VASH2 enhances KIF3C-mediated EGFR-endosomal recycling to promote aggression and chemoresistance of lung squamous cell carcinoma by increasing tubulin detyrosination.

Lung squamous cell carcinoma (LUSC) is associated with high mortality and has few therapeutic options. Chemotherapy remains the main treatment for LUSC patients, but multi-drug resistance has become the dominant challenge in the failure of chemotherapy in various cancers. Therefore, the effective therapeutic strategy for LUSC patients is an urgent unmet need. Here, we found vasohibin-2 (VASH2) was a prognostic biomarker for LUSC patients, and VASH2 promoted the malignant biological behaviors of LUSC cells and chemoresistance by increasing the detyrosination of α-tubulin. The high level of detyrosinated-tubulin was negatively associated with patient prognosis. Blocking the tubulin carboxypeptidase (TCP) activity of VASH2 inhibited the xenograft tumor growth and improved the treatment efficacy of paclitaxel in vivo. Results revealed that VASH2-induced increase in tubulin detyrosination boosted the binding of kinesin family member 3C (KIF3C) to microtubules and enhanced KIF3C-dependent endosomal recycling of EGFR, leading to the prolonged activation of PI3K/Akt/mTOR signaling. This study demonstrated that VASH2 was not only a prognostic biomarker but also a promising therapeutic target in LUSC, which offers a novel insight that combination of chemotherapy and EpoY, a TCP inhibitor, may be a promising treatment strategy for LUSC patients.

Aberrant Super-Enhancer Landscape in Enzalutamide-Resistant Prostate Cancer Cells.

Background: Castration-resistant prostate cancer (CRPC), which has developed resistance to next-generation antiandrogens, such as enzalutamide (Enz), is a lethal disease. Furthermore, transcriptional regulation by super enhancers (SEs) is crucial for the growth and spread of prostate cancer, as well as drug resistance. The functions of SEs, a significant class of noncoding DNA cis-regulatory elements, have been the subject of numerous recent studies in the field of cancer research. Materials and Methods: The goal of this research was to identify SEs associated with Enz resistance in C4-2B cells using chromatin immunoprecipitation sequencing and cleavage under targets and tagmentation (CUT&Tag). Using HOMER analysis to predict protein/gene-binding motifs, we identified master transcription factors (TFs) that may bind to SE sites. Using small interfering RNA, WST-1 assays, and qRT-PCR, we then confirmed the associations between TFs of SEs and Enz resistance. Results: A total of 999 SEs were screened from C4-2B EnzR cells in total. Incorporating analysis with RNA-seq data revealed 41 SEs to be strongly associated with the promotion of Enz resistance. In addition, we finally predicted that master TFs bind to SE-binding regions. Subsequently, we selected zinc finger protein 467 (ZFP467) and SMAD family member 3 to confirm the functional connections of master TFs with Enz resistance through SEs (ZNF467). Conclusions: In this study, SMAD3 and ZNF467 were found to be closely related to Enz-resistant CRPC. Our research uncovered a sizable group of SEs linked to Enz resistance in prostate cancer, dissected the mechanisms underlying SE Enz resistance, and shed light on potential clinical uses for SEs.

Macrophage-coated tumor cluster aggravates hepatoma invasion and immunotherapy resistance via generating local immune deprivation.

Immune checkpoint inhibitors (ICIs) represent a promising treatment for hepatocellular carcinoma (HCC) due to their capacity for abundant lymphocyte infiltration. However, some patients with HCC respond poorly to ICI therapy due to the presence of various immunosuppressive factors in the tumor microenvironment. Our research reveals that a macrophage-coated tumor cluster (MCTC) signifies a unique spatial structural organization in HCC correlating with diminished recurrence-free survival and overall survival in a total of 572 HCC cases from 3 internal cohorts and 2 independent external validation cohorts. Mechanistically, tumor-derived macrophage-associated lectin Mac-2 binding protein (M2BP) induces MCTC formation and traps immunocompetent cells at the edge of MCTCs to induce intratumoral cytotoxic T cell exclusion and local immune deprivation. Blocking M2BP with a Mac-2 antagonist might provide an effective approach to prevent MCTC formation, enhance T cell infiltration, and thereby improve the efficacy of ICI therapy in HCC.

Oncogenic PIK3CA recruits myeloid-derived suppressor cells to shape the immunosuppressive tumour microenvironment in luminal breast cancer through the 5-lipoxygenase-dependent arachidonic acid pathway.

