Identification of drugs including a dopamine receptor antagonist that selectively target cancer stem cells.

Selective targeting of cancer stem cells (CSCs) offers promise for a new generation of therapeutics. However, assays for both human CSCs and normal stem cells that are amenable to robust biological screens are limited. Using a discovery platform that reveals differences between neoplastic and normal human pluripotent stem cells (hPSC), we identify small molecules from libraries of known compounds that induce differentiation to overcome neoplastic self-renewal. Surprisingly, thioridazine, an antipsychotic drug, selectively targets the neoplastic cells, and impairs human somatic CSCs capable of in vivo leukemic disease initiation while having no effect on normal blood SCs. The drug antagonizes dopamine receptors that are expressed on CSCs and on breast cancer cells as well. These results suggest that dopamine receptors may serve as a biomarker for diverse malignancies, demonstrate the utility of using neoplastic hPSCs for identifying CSC-targeting drugs, and provide support for the use of differentiation as a therapeutic strategy.

FTO negatively regulates the cytotoxic activity of natural killer cells.

N6 -Methyladenosine (m6 A) is the most abundant epitranscriptomic mark and plays a fundamental role in almost every aspect of mRNA metabolism. Although m6 A writers and readers have been widely studied, the roles of m6 A erasers are not well-understood. Here, we investigate the role of FTO, one of the m6 A erasers, in natural killer (NK) cell immunity. We observe that FTO-deficient NK cells are hyperactivated. Fto knockout (Fto-/- ) mouse NK cells prevent melanoma metastasis in vivo, and FTO-deficient human NK cells enhance the antitumor response against leukemia in vitro. We find that FTO negatively regulates IL-2/15-driven JAK/STAT signaling by increasing the mRNA stability of suppressor of cytokine signaling protein (SOCS) family genes. Our results suggest that FTO is an essential modulator of NK cell immunity, providing a new immunotherapeutic strategy for allogeneic NK cell therapies.

Effects of Baclofen on Central Paroxysmal Positional Downbeat Nystagmus.

Paroxysmal positional nystagmus frequently occurs in lesions involving the cerebellum, and has been ascribed to disinhibition and enhanced canal signals during positioning due to cerebellar dysfunction. This study aims to elucidate the mechanism of central positional nystagmus (CPN) by determining the effects of baclofen on the intensity of paroxysmal positional downbeat nystagmus due to central lesions. Fifteen patients with paroxysmal downbeat CPN were subjected to manual straight head-hanging before administration of baclofen, while taking baclofen 30 mg per day for at least one week, and two weeks after discontinuation of baclofen. The maximum slow phase velocity (SPV) and time constant (TC) of the induced paroxysmal downbeat CPN were analyzed. The positional vertigo was evaluated using an 11-point numerical rating scale (0 to 10) in 9 patients. After treatment with baclofen, the median of the maximum SPV of paroxysmal downbeat CPN decreased from 30.1°/s [interquartile range (IQR) = 19.6-39.0°/s] to 15.2°/s (IQR = 11.2-22.0°/s, Wilcoxon signed rank test, p < 0.001) with the median decrement ratio at 40.2% (IQR = 28.2-50.6%). After discontinuation of baclofen, the maximum SPV re-increased to 24.6°/s (IQR = 13.1-34.4°/s, Wilcoxon signed rank test, p = 0.001) with the median increment ratio at 23.5% (IQR = 5.2-87.9%). In contrast, the TCs of paroxysmal downbeat CPN remained unchanged at approximately 3.0 s throughout the evaluation. The positional vertigo also decreased with the medication (Wilcoxon signed rank test, p = 0.020), and remained unchanged even after discontinuation of medication (Wilcoxon signed rank test, p = 0.737). The results of this study support the prior presumption that paroxysmal CPN is caused by enhanced responses of the semicircular canals during positioning due to cerebellar disinhibition. Baclofen may be tried in symptomatic patients with paroxysmal CPN.

Solution-processed zirconium acetylacetonate charge-trap layer for multi-bit nonvolatile thin-film memory transistors.

