gebhart/patrepeval huggingface dataset:
Sabutoclax, a Novel Pan BCL2 Family Inhibitor, Sensitizes Dormant Blast Crisis Chronic Myeloid Leukemia Stem Cells to Dasatinib (2012)

Abstract Abstract 3739 Leukemia stem cells (LSC) represent a frequently dormant self-renewing population integral to the initiation, maintenance, and progression of human chromic myeloid leukemia (CML). The current standard of care dasatinib, a BCR-ABL targeted tyrosine kinase inhibitor (TKI), effectively eradicates the bulk of CML cells but frequently fails to affect the LSC population that is thought to drive CML relapse. Members in the BCL2 family are proteins that regulate apoptosis, 6 of which regulate cell survival. Each of these 6 members has a long and short isoform with opposing functions; generally, long isoforms promote cell survival while the short isoforms promote apoptosis. Previously, we demonstrated that upregulation of pro-survival BCL2 proteins in CML LSC contributes to chemotherapy resistance and LSC quiescence in protective hematopoietic niches. LSC found in different hematopoietic niches differ in their response to TKI treatment. Niche affects LSC cell cycle, either by maintaining quiescence or by promoting rapid cell cycling. Quiescent cells are a hurdle for traditional chemotherapy, which usually targets rapidly cycling cells, leaving the quiescent LSC untouched. We hypothesize that the inhibition of pro-survival BCL2 protein family members will sensitize LSC to dasatinib therapy and therefore prevent CML relapse. We tested a novel pan pro-survival BCL2 family protein inhibitor, sabutoclax, delivered by intravenous injection either alone or in combination with oral dasatinib in immunodeficient RAG2−/-gc−/- mice engrafted with BC CML patient samples. After treatment, LSC burden, self-renewal, and cell cycle status were quantified using FACS. Our results showed a reduction in the LSC burden in combination treated mice when compared to mice that received either drug alone. Mice treated with the combination regimen were found to have fewer quiescent human leukemic cells than their counterparts that received single agent treatments. Immunofluorescence staining confirmed the reduction of quiescent cells in the bone marrow after combination treatment when compared to single agent or vehicle treatments. We validated the molecular targets by using human specific splice isoform primers to perform RT-qPCR on FACS sorted LSC and showed a reduction in the BCL2 long to short isoform ratio in sabutoclax versus vehicle treated animals, indicating a skewing towards the pro-apoptotic splice variant. Together, these results indicate that the combination strategy with a pan pro-survival BCL2 family inhibitor and a tyrosine kinase inhibitor may be the foundation for a promising clinical strategy to effectively eliminate LSC and prevent cancer progression and relapse. Disclosures: No relevant conflicts of interest to declare.
On the Use of Uplink Received Signal Strength Measurements for Handover (2008)

In most cellular systems, handover decisions are based on measurements of the downlink signal strength. When the average path gain in downlink and uplink is similar, such principles yield good performance in both directions of transmission. In cases with systematic imbalances between downlink and uplink however, it is not evident that the uplink performance is optimized. In this paper, a handover scheme based on a combination of downlink and uplink path gain measurements is outlined, and its performance is evaluated in a system with systematic downlink and uplink imbalances. As a reference, a downlink-based only mechanism is used. Results indicate that the combined scheme yields an insignificant gain in uplink signal to interference ratio (SINR). This gain is considerably lower than the corresponding loss in the SINR of users in the downlink. The reason for the low uplink gain is that uplink interference is higher in the cells with higher uplink/downlink imbalance ratio than in adjacent cells in equally loaded cells. As a result, users which are connected to cells with better uplink/downlink imbalance ratio than their adjacent cells also experience higher interference levels, which results in a limited gain in signal-to-interference ratio.
Host Immunity to Clostridium difficile PCR Ribotype 017 Strains (2014)