BACKGROUND: Oncogenic PIK3CA mutations (PIK3CAmut ) frequently occur in a higher proportion in luminal breast cancer (LBC), especially in refractory advanced cases, and are associated with changes in tumour cellular metabolism. Nevertheless, its effect on the progression of the immune microenvironment (TIME) within tumours and vital molecular events remains veiled. METHODS: Multiplex immunohistochemistry (mIHC) and single-cell mass cytometry (CyTOF) was used to describe the landscape of TIME in PIK3CAmut LBC. The PIK3CA mutant cell lines were established using CRISPER/Cas9 system. The gene expression levels, protein secretion and activity of signaling pathways were measured by real-time RT-PCR, ELISA, immunofluorescence staining or western blotting. GSEA analysis, transwell chemotaxis assay, live cell imaging, flow cytometry metabolite analysis targeting arachidonic acid, Dual-luciferase reporter assay, and Chromatin immunoprecipitation assay were used to investigate the underlying function and mechanism of the PI3K/5-LOX/LTB4 axis. RESULTS: PIK3CAmut LBC cells can induce an immunosuppressive TIME by recruiting myeloid-derived suppressor cells (MDSCs) and excluding cytotoxic T cells via the arachidonic acid (AA) metabolism pathway. Mechanistically, PIK3CAmut activates the transcription of 5-lipoxygenase (5-LOX) in a STAT3-dependent manner, which in turn directly results in high LTB4 production, binding to BLT2 on MDSCs and promoting their infiltration. Since a suppressive TIME is a critical barrier for the success of cancer immunotherapy, the strategies that can convert "cold" tumours into "hot" tumours were compared. Targeted therapy against the PI3K/5-LOX/LTB4 axis synergizing with immune checkpoint blockade (ICB) therapy achieved dramatic shrinkage in vivo. CONCLUSIONS: The results emphasize that PIK3CAmut can induce immune evasion by recruiting MDSCs through the 5-LOX-dependent AA pathway, and combination targeted therapy with ICB may provide a promising treatment option for refractory advanced LBC patients.

Wafer-Level, High-Performance, Flexible Sensors Based on Organic Nanoforests for Human-Machine Interactions.

High-performance flexible sensors are essential for real-time information analysis and constructing noncontact communication modules for emerging human-machine interactions. In these applications, batch fabrication of sensors that exhibit high performance at the wafer level is in high demand. Here, we present organic nanoforest-based humidity sensor (NFHS) arrays on a 6 in. flexible substrate prepared via a facile, cost-effective manufacturing approach. Such an NFHS achieves state-of-the-art overall performance: high sensitivity and fast recovery time; the best properties are at a small device footprint. The high sensitivity (8.84 pF/% RH) and fast response time (5 s) of the as-fabricated organic nanoforests are attributed to the abundant hydrophilic groups, the ultra-large surface area with a huge number of nanopores, and the vertically distributed structures beneficial to the transfer of molecules up and down. The NFHS also exhibits excellent long-term stability (90 days), superior mechanical flexibility, and good performance repeatability after bending. With these superiorities, the NFHS is further applied as a smart noncontact switch, and the NFHS array is used as the motion trajectory tracker. The wafer-level batch fabrication capability of our NFHS provides a potential strategy for developing practical applications of such humidity sensors.

SOCS3 deficiency-dependent autophagy repression promotes the survival of early-stage myeloid-derived suppressor cells in breast cancer by activating the Wnt/mTOR pathway.

Early-stage myeloid-derived suppressor cells are a newly defined subset of myeloid-derived suppressor cells in breast cancer tissues and related to poor prognosis in patients with breast cancer. Compared with classical myeloid-derived suppressor cells, early-stage myeloid-derived suppressor cells display exceptional immunosuppressive ability and accumulate in the tumor microenvironment to suppress innate and adaptive immunity. Previously, we demonstrated that early-stage myeloid-derived suppressor cells were SOCS3 deficiency dependent and correlated with differentiation arrest in the myeloid lineage. Autophagy is a major regulator of myeloid differentiation, but the mechanism by which autophagy regulates the development of early-stage myeloid-derived suppressor cells has not been elucidated. Here, we constructed EO771 mammary tumor-bearing conditional myeloid SOCS3 knockout mice (SOCS3MyeKO) characterized by abundant tumor-infiltrating early-stage myeloid-derived suppressor cells and exacerbated immunosuppression in vitro and in vivo. We found that early-stage myeloid-derived suppressor cells isolated from SOCS3MyeKO mice showed differentiation arrest in the myeloid lineage, which was caused by limited autophagy activation in an Wnt/mTOR-dependent manner. RNA sequencing and microRNA microarray assays revealed that miR-155-induced C/EBPß downregulation activated the Wnt/mTOR pathway and promoted autophagy repression and differentiation arrest in early-stage myeloid-derived suppressor cells. Furthermore, inhibition of Wnt/mTOR signaling suppressed both tumor growth and the immunosuppressive functions of early-stage myeloid-derived suppressor cells. Thus, SOCS3 deficiency-dependent autophagy repression and their regulatory mechanisms could contribute to the immunosuppressive tumor microenvironment. Our study proposes a novel mechanism for promoting early-stage myeloid-derived suppressor cell survival, which might shed new light on a potential target of oncologic therapy.

