Prostein expression on circulating tumor cells as a prognostic marker in metastatic castration-resistant prostate cancer.

BACKGROUND: Identification of emerging molecular biomarkers on circulating tumor cells (CTCs) represents an attractive feature of liquid biopsy that facilitates precision and tailored medicine in the management of metastatic castration-resistant prostate cancer (mCRPC). Prostein is an androgen-regulated transmembrane protein with high prostate specificity. Prostein-positive circulating tumor cell (CTC) was recently suggested to have diagnostic potential; however, no study has been conducted to evaluate its prognostic value in mCRPC. METHODS: CTCs from mCRPC patients were enumerated using the CellSearch System. Prostein-positive CTCs were identified by immunostaining results. The relationships between prostein expression on CTCs and PSA response rate, PSA progression-free survival (PSA-PFS), radiographic progression-free survival (PFS), and overall survival (OS) were tested by Fisher's exact test or evaluated using Kaplan-Meier and multivariate Cox analyses. RESULTS: Prostein-positive CTCs were identified in 31 of 87 baseline samples from mCRPC patients and 16 of 51 samples collected at the first follow-up visit. PSA response rates were significantly lower in baseline prostein-positive patients (0%, 0/31) than in prostein-negative patients (19.6%, 11/56) (p = 0.007). The 31 prostein-positive patients had significantly shorter PSA-PFS (p < 0.001), radiographic PFS (p < 0.001), and OS (p = 0.018), compared to the 56 prostein-negative patients at baseline. The association with PSA-PFS maintained its significance (p = 0.028) in multivariate analyses. Analyzing prostein expression at the first follow-up as well as the conversion of prostein expression from baseline to follow-up samples not only confirmed the association with PSA-PFS, but also demonstrated prognostic significance with OS. CONCLUSION: Our study provides the first evidence to support the potential of prostein expression on CTCs to serve as a novel prognostic marker in mCRPC patients. Future large-scale prospective studies are needed to validate our findings.

Sigma1 Regulates Lipid Droplet-mediated Redox Homeostasis Required for Prostate Cancer Proliferation.

Lipid droplets (LD) are dynamic organelles that serve as hubs of cellular metabolic processes. Emerging evidence shows that LDs also play a critical role in maintaining redox homeostasis and can mitigate lipid oxidative stress. In multiple cancers, including prostate cancer, LD accumulation is associated with cancer aggressiveness, therapy resistance, and poor clinical outcome. Prostate cancer arises as an androgen receptor (AR)-driven disease. Among its myriad roles, AR mediates the biosynthesis of LDs, induces autophagy, and modulates cellular oxidative stress in a tightly regulated cycle that promotes cell proliferation. The factors regulating the interplay of these metabolic processes downstream of AR remain unclear. Here, we show that Sigma1/SIGMAR1, a unique ligand-operated scaffolding protein, regulates LD metabolism in prostate cancer cells. Sigma1 inhibition triggers lipophagy, an LD selective form of autophagy, to prevent accumulation of LDs which normally act to sequester toxic levels of reactive oxygen species (ROS). This disrupts the interplay between LDs, autophagy, buffering of oxidative stress and redox homeostasis, and results in the suppression of cell proliferation in vitro and tumor growth in vivo. Consistent with these experimental results, SIGMAR1 transcripts are strongly associated with lipid metabolism and ROS pathways in prostate tumors. Altogether, these data reveal a novel, pharmacologically responsive role for Sigma1 in regulating the redox homeostasis required by oncogenic metabolic programs that drive prostate cancer proliferation. SIGNIFICANCE: To proliferate, cancer cells must maintain productive metabolic and oxidative stress (eustress) while mitigating destructive, uncontrolled oxidative stress (distress). LDs are metabolic hubs that enable adaptive responses to promote eustress. Targeting the unique Sigma1 protein can trigger distress by disrupting the LD-mediated homeostasis required for proliferation.

Review of Cardiovascular Risk of Androgen Deprivation Therapy and the Influence of Race in Men with Prostate Cancer.

