TIPRL Regulates Stemness and Survival in Lung Cancer Stem Cells through CaMKK2-CaMK4-CREB Feedback Loop Activation.

Frequent recurrence and metastasis caused by cancer stem cells (CSCs) are major challenges in lung cancer treatment. Therefore, identifying and characterizing specific CSC targets are crucial for the success of prospective targeted therapies. In this study, it is found that upregulated TOR Signaling Pathway Regulator-Like (TIPRL) in lung CSCs causes sustained activation of the calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) signaling pathway by binding to CaMKK2, thereby maintaining stemness and survival. CaMKK2-mediated activation of CaM kinase 4 (CaMK4) leads to phosphorylation of cAMP response element-binding protein (CREB) at Ser129 and Ser133, which is necessary for its maximum activation and the downstream constitutive expression of its target genes (Bcl2 and HMG20A). TIPRL depletion sensitizes lung CSCs to afatinib-induced cell death and reduces distal metastasis of lung cancer in vivo. It is determined that CREB activates the transcription of TIPRL in lung CSCs. The positive feedback loop consisting of CREB and TIPRL induces the sustained activation of the CaMKK2-CaMK4-CREB axis as a driving force and upregulates the expression of stemness- and survival-related genes, promoting tumorigenesis in patients with lung cancer. Thus, TIPRL and the CaMKK2 signaling axis may be promising targets for overcoming drug resistance and reducing metastasis in lung cancer.

Neurophysiological analysis of disadvantageous social inequity: Exploring emotional behavior changes and c-Fos expression in a male rat model.

Humans and other animals exhibit aversive behavioral and emotional responses to unequal reward distributions compared with their conspecifics. Despite the significance of this phenomenon, experimental animal models designed to investigate social inequity aversion and delve into the underlying neurophysiological mechanisms are limited. In this study, we developed a rat model to determine the effects of socially equal or unequal reward and stress on emotional changes in male rats. During the training session, the rats were trained to escape when a sound cue was presented, and they were assigned to one of the following groups: all escaping rats [advantageous equity (AE)], freely moving rats alongside a restrained rat [advantageous inequity (AI)], all restrained rats [disadvantageous equity (DE)], and a rat restrained in the presence of freely moving companions [disadvantageous inequity (DI)]. During the test session, rats in the advantageous group (AE and AI) escaped after the cue sound (expected reward acquisition), whereas rats in the disadvantageous group (DE and DI) could not escape despite the cue being presented (expected reward deprivation). Emotional alteration induced by exposure to restraint stress under various social interaction circumstances was examined using an open field test. Notably, the DI group displayed reduced exploration of the center zone during the open field tests compared with the other groups, indicating heightened anxiety-like behaviors in response to reward inequity. Immunohistochemical analysis revealed increased c-Fos expression in the medial prefrontal and orbitofrontal cortices, coupled with reduced c-Fos expression in the striatum and nucleus accumbens under DI conditions, in contrast to the other experimental conditions. These findings provide compelling evidence that rats are particularly sensitive to reward inequity, shedding light on the neurophysiological basis for distinct cognitive processes that manifest when individuals are exposed to social equity and inequity situations.

Reconfigurable Manipulation of Oxygen Content on Metal Oxide Surfaces and Applications to Gas Sensing.

Oxygen vacancies and adsorbed oxygen species on metal oxide surfaces play important roles in various fields. However, existing methods for manipulating surface oxygen require severe settings and are ineffective for repetitive manipulation. We present a method to manipulate the amount of surface oxygen by modifying the oxygen adsorption energy by electrically controlling the electron concentration of the metal oxide. The surface oxygen control ability of the method is verified using first-principles calculations based on density functional theory (DFT), X-ray photoelectron spectroscopy (XPS), and electrical resistance analysis. The presented method is implemented by fabricating oxide thin film transistors with embedded microheaters. The method can reconfigure the oxygen vacancies on the In2O3, SnO2, and IGZO surfaces so that specific chemisorption dominates. The method can selectively increase oxidizing (e.g., NO and NO) and reducing gas (e.g., H2S, NH3, and CO) reactions by electrically controlling the metal oxide surface to be oxygen vacancy-rich or adsorbed oxygen species-rich. The proposed method is applied to gas sensors and overcomes their existing limitations. The method makes the sensor insensitive to one gas (e.g., H2S) in mixed-gas environments (e.g., NO2+H2S) and provides a linear response (R2 = 0.998) to the target gas (e.g., NO2) concentration within 3 s. We believe that the proposed method is applicable to applications utilizing metal oxide surfaces.

