Miracle-dz/UniFAR-FTUs huggingface dataset:
Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group.

BACKGROUND The combination of fluorouracil and leucovorin has until recently been standard therapy for metastatic colorectal cancer. Irinotecan prolongs survival in patients with colorectal cancer that is refractory to treatment with fluorouracil and leucovorin. In a multicenter trial, we compared a combination of irinotecan, fluorouracil and leucovorin with bolus doses of fluorouracil and leucovorin as first-line therapy for metastatic colorectal cancer. A third group of patients received irinotecan alone. METHODS Patients were randomly assigned to receive irinotecan (125 mg per square meter of body-surface area intravenously), fluorouracil (500 mg per square meter as an intravenous bolus), and leucovorin (20 mg per square meter as an intravenous bolus) weekly for four weeks every six weeks; fluorouracil (425 mg per square meter as an intravenous bolus) and leucovorin (20 mg per square meter as an intravenous bolus) daily for five consecutive days every four weeks; or irinotecan alone (125 mg per square meter intravenously) weekly for four weeks every six weeks. End points included progression-free survival and overall survival. RESULTS Of 683 patients, 231 were assigned to receive irinotecan, fluorouracil, and leucovorin; 226 to receive fluorouracil and leucovorin; and 226 to receive irinotecan alone. In an intention-to-treat analysis, as compared with treatment with fluorouracil and leucovorin, treatment with irinotecan, fluorouracil, and leucovorin resulted in significantly longer progression-free survival (median, 7.0 vs. 4.3 months; P=0.004), a higher rate of confirmed response (39 percent vs. 21 percent, P<0.001), and longer overall survival (median, 14.8 vs. 12.6 months; P=0.04). Results for irinotecan alone were similar to those for fluorouracil and leucovorin. Grade 3 (severe) diarrhea was more common during treatment with irinotecan, fluorouracil, and leucovorin than during treatment with fluorouracil and leucovorin, but the incidence of grade 4 (life-threatening) diarrhea was similar in the two groups (<8 percent). Grade 3 or 4 mucositis, grade 4 neutropenia, and neutropenic fever were less frequent during treatment with irinotecan, fluorouracil, and leucovorin. Adding irinotecan to the regimen of fluorouracil and leucovorin did not compromise the quality of life. CONCLUSIONS Weekly treatment with irinotecan plus fluorouracil and leucovorin is superior to a widely used regimen of fluorouracil and leucovorin for metastatic colorectal cancer in terms of progression-free survival and overall survival.
Functional IP3‐ and ryanodine‐sensitive calcium stores in presynaptic varicosities of NG108–15 (rodent neuroblastoma × glioma hybrid) cells

1 Presynaptic varicosities of the model neuronal cell line NG108–15, a cholinergic neuroblastoma cell × glioma cell hybrid capable of innervating striated myotubes, were examined for the presence of inositol 1,4,5‐trisphosphate (IP3)‐sensitive and Ca2+‐activated (ryanodine‐sensitive) Ca2+ stores using confocal microscopic imaging of Ca2+‐sensitive fluorescent dye loaded into the cells. 2 Initial demonstration of the presence of IP3 receptors and ryanodine receptors in the NG108–15 varicosities was obtained using immunocytochemistry. 3 Treatment of NG108–15 cells with bradykinin (0.1 μM), whose receptor is linked to IP3 generation, and separately, caffeine (10 mM), an activator of endoplasmic reticulum ryanodine receptors, resulted in substantial increases in [Ca2+]i in the varicosities. 4 K+‐evoked changes in [Ca2+]i in the varicosities were reduced (52 %) after emptying the ryanodine‐sensitive Ca2+ store using caffeine (10 mM), but were not affected by prior depletion of the IP3‐sensitive Ca2+ store using thapsigargin (1 μM). 5 Bradykinin‐induced changes in [Ca2+]i were abolished following depletion of the IP3‐sensitive Ca2+ store using thapsigargin (1 μM) and were reduced (72 %) by prior emptying of the ryanodine‐sensitive Ca2+ store with caffeine (10 mM). 6 The same results were obtained when the varicosities of the NG108–15 cells had formed synaptic junctions with co‐cultured rat hindlimb myotubes. 7 Taken together, the results suggest that, in the varicosities, activation of the IP3 pathway evoked the release of Ca2+ from the IP3‐sensitive store, which, in turn, secondarily induced the release of Ca2+ from the ryanodine‐sensitive store via Ca2+‐induced Ca2+ release, and that depolarization‐induced Ca2+ entry evoked Ca2+‐induced Ca2+ release only from the ryanodine‐sensitive store. Thus, functional internal Ca2+ stores are inherent components of presynaptic varicosities in this neural cell line.
Role of latent feline leukemia virus infection in nonregenerative cytopenias of cats.

