Targeting interleukin-6 as a strategy to overcome stroma-induced resistance to chemotherapy in gastric cancer.

BACKGROUND: Although the tumor stroma in solid tumors like gastric cancer (GC) plays a crucial role in chemo-resistance, specific targets to inhibit the interaction between the stromal and cancer cells have not yet been utilized in clinical practice. The present study aims to determine whether cancer-associated fibroblasts (CAFs), a major component of the tumor stroma, confer chemotherapeutic resistance to GC cells, and to discover potential targets to improve chemo-response in GC. METHODS: To identify CAF-specific proteins and signal transduction pathways affecting chemo-resistance in GC cells, secretome and transcriptome analyses were performed. We evaluated the inhibiting effect of CAF-specific protein in in vivo and in vitro models and investigated the expression of CAF-specific protein in human GC tissues. RESULTS: Secretome and transcriptome data revealed that interleukin-6 (IL-6) is a CAF-specific secretory protein that protects GC cells via paracrine signaling. Furthermore, CAF-induced activation of the Janus kinase 1-signal transducer and activator of transcription 3 signal transduction pathway confers chemo-resistance in GC cells. CAF-mediated inhibition of chemotherapy-induced apoptosis was abrogated by the anti-IL-6 receptor monoclonal antibody tocilizumab in various experimental models. Clinical data revealed that IL-6 was prominently expressed in the stromal portion of GC tissues, and IL-6 upregulation in GC tissues was correlated with poor responsiveness to chemotherapy. CONCLUSIONS: Our data provide plausible evidence for crosstalk between GC cells and CAFs, wherein IL-6 is a key contributor to chemoresistance. These findings suggest the potential therapeutic application of IL-6 inhibitors to enhance the responsiveness to chemotherapy in GC.

Discoidin domain receptor 1 activity drives an aggressive phenotype in gastric carcinoma.

BACKGROUND: Discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase that utilizes collagen as a ligand, is a key molecule in the progression of solid tumors as it regulates the interaction of cancer cells with the tumor stroma. However, the clinical relevance of DDR1 expression in gastric carcinoma is yet to be investigated. Here, we assessed the role of DDR1 in mediating the aggressive phenotype of gastric carcinoma and its potential as a therapeutic target. METHODS: We conducted DDR1 immunohistochemistry using a tissue microarray of 202 gastric carcinoma specimens. We examined the effect of collagen-induced activation of DDR1 on cell signaling, tumorigenesis, and cell migration in gastric cancer cell lines, and tumor growth in a xenograft animal model of gastric cancer. RESULTS: Our results showed that 50.5% of gastric cancer tissues are positive for DDR1 expression, and positive DDR1 expression was significantly correlated with a poor prognosis (P = 0.015). In a subgroup analysis, DDR1 expression was prognostically meaningful only in patients receiving adjuvant treatment (P = 0.013). We also demonstrated that collagen was able to activate DDR1 and increase the clonogenicity and migration of gastric cancer cells. We observed that a DDR1 inhibitor, 7rh benzamide, suppressed tumor growth in gastric cancer xenografts. CONCLUSIONS: Our findings suggest a key role for DDR1 signaling in mediating the aggressive phenotype of gastric carcinoma. Importantly, inhibition of DDR1 is an attractive strategy for gastric carcinoma therapy.

Recent Advances in Means Safety as a Suicide Prevention Strategy.

Despite advances in theory and the development and implementation of evidence-based treatments, the United States suicide rate has been rising continuously for over a decade. Although this does not indicate that traditional treatment approaches should be abandoned, it does highlight the need to supplement such approaches with alternatives. One seemingly highly valuable option is means safety, defined as the reduced access to and/or increased safe storage of potentially lethal methods for suicide. This paper provides a review of the current literature on the prevalence of six methods for suicide and preventative efforts aimed to reduce suicide rates. The majority of means safety interventions seem promising given that these methods are common and highly lethal. However, cultural and practical barriers will need to be taken into consideration when implementing these plans. Overall, means safety efforts and preventative measures seem to be promising ways to reduce the national suicide rate if implemented.

Anisotropic Electron Mobility and Contact Resistance of ß-Ga2O3 Obtained via Radio Frequency Transmission Line Methods on Schottky Devices.

