Superconducting nanowire single-photon detector with polarization insensitivity, ultrafast response, and high efficiency.

This study proposed what we believe to be a novel method for fabricating superconducting nanowire single-photon detectors (SNSPDs) with high efficiency, polarization insensitivity, and ultrafast response. To achieve these properties in niobium nitride (NbN) SNSPDs, the periodic four-split rings (PFSR) were positioned above the nanowires. This design uses the localized surface plasmon resonance to enhance the electric field around nanowires. For an incident light with a wavelength of 1550 nm, the PFSR-SNSPD structure achieved a polarization extinction ratio of 1.0064 and absorptions of 88.94% and 88.37% under TE and TM polarizations, respectively. The nanowire length was reduced by 85% using a meandering nanowire arrangement with a fill factor of 0.074.

Pretreatment soluble Siglec-5 protein predicts early progression and R-CHOP efficacy in diffuse large B-cell lymphoma.

Aims: To explore the clinical association between soluble Siglec-5/CD163 and clinical feature and prognosis in peripheral blood samples of patients with diffuse large B-cell lymphoma. Method: Significantly elevated cytokines in peripheral blood were characterized by cytokines array and validated by ELISA. Results: Compared with CD163, Siglec-5 exhibited superiority in discriminating patients into low- and high-risk subgroups based on overall survival and progression-free survival. In addition, Siglec-5 was an indicator of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) treatment efficacy. Conclusion: Siglec-5 may be applied as a reliable independent immune indicator for overall survival and progression-free survival. It may also predict R-CHOP efficacy in diffuse large B-cell lymphoma.

The phospholipid flippase ATP9A enhances macropinocytosis to promote nutrient starvation tolerance in hepatocellular carcinoma.

Macropinocytosis is an effective strategy to mitigate nutrient starvation. It can fuel cancer cell growth in nutrient-limited conditions. However, whether and how macropinocytosis contributes to the rapid proliferation of hepatocellular carcinoma cells, which frequently experience an inadequate nutrient supply, remains unclear. Here, we demonstrated that nutrient starvation strongly induced macropinocytosis in some hepatocellular carcinoma cells. It allowed the cells to acquire extracellular nutrients and supported their energy supply to maintain rapid proliferation. Furthermore, we found that the phospholipid flippase ATP9A was critical for regulating macropinocytosis in hepatocellular carcinoma cells and that high ATP9A levels predicted a poor outcome for patients with hepatocellular carcinoma. ATP9A interacted with ATP6V1A and facilitated its transport to the plasma membrane, which promoted plasma membrane cholesterol accumulation and drove RAC1-dependent macropinocytosis. Macropinocytosis inhibitors significantly suppressed the energy supply and proliferation of hepatocellular carcinoma cells characterised by high ATP9A expression under nutrient-limited conditions. These results have revealed a novel mechanism that overcomes nutrient starvation in hepatocellular carcinoma cells and have identified the key regulator of macropinocytosis in hepatocellular carcinoma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

ALG8 Fuels Stemness Through Glycosylation of the WNT/Beta-Catenin Signaling Pathway in Colon Cancer.

Cancer stem cells (CSCs) drive tumor relapse, which is a major clinical challenge in colon cancer. Targeting CSCs presents a great opportunity in eradicating cancer cells and thus treatment of patients with cancer. However, the epigenetic control of the CSC signature and key molecules involved in colon cancer remains undefined. In this study, we demonstrated that alpha-1,3-glucosyltransferase (ALG8) is upregulated in colon cancer tissues compared with normal tissues. Overexpression of the ALG8 gene predicted poor overall survival and disease-free survival in colon cancer patients. Silencing of the ALG8 gene repressed the stemness of colon tumor cells. Xenograft mice transplanted with ALG8-deficient tumor cells significantly alleviated tumor burden and prolonged survival in comparison with control mice. Further analysis showed that ALG8 gene promoted cancer stemness through inducing glycosylation of LRP6, which activates the WNT/beta-catenin signaling pathway. Importantly, attenuation of the glycosylation using tunicamycin abrogated the effect of ALG8 gene on cancer stemness. Taken together, our findings demonstrated that ALG8 enhances colon tumorigenesis by activating the WNT/beta-catenin signaling pathway. Therefore, ALG8 gene is a potential therapeutic target in colon cancer.

