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We analyzed the FGF/FGFR and co-alteration cancer landscape, hypothesizing that combination therapy might be useful in the presence of co-drivers.We describe FGF/FGFR-altered pathways, prognosis, and co-alterations [cBioPortal (N = 7574)] and therapeutic outcomes [University of California San Diego Molecular Tumor Board (MTB) (N = 16)].Patients whose cancers harbored FGF/FGFR alterations (N = 1074) versus those without them (N = 6500) had shorter overall survival (OS) (median: 23.1 versus 26.4 months, P = 0.038) (cBioPortal). Only 6.1% (65/1074 patients) had no pathogenic co-alterations accompanying FGF/FGFR axis abnormalities. The most frequently co-altered pathways/genes involved: TP53 (70%); cell cycle (58%); PI3K (55%); and receptor tyrosine kinases and mitogen-activated protein kinase (MAPK) (65%). Harboring alterations in both FGF/FGFR and in the TP53 pathway or in the cell cycle pathway correlated with shorter OS (versus FGF/FGFR-altered without those co-altered signals) (P = 0.0001 and 0.0065). Four of 16 fibroblast growth factor receptor (FGFR) inhibitor-treated patients presented at MTB attained durable partial responses (PRs) (9, 12, 22+, and 52+ months); an additional two, stable disease (SD) of ≥6 months (13+ and 15 months) [clinical benefit rate (SD ≥ 6 months/PR) = 38%]. Importantly, six patients with cyclin pathway co-alterations received the CDK4/6 inhibitor palbociclib (75 mg p.o. 3 weeks on, 1 week off) and the multikinase FGFR inhibitor lenvatinib (10 mg p.o. daily); three (50%) achieved a PR [9 (ovarian), 12 (biliary), and 52+ months (osteosarcoma)]. Palbociclib and lenvatinib were tolerated well.FGF/FGFR alterations portend a poor prognosis and are frequently accompanied by pathogenic co-aberrations. Malignancies harboring co-alterations that activate both cyclin and FGFR pathways can be co-targeted by CDK4/6 and FGFR inhibitors.

Cek8 and low affinity NGF receptor (LNGFR) are expressed at high levels on the chick spinal motoneurons of the brachial and lumbar segments from embryonic day (E) 5 to E7, but weakly on the motoneurons of the non-limb-innervating segments. We determined by means of heterotopic neural tube transplantation, that the expression of these molecules was already intrinsically determined at E2. We used these spatiotemporal specific molecules as markers of motoneuron subpopulations. To analyze how motoneurons acquire regional specification along the anterior-posterior (A-P) axis and in the transverse plane, we observed the expression of these molecules on ectopic motoneurons induced by implanting a supernumerary notochord or floor plate at E2. The ectopic motoneurons induced by the graft obtained from either the thoracic or lumbar segments had the same expression profile as the normal motoneurons at each A-P level. These findings suggest that regional specification of motoneurons, at least of Cek8 and LNGFR expression, is independent of the notochord and the floor plate and that the whole neural tube appears to be committed to differentiate into the motoneuron subtypes along the A-P axis at the operative stages.

Chicken ovalbumin upstream promoter-transcription factor (COUP-TF) and hepatocyte nuclear factor-4 (HNF-4) are orphan members of the steroid/thyroid receptor superfamily and exhibit ubiquitous and liver-enriched tissue distribution, respectively. The gene for rat ornithine transcarbamylase (OTC), an ornithine cycle enzyme, is mainly expressed in the liver and is under the control of the promoter and the 11-kilobase upstream enhancer, both of which are liver-selective. Two sites of the promoter region and two sites of the enhancer region of the OTC gene, as well as the ovalbumin promoter site, were recognized by both HNF-4 and COUP-TF, showing that these two factors have closely related binding specificities. Since HNF-4 activated expression from the OTC promoter in cotransfection analysis, this factor appears to participate in liver-selective activation of the OTC gene. On the other hand, COUP-TF repressed the expression from the OTC promoter, whereas it activated expression from several other promoters. Therefore, COUP-TF plays a dual regulatory role depending on the promoter context. Repression of a tissue-specific promoter by a ubiquitous transactivator and derepression by a related tissue-enriched transactivator is potentially an important mechanism for tissue-specific activation of a gene.

