gebhart/patrepeval huggingface dataset:
Pharmacokinetics of Recombinant Factor IX after Intravenous and Subcutaneous Administration in Dogs and Cynomolgus Monkeys (2002)

Hemophilia B therapy requires intravenous (IV) infusions of large volumes of factor IX due to the low concentration of factor IX in concentrates (approximately 100 IU/mL). High concentration recombinant factor IX (rFIX) could be a significant advance since it would reduce the large volumes necessary for IV dosing and allow for low-volume subcutaneous (SC) administration. To evaluate high concentration factor IX, we produced formulations with either 2,000 or 4,000 IU/mL and studied the SC bioavailability in beagle dogs, cynomolgus monkeys and hemophilia B dogs along with efficacy in hemophilia B dogs. Beagle dog SC bioavailability was 86.4% using a 2000 IU/mL formulation and 77.0% using a 4000 IU/mL formulation. Monkey bioavailability of a 4000 IU/mL formulation of rFIX was 34.8%. A single SC administration of 200 IU/kg (4000 IU/mL) of rFIX to hemophilia B dogs, produced factor IX clotting activity above 5% for 5 days with a bioavailability of 48.6%. High concentration SC rFIX has an acceptable pharmacokinetic profile in monkeys and dogs, and produces a sustained FIX activity in hemophilic dogs.
Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells (2020)

The craniofacial developmental disorder Burn-McKeown Syndrome (BMKS) is caused by biallelic variants in the pre-messenger RNA splicing factor gene TXNL4A/DIB1. The majority of affected individuals with BMKS have a 34 base pair deletion in the promoter region of one allele of TXNL4A combined with a loss-of-function variant on the other allele, resulting in reduced TXNL4A expression. However, it is unclear how reduced expression of this ubiquitously expressed spliceosome protein results in craniofacial defects during development. Here we reprogrammed peripheral mononuclear blood cells from a BMKS patient and her unaffected mother into induced pluripotent stem cells (iPSCs) and differentiated the iPSCs into induced neural crest cells (iNCCs), the key cell type required for correct craniofacial development. BMKS patient-derived iPSCs proliferated more slowly than both mother- and unrelated control-derived iPSCs, and RNA-Seq analysis revealed significant differences in gene expression and alternative splicing. Patient iPSCs displayed defective differentiation into iNCCs compared to maternal and unrelated control iPSCs, in particular a delay in undergoing an epithelial-to-mesenchymal transition (EMT). RNA-Seq analysis of differentiated iNCCs revealed widespread gene expression changes and mis-splicing in genes relevant to craniofacial and embryonic development that highlight a dampened response to WNT signalling, the key pathway activated during iNCC differentiation. Furthermore, we identified the mis-splicing of TCF7L2 exon 4, a key gene in the WNT pathway, as a potential cause of the downregulated WNT response in patient cells. Additionally, mis-spliced genes shared common sequence properties such as length, branch point to 3' splice site (BPS-3'SS) distance and splice site strengths, suggesting that splicing of particular subsets of genes is particularly sensitive to changes in TXNL4A expression. Together, these data provide the first insight into how reduced TXNL4A expression in BMKS patients might compromise splicing and NCC function, resulting in defective craniofacial development in the embryo.
Necrotizing Enterocolitis in Horses: A Retrospective Study (1996)

