Age-related cholesterol and colorectal cancer progression: Validating squalene epoxidase for high-risk cases.

As people age, the risk and progression of colorectal cancer (CRC), along with cholesterol levels, tend to increase. Nevertheless, epidemiological studies on serum lipids and CRC have produced conflicting results. We previously demonstrated that the reduction of squalene epoxidase (SQLE) due to accumulated cholesterol within cells accelerates CRC progression through the activation of the ß-catenin pathway. This study aimed to investigate the mechanism by which age-related cholesterol accumulation within tissue accelerates CRC progression and to assess the clinical significance of SQLE in older individuals with elevated CRC risk. Using machine learning-based digital image analysis with fluorescence-immunohistochemistry, we assessed SQLE, GSK3ßpS9 (GSK3ß activity inhibition through serine 9 phosphorylation at GSK3ß), p53 wild-type (p53WT), and p53 mutant (p53MT) levels in CRC tissues. Our analysis revealed a significant reduction in SQLE, p53WT, and p53MT and increase in GSK3ßpS9 levels, all associated with the substantial accumulation of intra-tissue cholesterol in aged CRCs. Cox analysis underscored the significant influence of SQLE on overall survival and progression-free survival in grade 2-3 CRC patients aged over 50. SQLE and GSK3ßpS9 consistently exhibited outstanding prognostic and diagnostic performance, particularly in older individuals. Furthermore, combining SQLE with p53WT, p53MT, and GSK3ßpS9 demonstrated a robust diagnostic ability in the older population. In conclusion, we have identified that individuals aged over 50 face an increased risk of CRC progression due to aging-linked cholesterol accumulation within tissue and the subsequent reduction in SQLE levels. This study also provides valuable biomarkers, including SQLE and GSK3ßpS9, for older patients at elevated risk of CRC.

Defect-Engineered Semiconducting van der Waals Thin Film at Metal-Semiconductor Interface of Field-Effect Transistors.

The significance of metal-semiconductor interfaces and their impact on electronic device performance have gained increasing attention, with a particular focus on investigating the contact metal. However, another avenue of exploration involves substituting the contact metal at the metal-semiconductor interface of field-effect transistors with semiconducting layers to introduce additional functionalities to the devices. Here, a scalable approach for fabricating metal-oxide-semiconductor (channel)-semiconductor (interfacial layer) field-effect transistors is proposed by utilizing solution-processed semiconductors, specifically semiconducting single-walled carbon nanotubes and molybdenum disulfide, as the channel and interfacial semiconducting layers, respectively. The work function of the interfacial MoS2 is modulated by controlling the sulfur vacancy concentration through chemical treatment, which results in distinctive energy band alignments within a single device configuration. The resulting band alignments lead to multiple functionalities, including multivalued transistor characteristics and multibit nonvolatile memory (NVM) behavior. Moreover, leveraging the stable NVM properties, we demonstrate artificial synaptic devices with 88.9% accuracy of MNIST image recognition.

Malnutrition and Associated Factors in Acute and Subacute Stroke Patients with Dysphagia.

Most patients with stroke suffer from complications and these include dysphagia. Dysphagia can cause malnutrition, and malnutrition affects prognosis and recovery. However, there is a lack of accurate studies on the nutritional status of stroke patients with dysphagia and its associated factors in different phases of stroke. This study retrospectively investigated 620 stroke patients who underwent a videofluoroscopic swallowing study (VFSS) due to dysphagia, from March 2018 to February 2021. The study aimed to evaluate the nutritional state and associated factors of malnutrition in acute and subacute stroke patients with dysphagia. Serum albumin and percentage of current weight to ideal weight were used to determine nutritional status. Malnutrition was observed in 58.9 and 78.9% of acute and subacute stroke patients. Exact logistic regression analysis revealed that old age and high penetration-aspiration scale score were significantly associated factors for malnutrition in patients with acute stroke. Old age, stroke history, bilateral hemiplegia, high modified Rankin score, low Korean Mini-Mental State Examination, pneumonia, and high functional dysphagia score were significantly associated factors for malnutrition in patients with subacute stroke. Patients with these associated factors in each phase of stroke require active nutritional assessment and care to decrease the risk of malnutrition.

Flexoelectricity-Driven Mechanical Switching of Polarization in Metastable Ferroelectrics.

