Impact of deep learning on radiologists and radiology residents in detecting breast cancer on CT: a cross-vendor test study.

AIM: To investigate the effect of deep learning on the diagnostic performance of radiologists and radiology residents in detecting breast cancers on computed tomography (CT). MATERIALS AND METHODS: In this retrospective study, patients undergoing contrast-enhanced chest CT between January 2010 and December 2020 using equipment from two vendors were included. Patients with confirmed breast cancer were categorised as the training (n=201) and validation (n=26) group and the testing group (n=30) using processed CT images from either vendor. The trained deep-learning model was applied to test group patients with (30 females; mean age = 59.2 ± 15.8 years) and without (19 males, 21 females; mean age = 64 ± 15.9 years) breast cancer. Image-based diagnostic performance of the deep-learning model was evaluated with the area under the receiver operating characteristic curve (AUC). Two radiologists and three radiology residents were asked to detect malignant lesions by recording a four-point diagnostic confidence score before and after referring to the result from the deep-learning model, and their diagnostic performance was evaluated using jackknife alternative free-response receiver operating characteristic analysis by calculating the figure of merit (FOM). RESULTS: The AUCs of the trained deep-learning model on the validation and test data were 0.976 and 0.967, respectively. After referencing with the result of the deep learning model, the FOMs of readers significantly improved (reader 1/2/3/4/5: from 0.933/0.962/0.883/0.944/0.867 to 0.958/0.968/0.917/0.947/0.900; p=0.038). CONCLUSION: Deep learning can help radiologists and radiology residents detect breast cancer on CT.

CT findings in 11 patients with TAFRO syndrome: a variant of multicentric Castleman's disease.

AIM: To assess detailed computed tomography (CT) findings in patients with the recently described thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) syndrome, in order to contribute to imaging interpretation in the challenging diagnosis of this disease. MATERIALS AND METHODS: The institutional review board approved this retrospective study and waived the need for informed consent. Eleven patients (six men, five women; mean age, 52.5 years) with confirmed TAFRO syndrome were included in this study. Chest-to-pelvis CT images were analysed for the presence of anasarca, organomegaly, bone lesions, and lung lesions. RESULTS: Anasarca was present in all patients and involved multiple cavities and tissues; pleural effusion and ascites were found in 100% of patients; pericardial effusion in 64%; periportal collar in 91%; gallbladder wall oedema in 78%; subcutaneous oedema in 91%; retroperitoneal oedema in 100%; and mesenteric oedema in 100%. Organomegaly involved multiple organs: hepatomegaly in 73%, splenomegaly in 82%, lymphadenopathy in 100%, and enlarged anterior mediastinum in 64% (solitary, well-circumscribed mass, 0%; infiltrative mass, 0%; non-mass-forming infiltrative lesion, 64%). Bone lesions were present in 91% patients and all bone lesions had ground-glass density with diffuse distribution. None of the patients had any lesions in their lungs. CONCLUSION: The present study revealed that the findings of anasarca, organomegaly, and diffuse bony ground-glass appearance were observed in detail on CT in patients with TAFRO syndrome. A "matted" appearance of the enlarged anterior mediastinum is the characteristic CT finding of TAFRO syndrome, and it is possible to diagnose TAFRO syndrome from the combination of several CT findings.

Optimisation of Radiation Therapy in Bladder Preservation Therapy for Patients With Clinical Stage T2N0M0 Bladder Cancer.