We describe three adult siblings with communicating hydrocephalus, corneal opacities, deafness, valvular heart disease, and deformed toes associated with glucosylceramide (glc-cer)-beta-glucosidase deficiency. The common manifestations of Gaucher disease were not evident. Supranuclear gaze palsies characteristic of type 3 were noted from early childhood, although the major signs were undeveloped until early adult life. Autopsy disclosed thickened leptomeninges with perivascular fibrosis, non-rheumatic calcified aortic and mitral stenosis with marked fibrosis, and mild infiltration of Gaucher cells in the reticuloendothelial organs. In contrast to the slight accumulation of glc-cer in the liver and spleen, the activity of glc-cer-beta-glucosidase was markedly decreased in the tissues, as much as in a patient with type 2 Gaucher disease. Common mutations were not found in the glucocerebrosidase gene.

A type-specific monoclonal antibody was used to examine the localization of type VI collagen in healing full-thickness corneal wounds (3 mm in diameter) in rabbits. By immunofluorescence, in 1-week-old wounds, type VI collagen was found only at the wound periphery. Subsequently, type VI collagen showed a rapid increase throughout the wounded area. In 3-week-old wounds, type VI collagen immunofluorescence had a laminar pattern as seen in normal corneal stroma, although it was irregular in arrangement. By electron-microscopic immunohistochemistry, type VI collagen was found in the pericellular region of fibroblastic cells possibly derived from keratocytes. These results suggest that type VI collagen might originate from the fibroblastic cells and play an important role in the regeneration of the corneal lamellar structure.

A compact system of wavelength tunable femtosecond soliton pulse generation is demonstrated using compact fiber laser and optical fibers. The wavelength can be changed linearly and continuously from 1.56 to 1.86 /spl mu/m by changing the power of pump pulse. The experimental results are almost in agreement with the results of numerical simulations. Since this system is very compact and reliable, it is useful as a practical ultrashort pulse light source.

The authors present an overview of the baseline configuration of the JEMRMS (Japanese Experiment Module Remote Manipulator System) and summarize the status of the system and element development tests. JEMRMS has mother-daughter type manipulators: a 10 m long mother arm (main arm) and a 2 m-long daughter arm (small fine arm). The main arm (MA) provides that capability of transferring, retrieving, and berthing user (mission) payload or a JEM element in the vicinity of the servicing bay, called the exposed facility. The small fine arm (SFA), which is attached to the MA, performs dexterous tasks such as assembly of antenna and change-out test samples. The MA is routinely controlled by an automatic control mode, but can also be controlled by a manual mode using a six degree-of-freedom hand controller. The SFA is controlled by a manual control mode mainly in a bilateral (force feedback) and master-slave fashion. The MA is commonly used for the SFA as will as the MA and provides a human operator with the feedback force detected by a force moment sensor at the SFA wrist. >

We introduce the hyper-redundant modular manipulator arm (HRMA) ground test system, which is the ground experimental model for the technology of orbital maintenance system (OMS). OMS consists of three steps: 1) inspecting the satellite, 2) re-orbiting the useless satellite, and 3) simply repairing satellites in space. This HRMA is the arm for inspecting of satellites, the first step of OMS. HRMA model consists of: modules of the control processor, actuators for 2-degree of freedom, and simply a joint mechanism which can be connected and disconnected by simple robotic motion and also resist inertia during space operation. In this paper, we introduce the HRMA system, its basic specifications, and the future plan.

Prophylactic intra-arterial infusion of anticancer drug on post hepatic resection for hepatic metastasis of colorectal carcinoma were performed 8 cases. In our cases consisted of 8 patients of mean age of 54.3 years (male 3 cases and female 5 cases, synchronous metastasis 4 cases and metachronous 4 cases). All patients were received intra-arterial bolus injection of MMC (4-8 mg/body) at day 1 and continuous infusion of 5-FU (250-750 mg/body) for 7 days on admission. After discharged, patients were received bolus injection of 5-FU (250-750 mg/body) for once a week. Side effect of this treatment was not appeared and all of them obtained very good QOL. There were no recurrence sign of residual liver and this procedure was very useful method for post hepatic resection for hepatic metastasis of colorectal cancer.