Flexoelectricity-based mechanical switching of ferroelectric polarization has recently emerged as a fascinating alternative to conventional polarization switching using electric fields. Here, we demonstrate hyperefficient mechanical switching of polarization exploiting metastable ferroelectricity that inherently holds a unique mechanical response. We theoretically predict that mechanical forces markedly reduce the coercivity of metastable ferroelectricity, thus greatly bolstering flexoelectricity-driven mechanical polarization switching. As predicted, we experimentally confirm the mechanical polarization switching via an unusually low mechanical force (100 nN) in metastable ferroelectric CaTiO_{3}. Furthermore, the use of low mechanical forces narrows the width of mechanically writable nanodomains to sub-10 nm, suggesting an ultrahigh data storage density of ≥1 Tbit cm^{-2}. This Letter sheds light on the mechanical switching of ferroelectric polarization as a viable key element for next-generation efficient nanoelectronics and nanoelectromechanics.

Stretchable colour-sensitive quantum dot nanocomposites for shape-tunable multiplexed phototransistor arrays.

High-performance photodetecting materials with intrinsic stretchability and colour sensitivity are key requirements for the development of shape-tunable phototransistor arrays. Another challenge is the proper compensation of optical aberrations and noises generated by mechanical deformation and fatigue accumulation in a shape-tunable phototransistor array. Here we report rational material design and device fabrication strategies for an intrinsically stretchable, multispectral and multiplexed 5 × 5 × 3 phototransistor array. Specifically, a unique spatial distribution of size-tuned quantum dots, blended in a semiconducting polymer within an elastomeric matrix, was formed owing to surface energy mismatch, leading to highly efficient charge transfer. Such intrinsically stretchable quantum-dot-based semiconducting nanocomposites enable the shape-tunable and colour-sensitive capabilities of the phototransistor array. We use a deep neural network algorithm for compensating optical aberrations and noises, which aids the precise detection of specific colour patterns (for example, red, green and blue patterns) both under its flat state and hemispherically curved state (radius of curvature of 18.4 mm).

TREX1 Deficiency Induces ER Stress-Mediated Neuronal Cell Death by Disrupting Ca2+ Homeostasis.

TREX1 is an exonuclease that degrades extranuclear DNA species in mammalian cells. Herein, we show a novel mechanism by which TREX1 interacts with the BiP/GRP78 and TREX1 deficiency triggers ER stress through the accumulation of single-stranded DNA and activates unfolded protein response (UPR) signaling via the disruption of the TREX1-BiP/GRP78 interaction. In TREX1 knockdown cells, the activation of ER stress signaling disrupted ER Ca2+ homeostasis via the ERO1α-IP3R1-CaMKII pathway, leading to neuronal cell death. Moreover, TREX1 knockdown dysregulated the Golgi-microtubule network through Golgi fragmentation and decreased Ac-α-tubulin levels, contributing to neuronal injury. These alterations were also observed in neuronal cells harboring a TREX1 mutation (V91M) that has been identified in hereditary spastic paraplegia (HSP) patients in Korea. Notably, this mutation leads to defects in the TREX1-BiP/GRP78 interaction and mislocalization of TREX1 from the ER and possible disruption of the Golgi-microtubule network. In summary, the current study reveals TREX1 as a novel regulator of the BiP/GRP78 interaction and shows that TREX1 deficiency promotes ER stress-mediated neuronal cell death, which indicates that TREX1 may hold promise as a therapeutic target for neurodegenerative diseases such as HSP.

Comparative Study on Overground Gait of Stroke Survivors With a Conventional Cane and a Haptic Cane.

The conventional cane (single cane) is widely used to promote gait ability of stroke survivors as it provides postural stability by extending the base of support. However, its use can reduce muscle activity in the user's paretic side and cause upper limb neuropathies due to the intermittent and excessive loading of the upper limb. The provision of low magnitude support and speed regulation may result in collective improvement of gait parameters such as symmetry, balance and muscle activation. In this paper, we developed a robotic Haptic Cane (HC) that is composed of a tilted structure with motorized wheels and sensors to allow continuous haptic contact with the ground while moving at a regulated speed, and carried out gait experiments to compare the HC with an Instrumented conventional Cane (IC). The results show that use of the HC involved more continuous ground support force of a comparatively lesser magnitude than the IC, and resulted in greater improvements in the swing symmetry ratio and significant improvements in the step length symmetry ratio. Percentage of Non-Paretic Activity (%NPA) of paretic muscles (vastus medialis obliquus (VMO), semitendinosus (SMT), tibialis anterior (TBA) and gastrocnemius medialis (GCM)) in swing phase was significantly improved by the use of either device at fast speed. However, the use of HC improved %NPA of paretic VMO and SMT more than the use of IC at both preferred and fast speeds. It also significantly improved %NPA of paretic GCM in stance phase. Furthermore, comfortable speed with the HC was higher than with the IC and exhibited better RMS of anteroposterior (AP) tilt. Thus, the developed device with a simple and intuitive mechanism can provide efficient assistance for overground gait of stroke patients with a high possibility of widespread use.