USP14 promotes tryptophan metabolism and immune suppression by stabilizing IDO1 in colorectal cancer.

Indoleamine 2,3 dioxygenase 1 (IDO1) is an attractive target for cancer immunotherapy. However, IDO1 inhibitors have shown disappointing therapeutic efficacy in clinical trials, mainly because of the activation of the aryl hydrocarbon receptor (AhR). Here, we show a post-transcriptional regulatory mechanism of IDO1 regulated by a proteasome-associated deubiquitinating enzyme, USP14, in colorectal cancer (CRC). Overexpression of USP14 promotes tryptophan metabolism and T-cell dysfunction by stabilizing the IDO1 protein. Knockdown of USP14 or pharmacological targeting of USP14 decreases IDO1 expression, reverses suppression of cytotoxic T cells, and increases responsiveness to anti-PD-1 in a MC38 syngeneic mouse model. Importantly, suppression of USP14 has no effects on AhR activation induced by the IDO1 inhibitor. These findings highlight a relevant role of USP14 in post-translational regulation of IDO1 and in the suppression of antitumor immunity, suggesting that inhibition of USP14 may represent a promising strategy for CRC immunotherapy.

[Corrigendum] Overexpression of HES6 has prognostic value and promotes metastasis via the Wnt/ß-catenin signaling pathway in colorectal cancer.

Subsequently to the publication of the above article, an interested reader drew to the authors' attention that Fig. 2 on p. 1266 and Fig. 5 on p. 1269 contained some apparent errors in terms of the assembly of the various data panels. Specifically, Fig. 2D appeared to contain a pair of overlapping images, and Figs. 5D and 8A also appeared to include overlapping images. However, the authors were able to consult their original data, and assess where the errors had been made during the compilation of these figures. The corrected versions of Figs. 2 (showing the correct data for the '5T' panel in Fig. 2D) and 5 (showing alternative data) are shown on the subsequent pages. The authors regret the errors that were made during the preparation of the published figures, and confirm that these errors did not grossly affect the conclusions reported in the study. The authors are grateful to the Editor of Oncology Reports for allowing them the opportunity to publish a Corrigendum, and all the authors agree to this Corrigendum. Furthermore, they apologize to the readership for any inconvenience caused. [the original article was published in Oncology Reports 40: 1261­1274, 2018; DOI: 10.3892/or.2018.6539].

Combined tumor-associated macrophages biomarker predicting extremely poor outcome of patients with primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is an aggressive and rare malignancy with poor prognosis. However, there are no reliable prognostic biomarkers for PCNSL in clinical practice. Here, we aimed to identify a reliable prognostic biomarker for predicting the survival of PCNSL patients. In this study, multiplex immunofluorescence and digital imaging analysis were used to characterize tumor-associated macrophages (TAMs) immunophenotypes and the expression of programmed cell death ligand 1 on TAMs, with regard to prognosis from diagnostic tumor tissue samples of 59 PCNSL patients. We found that the M2-to-M1 ratio was a more reliable prognostic biomarker for PCNSL than M1-like or M2-like macrophage infiltration. In addition, the combination of programmed death-ligand 1 (PD-L1) expression on TAMs and the M2-to-M1 ratio in PCNSL demonstrated improved performance in prognostic discrimination than PD-L1-positive TAMs or M2-to-M1 ratio. To validate the prognostic significance of the combined TAMs associated biomarkers, they were integrated into the International Extranodal Lymphoma Study Group (IELSG) index and termed as IELSG-M index. Kaplan-Meier plots showed that the IELSG-M index could discriminate patients into low-, intermediate- or high-risk subgroups, better than IELSG, in terms of prognosis. The areas under the receiver operating characteristic curves of IELSG-M was 0.844 for overall survival; superior to the IELSG model (0.580). Taken together, this study's findings showed that the combination of PD-L1 on TAMs and the M2-to-M1 ratio could be strong prognostic predictive biomarkers for PCNSL and the IELSG-M index had improved prognostic significance than the IELSG index.

ALG3 contributes to stemness and radioresistance through regulating glycosylation of TGF-ß receptor II in breast cancer.