Chicken ovalbumin upstream promoter-transcription factor (COUP-TF) and hepatocyte nuclear factor-4 (HNF-4) are orphan members of the steroid/thyroid receptor superfamily and exhibit ubiquitous and liver-enriched tissue distribution, respectively. The gene for rat ornithine transcarbamylase (OTC), an ornithine cycle enzyme, is mainly expressed in the liver and is under the control of the promoter and the 11-kilobase upstream enhancer, both of which are liver-selective. Two sites of the promoter region and two sites of the enhancer region of the OTC gene, as well as the ovalbumin promoter site, were recognized by both HNF-4 and COUP-TF, showing that these two factors have closely related binding specificities. Since HNF-4 activated expression from the OTC promoter in cotransfection analysis, this factor appears to participate in liver-selective activation of the OTC gene. On the other hand, COUP-TF repressed the expression from the OTC promoter, whereas it activated expression from several other promoters. Therefore, COUP-TF plays a dual regulatory role depending on the promoter context. Repression of a tissue-specific promoter by a ubiquitous transactivator and derepression by a related tissue-enriched transactivator is potentially an important mechanism for tissue-specific activation of a gene.

Intralenticular Na+ and rat lens H+ activities (aNa and pHi, respectively) were measured in vitro at the posterior cortical layers of lens fibers using ion-selective microelectrodes. In control HCO(3-)-free solution (K+: 5 mM; external pH (pHo): 7.3), intralenticular potential (Vm) was -61.5 +/- 2.4 mV, aNa was 19.4 +/- 4.6 mM and pHi was 6.90 +/- 0.06 (mean +/- SD). In O-mM K+ solution, Vm slightly depolarized, but aNa and pHi did not change. Increasing K+ concentration to 35 mM induced a large depolarization of Vm, associated with a reduction in aNa and an increase in pHi. pHi was decreased by lowering pHo, but internal acidification thus induced did not show a complete recovery upon reintroduction of a normal solution. The pHi was immediately increased by superfusion with a solution containing 20 mM NH4Cl, and subsequent removal of NH4Cl led to a sustained decrease in pHi. Ouabain and amiloride (a blocker of Na(+)-H+ exchanger) did not exert any effects on aNa or on pHi in normal solution at pHo 7.3. Amiloride applied after the removal of NH4Cl did not alter pHi. These results provide evidence that aNa and pHi at the posterior cortical fiber layers of the rat lens are influenced by Vm, and that, depending on the value of Vm, passive movements of Na+ and H+ can exert direct local effects on pHi and aNa.

The effect of an aldose reductase inhibitor (ARI) on the development of in utero galactose-induced cataract was evaluated by following the morphological changes as seen by light and transmission electron microscope. Pregnant rats were fed a 30% galactose diet until day 17, 18, 19 or 20 of gestation and then given a galactose diet containing ARI. The lenses of newborn rats when mothers were given an ARI diet after day 17, 18 or 19 of gestation showed no morphological change. On the other hand, in the lenses from newborn rats when mothers were given an ARI diet after day 20 of gestation, 30% of those tested showed small vacuoles limited to the posterior cortex, while 70% showed normal structure. When mothers were given a galactose diet during the entire term of pregnancy all lenses of newborn rats showed extensive vacuole formation. ARI was confirmed to completely inhibit congenital galactose cataracts in rats when it was given to the mother rat after day 19 of gestation (ie, on the last 3 days before delivery).

A 50-year-old woman was admitted under a diagnosis of abdominal tumor. Ultrasonography and CT scanning were performed, and a right retroperitoneal tumor was detected. Absolute curative resection was performed. The resected tumor was 13.5 x 11.5 x 9.0 cm, and histologically diagnosed as ganglioneuroma. To our knowledge, 99 cases have been reported in Japan. During a twelve-month follow-up period, the postoperative course was uneventful and no recurrence had been noted.

