USP24-i-101 targeting of USP24 activates autophagy to inhibit drug resistance acquired during cancer therapy.

Drug resistance in cancer therapy is the major reason for poor prognosis. Addressing this clinically unmet issue is important and urgent. In this study, we found that targeting USP24 by the specific USP24 inhibitors, USP24-i and its analogues, dramatically activated autophagy in the interphase and mitotic periods of lung cancer cells by inhibiting E2F4 and TRAF6, respectively. USP24 functional knockout, USP24C1695A, or targeting USP24 by USP24-i-101 inhibited drug resistance and activated autophagy in gefitinib-induced drug-resistant mice with doxycycline-induced EGFRL858R lung cancer, but this effect was abolished after inhibition of autophagy, indicating that targeting USP24-mediated induction of autophagy is required for inhibition of drug resistance. Genomic instability and PD-L1 levels were increased in drug resistant lung cancer cells and were inhibited by USP24-i-101 treatment or knockdown of USP24. In addition, inhibition of autophagy by bafilomycin-A1 significantly abolished the effect of USP24-i-101 on maintaining genomic integrity, decreasing PD-L1 and inhibiting drug resistance acquired in chemotherapy or targeted therapy. In summary, an increase in the expression of USP24 in cancer cells is beneficial for the induction of drug resistance and targeting USP24 by USP24-i-101 optimized from USP24-i inhibits drug resistance acquired during cancer therapy by increasing PD-L1 protein degradation and genomic stability in an autophagy induction-dependent manner.

Rab37 mediates trafficking and membrane presentation of PD-1 to sustain T cell exhaustion in lung cancer.

BACKGROUND: Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor expressed on the surface of T cells. High expression of PD-1 leads to T-cell dysfunction in the tumor microenvironment (TME). However, the mechanism of intracellular trafficking and plasma membrane presentation of PD-1 remains unclear. METHODS: Multiple databases of lung cancer patients were integratively analyzed to screen Rab proteins and potential immune-related signaling pathways. Imaging and various biochemical assays were performed in Jurkat T cells, splenocytes, and human peripheral blood mononuclear cells (PBMCs). Rab37 knockout mice and specimens of lung cancer patients were used to validate the concept. RESULTS: Here, we identify novel mechanisms of intracellular trafficking and plasma membrane presentation of PD-1 mediated by Rab37 small GTPase to sustain T cell exhaustion, thereby leading to poor patient outcome. PD-1 colocalized with Rab37-specific vesicles of T cells in a GTP-dependent manner whereby Rab37 mediated dynamic trafficking and membrane presentation of PD-1. However, glycosylation mutant PD-1 delayed cargo recruitment to the Rab37 vesicles, thus stalling membrane presentation. Notably, T cell proliferation and activity were upregulated in tumor-infiltrating T cells from the tumor-bearing Rab37 knockout mice compared to those from wild type. Clinically, the multiplex immunofluorescence-immunohistochemical assay indicated that patients with high Rab37+/PD-1+/TIM3+/CD8+ tumor infiltrating T cell profile correlated with advanced tumor stages and poor overall survival. Moreover, human PBMCs from patients demonstrated high expression of Rab37, which positively correlated with elevated levels of PD-1+ and TIM3+ in CD8+ T cells exhibiting reduced tumoricidal activity. CONCLUSIONS: Our results provide the first evidence that Rab37 small GTPase mediates trafficking and membrane presentation of PD-1 to sustain T cell exhaustion, and the tumor promoting function of Rab37/PD-1 axis in T cells of TME in lung cancer. The expression profile of Rab37high/PD-1high/TIM3high in tumor-infiltrating CD8+ T cells is a biomarker for poor prognosis in lung cancer patients.

Downregulation of microRNA-326 enhances ZNF322A expression, transcriptional activity and tumorigenic effects in lung cancer.

