gebhart/patrepeval huggingface dataset:
Learning from the Past: A Review of Clinical Trials Targeting Amyloid, Tau and Neuroinflammation in Alzheimer’s Disease (2020)

Alzheimer's Disease (AD) is the most common neurodegenerative disease and cause of dementia. Characterized by amyloid plaques and neurofibrillary tangles of hyperphosphorylated Tau, AD pathology has been intensively studied during the last century. After a long series of failed trials of drugs targeting amyloid or Tau deposits, currently, hope lies in the positive results of one Phase III trial, highly debated, and on other ongoing trials. In parallel, some approaches target neuroinflammation, another central feature of AD. Therapeutic strategies are initially evaluated on animal models, in which the various drugs have shown effects on the target (decreasing amyloid, Tau and neuroinflammation) and sometimes on cognitive impairment. However, it is important to keep in mind that rodent models have a less complex brain than humans and that the pathology is generally not fully represented. Although they are indispensable tools in the drug discovery process, results obtained from animal models must be viewed with caution. In this review, we focus on the current status of disease-modifying therapies targeting amyloid, Tau and neuroinflammation with particular attention on the discrepancy between positive preclinical results on animal models and failures in clinical trials.
A peptide mimetic of the mycobacterial mannosylated lipoarabinomannan: characterization and potential applications (2007)

Mannosylated lipoarabinomannan (ManLAM), a complex lipoglycan, is a major component of Mycobacterium tuberculosis, the agent of tuberculosis (TB), and is an antigen used for serological diagnosis of TB. Screening random phage-display peptide libraries with anti-ManLAM mAb CS40 for peptide epitope mimics (mimotopes) led to the isolation of a panel of peptides. One of these peptides (B11) was characterized as a ManLAM mimotope: it bound the anti-ManLAM CS40 mAb and competed with ManLAM for antibody binding. Mice immunized with keyhole limpet haemocyanin-conjugated B11 peptide in a proper adjuvant developed antibodies that recognized ManLAM. Competition experiments demonstrated that the B11 peptide inhibited binding of mAb CS40 to ManLAM in a concentration-dependent manner. The data indicated that the affinity of CS40 mAb to B11 (K(D) 1.33 x 10(-8)) is higher than its affinity to ManLAM (K(D) 3.00 x 10(-7)). The sera of TB patients, as well as the sera of mice experimentally infected with M. tuberculosis, contained significant levels of antibodies that recognized both the B11 peptide and ManLAM. The specificity and sensitivity of the ELISA B11-based test were similar to those of the ELISA ManLAM-based test, indicating that the B11 antigen could be a good substitute for ManLAM serology for the diagnosis of TB.
Chemistry and biochemistry of lipid peroxidation products (2010)

Oxidative stress and resulting lipid peroxidation is involved in various and numerous pathological states including inflammation, atherosclerosis, neurodegenerative diseases and cancer. This review is focused on recent advances concerning the formation, metabolism and reactivity towards macromolecules of lipid peroxidation breakdown products, some of which being considered as 'second messengers' of oxidative stress. This review relates also new advances regarding apoptosis induction, survival/proliferation processes and autophagy regulated by 4-hydroxynonenal, a major product of omega-6 fatty acid peroxidation, in relationship with detoxication mechanisms. The use of these lipid peroxidation products as oxidative stress/lipid peroxidation biomarkers is also addressed.
Electrons in Glass (1978)

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Expression of cancer-testis antigens as possible targets for antigen-specific immunotherapy in head and neck squamous cell carcinoma (2006)