The clinical and clinicopathologic characteristics of fatal necrotizing enterocolitis were examined in 16 horses (age 4 months to 12 years). At initial presentation, 8 of 16 horses were pyrexic (median temperature, 38.4 degrees C; range, 33.8 to 40.6 degrees C); all 16 were tachycardic (median heart rate, 93 bpm, range, 66 to 138 bpm); 13 of 16 were tachypneic (median heart rate, 36 bpm, range, 16 to 80 bpm), dehydrated, and had discolored mucous membranes. All horses that were pyrexic were also tachycardic and tachypneic. PCV was high (> 45%) in 14 horses. Six horses were leukopenic (< 5,000 cells/microL); 12 were neutropenic (< 2,300 cells/microL), and 14 had > 100 band neutrophils/microL. Twelve horses were acidemic (pH < 7.37; range, 6.88 to 7.33) and the venous bicarbonate concentration was low (< 23 mEq/L) in 14 horses. Median anion gap in 16 horses was 31.5 mEq/L (> 15 mEq/L in 15 horses). Eleven of 16 horses were hyponatremic (< 137 mEq/L), 1 horse was hypernatremic (> 143 mEq/L), 3 were hypokalemic (< 3.2 mEq/L), 6 were hyperkalemic (> 4.5 mEq/L), and 14 were hypochloremic (< 98 mEq/L). Serum creatinine concentrations were high (> 1.4 mg/dL) in 15 horses. Abdominal fluid was examined in 12 horses 4 had total protein concentrations > 2.5 g/dL and 6 had nucleated cell counts > 5,000/ microL and < 10,000/microL; none had > 10,000/microL. Eight of 12 samples revealed a nondegenerate neutrophilia (> 50%). Abdominal fluid collected from 4 horses immediately before death was normal in 2 horses and indicative of suppurative inflammation in 2. All 8 horses tested had low or nonexistent serum immunofluorescent antibody titers to Ehrlichia risticii. Four of 16 horses had Salmonella spp isolated from feces or tissues. All 16 horses either died (5 of 16; 31%) or were euthanized because of a grave prognosis. Median time to death was 45.5 hours (range, 7 to 113 hours) from the time of admission. Death was preceded by severe abdominal pain in 14 horses. Fatal necrotizing enterocolitis of horses is characterized by a brief course, profound dehydration, electrolyte derangements, acid-base abnormalities, and terminally, severe abdominal pain. Abdominal fluid analysis was frequently not indicative of the severity of disease.
Data-Free Learning of Student Networks (2019)

Learning portable neural networks is very essential for computer vision for the purpose that pre-trained heavy deep models can be well applied on edge devices such as mobile phones and micro sensors. Most existing deep neural network compression and speed-up methods are very effective for training compact deep models, when we can directly access the training dataset. However, training data for the given deep network are often unavailable due to some practice problems (\eg privacy, legal issue, and transmission), and the architecture of the given network are also unknown except some interfaces. To this end, we propose a novel framework for training efficient deep neural networks by exploiting generative adversarial networks (GANs). To be specific, the pre-trained teacher networks are regarded as a fixed discriminator and the generator is utilized for derivating training samples which can obtain the maximum response on the discriminator. Then, an efficient network with smaller model size and computational complexity is trained using the generated data and the teacher network, simultaneously. Efficient student networks learned using the proposed Data-Free Learning (DFL) method achieve 92.22% and 74.47% accuracies without any training data on the CIFAR-10 and CIFAR-100 datasets, respectively. Meanwhile, our student network obtains an 80.56% accuracy on the CelebA benchmark.
A Method for Preparing Oligodeoxynucleotides Containing an Apurinic Site (1990)

Abstract In three steps, 2‐deoxy‐ D ‐ribose has been converted into a phosphoramidite building block bearing a ( t ‐Bu)Me 2 Si protecting group at the OH function of the anomeric centre of the furanose ring. This building block was subsequently incorporated into DNA oligomers of various base sequences using the standard phosphoramidite protocol for automated DNA synthesis. The resulting silyl‐oligomers have been purified by HPLC and selectively desilylated to the corresponding free apurinic DNA sequences. The hexamer d (A‐A‐A‐A‐X‐A) (X representing the apurinic site) which was prepared in this way was characterized by 1 H‐ and 31 P‐NMR spectroscopy. The other sequences as well as their fragments, which formed upon treatment with alkali base, were analyzed by polyacrylamide gel electrophoresis.
Safety of fludarabine, mitoxantrone, and dexamethasone combined with rituximab in the treatment of stage IV indolent lymphoma. (2000)

Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA and IDEC Pharmaceutical Corporation, San Diego, CA) is an effective agent for the treatment of CD20-positive B-cell lymphomas. Because its toxicities are minimal and do not overlap with the toxicities of standard chemotherapy, it is an appealing agent to use in combination with chemotherapy. Moreover, there is evidence for synergy between rituximab and some chemotherapeutic agents. The combination of fludarabine/ mitoxantrone/dexamethasone (FND) has been a well-tolerated and effective regimen for the treatment of indolent lymphomas. When given together with prophylaxis for Pneumocystis carinii, infectious complications with FND have been modest. We report on preliminary safety data using FND in conjunction with rituximab, along with maintenance alpha interferon. Toxicity has been modest. The concurrent use of rituximab with FND modestly increases neutropenia, but has not resulted in any change in the pattern of infectious or other toxicity that occurs with FND alone.
Systemic Delivery of Synthetic MicroRNA-16 Inhibits the Growth of Metastatic Prostate Tumors via Downregulation of Multiple Cell-cycle Genes (2009)