The charge trap property of solution-processed zirconium acetylacetonate (ZAA) for solution-processed nonvolatile charge-trap memory (CTM) transistors is demonstrated. Increasing the annealing temperature of the ZAA from room temperature (RT) to 300°C in ambient, the carbon double bonds within the ZAA decreases. The RT-dried ZAA for the p-type organic-based CTM shows the widest threshold voltage shift (∆VTH ≈ 80 V), four distinct VTHs for a multi-bit memory operation and retained memory currents for 103 s with high memory on- and off-current ratio (IM,ON/IM,OFF ≈ 5Ⅹ104). The n-type oxide-based CTM (Ox-CTM) also shows a ∆VTH of 14 V and retained memory currents for 103 s with IM,ON/IM,OFF ≈ 104. The inability of the Ox-CTM to be electrically erasable is well explained with simulated electrical potential contour maps. It is deduced that, irrespective of the varied solution-processed semiconductor used, the RT-dried organic ZAA as CTL shows the best memory functionality in the fabricated CTMs. This implies that the high carbon double bonds in the low-temperature processed ZAA CTL are very useful for low-cost multi-bit CTMs in flexible electronics.

Highly stretchable and robust transparent conductive polymer composites for multifunctional healthcare monitoring.

Soft, stretchable, conductive thin films have propelled to the forefront of applications in stretchable sensors for on-skin health monitoring. Stretchable conductive films require high conformability, stretchability, and mechanical/chemical stability when integrated into the skin. Here, we present a highly stretchable, conductive, and transparent natural rubber/silver nanowire (AgNW)/poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) composite film. Overcoating the PEDOT:PSS layer results in outstanding mechanical robustness and chemical stability by suppressing the mechanical and chemical degradation of the nanowire networks. Moreover, the introduction of the organic surface modifier enhances the bonding strength between the natural rubber substrate and AgNW at the interface. The highly conformable composite films are integrated into multifunctional on-skin sensors for monitoring various human motions and biological signals with low-power consumption. We believe that the highly stretchable, robust, and conformable natural rubber/AgNW/PEDOT:PSS composite film can offer new opportunities for next-generation wearable sensors for body motion and physiological monitoring.

Clinical characteristics and pathological depths of syringomas in 94 Korean patients.

BACKGROUND: Syringoma is a common benign tumor with eccrine origin that typically occurs on the face of middle-aged women. Laser ablation with CO2 laser or Er:YAG laser has been widely used in the clinical field, often leading to scars due to its deep location. This study aimed to investigate clinical characteristics and pathological depths of the lesions in syringoma patients. MATERIALS AND METHODS: Syringoma patients, pathologically confirmed at Samsung medical center (Seoul, Korea) from January 1996 to March 2019, were analyzed. Clinical characteristics such as the location of lesion, age, and sex, and pathological depths of the lesions were investigated, and univariable and multivariable analyses were done for these factors. RESULTS: Of total 94 syringomas, 17.0% were located on periocular area, 10.6% on forehead, 34.0% on head and neck areas excluding periocular area and forehead, and 38.3% on trunk and extremities. The mean depth of syringoma from the surface including stratum corneum to the deepest stromal location was 1174.14 ± 1142.95 µm for periocular area, 1055.93 ± 247.76 µm for forehead, 1488.06 ± 1217.36 µm for other areas of head and neck including scalp, and 1169.53 ± 349.2 for the lesions located at trunk and extremities including external genitalia. No significant correlation was observed from univariable analysis and multivariable analysis by age, sex, and site of lesion. CONCLUSION: Our findings offer valuable information of the mean depth of syringoma at different sites, which can be taken into consideration for successful treatment without adverse events such as scarring.

Distinct gating mechanism of SOC channel involving STIM-Orai coupling and an intramolecular interaction of Orai in Caenorhabditis elegans.