Peripheral blood mitochondrial DNA (mtDNA) samples from 11 patients with acute optic neuritis or insidious optic atrophy were examined for the mutation at nt 11778 and nt 3460 in polymerase chain reaction products. The mtDNA mutation at nt 11778 was evident in 8 cases, which led to a definite diagnosis of Leber's hereditary optic neuropathy (LHON); 4 of the cases were familial and the remaining 4 cases were nonfamilial. None of the 11 patients showed the nt 3460 mutation. The symptoms and signs were variable among the LHON cases with nt 11778 mutation. Assessment of mtDNA provides a useful diagnostic aid for clinically undefined, seemingly nonfamilial or atypical cases of Leber's hereditary optic neuropathy, particularly in bilateral, insidious optic nerve disease in early childhood.

A 41-year-old man was admitted to our hospital because of an abnormal shadow which was pointed out on the chest x-ray film in mass screening. The operation was performed through left thoracotomy. The cyst was unilobular and 43 x 36 x 36 mm in size, located in the middle position of upper mediastinum. This localization has not been reported among 46 cases of the mediastinal lymphangiomas in Japan. Preoperative diagnosis is very difficult since roentogenographic feature is few for ruling out other mediastinal tumors. The complete resection of the cyst is recommended.

Brown Norway kininogen-deficient rats had very low levels of plasma kininogens and lower levels of plasma prekallikrein, compared with those of normal rats of the same strain. Systolic blood pressure, determined by the tail-cuff method, of 5-week-old kininogen-deficient rats (106 +/- 0.4 mm Hg, n = 7) and the rate of systolic blood pressure increase with age were not different from those in normal rats. Weekly injections of deoxycorticosterone acetate (5 mg/kg s.c.) with 1% sodium chloride solution in drinking water after uninephrectomy at 7 weeks of age caused a gradual increase in the blood pressure of normal rats, reaching a plateau at 18 weeks of age, whereas that of deficient rats rose rapidly to 158 +/- 6 mm Hg 2 weeks after the start of treatment and continued to increase slightly, becoming significantly higher than normal rats at 8, 9, 10, 11, and 12 weeks of age (p less than 0.05 or 0.01). The levels of urinary prokallikrein and active kallikrein were slightly higher in deficient rats before deoxycorticosterone acetate-salt treatment but were not significantly increased after this treatment, whereas these levels in normal rats were increased 3.6- and 4.7-fold by this treatment. Urinary free kinin, collected from the ureter in untreated deficient rats, was below the detection limit. The plasma level of low molecular weight kininogen, the substrate of glandular kallikrein, was decreased in normal rats during the treatment. Continuous subcutaneous injection of aprotinin by an osmotic pump to normal rats induced significant increase in blood pressure. These results indicate that glandular kallikrein may play a suppressive role in deoxycorticosterone acetate-salt hypertension.

We studied the inhibitory effects of chicken egg white ovomacroglobulin, a broad-spectrum protease inhibitor, and a synthetic protease inhibitory peptide, Bz-GFR-O-mercaptoanilide, on the growth of two strains of Serratia marcescens in a synthetic medium. The growth of the virulent protease-producing strain, S. marcescens kums 3958 (kums 3958), was more rapid than that of the strain producing minimal protease, S. marcescens kums NA (kums NA), and kums 3958 was inhibited in a dose-dependent manner by ovomacroglobulin. The synthetic inhibitor also inhibited the growth of kums 3958 weakly. Dose-dependent enhancement of growth of kums NA was observed in the medium treated with the serratial 56 kilo Dalton protease. By immunohistochemical methods using an antibody to the bacteria, the spreading of kums 3958 was also studied in corneal tissue in experimental keratitis of the guinea pig. In vivo, kums 3958 grew locally, and then spread widely by destroying stromal tissue 7-8 hours after intrastromal injection of the organisms (3 x 10(4) colony-forming units). On the other hand, when kums 3958 mixed with ovomacroglobulin was injected into the cornea, the organisms remained locally in the corneal stroma which showed a lower grade of damage. These results indicate that proteases secreted from S. marcescens destroyed corneal stroma, yielding the organisms enough space for further spreading.