Androgen deprivation therapy is the cornerstone of prostate cancer therapy. Recent studies have revealed an association between androgen deprivation therapy and cardiovascular adverse effects such as myocardial infarction and stroke. This review summarizes the available research on the cardiovascular risk of men using androgen deprivation therapy. We also discuss racial disparities surrounding both prostate cancer and cardiovascular disease, emphasizing the importance of biological/molecular and socioeconomic factors in assessing baseline risk in patients beginning androgen ablation. Based on the literature, we provide recommendations for monitoring patients who are at high risk for a cardiovascular adverse event while being treated on androgen deprivation therapy. This review aims to present the current research on androgen deprivation therapy and cardiovascular toxicity with an emphasis on racial disparities and provides a framework for clinicians to decrease the cardiovascular morbidity in men that are being treated with hormone therapy.

High-Performance, Flexible NO2 Chemiresistors Achieved by Design of Imine-Incorporated n-Type Conjugated Polymers.

Flexible and mechanically robust gas sensors are the key technologies for wearable and implantable electronics. Herein, the authors demonstrate the high-performance, flexible nitrogen dioxide (NO2 ) chemiresistors using a series of n-type conjugated polymers (CPs: PNDIT2/IM-x) and a polymer dopant (poly(ethyleneimine), PEI). Imine double bonds (C = N) are incorporated into the backbones of the CPs with different imine contents (x) to facilitate strong and selective interactions with NO2 . The PEI provides doping stability, enhanced electrical conductivity, and flexibility. As a result, the NO2 sensors with PNDIT2/IM-0.1 and PEI (1:1 by weight ratio) exhibit outstanding sensing performances, such as excellent sensitivity (ΔR/Rb = 240% @ 1 ppm), ultralow detection limit (0.1 ppm), high selectivity (ΔR/Rb < 8% @ 1 ppm of interfering analytes), and high stability, thereby outperforming other state-of-the-art CP-based chemiresistors. Furthermore, the thin film of PNDIT2/IM-0.1 and PEI blend is stretchable and mechanically robust, providing excellent flexibility to the NO2 sensors. Our study contributes to the rational design of high-performance flexible gas sensors.

Effects of the Selective Alkoxy Side Chain Position in Quinoxaline-Based Polymer Acceptors on the Performance of All-Polymer Solar Cells.

The effects of the position of alkoxy side chains in quinoxaline (Qx)-based polymer acceptors (PAs) on the characteristics of materials and the device parameters of all-polymer solar cells (all-PSCs) are investigated. The alkoxy side chains are selectively located at the meta, para, and both positions in pendant benzenes of Qx units, constructing PAs denoted as P(QxCN-T2)-m, P(QxCN-T2)-p, and P(QxCN-T2), respectively. Among them, P(QxCN-T2)-m exhibits the deepest energy levels owing to the enhanced electron-withdrawing effect of meta-positioned alkoxy chains, which is in contrast to P(QxCN-T2)-p where para-positioned alkoxy chains have an electron-donating property. In addition, the meta-positioned alkoxy chains induce good electron-conducting pathways, while the para-positioned ones significantly interrupt crystallization and intermolecular interactions between the conjugated backbones. Thus, when the PAs are applied to all-PSCs, a power conversion efficiency (PCE) of 5.07% is attained in the device using P(QxCN-T2)-m with efficient exciton dissociation and good electron-transporting ability. On the contrary, the P(QxCN-T2)-p-based counterpart has a PCE of only 1.62%. These results demonstrate that introducing alkoxy side chains at a proper location in the Qx-based PAs is crucial for their application to all-PSCs.

Sigmoidal Dependence of Electrical Conductivity of Thin PEDOT:PSS Films on Concentration of Linear Glycols as a Processing Additive.

We investigate the sigmoidal concentration dependence of electrical conductivity of poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) processed with linear glycol-based additives such as ethylene glycol (EG), diethylene glycol (DEG), triethylene glycol (TEG), hexaethylene glycol (HEG), and ethylene glycol monomethyl ether (EGME). We observe that a sharp transition of conductivity occurs at the additive concentration of ~0.6 wt.%. EG, DEG, and TEG are effective in conductivity enhancement, showing the saturation conductivities of 271.8, 325.4, and 326.2 S/cm, respectively. Optical transmittance and photoelectron spectroscopic features are rather invariant when the glycols are used as an additive. Two different figures of merit, calculated from both sheet resistance and optical transmittance to describe the performance of the transparent electrodes, indicate that both DEG and TEG are two most effective additives among the series in fabrication of transparent electrodes based on PEDOT:PSS films with a thickness of ~50-60 nm.