Store-operated calcium entry (SOCE), an important mechanism of Ca2+ signaling in a wide range of cell types, is mediated by stromal interaction molecule (STIM), which senses the depletion of endoplasmic reticulum Ca2+ stores and binds and activates Orai channels in the plasma membrane. This inside-out mechanism of Ca2+ signaling raises an interesting question about the evolution of SOCE: How did these two proteins existing in different cellular compartments evolve to interact with each other? We investigated the gating mechanism of Caenorhabditis elegans Orai channels. Our analysis revealed a mechanism of Orai gating by STIM binding to the intracellular 2-3 loop of Orai in C. elegans that is radically different from Orai gating by STIM binding to the N and C termini of Orai in mammals. In addition, we found that the conserved hydrophobic amino acids in the 2-3 loop of Orai1 are important for the oligomerization and gating of channels and are regulated via an intramolecular interaction mechanism mediated by the N and C termini of Orai1. This study identifies a previously unknown SOCE mechanism in C. elegans and suggests that, while the STIM-Orai interaction is conserved between invertebrates and mammals, the gating mechanism for Orai channels differs considerably.

Effect of photobiomodulation therapy on radiodermatitis in a mouse model: an experimental animal study.

This study aimed to evaluate the effect of photobiomodulation (PBM) for prevention of radiodermatitis in an irradiated mouse model and compare the efficacy of PBM using 633- or 830-nm wavelengths. Irradiated mice were randomly distributed into three groups: A (633 nm), B (830 nm), and C (without PBM). On post-irradiation days 7 and 21, we compared acute damage and recovery in treated skin samples to non-irradiated skin using H&E, Masson's trichrome, anti-CD45 and PCNA immunohistochemistry, and a TUNEL assay. Grade 3 radiodermatitis was evident only in group C. Compared with that in group C, the skin in groups A and B had significantly less epidermal hyperplasia, inflammatory cell infiltration, and thinner dermis on day 7 and less inflammatory cell infiltration, fewer apoptotic cells, and thinner dermis on day 21. However, there was no significant difference between groups A and B. This study indicates PBM could prevent severe radiodermatitis by reducing epidermal and dermal damage, inflammation, and apoptosis. There was no difference in PBM efficacy between the 633- and 830-nm wavelengths.

New Insights into the Transcriptional Regulation of Genes Involved in the Nitrogen Use Efficiency under Potassium Chlorate in Rice (Oryza sativa L.).

Potassium chlorate (KClO3) has been widely used to evaluate the divergence in nitrogen use efficiency (NUE) between indica and japonica rice subspecies. This study investigated the transcriptional regulation of major genes involved in the NUE in rice treated with KClO3, which acts as an inhibitor of the reducing activity of nitrate reductase (NR) in higher plants. A set of two KClO3 sensitive nitrate reductase (NR) and two nitrate transporter (NRT) introgression rice lines (BC2F7), carrying the indica alleles of NR or NRT, derived from a cross between Saeilmi (japonica, P1) and Milyang23 (indica, P2), were exposed to KClO3 at the seedling stage. The phenotypic responses were recorded 7 days after treatment, and samples for gene expression, physiological, and biochemical analyses were collected at 0 h (control) and 3 h after KClO3 application. The results revealed that Saeilmi (P1, japonica) and Milyang23 (P2, indica) showed distinctive phenotypic responses. In addition, the expression of OsNR2 was differentially regulated between the roots, stem, and leaf tissues, and between introgression lines. When expressed in the roots, OsNR2 was downregulated in all introgression lines. However, in the stem and leaves, OsNR2 was upregulated in the NR introgression lines, but downregulation in the NRT introgression lines. In the same way, the expression patterns of OsNIA1 and OsNIA2 in the roots, stem, and leaves indicated a differential transcriptional regulation by KClO3, with OsNIA2 prevailing over OsNIA1 in the roots. Under the same conditions, the activity of NR was inhibited in the roots and differentially regulated in the stem and leaf tissues. Furthermore, the transcriptional divergence of OsAMT1.3 and OsAMT2.3, OsGLU1 and OsGLU2, between NR and NRT, coupled with the NR activity pattern in the roots, would indicate the prevalence of nitrate (NO3¯) transport over ammonium (NH4+) transport. Moreover, the induction of catalase (CAT) and polyphenol oxidase (PPO) enzyme activities in Saeilmi (P1, KClO3 resistant), and the decrease in Milyang23 (P2, KClO3 sensitive), coupled with the malondialdehyde (MDA) content, indicated the extent of the oxidative stress, and the induction of the adaptive response mechanism, tending to maintain a balanced reduction-oxidation state in response to KClO3. The changes in the chloroplast pigments and proline content propose these compounds as emerging biomarkers for assessing the overall plant health status. These results suggest that the inhibitory potential of KClO3 on the reduction activity of the nitrate reductase (NR), as well as that of the genes encoding the nitrate and ammonium transporters, and glutamate synthase are tissue-specific, which may differentially affect the transport and assimilation of nitrate or ammonium in rice.