Zinc finger protein ZNF322A is an oncogenic transcription factor. Overexpression of ZNF322A activates pro-metastasis, cancer stemness, and neo-angiogenesis-related genes to enhance lung cancer progression. However, the upstream regulator of ZNF322A is not well defined. Dysregulation of microRNAs (miRNAs) can mediate cancer cell growth, migration, and invasion to promote tumorigenesis. Here, we uncover the mechanism of miRNA-mediated transcriptional regulation in ZNF322A-driven oncogenic events. ZNF322A harbors several putative miRNA-binding sites in the 3'-untranslated region (UTR). We validated that miR-326 downregulated ZNF322A-3'-UTR luciferase activity and mRNA expression. Furthermore, miR-326 suppressed the expression of ZNF322A-driven cancer-associated genes such as cyclin D1 and alpha-adducin. Reconstitution experiments by ectopic overexpression of ZNF322A abolished miR-326-suppressed cancer cell proliferation and cell migration capacity. Moreover, miR-326 attenuated ZNF322A-induced tumor growth and lung tumor metastasis in vivo. Clinically, the expression of miR-326 negatively correlated with ZNF322A mRNA expression in surgically resected tissues from 120 non-small cell lung cancer (NSCLC) patients. Multivariate Cox regression analysis demonstrated that NSCLC patients with low miR-326/high ZNF322A profile showed poor overall survival. Our results reveal that the deregulated expression of miR-326 leads to hyperactivation of ZNF322A-driven oncogenic signaling. Targeting the miR-326/ZNF322A axis would provide new therapeutic strategies for lung cancer patients.

Consistency between two subjective assessments of activities of daily living: Patient- and occupational therapist-reported judgments.

Purpose: To examine the consistency between patient- and occupational therapist-reported judgments of patients' ability and change in ADL abilities. Materials: Patient- and therapist-reported ADL abilities were assessed using a Visual Analogue Scale, whilst the changes in patients' ADL abilities were reported by patients and therapists using a 15-point Likert-type scale. Methods: Repeated assessments at a 3-week interval were used. 88 inpatients with stroke and 16 occupational therapists were recruited from rehabilitation wards in a medical center. Results: Moderate correlations (rs = .53-.56) were found between the patient- and therapist-reported ADL abilities. The patient-reported scores were significantly lower (ds = .45; ps < .001 at follow-up) than the therapist-reported scores. Only low correlation (r = .33) was found for the change scores. Conclusions: Our findings indicated that there was only a moderate to low correlation between the patients' reports and the therapists' judgments regarding the patients' ADL ability and its change. Because both patients' reports and therapists' judgments affect decisions on rehabilitation, frequent communication may be beneficial for reaching consensus and helpful in managing the interventions.

PTPN23 ubiquitination by WDR4 suppresses EGFR and c-MET degradation to define a lung cancer therapeutic target.

Aberrant overexpression or activation of EGFR drives the development of non-small cell lung cancer (NSCLC) and acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) by secondary EGFR mutations or c-MET amplification/activation remains as a major hurdle for NSCLC treatment. We previously identified WDR4 as a substrate adaptor of Cullin 4 ubiquitin ligase and an association of WDR4 high expression with poor prognosis of lung cancer. Here, using an unbiased ubiquitylome analysis, we uncover PTPN23, a component of the ESCRT complex, as a substrate of WDR4-based ubiquitin ligase. WDR4-mediated PTPN23 ubiquitination leads to its proteasomal degradation, thereby suppressing lysosome trafficking and degradation of wild type EGFR, EGFR mutant, and c-MET. Through this mechanism, WDR4 sustains EGFR and c-MET signaling to promote NSCLC proliferation, migration, invasion, stemness, and metastasis. Clinically, PTPN23 is downregulated in lung cancer and its low expression correlates with WDR4 high expression and poor prognosis. Targeting WDR4-mediated PTPN23 ubiquitination by a peptide that competes with PTPN23 for binding WDR4 promotes EGFR and c-MET degradation to block the growth and progression of EGFR TKI-resistant NSCLC. These findings identify a central role of WDR4/PTPN23 axis in EGFR and c-MET trafficking and a potential therapeutic target for treating EGFR TKI-resistant NSCLC.