Cancer-Testis (CT) antigens are by definition expressed in tumor but not in healthy tissue except testis and might represent ideal targets for antigen-specific immunotherapy. Here, we present the first comprehensive analysis of CT antigen expression in patients with head and neck squamous cell carcinoma (HNSCC). Tumor samples (N=51), and adjacent healthy tissue from patients with HNSCC were analyzed for the expression of 23 genes designated CT antigens using RT-PCR. Patient sera (N=39) were screened for IgG antibody responses against NY-ESO-1, MAGEA3, and SSX2. According to their expression pattern antigens were divided into four groups. ADAM2, LIP1, SLLP1, AKAP3, CTAGE, ZNF165, CAGE, and FTHL17 were expressed in tumor and healthy tissue at comparable frequencies. NY-TLU-57, GAGE1, SAGE1 were expressed more frequently in tumor samples than in healthy tissues. TPTE, LDHC, SPO11 were expressed neither in tumor samples nor in healthy tissue. 9 CT antigens were expressed only in the tumor tissue and may represent ideal candidates for active immunotherapy in HNSCC: MAGEA3 was expressed in 72%, SSX1 in 45%, MAGEC2 in 33%, MAGEC1 in 28%, BAGE in 17%, SSX2 in 16%, SCP1 in 12%, NY-ESO-1 in 6%, and HOM-TES-85 in 4% of cases. 86% of tumor samples expressed at least one, 69% expressed at least two, and 43% expressed at least three of these antigens. Three patients showed an antibody response against NY-ESO-1. In conclusion, we demonstrate here that HNSCC frequently express CT antigens. Furthermore, a relatively high percentage of tumors express more than one CT antigen opening the perspective for polyvalent antigen-specific immunotherapy.
Use of homologous recombination deficiency (HRD) score to enrich for niraparib sensitive high grade ovarian tumors. (2015)

5532 Background: The therapeutic potential of PARP inhibitors is predicted to extend beyond patients with germline BRCA mutations (BRCAmut) to those with homologous recombination deficient (HRD) cancers. An HRD test is being applied to patient samples to identify BRCA mutated tumors, provide a categorical determination of tumor HRD, and determine an enrichment strategy for patients with tumors that are sensitive to niraparib treatment. Methods: Archival FFPE tumor tissue obtained from ovarian cancer patients enrolled in an ongoing Phase III clinical study (ENGOT-OV16/NOVA, NCT 01847274) and a living tumor bank was subjected to HRD testing. The final HRD score is a numeric output ranging from 0-100. A predefined cut-off score of 42 was utilized to determine HRD status of each tumor and classify it as HR deficient (HRD score ≥ 42) or non-deficient (HRD score < 42). Classification of BRCA mutations from tissue was based on analysis criteria consistent with the laboratory’s approved diagnostic BRCA testing. Niraparib efficacy was evaluated utilizing a living tumor bank of orthotopic patient-derived ovarian xenografts. Intraperitoneal tumorgrafts were monitored for tumor growth with twice-weekly transabdominal ultrasound imaging. Results: One hundred and six high grade serous ovarian tumors from a living tumor bank were evaluated for HRD, BRCA1/2 mutations, and BRCA1 promoter hypermethylation. Twenty six tumors (25%) were BRCA deficient (a deleterious BRCA1/2 mutation or BRCA1 hypermethylation with a concomitant loss of heterozygosity). All BRCA1/2 deficient tumors had an HRD score of 42 or greater, with the exception of one tumor. The in-vivo response to niraparib monotherapy has been evaluated in 20 unique tumor models across a range of HRD scores. All responding tumors had an HRD score of 42 or above, irrespective of BRCA deficiency. Conclusions: HRD testing of ovarian cancer was predictive of BRCA deficiency. Response to niraparibwas only observed in HRD positive (HRD+) tumors. Our data are supportive of the use of HRD testing to enrich for niraparib responders in high grade ovarian cancer.
Unequal Erasure Protection and Object Bundle Protection with the Generalized Object Encoding Approach (2011)