BACKGROUND: Radiotherapy is a conventional and effective local treatment for breast cancer. However, residual or recurrent tumors appears frequently because of radioresistance. Novel predictive marker and the potential therapeutic targets of breast cancer radioresistance needs to be investigated. METHODS: In this study, we screened all 10 asparagine-linked glycosylation (ALG) members in breast cancer patients' samples by RT-PCR. Cell viability after irradiation (IR) was determined by CCK-8 assay and flow cytometry. The radiosensitivity of cell lines with different ALG3 expression was determined with the colony formation assay by fitting the multi-target single hit model to the surviving fractions. Cancer stem-like traits were assessed by RT-PCR, Western blot, and flow cytometry. The mechanisms of ALG3 influencing radiosensitivity was detected by Western blot and immunoprecipitation. And the effect of ALG3 on tumor growth after IR was verified in an orthotopic xenograft tumor models. The association of ALG3 with prognosis of breast cancer patients was confirmed by immunohistochemistry. RESULTS: ALG3 was the most significantly overexpressing gene among ALG family in radioresistant breast cancer tissue. Overexpression of ALG3 predicted poor clinicopathological characteristics and overall survival (OS), and early local recurrence-free survival (LRFS) in breast cancer patients. Upregulating ALG3 enhanced radioresistance and cancer stemness in vitro and in vivo. Conversely, silencing ALG3 increased the radiosensitivity and repressed cancer stemness in vitro, and more importantly inhibition of ALG3 effectively increased the radiosensitivity of breast cancer cells in vivo. Mechanistically, our results further revealed ALG3 promoted radioresistance and cancer stemness by inducing glycosylation of TGF-ß receptor II (TGFBR2). Importantly, both attenuation of glycosylation using tunicamycin and inhibition of TGFBR2 using LY2109761 differentially abrogated the stimulatory effect of ALG3 overexpression on cancer stemness and radioresistance. Finally, our findings showed that radiation played an important role in preventing early recurrence in breast cancer patients with low ALG3 levels, but it had limited efficacy in ALG3-overexpressing breast cancer patients. CONCLUSION: Our results suggest that ALG3 may serve as a potential radiosensitive marker, and an effective target to decrease radioresistance by regulating glycosylation of TGFBR2 in breast cancer. For patients with low ALG3 levels, radiation remains an effective mainstay therapy to prevent early recurrence in breast cancer.

LncRNA TUG1 competitively binds to miR-340 to accelerate myocardial ischemia-reperfusion injury.

The aberrant expression of long noncoding RNA (lncRNA) taurine-upregulated gene 1 (TUG1) has been previously associated with myocardial ischemia-reperfusion injury (MIRI), but the underlying molecular mechanisms remain elusive. The current study aimed to clarify the functional role of TUG1/microRNA (miR)-340/histone deacetylase 4 (HDAC4)/ß-catenin/glucose transporter type 1 (GLUT1) axes in MIRI. The database-based analyses performed predicted the downstream factors of lncRNA TUG1. In the MIRI mouse models and hypoxia/reoxygenation (H/R)-induced cardiomyocyte models, the expression of TUG1/miR-340/HDAC4/ß-catenin/GLUT1 was manipulated to examine their effects on the infarction area, cardiomyocyte viability and apoptosis employing the Evans blue/TTC double staining, CCK-8 and TUNEL assays. Furthermore, the dual luciferase reporter and RIP assays verified the binding affinity of miR-340 to TUG1 and HDAC4. Subsequently, a negative correlation between miR-340 and TUG1 or HDAC4 expression was identified in myocardial tissues of MIRI mice and H/R-induced cardiomyocyte models, along with a positive correlation between TUG1 and HDAC4. Additionally, it was established that TUG1 bound to miR-340, and miR-340 targeted HDAC4. TUG1 upregulated HDAC4 expression, thereby promoting MIRI in the mouse models. HDAC4 was proven to repress the expression of ß-catenin and its target gene GLUT1. Moreover, the in vivo experiments validated that the inhibition of TUG1/miR-340/HDAC4/ß-catenin/GLUT1 axes alleviated MIRI in mice. Collectively, the current study uncovered the role of TUG1/miR-340/HDAC4/ß-catenin/GLUT1 axes in MIRI mouse models and H/R-induced cardiomyocyte models which may be a potential therapeutic target for MIRI treatment.

The cross-talk between DDR1 and STAT3 promotes the development of hepatocellular carcinoma.