Effect of Threshold Voltage Window and Variation of Organic Synaptic Transistor for Neuromorphic System.

Synaptic devices, which are considered as one of the most important components of neuromorphic system, require a memory effect to store weight values, a high integrity for compact system, and a wide window to guarantee an accurate programming between each weight level. In this regard, memristive devices such as resistive random access memory (RRAM) and phase change memory (PCM) have been intensely studied; however, these devices have quite high current-level despite their state, which would be an issue if a deep and massive neural network is implemented with these devices since a large amount of current-sum needs to flow through a single electrode line. Organic transistor is one of the potential candidates as synaptic device owing to flexibility and a low current drivability for low power consumption during inference. In this paper, we investigate the performance and power consumption of neuromorphic system composed of organic synaptic transistors conducting a pattern recognition simulation with MNIST handwritten digit data set. It is analyzed according to threshold voltage (VT) window, device variation, and the number of available states. The classification accuracy is not affected by VT window if the device variation is not considered, but the current sum ratio between answer node and the rest 9 nodes varies. In contrast, the accuracy is significantly degraded as increasing the device variation; however, the classification rate is less affected when the number of device states is fewer.

Cyano-Functionalized Quinoxaline-Based Polymer Acceptors for All-Polymer Solar Cells and Organic Transistors.

Quinoxaline (Qx) derivatives are promising building units for efficient photovoltaic polymers owing to their strong light absorption and high charge-transport abilities, but they have been used exclusively in the construction of polymer donors. Herein, for the first time, Qx-based polymer acceptors (PA s) were developed by introducing electron-withdrawing cyano (CN) groups into the Qx moiety (QxCN). A series of QxCN-based PA s, P(QxCN-T2), P(QxCN-TVT), and P(QxCN-T3), were synthesized by copolymerizing the QxCN unit with bithiophene, (E)-1,2-di(thiophene-2-yl)ethene, and terthiophene, respectively. All of the PA s exhibited unipolar n-type characteristics with organic field-effect transistor (OFET) mobilities of around 10-2  cm2 V-1 s-1 . In space-charge-limited current devices, P(QxCN-T2) and P(QxCN-TVT) exhibited electron mobilities greater than 1.0×10-4  cm2 V-1 s-1 , due to the well-ordered structure with tight π-π stacking. When the PA s were applied in all-polymer solar cells (all-PSCs), the highest performance of 5.32 % was achieved in the P(QxCN-T2)-based device. These results demonstrate the significant potential of Qx-based PA s for high-performance all-PSCs and OFETs.

Enhancement of the response time in organic photorefractive composites using alkoxy-substituted PDCST as a nonlinear optical chromophore: publisher's note.

This publisher's note contains corrections to Opt. Lett.45, 6767 (2020)OPLEDP0146-959210.1364/OL.409743.

Solid-State Organic Electrolyte-Gated Transistors Based on Doping-Controlled Polymer Composites with a Confined Two-Dimensional Channel in Dry Conditions.

We report comprehensive and comparative studies on chemical and electrochemical controls of doping characteristics of various poly(3,4-ethylenedioxythiophene) (PEDOT) composites complexed with sulfonates. Chemical treatment of PEDOT composites was conducted with a dedoping agent, tetrakis(dimethylamino)ethylene (TDAE), resulting in the changes in conformation and bulk charge-carrier density. Electrochemical control of doping states was done with a solid-state ionogel based on an ionic liquid dispersed in a polymer matrix. With this approach, we can fabricate solid-state organic electrolyte-gated transistors (OEGTs) with a large current modulation, a high mobility of holes, and a low driving voltage. Our OEGTs are operational in a dry environment and, surprisingly, form the two-dimensional channel of the interfacial charge carriers modulating the conductance under gate bias, unlike conventional liquid-based OEGTs. The charge-carrier mobility and the on-to-off current ratio reach up to ∼7 cm2 V-1 s-1 and over 104, respectively, from the chemically dedoped PEDOT composites. The ionogel-based gating of the layer of TDAE-treated PEDOT composites induces a reversible transition between a highly doped bipolaronic state and neutral/polaronic states, as revealed by the absorption profiles under gate bias. We also demonstrate in-plane OEGTs, in which the dedoped channel and the conductive source/drain electrodes are made of a single PEDOT composite layer.