Superoxide radicals and their metabolite(s) have been postulated to play an important role in the pathogenesis of inflammation. Hence, superoxide dismutase (SOD) has been used to reduce tissue injury caused by reactive oxygens. However, protection of the cornea and other ocular tissues from oxygen toxicity could not be achieved by administering SOD presumably due to its unfavorable in vivo behavior. To scavenge superoxide radicals on the outer surface of corneal epithelial cells, the authors synthesized an acylated SOD derivative (AC-SOD) by linking capric acid. When instilled into rabbit eyes, a significant amount of AC-SOD remained bound to the corneal surface for a fairly long time. Intracorneal injection of lipopolysaccharide (LPS) triggered infiltration of polymorphonuclear leukocytes (PMNs) to the cornea and induced severe keratitis. Topical administration of AC-SOD to the LPS-treated cornea markedly inhibited the infiltration of PMNs and suppressed the occurrence of keratitis. Under identical conditions, topically administered SOD was rapidly removed by tears and, hence, did not inhibit LPS-induced keratitis. When the number of PMNs in the systemic circulation was reduced by intravenous administration of hydroxyurea, LPS-induced keratitis was inhibited markedly. These results indicate that superoxide radicals and circulating PMNs might play a critical role in LPS-induced keratitis.

The pathogenicities of three proteases from Serratia marcescens, two proteases from Pseudomonas aeruginosa, and one thermolysin from Bacillus stearothermophilus were examined. All proteases tested caused acute liquefactive necrosis of the cornea and descemetocele formation in guinea pig eyes after intrastromal injection, with the exception of the 60-kilodalton protease from S. marcescens, which produced only an opaque lesion. When injected into guinea pig skin, the protease also enhanced vascular permeability, which was followed by edema formation. The permeability-enhancing activity of the proteases increased in parallel with the concentration of the enzymes. When tested in vitro for its effect on these bacterial proteases, chicken egg white ovomacroglobulin (ovoM) inhibited the enzymatic activity of all the proteases after a short incubation period at an enzyme/inhibitor ratio (molar) of 1:1 to 1:4 or at a lower concentration after a longer incubation period. Such treatment of the proteases with chicken egg white ovoM before injection intrastromally into the eyes or intradermally into the clipped flanks of guinea pigs protected the cornea from destruction or completely prevented the permeability reaction and edema formation. No inhibitory effects of plasma protease inhibitors against these bacterial proteases were noted. Since the proteases are critical in the pathogenic processes caused by the bacteria, these results suggest a beneficial effect of ovoM against bacterial infections.

The methods of rotation viscometry have been applied in the field to a tholeiitic lava at 1130 degrees to 1135 degrees C containing about 25 percent crystals and 2 to 5 percent gas bubbles, using a stainless steel spindle inserted through the lava crust. The results agree well with the Bingham model. Yield values in the lava are 1200 and 700 dynes cm (super -2) , and the plastic constants are 6500 and 7500 poises. Laboratory studies in silicone fluid show gas bubbles enhance plastic behavior. In general, lavas must be treated as non-Newtonian fluids; the conditions that may cause different types of fluid behavior in tholeiitic lava are outlined.

In 4 Fallen von Rubeosis iridis wurde operativ gewonnenes und lebensfrisch fixiertes Irismaterial licht- und elektronenmikroskopisch untersucht. Im Bereich des Irisvorderblattes finden sich zahlreiche neugebildete Gefase. Das intervasculare Stroma ist reich an Mucoproteiden und homogenen Massen. Die Oberflache der Iris ist von zahlreichen, zum Teil stark aktivierten langgestreckten Zellen bedeckt, die sich schichtweise uberlappen und verschiedenartige Einschlusse enthalten.

Microwave emissions are observed with a long time duration after a beam turn‐off from a magnetized plasma that is heated by a high‐intensity short‐pulsewidth relativistic electron beam (500 keV, 2 kA, 3 ns). The emission has a frequency spectrum which has peaks near cyclotron harmonics (f=nfce, n=2, 3,...). These microwave emissions can be attributed to electrostatic waves excited by hot electrons which are created in the beam‐plasma interaction.