OBJECTIVE: To investigate the function of discoidin domain receptor 1 (DDR1) in hepatocellular carcinoma (HCC) and to further clarify the underlying mechanism. RESULTS: DDR1 was significantly increased in HCC tissues and cells, which was related to clinical staging and prognosis of HCC. Upregulation of DDR1 promoted EMT and glutamine metabolism in HCC cells, while loss of DDR1 showed the opposite effects. STAT3 bound with the promoter of DDR1, and facilitated the phosphorylation of STAT3. In turn, activation of STAT3 increased the expression of DDR1. Silencing of STAT3 removed the promoting effect of DDR1 on proliferation, migration and invasion of HCC cells. The in vivo tumor growth assay showed that the cross-talk between DDR1 and STAT3 promoted HCC tumorigenesis. CONCLUSIONS: Our research revealed the positive feedback of DDR1 and STAT3 promoted EMT and glutamine metabolism in HCC, which provided some experimental basis for clinical treatment or prevention of HCC. MATERIALS AND METHODS: The mRNA expression of DDR1 was detected by qRT-PCR. CCK8 assay, wound healing assay and transwell assay were used to detect the DDR1/ STAT3 function on proliferation, migration and invasion in HCC cells. Western blot was used to calculate protein level of DDR1, STAT3, epithelial-mesenchymal transition (EMT) related proteins.

TRIB3 confers radiotherapy resistance in esophageal squamous cell carcinoma by stabilizing TAZ.

Radioresistance becomes the major obstacle to reduce tumor recurrence and improve prognosis in the treatment of esophageal squamous cell carcinoma (ESCC). Thus new strategies for radioresistant ESCC are urgently needed. Herein, we reported that tribbles pseudokinase 3 (TRIB3) serves as a key regulator of radioresistance in ESCC. TRIB3 is overexpressed in ESCC tissues and cell lines. High expression of TRIB3 significantly correlates with poor radiotherapy response and prognosis in ESCC patients. Upregulation of TRIB3 in ESCC cells conferred radioresistance in vitro and in vivo by interacting with TAZ thus impeding ß-TrCP-mediated TAZ ubiquitination and degradation. Conversely, silencing TRIB3 sensitized ESCC cells to ionizing radiation. More importantly, TRIB3 was significantly correlated with TAZ activation in ESCC biopsies, and patients with high expression of both TRIB3 and TAZ suffered the worst radiotherapy response and survival. Our study uncovers the critical mechanism of ESCC resistance to radiotherapy, and provides a new pharmacological opportunity for developing a mechanism-based strategy to eliminate radioresistant ESCC in clinical practice.

Zinc finger protein 367 promotes metastasis by inhibiting the Hippo pathway in breast cancer.

Circulating tumor cells (CTC) disseminating is an important cause of distant metastasis. However, the mechanism involved in increasing the numbers of CTCs in breast cancer is unclear. Herein, Zinc finger protein 367 (ZNF367) was identified as a potential prometastatic gene in an integrative breast cancer datasets. ZNF367 was upregulated in breast cancer tissues and cell lines, and significantly correlated with poorer metastasis-free and overall survivals in patients. ZNF367 promoted tumor metastasis accompanied with increase of CTC numbers. Mechanistically, ZNF367 interacted with chromatin remodeling protein BRG1 and transcriptionally activated CIT and TP53BP2, leading to the inhibition of the Hippo pathway and activation of YAP1, which gave rise to the resistance of anoikis and increased CTCs in the blood circulation. More importantly, administration of a YAP1 inhibitor Verteporfin resensitized ZNF367-overexpressing breast cancer cells to anoikis and abrogated metastasis. Our findings addressed the importance of ZNF367 in breast cancer as a prognostic biomarker and offered a potential therapeutic strategy for the treatment of a subset of metastatic breast cancer with ZNF367 overexpression.

Epigenetic silencing of SALL2 confers tamoxifen resistance in breast cancer.

