gebhart/patrepeval huggingface dataset:
International trends and patterns of prostate cancer incidence and mortality (2000)

Prostate cancer is the most commonly diagnosed cancer in western men, and incidence is rising rapidly in most countries, including low-risk populations. Age-adjusted incidence and mortality rates from 15 and 13 countries between 1973-77 and 1988-92, respectively, were compared to provide leads for future analytic studies. Large increases in both incidence and mortality rates of prostate cancer were seen for all countries. For incidence, increases were more pronounced in the United States, Canada, Australia, France and the Asian countries, while the increases in medium-risk countries were moderate. Increases in incidence ranged from 25%-114%, 24%-55% and 15%-104% in high-, medium- and low-risk countries, respectively. Mortality rates rose more rapidly in Asian countries than in high-risk countries. Substantial differences in incidence and mortality across countries were evident, with U.S. blacks having rates that were 50-60 times higher than the rates in Shanghai, China. Increasing incidence rates in the United States and Canada are likely to be due in part to the widespread use of transurethral resection of the prostate and prostate-specific antigen testing, while increases in the Asian countries are probably related to westernization in these low-risk populations. The large disparities in incidence between high- and low-risk countries may be due to a combination of genetic and environmental factors. Future studies are needed to examine gene-gene and gene-environment interactions in various countries concurrently to shed light on the etiology of prostate cancer and to help elucidate reasons for the large differences in risk between populations.
Review of pseudoinverse control for use with kinematically redundant manipulators (1983)

Kinematically redundant manipulators have a number of potential advantages over current manipulator designs. For this type of arm, velocity control through pseudoinverses is suggested. Questions associated with pseudoinverse control are examined in detail and show that in some cases this control leads to undesired arm configurations. A method for distributing joint angles of a redundant arm in a good approximation to a true minimax criterion is described. In addition several numerical considerations are discussed.
Human eosinophils, acidic tetrapeptides (ECF-A) and histamine. Interactions in vitro and in vivo. (1977)

The ECF-A acidic tetrapeptides Val-Gly-Ser-Glu, Ala-Gly-Ser-Glu and the analogue Val-Gly-Asp-Glu were selectively chemotactic for human eosinophils over a narrow dose range although eosinophils from different individuals varied in their dose-response pattern. Histamine abrogated the chemotactic properties of the individual tetrapeptides. When Val-Gly-Ser-Glu and Ala-Gly-Ser-Glu were combined in various concentrations the resultant chemotaxis was either negligible or no greater than that produced when each peptide was tested separately. Val-Gly-Ser-Glu and Ala-Gly-Ser-Glu both promoted eosinophil accumulation when applied to the abraded skin of man or i.d. to the marmoset. Biopsies of marmoset skin revealed that peptide-induced eosinophilia was not associated with mast-cell degranulation. Histamine, which was chemotactic in vitro, did not lead to appreciable eosinophil accumulation in vivo, and combinations of histamine and the acidic tetrapeptides evoked little or no cutaneous eosinophil infiltration either in man or the marmoset. These studies suggest that there is a complex interaction between histamine and the ECF-A tetrapeptides; however, the tetrapeptides alone can promote the recruitment and localization of eosinophils by a mechanism apparently independent of mast-cell degranulation.
A Scalable, Non-blocking Approach to Transactional Memory (2007)

Transactional memory (TM) provides mechanisms that promise to simplify parallel programming by eliminating the need for locks and their associated problems (deadlock, livelock, priority inversion, convoying). For TM to be adopted in the long term, not only does it need to deliver on these promises, but it needs to scale to a high number of processors. To date, proposals for scalable TM have relegated livelock issues to user-level contention managers. This paper presents the first scalable TM implementation for directory-based distributed shared memory systems that is livelock free without the need for user-level intervention. The design is a scalable implementation of optimistic concurrency control that supports parallel commits with a two-phase commit protocol, uses write-back caches, and filters coherence messages. The scalable design is based on transactional coherence and consistency (TCC), which supports continuous transactions and fault isolation. A performance evaluation of the design using both scientific and enterprise benchmarks demonstrates that the directory-based TCC design scales efficiently for NUMA systems up to 64 processors
2-Hydroxypropyl-β-cyclodextrin Promotes Transcription Factor EB-mediated Activation of Autophagy (2014)