AIMS: A novel bladder preservation therapy, the OMC (Osaka Medical College) regimen, which combines radiation therapy with balloon-occluded arterial infusion of anticancer agents, is a treatment option for patients with muscle-invasive bladder cancer (MIBC). We retrospectively analysed the effects of changes in radiation dose and irradiation field on treatment efficacy and adverse events.The purpose of this study is to use the results of this study to help determine a course of radiation therapy for bladder preservation therapy of cT2N0M0 MIBC. MATERIALS AND METHODS: We examined 352 patients with clinical stage T2N0M0 (cT2N0M0) MIBC classified into the following groups based on the irradiation method: group A, the whole pelvis (50 Gy/25 fractions) + local bladder (10 Gy/5 fractions); group B, the small pelvis (50 Gy/25 fractions) + local bladder (10 Gy/5 fractions); group C, the whole pelvis (40 Gy/20 fractions) + local bladder (10 Gy/5 fractions). RESULTS: The complete response rate, 3-year overall survival and progression-free survival rates in group A were 92.9%, 94.9% and 82.1%, respectively; in group B were 87.2%, 86.7% and 76.7%, respectively; and in group C were 95.2%, 92.6% and 71.1%, respectively. No significant differences between the groups were noted. The incidence of ≥grade 3 urinary tract and gastrointestinal toxicities were not significantly different among the groups (group A: 7.8%, 1.7%; B, 11.1%, 0%; C, 7.1%, 1.8%, respectively). The 3-year progression-free rates of the common iliac lymph node (CILN) region in patients who received whole-pelvis and small-pelvis irradiation were 99.0 and 89.0% (P < 0.01), respectively, with the latter group having significantly high lymph node recurrence in the CILN region. CONCLUSIONS: Our findings showed that the optimal radiation therapy for patients with cT2N0M0 MIBC undergoing the OMC regimen is whole-pelvis irradiation including the CILN region, with a total dose of 50 Gy/25 fractions.

Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes.

AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) has various extra-pancreatic actions, in addition to its enhancement of insulin secretion from pancreatic beta cells. The GLP-1 receptor is produced in kidney tissue. However, the direct effect of GLP-1 on diabetic nephropathy remains unclear. Here we demonstrate that a GLP-1 receptor agonist, exendin-4, exerts renoprotective effects through its anti-inflammatory action via the GLP-1 receptor without lowering blood glucose. METHODS: We administered exendin-4 at 10 µg/kg body weight daily for 8 weeks to a streptozotocin-induced rat model of type 1 diabetes and evaluated their urinary albumin excretion, metabolic data, histology and morphometry. We also examined the direct effects of exendin-4 on glomerular endothelial cells and macrophages in vitro. RESULTS: Exendin-4 ameliorated albuminuria, glomerular hyperfiltration, glomerular hypertrophy and mesangial matrix expansion in the diabetic rats without changing blood pressure or body weight. Exendin-4 also prevented macrophage infiltration, and decreased protein levels of intercellular adhesion molecule-1 (ICAM-1) and type IV collagen, as well as decreasing oxidative stress and nuclear factor-κB activation in kidney tissue. In addition, we found that the GLP-1 receptor was produced on monocytes/macrophages and glomerular endothelial cells. We demonstrated that in vitro exendin-4 acted directly on the GLP-1 receptor, and attenuated release of pro-inflammatory cytokines from macrophages and ICAM-1 production on glomerular endothelial cells. CONCLUSIONS/INTERPRETATION: These results indicate that GLP-1 receptor agonists may prevent disease progression in the early stage of diabetic nephropathy through direct effects on the GLP-1 receptor in kidney tissue.

Nicastrin binds to membrane-tethered Notch.

The presenilins and nicastrin, a type 1 transmembrane glycoprotein, form high molecular weight complexes that are involved in cleaving the beta-amyloid precursor protein (betaAPP) and Notch in their transmembrane domains. The former process (termed gamma-secretase cleavage) generates amyloid beta-peptide (Abeta), which is involved in the pathogenesis of Alzheimer's disease. The latter process (termed S3-site cleavage) generates Notch intracellular domain (NICD), which is involved in intercellular signalling. Nicastrin binds both full-length betaAPP and the substrates of gamma-secretase (C99- and C83-betaAPP fragments), and modulates the activity of gamma-secretase. Although absence of the Caenorhabditis elegans nicastrin homologue (aph-2) is known to cause an embryonic-lethal glp-1 phenotype, the role of nicastrin in this process has not been explored. Here we report that nicastrin binds to membrane-tethered forms of Notch (substrates for S3-site cleavage of Notch), and that, although mutations in the conserved 312-369 domain of nicastrin strongly modulate gamma-secretase, they only weakly modulate the S3-site cleavage of Notch. Thus, nicastrin has a similar role in processing Notch and betaAPP, but the 312-369 domain may have differential effects on these activities. In addition, we report that the Notch and betaAPP pathways do not significantly compete with each other.