Recent reports have linked the expression of specific microRNAs (miRNAs) with tumorigenesis and metastasis. Here, we show that microRNA (miR)-16, which is expressed at lower levels in prostate cancer cells, affects the proliferation of human prostate cancer cell lines both in vitro and in vivo. Transient transfection with synthetic miR-16 significantly reduced cell proliferation of 22Rv1, Du145, PPC-1, and PC-3M-luc cells. A prostate cancer xenograft model revealed that atelocollagen could efficiently deliver synthetic miR-16 to tumor cells on bone tissues in mice when injected into tail veins. In the therapeutic bone metastasis model, injection of miR-16 with atelocollagen via tail vein significantly inhibited the growth of prostate tumors in bone. Cell model studies indicate that miR-16 likely suppresses prostate tumor growth by regulating the expression of genes such as CDK1 and CDK2 associated with cell-cycle control and cellular proliferation. There is a trend toward lower miR-16 expression in human prostate tumors versus normal prostate tissues. Thus, this study indicates the therapeutic potential of miRNA in an animal model of cancer metastasis with systemic miRNA injection and suggest that systemic delivery of miR-16 could be used to treat patients with advanced prostate cancer.
Clinical relevance of kallikrein-related peptidase 6 (KLK6) and 8 (KLK8) mRNA expression in advanced serous ovarian cancer (2016)

Most members of the kallikrein-related peptidase family have been demonstrated to be dysregulated in ovarian cancer and modulate tumor growth, migration, invasion, and resistance to chemotherapy. In the present study, we assessed the mRNA expression levels of KLK6 and KLK8 by quantitative PCR in 100 patients with advanced serous ovarian cancer FIGO stage III/IV. A pronounced correlation between KLK6 and KLK8 mRNA expression (rs = 0.636, p < 0.001) was observed, indicating coordinate expression of both peptidases. No significant associations of clinical parameters with KLK6, KLK8, and a combined score KLK6+KLK8 were found. In univariate Cox regression analysis, elevated mRNA levels of KLK6 were significantly linked with shortened overall survival (OS) (hazard ratio [HR] = 2.07, p = 0.007). While KLK8 values were not associated with patients' outcome, high KLK6+KLK8 values were significantly associated with shorter progression-free survival (HR = 1.82, p = 0.047) and showed a trend towards significance in the case of OS (HR = 1.82, p = 0.053). Strikingly, in multivariable analysis, elevated KLK6 mRNA values, apart from residual tumor mass, remained an independent predictive marker for poor OS (HR = 2.33, p = 0.005). As KLK6 mRNA and protein levels correlate, KLK6 may represent an attractive therapeutic target for potent and specific inhibitors of its enzymatic activity.
Total Synthesis of Pradimicinone, the Common Aglycon of the Pradimicin–Benanomicin Antibiotics (1999)

A benzo[a]naphthacenequinone core, an amino acid, and a disaccharide are the constituents of pradimicin-benanomicin antibiotics 1 (R<sup>1</sup> =disaccharide), a class of natural products with significant antifungal and anti-HIV activities. The first total synthesis of pradimicinone (benanomicinone, 1; R<sup>1</sup> =H), the common aglycon of this class of natural products, has now been achieved based on the transmission of chirality during the pinacol cyclization of 2,2'-biaryldicarbaldehydes.
Involvement of Brca1 in S-Phase and G 2 -Phase Checkpoints after Ionizing Irradiation (2001)