2-Hydroxypropyl-β-cyclodextrin (HPβCD) is a Food and Drug Administration-approved excipient used to improve the stability and bioavailability of drugs. Despite its wide use as a drug delivery vehicle and the recent approval of a clinical trial to evaluate its potential for the treatment of a cholesterol storage disorder, the cellular pathways involved in the adaptive response that is activated upon exposure to HPβCD are still poorly defined. Here, we show that cell treatment with HPβCD results in the activation of the transcription factor EB, a master regulator of lysosomal function and autophagy, and in enhancement of the cellular autophagic clearance capacity. HPβCD administration promotes transcription factor EB-mediated clearance of proteolipid aggregates that accumulate due to inefficient activity of the lysosome-autophagy system in cells derived from a patient with a lysosomal storage disorder. Interestingly, HPβCD-mediated activation of autophagy was found not to be associated with activation of apoptotic pathways. This study provides a mechanistic understanding of the cellular response to HPβCD treatment, which will inform the development of safe HPβCD-based therapeutic modalities and may enable engineering HPβCD as a platform technology to reduce the accumulation of lysosomal storage material.
In vivoblockade of CTLA-4 enhances the priming of responsive T cells but fails to prevent the induction of tumor antigen-specific tolerance (1999)

The efficacy of therapeutic vaccination for the treatment of cancer is limited by peripheral tolerance to tumor antigens. In vivo blockade of CTLA-4, a negative regulator of T cell function, can induce the regression of established tumors and can augment the tumor rejection achieved through therapeutic vaccination. These outcomes may reflect enhanced tumor-specific T cell priming and/or interference with the development of tolerance to tumor antigens. We examined the effect of CTLA-4 blockade on the fate and function of T cells specific for a model tumor antigen in the tumor-bearing host. We found that while CTLA-4 blockade enhanced the priming of responsive T cells, it did not prevent the induction of tolerance to tumor antigens. These results demonstrate that there is a critical window in which the combination of CTLA-4 blockade and vaccination achieves an optimal response, and they point to mechanisms other than CTLA-4 engagement in mediating peripheral T cell tolerance to tumor antigens.
Wild-type p53 mediates apoptosis by E1A, which is inhibited by E1B. (1993)

Transformation of primary rodent cells by the adenovirus E1A and E1B oncogenes is a two-step process, where E1A-dependent induction of proliferation is coupled to E1B-dependent suppression of programmed cell death (apoptosis). The E1B gene encodes two distinct transforming proteins, the 19K and 55K proteins, both of which independently cooperate with E1A. E1B 19K or 55K protein, or the human Bcl-2 protein, functions to suppress apoptosis and thereby permits transformation with E1A. The E1B 55K protein blocks p53 tumor suppressor protein function, indicating that p53 may mediate apoptosis by E1A. In the mutant conformation, p53 blocked induction of apoptosis by E1A and efficiently cooperated with E1A to transform primary cells. When p53 was returned to the wild-type conformation, E1A+p53 transformants underwent cell death by apoptosis. This induction of apoptosis by conformational shift of p53 from the mutant to the wild-type form was inhibited by expression of the E1B 19K protein. Thus, the p53 protein may function as a tumor suppressor by initiating a cell suicide response to deregulation of growth control by E1A. E1B 19K and 55K proteins provide separate mechanisms that disable the cell suicide pathway of p53.
The gene for Darier's disease maps to chromosome 12q23–q24.1 (1993)

Darier's disease is a rare autosomal dominant skin disorder in which there is abnormal adhesion between keratinocytes. It appears to be associated with an increased prevalence of neuropsychiatric disorders including mental retardation and epilepsy. In addition we have previously reported a family in which major affective disorder cosegregates with Darier's disease. In the present study we have localized the gene for Darier's disease to chromosome 12q23-q24.1 by linkage analysis in five British pedigrees. We obtained a maximum two point lod score of 4.29 with marker D12S84 at zero recombination fraction. All five families showed evidence of linkage between the disease gene and markers in this region. Subsequent identification of the Darier's disease gene will provide insights into normal mechanisms of cell adhesion and may be of importance in the genetic investigation of neuropsychiatric disorders as well as elucidating the pathogenesis of Darier's disease itself.
Astrocytes Are Primed by Chronic Neurodegeneration to Produce Exaggerated Chemokine and Cell Infiltration Responses to Acute Stimulation with the Cytokines IL-1β and TNF-α (2015)