BACKGROUND Nonregenerative cytopenias such as nonregenerative anemia, neutropenia, and thrombocytopenia in cats with feline leukemia virus (FeLV) antigen are assumed to be caused by the underlying FeLV infection. In addition, cats with negative FeLV antigen-test results that have cytopenias of unknown etiology often are suspected to suffer from latent FeLV infection that is responsible for the nonregenerative cytopenias. OBJECTIVE The purpose of this study was to assess the role of latent FeLV infection by polymerase chain reaction (PCR) in bone marrow of cats with nonregenerative cytopenias that had negative FeLV antigen test results in blood. ANIMALS Thirty-seven cats were included in the patient group. Inclusion criteria were (1) nonregenerative cytopenia of unknown origin and (2) negative FeLV antigen test result. Antigenemia was determined by detection of free FeLV p27 antigen by ELISA in serum. Furthermore, 7 cats with positive antigen test results with nonregenerative cytopenia were included as control group I, and 30 cats with negative antigen test results without nonregenerative cytopenia were included as control group II. METHODS Whole blood and bone marrow samples were tested by 2 different PCR assays detecting sequences of the envelope or long terminal repeat genes. FeLV immunohistochemistry was performed in bone marrow samples. RESULTS Two of the 37 cats (5.4%) in the patient group were positive on the bone marrow PCR results and thus were latently infected with FeLV. CONCLUSIONS AND CLINICAL IMPORTANCE The findings of this study suggest that FeLV latency is rare in cats with nonregenerative cytopenias.
Quantifying sperm egg interaction to assess the breeding efficiency through artificial insemination in guinea fowls

ABSTRACT 1. Guinea fowl hens were inseminated weekly once with two doses of spermatozoa (75 million and 100 million) in two different diluents, Beltsville poultry semen extender (BPSE), and Instruments for Veterinary Medicine (IMV), each with and without pre-insemination vaginal douching. Per cent fertility, hatchability, dead germ, dead in shells along with data on sperm egg interaction and vaginal microbial counts were recorded. 2. Artificial insemination had significantly improved the per cent fertility and hatchability compared to natural mating. Dose dependent improvement in fertility was noticed with both diluents. 3. There was a beneficial effect of vaginal douching, which was more pronounced at lower insemination doses. 4. For optimum fertility and hatchability in guinea fowl, insemination of 75 million spermatozoa diluted in BPSE once in 4 d and 100 million spermatozoa diluted in BPSE or IMV once in 5 d coupled with vaginal douching is recommended.
Active State in the Smooth Muscle of the Rat Portal Vein in Relation to Electrical Activity and Isometric Force

Contractile activity in smooth muscle is usually too variable to permit a meaningful analysis of the time course of the active state. A regular activity of uniform contractions was obtained in the present experiments on isolated rat portal veins by simultaneous increases in the external potassium and calcium concentrations. The contractions were associated with electrical discharges which lasted between 0.8 and 1.5 seconds. The active state during these uniform contractions was determined from the shortening velocities after isotonic releases and from the redevelopment of tension after controlled releases. Results obtained with the two methods agreed satisfactorily. The active state increased over the first 0.4–0.6 seconds. Suggestive evidence of a plateau phase was found in some experiments. The active state clearly began to fall about 1 second after the start of the contraction, and this fall coincided with the fall in the first time derivative of isometric force (dP/dt). The maximal intensity of the active state was, on the average, 173% of the maximal isometric force. During isometric contractions, the series elastic element was stretched by as much as 15% of the total muscle length. Active-state values were therefore corrected for changes in contractile element length. The curve then obtained might represent the time course of the level of activation, reflect variations in internal calcium concentration, and relate to the electrical response. Concepts developed for the mechanics of striated muscle can apparently be applied to propagating vascular smooth muscle, and this applicability might help to clarify electromechanical relations and the actions of vasoactive substances in blood vessels.
The Effects of Macroeconomic News on High Frequency Exchange Rate Behavior