Monoclinic semiconducting ß-Ga2O3 has drawn attention, particularly because its thin film could be achieved via mechanical exfoliation from bulk crystals, which is analogous to van der Waals materials' behavior. For the transistor devices with exfoliated ß-Ga2O3, the channel direction becomes [010] for in-plane electron transport, which changes to vertical [100] near the source/drain (S/D) contact. Hence, anisotropic transport behavior is certainly worth to study but rarely reported. Here we achieve the vertical [100] direction electron mobility of 4.18 cm2/(V s) from Pt/ß-Ga2O3 Schottky diodes with various thickness via radio frequency-transmission line method (RF-TLM), which is recently developed. The specific contact resistivity (ρc) could also be estimated from RF-TLM, to be 4.72 × 10-5 Ω cm2, which is quite similar to the value (5.25 × 10-5 Ω cm2) from conventional TLM proving the validity of RF-TLM. We also fabricate metal-semiconductor field-effect transistors (MESFETs) to study anisotropic transport behavior and contact resistance (RC). RC-free [010] in-plane mobility appears as high as maximum ∼67 cm2/(V s), extracted from total resistance in MESFETs.

5 nm Ultrathin Crystalline Ferroelectric P(VDF-TrFE)-Brush Tuned for Hysteresis-Free Sub 60 mV dec-1 Negative-Capacitance Transistors.

Negative-capacitance field-effect transistors (NC-FETs) have gathered enormous interest as a way to reduce subthreshold swing (SS) and overcome the issue of power dissipation in modern integrated circuits. For stable NC behavior at low operating voltages, the development of ultrathin ferroelectrics (FE), which are compatible with the industrial process, is of great interest. Here, a new scalable ultrathin ferroelectric polymer layer is developed based on trichloromethyl (CCl3 )-terminated poly(vinylidene difluoride-co-trifloroethylene) (P(VDF-TrFE)) to achieve the state-of-the-art performance of NC-FETs. The crystalline phase of 5-10 nm ultrathin P(VDF-TrFE) is prepared on AlOX by a newly developed brush method, which enables an FE/dielectric (DE) bilayer. FE/DE thickness ratios are then systematically tuned at ease to achieve ideal capacitance matching. NC-FETs with optimized FE/DE thickness at a thickness limit demonstrate hysteresis-free operation with an SS of 28 mV dec-1 at ≈1.5 V, which competes with the best reports. This P(VDF-TrFE)-brush layer can be broadly adapted to NC-FETs, opening an exciting avenue for low-power devices.

Human parathyroid hormone increases the mRNA expression of the IGF system and hematopoietic growth factors in osteoblasts, but does not influence expression in mesenchymal stem cells.

Osteoblasts, which are derived from pluripotent mesenchymal stem cells (MSCs), play an important role in hematopoiesis. Human parathyroid hormone (hPTH) induces osteoblasts to produce many factors that are essential to hematopoietic stem cells. However, little is known about the impact of hPTH on MSCs to enhance hematopoiesis. We determined the optimal dose of hPTH that was necessary in vitro for increased osteoblast function. In addition, we compared MSC and osteoblast function to explore the role of hPTH in hematopoiesis. The mRNA expression levels of granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin 6, stromal cell-derived factor 1, insulin-like growth factor 1 (IGF-1), IGF-2, insulin-like growth factor-binding protein 1 (IGFBP-1), IGFBP-2, and IGFBP-3 were comparable in osteoblasts and human cord blood-derived MSCs. However, G-CSF, GM-CSF, IGF-2, IGFBP-1, IGFBP-2, and IGFBP-3 expression levels in osteoblasts were markedly increased after treatment with 50 or 100 nM of hPTH. In conclusion, hPTH does not affect the ability of MSCs to differentiate into osteoblasts. In addition, hPTH may enhance hematopoiesis by activating the IGF system (IGF-2, IGFBP-1, IGFBP-2, and IGFBP-3) and hematopoietic growth factors (G-CSF and GM-CSF) in osteoblasts, but not in MSCs.

HLA-A2 Promotes the Therapeutic Effect of Umbilical Cord Blood-Derived Mesenchymal Stem Cells in Hyperoxic Lung Injury.