Clostridium difficile is an important nosocomial pathogen and the leading cause of antibiotic-associated diarrhea. Multilocus sequence typing indicates that C. difficile strains belong to five distinct genetic clades encompassing several PCR ribotypes (RT). Since their emergence in 2003, hypervirulent RT027 strains have been a major focus of research; in contrast, our current understanding of RT017-mediated disease pathogenesis lags far behind. In this study, we aimed to characterize host immunity to CF5 and M68, two genetically well-defined RT017 strains. Both strains engaged with host Toll-like receptor 2/6 (TLR2/6), TLR2-CD14, and TLR5 to similar extents in a model cell line. Despite this, CF5 mediated significantly greater dendritic cell (DC) interleukin-12 (IL-12), IL-27, and IL-10 immunity than M68. Both strains elicited similar IL-1β mRNA levels, and yet only M68 caused a marked increase in secretory IL-1β. A CF5 cocultured-DC cytokine milieu drove an equipotent Th1 and Th17 response, while M68 promoted greater Th17 immunity. Human gastrointestinal ex vivo cytokine responses to both strains were characterized. Taken together, our data suggest that C. difficile strains mediate overlapping and yet distinct mucosal and DC/T cell immunity. Finally, toxin-driven IL-1β release supports the hypothesis that this cytokine axis is a likely target for therapeutic intervention for C. difficile infection.
Acoustic Sensing with Correlation and Coherent Detection using an Integrated Coherent Transceiver (2023)

Fiber optic sensing is becoming an important means to physically secure today's network infrastructure. However, a network-wide deployment of the monitors will require cost reduction of the interrogator system, which can only be achieved by highly integrated system components. In this contribution, we report on the use of an in-house designed single-chip coherent transceiver for acoustic fiber sensing. The transceiver on the basis of silicon photonics contains a high-speed dual-polarization IQ-modulator as well as a coherent receiver with balanced photodiodes and trans-impedance amplifiers, as defined by the OIF integrated coherent transmit-receive optical sub assembly (IC-TROSA) implementation agreement. The laser, used for transmission and as local oscillator, is provided external to the photonic integrated circuit and can be chosen according to the line-width requirements of the sensing system. The acoustic sensing demonstration is using a correlation-based optical time domain reflectometry with coherent detection. This method is able to detect, besides the amplitude information, the phase of the back-scattered signal, which has a significantly higher sensitivity to environmental effects on the fiber, like temperature and strain. As a proof of concept, sensing of an acoustic signal after a fiber span of 20 km is demonstrated by evaluating the obtained phase information, providing information on external dynamic events up to a frequency of 1.75 kHz.
Metamaterials for hydrodynamics: Refraction, focusing and beam steering for particles and cells (2007)

We show that it is possible to direct particles in a fluid much like rays of light in optics. We demonstrate refractive, focusing and dispersive elements for particles flowing through suitably constructed metamaterials: obstacle arrays with built-in asymmetry. We also configure these elements to address the problem of diffusion limited mixing in microfluidics. We show it is possible to cross dye or particle jets with a second particle stream and apply this concept to on-chip, continuous flow, “label &amp; wash” of blood platelets. The unusual aspects of these hydronic metamaterials could be of great use for on-chip bio-particle mixing, separation and analysis.
A novel clinical method to measure skin staining reveals activation of skin damage pathways by cigarette smoke (2021)

CS stained skin and activated pathways known to be associated with skin damage. THPs and ECs produced significantly lower values, suggesting they could offer hygiene and cosmetic benefits for consumers who switch exclusively from smoking cigarettes. Further studies are required to assess longer-term effects of ECs and THPs on skin function.
Cryotherapy Enhances Intravitreal Dispersion of Viable Retinal Pigment Epithelial Cells (1985)

Proliferative vitreoretinopathy (PVR) is the most common cause of failure in retinal reattachment surgery. Giant retinal tears are associated with a particularly high incidence of PVR. It involves the formation of cellular membranes that contract and cause traction retinal detachments. Retinal pigment epithelial (RPE) cells are a major component of these cellular membranes. Displacement of viable RPE cells from their normal position into the vitreous cavity is necessary for membrane formation to occur. This study demonstrates that cryotherapy, but not diathermy, enhances intravitreal dispersion of viable RPE cells in bovine eyes in vitro. This suggests that in some circumstances, excessive cryotherapy may play an exacerbating role in the initiation of PVR.
High‐Speed Fabrication of Lithium‐Ion Battery Electrodes by UV‐Curing (2015)