The emerging genetic diversity of hereditary spastic paraplegia in Korean patients.

Hereditary Spastic Paraplegias (HSP) are a group of rare inherited neurological disorders characterized by progressive loss of corticospinal motor-tract function. Numerous patients with HSP remain undiagnosed despite screening for known genetic causes of HSP. Therefore, identification of novel genetic variations related to HSP is needed. In this study, we identified 88 genetic variants in 54 genes from whole-exome data of 82 clinically well-defined Korean HSP families. Fifty-six percent were known HSP genes, and 44% were composed of putative candidate HSP genes involved in the HSPome and originally reported neuron-related genes, not previously diagnosed in HSP patients. Their inheritance modes were 39, de novo; 33, autosomal dominant; and 10, autosomal recessive. Notably, ALDH18A1 showed the second highest frequency. Fourteen known HSP genes were firstly reported in Koreans, with some of their variants being predictive of HSP-causing protein malfunction. SPAST and REEP1 mutants with unknown function induced neurite abnormality. Further, 54 HSP-related genes were closely linked to the HSP progression-related network. Additionally, the genetic spectrum and variation of known HSP genes differed across ethnic groups. These results expand the genetic spectrum for HSP and may contribute to the accurate diagnosis and treatment for rare HSP.

A Bioinspired Stretchable Sensory-Neuromorphic System.

Conventional stretchable electronics that adopt a wavy design, a neutral mechanical plane, and conformal contact between abiotic and biotic interfaces have exhibited diverse skin-interfaced applications. Despite such remarkable progress, the evolution of intelligent skin prosthetics is challenged by the absence of the monolithic integration of neuromorphic constituents into individual sensing and actuating components. Herein, a bioinspired stretchable sensory-neuromorphic system, comprising an artificial mechanoreceptor, artificial synapse, and epidermal photonic actuator is demonstrated; these three biomimetic functionalities correspond to a stretchable capacitive pressure sensor, a resistive random-access memory, and a quantum dot light-emitting diode, respectively. This system features a rigid-island structure interconnected with a sinter-free printable conductor, which is optimized by controlling the evaporation rate of solvent (≈160% stretchability and ≈18 550 S cm-1 conductivity). Devised design improves both areal density and structural reliability while avoiding the thermal degradation of heat-sensitive stretchable electronic components. Moreover, even in the skin deformation range, the system accurately recognizes various patterned stimuli via an artificial neural network with training/inferencing functions. Therefore, the new bioinspired system is expected to be an important step toward implementing intelligent wearable electronics.

A Soft Pressure Sensor Array Based on a Conducting Nanomembrane.

Although skin-like pressure sensors exhibit high sensitivity with a high performance over a wide area, they have limitations owing to the critical issue of being linear only in a narrow strain range. Various strategies have been proposed to improve the performance of soft pressure sensors, but such a nonlinearity issue still exists and the sensors are only effective within a very narrow strain range. Herein, we fabricated a highly sensitive multi-channel pressure sensor array by using a simple thermal evaporation process of conducting nanomembranes onto a stretchable substrate. A rigid-island structure capable of dissipating accumulated strain energy induced by external mechanical stimuli was adopted for the sensor. The performance of the sensor was precisely controlled by optimizing the thickness of the stretchable substrate and the number of serpentines of an Au membrane. The fabricated sensor exhibited a sensitivity of 0.675 kPa-1 in the broad pressure range of 2.3-50 kPa with linearity (~0.990), and good stability (>300 Cycles). Finally, we successfully demonstrated a mapping of pressure distribution.

The Human TOR Signaling Regulator Is the Key Indicator of Liver Cancer Patients' Overall Survival: TIPRL/LC3/CD133/CD44 as Potential Biomarkers for Early Liver Cancers.