Early myeloid-derived suppressor cells accelerate epithelial-mesenchymal transition by downregulating ARID1A in luminal A breast cancer.

Early myeloid-derived suppressor cells (eMDSCs) are a newly characterized subclass of MDSCs, which exhibit more potent immunosuppressive capacity than classical MDSCs. Previously, we found high eMDSCs infiltration was correlated with poor prognosis of breast cancer, though the regulatory mechanisms have not been fully understood. Here, we constructed a 21-gene signature to evaluate the status of eMDSCs infiltration within breast cancer tissues and found that highly infiltrated eMDSCs affected the prognosis of breast cancer patients, especially in luminal A subtype. We also found that eMDSCs promoted epithelial-mesenchymal transition (EMT) and accelerated cell migration and invasion in vitro. Meanwhile, eMDSCs significantly downregulated ARID1A expression in luminal A breast cancer, which was closely associated with EMT and was an important prognostic factor in breast cancer patients. Moreover, significant changes of EMT-related genes were detected in luminal A breast cancer cells after co-cultured with eMDSCs or ARID1A knock-down and overexpression of ARID1A significantly reversed this procedure. These results implied that eMDSCs might suppress the ARID1A expression to promote EMT in luminal A breast cancer cells, which might provide a new light on developing novel treatment regimens for relapsed luminal A breast cancer after conventional therapies.

A nanoforest-based humidity sensor for respiration monitoring.

Traditional humidity sensors for respiration monitoring applications have faced technical challenges, including low sensitivity, long recovery times, high parasitic capacitance and uncalibrated temperature drift. To overcome these problems, we present a triple-layer humidity sensor that comprises a nanoforest-based sensing capacitor, a thermistor, a microheater and a reference capacitor. When compared with traditional polyimide-based humidity sensors, this novel device has a sensitivity that is improved significantly by 8 times within a relative humidity range of 40-90%. Additionally, the integration of the microheater into the sensor can help to reduce its recovery time to 5 s. The use of the reference capacitor helps to eliminate parasitic capacitance, and the thermistor helps the sensor obtain a higher accuracy. These unique design aspects cause the sensor to have an excellent humidity sensing performance in respiration monitoring applications. Furthermore, through the adoption of machine learning algorithms, the sensor can distinguish different respiration states with an accuracy of 94%. Therefore, this humidity sensor design is expected to be used widely in both consumer electronics and intelligent medical instrument applications.

A Thermopile Infrared Sensor Array Pixel Monolithically Integrated with an NMOS Switch.

In this article, we present the design, fabrication, and characterization of a thermopile infrared sensor array (TISA) pixel. This TISA pixel is composed of a dual-layer p+/n- poly-Si thermopile with a closed membrane and an n-channel metal oxide semiconductor (NMOS) switch. To address the challenges in fabrication through the 3D integration method, the anode of the thermopile is connected to the drain of the NMOS, both of which are fabricated on the same bulk wafer using a CMOS compatible monolithic integration process. During a single process sequence, deposition, etching, lithography, and ion implantation steps are appropriately combined to fabricate the thermopile and the NMOS simultaneously. At the same time as ensuring high thermoelectric characteristics of the dual-layer p+/n- poly-Si thermopile, the basic switching functions of NMOS are achieved. Compared with a separate thermopile, the experimental results show that the thermopile integrated with the NMOS maintains a quick response, high sensitivity and high reliability. In addition, the NMOS employed as a switch can effectively and quickly control the readout of the thermopile sensing signal through the voltage, both on and off, at the gate of NMOS. Thus, such a TISA pixel fabricated by the monolithic CMOS-compatible integration approach is low-cost and high-performance, and can be applied in arrays for high-volume production.