UBE1C is upregulated and promotes neddylation of p53 in lung cancer.

NEDDylation is a type of protein post-translational modification that has high similarity to ubiquitination. UBE1C encodes NEDDylation E1 enzyme, locates at chromatin region 3p14.1 and shows high gene dosage amplification frequency in both Asian and Caucasian lung cancer patients. However, its NEDDylation substrates and roles in tumorigenesis remain elucidated. In this study, we aim to investigate the oncogenic role of UBE1C and its involvement in how NEDDylation regulates p53 in lung cancer. We found that UBE1C mRNA overexpression and DNA amplification in most of the lung cell lines and cancer patients. Patients with UBE1C overexpression showed poor prognosis. Moreover, we demonstrated that overexpression of UBE1C and NEDD8, a NEDDylation moiety, resulted in the p53 NEDDylation with inhibition of p53 acetylation at K373 residue. Importantly, UBE1C-mediated NEDDylation downregulated the transcriptional activity of p53 by inhibiting p53 ability to target promoter regions of its downstream transcription targets, consequently inhibiting the promoter activities and the expression of mRNA and protein of the p53 downstream genes including p21 and PTEN. In addition, UBE1C and NEDD8 overexpression promoted migration, invasion, and proliferation of lung cancer cells. Our findings suggest that UBE1C acts as an oncogene with prognostic potential and highlight a potential role of UBE1C-mediated NEDDylation in downregulation of p53 transcriptional activity in lung cancer.

Secretory autophagy-promoted cargo exocytosis requires active RAB37.

RAB37 GTPase regulates cargo exocytosis by cycling between an inactive GDP-bound form and an active GTP-bound form. We reveal that RAB37 simultaneously regulates autophagy activation and tissue inhibitor of metalloproteinase 1 (TIMP1) secretion in lung cancer cells under starvation conditions. TIMP1, an inflammatory cytokine, is a known inhibitory molecule of matrix metalloproteinases matrix metalloproteinase 9 and suppresses the mobility of lung cancer cells both in vitro and in vivo through conventional exocytosis under serum-free conditions. Notably, we disclosed that secretory autophagy participates in TIMP1 secretion in a RAB37- and Sec22b-dependent manner. Sec22b, a SNARE family protein, participates in vesicle and membrane fusion of secretory autophagy. Knockdown of Sec22b decreased TIMP1 secretion and cell motility but did not affect cell proliferation under starvation conditions. We confirmed that starvation-activated RAB37 accompanied by Sec22b is essential for secretory autophagy to further enhance TIMP1 exocytosis. We further use an off-label drug amiodarone to demonstrate that autophagy induction facilitates TIMP1 secretion and suppresses the motility and metastasis of lung cancer cells in a RAB37-dependent manner in the lung-to-lung mouse model. In conclusion, we demonstrated that the RAB37 activation plays a pivotal regulatory role in secretory autophagy for TIMP1 secretion in lung cancer.Abbreviations: ATG: autophagy-related gene; GDP: guanosine diphosphate; GTP: guanosine triphosphate; LC3: microtubule-associated protein 1A/1B-light chain 3; SNARE: soluble N-ethylmaleimide-sensitive-factor attachment protein receptor; TIMP1: tissue inhibitor matrix metalloproteinase 1.

Development of a 13-item Short Form for Fugl-Meyer Assessment of Upper Extremity Scale Using a Machine Learning Approach.