When a data flow contains information of different priority levels, it is natural to try to offer an unequal protection where the high priority data benefits from a higher protection than the rest of data. In this work we focus on the "erasure channel", for instance the Internet where the UDP/IP datagram integrity is guaranteed by the physical layer FCS (or CRC) and the UDP checksum. In this context UEP refers to an Unequal Erasure Protection (rather than Error) and the FEC code being used is one of the various Application-Layer Forward Erasure Correction (AL-FEC) codes that have been designed and standardized in the past years, like Reed-Solomon, one of the LDPC variants, or Raptor(Q) codes. Offering an unequal protection in this context can be achieved by one of the following three general approaches: by using dedicated UEP-aware FEC codes, by using a dedicated UEP-aware packetization scheme, or by using an UEP-aware signaling scheme. In this work we ignore the first approach as we want to reuse existing AL-FEC codes. Instead we focus on and compare the last two approaches and more precisely the well known Priority Encoding Transmission (PET) scheme that belongs to the UEP-aware packetization category and a Generalized Object Encoding (GOE) scheme, we propose, that belongs to the UEP-aware signaling category. We compare them both from an analytical point of view (we use an N-truncated negative binomial distribution to that purpose) and from an experimental, simulation based, point of view. Since we want to derive practical recommendations, we consider erasure recovery metrics, but also processing load and peak memory requirements metrics that can be of high importance. We show that the GOE approach, by the flexibility it offers, its simplicity, its backward compatibility and its good recovery capabilities, is highly recommendable for practical systems requiring UEP. In a second part of the paper we consider the use of PET, more precisely an extension called Universal Object Delivery (UOD), and GOE in situations where one needs to send a bundle of small object (e.g. files). If both solutions can address this need, we show that once again the GOE scheme is highly recommendable for practical realizations.
Degradation behavior of poly(glycerol sebacate) (2008)

Poly(glycerol sebacate) (PGS), a promising scaffold material for soft tissue engineering applications, is a soft, tough elastomer with excellent biocompatibility. However, the rapid in vivo degradation rate of PGS limits its use as a scaffold material. To determine the impact of crosslink density on degradation rate, a family of PGS materials was synthesized by incrementally increasing the curing time from 42 to 144 h, at 120 degrees C and 10 mTorr vacuum. As expected, PGS became a stiffer, tougher, and stronger elastomer with increasing curing time. PGS disks were subcutaneously implanted into rats and periodically harvested; only mild tissue responses were observed and the biocompatibility remained excellent. Regardless of crosslink density, surface erosion degradation was observed. The sample dimensions linearly decreased with implantation time, and the mass loss rates were constant after 1-week implantation. As surface erosion degradation frequently correlates with enzymatic digestion, parallel in vitro digestion studies were conducted in lipase solutions which hydrolyze ester bonds. Enzymatic digestion played a significant role in degrading PGS, and the mass loss rates were not a function of curing time. Alternative chemistry approaches will be required to decrease the enzymatic hydrolysis rate of the ester bonds in PGS polymers.
Cell cycle dependent effects of u.v.-radiation on p53 expression and retinoblastoma protein phosphorylation. (1995)

Control of fate of cells encountered with DNA damaging agents is pivotal for normal cellular homeostasis. DNA damage leads in many cases to growth arrest of the cells ensuring sufficient time for damage repair. Growth arrest can be mediated by p53 tumor suppressor protein and loss of its function leads to inability of the cells to both growth arrest and undergo apoptosis. We show here that followed by genotoxic stress, the retinoblastoma gene product, pRB, is associated with growth arrest of cells in a p53 independent manner. In u.v.-treated human and mouse fibroblasts, pRB is rapidly dephosphorylated. pRB dephosphorylation occurs concomitant with growth arrest of cells including cells with p53 mutations (SW 480 colon carcinoma cells), cells expressing SV40 T antigen and rat-transformed cells (T-24 bladder carcinoma cells) unresponsive in regard to p53 stimulation. Furthermore, flow cytometry analysis of u.v.-radiated synchronized G1 cells indicates that the cells transiently arrest in G1 for 10-12 h with pRB dominating in its underphosphorylated form, whereas p53 accumulation occurs only after the cells have entered into S-phase. In addition, u.v.-radiation of late S- and G2/M-phase cells leads to p53 accumulation and cell cycle arrest. The results indicate that p53 accumulation upon u.v.-radiation occurs during DNA replication and is thus not involved in G1 arrest. We suggest that the events that lead to pRB dephosphorylation upon u.v.-radiation provide the cell an efficient G1 arrest which occurs prior and independently of p53.
A Newly Emergent Genotype of West Nile Virus Is Transmitted Earlier and More Efficiently by Culex Mosquitoes (2007)