RNA-Seq and Electrical Penetration Graph Revealed the Role of Grh1-Mediated Activation of Defense Mechanisms towards Green Rice Leafhopper (Nephotettix cincticeps Uhler) Resistance in Rice (Oryza sativa L.).

The green rice leafhopper (GRH, Nephotettix cincticeps Uhler) is one of the most important insect pests causing serious damage to rice production and yield loss in East Asia. Prior to performing RNA-Seq analysis, we conducted an electrical penetration graph (EPG) test to investigate the feeding behavior of GRH on Ilpum (recurrent parent, GRH-susceptible cultivar), a near-isogenic line (NIL carrying Grh1) compared to the Grh1 donor parent (Shingwang). Then, we conducted a transcriptome-wide analysis of GRH-responsive genes in Ilpum and NIL, which was followed by the validation of RNA-Seq data by qPCR. On the one hand, EPG results showed differential feeding behaviors of GRH between Ilpum and NIL. The phloem-like feeding pattern was detected in Ilpum, whereas the EPG test indicated a xylem-like feeding habit of GRH on NIL. In addition, we observed a high death rate of GRH on NIL (92%) compared to Ilpum (28%) 72 h post infestation, attributed to GRH failure to suck the phloem sap of NIL. On the other hand, RNA-Seq data revealed that Ilpum and NIL GRH-treated plants generated 1,766,347 and 3,676,765 counts per million mapped (CPM) reads, respectively. The alignment of reads indicated that more than 75% of reads were mapped to the reference genome, and 8859 genes and 15,815,400 transcripts were obtained. Of this number, 3424 differentially expressed genes (DEGs, 1605 upregulated in Ilpum and downregulated in NIL; 1819 genes upregulated in NIL and downregulated in Ilpum) were identified. According to the quantile normalization of the fragments per kilobase of transcript per million mapped reads (FPKM) values, followed by the Student's t-test (p < 0.05), we identified 3283 DEGs in Ilpum (1935 upregulated and 1348 downregulated) and 2599 DEGs in NIL (1621 upregulated and 978 downregulated) with at least a log2 (logarithm base 2) twofold change (Log2FC ≥2) in the expression level upon GRH infestation. Upregulated genes in NIL exceeded by 13.3% those recorded in Ilpum. The majority of genes associated with the metabolism of carbohydrates, amino acids, lipids, nucleotides, the activity of coenzymes, the action of phytohormones, protein modification, homeostasis, the transport of solutes, and the uptake of nutrients, among others, were abundantly upregulated in NIL (carrying Grh1). However, a high number of upregulated genes involved in photosynthesis, cellular respiration, secondary metabolism, redox homeostasis, protein biosynthesis, protein translocation, and external stimuli response related genes were found in Ilpum. Therefore, all data suggest that Grh1-mediated resistance against GRH in rice would involve a transcriptome-wide reprogramming, resulting in the activation of bZIP, MYB, NAC, bHLH, WRKY, and GRAS transcription factors, coupled with the induction of the pathogen-pattern triggered immunity (PTI), systemic acquired resistance (SAR), symbiotic signaling pathway, and the activation of genes associated with the response mechanisms against viruses. This comprehensive transcriptome profile of GRH-responsive genes gives new insights into the molecular response mechanisms underlying GRH (insect pest)-rice (plant) interaction.