Mesenchymal stem cells (MSCs) are one of the most extensively studied stem cell types owing to their capacity for differentiation into multiple lineages as well as their ability to secrete regenerative factors and modulate immune functions. However, issues remain regarding their further application for cell therapy. Here, to demonstrate the superiority of the improvement of MSCs, we divided umbilical cord blood-derived MSCs (UCB-MSCs) from 15 donors into two groups based on efficacy and revealed donor-dependent variations in the anti-inflammatory effect of MSCs on macrophages as well as their immunoregulatory effect on T cells. Through surface marker analyses (242 antibodies), we found that HLA-A2 was positively related to the anti-inflammatory and immunoregulatory function of MSCs. Additionally, HLA-A2 mRNA silencing in MSCs attenuated their therapeutic effects in vitro; namely, the suppression of LPS-stimulated macrophages and phytohemagglutinin-stimulated T cells. Moreover, HLA-A2 silencing in MSCs significantly decreased their therapeutic effects in a rat model of hyperoxic lung damage. The present study provides novel insights into the quality control of donor-derived MSCs for the treatment of inflammatory conditions and diseases.

A neurovascular-unit-on-a-chip for the evaluation of the restorative potential of stem cell therapies for ischaemic stroke.

The therapeutic efficacy of stem cells transplanted into an ischaemic brain depends primarily on the responses of the neurovascular unit. Here, we report the development and applicability of a functional neurovascular unit on a microfluidic chip as a microphysiological model of ischaemic stroke that recapitulates the function of the blood-brain barrier as well as interactions between therapeutic stem cells and host cells (human brain microvascular endothelial cells, pericytes, astrocytes, microglia and neurons). We used the model to track the infiltration of a number of candidate stem cells and to characterize the expression levels of genes associated with post-stroke pathologies. We observed that each type of stem cell showed unique neurorestorative effects, primarily by supporting endogenous recovery rather than through direct cell replacement, and that the recovery of synaptic activities is correlated with the recovery of the structural and functional integrity of the neurovascular unit rather than with the regeneration of neurons.

Ambipolar Channel p-TMD/n-Ga2 O3 Junction Field Effect Transistors and High Speed Photo-sensing in TMD Channel.

Highly crystalline 2D/3D-mixed p-transition metal dichalcogenide (TMD)/n-Ga2 O3 heterojunction devices are fabricated by mechanical exfoliation of each p- and n-type material. N-type ß-Ga2 O3 and p-type TMD separately play as a channel for junction field effect transistors (JFETs) with each type of carriers as well as materials for a heterojunction PN diode. The work thus mainly focuses on such ambipolar channel transistors with two different types of channel in a single device architecture. For more extended applications, the transparency of high energy band gap ß-Ga2 O3 (Eg  ≈ 4.8 eV) is taken advantage of, firstly to measure the electrical energy gap of p-TMDs receiving visible or near infrared (NIR) photons through the ß-Ga2 O3 . Next, the p-TMD/n-Ga2 O3 JFETs are put to high speed photo-sensing which is achieved from the p-TMD channel under reverse bias voltages on n-Ga2 O3 . The photo-switching cutoff frequency appears to be ≈16 and 29 kHz for visible red and NIR illuminations, respectively, on the basis of -3 dB photoelectric power loss. Such a high switching speed of the JFET is attributed to the fast transport of photo-carriers in TMD channels. The 2D/3D-mixed ambipolar channel JFETs and their photo-sensing applications are regarded novel, promising, and practically easy to achieve.

Reduced extrinsic recombination process in anatase and rutile TiO2 epitaxial thin films for efficient electron transport layers.

TiO2 is the most widely used material for the electron transport layers (ETLs) because it is characterized by proper band alignment with light absorbers, adequate optical transmittance, and high electron mobility. There are two thermodynamically stable crystal phases of TiO2: anatase and rutile. However, understanding which phase is more effective as the ETL is still required. In this paper, we demonstrate the different effects of using epitaxial anatase TiO2 and epitaxial rutile TiO2 (both grown using pulsed laser deposition) as the ETL material on the electrical and optical properties. Epitaxial Nb-doped TiO2 layers were used as the common electrode material for the both epitaxial ETLs for which the crystalline structural analysis revealed high crystalline qualities and good coherency for both phases. By analyzing the recombination kinetics, the anatase phase shows a preferable performance in comparison with the rutile phase, although both epitaxial phases show remarkably reduced extrinsic recombination properties, such as trap-assisted recombination. This study demonstrates not only a better electron transporting performance of anatase phase but also reduced extrinsic recombination through epitaxy growth.