Abstract This paper studies the high frequency reaction of the DEM/USD exchange rate to publicly announced macroeconomic information emanating from Germany and the U.S. By using data sampled at a five-minute frequency, we are able to identify significant impacts of most announcements on the exchange rate change in the 15 minutes post-announcement, although the significance of these effects decreases rapidly as the interval over which the post-announcement change in exchange rates is increased. The direction of the exchange rate response conforms, in general, with a reaction function interpretation whereby reactions to macroeconomic news are driven by the likely operations of monetary authorities in domestic money markets. Further, we detect influences of German monetary policy decisions on the reaction of the exchange rate, and also differences between U.S. and German announcements in the exchange rate reaction time pattern.
Oxidation of homogentistic acid by cell-free extracts of a vibrio.

SUMMARY: Acetoacetic acid is a product of degradation of homogentisic acid by cell-free extracts of a vibrio grown with phenylacetic acid as sole carbon source. 4-Maleylacetoacetate was identified as a reaction intermediate; reduced glutathione was a cofactor for this enzymic degradation. These reactions are similar to those catalysed by enzymes of rat liver.
ABC of clinical haematology: Bone marrow and stem cell transplantation

Experiments in the 1950s showed that haemopoiesis could be restored in irradiated animals by engraftment of transfused marrow. Attempts to translate this into clinical practice were hindered by immunological problems of transfer between individuals which we now recognise as rejection and graft versus host disease. With further understanding of the human leucocyte antigen system, rapid clinical progress was made during the 1970s such that bone marrow transplantation soon became an established treatment for some immune deficiency and malignant diseases. Early animal studies of bone marrow transplantation were translated into clinical practice with understanding of the human leucocyte antigen (HLA) system and immunosuppressive therapy Transplant terminology. Transplantation is the reconstitution of the full haemopoietic system by transfer of the pluripotent cells present in the bone marrow (stem cells). This usually requires prior ablation of the patient's own marrow by intensive chemotherapy or chemoradiotherapy. The most appropriate generic term for the procedure is haemopoietic transplantation, which may be subdivided according to the donor source and further subdivided into the site of stem cell procurement. Allogeneic transplantation is when another individual acts as the donor–usually a sibling of the patient, sometimes a normal volunteer. All cases, however, require a full or near HLA match–that is, they should be HLA compatible. Autologous transplantation is when the patient acts as his or her own source of stem cells. The aim of haemopoietic transplantation is the elimination of the underlying disease in the recipient, together with full restoration of haemopoietic and immune function Originally, stem cells were procured from the bone marrow by direct puncture and aspiration of bone marrow and reinfused intravenously, a procedure known as bone marrow transplantation. Recently, it has been shown that stem cells derived from the bone marrow can be liberated into the peripheral blood, where the cells are harvested with …
Emissions of organic carbon and methane from petroleum and dairy operations in California's San Joaquin Valley