OBJECTIVE: To develop and validate a short form of the Fugl-Meyer Assessment of Upper Extremity Scale (FMA-UE) using a machine learning approach (FMA-UE-ML). In addition, scores of items not included in the FMA-UE-ML were predicted. DESIGN: Secondary data from a previous study, which assessed individuals post-stroke using the FMA-UE at 4 time points: 5-30 days post-stroke screen, 2-month post-stroke baseline assessment, 6-month post-stroke assessment, and 12-month post-stroke assessment. SETTING: Rehabilitation units in hospitals. PARTICIPANTS: A total of 408 individuals post-stroke (N=408). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The 30-item FMA-UE. RESULTS: We established 29 candidate versions of the FMA-UE-ML with different numbers of items, from 1 to 29, and examined their concurrent validity and responsiveness. We found that the responsiveness of the candidate versions obviously declined when the number of items was less than 13. Thus, the 13-item version was selected as the FMA-UE-ML. The concurrent validity was good (intra-class correlation coefficients ≥0.99). The standardized response means of the FMA-UE-ML and FMA-UE were 0.54-0.88 and 0.52-0.91, respectively. The Pearson's rs between the change scores of the FMA-UE-ML and those of the FMA-UE were 0.96-0.98. The predicted item scores had acceptable to good accuracy (Kappa=0.50-0.92). CONCLUSIONS: The FMA-UE-ML seems a promising short form to improve administrative efficiency while retaining good concurrent validity and responsiveness. In addition, the FAM-UE-ML can provide all item scores of the FMA-UE for users.

Nutlin-3 acts as a DNA methyltransferase inhibitor to sensitize esophageal cancer to chemoradiation.

Esophageal squamous cell carcinoma (ESCC) is highly resistant to chemoradiation therapy. We aimed to examine whether Nutlin-3, a molecule that suppresses murine double min 2 (MDM2)-mediated p53 and Retinoblastoma (RB) protein degradation leading to downregulation of DNA methyltransferases (DNMTs), can be a novel therapeutic agent for ESCC. We used wild-type and chemoradiation-resistant ESCC cell lines in this study. The expression of DNMTs, p53 and RB, and methylation level of tumor suppressor genes (TSG) were analyzed upon Nutlin-3 treatment. The antitumor efficacy of Nutlin-3 was investigated in ESCC cell lines and xenograft tumor model. TSG protein expression was checked in the excised tumor tissue. Nutlin-3 induced upregulation of p53 and RB and downregulation of DNMTs proteins in the chemoradiation-resistant and aggressive ESCC cells. The methylation level of TSGs was decreased by Nutlin-3. Nutlin-3 inhibits clonogenic growth of ESCC cells and exerts a synergistic cytotoxic-effect when combined with chemotherapeutic agent cisplatin. Moreover, xenograft tumor growth in SCID mice was suppressed by Nutlin-3. The protein expression level of DNMTs was downregulated, and that of TSGs was upregulated by Nutlin-3 treatment in the excised tumor tissue. In conclusion, Nutlin-3 is a potential therapeutic agent that can potentiate the treatment efficacy of chemoradiation-resistant ESCC.

Test-retest reliabilities and minimal detectable changes of 5 versions of the Alzheimer's Disease Assessment Scale-Cognitive Subscale in people with dementia.

PURPOSE: To compare the test-retest reliability and minimal detectable change (MDC) of the commonly used versions of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) (the ADAS-Cog-11 (11 items), ADAS-Cog-3 (three items), ADAS-Cog-5-Subset (five items), ADAS-Cog-6-Subset (six items), and ADAS-Rasch (11 items)) in people with dementia. MATERIALS AND METHODS: A repeated-assessments design (2 weeks apart) was used to examine the ADAS-Cog-11, ADAS-Cog-3, ADAS-Cog-5-Subset, ADAS-Cog-6-Subset, and ADAS-Rasch. Participants with dementia were recruited from one hospital, one elder care center, and two day-care centers using convenience sampling. RESULTS: Fifty-two participants finished the assessments twice in two weeks. All versions showed high intraclass correlation coefficients (ICCs) (0.82-0.96), minimal standardized response means (-0.07 to 0.08) and low to acceptable MDC% (9.2-28.6%). The ADAS-Rasch had the highest ICC (0.96) and the lowest MDC%. The ADAS-Cog-3 had an ICC lower than 0.90 (0.82) and the highest MDC% (28.6%). CONCLUSIONS: The ADAS-Rasch seems to be the most reliable version of the ADAS-Cog for group- and individual-level comparisons. The ADAS-Cog-3 may be a better choice for researchers for group-level comparisons because it requires fewer items to achieve acceptable reliability. The ADAS-Cog-11, ADAS-Cog-5-Subset, ADAS-Cog-6-Subset, and ADAS-Rasch could be considered for clinical usage for individual-level comparisons.Implications for rehabilitationThe ADAS-Rasch is the most reliable version of the ADAS-Cog for group- and individual-level comparisons due to its excellent test-retest reliability, lowest random measurement error and absence of a practice effect.The ADAS-Cog-5-Subset and ADAS-Cog-6-Subset might be good substitutes for the ADAS-Rasch in clinical settings because of their comparable reliability features and superior administration efficiency.