Recently, we reported the involvement of TIPRL/LC3/CD133 in liver cancer aggressiveness. This study assessed the human TOR signaling regulator (TIPRL)/microtubule-associated light chain 3 (LC3)/prominin-1 (CD133)/cluster of differentiation 44 (CD44) as potential diagnostic and prognostic biomarkers for early liver cancer. For the assessment, we stained tissues of human liver disease/cancer with antibodies against TIPRL/LC3/CD133/CD44/CD46, followed by confocal observation. The roles of TIPRL/LC3/CD133/CD44/CD46 in liver normal and cancer cell lines were determined by in vitro studies. We analyzed the prognostic and diagnostic potentials of TIPRL/LC3/CD133/CD44/CD46 using the receiver-operating characteristic curve, a Kaplan-Meier and uni-/multi-Cox analyses. TIPRL and LC3 were upregulated in tissues of HCCs and adult hepatocytes-derived liver diseases while downregulated in iCCA. Intriguingly, TIPRL levels were found to be critically associated with liver cancer patients' survivability, and TIPRL is the key player in liver cancer cell proliferation and viability via stemness and self-renewal induction. Furthermore, we demonstrate that TIPRL/LC3/CD133 have shown prominent efficiency for diagnosing patients with grade 1 iCCA. TIPRL/LC3/CD133/CD44 have also provided excellent potential for prognosticating patients with grade 1 iCCA and grade 1 HCCs, together with demonstrating that TIPRL/LC3/CD133/CD44 are, either individually or in conjunction, potential biomarkers for early liver cancer.

Corrigendum: Characteristics of Genetic Variations Associated With Lennox-Gastaut Syndrome in Korean Families.

[This corrects the article DOI: 10.3389/fgene.2020.590924.].

Reduction of Squalene Epoxidase by Cholesterol Accumulation Accelerates Colorectal Cancer Progression and Metastasis.

BACKGROUND & AIMS: Squalene epoxidase (SQLE), a rate-limiting enzyme in cholesterol biosynthesis, is suggested as a proto-oncogene. Paradoxically, SQLE is degraded by excess cholesterol, and low SQLE is associated with aggressive colorectal cancer (CRC). Therefore, we studied the functional consequences of SQLE reduction in CRC progression. METHODS: Gene and protein expression data and clinical features of CRCs were obtained from public databases and 293 human tissues, analyzed by immunohistochemistry. In vitro studies showed underlying mechanisms of CRC progression mediated by SQLE reduction. Mice were fed a 2% high-cholesterol or a control diet before and after cecum implantation of SQLE genetic knockdown/control CRC cells. Metastatic dissemination and circulating cancer stem cells were demonstrated by in vivo tracking and flow cytometry analysis, respectively. RESULTS: In vitro studies showed that SQLE reduction helped cancer cells overcome constraints by inducing the epithelial-mesenchymal transition required to generate cancer stem cells. Surprisingly, SQLE interacted with GSK3ß and p53. Active GSK3ß contributes to the stability of SQLE, thereby increasing cell cholesterol content, whereas SQLE depletion disrupted the GSK3ß/p53 complex, resulting in a metastatic phenotype. This was confirmed in a spontaneous CRC metastasis mice model, where SQLE reduction, by a high-cholesterol regimen or genetic knockdown, strikingly promoted CRC aggressiveness through the production of migratory cancer stem cells. CONCLUSIONS: We showed that SQLE reduction caused by cholesterol accumulation aggravates CRC progression via the activation of the ß-catenin oncogenic pathway and deactivation of the p53 tumor suppressor pathway. Our findings provide new insights into the link between cholesterol and CRC, identifying SQLE as a key regulator in CRC aggressiveness and a prognostic biomarker.

Coiled-coil domain containing 50-V2 protein positively regulates neurite outgrowth.

The coiled-coil domain containing 50 (CCDC50) protein is a phosphotyrosine-dependent signalling protein stimulated by epidermal growth factor. It is highly expressed in neuronal cells in the central nervous system; however, the roles of CCDC50 in neuronal development are largely unknown. In this study, we showed that the depletion of CCDC50-V2 impeded the neuronal development process, including arbor formation, spine density development, and axonal outgrowth, in primary neurons. Mechanistic studies revealed that CCDC50-V2 positively regulated the nerve growth factor receptor, while it downregulated the epidermal growth factor receptor pathway. Importantly, JNK/c-Jun activation was found to be induced by the CCDC50-V2 overexpression, in which the interaction between CCDC50-V2 and JNK2 was also observed. Overall, the present study demonstrates a novel mechanism of CCDC50 function in neuronal development and provides new insight into the link between CCDC50 function and the aetiology of neurological disorders.