Stimulation of neuronal neurite outgrowth using functionalized carbon nanotubes.

Low concentrations (0.11-1.7 microg ml(-1)) of functionalized carbon nanotubes (CNTs), which are multi-walled CNTs modified by amino groups, when added with nerve growth factor (NGF), promoted outgrowth of neuronal neurites in dorsal root ganglion (DRG) neurons and rat pheochromocytoma cell line PC12h cells in culture media. The quantity of active extracellular signal-regulated kinase (ERK) was higher after the addition of both 0.85 microg ml(-1) CNTs and NGF than that with NGF alone. CNTs increased the number of cells with neurite outgrowth in DRG neurons and PC12h cells after the inhibition of the ERK signaling pathway using a mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) inhibitor. Active ERK proteins were detected in MEK inhibitor-treated neurons after the addition of CNTs to the culture medium. These results demonstrate that CNTs may stimulate neurite outgrowth by activation of the ERK signaling pathway. Thus, CNTs are biocompatible and are promising candidates for biological applications and devices.

Impact of blood storage duration on hematologic, blood gas, biochemical, and oxidative stress variables in sheep undergoing allogeneic blood transfusions.

BACKGROUND: Hemotherapy in ruminants is limited to whole blood transfusions, sometimes with stored blood for up to 42 days, but little attention has been given to the effect of blood storage times and recipient responses after transfusions. OBJECTIVES: We aimed to evaluate the hematologic and serum biochemical effects after allogeneic blood transfusion with either fresh or stored blood in sheep. We also sought to examine hematologic and biochemical analyte changes in the store blood. METHODS: Eighteen sheep underwent a single phlebotomy to remove 40% of their blood volume. The sheep were divided into three experimental groups, G0, G15, and G35, which included six animals, each receiving 20 mL/kg of either fresh blood or blood stored in citrate, phosphate, dextrose, and adenine (CPDA-1) bags for 15 and 35 days, respectively. Biochemical, hematologic, coagulation, blood gas, lipid peroxidation, and oxidative stress test evaluations were performed using the blood samples gathered at T0 (before transfusion), 30 minutes (T30m), 6, 12, 24, 48, 72, and 96 hours (T6h-T96h), 8 days (T8d), and 16 days (T16d) after transfusions. RESULTS: Sheep exhibited increases in packed cell volumes, red blood cell counts, and total hemoglobin concentrations at T30m (P < .05). G35 animals had greater plasma hemoglobin concentrations at T12h and decreased blood pH values at T6h, characterized by slight metabolic acidemia. Regarding oxidative stress, G35 animals had decreased catalase activities from T0 at T30m, T6h, T12h, and T24h, indicating that hemolysis had occurred, which was supported by concomitant increases in bilirubin. CONCLUSIONS: Sheep transfused with 35-day stored blood exhibited greater hematologic, blood gas, biochemical, and oxidative alterations; however, anemic animals without comorbidities effectively reversed those alterations.

Microtubule-organizing centers abnormal in number, structure, and nucleating activity in x-irradiated mammalian cells.