Comparison of responsiveness of the Barthel Index and modified Barthel Index in patients with stroke.

PURPOSE: To compare the group- and individual-level responsiveness of the Barthel Index (BI) and modified BI (MBI) in patients with early subacute stroke. MATERIALS AND METHODS: The BI and MBI scores of 63, 63, and 55 patients were retrieved at 3 time points with a 3-weeks interval. The group-level responsiveness was examined using paired t-test and standardized response mean (SRM). The individual-level responsiveness was examined by the percentage of patients who achieved significant improvement exceeding the corresponding minimal detectable change. RESULTS: At the group level, the MBI showed significantly larger SRMs than did the BI in the 1st-2nd assessment (1.10 vs. 0.81 [95% CI of mean difference = 0.05-0.38]) and the 2nd-3rd assessment (0.94 vs. 0.72 [95% CI of mean difference = 0.04-0.41]). At the individual level, the MBI detected significantly more patients with significant improvement than the BI for the 1st-2nd assessments only (34.9 vs. 25.4% [95% CI of mean differences = 3.2-17.5]). CONCLUSIONS: The MBI has better responsiveness than the BI at both the group and individual levels in the patients with early subacute stroke. The MBI is recommended for clinical and research use as an outcome measure for patients with stroke.IMPLICATIONS FOR REHABILITATIONThe MBI is recommended for clinical and research applications because of its superior ability to detect subtle changes in ADL performance in patients with subacute stroke.The MBI and the BI have equal responsiveness for patients whose magnitude of improvement of ADL is substantial.

Secretory autophagy promotes RAB37-mediated insulin secretion under glucose stimulation both in vitro and in vivo.

High blood glucose is one of the risk factors for metabolic disease and INS (insulin) is the key regulatory hormone for glucose homeostasis. Hypoinsulinemia accompanied with hyperglycemia was diagnosed in mice with pancreatic ß-cells exhibiting autophagy deficiency; however, the underlying mechanism remains elusive. The role of secretory autophagy in the regulation of metabolic syndrome is gaining more attention. Our data demonstrated that increased macroautophagic/autophagic activity leads to induction of insulin secretion in ß-cells both in vivo and in vitro under high-glucose conditions. Moreover, proteomic analysis of purified autophagosomes from ß-cells identified a group of vesicular transport proteins participating in insulin secretion, implying that secretory autophagy regulates insulin exocytosis. RAB37, a small GTPase, regulates vesicle biogenesis, trafficking, and cargo release. We demonstrated that the active form of RAB37 increased MAP1LC3/LC3 lipidation (LC3-II) and is essential for the promotion of insulin secretion by autophagy, but these phenomena were not observed in rab37 knockout (rab37-/-) cells and mice. Unbalanced insulin and glucose concentration in the blood was improved by manipulating autophagic activity using a novel autophagy inducer niclosamide (an antihelminthic drug) in a high-fat diet (HFD)-obesity mouse model. In summary, we reveal that secretory autophagy promotes RAB37-mediated insulin secretion to maintain the homeostasis of insulin and glucose both in vitro and in vivo.

Rasch Analysis of the Stroke Impact Scale-16.