A Skin-Conformal, Stretchable, and Breathable Fiducial Marker Patch for Surgical Navigation Systems.

Augmented reality (AR) surgical navigation systems have attracted considerable attention as they assist medical professionals in visualizing the location of ailments within the human body that are not readily seen with the naked eye. Taking medical imaging with a parallel C-shaped arm (C-arm) as an example, surgical sites are typically targeted using an optical tracking device and a fiducial marker in real-time. These markers then guide operators who are using a multifunctional endoscope apparatus by signaling the direction or distance needed to reach the affected parts of the body. In this way, fiducial markers are used to accurately protect the vessels and nerves exposed during the surgical process. Although these systems have already shown potential for precision implantation, delamination of the fiducial marker, which is a critical component of the system, from human skin remains a challenge due to a mechanical mismatch between the marker and skin, causing registration problems that lead to poor position alignments and surgical degradation. To overcome this challenge, the mechanical modulus and stiffness of the marker patch should be lowered to approximately 150 kPa, which is comparable to that of the epidermis, while improving functionality. Herein, we present a skin-conformal, stretchable yet breathable fiducial marker for the application in AR-based surgical navigation systems. By adopting pore patterns, we were able to create a fiducial marker with a skin-like low modulus and breathability. When attached to the skin, the fiducial marker was easily identified using optical recognition equipment and showed skin-conformal adhesion when stretched and shrunk repeatedly. As such, we believe the marker would be a good fiducial marker candidate for patients under surgical navigation systems.

Characteristics of Genetic Variations Associated With Lennox-Gastaut Syndrome in Korean Families.

Lennox-Gastaut syndrome (LGS) is a severe type of childhood-onset epilepsy characterized by multiple types of seizures, specific discharges on electroencephalography, and intellectual disability. Most patients with LGS do not respond well to drug treatment and show poor long-term prognosis. Approximately 30% of patients without brain abnormalities have unidentifiable causes. Therefore, accurate diagnosis and treatment of LGS remain challenging. To identify causative mutations of LGS, we analyzed the whole-exome sequencing data of 17 unrelated Korean families, including patients with LGS and LGS-like epilepsy without brain abnormalities, using the Genome Analysis Toolkit. We identified 14 mutations in 14 genes as causes of LGS or LGS-like epilepsy. 64 percent of the identified genes were reported as LGS or epilepsy-related genes. Many of these variations were novel and considered as pathogenic or likely pathogenic. Network analysis was performed to classify the identified genes into two network clusters: neuronal signal transmission or neuronal development. Additionally, knockdown of two candidate genes with insufficient evidence of neuronal functions, SLC25A39 and TBC1D8, decreased neurite outgrowth and the expression level of MAP2, a neuronal marker. These results expand the spectrum of genetic variations and may aid the diagnosis and management of individuals with LGS.

A Novel X-Linked Variant of IQSEC2 is Associated with Lennox-Gastaut Syndrome and Mild Intellectual Disability in Three Generations of a Korean Family.

Aim: Lennox-Gastaut syndrome (LGS) is a severe type of childhood-onset epilepsy with multiple types of seizures, specific discharges on electroencephalography, and intellectual disability. However, LGS-related genes are largely unknown. To identify causative genes related to LGS, we collected and analyzed data from a three-generation Korean family in which one member had LGS and two had intellectual disability. Methods: Genomic DNAs were extracted from blood samples of all participants and used in whole-exome sequencing (WES). Genetic variants were detected by the Genome Analysis Toolkit and confirmed by Sanger sequencing. Variant pathogenicity was evaluated by prediction programs and the American College of Medical Genetics criteria. The LGS patient had generalized slow spike-and-wave discharges, multiple types of seizures, and developmental delay. Results: Analyses of the WES data from the family revealed a novel variant (c.1048G>A, p.Ala350Thr) in the IQ motif and Sec7 domain 2 (IQSEC2). This variant is within a highly evolutionarily conserved IQ-like motif, indicating a decrease in the calmodulin-binding capacity or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid transmission. The hemizygous variant in the male with LGS was a maternally inherited X-linked variant from the heterozygous maternal grandmother and mother, both of whom had intellectual disability. Conclusion: These findings indicate that the variant of IQSEC2 triggered both LGS and intellectual disability dependent on sex in this family. We report a novel X-linked inherited IQSEC2 variant for LGS and intellectual disability, which enhances the spectrum of variants in the IQ-like motif of IQSEC2.

