gebhart/patrepeval huggingface dataset:
The Triple Classification of Dry Eye for Practical Clinical Use (2005)

The following classification has been established: First, a classification of the etio-pathogenesis, distributed in ten groups: age-related, hormonal, pharmacologic, immunopathic, hyponutritional, dysgenic, infectious/inflammatory, traumatic, neurologic and tantalic. Second, a classification of the affected glands and tissues, which under the acronym of ALMEN includes the Aqueo-serousdeficient, Lipodeficient, Mucindeficient and Epitheliopatic dry eyes, and the Non dacryological affected exocrine glands (saliva, nasal secretion, tracheo-pharyngeal secretion, etc). And thirdly, a classification of severity, in three grades: Grade 1 or mild (symptoms without slitlamp signs), grade 2 or moderate (symptoms with reversible signs), and grade 3 or severe (symptoms with permanent signs).
Estrogen receptor modulator review (2006)

The past few years have seen considerable advances in the development of estrogen receptor (ER) modulators and in the understanding of their interaction on estrogen pathways. Whilst prototypical steroidal estrogen agonists have long been appreciated for their use in female contraception and estrogen replacement therapy, more recent investigations have focused on subtype estrogen receptor modulators with selectivity for use in rapidly expanding treatment modalities. As estrogenic effects are primarily mediated through two receptors, defined as ERα and ERβ, significant interest has been dedicated to identifying subtype-selective agonists, antagonists and selective estrogen receptor modulators (SERMs). Additional effort has been dedicated to finding non-subtype-selective SERMs with new utility or improved profiles. Many of these recently identified ligands represent real advances in terms of their preclinical profile with the potential to one day provide novel treatments. This review highlights recent developments on the structural and biological data reported for ER modulators in the patent and scientific literature during the period 2003 – 2005.
Gene therapy for hemoglobinopathies: are we there yet? (2004)

beta-Thalassemia and sickle cell disease constitute the most common single gene defect in humans and are characterized by absent/reduced and abnormal beta-globin, respectively. Patients with these hemoglobinopathies require chronic blood transfusions and rely on bone marrow transplant for a potential cure. Gene therapy provides a viable alternative by permanent correction of the defect in hematopoietic stem cells, but it has suffered from problems of vector instability, low viral titers, and variable expression of globin genes for more than a decade. This paper reviews the field of gene therapy for hemoglobinopathies with emphasis on the complexities of the beta-globin gene and its regulation, obstacles that have impeded progress, and recent advances in vector technology that will take this field forward toward the goal of successful genetic correction of these devastating diseases.
Telomeres and telomerase in cancer (2009)

Myriad genetic and epigenetic alterations are required to drive normal cells toward malignant transformation. These somatic events commandeer many signaling pathways that cooperate to endow aspiring cancer cells with a full range of biological capabilities needed to grow, disseminate and ultimately kill its host. Cancer genomes are highly rearranged and are characterized by complex translocations and regional copy number alterations that target loci harboring cancer-relevant genes. Efforts to uncover the underlying mechanisms driving genome instability in cancer have revealed a prominent role for telomeres. Telomeres are nucleoprotein structures that protect the ends of eukaryotic chromosomes and are particularly vulnerable due to progressive shortening during each round of DNA replication and, thus, a lifetime of tissue renewal places the organism at risk for increasing chromosomal instability. Indeed, telomere erosion has been documented in aging tissues and hyperproliferative disease states-conditions strongly associated with increased cancer risk. Telomere dysfunction can produce the opposing pathophysiological states of degenerative aging or cancer with the specific outcome dictated by the integrity of DNA damage checkpoint responses. In most advanced cancers, telomerase is reactivated and serves to maintain telomere length and emerging data have also documented the capacity of telomerase to directly regulate cancer-promoting pathways. This review covers the role of telomeres and telomerase in the biology of normal tissue stem/progenitor cells and in the development of cancer.
Simulation study of reticle enhancement technology applications for 157-nm lithography (2002)