IMPORTANCE: Because the psychometric evidence supporting the use of the Stroke Impact Scale-16 (SIS-16) is limited, an examination of its psychometric properties is warranted. OBJECTIVE: To evaluate the psychometric properties of the SIS-16 using Rasch analysis. DESIGN: Secondary data analysis of responses to the SIS-16 from the published Field Administration of Stroke Therapy-Magnesium Trial database. SETTING: Emergency medical system agencies and acute care receiving hospitals. PARTICIPANTS: A total of 1,010 people with stroke. OUTCOMES AND MEASURES: We examined the item difficulty hierarchy, item fit, person-item match, separation index, person reliability coefficient, and ceiling and floor effect of the SIS-16. RESULTS: The item "climb a flight of stairs" was the most difficult, and "sit without losing balance" was the easiest. Four items misfit the Rasch partial-credit measurement model. Overall, the average patient ability estimate of 2.1 logits (SD = 2.0) was higher than the average item difficulty estimate of 0.0 logits (SD = 1.1). With a separation index of 2.85, the SIS-16 can differentiate people into 4.1 statistically distinct strata. The person reliability coefficient was .89. Given that 24.2% (n = 244) obtained the maximum score and 0.2% (n = 2) obtained the minimum score, the SIS-16 had a ceiling effect in this patient sample. CONCLUSIONS AND RELEVANCE: Results partially support the validity and clinical use of the SIS-16 in subacute stroke clinical settings. Further research is warranted to examine the psychometric properties of the SIS-16 in patients with chronic stroke. What This Article Adds: Our results partially support the use of the SIS-16 in clinical and research settings.

Secretory autophagy promotes Rab37-mediated exocytosis of tissue inhibitor of metalloproteinase 1.

BACKGROUND: Rab37-mediated exocytosis of tissue inhibitor of metalloproteinase 1 (TIMP1), an inflammatory cytokine, under serum-depleted conditions which leads to suppression of lung cancer cell metastasis has been reported. Starvation is also a stimulus of autophagic activity. Herein, we reveal that starvation activates Rab37 and induces autophagy. METHODS: We used an overexpression/knockdown system to determine the relationship between autophagy and Rab37 in vitro and in vivo. The autophagy activity was detected by immunoblotting, transmission electron microscope, autophagosome purification, and immunofluorescence under the confocal microscope. Lung-to-lung metastasis mouse model was used to clarify the role of autophagy and Rab37 in lung cancer. Clinical lung cancer patient specimens and an online big database were analyzed. RESULTS: Initially, we demonstrated that active-form Rab37 increased LC3-II protein level (the marker of autophagosome) and TIMP1 secretion. Accordingly, silencing of Rab37 gene expression alleviated Rab37 and LC3-II levels as well as TIMP1 secretion, and induction of autophagy could not increase TIMP1 exocytosis under such conditions. Moreover, silencing the Atg5 or Atg7 gene of lung cancer cells harboring active-mutant Rab37 (Q89L) led to decreased autophagy activity and TIMP1 secretion. In the lung-to-lung metastasis mouse model, increased TIMP1 expression accompanied by amiodarone-induced autophagy led to decreased tumor nodules and cancer cell metastasis. These phenomena were reversed by silencing the Atg5 or Atg7 gene. Notably, increasing autophagy activity alone showed no effect on TIMP1 secretion under either Rab37 or Sec22b silencing conditions. We further detected colocalization of LC3 with either Rab37 or TIMP1, identified Rab37 and Sec22b proteins in the purified autophagosomes of the lung cancer cells harboring the active-form Rab37 gene, and confirmed that these proteins are involved in the secretion of TIMP1. We reveal that autophagic activity was significantly lower in the tumors compared to the non-tumor parts and was associated with the overall lung cancer patient survival rate. CONCLUSIONS: We are the first to report that autophagy plays a promoting role in TIMP1 secretion and metastasis in a Rab37-dependent manner in lung cancer cells and the lung-to-lung mouse model.

