Vincristine is a core chemotherapeutic drug administered to pediatric acute lymphoblastic leukemia patients. Despite its efficacy in treating leukemia, it can lead to severe peripheral neuropathy in ...a subgroup of the patients. Peripheral neuropathy is a debilitating and painful side-effect that can severely impact an individual's quality of life. Currently, there are no established predictors of peripheral neuropathy incidence during the early stage of chemotherapeutic treatment. As a result, patients who are not susceptible to peripheral neuropathy may receive sub-therapeutic treatment due to an empirical upper cap on the dose, while others may experience severe neuropathy at the same dose. Contrary to previous genomics based approaches, we employed a metabolomics approach to identify small sets of metabolites that can be used to predict a patient's susceptibility to peripheral neuropathy at different time points during the treatment. Using those identified metabolites, we developed a novel strategy to predict peripheral neuropathy and subsequently adjust the vincristine dose accordingly. In accordance with this novel strategy, we created a free user-friendly tool, VIPNp, for physicians to easily implement our prediction strategy. Our results showed that focusing on metabolites, which encompasses both genotypic and phenotypic variations, can enable early prediction of peripheral neuropathy in pediatric leukemia patients.
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To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high ...risk of myeloid malignancies at an early age. To define the mechanistic basis of clonal hematopoiesis in SDS, we investigate somatic mutations acquired by patients with SDS followed longitudinally. Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53. We show that germline SBDS deficiency establishes a fitness constraint that drives selection of somatic clones via two distinct mechanisms with different clinical consequences. EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness. TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect. Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations. These results mechanistically link leukemia predisposition to germline genetic constraints on cellular fitness, and provide a rational framework for clinical surveillance strategies.
The organic anion-transporting polypeptides represent an important family of drug uptake transporters that mediate the cellular uptake of a broad range of substrates including numerous drugs. ...Doxorubicin is a highly efficacious and well-established anthracycline chemotherapeutic agent commonly used in the treatment of a wide range of cancers. Although doxorubicin is a known substrate for efflux transporters such as P-glycoprotein (P-gp; MDR1, ABCB1), significantly less is known regarding its interactions with drug uptake transporters. Here, we investigated the role of organic anion transporting polypeptide (OATP) transporters to the disposition of doxorubicin. A recombinant vaccinia-based method for expressing uptake transporters in HeLa cells revealed that OATP1A2, but not OATP1B1 or OATP1B3, and the rat ortholog Oatp1a4 were capable of significant doxorubicin uptake. Interestingly, transwell assays using Madin-Darby canine kidney II cell line cells stably expressing specific uptake and/or efflux transporters revealed that OATP1B1, OATP1B3, and OATP1A2, either alone or in combination with MDR1, significantly transported doxorubicin. An assessment of polymorphisms in SLCO1A2 revealed that four variants were associated with significantly impaired doxorubicin transport in vitro. In vivo doxorubicin disposition studies revealed that doxorubicin plasma area under the curve was significantly higher (1.7-fold) in Slco1a/1b
versus wild-type mice. The liver-to-plasma ratio of doxorubicin was significantly decreased (2.3-fold) in Slco1a/1b2
mice and clearance was reduced by 40% compared with wild-type mice, suggesting Oatp1b transporters are important for doxorubicin hepatic uptake. In conclusion, we demonstrate important roles for OATP1A/1B in transporter-mediated uptake and disposition of doxorubicin.
Using fluorescence resonance energy transfer to monitor distances within single molecules of abortively initiating transcription initiation complexes, we show that initial transcription proceeds ...through a "scrunching" mechanism, in which RNA polymerase (RNAP) remains fixed on promoter DNA and pulls downstream DNA into itself and past its active center. We show further that putative alternative mechanisms for RNAP active-center translocation in initial transcription, involving "transient excursions" of RNAP relative to DNA or "inchworming" of RNAP relative to DNA, do not occur. The results support a model in which a stressed intermediate, with DNA-unwinding stress and DNA-compaction stress, is formed during initial transcription, and in which accumulated stress is used to drive breakage of interactions between RNAP and promoter DNA and between RNAP and initiation factors during promoter escape.