The acceleration of the International Technology Roadmap for Semiconductors (ITRS) is placing significant pressure on the industry's infrastructure, particularly the lithography equipment. As recently as 1997, there was no optical solution offered past the 130 nm design node. The current roadmap has the 65 nm node (reduced from 70 nm) pulled in one year to 2007. Both 248 nm and 193 nm wavelength lithography tools will be pushed to their practical resolution limits in the near term. Very high numerical aperture (NA) 193 nm exposure tools in conjunction with resolution enhancement techniques (RET) will postpone the requirement for 157 nm lithography in manufacturing. However, ICs produced at 70 nm design rules with manufacturable k 1 values will require that 157 nm wavelength lithography tools incorporate the same RETs utilized in 248nm, and 193 nm tools. These enhancements will include Alternating Phase Shifting Masks (AltPSM) and Optical Proximity Correction (OPC) on F 2 doped quartz reticle substrates. This study investigates simulation results when AltPSM is applied to sub-100 nm test patterns in 157 nm lithography in order to maintain Critical Dimension (CD) control for both nested and isolated geometries. Aerial image simulations are performed for a range of numerical apertures, chrome regulators, gate pitches and gate widths. The relative performance for phase shifted versus binary structures is also compared. Results are demonstrated in terms of aerial image contrast and process window changes. The results clearly show that a combination of high NA and RET is necessary to achieve usable process windows for 70 nm line/space structures. In addition, it is important to consider two-dimensional proximity effects for sub-100 nm gate structures.
Formation of the 67-kDa laminin receptor by acylation of the precursor (1998)

Even though the involvement of the 67-kDa laminin receptor (67LR) in tumor invasiveness has been clearly demonstrated, its molecular structure remains an open problem, since only a full-length gene encoding a 37-kDa precursor protein (37LRP) has been isolated so far. A pool of recently obtained monoclonal antibodies directed against the recombinant 37LRP molecule was used to investigate the processing that leads to the formation of the 67-kDa molecule. In soluble extracts of A431 human carcinoma cells, these reagents recognize the precursor molecule as well as the mature 67LR and a 120-kDa molecule. The recovery of these proteins was found to be strikingly dependent upon the cell solubilization conditions: the 67LR is soluble in NP-40-lysis buffer whereas the 37LRP is NP-40-insoluble. Inhibition of 67LR formation by cerulenin indicates that acylation is involved in the processing of the receptor. It is likely a palmitoylation process, as indicated by sensitivity of NP-40-soluble extracts to hydroxylamine treatment. Immunoblotting assays performed with a polyclonal serum directed against galectin3 showed that both the 67- and the 120-kDa proteins carry galectin3 epitopes whereas the 37LRP does not. These data suggest that the 67LR is a heterodimer stabilized by strong intramolecular hydrophobic interactions, carried by fatty acids bound to the 37LRP and to a galectin3 cross-reacting molecule.
Analysis of stacked rotated gratings (2007)

We study the rigorous design and analysis of stacked rotated gratings (SRGs) for novel photonic devices. A concept of sampling frequency is proposed to systematically design SRGs. With the help of a rectangular sampling lattice, we extend the standard 3D rigorous coupled-wave analysis (RCWA) algorithm to the analysis of SRGs. The resultant SRG-RCWA algorithm can be used to exactly analyze SRGs that have grating parameters that match the Fourier expansion represented by the sampling lattice. SRGs that do not fall in this category can often still be closely approximated with our approach. The SRG-RCWA algorithm has been successfully applied to the characterization of two fabricated SRGs that are designed to function as circular polarization filters for an IR imaging polarimetry system. The agreement between numerical SRG-RCWA results and experimental measurements demonstrates its validity and usefulness.
Hemodynamic Response to Pharmacological Treatment of Portal Hypertension and Long–Term Prognosis of Cirrhosis (2003)