Microgliosis and astrogliosis are standard pathological features of neurodegenerative disease. Microglia are primed by chronic neurodegeneration such that toll-like receptor agonists, such as LPS, drive exaggerated cytokine responses on this background. However, sterile inflammatory insults are more common than direct CNS infection in the degenerating brain and these insults drive robust IL-1β and TNF-α responses. It is unclear whether these pro-inflammatory cytokines can directly induce exaggerated responses in the degenerating brain. We hypothesized that glial cells in the hippocampus of animals with chronic neurodegenerative disease (ME7 prion disease) would display exaggerated responses to central cytokine challenges. TNF-α or IL-1β were administered intrahippocampally to ME7-inoculated mice and normal brain homogenate-injected (NBH) controls. Both IL-1β and TNF-α produced much more robust IL-1β synthesis in ME7 than in NBH animals and this occurred exclusively in microglia. However, there was strong nuclear localization of the NFκB subunit p65 in the astrocyte population, associated with marked astrocytic synthesis of the chemokines CXCL1 and CCL2 in response to both cytokine challenges in ME7 animals. Conversely, very limited expression of these chemokines was apparent in NBH animals similarly challenged. Thus, astrocytes are primed in the degenerating brain to produce exaggerated chemokine responses to acute stimulation with pro-inflammatory cytokines. Furthermore, this results in markedly increased neutrophil, T-cell, and monocyte infiltration in the diseased brain. These data have significant implications for acute sterile inflammatory insults such as stroke and traumatic brain injury occurring on a background of aging or neurodegeneration.
Limitations of Impedance Plethysmography in the Diagnosis of Clinically Suspected Deep-Vein Thrombosis (1993)

At our center, IPG has a far lower sensitivity for proximal-vein thrombosis than has been previously reported for symptomatic outpatients. The reason for this low sensitivity is unclear. Our findings indicate that centers using IPG as the initial diagnostic test for suspected DVT should be aware of this potential problem and should consider re-evaluating the sensitivity of their IPG machines by performing venography in a cohort of their patients with normal test results.
Combined targeting of HER2 and VEGFR2 for effective treatment ofHER2-amplified breast cancer brain metastases (2012)

Brain metastases are a serious obstacle in the treatment of patients with human epidermal growth factor receptor-2 (HER2)-amplified breast cancer. Although extracranial disease is controlled with HER2 inhibitors in the majority of patients, brain metastases often develop. Because these brain metastases do not respond to therapy, they are frequently the reason for treatment failure. We developed a mouse model of HER2-amplified breast cancer brain metastasis using an orthotopic xenograft of BT474 cells. As seen in patients, the HER2 inhibitors trastuzumab and lapatinib controlled tumor progression in the breast but failed to contain tumor growth in the brain. We observed that the combination of a HER2 inhibitor with an anti-VEGF receptor-2 (VEGFR2) antibody significantly slows tumor growth in the brain, resulting in a striking survival benefit. This benefit appears largely due to an enhanced antiangiogenic effect: Combination therapy reduced both the total and functional microvascular density in the brain xenografts. In addition, the combination therapy led to a marked increase in necrosis of the brain lesions. Moreover, we observed even better antitumor activity after combining both trastuzumab and lapatinib with the anti-VEGFR2 antibody. This triple-drug combination prolonged the median overall survival fivefold compared with the control-treated group and twofold compared with either two-drug regimen. These findings support the clinical development of this three-drug regimen for the treatment of HER2-amplified breast cancer brain metastases.
Regressions and cures of melanoma xenografts following treatment with monoclonal antibody beta-lactamase conjugates in combination with anticancer prodrugs. (1995)