Abstract In this study, UV‐curing was investigated as an alternative method to provide fast production of composite cathodes and significantly reduce the time and energy required for solvent removal in lithium‐ion battery fabrication. To serve our purpose, low‐molecular‐weight polysiloxane acrylate (PSA) was designed and synthesized from a polysiloxane epoxide precursor. In the presence of the acrylic acid additive LiNi 1/3 Mn 1/3 Co 1/3 O 2 (NMC), electrode laminates containing 10 wt % PSA binder were successfully fabricated by UV‐curing. The cured electrode exhibited good mechanical and electrochemical properties. At current rates up to C /3, the cell performance of the UV‐cured NMC electrode was comparable to that of conventional polyvinylidene fluoride (PVDF)‐bound NMC electrode. Our initial success in applying high‐speed UV‐curing in composite electrode fabrication has proved that it is a promising route to substantially reducing the capital and operation costs of lithium‐ion battery electrode manufacturing and additionally bringing about important environmental benefits.
Intraoperative electrical stimulation for identification of cranial nerve nuclei (1999)

The purpose of this study was to evaluate the feasibility and usefulness of cranial nerve nuclei monitoring during resection of brainstem cavernous malformations. Eleven patients with brainstem cavernous malformations underwent resection of their malformations utilizing cranial nerve nuclei monitoring. Cranial nerves V and VII were monitored by placing electrodes in muscle groups innervated by these nerves and recording manipulation-induced neurotonic discharges and triggered electromyographic (EMG) activity, after electrical stimulation of the corresponding brainstem nuclei. Seven of 11 procedures (64%) with cranial nerve nuclei monitoring were noted to have cranial nerve nuclei activity corresponding to manipulation of the nuclei. The cavernous malformation was completely resected in 5 of 7 cases with cranial nerve nuclei activity and in all 4 cases without activity. In the remaining 2 cases, the cavernous malformation was not resected due to the proximity of the monitored cranial nerve nuclei to the cavernous malformation and to increasing neurotonic activity as the cavernous malformation was approached. None of the 11 patients had new permanent postoperative deficits corresponding to the cranial nerve nuclei monitored; 1 patient had a transient partial facial palsy lasting 2 days. Preliminary results indicate that cranial nerve nuclei monitoring proves useful in preserving neurologic function and reducing surgical morbidity during resection of brainstem cavernous malformations, particularly indicating when lesion resection places these nuclei at risk.
Magnetic cross-relaxation among protons in protein solutions (1978)

The magnetic spin-lattice relaxation rates of solvent water nuclei are known to increase upon addition of diamagnetic solute protein. This enhancement of the relaxation rate is a function of magnetic field, and the orientational relaxation time of the protein molecules can be deduced from analysis of the field-dependent relaxation rates. Although the nature of the interactions that convey information about the dynamics of protein motion to the solvent molecules is not established, it is known that there is a contribution to the relaxation rates of solvent protons that plays no role in the relaxation of solvent deuterons and 17O nuclei. We show here that the additional interaction arises from a cross-relaxation process between solvent and solute protons. We introduce a heuristic three-parameter model in which protein protons and solvent protons are considered as two separate thermodynamic systems that interact across the protein-solvent interface. The three parameters are the intrinsic relaxation rates of each system and a cross-relaxation term. The sign of the latter term must always be positive, for all values of magnetic field, in order for magnetization energy to flow from the hotter to the cooler system. We find that the magnetic field-dependence of the cross-relaxation contribution is much like that of the remaining solvent proton relaxation, i.e., about the same as the deuteron relaxation field dependence. This finding is not compatible with the predictions of expressions for the cross-relaxation that have been used by other authors, but not applied to data over a wide range of magnetic field strength. The model predicts that the relaxation behavior of both the protein protons and the solvent protons is the sum of two exponentials, the relative contributions of which would vary with protein concentration and solvent isotopic composition in a fashion suggestive of the presence of two classes of protein protons, when there is in reality only one. This finding has immediate implications for the interpretation of published proton relaxation rates in complex systems such as tissues; these data should be reexamined with cross-relaxation taken into account.
Methylation-mediated transcriptional repression of microRNAs during cervical carcinogenesis (2013)