Enhancement of the response time in organic photorefractive composites using alkoxy-substituted PDCST as a nonlinear optical chromophore.

The ease of the molecular orientation of a chromophore has an important effect on the electro-optical (EO) properties of polymeric photorefractive (PR) composites. A derivative of 4-piperidinobenzylidene-malononitrile (PDCST) with an alkoxy group added as a side branch was synthesized to improve the molecular orientation characteristics. Electrophoresis was performed on the polymeric PR composite to which the improved PDCST had been added. The optical properties and response times were examined to evaluate the effects of the substitution of the alkoxy group. PDCST substituted with the alkoxy group showed enhanced EO properties and a PR grating formation rate.

Impact of Chlorination Patterns of Naphthalenediimide-Based Polymers on Aggregated Structure, Crystallinity, and Device Performance of All-Polymer Solar Cells and Organic Transistors.

The aggregation properties of conjugated polymers can play a crucial role in their thin film structures and performance of electronic devices. Control of these aggregated structures is particularly important in producing efficient all-polymer solar cells (all-PSCs), considering that strong demixing of the polymer donor and polymer acceptor typically occurs during film formation because of the low entropic contribution to the thermodynamics of the system. Here, three naphthalenediimide (NDI)-based polymer acceptors with different backbone chlorination patterns are developed to investigate the effect of the chlorination patterns on the aggregation tendencies of the polymer acceptors, which greatly influence their crystalline structures, electrical properties, and device performances of the resultant all-PSCs and organic field-effect transistors (OFETs). The counterparts of NDI units, dichlorinated bithiophene (Cl2T2), monochlorinated bithiophene (ClT2), and dichlorinated thienylene-vinylene-thienylene (Cl2TVT), are employed to synthesize a series of P(NDIOD-Cl2T2), P(NDIOD-ClT2), and P(NDIOD-Cl2TVT) polymers. The P(NDIOD-Cl2T2) polymer takes advantage of strong noncovalent bonding induced by its chlorine substituents, resulting in the formation of optimal face-on oriented crystalline structures which are suitable for efficient all-PSC devices. In comparison, the P(NDIOD-Cl2TVT) polymer forms bimodal crystalline structures in thin films to yield optimal performances in the resultant OFETs. When the three chlorinated polymers are applied to all-PSCs with the PBDTTTPD polymer donor, P(NDIOD-Cl2T2) achieves a maximum power conversion efficiency (PCE) of 7.22% with an appropriate blend morphology and high fill factor, outperforming P(NDIOD-ClT2) (PCE = 4.80%) and P(NDIOD-Cl2TVT) (PCE = 5.78%). Our observations highlight the effectiveness of the chlorination strategy for developing efficient polymer acceptors and demonstrate the important role of polymer aggregation in modulating the blend morphology and all-PSC performance.

Selective Ammonia-Sensing Platforms Based on a Solution-Processed Film of Poly(3-Hexylthiophene) and p-Doping Tris(Pentafluorophenyl)Borane.

Here, we fabricate ammonia sensors based on organic transistors by using poly(3-hexylthiophene) (P3HT) blended with tris(pentafluorophenyl)borane (TPFB) as an active layer. As TPFB is an efficient p-type dopant for P3HT, the current level of the blend films can be easily modulated by controlling the blend ratio. The devices exhibit significantly increased on-state and off-state current levels owing to the ohmic current originated from the large number of charge carriers when the active polymer layer contains TPFB with concentrations up to 20 wt % (P3HT:TPFB = 8:2). The current is decreased at 40 wt % of TPFB (P3HT:TPFB = 6:4). The P3HT:TPFB blend with a weight ratio of 9:1 exhibits the highest sensing performances for various concentrations of ammonia. The device exhibits an increased percentage current response compared to that of a pristine P3HT device. The current response of the P3HT:TPFB (9:1) device at 100 ppm of ammonia is as high as 65.8%, 3.2 times that of the pristine P3HT (20.3%). Furthermore, the sensor based on the blend exhibits a remarkable selectivity to ammonia with respect to acetone, methanol, and dichloromethane, owing to the strong interaction between the Lewis acid (TPFB) and Lewis base (ammonia).