A possible cause and the difference in clinical severity of serratial keratitis were investigated. Two strains of Serratia marcescens were isolated: one from a patient with severe liquefactive keratitis, who had diabetes mellitus, and one from a patient with mild superficial keratitis, but who had no underlying disease. When the same numbers of bacteria were injected separately into corneas of the same rabbits or guinea pigs, the strain from the first patient elicited severe corneal destruction, remarkable intracorneal edema; and liquefactive necrosis, but the strain from the second caused mild keratitis with erosion or intracorneal abscess. The keratitis induced by the former strain required a longer time to heal, and the prognosis was poorer than that for the other keratitis. Therefore, the difference in severity between the two cases of experimentally induced keratitis paralleled that of the clinical cases. Thus, the severity of the serratial keratitis might be attributed more to the virulence of the bacteria than the condition of the host. The virulence factor seemed to be a heat-labile metabolic product (or products) of the bacteria. To clarify this virulence factor, the major secretory protease (56K protease) produced by these two strains of bacteria was compared by using in vitro and in vivo systems. The virulent strain produced about ten times more protease during culture than the less virulent strain. When injected into the corneas of experimental animals, the 56K protease from the virulent strain induced severe lesions similar to those caused by the living virulent strain of bacteria. These results indicated that one of the major factors causing the virulence was correlated with the tissue destructive 56K protease produced by S. marcescens.

A method for preparation of highly ordered monolayer cultures of the corneal endothelium was described. The technique of agar and palladium double-coating of culture plates was utilized for demarcation of the haptotactic area. The culture plate was prepared by precoating with agar and subsequent coating with palladium to define areas where growth of corneal endothelial cells was allowed. A micro-mass culture of corneal endothelial cells on the area defined by the palladium coating demonstrated their active growth and their reconstitution of the typical cellular pattern of the corneal endothelium.

In principle, the following three steps are considered for by-pass surgery; I. A gastric tube is moved up to the retro-sternal or to the ante-thoracic position. A T-tube is the inserted in the mid position of the gastric tube for decompression and drainage. 2. A retention vinyl tube is inserted in to the excluded esophagus for the purpose of post infusion therapy and for evaluation of the therapy. 3. A Roux-Y anastomotic internal fistula is placed at the distal site of the excluded esophagus. As a plan for combined therapy, PANa-Oil bleomycin (oil bleomycin 30 mg, PANa 0.5 g) is the infused into the isolated esophagus after the by-pass operation and the clinical effect is evaluated by introducing a radiopaque medium into the excluded esophagus via an inserted vinyl tube. Such infusion therapy after by-pass surgery was given to 3 patients and in 1 patient it was very effective. This suggested a positive effect on survival in cases of non-resectable esophageal cancer without side effects.

Clinical findings of ocular involvement in two patients with familial amyloidotic polyneuropathy are described. Both cases revealed irregular pupillary margin, white membranous material on the pupillary border and on the lens surface. Open-angle glaucoma was found in one case, and ocular hypertension in the other. Histopathological examination of the tissues obtained during trabeculectomy in Case 1 revealed a large amount of amyloid substance around the vessels of the conjunctiva and the iris and in the endothelial meshwork of the chamber angle. Electron microscopic observation revealed that amyloid fibrils had formed in the basement membrane of the endothelial cells of the blood vessels in the conjunctiva and the iris. However, no amyloid fibrils were observed in the endothelial cells of the trabecular meshwork. Crossed immunoelectrophoresis of the aqueous humor of Case 1 showed a high-protein content, especially of alpha 1-lipoprotein and ceruloplasmin. The findings described above suggest that glaucoma or ocular hypertension in association with familial amyloidotic polyneuropathy is a result of the accumulation of amyloid substance in the endothelial meshwork.

Crossed immunoelectrophoresis having high resolving power and sensitivity was applied to the human aqueous humor, in an attempt to determine which of the following is the most appropriate parameter for detecting the concentration of protein components: 1) the height of the precipitation line, 2) the length of the line itself or 3) the area under the precipitation line. Furthermore, the concentrations of several proteins were determined in the aqueous humor from normal subjects. Although it has been reported that the area under the precipitation line was proportional to the concentration of the protein, the present study showed that both the height and the length of the precipitation line are also equally valid for concentration determinations. The amount of protein antigens in 100 ml of the normal human aqueous humor were prealbumin 0.31-0.41 mg, albumin 5.4-6.5 mg, alpha 1-acid glycoprotein 0.05-0.17 mg and transferrin 1.3-1.7 mg.