Deregulated expression of microRNAs (miRNAs) is common and biologically relevant in cervical carcinogenesis and appears only partly related to chromosomal changes. We recently identified 32 miRNAs showing decreased expression in high-grade cervical intraepithelial neoplasia (CIN) and carcinomas not associated with a chromosomal loss, 6 of which were located within a CpG island. This study aimed to investigate to what extent these miRNAs are subject to DNA methylation-mediated transcriptional repression in cervical carcinogenesis. Methylation-specific PCR (MSP) analysis on a cell line panel representing different stages of human papillomavirus (HPV) induced transformation revealed an increase in methylation of hsa-miR-149, -203 and -375 with progression to malignancy, whereas expression of these miRNAs was restored upon treatment with a demethylating agent. All three miRNAs showed significantly increased levels of methylation in cervical carcinomas, whereas methylation levels of hsa-miR-203 and -375 were also significantly increased in high-grade CIN. A pilot analysis showed that increased hsa-miR-203 methylation was also detectable in HPV-positive cervical scrapes of women with high-grade CIN compared with controls. Similar to recent findings on hsa-miR-375, ectopic expression of hsa-miR-203 in cervical cancer cells decreased both the proliferation rate and anchorage independent growth. We found evidence for methylation-mediated transcriptional repression of hsa-miR-149, -203 and -375 in cervical cancer. Methylation of the latter two was already apparent in precancerous lesions and represent functionally relevant events in HPV-mediated transformation. Increased hsa-miR-203 methylation was detectable in scrapes of women with high-grade CIN, indicating that methylated miRNAs may provide putative markers to assess the presence of (pre)cancerous lesions.
Aberrant Overexpression Of CD14 In Granulocytes Sensitizes Innate Immune Response In mDia1 Heterozygous Myelodysplastic Syndromes (2013)

Abstract The myelodysplastic syndromes (MDS) are a group of pre-leukemic diseases characterized by increased risk of acute myeloid leukemia (AML). Heterozygous loss of chromosome 5q (5q-) is the most common cytogenetic abnormality in MDS. DIAPH1 is localized to 5q31 and encodes one of the formin family proteins, mDia1, involved in the regulation of linear actin polymerization. Mice with mDia1 deficiency develop hematologic features mimicking human myeloproliferative neoplasm, but its role in the pathogenesis of MDS is unclear. Here we report that mDia1 is largely dispensable for normal hematopoiesis. However, the committed or mature granulocytes in mDia1 heterozygous and knockout mice were activated and showed increased actin polarization. Strikingly, CD14 was aberrantly overexpressed in the bone marrow and peripheral granulocytes of mDia1 heterozygous and knockout mice in a cell-autonomous manner, leading to a hypersensitivity of the innate immune response to lipopolysaccharide (LPS) stimuli through CD14-Toll like receptor 4 (TLR4) signaling. Chronic stimulation with LPS accelerated the occurrence of MDS in mDia1 heterozygous and knockout mice. Similar findings of CD14 overexpression were observed in the bone marrow granulocytes of 5q- MDS patients, but not normal patients or MDS patients without 5q deletion. These patients exhibited relatively frequent infections with long duration of disease. Mechanistically, mDia1 was required for the endocytosis of CD14 upon LPS stimulation. Heterozygosity and loss of mDia1 led to diminished interferon expression that is dependent on CD14 endocytosis. Thus, our study revealed an essential role of the innate immune signaling in the pathogenesis of 5q- MDS. Specifically, heterozygosity or loss of mDia1 leads to a cell autonomous hypersensitivity of innate immune system in the granulocytes that causes myeloid dysplasia. Together with previous reported evidence of dyserythropoiesis due to loss of RPS14, and dysmegakaryopoiesis due to loss of mir-145/146a, these data fully recapitulate the pathogenesis of tri-lineage dysplasia in 5q- MDS. In addition, our study highlighted the significance of the activated CD14/TLR signaling pathway in the pathogenesis of MDS, which could serve as a novel target for therapeutic management. Disclosures: No relevant conflicts of interest to declare.
Multi-Target Stool DNA Has a High Positive Predictive Value as an Interval Test After Colonoscopy (2018)