Nanostructural Manipulation of Poly(3-hexylthiophene) Aggregates for Organic Electrolyte-Gated Transistors.

In this study, we combine solubility-driven formation of poly(3-hexylthiophene) (P3HT) nanoaggregates and ion-gel-based organic electrolyte-gated transistors (OEGTs), to develop high-performance low-voltage switching devices. By in-situ solution blending of a good solvent (chloroform) and a poor solvent (acetone), we obtain dispersions of P3HT nanoaggregates. The aggregation and molecular ordering of P3HT are analyzed by UV-Vis absorption spectroscopy, atomic force microscopy imaging, and X-ray diffraction. The resulting P3HT aggregates are used as an active component of high-capacitance ion-gel dielectric based on P(VDF-HFP)/[EMIM][TFSI]. Wellconnected conductive channels in thin films of P3HT aggregates allow the effective modulation of current in ion gel-gated transistors with an on-state current above 10-3 A at an operational voltage less than -1 V. In searching for the optimal ratio of solvents, the highest mobility of 1.36 cm² V-1 s-1 in the tested OEGTs was observed when 5 vol% of acetone was incorporated into the stock solution of P3HT. This observation suggests that the nanostructural manipulation of polythiophene-based semiconductor is an effective method to produce efficient pathways for charge transport in OEGTs.

Haloperidol and Prostate Cancer Prevention: More Epidemiologic Research Needed.

CONTEXT: The antipsychotic drug haloperidol has antiproliferative and growth-inhibiting properties on prostate cancer cell lines in vitro by binding the sigma 1 protein. Evidence is needed regarding a possible preventive association in men. OBJECTIVE: To examine whether our epidemiologic data support an inverse association of haloperidol use with risk of prostate cancer. DESIGN: These case-control analyses used conditional logistic regression to estimate relative risk by odds ratios (ORs) adjusting for race/ethnicity and aspects of medical care related to detection of prostate cancer. We tested 3 other commonly used antipsychotic drugs, risperidone, quetiapine, and olanzapine, for sigma 1 protein binding and inhibition of clonogenic growth of prostate cancer cells. Use of any of these by men was considered use of a comparator drug. MAIN OUTCOME MEASURES: 1) association of haloperidol with prostate cancer; 2) sigma 1 binding and clonogenic growth. RESULTS: Probably owing to small numbers of haloperidol recipients, evidence of a preventive association was inconsistent, depending on the definition of long-term use. If duration of use was greater than 1 year, the odds ratio (OR) was 0.38 (95% confidence interval (CI) = 0.14-1.01) for haloperidol and 0.80 (95% CI = 0.66-0.98) for the comparator drug; if the duration of use was greater than 2 years, the OR was 0.66 (95% CI = 0.24-1.76) for haloperidol and 0.84 (95% CI = 0.66-1.08) for the comparator drug. Unlike haloperidol, risperidone, quetiapine, and olanzapine did not bind sigma 1 or inhibit clonogenic growth. CONCLUSION: Given the laboratory evidence, our ambiguous epidemiologic findings should encourage more epidemiologic evaluation of haloperidol use and risk of prostate cancer. Finding a negative association could be a scientific advance in prostate cancer prevention but would not be sufficient basis for recommending the prescription of haloperidol for that purpose.

Small-Molecule Modulators of Sigma1 and Sigma2/TMEM97 in the Context of Cancer: Foundational Concepts and Emerging Themes.