Omega-3-Rich Fish-Oil-Influenced Mouse Gut Microbiome Shaped by Intermittent Consumption of Beef.

Beef consumption can provide various amino acids, lipids, vitamins, and minerals; however, excessive intake causes metabolic disorders and increases the probability of obesity, atherosclerosis, and colorectal cancer. The intake of omega-3 fatty acids can ameliorate metabolic disorders by lowering blood glucose and triglyceride levels. In the present study, we investigated the effect of omega-3-rich fish oil on body performance and the gut microbiome in a beef-rich diet. Four-week-old C57BL/6 mice were distributed into four groups (chow diet [Chow], chow with beef diet [Beef], chow with omega-3 diet [Cw3], and chow with beef and omega-3 diet [Bw3]). We observed that body weight was unaltered between groups, and serum triglyceride levels were reduced in the omega-3 supplemented groups. The beta diversity indices, unweighted UniFrac distance (P = 0.001), and Jaccard distance (P = 0.001) showed statistically significant differences, and the principal coordinates analysis plot showed a clear separation between groups. In addition, the taxonomic comparison revealed that beef consumption increased numerous potentially pathogenic bacteria, including Escherichia-Shigella, Mucispirillum, Helicobacter, and Desulfovibrio, which were decreased following omega-3 supplementation. Metabolic comparison based on 16S rRNA revealed that energy and glucose metabolism were higher in omega-3 supplemented groups. Our findings suggest that the omega-3 supplementation under intermittent beef consumption contributes to changes in the gut microbiome and microbial metabolic pathways.

Recovery of off-state stress-induced damage in FET-type gas sensor using self-curing method.

The need for high-performance gas sensors is driven by concerns over indoor and outdoor air quality, and industrial gas leaks. Due to their structural diversity, vast surface area, and geometric tunability, metal oxides show significant potential for the development of gas sensing systems. Despite the fact that several previous reports have successfully acquired a suitable response to various types of target gases, it remains difficult to maintain the reliability of metal oxide-based gas sensors. In particular, the degradation of the sensor platform under repetitive operation, such as off-state stress (OSS) causes significant reliability issues. We investigate the impact of OSS on the gas sensing performances, including response, low-frequency noise, and signal-to-noise ratio of horizontal floating-gate field-effect-transistor (FET)-type gas sensors. The 1/f noise is increased after the OSS is applied to the sensor because the gate oxide is damaged by hot holes. Therefore, the SNR of the sensor is degraded by the OSS. We applied a self-curing method based on a PN-junction forward current at the body-drain junction to repair the damaged gate oxide and improve the reliability of the sensor. It has been demonstrated that the SNR degradation caused by the OSS can be successfully recovered by the self-curing method.

In-Memory-Computed Low-Frequency Noise Spectroscopy for Selective Gas Detection Using a Reducible Metal Oxide.

Concerns about indoor and outdoor air quality, industrial gas leaks, and medical diagnostics are driving the demand for high-performance gas sensors. Owing to their structural variety and large surface area, reducible metal oxides hold great promise for constructing a gas-sensing system. While many earlier reports have successfully obtained a sufficient response to various types of target gases, the selective detection of target gases remains challenging. In this work, a novel method, low-frequency noise (LFN) spectroscopy is presented, to achieve selective detection using a single FET-type gas sensor. The LFN of the sensor is accurately modeled by considering the charge fluctuation in both the sensing material and the FET channel. Exposure to different target gases produces distinct corner frequencies of the power spectral density that can be used to achieve selective detection. In addition, a 3D vertical-NAND flash array is used with the fast Fourier transform method via in-memory-computing, significantly improving the area and power efficiency rate. The proposed system provides a novel and efficient method capable of selectively detecting a target gas using in-memory-computed LFN spectroscopy and thus paving the way for the further development in gas sensing systems.