In cirrhotic patients under pharmacologic treatment for portal hypertension, a reduction in hepatic venous pressure gradient (HVPG) of ≥20% of baseline or to ≤12 mm Hg markedly reduces the risk of variceal rebleeding. This study was aimed at evaluating whether these hemodynamic targets also prevent other complications of portal hypertension and improve long–term survival. One hundred five cirrhotic patients included in prospective trials for the prevention of variceal rebleeding were studied. Seventy–three of the patients had 2 separate HVPG measurements, at baseline and under pharmacologic therapy with propranolol ± isosorbide mononitrate. Patients were followed for up to 8 years. Survival and risk of developing portal hypertension–related complications were compared between responders and nonresponders. Twenty–eight patients showed a reduction of HVPG ≥20% of baseline or to ≤12 mm Hg (responders), and 45 patients were nonresponders. Nonresponders had a significantly greater risk of developing variceal rebleeding ( P = .013), ascites ( P = .025), spontaneous bacterial peritonitis ( P = .003), hepatorenal syndrome ( P = .026), and hepatic encephalopathy ( P = .024) than responders. Eight–year cumulative probability of survival was significantly lower in nonresponders than in responders (52% vs. 95%, respectively, P = .003). At multivariate analysis, being a nonresponder was independently associated with the risk of developing rebleeding, ascites, spontaneous bacterial peritonitis, and lower survival. In conclusion, in cirrhotic patients receiving pharmacologic treatment for prevention of variceal rebleeding, a decrease in HVPG ≥20% or to ≤12 mm Hg is associated with a marked reduction in the long–term risk of developing complications of portal hypertension and with improved survival. (Hepatology 2003;37:902–908.)
Opposing Roles for ATF6α and ATF6β in Endoplasmic Reticulum Stress Response Gene Induction (2004)

The endoplasmic reticulum (ER) transmembrane proteins, ATF6alpha and ATF6beta, are cleaved in response to ER stress, which can be induced by tunicamycin. The resulting N-terminal fragments of both ATF6 isoforms, which have conserved basic leucine-zipper and DNA binding domains but divergent transcriptional activation domains, translocate to the nucleus where they bind to ER stress-response elements (ERSE) in ER stress-response genes (ERSRG), such as GRP78. Although it is known that ATF6alpha is a potent activator of ERSRGs, the transcriptional potency and functions of ATF6beta remain to be explored. Accordingly, N-terminal fragments of each ATF6 isoform (N-ATF6alpha and N-ATF6beta) were overexpressed in HeLa cells and the effects on GRP78 induction were assessed. When expressed at similar levels, N-ATF6alpha conferred approximately 200-fold greater GRP78 promoter activation than N-ATF6beta. Because ER stress activates nuclear translocation of both ATF6alpha and beta and because both bind to ERSEs, the effect of co-expressing them on GRP78 induction was assessed. Surprisingly, N-ATF6beta inhibited N-ATF6alpha-mediated GRP78 promoter activation in a dominant-negative manner. Moreover, N-ATF6beta inhibited TN-mediated GRP78 promoter activation, which requires endogenous ATF6alpha. ATF6 isoform-specific small inhibitory RNAs were used to show that, as expected, endogenous ATF6alpha was required for maximal ERSRG induction; however, endogenous ATF6beta moderated ERSRG induction. These results indicate that compared with ATF6alpha, ATF6beta is a very poor activator of ERSRG induction and it represses ATF6alpha-mediated ERSRG induction. Thus, ATF6beta may serve as a transcriptional repressor functioning in part to regulate the strength and duration of ATF6alpha-mediated ERSRG activation during the ER stress response.
Soluble T Cell Immunoglobulin Mucin Domain 3 Is Shed from CD8 + T Cells by the Sheddase ADAM10, Is Increased in Plasma during Untreated HIV Infection, and Correlates with HIV Disease Progression (2015)

Despite the overall success of HAART in slowing the progression to AIDS in HIV-infected subjects, chronic immune activation and T cell exhaustion contribute to the eventual deterioration of the immune system. Understanding these processes will aid in the development of interventions and therapeutics to be used in combination with HAART to slow or reverse this deterioration. Here, we show that a soluble form of T cell exhaustion associated coinhibitory molecule 3, sTim-3, is shed from the surface of T cells. Furthermore, sTim-3 is elevated in the plasma of treatment-naive subjects with acute or chronic HIV infection and is associated with markers of disease progression. This is the first study to characterize sTim-3 in human plasma, its source, and mechanism of production. While it is still unclear whether sTim-3 contributes to HIV pathogenesis, sTim-3 may represent a new correlate of HIV disease progression.
A Sequence of the CIS Gene Promoter Interacts Preferentially with Two Associated STAT5A Dimers: a Distinct Biochemical Difference between STAT5A and STAT5B (1998)