There are two known subtypes of the so-called sigma receptors, Sigma1 and Sigma2. Sigma1 (encoded by the SIGMAR1 gene and also known as Sigma-1 receptor, S1R) is a unique pharmacologically regulated integral membrane chaperone or scaffolding protein that allosterically modulates the activity of its associated proteins. Sigma2, recently identified as transmembrane protein 97 (TMEM97), is an integral membrane protein implicated in cellular cholesterol homeostasis. A number of publications over the past two decades have suggested a role for both sigma proteins in tumor biology. Although there is currently no clinically used anti-cancer drug that targets Sigma1 or Sigma2/TMEM97, a growing body of evidence supports the potential of small-molecule compounds with affinity for these proteins, putative sigma ligands, as therapeutic agents to treat cancer. In preclinical models, these compounds have been reported to inhibit cancer cell proliferation, survival, adhesion, and migration; furthermore, they have been demonstrated to suppress tumor growth, to alleviate cancer-associated pain, and to exert immunomodulatory properties. Here, we will address the known knowns and the known unknowns of Sigma1 and Sigma2/TMEM97 ligand actions in the context of cancer. This review will highlight key discoveries and published evidence in support of a role for sigma proteins in cancer and will discuss several fundamental questions regarding the physiological roles of sigma proteins in cancer and sigma ligand mechanism of action.

Selective Wet-Etching of Polymer/Fullerene Blend Films for Surface- and Nanoscale Morphology-Controlled Organic Transistors and Sensitivity-Enhanced Gas Sensors.

Surface and nanoscale morphology of thin poly(3-hexylthiophene) (P3HT) films are effectively controlled by blending the polymer with a soluble derivative of fullerene, and then selectively dissolving out the fullerene from the blend films. A combination of the polymer blending with fullerene and a use of diiodooctane (DIO) as a processing additive enhances the molecular ordering of P3HT through nanoscale phase separation, compared to the pristine P3HT. In organic thin-film transistors, such morphological changes in the blend induce a positive effect on the field-effect mobility, as the mobility is ~5-7 times higher than in the pristine P3HT. Simple dipping of the blend films in butyl acetate (BA) causes a selective dissolution of the small molecular component, resulting in a rough surface with nanoscale features of P3HT films. Chemical sensors utilizing these morphological features show an enhanced sensitivity in detection of gas-phase ammonia, water, and ethanol.

Synergistic Effects of Processing Additives and Thermal Annealing on Nanomorphology and Hole Mobility of Poly(3-hexylthiophene) Thin Films.

Control of the nanoscale molecular ordering and charge-carrier mobility of poly(3-hexylthiophene-2,5-diyl) (P3HT) was achieved by the combined use of processing additives and thermal annealing. Evaluation of four processing additives (1,8-octanedithiol (ODT), diphenyl ether (DPE), 1-chloronaphthalene (CN), and 1,8-diiodooctane (DIO), which are commonly used for the fabrication of organic solar cells, revealed that the nanoscale molecular ordering and, therefore, the charge-carrier mobility, are largely affected by the additives, as demonstrated by spectral absorption, X-ray diffraction, and atomic force microscopy. Thermal annealing selectively influenced the morphological changes, depending on the solubility of P3HT in the additive at high temperature. In the case of CN, in which P3HT can be dissolved at moderate temperature, significant molecular ordering was observed even without thermal annealing. For DIO, in which P3HT is only soluble at elevated temperature, the mobility reached 1.14 × 10-1 cm² V-1 s-1 only after annealing. ODT and DPE were not effective as processing additives in a single-component P3HT. This study provides insight for designing the processing conditions to control the morphology and charge-transport properties of polymers.

The Influence of X-Ray Computed Tomography Acquisition Parameters on Image Quality and Probability of Detection of Additive Manufacturing Defects.

X-ray computed tomography (XCT) is a promising nondestructive evaluation technique for additive manufacturing (AM) parts with complex shapes. Industrial XCT scanning is a relatively new development, and XCT has several acquisition parameters that a user can change for a scan whose effects are not fully understood. An artifact incorporating simulated defects of different sizes was produced using laser powder bed fusion (LPBF) AM. The influence of six XCT acquisition parameters was investigated experimentally based on a fractional factorial designed experiment. Twenty experimental runs were performed. The noise level of the XCT images was affected by the acquisition parameters, and the importance of the acquisition parameters was ranked. The measurement results were further analyzed to understand the probability of detection (POD) of the simulated defects. The POD determination process is detailed, including estimation of the POD confidence limit curve using a bootstrap method. The results are interpreted in the context of the AM process and XCT acquisition parameters.