Nonvolatile and Neuromorphic Memory Devices Using Interfacial Traps in Two-Dimensional WSe2/MoTe2 Stack Channel.

Very recently, stacked two-dimensional materials have been studied, focusing on the van der Waals interaction at their stack junction interface. Here, we report field effect transistors (FETs) with stacked transition metal dichalcogenide (TMD) channels, where the heterojunction interface between two TMDs appears useful for nonvolatile or neuromorphic memory FETs. A few nanometer-thin WSe2 and MoTe2 flakes are vertically stacked on the gate dielectric, and bottom p-MoTe2 performs as a channel for hole transport. Interestingly, the WSe2/MoTe2 stack interface functions as a hole trapping site where traps behave in a nonvolatile manner, although trapping/detrapping can be controlled by gate voltage (VGS). Memory retention after high VGS pulse appears longer than 10000 s, and the Program/Erase ratio in a drain current is higher than 200. Moreover, the traps are delicately controllable even with small VGS, which indicates that a neuromorphic memory is also possible with our heterojunction stack FETs. Our stack channel FET demonstrates neuromorphic memory behavior of ∼94% recognition accuracy.

Reconfigurable Dipole-Induced Resistive Switching of MoS2 Thin Layers on Nb:SrTiO3.

The controllable band gap and charge-trapping capability of MoS2 render it suitable for use in the fabrication of various electrical devices with high-k dielectric oxides. In this study, we investigated reconfigurable resistance states in a MoS2/Nb:SrTiO3 heterostructure by using conductive atomic force microscopy. Low-resistance and high-resistance states were observed in all MoS2 because of barrier height modification resulting from redistribution of charge and oxygen vacancies in the vicinity of interfaces. In a thin layer of the MoS2 film, the carrier density was high, and layer-dependent transport properties appeared because of the charge separation in MoS2. The hysteresis and switching voltage of the MoS2/Nb:SrTiO3 heterostructure could be varied by controlling the number of layers of MoS2.

Virtual Out-of-Plane Piezoelectric Response in MoS2 Layers Controlled by Ferroelectric Polarization.

The MoS2 carrier distribution can be controlled with the use of a dielectric environment substrate. Ferroelectric thin films are used to investigate the electrical responses at the MoS2 layer. The MoS2/(111)-PbTiO3 vertical heterostructure is investigated, and the electrical responses, including piezoelectricity, are obtained using piezoresponse force microscopy. The piezoelectric response modifications obtained at the MoS2 layer on the ferroelectric thin films are a result of the depolarizing effect. In particular, the piezoelectricity enhancement is observed at the 19-layer MoS2 because of an induced dipole effect. By considering the polarization effects of ferroelectric thin films, the electrical responses at the MoS2 layers can be controlled, and the interfacial carrier distribution at the interface results in different electrical performances at the MoS2.

The intensity of suicidal ideation at the worst point and its association with suicide attempts.

This study seeks to determine if the severity of suicidal ideation at the worst point can differentiate individuals who think about suicide (ideators) from those who make a suicide attempt (attempters). Subsequently, the indirect effect of worst point ideation on differentiating ideators from attempters through various pathways such as an increased capability for suicide, painful and provocative experiences, non-suicidal self-injury (NSSI), and planning for suicide was examined. The sample included 229 adults with a lifetime history of suicidal ideation who were recruited through Amazon's Mechanical Turk program and asked to complete a battery of self-report questionnaires. Furthermore, the sample was oversampled on the basis of prior suicide attempts. Our results suggest that there is a strong relationship between worst point ideation and suicide attempts such that there is a greater likelihood of endorsing past suicide attempts when individuals reported high intensity at the worst point of their suicidal ideation. An elevated level of painful and provocative events partially accounted for the aforementioned relationship while a heightened capability for suicide. The results from the present study suggest utility in managing intensity of suicidal ideation and the importance of addressing painful and provocative behaviors to prevent potentially lethal suicide attempts in the future.

Personality pathology and intentional self-harm: cross-cutting insights from categorical and dimensional models.