Random Al2O3 nanoparticle-based polymer composite films as outcoupling layers for flexible organic light-emitting diodes.

Random Al2O3 nanoparticle-based polymer composite films are investigated as external scattering layers to enhance light extraction from flexible organic light-emitting diodes (OLEDs). We found that the size and concentration of the nanoparticles (NPs) in the polymer film play a crucial role in improving light extraction. It turned out that their increase has a favorable impact on the light output of the devices, as the high concentration of the NPs leads to the formation of large nanoparticle clusters, which, in turn, yield pore-containing films. As a result, light extraction efficiency of the flexible OLEDs on PEN substrates was enhanced by a factor of 1.65 by the incorporation of the scattering layer, with the highest Al2O3 NP concentration of 99 wt%. This outcome is attributed to the reduction of the waveguide mode and total internal reflection at the substrate/air interface induced by the randomly distributed NPs in the flexible scattering layer. Our work demonstrates an efficient, solution-processable, and low-cost light-outcoupling structure for large-area and flexible OLED applications.

Outcoupling efficiency enhancement of a bottom-emitting OLED with a visible parylene film.

We have investigated an effective and a single-step chemical vapor deposition (CVD) method to achieve conformal visible poly-dichloro-para-xylylene (parylene C) film for light extraction enhancement in bottom-emitting organic light-emitting diodes (OLEDs) at room temperature. We report that sublimed parylene dimers pyrolyzed between 400 °C and 500 °C resulted in visible parylene films with tunable transmittance and haze, exhibiting light scattering properties due to the formation of uniformly distributed dimer crystals. We achieved a novel conformal visible parylene film with total transmittance and high haze of 79.5% and 93.6%, respectively. It is observed that the outcoupling efficiency of the OLEDs employing the visible parylene film is enhanced up to 45.8%. Additionally, the OLED with the visible parylene light extraction film shows limited angle-dependency of emission spectrum over viewing angles. The single-step room temperature fabrication process of this conformal outcoupling film paves the way to achieving commercial high-performance OLEDs.

Effect of Triclosan Exposure on Developmental Competence in Parthenogenetic Porcine Embryo during Preimplantation.

Triclosan (TCS) is included in various healthcare products because of its antimicrobial activity; therefore, many humans are exposed to TCS daily. While detrimental effects of TCS exposure have been reported in various species and cell types, the effects of TCS exposure on early embryonic development are largely unknown. The aim of this study was to determine if TCS exerts toxic effects during early embryonic development using porcine parthenogenetic embryos in vitro. Porcine parthenogenetic embryos were cultured in in vitro culture medium with 50 or 100 µM TCS for 6 days. Developmental parameters including cleavage and blastocyst formation rates, developmental kinetics, and the number of blastomeres were assessed. To determine the toxic effects of TCS, apoptosis, oxidative stress, and mitochondrial dysfunction were assessed. TCS exposure resulted in a significant decrease in 2-cell rate and blastocyst formation rate, as well as number of blastomeres, but not in the cleavage rate. TCS also increased the number of apoptotic blastomeres and the production of reactive oxygen species. Finally, TCS treatment resulted in a diffuse distribution of mitochondria and decreased the mitochondrial membrane potential. Our results showed that TCS exposure impaired porcine early embryonic development by inducing DNA damage, oxidative stress, and mitochondrial dysfunction.

Importance of Purcell factor for optimizing structure of organic light-emitting diodes.