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Objective: To investigate the psychometric properties of the supine-to-stand test in people with stroke.
Design: Cross-sectional design.
Subjects: Fifty-two people with stroke (mean (standard ...deviation) age 63.13 (6.09) years; time post-stroke 93.13 (61.36) months) and 49 healthy older adults (61.90 (7.29) months).
Methods: Subjects with stroke were recruited from the community dwelling in Hong Kong and assessed with the supineto- stand test, Fugl-Meyer Motor Assessment, ankle muscle strength test, Berg Balance Scale, limit of stability test, Timed Up-and-Go Test, Six-Minute Walk Test, Chinese version of Activities-specific Balance Confidence scale, Community Integration Measure (CIM-C), and 12-item Short-Form Health Survey (SF-12) in a university-based rehabilitation laboratory.
Results: The supine-to-stand test completion time demonstrated excellent intra-rater, inter-rater and test-retest reliability (intraclass correlation coefficient 0.946–1.000) for the people with stroke. The completion time was significantly negatively correlated with Berg Balance Scale, Six-Minute Walk Test, limit of stability – maximal excursion, and limit of stability – endpoint excursion results (r = –0.391 to –0.507), whereas it was positively correlated with the Timed Up-and-Go test results (r = 0.461). The optimal cut-off supine-to-stand test completion time of 5.25 s is feasible for a clinical measure to distinguish the performance of people with stroke from healthy older adults (area under the curve = 0.852, sensitivity = 81.1%, specificity = 84.0%).
Conclusion: The supine-to-stand test is a reliable, sensitive, specific and easy-to-administer clinical test for assessing the supine-to-stand ability of people with stroke.
In ARDS, elevated pulmonary dead-space fraction (V
/V
) is a particularly strong indicator of mortality risk. Whether the magnitude of V
/V
is modified by the underlying etiology of ARDS and whether ...this influences the strength of its association with mortality remains unknown. We sought to elucidate the impact of ARDS etiology on V
/V
and also to determine whether ARDS severity, as classified by the Berlin definition, has correspondence with changes in V
/V
.
This single-center, retrospective, observational study (2010-2016) measured V
/V
in 685 subjects with ARDS as part of clinical management with lung-protective ventilation. Volumetric capnography was used to measure V
/V
with 99% of measurements occurring within 48 h of ARDS onset. Demographic information as well as illness severity scores and pulmonary mechanics data also were collected. Multivariate logistic regression modeling was done to assess the strength of association between V
/V
and mortality.
V
/V
was elevated across etiologies, with aspiration and pneumonia having significantly higher V
/V
than non-pulmonary sepsis or trauma. Differences in the magnitude of V
/V
across etiologies did not necessarily correspond with mortality between etiologies. However, within each etiology grouping, V
/V
was significantly elevated in non-survivors versus survivors. The same results were found in both moderate and severe (but not mild) ARDS using the Berlin definition. In the final adjusted model, the strongest mortality risk was V
/V
, wherein the risk of death increased by 22% for every 0.05 increase in V
/V
.
V
/V
magnitude varies by ARDS etiology, as does mortality. Only in mild ARDS does V
/V
fail to distinguish non-survivors from survivors. Nonetheless, V
/V
has the strongest association with mortality risk in those with ARDS.