Abstract. Petroleum and dairy operations are prominent sources of gas-phase organic compounds in California's San Joaquin Valley. It is essential to understand the emissions and air quality impacts of these relatively understudied sources, especially for oil/gas operations in light of increasing US production. Ground site measurements in Bakersfield and regional aircraft measurements of reactive gas-phase organic compounds and methane were part of the CalNex (California Research at the Nexus of Air Quality and Climate Change) project to determine the sources contributing to regional gas-phase organic carbon emissions. Using a combination of near-source and downwind data, we assess the composition and magnitude of emissions, and provide average source profiles. To examine the spatial distribution of emissions in the San Joaquin Valley, we developed a statistical modeling method using ground-based data and the FLEXPART-WRF transport and meteorological model. We present evidence for large sources of paraffinic hydrocarbons from petroleum operations and oxygenated compounds from dairy (and other cattle) operations. In addition to the small straight-chain alkanes typically associated with petroleum operations, we observed a wide range of branched and cyclic alkanes, most of which have limited previous in situ measurements or characterization in petroleum operation emissions. Observed dairy emissions were dominated by ethanol, methanol, acetic acid, and methane. Dairy operations were responsible for the vast majority of methane emissions in the San Joaquin Valley; observations of methane were well correlated with non-vehicular ethanol, and multiple assessments of the spatial distribution of emissions in the San Joaquin Valley highlight the dominance of dairy operations for methane emissions. The petroleum operations source profile was developed using the composition of non-methane hydrocarbons in unrefined natural gas associated with crude oil. The observed source profile is consistent with fugitive emissions of condensate during storage or processing of associated gas following extraction and methane separation. Aircraft observations of concentration hotspots near oil wells and dairies are consistent with the statistical source footprint determined via our FLEXPART-WRF-based modeling method and ground-based data. We quantitatively compared our observations at Bakersfield to the California Air Resources Board emission inventory and find consistency for relative emission rates of reactive organic gases between the aforementioned sources and motor vehicles in the region. We estimate that petroleum and dairy operations each comprised 22% of anthropogenic non-methane organic carbon at Bakersfield and were each responsible for 8–13% of potential precursors to ozone. Yet, their direct impacts as potential secondary organic aerosol (SOA) precursors were estimated to be minor for the source profiles observed in the San Joaquin Valley.
Determination of netropsin-DNA binding constants from footprinting data.

A theory for deriving drug-DNA site binding constants from footprinting data is presented. Plots of oligonucleotide concentration, as a function of drug concentration, for various cutting positions on DNA are required. It is assumed that the rate of cleavage at each nucleotide position is proportional to the concentration of enzyme at that nucleotide and to the probability that the nucleotide is not blocked by drug. The probability of a nucleotide position not being blocked is calculated by assuming a conventional binding equilibrium for each binding site with exclusions for overlapping sites. The theory has been used to evaluate individual site binding constants for the antiviral agent netropsin toward a 139 base pair restriction fragment of pBR-322 DNA. Drug binding constants, evaluated from footprinting data in the presence of calf thymus DNA and poly(dGdC) as carrier and in the absence of carrier DNA, were determined by obtaining the best fit between calculated and experimental footprinting data. Although the strong sites on the fragment were all of the type (T.A)4, the value of the binding constant was strongly sequence dependent. Sites containing the dinucleotide sequence 5'-TA-3' were found to have significantly lower binding constants than those without this sequence, suggesting that an adenine-adenine clash produces a DNA structural alteration in the minor groove which discourages netropsin binding to DNA. The errors, scope, and limitations associated with the method are presented and discussed.
Isolation and Characterization of Ftsz Genes in Cassava

The filamenting temperature-sensitive Z proteins (FtsZs) play an important role in plastid division. In this study, three FtsZ genes were isolated from the cassava genome, and named MeFtsZ1, MeFtsZ2-1, and MeFtsZ2-2, respectively. Based on phylogeny, the MeFtsZs were classified into two groups (FtsZ1 and FtsZ2). MeFtsZ1 with a putative signal peptide at N-terminal, has six exons, and is classed to FtsZ1 clade. MeFtsZ2-1 and MeFtsZ2-2 without a putative signal peptide, have seven exons, and are classed to FtsZ2 clade. Subcellular localization found that all the three MeFtsZs could locate in chloroplasts and form a ring in chloroplastids. Structure analysis found that all MeFtsZ proteins contain a conserved guanosine triphosphatase (GTPase) domain in favor of generate contractile force for cassava plastid division. The expression profiles of MeFtsZ genes by quantitative reverse transcription-PCR (qRT-PCR) analysis in photosynthetic and non-photosynthetic tissues found that all of the MeFtsZ genes had higher expression levels in photosynthetic tissues, especially in younger leaves, and lower expression levels in the non-photosynthetic tissues. During cassava storage root development, the expressions of MeFtsZ2-1 and MeFtsZ2-2 were comparatively higher than MeFtsZ1. The transformed Arabidopsis of MeFtsZ2-1 and MeFtsZ2-2 contained abnormally shape, fewer number, and larger volume chloroplasts. Phytohormones were involved in regulating the expressions of MeFtsZ genes. Therefore, we deduced that all of the MeFtsZs play an important role in chloroplast division, and that MeFtsZ2 (2-1, 2-2) might be involved in amyloplast division and regulated by phytohormones during cassava storage root development.
The Cytoplasmic Domain of A Disintegrin and Metalloproteinase 10 (ADAM10) Regulates Its Constitutive Activity but Is Dispensable for Stimulated ADAM10-dependent Shedding*