Highly Selective and Low-Power Carbon Monoxide Gas Sensor Based on the Chain Reaction of Oxygen and Carbon Monoxide to WO3.

Carbon monoxide (CO) poisoning can easily occur in industrial and domestic settings, causing headaches, loss of consciousness, or death from overexposure. Commercially available CO gas sensors consume high power (typically 38 mW), whereas low-power gas sensors using nanostructured materials with catalysts lack reliability and uniformity. A low-power (1.8 mW @ 392 °C), sensitive, selective, reliable, and practical CO gas sensor is presented. The sensor adopts floated WO3 film as a sensing material to utilize the unique reaction of lattice oxide of WO3 with CO gas. The sensor locally modulates the electron concentration in the WO3 film, allowing O2 and CO gases to react primarily in different sensing areas. Electrons generated by the CO gas reaction can be consumed for O2 gas adsorption in a remote area, and this promotes the additional reaction of CO gas, boosting sensitivity and selectivity. The proposed sensor exhibits a 39.5 times higher response than the conventional resistor-type gas sensor fabricated on the same wafer. As a proof of concept, sensors with In2O3 film are fabricated, and the proposed sensor platform shows no advantage in detecting CO gas. Fabrication of the proposed sensor is reproducible and inexpensive due to conventional silicon-based processes, making it attractive for practical applications.

Synergistic improvement of sensing performance in ferroelectric transistor gas sensors using remnant polarization.

Gaseous pollutants, including nitrogen oxides, pose a severe threat to ecosystems and human health; therefore, developing reliable gas-sensing systems to detect them is becoming increasingly important. Among the various options, metal-oxide-based gas sensors have attracted attention due to their capability for real-time monitoring and large response. In particular, in the field of materials science, there has been extensive research into controlling the morphological properties of metal oxides. However, these approaches have limitations in terms of controlling the response, sensitivity, and selectivity after the sensing material is deposited. In this study, we propose a novel method to improve the gas-sensing performance by utilizing the remnant polarization of ferroelectric thin-film transistor (FeTFT) gas sensors. The proposed FeTFT gas sensor has IGZO and HZO as the conducting channel and ferroelectric layer, respectively. It is demonstrated that the response and sensitivity of FeTFT gas sensors can be modulated by engineering the polarization of the ferroelectric layer. The amount of reaction sites in IGZO, including electrons and oxygen vacancy-induced negatively charged oxygen, is changed depending on upward and downward polarization. The results of this study provide an essential foundation for further development of gas sensors with tunable sensing properties.

PBK/TOPK Is a Favorable Prognostic Biomarker Correlated with Antitumor Immunity in Colon Cancers.

Immune checkpoint inhibitor therapy has proven efficacy in a subset of colon cancer patients featuring a deficient DNA mismatch repair system or a high microsatellite instability profile. However, there is high demand for more effective biomarkers to expand the colon cancer population responding to ICI therapy. PBK/TOPK, a serine/threonine kinase, plays a role in cell cycle regulation and mitotic progression. Here, we investigated the correlation between PBK/TOPK expression and tumor immunity and its prognostic value in colon cancer. Based on large-scale bioinformatics analysis, we discovered that elevated PBK/TOPK expression predicted a favorable outcome in patients with colon cancer and was positively associated with immune infiltration levels of CD8+ T cells, CD4+ T cells, natural killer cells, and M1 macrophages. In contrast, a negative correlation was found between PBK/TOPK expression and immune suppressor cells, including regulatory T cells and M2 macrophages. Furthermore, the expression of PBK/TOPK was correlated with the expression of T-cell cytotoxicity genes in colon cancer. Additionally, high PBK/TOPK expression was associated with mutations in DNA damage repair genes, and thus with increased tumor mutation and neoantigen burden. These findings suggest that PBK/TOPK may serve as a prognostic and predictive biomarker for immunotherapy in colon cancer.

