polymorphisms (or combinations of these polymorphisms) and risk of astrocytomas, EGFR expression or survival was found. Our findings suggest that modulation of the EGFR c.2073A>T polymorphism could play a role in future therapeutic approaches to astrocytoma.

Experimental nodel of C6 brain tumors in athymic rats.

Malignant brain tumor experimental models tend to employ cells that are immunologically compatible with the receptor animal. In this study, we have proposed an experimental model of encephalic tumor development by injecting C6 cells into athymic Rowett rats, aiming at reaching a model which more closely resembles to the human glioma tumor. In our model, we observed micro-infiltration of tumor cell clusters in the vicinity of the main tumor mass, and of more distal isolated tumor cells immersed in normal encephalic parenchyma. This degree of infiltration is superior to that usually observed in other C6 models.

Experimental nodel of C6 brain tumors in athymic rats / Modelo experimental de tumor cerebral C6 em ratos atímicos

Malignant brain tumor experimental models tend to employ cells that are immunologically compatible with the receptor animal. In this study, we have proposed an experimental model of encephalic tumor development by injecting C6 cells into athymic Rowett rats, aiming at reaching a model which more closely resembles to the human glioma tumor. In our model, we observed micro-infiltration of tumor cell clusters in the vicinity of the main tumor mass, and of more distal isolated tumor cells immersed in normal encephalic parenchyma. This degree of infiltration is superior to that usually observed in other C6 models.

Modelos experimentais de tumores cerebrais malignos geralmente utilizam células imunologicamente compatíveis com o animal receptor. Neste estudo apresentamos um modelo experimental baseado na inoculação de células C6 em ratos atímicos Rowett, visando obter um tumor que se assemelhe mais àqueles observados nos seres humanos. Neste modelo observamos microinfiltração de ilhotas de células na periferia da massa tumoral principal e nas áreas mais distantes, células tumorais isoladas no tecido cerebral normal. Este grau de infiltração é superior àquele observado em outros modelos utilizando as células C6.

Does the permanent portacaval shunt for a small-for-size graft in a living donor liver transplantation do more harm than good?

In order to obviate a small-for-size graft syndrome (SFSGS), a portacaval (PC) shunt had been considered in a case of adult-to-adult living donor liver transplantation (AA-LDLT). In a recent AA-LDLT case, we adopted the PC shunt to resolve SFSGS; however, graft atrophy was observed in the late period of LDLT, thereby resulting in liver dysfunction. Due to the surgical closure of the PC shunt at 11 months post-LDLT, the graft regenerated gradually and resulted in the recovery of the liver function. This experience indicates that the portacaval shunt would overcome SFSGS in the early period of LDLT, while it would cause the graft atrophy and the graft dysfunction in the late period of LDLT.

Association of TP53 mutation, p53 overexpression, and p53 codon 72 polymorphism with susceptibility to apoptosis in adult patients with diffuse astrocytomas.

Clarification of TP53 alterations is important to understand the mechanisms underlying the development of diffuse astrocytomas. It has been suggested that the alleles of TP53 at codon 72 differ in their ability to induce apoptosis in human cancers. The aim of this study was to analyze the possible association of TP53 mutation, p53 overexpression, and p53 codon 72 polymorphism with susceptibility to apoptosis in adult Brazilian patients with diffuse astrocytomas. We analyzed 56 surgical specimens of diffuse astrocytomas for alterations of TP53, using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) direct sequencing. p53 and cleaved caspase 3 protein expression were assessed by immunohistochemistry. We found TP53 mutations in 19.6% (11 out of 56) of tumors tested, with the lowest mutation rate found in the cases of glioblastomas (8.8%) (p = 0.03). Only 16.1% of tumors tested showed cleaved caspase 3-positive staining, demonstrating that apoptosis is very inhibited in these tumors. All tumors having TP53 mutation and p53 accumulation had no expression of cleaved caspase 3. Additionally, no association was observed in tumors having proline and arginine alleles and expression of cleaved caspase 3. We concluded that clarification of the TP53 alterations allows a better understanding of the mechanisms involved in the progression of diffuse astrocytomas, and the allele status at codon 72 was not associated with apoptosis in these tumors.

Diagnosis of acute brain-stem infarcts using diffusion-weighed MRI.

There are many reports on acute cerebral infarcts diagnosed by diffusion-weighted MRI (DWI), but few describe brain-stem infarcts diagnosed by this method. Using the apparent diffusion coefficient (ADC), we studied 18 consecutive patients with brain-stem infarcts who underwent DWI during the acute phase. We calculated and compared the ADC ratio (lesion ADC/contralateral ADC) in 10 patients with brain-stem and 23 with supratentorial cortical infarcts examined within 24 h of the onset of stroke. Ischaemic brain-stem lesions were detected in all 15 patients who underwent DWI more than 3 h after the onset, but not in two who had DWI within 3 h of the onset; their ADC ratio was more than 0.95. ADC ratios in patients with brain-stem infarcts decreased as the interval between onset and DWI increased; the decrease was slower than in patients with supratentorial cortical infarcts.