Dysregulation of SOX17/NRF2 axis confers chemoradiotherapy resistance and emerges as a novel therapeutic target in esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is the sixth leading cause of cancer-associated death worldwide with a dismal overall 5-year survival rate of less than 20%. The standard first-line therapy for advanced ESCC is concomitant chemo-radiation therapy (CCRT); however, patients usually develop resistance, resulting in unfavorable outcomes. Therefore, it is urgent to identify the mechanisms underlying CCRT resistance and develop effective treatment strategies. METHODS: Patients' endoscopic biopsy tumor tissues obtained before CCRT treatment were used to perform RNA-seq and GSEA analysis. Immunohistochemical (IHC) staining, chromatin immunoprecipitation (ChIP), and promoter reporter analyses were conducted to investigate the relationship between SOX17 and NRF2. Xenograft mouse models were used to study the role of SOX17/NRF2 axis in tumor growth and the efficacy of carboxymethyl cellulose-coated zero-valent-iron (ZVI@CMC). RESULTS: In this study, a notable gene expression signature associated with NRF2 activation was observed in the poor CCRT responders. Further, IHC staining of endoscopic biopsy of 164 ESCC patients revealed an inverse correlation between NRF2 and SOX17, a tumor-suppressive transcription factor with low expression in ESCC due to promoter hypermethylation. Using ChIP and promoter reporter analyses, we demonstrated that SOX17 was a novel upstream transcriptional suppressor of NRF2. In particular, SOX17low/NRF2high nuclear level significantly correlated with poor CCRT response and poor survival, indicating that the dysregulation of SOX17/NRF2 axis played a pivotal role in CCRT resistance and tumor progression. Notably, the in-house developed nanoparticle ZVI@CMC functioned as an inhibitor of DNA methyltransferases to restore expression of SOX17 that downregulated NRF2, thereby overcoming the resistance in ESCC. Additionally, the combination of ZVI@CMC with radiation treatment significantly augmented anticancer efficacy to inhibit tumor growth in CCRT resistant cancer. CONCLUSION: This study identifies a novel SOX17low/NRF2high signature in ESCC patients with poor prognosis, recognizes SOX17 as a transcriptional repressor of NRF2, and provides a promising strategy targeting SOX17/NRF2 axis to overcome resistance.

Emerging roles of plasma gelsolin in tumorigenesis and modulating the tumor microenvironment.

The protein expression of gelsolin, an actin scavenger controlling cytoskeletal remodeling, cell morphology, differentiation, movement, and apoptosis, has been found to be significantly decreased in several pathological conditions including neurodegenerative diseases, inflammatory disorders, and cancers. Its extracellular isoform, called plasma gelsolin (pGSN), is one of the most abundant plasma proteins in the circulation, and has emerged as a novel diagnostic biomarker for early disease detection. Current evidence reveals that gelsolin can function as either an oncoprotein or a tumor suppressor depending on the carcinoma type. Interestingly, recent studies have shown that pGSN is also involved in immunomodulation, revealing the multifunctional roles of pGSN in tumor progression. In this review, we discuss the current knowledge focusing on the roles of gelsolin in inflammation and wound healing, cancers, and tumor microenvironment. Future prospects of pGSN related studies and clinical application are also addressed.

Recent advances in conventional and unconventional vesicular secretion pathways in the tumor microenvironment.

All cells in the changing tumor microenvironment (TME) need a class of checkpoints to regulate the balance among exocytosis, endocytosis, recycling and degradation. The vesicular trafficking and secretion pathways regulated by the small Rab GTPases and their effectors convey cell growth and migration signals and function as meditators of intercellular communication and molecular transfer. Recent advances suggest that Rab proteins govern conventional and unconventional vesicular secretion pathways by trafficking widely diverse cargoes and substrates in remodeling TME. The mechanisms underlying the regulation of conventional and unconventional vesicular secretion pathways, their action modes and impacts on the cancer and stromal cells have been the focus of much attention for the past two decades. In this review, we discuss the current understanding of vesicular secretion pathways in TME. We begin with an overview of the structure, regulation, substrate recognition and subcellular localization of vesicular secretion pathways. We then systematically discuss how the three fundamental vesicular secretion processes respond to extracellular cues in TME. These processes are the conventional protein secretion via the endoplasmic reticulum-Golgi apparatus route and two types of unconventional protein secretion via extracellular vesicles and secretory autophagy. The latest advances and future directions in vesicular secretion-involved interplays between tumor cells, stromal cell and host immunity are also described.