Two distinct genes encode the closely related signal transducer and activator of transcription proteins STAT5A and STAT5B. The molecular mechanisms of gene regulation by STAT5 and, particularly, the requirement for both STAT5 isoforms are still undetermined. Only a few STAT5 target genes, among them the CIS (cytokine-inducible SH2-containing protein) gene, have been identified. We cloned the human CIS gene and studied the human CIS gene promoter. This promoter contains four STAT binding elements organized in two pairs. By electrophoretic mobility shift assay studies using nuclear extracts of UT7 cells stimulated with erythropoietin, we showed that these four sequences bound to STAT5-containing complexes that exhibited different patterns and affinities: the three upstream STAT binding sequences bound to two distinct STAT5-containing complexes (C0 and C1) and the downstream STAT box bound only to the slower-migrating C1 band. Using nuclear extracts from COS-7 cells transfected with expression vectors for the prolactin receptor, STAT5A, and/or STAT5B, we showed that the C1 complex was composed of a STAT5 tetramer and was dependent on the presence of STAT5A. STAT5B lacked this property and bound with a stronger affinity than did STAT5A to the four STAT sequences as a homodimer (C0 complex). This distinct biochemical difference between STAT5A and STAT5B was confirmed with purified activated STAT5 recombinant proteins. Moreover, we showed that the presence on the same side of the DNA helix of a second STAT sequence increased STAT5 binding and that only half of the palindromic STAT binding sequence was sufficient for the formation of a STAT5 tetramer. Again, STAT5A was essential for this cooperative tetrameric association. This property distinguishes STAT5A from STAT5B and could be essential to explain the transcriptional regulation diversity of STAT5.
Uganda - Second Private Sector Export Competitiveness Project : environmental assessment (2004)

Within the framework of the Second Private Sector Export Competitiveness Project, it is intended to construct an industrial and business park at Namanve, close to the capital city of Kampala. A certain area (some fifty percent of land in Namanve South) within this park, comprises wetlands, and natural drainage areas, consequently, a high percentage of the road network will be constructed on imported fill material, which given the topography and ground conditions, presents difficult site drainage, and thus, further inconveniences concerning sewage treatment works. Adverse environmental impacts expected during construction, and operational phases have been identified on topography, geology and soils, flora and fauna, wetland areas, water, air, noise and dust pollution, waste handlings and soil contamination, and, socioeconomic impacts. Mitigation measures stipulate the following. A newly created Business Park Authority shall be responsible for monitoring and reporting on industry performance, and to disseminate public information, and, on training the work force. The use of borrow sites shall be regulated, while low swampy areas will not be classified for construction of buildings. Large scale grading and excavation will be minimized to ensure adequate drainage, and sewage treatment works. Selected areas should be identified for stockpiling topsoil for future landscaping, and, illegal mining or quarrying operations will not be permitted. The Uganda Wildlife Authority and other agencies, will be responsible of conserving, and managing endangered species, including indigenous species, while Business Park officials shall monitor all operations, such as forest conservation, vegetation, and natural habitats. Effluents shall be pre-treated by industries prior to being channeled to the sewage treatment works, to mitigate passage through wetlands, and, in addition, water quality will be tested. Traffic emissions will be monitored in compliance with emission standards, while construction should be limited to daytime schedules to reduce noise disturbances. Contingency plans will ensure compliance with standard practices to minimize, handle, and store hazardous wastes. Similarly, water pollution control shall include pre-treatment of effluents, enforcing waste treatment and effluent standards. Reduction and recycling of solid wastes will be encouraged, through a waste management plan, and disposal plan.
Sacituzumab Govitecan (IMMU-132), an Anti-Trop-2/SN-38 Antibody–Drug Conjugate: Characterization and Efficacy in Pancreatic, Gastric, and Other Cancers (2015)

Sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate (ADC) made from a humanized anti-Trop-2 monoclonal antibody (hRS7) conjugated with the active metabolite of irinotecan, SN-38. In addition to its further characterization, as the clinical utility of IMMU-132 expands to an ever-widening range of Trop-2-expressing solid tumor types, its efficacy in new disease models needs to be explored in a nonclinical setting. Unlike most ADCs that use ultratoxic drugs and stable linkers, IMMU-132 uses a moderately toxic drug with a moderately stable carbonate bond between SN-38 and the linker. Flow cytometry and immunohistochemistry disclosed that Trop-2 is expressed in a wide range of tumor types, including gastric, pancreatic, triple-negative breast (TNBC), colonic, prostate, and lung. While cell-binding experiments reveal no significant differences between IMMU-132 and parental hRS7 antibody, surface plasmon resonance analysis using a Trop-2 CM5 chip shows a significant binding advantage for IMMU-132 over hRS7. The conjugate retained binding to the neonatal receptor, but it lost greater than 60% of the antibody-dependent cell-mediated cytotoxicity activity compared to that of hRS7. Exposure of tumor cells to either free SN-38 or IMMU-132 demonstrated the same signaling pathways, with pJNK1/2 and p21(WAF1/Cip1) upregulation followed by cleavage of caspases 9, 7, and 3, ultimately leading to poly-ADP-ribose polymerase cleavage and double-stranded DNA breaks. Pharmacokinetics of the intact ADC in mice reveals a mean residence time (MRT) of 15.4 h, while the carrier hRS7 antibody cleared at a similar rate as that of the unconjugated antibody (MRT ∼ 300 h). IMMU-132 treatment of mice bearing human gastric cancer xenografts (17.5 mg/kg; twice weekly × 4 weeks) resulted in significant antitumor effects compared to that of mice treated with a nonspecific control. Clinically relevant dosing schemes of IMMU-132 administered either every other week, weekly, or twice weekly in mice bearing human pancreatic or gastric cancer xenografts demonstrate similar, significant antitumor effects in both models. Current Phase I/II clinical trials ( ClinicalTrials.gov , NCT01631552) confirm anticancer activity of IMMU-132 in cancers expressing Trop-2, including gastric and pancreatic cancer patients.
Central administration of GLP-1-(7-36) amide inhibits food and water intake in rats (1996)

Glucagon-like peptide (GLP)-1-(7-36) amide and its pancreatic receptors are important for control of blood glucose levels. However, rat GLP-1 receptors are also localized in the brain, in hypothalamus, and in areas without a blood-brain barrier. When rats were kept on a food restriction schedule, intracerebroventricular injection of GLP-1 just before food was offered inhibited food intake. However, peripheral GLP-1 administration by intraperitoneal injection had little effect. GLP-1 effects on water intake and output were also investigated. Intracerebroventricular GLP-1 profoundly inhibited angiotensin II-induced drinking behavior in rats, and water intake was suppressed by exogenous GLP-1 in rats habituated to a water restriction schedule. These effects were reproduced by intraperitoneal administration of GLP-1. Furthermore, intracerebroventricular GLP-1 stimulated urinary excretion of water and sodium. The centrally elicited effects were blocked by the GLP-1 antagonist exendin-(9-39) amide, whereas the N-terminally extended and inactive GLP-1-(1-36) amide had no effect on feeding and drinking. GLP-1 had no effect in behavioral assays measuring exploratory locomotor activity and conditioned taste aversion. In conclusion, GLP-1 may play a physiological role in regulation of both ingestion and the water and salt homeostasis.
Use of Virologic Markers in Clinical Practice (1997)

A number of virologic and immunologic markers, including serum human immunodeficiency virus (HIV)-1 p24 antigen levels, quantitative HIV-1 microculture of plasma or peripheral blood mononuclear cells, and CD4 cell counts, have been used over the past decade to monitor progression of HIV infection. Although these markers are useful, they have not provided a reliable means of assessing prognosis at all stages of the disease or response to antiretroviral treatment. New molecular techniques are now available that measure viral load in HIV-infected patients by detecting and quantifying virion-associated RNA circulating in plasma. These plasma HIV-1 RNA levels appear to correlate with the clinical disease stage and reflect the response to antiretroviral treatment. Because recent studies have demonstrated that baseline plasma HIV-1 RNA levels and changes in these levels are predictive of clinical outcome, it is strongly recommended that these markers be measured routinely and used as a guide in the management of all patients with HIV disease.