The ratio of spontaneous emission inside a diode structure to that in free space is called the Purcell factor (F(λ)). The structure of organic light-emitting diodes (OLEDs) has a significant influence on the spontaneous emission rate of dipole emitters. Therefore, to describe the optical properties of OLEDs, it is essential to incorporate F(λ) in the description. However, many optical studies on OLEDs continue to be conducted without considering F(λ) for simplicity's sake. Hence, in this study, using carefully designed bottom- and top-emitting OLEDs, we show that the external quantum efficiency obtained without considering F(λ) can be over- or under-estimated, and in some cases, the margin of error may be significant. We also reveal that the subtle distribution of the electroluminescence spectrum can be explained properly only by including F(λ). Both these results stipulate the importance of including F(λ) to maintain a quantitative agreement between theoretical and experimental data. Hence, the inclusion of F(λ) is important for designing OLEDs with enhanced efficiency or desired spectral characteristics.

Enhanced light extraction from organic light-emitting diodes using a quasi-periodic nano-structure.

Organic light-emitting diodes with a quasi-periodic nano-structure (QPS) were fabricated via a combination of laser interference lithography (LIL) and reactive ion etching (RIE). The LIL process was used to generate a periodic pattern, whereas the RIE process was used as a supplement to add randomness to the periodic pattern. The period of the fabricated periodic pattern was determined by finite difference time domain solutions. The height and density of the QPS were controlled by the RIE etching time and were optimized. The resulting quasi-periodic nanostructure comprised silicon dioxide (SiO2) with a low refractive index (n = 1.4-1.5), and an external quantum efficiency enhancement of 18% was achieved using the QPS device, without any viewing angle problems or spectral distortion, which are serious drawbacks of periodic patterns.

Enhanced outcoupling in down-conversion white organic light-emitting diodes using imprinted microlens array films with breath figure patterns.

We demonstrate high-performance down-conversion microlens array (DC-MLA) films for white organic light-emitting diodes (OLEDs). The DC-MLA films are readily fabricated by an imprinting method based on breath figure patterns, which are directly formed on the polymer substrate with a novel concept. The DC-MLA films result in high-quality white light as well as enhanced light outcoupling efficiency for white OLEDs. The external quantum efficiency and power efficiency of OLEDs with DC-MLA films are increased by a factor of 1.35 and 1.86, respectively, compared to OLEDs without outcoupling films. Moreover, the white OLEDs with DC-MLA films achieve a high color-rendering index of 84.3. It is anticipated that the novel DC-MLA films fabricated by the simple imprinting process with breath figure patterns can contribute to the development of efficient white OLEDs.

Color-tunable organic light-emitting diodes with vertically stacked blue, green, and red colors for lighting and display applications.

We demonstrate independently and simultaneously controlled color-tunable organic light-emitting diodes (OLEDs) with vertically stacked blue, green, and red elements. The blue, green, and red elements were placed at the bottom, middle, and top positions, respectively, forming color-tunable OLEDs. The independently driven blue, green, and red elements in the color-tunable OLEDs exhibited low driving voltages of 5.3 V, 3.0 V, and 4.6 V, as well as high external quantum efficiencies of 11.1%, 10.9%, and 9.6%, respectively, at approximately 1000 cd/m2. Each element in the color-tunable OLEDs showed high-purity blue, green, and red colors with little parasitic emission owing to the delicately designed device structure resultant from optical simulations. The color-tunable OLEDs could produce any colors inside the triangle formed with blue (0.136, 0.261), green (0.246, 0.697), and red (0.614, 0.386) Commission Internationale de l'éclairage (CIE) 1931 color coordinates. In addition, the correlated color temperatures (CCTs) of white colors in the color-tunable OLED can be easily changed from the warm white to the cool white by controlling the red, green, and blue emissions simultaneously. The white colors in the color-tunable OLED have the CIE 1931 color coordinate of (0.304, 0.351), with a CCT of 6289 K and (0.504, 0.440), with a CCT of 2407K at the driving voltage of 5 V (blue), 2.8 V (green), 4.4 V (red), and 4.6 V (blue), 3 V (green), 5 V (red), respectively. Furthermore, the white color in the color-tunable OLED exhibited a high color rendering index (~88.7) due to vertically stacked three color system. Moreover, we successfully fabricated a large-sized, 14 × 12 pixel array of the color-tunable OLEDs to demonstrate lighting and display applications, respectively.