Metal-Organic Framework-Derived Electrocatalysts Competent for the Conversion of Acrylonitrile to Adiponitrile.

Electrochemical conversion of acrylonitrile (AN) to produce adiponitrile (ADN), the raw material for the production of Nylon 66, has become a crucial process owing to the increasing market demand of Nylon 66. Although the metallic Pb or Cd electrodes are commonly used for this reaction, the use of electrocatalysts or electrodes modified with catalysts has been barely investigated. In this study, nanoporous and electrically conductive metal-organic framework (MOF)-derived materials composed of Pb, PbO, and carbon are synthesized by carbonizing a Pb-based MOF through thermal treatments, and these MOF-derived materials are served as electrocatalysts for the electrosynthesis of ADN. The crystallinity, morphology, elemental composition, porosity, electrical conductivity, and electrochemically active surface area of each MOF-derived material are investigated. Mass-transport-corrected Tafel analysis is used to probe the enhanced kinetics for the electrochemical reduction of AN occurring at the electrode modified with the MOF-derived material. Electrolytic experiments at various applied potentials are conducted to quantify the production rate and Faradaic efficiency toward ADN, and the result shows that the MOF-derived materials can act as electrocatalysts to initiate the electrochemical reduction of AN to produce ADN at a reduced overpotential. The optimal MOF-derived electrocatalyst can achieve a Faradaic efficiency of 67% toward ADN at an applied potential of -0.85 V versus reversible hydrogen electrode─a much lower overpotential compared to that typically required for this reaction without the use of catalysts. Findings here shed light on the design and development of advanced electrocatalysts to boost the performances for the electrosynthesis of ADN.

YAP1 acts as a negative regulator of pro-tumor TAZ expression in esophageal squamous cell carcinoma.

PURPOSE: Although YAP1 and TAZ are believed to be equivalent downstream effectors of the Hippo pathway, differential expression of YAP1 or TAZ suggests distinct functions during cancer progression. The exact role of YAP1 and TAZ in esophageal cancer, the 6th leading cancer-related mortality in the world, remains elusive. METHODS: Following single or double manipulation of YAP1 or TAZ expression, we subjected these manipulated cells to proliferation, migration, invasion, and xenograft tumorigenesis assays. We used RT-qPCR and Western blotting to examine their expression in the manipulated cells with or without inhibition of transcription or translation. We also examined the impact of YAP1 or TAZ deregulation on clinical outcome of esophageal cancer patients from the TCGA database. RESULTS: We found that YAP1 functions as a tumor suppressor whereas TAZ exerts pro-tumor functions in esophageal cancer cells. We also found a significant increase in TAZ mRNA expression upon YAP1 depletion, but not vice versa, despite the downregulation of CTGF and CYR61, shared targets of YAP1 and TAZ, in xenografted tissue cells. In addition to transcriptional regulation, YAP1-mediated TAZ expression was found to occur via protein synthesis. Restored TAZ expression mitigated YAP1-mediated suppression of cellular behavior. By contrast, TAZ silencing reduced the promoting effect exerted by YAP1 depletion on cellular behaviors. The observed anti-tumor function of YAP1 was further supported by a better overall survival among esophageal cancer patients with a high YAP1 expression. CONCLUSION: From our data we conclude that YAP1 functions as a suppressor and negatively regulates pro-tumor TAZ expression via transcriptional and translational control in esophageal cancer.