Cephalosporin doxorubicin (C-Dox) and 7-(4-carboxybutanamido)-cephalosporin mustard (CCM) are prodrugs that are catalytically converted by Enterobacter cloacae beta-lactamase (bL) to the active anticancer agents doxorubicin and phenylenediamine mustard, respectively. Both prodrugs were less cytotoxic to the 3677 human melanoma line than their respective drugs and were activated in an immunologically specific manner by 96.5-bL, a mAb-bL conjugate that binds to 3677 cell surface antigens. Similar results were obtained using the CCM prodrug on SK-MEL 28 human melanoma cells. Experiments in mice with established s.c. 3677 tumors demonstrated that although no tumors were cured in mice receiving the 96.5-bL/C-Dox combination, the activities were greater than those obtained from systemic doxorubicin treatment or from administration of the nonbinding conjugate P1.17-bL in combination with C-Dox. In contrast, when CCM was used as a prodrug, cures of established 3677 tumors were obtained in 80% of the 96.5-bL treated animals. This combination was also able to induce regressions of large 3677 tumor masses (800 mm3) without any apparent toxic side effects. We conclude that 96.5-bL in combination with C-Dox or CCM has greater antitumor activity than systemic treatment with the corresponding drugs and that CCM is a more effective prodrug than C-Dox for treating human 3677 melanoma xenografts.
Properties of 13C-Substituted Arginine in Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) (2002)

We have recently described a method, stable isotope labeling by amino acids in cell culture (SILAC) for the accurate quantitation of relative protein abundances. Cells were metabolically labeled with deuterated leucine, leading to complete incorporation within about five cell doublings. Here, we investigate fully substituted 13C-labeled arginine in the SILAC method. After tryptic digestion, there is a single label at the C-terminal position in half of the peptides. Labeled and unlabeled peptides coelute in liquid chromatography-mass spectrometric analysis, eliminating quantitation error due to unequal sampling of ion profiles. Tandem mass spectrum interpretation and database identification are aided by the predictable shift of the y-ions in the labeled form. The quantitation of mixtures of total cell lysates in known ratios resolved on a one-dimensional SDS-PAGE gel produced consistent and reproducible results with relative standard deviations better than five percent under optimal conditions.
A comparative study of the effect of clonidine and tramadol on post-spinal anaesthesia shivering (2011)

The aim of this study was to evaluate the efficacy, potency and side effects of clonidine as compared to tramadol in post-spinal anaesthesia shivering. In this prospective double-blind randomized controlled clinical trial, 80 American Society of Anaesthesiologists grade-l (ASAI) patients aged between 18 and 45 years scheduled for various surgical procedures under spinal anaesthesia, who developed shivering were selected.The patients were divided into two groups: Group C (n=40) comprised of patients who received clonidine 0.5mg/kg intravenously (IV) and group patients who received tramadol 0.5 mg/kg IV. Grade of shivering, disappearance of shivering, haemodynamics and side effects were observed at scheduled intervals. Disappearance of shivering was significantly earlier in group C (2.54±0.76) than in group T (5.01±1.02) (P=.0000001). Response rate to treatment in group C was higher (97.5%) than in group T (92.5%), but the difference was not significant. Nausea, vomiting and dizziness were found to be higher in group T (P=0.001, 0.005, 0.001, respectively), while the patients in group C were comparatively more sedated (sedation level, 2; group C, 25%). We conclude that clonidine gives better thermodynamics than tramadol, with fewer side effects.
Nonlocality in mesoscopic Josephson junctions with strip geometry (1999)

We study the current in a clean superconductor--normal-metal--superconductor junction of length d and width w in the presence of an applied magnetic field H. We show that both the geometrical pattern of the current density and the critical current ${I}_{c}(\ensuremath{\Phi}),$ where $\ensuremath{\Phi}$ is the total flux in the junction, depend on the ratio of the Josephson vortex distance ${a}_{0}={\ensuremath{\Phi}}_{0}/Hd$ and the range $r\ensuremath{\sim}\sqrt{d{\ensuremath{\xi}}_{N}}$ of the nonlocal electrodynamics $[{\ensuremath{\Phi}}_{0}=hc/2e,$ ${\ensuremath{\xi}}_{N}=\ensuremath{\Elzxh}{v}_{F}/2\ensuremath{\pi}T,$ and $r(\stackrel{\ensuremath{\rightarrow}}{T}0)\ensuremath{\sim}d].$ In particular, the critical current has the periodicity of the superconducting flux quantum ${\ensuremath{\Phi}}_{0}$ only for $r&lt;{a}_{0}$ and becomes, due to boundary effects, $2{\ensuremath{\Phi}}_{0}$ (pseudo)periodic for strong nonlocality, $r&gt;{a}_{0}.$ Comparing our results to recent experiments of Heida et al. [Phys. Rev. B 57, R5618 (1998)] we find good agreement.
Time domain solution of fault distance estimation and arcing faults detection on overhead lines (1999)