Background: Release of membrane proteins from the cell surface by the metalloproteinase ADAM10 is post-translationally regulated. Results: The cytoplasmic domain of ADAM10 negatively controls its constitutive activity but is dispensable for its stimulation. Conclusion: Post-translational stimulation of ADAM10 requires its transmembrane and/or extracellular domain. Significance: Elucidating the regulation of ADAM10 is crucial for understanding the control of ADAM10-dependent cell surface proteolysis. The membrane-anchored metalloproteinase a disintegrin and metalloprotease 10 (ADAM10) is required for shedding of membrane proteins such as EGF, betacellulin, the amyloid precursor protein, and CD23 from cells. ADAM10 is constitutively active and can be rapidly and post-translationally enhanced by several stimuli, yet little is known about the underlying mechanism. Here, we use ADAM10-deficient cells transfected with wild type or mutant ADAM10 to address the role of its cytoplasmic and transmembrane domain in regulating ADAM10-dependent protein ectodomain shedding. We report that the cytoplasmic domain of ADAM10 negatively regulates its constitutive activity through an ER retention motif but is dispensable for its stimulated activity. However, chimeras with the extracellular domain of ADAM10 and the transmembrane domain of ADAM17 with or without the cytoplasmic domain of ADAM17 show reduced stimulated shedding of the ADAM10 substrate betacellulin, whereas the ionomycin-stimulated shedding of the ADAM17 substrates CD62-L and TGFα is not affected. Moreover, we show that influx of extracellular calcium activates ADAM10 but is not essential for its activation by APMA and BzATP. Finally, the rapid stimulation of ADAM10 is not significantly affected by incubation with proprotein convertase inhibitors for up to 8 h, arguing against a major role of increased prodomain removal in the rapid stimulation of ADAM10. Thus, the cytoplasmic domain of ADAM10 negatively influences constitutive shedding through an ER retention motif, whereas the cytoplasmic domain and prodomain processing are not required for the rapid activation of ADAM10-dependent shedding events.
The effect of probe depth on histamine levels in humans. In vivo cutaneous microdialysis

Background/aims: Microdialysis technique, for the in vivo estimation of endogenous and exogenous substances in tissues, is gaining increasing use in human experimentation. The cutaneous microdialysis technique has interesting applications in several fields, including the study of skin inflammation and percutaneous absorption. One of the aspects of cutaneous microdialysis which needs clarification is the influence on results of the exact position of the microdialysis probe in the dermis.
Novel Polyomavirus Detected in the Feces of a Chimpanzee by Nested Broad-Spectrum PCR

ABSTRACT In order to screen for new polyomaviruses in samples derived from various animal species, degenerated PCR primer pairs were constructed. By using a nested PCR protocol, the sensitive detection of nine different polyomavirus genomes was demonstrated. The screening of field samples revealed the presence of a new polyomavirus, tentatively designated chimpanzee polyomavirus (ChPyV), in the feces of a juvenile chimpanzee (Pan troglodytes). Analysis of the region encoding the major capsid protein VP1 revealed a unique insertion in the EF loop of the protein and showed that ChPyV is a distinct virus related to the monkey polyomavirus B-lymphotropic polyomavirus and the human polyomavirus JC polyomavirus.