Microtubule-organizing centers (MTOCs) in x-irradiated cells were visualized by immunofluorescence using antibody against tubulin. From two to ten reassembly sites of microtubules appeared after microtubule depolymerization at low temperature in an irradiated mitotic cell, in contrast to nonirradiated mitotic cells, which predominantly show 2 MTOCs. A time-course examination of MTOCs in synchronously cultured cells revealed that the multiple MTOCs appeared not immediately after irradiation but at the time of mitosis. Those multiple MTOCs formed at mitosis were inherited by the daughter cells in the next generation. The structure and capacity of the centrosomes to nucleate microtubules in vitro were then examined by electron microscopy of whole-mount preparations as well as by dark-field microscopy. About 70-80% of the centrosomes derived from nonirradiated cells were composed of a pair of centrioles and pericentriolar material, which initiated greater than 100 microtubules. The fraction of fully active complete centrosomes decreased with time of incubation after irradiation. These were replaced by disintegrated centrosomal components such as dissociated centrioles and pericentriolar cloud, a nucleating site with a single centriole, or only an amorphous structure of pericentriolar cloud. Assembly of less than 20 microtubules onto the amorphous cloud without centrioles was seen in 54% of the initiating sites in mitotic cells 2 d after irradiation. These results suggest that x-irradiation causes disintegration of centrosomes at mitosis when the structural and functional reorganization of centrosomes is believed to occur.

Effect upon mitogenic stimulation of calcium-dependent phosphorylation of cytoskeleton-associated 350,000- and 80,000-mol-wt polypeptides in quiescent 3Y1 cells.

Rabbit antiserum raised against highest molecular weight microtubule-associated protein (MAP-1) of brain immunoprecipitated 350,000-, 300,000-, and 80,000-mol-wt phosphoproteins of rat embryo fibroblasts (3Y1-B). The 350,000-mol-wt protein was sensitive to heat as was brain MAP-1, but the 300,000- and 80,000-mol-wt proteins were not. These polypeptides were hardly phosphorylated in cells in the quiescent G0 phase but were rapidly phosphorylated after addition of serum, epidermal growth factor, phorbol ester, insulin, or transferrin in the presence of calcium ions. All these agents also induced incorporation of [3H]-thymidine into DNA. These polypeptides were detected in isolated microtubules and cold-resistant filaments by immunoblotting. Since the 350,000-mol-wt polypeptide was detected in the membrane, the cytoskeletons, and the nucleus, and has been suggested to function as a linker, its rapid phosphorylation might represent an early process in transduction of the signal of mitogenic stimulation to the nucleus.

Molecular identification of a eukaryotic, stretch-activated nonselective cation channel.

Calcium-permeable, stretch-activated nonselective cation (SA Cat) channels mediate cellular responses to mechanical stimuli. However, genes encoding such channels have not been identified in eukaryotes. The yeast MID1 gene product (Mid1) is required for calcium influx in the yeast Saccharomyces cerevisiae. Functional expression of Mid1 in Chinese hamster ovary cells conferred sensitivity to mechanical stress that resulted in increases in both calcium conductance and the concentration of cytosolic free calcium. These increases were dependent on the presence of extracellular calcium and were reduced by gadolinium, a blocker of SA Cat channels. Single-channel analyses with cell-attached patches revealed that Mid1 acts as a calcium-permeable, cation-selective stretch-activated channel with a conductance of 32 picosiemens at 150 millimolar cesium chloride in the pipette. Thus, Mid1 appears to be a eukaryotic, SA Cat channel.

Estimation of the absorption coefficients of two-layered media by a simple method using spatially and time-resolved reflectances.

Our newly developed method using spatially and time-resolved reflectances can easily estimate the absorption coefficients of each layer in a two-layered medium if the thickness of the upper layer and the reduced scattering coefficients of the two layers are known a priori. We experimentally validated this method using phantoms and examined its possibility of estimating the absorption coefficients of the tissues in human heads. In the case of a homogeneous plastic phantom (polyacetal block), the absorption coefficient estimated by our method agreed well with that obtained by a conventional method. Also, in the case of two-layered phantoms, our method successfully estimated the absorption coefficients of the two layers. Furthermore, the absorption coefficients of the extracerebral and cerebral tissue inside human foreheads were estimated under the assumption that the human heads were two-layered media. It was found that the absorption coefficients of the cerebral tissues were larger than those of the extracerebral tissues.

Comparison of full-length sequences of interferon-sensitive and resistant hepatitis C virus 1b. Sensitivity to interferon is conferred by amino acid substitutions in the NS5A region.