In this paper a new numerical algorithm for arcing faults detection and fault distance estimation is presented. The solution is given in the time domain. It is based on the line terminal voltages and currents processing. A simple new mathematical model of arc voltage is introduced in the estimation. Thereby, the more accurate approach to fault location is derived, particularly for the close-in faults. The new algorithm can be utilized for blocking the automatic reclosing. The unknown model parameters, including the line resistance and inductance, fault resistance and arc voltage amplitude, are estimated by using the least error squares method. The new algorithm is successfully tested through computer simulation and laboratory tests.
Zone-plate array lithography (ZPAL): a new maskless approach (1999)

This paper reviews recent progress in our development of a new maskless lithography scheme which utilizes an array of Fresnel zone plates to write arbitrary patterns on a wafer. Maskless, zone-plate-array lithography (ZPAL) should be capable of producing 25 nm feature sizes at a throughput of 1 cm<SUP>2</SUP>/second using 4.5 nm radiation form an undulator on a compact synchrotron. This wavelength will allow a large depth-of-focus with essentially no proximity effect at a large gap between the zone-plate array and the substrate. We present a detailed ZPAL system design, and show calculations and simulations which address issues of resolution, contrast, throughput, source characteristics, and micromechanical modulation schemes for x-ray beamlets in ZPAL. We review our experimental efforts in ZPAL in the x- ray and UV regions.
Limitations of Animal Studies for Predicting Toxicity in Clinical Trials (2019)

Animal testing is used in pharmaceutical and industrial research to predict human toxicity, and yet analysis suggests that animal models are poor predictors of drug safety in humans. The cost of animal research is high-in dollars, delays in drug approval, and in the loss of potentially beneficial drugs for human use. Human subjects have been harmed in the clinical testing of drugs that were deemed safe by animal studies. Increasingly, investigators are questioning the scientific merit of animal research. This review discusses issues in using animals to predict human toxicity in pharmaceutical development. Part 1 focuses on scientific concerns over the validity of animal research. Part 2 will discuss alternatives to animal research and their validation and use in production of human pharmaceuticals.
Tamandarins A and B:  New Cytotoxic Depsipeptides from a Brazilian Ascidian of the Family Didemnidae (1999)

The structures of two new, naturally occurring cytotoxic depsipeptides, tamandarins A and B (1 and 2), are presented. The tamandarins were isolated from an unidentified Brazilian marine ascidian of the family Didemnidae. The structures of the new cytotoxins were assigned by interpretation of FABMS data and by extensive 2D NMR analyses. The absolute configurations of the tamandarins were assigned by acid and alkaline hydrolysis to yield their corresponding amino acids, which were then analyzed as their Marfey derivatives. The cytotoxicity of tamandarin A (1) was evaluated against various human cancer cell lines and shown to be slightly more potent than didemnin B. A qualitative discussion of the conformation of tamandarin A (1) in solution, obtained from NMR J-value data, variable temperature experiments, and NOESY/ROESY data, is included.
Role of melatonin in cancer treatment. (2012)

Melatonin has revealed itself to be a pleiotropic and multitasking molecule. The mechanisms that control its synthesis and the biological clock processes that modulate the circadian production of melatonin in the pineal gland have been well-characterized. A feature that characterizes melatonin is the variety of mechanisms it employs to modulate the physiology and molecular biology of cells. Research has implicated the pineal gland and melatonin in the processes of both aging and age-related diseases. The decline in the production of melatonin with age is thought to contribute to immunosenescence and potential development of neoplastic diseases. Melatonin has been shown to inhibit growth of different tumors under both in vitro and in vivo conditions. There is evidence that the administration of melatonin alone or in combination with interleukin-2 in conjunction with chemoradiotherapy and/or supportive care in cancer patients with advanced solid tumors, has been associated with improved outcomes of tumor regression and survival. Moreover, chemotherapy has been shown to be better tolerated in patients treated with melatonin.