Comparisons of effects of SOX and mFOLFOX6 chemotherapy regimens on patients with locally advanced gastric cancer.

The neoadjuvant chemotherapy plays an important role in locally advanced gastric cancer, but its efficacy, safety profiles and clinical outcomes among different regimens still remain controversial. In this study, totally 231 eligible patients with locally advanced gastric cancer were enrolled. These patients were divided into the observation group (SOX regimen, n = 123) and control group (mFOLFOX6 regimen, n = 108) according to different chemotherapy regimens. Then, the differences in chemotherapy efficacy, adverse reactions, surgical characteristics, complications and survival condition were compared. No significant differences were observed in clinical efficacy of chemotherapy, the rate of D2 lymph node clearance, R0 resection, complications, responses of neoadjuvant chemotherapy and survival condition between two groups (P > 0.05). The incidence of abdominal pain, diarrhoea, nausea and vomiting in the observation group were significantly lower than those in the control group (16.26% vs 29.63%, χ2 = 5.893, P < 0.05; 11.38% vs 26.85%, χ2 = 9.084, P < 0.05; 35.77% vs 53.70%, χ2 = 7.499, P < 0.05). The SOX regimen and mFOLFOX6 regimen have similar chemotherapy efficacy for locally advanced gastric cancer, but SOX regimen has a lower risk of gastrointestinal adverse reactions comparing with mFOLFOX6 regimen.

The enrichment of eggs with docosahexaenoic acid and eicosapentaenoic acid through supplementation of the laying hen diet.

The enrichment and transformation of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) enriched phospholipids for eggs deserve attention. The aim of the present study was to elucidate the comparative effects of DHA and EPA enriched phospholipids and triacylglycerols on egg fortification by determining the fatty acid composition of egg yolk after intervention with fish oil (15 g/kg) and krill oil (15 and 30 g/kg) for three consecutive weeks. The results indicated that laying hens could incorporate over 300 mg DHA and EPA into one egg. Greater retention efficiency of DHA and EPA in eggs was observed in fish oil supplementation compared with krill oil at equivalent dietary levels. DHA and EPA were prone to locate at the sn-2 position of phosphatidylcholine. Consequently, fish oil possessed high DHA content and conversion rate, and krill oil could raise the proportion of DHA-containing phospholipids in eggs.

Snf5 and Swi3 subcomplex formation is required for SWI/SNF complex function in yeast.

The SWI/SNF chromatin remodeling complex, which alters nucleosome positions by either evicting histones or sliding nucleosomes on DNA, is highly conserved from yeast to humans, and 20% of all human cancers have mutations in various subunits of the SWI/SNF complex. Here, we reported the crystal structure of the yeast Snf5-Swi3 subcomplex at a resolution of 2.65 Å. Our results showed that the Snf5-Swi3 subcomplex assembles into a heterotrimer with one Snf5 molecule bound to two distinct Swi3 molecules. In addition, we demonstrated that Snf5-Swi3 subcomplex formation is required for SWI/SNF function in yeast. These findings shed light on the important role of the Snf5-Swi3 subcomplex in the assembly and functional integrity of the SWI/SNF complex.

Application of Plackett-Burman Design in Screening of Natural Antioxidants Suitable for Anchovy Oil.

Considering the safety of synthetic antioxidants, more and more natural antioxidants have been developed and utilized in foods. This study aimed to screen out a natural antioxidant combination from many antioxidants, which could significantly affect the oxidation stability of anchovy oil, while Plackett-Burman design (PBD) methodology was employed in this screening. According to the statistical results of this design, sesamol, dihydromyricetin, teapolyphenol, and rosemary acid were four significant parameters on the oxidation stability of anchovy oil. Moreover, dihydromyricetin presented the best antioxidant effect among nine kinds of selected antioxidants when they were used alone in anchovy oil. Meanwhile, a combination including sesamol (0.02%), teapolyphenol (0.02%). and rosemary acid (0.02%) was adopted, and its antioxidant ability was similar to that of tert-butylhydroquinone (TBHQ). Additionally, phytic acid as a synergist was used and combined with sesamol, and the antioxidant ability of this combination was better than that of TBHQ. This study presented a reference for the industrial applications of natural antioxidants and synergists in anchovy oil.