Overcoming the efficiency limit of organic light-emitting diodes using ultra-thin and transparent graphene electrodes.

We propose an effective way to enhance the out-coupling efficiencies of organic light-emitting diodes (OLEDs) using graphene as a transparent electrode. In this study, we investigated the detrimental adsorption and internal optics occurring in OLEDs with graphene anodes. The optical out-coupling efficiencies of previous OLEDs with transparent graphene electrodes barely exceeded those of OLEDs with conventional transparent electrodes because of the weak microcavity effect. To overcome this issue, we introduced an internal random scattering layer for light extraction and reduced the optical absorption of the graphene by reducing the number of layers in the multilayered graphene film. The efficiencies of the graphene-OLEDs increased significantly with decreasing the number of graphene layers, strongly indicating absorption reduction. The maximum light extraction efficiency was obtained by using a single-layer graphene electrode together with a scattering layer. As a result, a widened angular luminance distribution with a remarkable external quantum efficiency and a luminous efficacy enhancement of 52.8% and 48.5%, respectively, was achieved. Our approach provides a demonstration of graphene-OLED having a performance comparable to that of conventional OLEDs.

Brief Report: Human Acute Myeloid Leukemia Reprogramming to Pluripotency Is a Rare Event and Selects for Patient Hematopoietic Cells Devoid of Leukemic Mutations.

Induced pluripotent stem cell reprogramming has provided critical insights into disease processes by modeling the genetics and related clinical pathophysiology. Human cancer represents highly diverse genetics, as well as inter- and intra-patient heterogeneity, where cellular model systems capable of capturing this disease complexity would be invaluable. Acute myeloid leukemia (AML) represents one of most heterogeneous cancers and has been divided into genetic subtypes correlated with unique risk stratification over the decades. Here, we report our efforts to induce pluripotency from the heterogeneous population of human patients that represents this disease in the clinic. Using robust optimized reprogramming methods, we demonstrate that reprogramming of AML cells harboring leukemic genomic aberrations is a rare event with the exception of those with de novo mixed-lineage leukemia (MLL) mutations that can be reprogrammed and model drug responses in vitro. Our findings indicate that unlike hematopoietic cells devoid of genomic aberrations, AML cells harboring driver mutations are refractory to reprogramming. Expression of MLL fusion proteins in AML cells did not contribute to induced reprogramming success, which continued to select for patient derived cells devoid of AML patient-specific aberrations. Our study reveals that unanticipated blockades to achieving pluripotency reside within the majority of transformed AML patient cells. Stem Cells 2017;35:2095-2102.

Urine IP-10 as a biomarker of therapeutic response in patients with active pulmonary tuberculosis.

BACKGROUND: Prior to clinical trials of new TB drugs or therapeutic vaccines, it is necessary to develop monitoring tools to predict treatment outcomes in TB patients. Urine interferon gamma inducible protein 10 (IP-10) is a potential biomarker of treatment response in chronic hepatitis C virus infection and lung diseases, including tuberculosis. In this study, we assessed IP-10 levels in urine samples from patients with active TB at diagnosis, during treatment, and at completion, and compared these with levels in serum samples collected in parallel from matched patients to determine whether urine IP-10 can be used to monitor treatment response in patients with active TB. METHODS: IP-10 was measured using enzyme-linked immunosorbent assays in urine and serum samples collected concomitantly from 23 patients with active TB and 21 healthy adults (44 total individuals). The Mann-Whitney U test and Wilcoxon matched-pairs signed rank test were used for comparisons among healthy controls and patients at three time points, and LOESS regression was used for longitudinal data. RESULTS: The levels of IP-10 in urine increased significantly after 2 months of treatment (P = 0.0163), but decreased by the completion of treatment (P = 0.0035). Serum IP-10 levels exhibited a similar trend, but did not increase significantly after 2 months of treatment in patients with active TB. CONCLUSIONS: Unstimulated IP-10 in urine can be used as a biomarker to monitor treatment response in patients with active pulmonary TB.