Studies examining the evolution of West Nile virus since its introduction into North America have identified the emergence of a new dominant genotype (WN02) that has displaced the introduced genotype (NY99). The mechanistic basis for this displacement, however, remains obscure. Although we found no detectable difference in vitro between the genotypes in either replication or fitness, there were significant differences in vivo in Culex mosquitoes. After peroral infection, the extrinsic incubation period (EIP) of the WN02 genotype was up to 4 days shorter than the EIP of the NY99 genotype; however, after intrathoracic inoculation, there was no difference in EIP between the genotypes, suggesting that differences in genotype interaction with the mosquito midgut are likely to play a role in this phenotype. These results suggest a model for the displacement of the NY99 genotype, where earlier transmission of WN02 viruses leads to higher WN02 infection rates in avian reservoir hosts.
Polynucleotides containing 2'-amino-2'-deoxyribose and 2'-azido-2'-deoxyribose (1973)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTPolynucleotides containing 2'-amino-2'-deoxyribose and 2'-azido-2'-deoxyriboseJohn Hobbs, Hans Sternbach, Mathias Sprinzl, and Fritz EcksteinCite this: Biochemistry 1973, 12, 25, 5138–5145Publication Date (Print):December 1, 1973Publication History Published online1 May 2002Published inissue 1 December 1973https://pubs.acs.org/doi/10.1021/bi00749a018https://doi.org/10.1021/bi00749a018research-articleACS PublicationsRequest reuse permissionsArticle Views178Altmetric-Citations50LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Novel Small-Molecule Inhibitors of Bcl-XL to Treat Lung Cancer (2013)

Bcl-XL is a major antiapoptotic protein in the Bcl-2 family whose overexpression is more widely observed in human lung cancer cells than that of Bcl-2, suggesting that Bcl-XL is more biologically relevant and therefore a better therapeutic target for lung cancer. Here, we screened small molecules that selectively target the BH3 domain (aa 90-98) binding pocket of Bcl-XL using the UCSF DOCK 6.1 program suite and the NCI chemical library database. We identified two new Bcl-XL inhibitors (BXI-61 and BXI-72) that exhibit selective toxicity against lung cancer cells compared with normal human bronchial epithelial cells. Fluorescence polarization assay reveals that BXI-61 and BXI-72 preferentially bind to Bcl-XL protein but not Bcl2, Bcl-w, Bfl-1/A1, or Mcl-1 in vitro with high binding affinities. Treatment of cells with BXI-72 results in disruption of Bcl-XL/Bak or Bcl-XL/Bax interaction, oligomerization of Bak, and cytochrome c release from mitochondria. Importantly, BXI-61 and BXI-72 exhibit more potent efficacy against human lung cancer than ABT-737 but less degree in platelet reduction in vivo. BXI-72 overcomes acquired radioresistance of lung cancer. On the basis of our findings, the development of BXI(s) as a new class of anticancer agents is warranted and represents a novel strategy for improving lung cancer outcome.
Phospholipid binding and lecithin-cholesterol acyltransferase activation properties of apolipoprotein A-I mutants (1995)