We have studied phase separation in polyfluorene-based electroluminescent polymer blends consisting of poly(2,7-(9,9-di-n-octylfluorene-alt-benzothiadiazole) (F8BT) and ...poly(2,7-(9,9-di-n-octylfluorene)-alt-(1,4-phenylene-((4-sec-butylphenyl)imino)-1,4-phenylene)) (TFB). We present detailed studies on spin-cast thin-film morphology of the blends, using micro-Raman spectroscopy and X-ray photoelectron spectroscopy. Micron-scale lateral phase separation is observed in these blend thin films. However, these phase-separated domains are not pure at the submicron length scale, and a nanoscale vertical phase segregation occurs with enrichment of the lower surface energy component (TFB) at both air and substrate interfaces. Imaging of the spatial uniformity of electroluminescence emission on the microscopic scale indicates spatially localised charge-carrier recombination in light-emitting diodes (LEDs) fabricated with these blends. On the basis of these studies, we propose a model for the development of thin-film phase-separated structure in spin-cast F8BT:TFB blends. LEDs without an additional hole-injection/transporting layer such as a poly(styrenesulfonate)-doped poly(3,4-ethylenedioxythiophene) (PEDT:PSS) have also been characterized to examine the self-organized vertical phase structure found in these blends. The results show that initial performance equivalent to devices with a PEDT:PSS layer is achievable in LEDs which contain only a single layer of F8BT:TFB blend material, confirming that the TFB wetting layer acts efficiently as a hole-accepting/transporting layer.
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28.
A Rare-Cell Detector for Cancer Krivacic, Robert T.; Ladanyi, Andras; Curry, Douglas N. ...
Proceedings of the National Academy of Sciences - PNAS,
07/2004, Volume:
101, Issue:
29
Journal Article
Peer reviewed
Open access
Although a reliable method for detection of cancer cells in blood would be an important tool for diagnosis and monitoring of solid tumors in early stages, current technologies cannot reliably detect ...the extremely low concentrations of these rare cells. The preferred method of detection, automated digital microscopy (ADM), is too slow to scan the large substrate areas. Here we report an approach that uses fiber-optic array scanning technology (FAST), which applies laser-printing techniques to the rare-cell detection problem. With FAST cytometry, laser-printing optics are used to excite 300,000 cells per sec, and emission is collected in an extremely wide field of view, enabling a 500-fold speed-up over ADM with comparable sensitivity and superior specificity. The combination of FAST enrichment and ADM imaging has the performance required for reliable detection of early-stage cancer in blood.
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Achieving balanced electron-hole injection and perfect recombination
of the charge carriers is central to the design of efficient polymer light-emitting
diodes (LEDs). A number of approaches have ...focused on modification
of the injection contacts, for example by incorporating an additional conducting-polymer
layer at the indium-tin oxide (ITO) anode. Recently, the
layer-by-layer polyelectrolyte deposition route has been developed for the
fabrication of ultrathin polymer layers. Using this route,
we previously incorporated ultrathin (<100 ) charge-injection interfacial
layers in polymer LEDs. Here we show how molecular-scale engineering
of these interlayers to form stepped and graded electronic profiles can lead
to remarkably efficient single-layer polymer LEDs. These devices exhibit nearly
balanced injection, near-perfect recombination, and greatly reduced pre-turn-on
leakage currents. A green-emitting LED comprising a poly(p-phenylene
vinylene) derivative sandwiched between a calcium cathode and the modified
ITO anode yields an external forward efficiency of 6.0 per cent (estimated
internal efficiency, 15-20 per cent) at a luminance of 1,600 candelas
per m2 at 5 V.
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30.
All-Polymer Optoelectronic Devices Peter K. H. Ho; Thomas, D. Stephen; Friend, Richard H. ...
Science (American Association for the Advancement of Science),
07/1999, Volume:
285, Issue:
5425
Journal Article
Peer reviewed
Composites of nanoparticles and conjugated polymers that exhibit composition-tunable optical constants have been developed for use in semiconducting photonic structures. For example, the ...550-nanometer wavelength in-plane refractive index of poly(p-phenylenevinylene)-silica composites can be tailored over the range of 1.6 to 2.7, allowing efficient distributed Bragg reflectors and waveguides to be fabricated. Low levels of chemical doping improve electrical conductivity through these structures without detriment to their photonic properties. Exemplifying these concepts, all-polymer microcavities and microcavity light-emitting diodes were demonstrated. Appropriate confinement of photons and electron-hole pairs in these organic semiconductor-based structures can be achieved.
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