Cell cycle arrests in the G(1), S, and G(2) phases occur in mammalian cells after ionizing irradiation and appear to protect cells from permanent genetic damage and transformation. Though Brca1 clearly participates in cellular responses to ionizing radiation (IR), conflicting conclusions have been drawn about whether Brca1 plays a direct role in cell cycle checkpoints. Normal Nbs1 function is required for the IR-induced S-phase checkpoint, but whether Nbs1 has a definitive role in the G(2)/M checkpoint has not been established. Here we show that Atm and Brca1 are required for both the S-phase and G(2) arrests induced by ionizing irradiation while Nbs1 is required only for the S-phase arrest. We also found that mutation of serine 1423 in Brca1, a target for phosphorylation by Atm, abolished the ability of Brca1 to mediate the G(2)/M checkpoint but did not affect its S-phase function. These results clarify the checkpoint roles for each of these three gene products, demonstrate that control of cell cycle arrests must now be included among the important functions of Brca1 in cellular responses to DNA damage, and suggest that Atm phosphorylation of Brca1 is required for the G(2)/M checkpoint.
SEDA: An Architecture for Scalable, Well-Conditioned Internet Services (2001)

We were able to show that the use of HRT before the diagnosis of breast cancer results in more favorable primary tumors, with a lower incidence of recurrences and a better overall survival rate. This might be due to normalized bone metabolism by the use of HRT, which may lower the conditions of tumor cell seeding.
Insulin Analogues with Modifications at Position B26. Divergence of Binding Affinity and Biological Activity (2008)

In this study, we prepared several shortened and full-length insulin analogues with substitutions at position B26. We compared the binding affinities of the analogues for rat adipose membranes with their ability to lower the plasma glucose level in nondiabetic Wistar rats in vivo after subcutaneous administration, and also with their ability to stimulate lipogenesis in vitro. We found that [NMeHisB26]-DTI-NH 2 and [NMeAlaB26]-DTI-NH 2 were very potent insulin analogues with respect to their binding affinities (214 and 465%, respectively, compared to that of human insulin), but they were significantly less potent than human insulin in vivo. Their full-length counterparts, [NMeHisB26]-insulin and [NMeAlaB26]-insulin, were less effective than human insulin with respect to binding affinity (10 and 21%, respectively) and in vivo activity, while [HisB26]-insulin exhibited properties similar to those of human insulin in all of the tests we carried out. The ability of selected analogues to stimulate lipogenesis in adipocytes was correlated with their biological potency in vivo. Taken together, our data suggest that the B26 residue and residues B26-B30 have ambiguous roles in binding affinity and in vivo activity. We hypothesize that our shortened analogues, [NMeHisB26]-DTI-NH 2 and [NMeAlaB26]-DTI-NH 2, have different modes of interaction with the insulin receptor compared with natural insulin and that these different modes of interaction result in a less effective metabolic response of the insulin receptor, despite the high binding potency of these analogues.
Hybrid Cone-Beam Tomographic Reconstruction: Incorporation of Prior Anatomical Models to Compensate for Missing Data (2010)

We propose a method for improving the quality of cone-beam tomographic reconstruction done with a C-arm. C-arm scans frequently suffer from incomplete information due to image truncation, limited scan length, or other limitations. Our proposed "hybrid reconstruction" method injects information from a prior anatomical model, derived from a subject-specific computed tomography (CT) or from a statistical database (atlas), where the C-arm X-ray data is missing. This significantly reduces reconstruction artifacts with little loss of true information from the X-ray projections. The methods consist of constructing anatomical models, fast rendering of digitally reconstructed radiograph (DRR) projections of the models, rigid or deformable registration of the model and the X-ray images, and fusion of the DRR and X-ray projections, all prior to a conventional filtered back-projection algorithm. Our experiments, conducted with a mobile image intensifier C-arm, demonstrate visually and quantitatively the contribution of data fusion to image quality, which we assess through comparison to a "ground truth" CT. Importantly, we show that a significantly improved reconstruction can be obtained from a C-arm scan as short as 90° by complementing the observed projections with DRRs of two prior models, namely an atlas and a preoperative same-patient CT. The hybrid reconstruction principles are applicable to other types of C-arms as well.
Developmental Biology Protocols (2000)

Cover illustration taken from Fig. I in this series. It is a composite three-dimensional view of epifluorescence micrographs of representative stages of the developing rat embryo coated with acridine orange and imaged in toto by confocal laser-scanning microscopy.
Predictive Parameters of Successful Varicocele Repair (1986)