Introduction: Colorectal cancer (CRC) has been reported in 6-9% of individuals within 3-5 years of reportedly negative screening colonoscopy. Approximately one quarter of patients with prior screening colonoscopy are found to have advanced colorectal neoplasia (CRN) detected by multi-target stool DNA (MT-sDNA) testing. However, the use of MT-sDNA as an interval test to identify CRN between screening colonoscopies has not been studied. Therefore, we aimed to investigate the positive predictive value (PPV) of MT-sDNA ordered in routine clinical practice stratified by time since most recent colonoscopy. Methods: In a large multi-setting practice, we identified all patients with positive MT-sDNA testing between 10/1/2014 and 12/31/2016. From the medical record, we abstracted patients’ exposure to prior CRC screening by colonoscopy, date of prior colonoscopy, date of positive MT-sDNA, and presence of factors that increase CRN risk above average. Diagnostic colonoscopy and pathology reports were reviewed to enumerate CRN findings. Positive predictive values were calculated for each endpoint, stratified by time since prior colonoscopy (0-5 years, 6-9 years, 10 years or ≥11 years), and compared using Mantel-Haenszel Chi-Square and Fisher exact tests. Results: Of the 1035 patients identified with positive MT-sDNA testing, 444 had both confirmed prior screening colonoscopy and post MT-sDNA diagnostic colonoscopy. 395 (89%) were found to be at average risk for CRC, while 49 (11%) were at increased risk. Median age was 71 (IQR 66-77) years. Time between prior colonoscopy and MT-sDNA was 0-5 years in 50/444 (11%), 6-9 years in 74 (17%), 10 years in 55 (12%), and ≥11 years in 265 (60%). PPV of MT-sDNA for any CRN was 62% at 0-5 years, 65% at 6-9 years, 62% at 10 years and 64% at ≥11 years (p=0.91 for trend). Overall, any CRN was found in 282/444 patients (64%), advanced CRN in 107 patients (24%), and any SSP in 106 patients (24%). CRC was identified in 4 patients (1%), 6-17 years since colonoscopy. In the 437 patients in whom lesion location was documented, right sided CRN was identified in 235 (54%). PPV stratified by time for any endpoint was not significant either for the overall cohort (Figure) or when only average-risk patients were analyzed. Conclusion: MT-sDNA has high PPV for CRN even when used ≤5 years since prior colonoscopy. Prospective studies investigating the use of MT-sDNA as an interval test between screening colonoscopies are justified.291 Figure 1. Positive predictive value of multi-target stool DNA testing for colorectal neoplasms, stratified by time since prior colonoscopy
Photoinduced electron transfer of nanohybrids of carbon nanohorns with amino groups and tetrabenzoic acid porphyrin in aqueous media (2009)

Amino carbon nanohorns (CNH–NH2) are covalently and non-covalently functionalized with tetrabenzoic acid porphyrin (H2P(CO2H)4) forming dispersible nanohybrids in aqueous solution; the nanohybrids are characterized by spectroscopy and electron microscopy. Photoinduced electron-transfer processes of the nanohybrids of carbon nanohorns in aqueous solution are revealed with time-resolved absorption and fluorescence measurements. From the observed fluorescence quenching of the H2P(CO2H)4 moieties by CNH–NH2, charge separation via the excited singlet state of the H2P moieties, generating radical cations localized in the H2P moieties and electrons trapped in CNH, is suggested. In the presence of methylviologen dication (MV2+) and a hole-shifting reagent, electron pooling is observed by the light-illumination of the H2P(CO2H)4 moieties in CNH–NH2 nanohybrids, suggesting that the electron generated by the charge-separation migrates to MV2+ in aqueous solution.
Flow Control Over Sharp-Edged Wings (2007)

Wings swept by 30 to 40 degrees with sharp leading edges are today very common on flghter aircraft. There is very little work devoted to the understanding of the aerodynamics of such wings. The problem is That such wings may be able to sustain attached flow, even if their tip vortices are broken down, or stall like two-dimensional wings. The aerodynamics of such wings were studied and investigated experimentally. Pressure distributions and velocity fields were obtained in a wind tunnel and a water tunnel. The effectiveness of leading-edge control of the flow over such wings was explored. Oscillating mini-flaps and pulsed jets along the leading edge were employed. The results indicate that two-D-like vortices are periodically generated and shed. It was also discovered that an underline feature of the flow, a streamwise vortex is periodically activated, penetrating the separated flow, eventually emerging downstream of the trailing edge of the wing. The results indicate that significant increases in tilt can be achieved in the average, by managing the development of streamwise and spanwise vortices. The technique is effective in the range of angles of attack of 10 to 20 degrees, for which the uncontrolled flow is stalled.