Long-term therapeutic effects of voglibose, a potent intestinal alpha-glucosidase inhibitor, in spontaneous diabetic GK rats.

The effect of long-term (6 months) administration of voglibose in a dietary mixture (10 ppm) on intestinal disaccharidase activity was examined in non obese type 2 diabetes model Goto-Kakizaki (GK) rats. The postprandial blood glucose level in voglibose-treated GK rats was significantly lower than in untreated GK rats (190+/-19 vs. 250+/-25 mg/dl, P<0.01; 1 h, 212+/-23 vs. 256+/-20, P<0.05; 2 h), and the activities of maltase, sucrase, and isomaltase remained significantly lower throughout the 6 months of voglibose treatment. The expressions of protein and mRNA of sucrase-isomaltase (SI) complex were significantly higher in voglibose-treated GK rats. Voglibose administration then was stopped after 6 months of treatment. The mRNA level and protein level of the SI complex became normalized during the interruption of drug administration, and disaccharidase activities increased almost to the level of the untreated group 1 month after treatment was stopped. After 1 day of re-administration of the drug, however, disaccharidase activities again became significantly inhibited. These results indicate that voglibose may improve glucose tolerance since it inhibits activities of disaccharidases in spite of increasing the expression of them on intestine, furthermore voglibose may be reversible and reproducible through interruption and re-administration.

Raised plasma oxidised LDL in acute cerebral infarction.

BACKGROUND: The association between oxidised low density lipoprotein (OxLDL) and cerebral infarction is suspected but not established. OBJECTIVES: To determine whether plasma OxLDL is a useful marker for monitoring oxidative stress in stroke patients. METHODS: Plasma OxLDL concentrations were determined in 56 stroke patients with cerebral infarction (n = 45) or cerebral haemorrhage (n = 11), and in 19 age matched controls, using a novel sandwich enzyme linked immunosorbent assay. RESULTS: Compared with the controls (0.130 (0.007) ng/ micro g LDL, mean (SEM)), OxLDL was significantly raised in patients with cerebral infarction (0.245 (0.022); p < 0.0001) but not in those with haemorrhage (0.179 (0.023)). Patients with cortical ischaemic infarcts (n = 22) had higher OxLDL levels than either the controls (p < 0.0001) or the patients with non-cortical ischaemic infarcts (n = 23) (p < 0.001). Increased OxLDL concentrations in patients with cortical infarcts persisted until the third day after stroke onset. The National Institutes of Health stroke scales in patients with cortical infarction were higher than in those with non-cortical infarction (p < 0.01). CONCLUSIONS: There is a significant association between raised plasma OxLDL and acute cerebral infarction, especially cortical infarction. Plasma OxLDL may reflect oxidative stress in stroke patients.

A characteristic feature of acute haematomas in the brain on echo-planar diffusion-weighted imaging.

Diffusion-weighted MRI (DWI) is used in the diagnosis of acute ischaemic disease of the brain, but it is not clear whether or not it can be used to differentiate an acute haematoma from an infarct. Our purpose was to identify any characteristic feature of acute haematomas which can be recognised on DWI and to evaluate the usefulness of DWI in acute cerebral stroke. We examined nine patients with acute haemorrhage using CT and MRI including DWI. We measured the volume and apparent diffusion coefficient (ADC) of the haematomas. All showed heterogeneous signal on DWI, and the centre of the large (>20 ml) haematomas especially a mixed pattern with high and low signal. The characteristic feature of acute haematomas was a peripheral low-signal region, found in all subjects regardless of the size of the haematoma; acute infarcts did not show this. This low-signal rim on DWI may be useful for differentiating an acute haematoma from an infarct.

Anti-HER2-antibody enhances irradiation-induced growth inhibition in head and neck carcinoma.

To explore the antiproliferative effects of rhumAbHER2 on head and neck squamous carcinoma cell (HNSCC) lines and breast cancer cell lines (BCCLs) and to evaluate the combined effects with irradiation, 2 human HNSCC lines and 2 BCCLs were exposed to rhumAbHER2 with or without irradiation. The results showed that combined treatment enhanced the growth and colonization inhibitory effects of rhumAbHER2 or irradiation. Interestingly, the apoptotic cell fraction produced by irradiation disappeared on combined treatment. This disappearance was associated with repression of p53 and Bax upregulation induced by irradiation, but conservation of the upregulation of p27. Based on these results, rhumAbHER2 and irradiation may be a new strategy for treating HNSCC and breast cancers. In addition, the upregulation of cyclin-dependent kinase inhibitors by rhumAbHER2 may occur upstream of irradiation-induced p53 upregulation.