A total of 130 men presenting with oligospermia and clinically identifiable scrotal varicoceles was evaluated, treated surgically and followed for 1 year for pregnancy rate. The treatment outcome was compared to an age-matched cohort of 83 oligospermic men who had received empirical medical therapy with clomiphene citrate (25 mg. per day) for the same 1-year interval. This study was done to contrast treatment modalities in infertility and not as a strict control. Only eugonadotropic patients in both groups were used for comparison. In the varicocele group the over-all pregnancy rate was 38.5 per cent. Four variables (a lack of testicular atrophy, sperm density greater than 50 million per ejaculate, sperm motility 60 per cent or more and serum follicle-stimulating hormone values less than 300 ng. per ml.) proved to be accurate preoperative predictors of postoperative pregnancy success. Four other variables (varicocele size and laterality, sperm forward progression greater than 2 and normal sperm morphology 60 per cent or more) did not yield statistically significant rates of improvement in pregnancy postoperatively. The pregnancy rate of the eugonadotropic patients undergoing varicocele repair was 45.8 per cent. Despite statistical similarity in patient age, sperm density and mean gonadotropin levels the medically treated patients had a pregnancy rate of only 25.5 per cent, significantly lower than the surgically treated patients. In summary, patients with an identifiable varicocele had a greater chance of achieving a pregnancy following surgical correction than did those treated with empirical drug therapy. In addition, certain preoperative variables in the physical and laboratory analyses appeared to portend a greater surgical response.
Nanoscale Resolution in the Focal Plane of an Optical Microscope (2005)

Utilizing single fluorescent molecules as probes, we prove the ability of a far-field microscope to attain spatial resolution down to 16 nm in the focal plane, corresponding to about 1/50 of the employed wavelength. The optical bandwidth expansion by nearly an order of magnitude is realized by a saturated depletion through stimulated emission of the molecular fluorescent state. We demonstrate that en route to the molecular scale, the resolving power increases with the square root of the saturation level, which constitutes a new law regarding the resolution of an emerging class of far-field light microscopes that are not limited by diffraction.
Clinical, pathological, cellular and molecular lesions caused by oral smokeless tobacco – a review (2007)

While carcinogenicity of smokeless tobacco (ST) to humans is well established the oral lesions that precede development of cancer are less well characterized. The clinical appearances of ST-associated lesions are variable. Epidemiological studies show a strong significant association of risk with chronic daily use but population differences are noted because of various commercial products in use. Morphological features observed are some what different to oral lesions caused by smoking and oral dysplasia in ST-associated lesions is less common. Effects of ST on oral keratinocytes observed in vitro include alterations in cell proliferation, apoptosis and activation of inflammatory markers. Genetic aberrations caused by ST include activation of ras, uncommon in smokers but mutational hot spots in p53 encountered are similar to those in smokers.
Isolation and Characterization of Two Major Urinary Metabolites of Δ 1 -Tetrahydrocannabinol (1972)

Two of the major metabolites which appear in rabbit urine after the administration of Delta(1)-tetrahydrocannabinol have been isolated and their structures have been tentatively established. The available evidence indicates that they are 7-carboxy-Delta(1)-tetrahydrocannabinols with an additional hydroxyl group on the side chain. The substances occur both free and as conjugates.
Preparation and Characterization of MKT-077 Nanoparticles for Treatment of Alzheimer’s Disease and Other Tauopathies (2015)

Alzheimer’s disease is one of the most common causes of dementia and death in elderly populations. However, therapeutic intervention in Alzheimer’s disease is limited by the blood-brain barrier, which not only protects the brain by limiting the permeation of potential toxins into neural tissue but also by blocking certain drugs aimed at neurological disorders. MKT-077 is one such drug, which has shown promise in reducing Alzheimer’s disease- related pathology in cellular models but has limited brain permeation due to blockage by the blood-brain barrier. Herein, we describe the formulation and characterization of brain-targeted PEG-PLGA nanoparticles coated in 2% w/v glutathione to get higher blood-brain barrier permeation. Average nanoparticle size was found to be 230nm, suitable for intravenous administration and brain permeation. The nanoparticles showed steady, sustained release of MKT-077 in in vitro settings. Transwell in vitro blood-brain barrier model permeation studies showed the permeation of nanoparticles across the Transwell model to be greater than drug solution over 48 hours. The proposed model shows promise as a potential therapy against Alzheimer’s disease and other tauopathies.