We have previously demonstrated that sensitivity to interferon is different among hepatitis C virus (HCV) quasispecies simultaneously detected in same individuals and that interferon-resistant HCV quasispecies are selected during the treatment. To determine the genetic basis of their resistance to interferon, HCV genotype-1b was obtained from serum of three patients before and during interferon therapy, and their full-length nucleotide and deduced amino acid sequences were determined. Comparison of the pairs of interferon-resistant and interferon-sensitive HCV isolates in respective individuals demonstrated clusters of amino acid differences in the COOH-terminal half of the NS5A region (codon 2154-2383), which contained a common unique amino acid difference at codon 2218. Additional sequence data of the COOH-terminal half of the NS5A region obtained from six interferon-resistant and nine interferon-sensitive HCV confirmed the exclusive existence of missense mutations in a 40 amino acid stretch of the NS5A region around codon 2218 (from codon 2209 to 2248) in interferon-sensitive HCV. On the other hand, this region of interferon-resistant HCV was identical to that of prototype HCV genotype-1b (HCV-J, HCV-JTa, or HC-J4). We designated this region as the interferon sensitivity determining region. Thus, HCV genotype-1b with the prototype interferon sensitivity determining region appears to be interferon-resistant strains. The specific nature of these mutations might make it possible to predict prognostic effects of interferon treatment.

Resistance to oncogenic transformation in revertant R1 of human ras-transformed NIH 3T3 cells.

A flat revertant, R1, was isolated from human activated c-Ha-ras-1 (hu-ac-Ha-ras) gene-transformed NIH 3T3 cells (EJ-NIH 3T3) treated with mutagens. R1 contained unchanged transfected hu-ac-Ha-ras DNA and expressed high levels of hu-ac-Ha-ras-specific mRNA and p21 protein. Transfection experiments revealed that NIH 3T3 cells could be transformed by DNA from R1 cells but R1 cells could not be retransformed by Kirsten sarcoma virus, DNA from EJ-NIH 3T3 cells, hu-ac-Ha-ras, v-src, v-mos, simian virus 40 large T antigen, or polyomavirus middle T antigen. Somatic cell hybridization studies showed that R1 was not retransformed by fusion with NIH 3T3 cells and suppressed anchorage independence of EJ-NIH 3T3 and hu-ac-Ha-ras gene-transformed rat W31 cells in soft agar. These results suggest that the reversion and resistance to several oncogenes in R1 is due not to cellular defects in the production of the transformed phenotype but rather to enhancement of cellular mechanisms that suppress oncogenic transformation.

Releasing Mechanism of Neurotrophic Factors via Polysialic Acid.

Neurotrophins are well-characterized neurologically active molecules in the central nervous system. The regulation of these signaling molecules, which are involved in cell growth, differentiation, and survival, is critical for normal brain function. Among the different types of neurotrophins, brain-derived neurotrophic factor (BDNF) is involved in various brain functions, including memory consolidation, synaptic plasticity, and adult neurogenesis, and is therefore a key molecule for understanding comprehensive brain function and neurodevelopmental and psychiatric diseases. The concentration of BDNF in body fluid is highly related to several neurodevelopmental and psychiatric diseases, including Alzheimer's diseases, depression, schizophrenia, and bipolar disorder. In the present review, the mechanisms by which BDNF is released from secretory vesicles are reviewed, with a particular focus on the recently described glycan-mediated release. In addition, the impact of glycan-mediated BDNF release on psychiatric disorders is also discussed.

Early decrease in hyaluronidase-sensitive cell surface charge during the differentiation of Friend erythroleukemic cells by dimethyl sulfoxide.