This paper reviews current literature on the links between personality pathology and intentional self-harm, including nonsuicidal self-injury (NSSI) and suicidal behaviors. Specifically, this review highlights recent advances stemming from longitudinal, epidemiological, and health registry studies, as well as emerging research on pathological personality traits and intentional self-harm, and integrates current knowledge across dimensional and categorical frameworks to provide recommendations for clinical practice and future research. This review provides strong evidence that personality disorders marked by intense and unstable negative affect, detachment/low extraversion, aggression/hostility, and specific facets of impulsivity may be considered risk factors for suicidal behaviors. Further, there is some evidence of a stronger relation between maladaptive personality traits and suicidal versus non-suicidal intentional self-harm.

Inhibition of Discoidin Domain Receptor 1 Prevents Stroma-Induced Peritoneal Metastasis in Gastric Carcinoma.

Discoidin domain receptor 1 (DDR1) is activated by fibrillar (triple-helical) collagens and collagen IV, which are major components of tumor stroma; thus, DDR1 might be a critical mediator of communication between cancer cells and stroma. The aim of this study was to investigate the effect of DDR1 inhibition on stroma-induced peritoneal metastasis in gastric carcinoma. We analyzed by immunohistochemistry the correlation between DDR1 expression and the pattern of recurrence in gastric carcinoma tissues from a previously characterized and established gastric carcinoma patient cohort. We also cocultured human gastric carcinoma cell lines with gastric cancer-associated fibroblasts (CAF) and investigated DDR1 expression and activation. We evaluated CAF-induced tumorigenic properties of gastric carcinoma cell lines and the effect of a DDR1-specific inhibitor in organotypic cultures and in a peritoneal seeding xenograft animal model. The expression of DDR1 in gastric cancer tissues was positively associated with early recurrence (P = 0.043) and a high incidence of peritoneal recurrence (P = 0.036). We confirmed that coculturing with CAFs elevated DDR1 protein expression in gastric carcinoma cell lines and enhanced gastric carcinoma cell line spheroid formation in organotypic cultures in a tumor cell DDR1-dependent manner. Coimplantation of CAFs with gastric carcinoma cells enhanced peritoneal tumor formation in vivo, an effect that was sensitive to pharmacologic inhibition of DDR1.Implications: This study highlights that CAF-induced elevation of DDR1 expression in gastric carcinoma cells enhances peritoneal tumorigenesis, and that inhibition of DDR1 is an attractive strategy for the treatment of gastric carcinoma peritoneal metastasis. Mol Cancer Res; 16(10); 1590-600. ©2018 AACR.

Non-suicidal self-injury and frequency of suicide attempts: The role of pain persistence.

BACKGROUND: Non-suicidal self-injury (NSSI) and suicidal behavior exhibit a robust association with one another. Research on the contexts within which this relationship is stronger or weaker, however, is limited. The interpersonal theory of suicidal behavior (ITS) posits that NSSI influences suicidal behavior through a habituation to physical pain and, as such, pain tolerance has been theorized to play an important role. We tested whether pain persistence, the difference between pain threshold and pain tolerance, would moderate the relationship between frequency of NSSI and suicidal behavior in both an undergraduate and community sample. METHOD: Study 1 assessed healthy undergraduates, whereas Study 2 was comprised of community members recruited largely based upon a history of suicidal behavior. Across both samples, participants completed self-report measures of NSSI and a structured interview on suicidal behavior. In both studies, pain was measured using a pressure algometer and, in Study 2, persistence was also assessed using the Enhanced Distress Tolerance Test (DTT-E). RESULTS: Consistent with the notion that suicidal behavior requires persistence amidst pain and distress, results indicated that the willingness to remain engaged with pain and distress may significantly influence the degree to which NSSI is related to suicidal behavior. LIMITATIONS: Both studies were limited by a cross-sectional design, which precluded assessments of causality and directionally of effects. CONCLUSIONS: These results call attention to the potential importance of persistence through pain and/or distress in the association between NSSI and suicidal behavior.

Treating the Capability for Suicide: A Vital and Understudied Frontier in Suicide Prevention.