Effect of charge storage engineering on the NO2 gas sensing properties of a WO3 FET-type gas sensor with a horizontal floating-gate.

In this paper, we investigate the effects of charge storage engineering (CSE) on the NO2 gas sensing properties such as response, recovery, and sensitivity of a FET-type gas sensor with a horizontal floating-gate (FG) having tungsten trioxide (WO3) as a sensing layer. When the FET transducer is set at an erase state (ΔVth = -2 V), the holes injected into the FG by Fowler-Nordheim (F-N) tunneling increase the electron concentration at the WO3-passivation layer interface. Accordingly, an oxidizing gas, NO2, can take more electrons from WO3, which increases the change in the FG voltage (ΔVFG) by a factor of 2.4. Also, the recovery speed of the sensor in the erase state can be improved by applying pre-bias (Vpre) which is larger than the read bias (Vread). As the carriers in the WO3 film that can interact with NO2 increase by the excess holes stored in the FG by the erase operation, the sensitivity of the sensor also increases 3.2 times. The effects of CSE on various sensing performances are explained using energy band diagrams.

Proposition of deposition and bias conditions for optimal signal-to-noise-ratio in resistor- and FET-type gas sensors.

In the field of gas sensor studies, most researchers are focusing on improving the response of the sensors to detect a low concentration of gas. However, factors that make a large response, such as abundant or strong adsorption sites, also work as a source of noise, resulting in a trade-off between response and noise. Thus, the response alone cannot fully evaluate the performance of sensors, and the signal-to-noise-ratio (SNR) should additionally be considered to design gas sensors with optimal performance. In this regard, thin-film-type sensing materials are good candidates thanks to their moderate response and noise level. In this paper, we investigate the effects of radio frequency (RF) sputtering power for deposition of sensing materials on the SNR of resistor- and field-effect transistor (FET)-type gas sensors fabricated on the same Si wafer. In the case of resistor-type gas sensors, the deposition conditions that improve the response also worsen the noise either by increasing the scattering at the bulk or damaging the interface of the sensing material. Among resistor-type gas sensors with sensing materials deposited with different RF powers, a sensor with low noise shows the largest SNR despite its small response. However, the noise of FET-type gas sensors is not affected by changes in RF power and thus there is no trade-off between response and noise. The results reveal different noise sources depending on the deposition conditions of the sensing material, and provide design guidelines for resistor- and FET-type gas sensors considering noise for optimal performance.

Observation of physisorption in a high-performance FET-type oxygen gas sensor operating at room temperature.

Oxygen (O2) sensors are needed for monitoring environment and human health. O2 sensing at low temperature is required, but studies are lacking. Here we report, for the first time, that the performance of a field effect transistor (FET)-type O2 sensor operating at 25 °C was improved greatly by a physisorption sensing mechanism. The sensing material was platinum-doped indium oxide (Pt-In2O3) nanoparticles formed by an inkjet printer. The FET-type sensor showed excellent repeatability under a physisorption mechanism and showed much better sensing performance than a resistor-type sensor fabricated on the same wafer at 25 °C. The sensitivity of the sensor increased with increasing Pt concentration up to ∼10% and decreased with further increasing Pt concentration. When the sensing temperature reached 140 °C, the sensing mechanism of the sensor changed from physisorption to chemisorption. Interestingly, the pulse pre-bias before the read bias affected chemisorption but had no effect on physisorption.

Strategies to overcome acquired resistances conferred by mutations in the kinase domain of EGFR.

Deregulation of EGFR is involved in the development of many cancers. The inhibition of EGFR kinase activity has been clinically validated as a promising approach for the treatment of non-small-cell lung cancer (NSCLC). However, all NSCLC patients who initially benefited from first-generation EGFR inhibitors eventually develop drug resistance. A point mutation at the gatekeeper position, T790M in EGFR kinase domain accounts for more than 50% of acquired resistance. Therefore, second- and third-generation EGFR inhibitors have been developed to overcome the resistance conferred by the gatekeeper mutation. This review has highlighted recent advances in overcoming acquired resistance for the development of each generation of EGFR inhibitors along with their potential issues, and urgent quest for the development of new generation of EGFR inhibitors.