Diagnostic value of HMGB1 immunostaining on cell blocks from residual liquid-based gynecologic cytology specimens.

Aberrant expression of high mobility group box 1 (HMGB1) is associated with tumor development and progression. The current study was conducted to evaluate the significance of HMGB1 immunostaining on cell block (CB) preparations in the diagnosis of neoplastic and preneoplastic lesions of the cervix. The CBs were prepared from 157 residual liquid-based gynecologic cytology specimens which were collected from women whose cervical lesions had been confirmed by histopathology. The expression of HMGB1 and p16INK4A (p16) was visualized by immunocytochemistry on the CB preparations, and the association of their expression patterns was correlated with the severity of cervical lesions. HeLa cells were used as positive control. HMGB1 expression was observed in dysplastic and neoplastic cells and increased along with the progression of cervical neoplasia. The rates of positive staining for HMGB1 in cervical intraepithelial neoplasia 1 (CIN-1), CIN-2, CIN-3, and invasive squamous cell carcinomas (ISCCs) were 69.4, 96.9, 100.0, and 100.0%, respectively. The differences between positive rates of patients with chronic cervicitis and various CINs as well as ISCCs were significant (P < 0.005). The differences in positive staining rates between each two CIN groups, and differences between CIN-1/2 and ISCCs, were also significant (P < 0.005). The expression pattern of HMGB1 was generally correlated with that of p16 (P < 0.001). HMGB1 staining was observed in some p16-negative specimens. HMGB1 immunostaining on a CB from gynecologic cytology specimens is potentially valuable for the screening of cervical lesions in cases with questionable cytology.

Olfactomedin 4 is a marker for progression of cervical neoplasia.

INTRODUCTION: Olfactomedin 4 (OLFM4) is expressed in gastrointestinal cancers and related to progression and differentiation of these malignancies. However, whether OLFM4 contributes to tumorigenesis of other tissues has not been thoroughly investigated. The purpose of the study was to investigate OLFM4 expression in cervical epithelium and its association with progression of cervical neoplasia and differentiation of cervical carcinomas. METHODS: Immunohistochemistry and real-time reverse transcription-polymerase chain reaction were used to evaluate the expression and distribution of OLFM4 in cervical intraepithelial neoplasia (CIN) and invasive squamous cell carcinomas (ISCCs). RESULTS: The overall positive OLFM4 staining levels in normal cervical epithelia, CIN I, CIN II, CIN III, and ISCCs are 22.0%, 94.2%, 93.7%, 94.6%, and 96.7%, respectively. The intensity of OLFM4 staining was enhanced according to increased pathologic grade of cervical squamous intraepithelial lesion. The immunoreactivity to OLFM4 was stronger in well-differentiated ISCCs than in poorly differentiated ISCCs. CONCLUSIONS: Olfactomedin 4 expression has been associated with progression of CIN and differentiation of cervical cancer. The results provide new evidence that OLFM4 plays an important role in tumorigenesis in the female reproductive tract.

Diet and gastric cancer: a casecontrol study in Fujian Province, China.

AIM:To explore the relationship between consumption of fish sauce, other dietary factors, living habits and the rish kf gastric cancer.METHODS:From May 1994 to July 1995, a population-based 1 2 case-control study was in Carried out inhigh-risk areas of gastric cancer, Changle and Fuqing cities, Fujian Province. Totally 272 cases and 544 age, gender-matched controls were included. Risk state analyses were made by ASRS package.RESULTS:Risk state single-factor analysis indicated that gastric cancer risk rose with high intake of fish sauce(OR =2.57), salted vegetables (OR =1.41), salted/fried fish and small shrimps (OR =1.57), low consumption of fresh vegetables (OR =1.95), fresh citrus fruits (OR =1.41), other fresh fruits (OR =1.31), green tea (OR =1.72), exposure to moldy foods (OR =2.32), irregular dinners (OR =5.47) and familial history of malignancy (OR =3.27).No significant relationship was observed between smoking, drinking, salt intake, use of refrigerator and gastric cancer rish. The results of rish state conditional Logistic regression showed that fish sauce, salted/dried fish and small shrimps, irregular dinners, familial history of malignancy were included in the best rish set. The summary ARS for the four factors was 75.49%.CONCLUSION:High intake of fish sauce, salted foods, moldy foods, irregular dinners and familial history of malignancy were possible risk factors for gastric cancer, whereas fresh vegetables and fruits.and green tea might have protective effects for gastric cancer.