Current efforts at suicide prevention center largely on reducing suicidal desire among individuals hospitalized for suicidality or being treated for related psychopathology. Such efforts have yielded evidence-based treatments, and yet the national suicide rate has continued to climb. We propose that this disconnect is heavily influenced by an unmet need to consider population-level interventions aimed at reducing the capability for suicide. Drawing on lessons learned from other public health phenomena that have seen drastic declines in frequency in recent decades (HIV, lung cancer, motor vehicle accidents), we propose that current suicidality treatment efforts trail current suicidality theories in their lack of focus on the extent to which individuals thinking about suicide are capable of transitioning from ideation to attempt. We summarize extant evidence for specific capability-centered approaches (e.g., means safety) and propose other options for improving our ability to address this largely overlooked variable. We also note that population-level approaches in this regard would represent an important opportunity to decrease risk in individuals who either lack access to evidence-based care or underreport suicidal ideation, as a reduced capability for suicide would theoretically diminish the potency of suicidal desire and, in this sense, lower the odds of a transition from ideation to attempt.

Preoperative serum levels of insulin-like growth factor-binding protein 2 predict prognosis of gastric cancer patients.

It has been reported that serum insulin-like growth factor-binding protein 2 (IGFBP2) levels are elevated in various types of cancers. However, the clinicopathologic and prognostic implications of circulating IGFBP2 have never been investigated in gastric cancer. We tested IGFBP2 levels in the sera of 118 gastric cancer patients and 34 healthy controls using enzyme-linked immunosorbent assay (ELISA). The mean serum IGFBP2 level was significantly elevated in the gastric cancer patients compared to controls (805.23 ± 590.56 ng/ml vs. 459.61 ± 277.01 ng/ml; P < 0.001). Serum IGFBP2 levels were significantly higher in larger (> 6 cm) tumors (956.8 ± 734.0 ng/ml vs. 548.6 ± 364.0 ng/ml; P = 0.007) and in higher (T3/4) T stages (854.8 ± 621.4 ng/ml vs. 546.5 ± 315.1 ng/ml; P = 0.037). Multivariate Cox analysis showed that higher serum IGFBP2 level (> 400.01 ng/ml) was an independent prognostic factor predicting worse overall survival in patients with gastric cancer (hazard ratio (HR): 3.749, P = 0.034). When we divided patients into four groups based on blood IGFBP2 levels, survival was stratified. The HRs for death in the 3rd and 4th quartiles of serum IGFBP2 levels in comparison to that in the 1st quartile were 2.527 (P = 0.043) and 3.092 (P = 0.012). In conclusion, circulating IGFBP2 has potential as a biomarker predicting prognosis for gastric cancer patients.

A multicellular spheroid formation and extraction chip using removable cell trapping barriers.

This paper presents a multicellular spheroid chip capable of forming and extracting three-dimensional (3D) spheroids using removable cell trapping barriers. Compared to the conventional macro-scale spheroid formation methods, including spinning, hanging-drop, and liquid-overlay methods, the recent micro-scale spheroid chips have the advantage of forming smaller spheroids with better uniformity. The recent micro spheroid chips, however, have difficulties in extracting the spheroids due to fixed cell trapping barriers. The present spheroid chip, having two PDMS layers, uses removable cell trapping barriers, thereby making it easy to form and extract uniform and small-sized spheroids. We have designed, fabricated and characterized a 4 × 1 spheroid chip, where membrane cell trapping barriers are inflated at a pressure of 50 kPa for spheroid formation and are deflated at zero gauge pressure for simple and safe extraction of the spheroids formed. In this experimental study, the cell suspension of non-small lung cancer cells, H1650, is supplied to the fabricated spheroid chip in the pressure range 145-155 Pa. The fabricated spheroid chips collect the cancer cells in the cell trapping regions from the cell suspension at a concentration of 2 × 10(6) ml(-1), thus forming uniform 3D spheroids with a diameter of 197.2 ± 11.7 µm, after 24 h incubation at 5% CO(2) and 37°C environment. After the removal of the cell trapping barriers, the spheroids formed were extracted through the outlet ports at a cell inlet pressure of 5 kPa. The cells in the extracted spheroids showed a viability of 80.3 ± 7.7%. The present spheroid chip offers a simple and effective method of obtaining uniform and small-sized 3D spheroids for the next stage of cell-based biomedical research, such as gene expression analysis and spheroid inoculation in animal models.