Identification of ß-Lapachone Analogs as Novel MALT1 Inhibitors To Treat an Aggressive Subtype of Diffuse Large B-Cell Lymphoma.

The treatment of activated B cell-like DLBCL (ABC-DLBCL) is one of the urgent unmet medical needs because it is the most resistant DLBCL subtype to current therapies eagerly awaiting effective therapeutic strategies. Recently, the paracaspase MALT1 has emerged as a promising therapeutic target for the treatment of ABC-DLBCL. Herein, we report a new class of MALT1 inhibitors developed by high-throughput screening and structure-based drug design. The original hit, 4-amino-1,2-naphthoquinone series inhibited MALT1 activity but suffered from poor cellular activity. The extensive pharmacophore search led to the discovery of structurally similar ß-lapachone that is a direct inhibitor of MALT1 and possesses favorable physicochemical properties. Molecular simulation studies suggested the possibility of the formation of a covalent bond between MALT1 and ß-lapachone, which was corroborated by experimental wash-out studies. Inspired by this, we explored the structure-activity relationships by incorporating electron-withdrawing substituents at C8 position of ß-lapachone. These MALT1 inhibitors exhibited potent antiproliferative activity to OCI-LY3 cell line and inhibited the cleavage of CYLD mediated MALT1.

Discovery of wrightiadione as a novel template for the TrkA kinase inhibitors.

Enzymatic kinase assays and docking simulation studies have shown that the natural product wrightiadione displays inhibitory activity toward TrkA and PLK3. In this study, the template of wrightiadione served as a starting point for Trk inhibitor development campaigns. Molecular simulation provided structural insights for the design of derivatives that were efficiently generated by our recently developed 3-step tandem synthetic approach, resulting in the discovery of compound 2h with biochemical potency at the single-digit micromolar level.

Rh(III)-catalyzed direct C-H/C-H cross-coupling of quinones with arenes assisted by a directing group: identification of carbazole quinones as GSKß inhibitors.

Rh-catalyzed direct C-H/C-H cross-coupling reaction of various (hetero)arenes with quinones is developed. This protocol is effective for a broad range of both quinone and arene substrates and a wide range of directing groups for this reaction, affording structurally diverse aryl-substituted quinones with high synthetic utility. Moreover, the present synthetic route allowed for the rapid construction of the carbazole quinone moiety that was identified as a new inhibitor scaffold for GSKß.

Selective and potent small-molecule inhibitors of PI3Ks.

Class I PI3Ks are composed of four catalytic subunit variants (p110α, p110ß, p110δ and p110γ). The PI3K pathway is among the most frequently activated pathways in many diseases, and has emerged as an attractive target for drug development, in particular for the treatment of many human cancers including breast, prostate, ovarian, gastric, colon and hepatocellular cancers. One of the challenges in the discovery of drugs that target kinases is designing small-molecule inhibitors that are sufficiently selective to minimize off-target activity and reduce the risk of potential toxicity. This review explores the current landscape of PI3K-selective inhibitor development and highlights recent advances in achieving selectivity for PI3Ks over other protein kinases, with an emphasis on available structural information.

Suppression of tumor proliferation and angiogenesis of hepatocellular carcinoma by HS-104, a novel phosphoinositide 3-kinase inhibitor.

Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR signaling pathway frequently instigates tumorigenesis leading to hepatocellular carcinoma (HCC). We synthesized N-(5-(3-(3-methyl-1,2,4-oxadiazol-3-yl)imidazo[1,2-a]pyridin-6-yl)pyridin-3-yl)benzenesulfonamide (HS-104), a novel PI3K inhibitor, and investigated its in vitro anticancer effect and in vivo capacity in an animal xenograft model. The inhibition of cell growth by HS-104 revealed that it was effective against HCC cell lines. Also, the activation of the AKT/mTOR signal cascade was inhibited by HS-104 treatment in a dose dependent manner. Flow cytometry analysis showed an accumulation of HCC cells in the G2/M phase with concomitant loss of cells in the S phase. The apoptotic effect of HS-104 was accompanied by increased evidence of cleaved caspase-3 and PARP, as well as DNA fragmentation. In angiogenesis studies, HS-104 inhibited the tube formation of vascular endothelial growth factor (VEGF)-induced human umbilical vein endothelial cells (HUVECs), and suppressed microvessel sprouting from a rat aortic ring, ex vivo, and blood vessel formation in the Matrigel plug assay in mice. HS-104 inhibited the expression of the downstream proteins of PI3K including p-AKT, p-mTOR and p-p70S6K in VEGF-induced HUVECs. In the xenograft animal model, HS-104 significantly delayed tumor growth in a dose dependent manner and suppressed the expression of PCNA, CD34 and cleaved caspase-3 in tumor tissue. These studies show that HS-104 inhibited the PI3K/AKT/mTOR signaling pathway resulting in cell growth/angiogenesis inhibition and apoptosis induction. Therefore, HS-104 is considered as a novel drug candidate for the treatment of HCC.

IPD-196, a novel phosphatidylinositol 3-kinase inhibitor with potent anticancer activity against hepatocellular carcinoma.

As the activation of phosphatidylinositol 3-kinase (PI3K) is associated with a wide variety of human malignancies, it is emerging as an attractive target for cancer treatment. In this study we synthesized a novel PI3Kα inhibitor, IPD-196 [ethyl 6-(5-(2,4-difluorophenylsulfonamido)pyridin-3-yl)imidazo[1,2-a]pyridine-3-carboxylate], and evaluated its anticancer effects on human hepatocellular carcinoma (HCC) cells. IPD-196 effectively inhibited the phosphorylation of downstream PI3K effectors such as Akt, mTOR, p70S6K, and 4E-BP1, and its antiproliferative effect was more potent than that of sorafenib or LY294002. It also induced cell cycle arrest at the G0/G1 phase as well as apoptosis by increasing the proportion of sub-G1 apoptotic cells, and the levels of cleaved PARP, caspase-3, and caspase-9. Furthermore, it decreased the expression of HIF-1α and VEGF in Huh-7 cells, and inhibited tube formation and migration of human umbilical vein endothelial cells, which was confirmed by a Matrigel plug assay in mice. Taken together, IPD-196 exhibited its anticancer activity through disruption of the PI3K/Akt pathway that caused cell cycle arrest, apoptosis induction, and inhibition of angiogenesis in human HCC cells. We therefore suggest that IPD-196 may be a potential candidate drug for targeted HCC therapy.

A novel imidazopyridine derivative, HS-106, induces apoptosis of breast cancer cells and represses angiogenesis by targeting the PI3K/mTOR pathway.

Abnormal activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is an essential step for the formation and growth of tumors in humans. HS-106 is an imidazopyridine derivative that inhibits the kinase activity of PI3K by binding to the ATP-binding cleft. We found that this compound suppressed breast cancer cell proliferation and induced apoptosis by specifically inhibiting the activity of target proteins in the PI3K/Akt/mTOR signaling pathway. Cell cycle analysis revealed that treatment with HS-106 resulted in cell cycle arrest at the G(2)/M phase due to up-regulation of p-cdc25 and down-regulation of cyclin B1. Also, HS-106 induced apoptosis by increasing the levels of cleaved caspase-3 and cleaved PARP. In addition, chromatin condensation and apoptotic bodies were detected in HS-106-treated breast cancer cells. Furthermore, HS-106 decreased the expression of hypoxia-inducible factor 1α (HIF-1α), and inhibited tube formation and migration of human umbilical vein endothelial cells (HUVECs) in vitro and blood vessel formation in an in vivo Matrigel plug assay. These results show that HS-106 may be an effective novel therapeutic candidate in clinical trials as a potential treatment for human breast cancers or other advanced malignancies with aberrant PI3K/Akt/mTOR signaling.