Recombinant human apolipoprotein A-I (apo A-I) and three deletion mutants: apo A-I(delta Leu44-Leu126), apo A-I(delta Glu139-Leu170), and apo A-I(delta Ala190-Gln243), purified from the periplasmic space of Escherichia coli, were studied. The rate of turbidity decrease following mixing of apo A-I(delta Ala190-Gln243) with dimyristoylphosphatidylcholine (DMPC) vesicles at 23 degrees C was 10-fold lower than that of the other apo A-I proteins, confirming that the carboxy-terminal region of apo A-I plays a role in rapid lipid binding. The Stokes radii of reconstituted high-density lipoproteins (rHDL), containing dipalmitoylphosphatidylcholine and cholesterol, were larger for the three apo A-I mutants [6.3 nm for apo A-I(delta Leu44-Leu126), 6.1 nm for apo A-I(delta Glu139-Leu170), and 6.5 nm for apo A-I(delta Ala190-Gln243)] than for intact apo A-I (5.0 nm). The mutant rHDL all contained 4 apo A-I molecules per particle as compared to 2 for intact apo A-I. Circular dichroism measurements revealed 8 alpha-helices per apo A-I molecule, 5 per apo A-I(delta Leu44-Leu126), 6 per apo A-I(delta Glu139-Leu170), and 4 per apo A-I(delta Ala190-Gln243) molecule as compared to predicted values of 8, 5, 6, and 6 alpha-helices, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Identification of adeno-associated virus contamination in cell and virus stocks by PCR (2004)

To further understand the biology of adeno-associated virus (AAV) and identify the presence of AAV in laboratory samples, we have developed a sensitive PCR-based assay using degenerate primers based on the sequence of seven diverse AAV isolates. Using these primers, we can detect free virus in viral stocks, cleared cell lysate, as well as in latently infected cells. The method can detect as little as 10 viral copies/microL of sample and can be adapted for high-throughput screening technology. With this method, we have also detected a new AAV isolate from a stock of bovine adenovirus.
Comparison of the efficacy of dexmedetomidine, ketamine, and a mixture of both for pediatric MRI sedation (2013)

AimTo compare the efficacy of intramuscular ketamine, dexmedetomidine, and a mixture of both for pediatric MRI sedation.
IL-7 Gene Therapy in Aging Restores Early Thymopoiesis without Reversing Involution (2004)

Thymic involution begins early in life and continues throughout adulthood, resulting in a decreased population of naive T cells in the periphery and a reduced ability to fight off newly encountered infectious diseases. We have previously shown that the first step of thymopoiesis is specifically blocked in aging. This block at the DN1 to DN2 transition and the subsequent loss of thymic output in old age mirrors the changes seen in IL-7-deficient mice, and it is hypothesized that decreased intrathymic IL-7 is involved in age-related thymic involution. To separate the effect of IL-7 on thymic involution from its function as a peripheral lymphocyte growth cofactor, we injected IL-7-secreting stromal cells into the thymi of recipient mice. The increased local concentration of IL-7 maintained the first step of thymopoiesis at a level far higher than was seen in age-matched controls. However, despite this success, there was no decrease in thymic involution or increase in T cell output. The inability of IL-7 to prevent involution led us to the discovery of an additional age-sensitive step in thymopoiesis, proliferation of the DN4 population, which is unaffected by IL-7 expression.
Emerging Bacterial Zoonotic and Vector-Borne Diseases (1996)

Among the etiologic agents of emerging infectious diseases are several bacterial organisms that naturally reside in animal and arthropod hosts. The most compelling emerging bacterial zoonotic and vector-borne diseases in the United States are Lyme disease; a Southern erythema migrans—like illness; human monocytic ehrlichiosis; human granulocytic ehrlichiosis; a novel cat flea—associated typhus group rickettsiosis; bartonelloses of immunocompetent and immunocompromised persons, particularly with AIDS; and sylvatic plague. Some of these antimicrobial-treatable infections are life threatening. During the acute stage of illness when antimicrobial agents are most effective, the flulike clinical signs and symptoms and available laboratory tests frequently do not point to a particular diagnosis. Epidemiological factors determined by the ecology of the bacteria are often the most useful diagnostic clues. The recognition of these evolving problems emphasizes the need for development of better laboratory diagnostic methods, for surveillance for and tracking of disease, and for continued research into factors contributing to transmission of the organisms. The continual appearance of previously unidentified bacterial infections requires prospective national strategies for timely recognition of the syndrome, identification of the agent, establishment of criteria and methods for diagnosis, optimization of the treatment regimen, and determination of successful approaches to prevention and control. (<i>JAMA</i>. 1996;275:463-469)