TIPRL potentiates survival of lung cancer by inducing autophagy through the eIF2α-ATF4 pathway.

Autophagy, an intracellular system of degrading damaged organelles and misfolded proteins, is essential for cancer cell survival. Despite the progress made towards understanding the mechanism, identification of novel autophagy regulators presents a major obstacle in developing anticancer therapies. Here, we examine the association between the TOR signaling pathway regulator-like (TIPRL) protein and autophagy in malignant transformation of tumors. We show that TIPRL upregulation in non-small cell lung cancer (NSCLC) potentiated autophagy activity and enabled autophagic clearance of metabolic and cellular stress, conferring a survival advantage to cancer cells. Importantly, the interaction of TIPRL with eukaryotic initiation factor 2α (eIF2α) led to eIF2α phosphorylation and activation of the eIF2α-ATF4 pathway, thereby inducing autophagy. Conversely, TIPRL depletion increased apoptosis by reducing autophagic clearance, which was markedly enhanced in TIPRL-depleted A549 xenografts treated with 2-deoxy-D-glucose. Overall, the study indicated that TIPRL is a potential regulator of autophagy and an important drug target for lung cancer therapy.

The positive correlation of TIPRL with LC3 and CD133 contributes to cancer aggressiveness: potential biomarkers for early liver cancer.

Studies have reported dysregulation of TIPRL, LC3 and CD133 in liver cancer tissues. However, their respective relationships to liver cancer and roles as biomarkers for prognosis and diagnosis of liver cancer have never been studied. Here we report that the level of TIPRL is significantly correlated with levels of LC3 (Spearman r = 0.9) and CD133 (r = 0.7) in liver cancer tissues. We observed significant upregulations of TIPRL, LC3 and CD133 in hepatocellular carcinomas (HCCs) compared with adjacent normal tissues. Importantly, TIPRL, tested among additional variables, showed a significant impact on the prognosis of HCC patients. TIPRL knockdown significantly reduced expressions of LC3, CD133, stemness-related genes, as well as viability and stemness of liver cancer cell-lines, which were promoted by ectopic TIPRL expression. Either alone or as a combination, TIPRL, LC3 and CD133 showed significant values of area under the curve (AUC) and sensitivity/specificity in early liver cancer tissues. Furthermore, the statistical association and the diagnostic efficacies of TIPRL, LC3 and CD133 in HCC tissues were confirmed in a different IHC cohort. This data demonstrates that the complex involvement of TIPRL/LC3/CD133 in liver cancer aggressiveness can together or individually serve as potential biomarkers for the early detection of liver cancer.

Novel indazole-based small compounds enhance TRAIL-induced apoptosis by inhibiting the MKK7-TIPRL interaction in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most malignant tumors. Although various treatments, such as surgery and chemotherapy, have been developed, a novel alternative therapeutic approach for HCC therapy is urgently needed. Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a promising anti-cancer agent, but many cancer cells are resistant to TRAIL-induced apoptosis. To help overcome TRAIL resistance in HCC cancer cells, we have identified novel chemical compounds that act as TRAIL sensitizers. We first identified the hit compound, TRT-0002, from a chemical library of 6,000 compounds using a previously developed high-throughput enzyme-linked immunosorbent assay (ELISA) screening system, which was based on the interaction of mitogen-activated protein kinase kinase 7 (MKK7) and TOR signaling pathway regulator-like (TIPRL) proteins and a cell viability assay. To increase the efficacy of this TRAIL sensitizer, we synthesized 280 analogs of TRT-0002 and finally identified two lead compounds (TRT-0029 and TRT-0173). Co-treating cultured Huh7 cells with either TRT-0029 or TRT-0173 and TRAIL resulted in TRAIL-induced apoptosis due to the inhibition of the MKK7-TIPRL interaction and subsequent phosphorylation of MKK7 and c-Jun N-terminal kinase (JNK). In vivo, injection of these compounds and TRAIL into HCC xenograft tumors resulted in tumor regression. Taken together, our results suggest that the identified lead compounds serve as TRAIL sensitizers and represent a novel strategy to overcome TRAIL resistance in HCC.