Early membrane events in erythroid differentiation were investigated by means of cell electrophoresis utilizing cultured Friend erythroleukemia cell clones of different inducibility. The cell electrophoretic mobility decreased by 18% within 30 min of treatment with 1.5% dimethyl sulfoxide (DMSO) in highly inducible clones but not in noninducible clones. The reduced mobility persisted for 5 days of incubation with DMSO until hemoglobin synthesis. DMSO treatment for less than 16 hr and subsequent incubation without the drug resulted in the complete recovery of the mobility and no hemoglobin synthesis. Longer exposure to DMSO resulted in the loss of recovery of mobility and an increasing fraction of benzidine-positive cells seen on Day 5. Measurement of the electrophoretic mobility after the removal of acidic sugars by their specific enzymes suggested that hyaluronidase-sensitive negative charges were lost from the cell surface only in highly inducible clones. The mobility reduction associated with hyaluronic acid was also caused by other potent inducers (sodium butyrate, N-methylacetamide, and N,N-dimethylacetamide). These results suggest that the decrease in cell surface glycocalyx might be an early step in the induction of differentiation of Friend erythroleukemia cells.

Differentiation-associated cellular complex formation of murine thymocytes with thymic stromal cells.

Properties of normal murine thymocytes forming in vitro cellular complexes with thymic epithelial-like stromal cells in the form of pseudoemperipolesis were studied. The complex-forming cells were low-buoyant-density blasts primarily localized to the subcapsular zone. After transition into small cortical lymphocytes, their capacity for complex formation was lost. The complex-forming cells were relatively resistant to cortisone acetate and low-dose (170 rads) whole-body X-irradiation. Their number increased sharply in the early stage of thymic regeneration, corresponding to an increase in the percentage of large thymic lymphocytes 4 to 5 days after cortisone treatment or X-irradiation. However, after the thymus was repopulated with small lymphocytes, the percentage of complex-forming lymphocytes decreased rapidly to the normal level. A possible relationship between a step in thymic leukemogenesis and intrathymic T-cell differentiation is discussed.

Properties of acidic saccharides produced by B16 melanoma cells treated with 1-methyl-3-isobutylxanthine.

A cyclic nucleotide phosphodiesterase inhibitor, 1-methyl-3-isobutylxanthine, promoted the differentiation and maturation of B16 melanoma cells, phenomena associated with biological alterations in the surface properties of the cells. 1-Methyl-3-isobutylxanthien inhibited cell replication and increased the intracellular content of melanin and cyclic adenosine 3':5'-monophosphate. Significantly greater amounts of sialoglycoproteins were associated with 1-methyl-3-isobutylxanthine-treated cells. However, the total amount of [3H] glucosamine incorporated into anionic polysaccharide (both sialoglycopeptide and mucopolysaccharides) was not significantly changed.

The production of acidic polysaccharides by 5-bromodeoxyuridine-treated B16 mouse melanoma cells.

B16 melanoma cells were treated in culture with 5-bromo-2-deoxyuridine. The cell-associated and released proteoglycans and sialoglycopeptides were compared to those of control cultures treated with thymidine. The 5-bromo-2-deoxyuridine-treated cultures showed a marked reduction in the proportion of cell-associated proteoglycans and sialoglycopeptides, an increase in the synthesis of hyaluronic acid, the absence of high-molecular-weight chondroitin sulfate, and the presence of increased amounts of heparan sulfate in the media. In addition, the 5-bromo-2-deoxyuridine-treated cells had a higher DNA content and were larger than controls.

Effects of hyperthermia on cell surface charge and cell survival in mastocytoma cells.

Changes in the structure of the surface of mastocytoma cells were induced by hyperthermia and were investigated by means of cell electrophoresis. A decrease in the cell electrophoretic mobility was detected as early as 15 min after treatment at 42 degrees and progressed more rapidly under hypoxic conditions than under oxic conditions. Subsequent recovery of electrophoretic mobility at 37 degrees was dependent on the length of heat treatment and oxygenation. The surviving fraction of cells detected by their colony-forming ability and the fraction of electrophoretically recovered cells 24 hr after exposure to hyperthermia showed a good statistical correlation. It was suggested that the mechanism of electrophoretic mobility reduction by heating was the vertical translocation of hyaluronidase-sensitive charge from the peripheral layer into a deeper layer by combined use of specific enzymes and stepwise different ionic strengths. These results suggest the importance of irreparable changes of membrane conformation in the loss of colony-forming ability of heated tumor cells.