Resistance to tamoxifen is a clinically major challenge in breast cancer treatment. Although downregulation of estrogen receptor-alpha (ERα) is the dominant mechanism of tamoxifen resistance, the reason for ERα decrease during tamoxifen therapy remains elusive. Herein, we reported that Spalt-like transcription factor 2 (SALL2) expression was significantly reduced during tamoxifen therapy through transcription profiling analysis of 9 paired primary pre-tamoxifen-treated and relapsed tamoxifen-resistant breast cancer tissues. SALL2 transcriptionally upregulated ESR1 and PTEN through directly binding to the DNA promoters. By contrast, silencing SALL2 induced downregulation of ERα and PTEN and activated the Akt/mTOR signaling, resulting in estrogen-independent growth and tamoxifen resistance in ERα-positive breast cancer. Furthermore, hypermethylation of SALL2 promoter was found in tamoxifen-resistant breast cancer. Importantly, in vivo experiments showed that DNA methyltransferase inhibitor-mediated SALL2 restoration resensitized tamoxifen-resistant breast cancer to tamoxifen therapy. These findings shed light on the mechanism of SALL2 in regulation of ER and represent a potential clinical signature that can be used to categorize breast cancer patients who may benefit from co-therapy with tamoxifen and DNMT inhibitor.

AKIP1 promotes early recurrence of hepatocellular carcinoma through activating the Wnt/ß-catenin/CBP signaling pathway.

The early recurrence of hepatocellular carcinoma (HCC) is the main obstacle for long-term survival of patients. Wnt/ß-catenin signaling has been involved in the development and progression of HCC. However, the molecular changes that link Wnt/ß-catenin activation and HCC early recurrence remain poorly understood. Here we identified AKIP1 as a binding partner of ß-catenin. AKIP1 interacted with and sustained ß-catenin in the nuclear by blocking its interaction with adenomatous polyposis coli protein (APC). Moreover, AKIP1 enhanced the protein kinase A catalytic subunit (PKAc)-mediated phosphorylation of ß-catenin, leading to recruitment of cyclic AMP response element-binding protein (CBP) and activation of ß-catenin downstream transcription. Increased AKIP1 expression was observed in HCC clinical samples and correlated with early recurrence and poor prognosis of HCC. AKIP1 promoted invasion and colony outgrowth in vitro and increased intrahepatic and lung metastasis in vivo. Treatment with a CBP inhibitor ICG-001 effectively inhibited the metastatic progression of HCC tumors that had elevated AKIP1 in both cell line and patient-derived xenograft mouse models. Our findings not only establish AKIP1 as a novel regulator of Wnt/ß-catenin signaling as well as HCC early recurrence but also highlight targeting the AKIP1/ß-catenin/CBP axis as attractive therapies for combating HCC metastatic relapse.

Nuclear orphan receptor NR2F6 confers cisplatin resistance in epithelial ovarian cancer cells by activating the Notch3 signaling pathway.

The primary challenge facing treatment of epithelial ovarian cancer (EOC) is the high frequency of chemoresistance, which severely impairs the quality of life and survival of patients with EOC. Our study aims to investigate the mechanisms by which upregulation of NR2F6 induces chemoresistance in EOC. The biological roles of NR2F6 in EOC chemoresistance were explored in vitro by Sphere, MTT and AnnexinV/PI assay, and in vivo using an ovarian cancer orthotopic transplantation model. Bioinformatics analysis, luciferase assay, CHIP and IP assays were performed to identify the mechanisms by which NR2F6 promotes chemoresistance in EOC. The expression of NR2F6 was significantly upregulated in chemoresistant EOC tissue, and NR2F6 expression was correlated with poorer overall survival. Moreover, overexpression of NR2F6 promotes the EOC cancer stem cell phenotype; conversely, knockdown of NR2F6 represses the EOC cancer stem cell phenotype and sensitizes EOC to cisplatin in vitro and in vivo. Our results further demonstrate that NR2F6 sustains activated Notch3 signaling, resulting in chemoresistance in EOC cells. Notably, NR2F6 acts as an informative biomarker to identify the population of EOC patients who are likely to experience a favorable objective response to gamma-secretase inhibitors (GSI), which inhibit Notch signaling. Therefore, concurrent inhibition of NR2F6 and treatment with GSI and cisplatin-based chemotherapy may be a novel therapeutic approach for NR2F6-overexpressing EOC. In summary, we have, for the first time, identified an important role for NR2F6 in EOC cisplatin resistance. Our study suggests that GSI may serve as a potential targeted treatment for patients with NR2F6-overexpressing EOC.

Analysis of the Learning Curve in Mitral Valve Replacement Through the Right Anterolateral Minithoracotomy Approach: A Surgeon's Experience with the First 100 Patients.

BACKGROUND: To apply the cumulative sum (CUSUM) failure analysis to assess the performance of a single surgeon during mitral valve replacement via the right anterolateral minithoracotomy (RAMT) approach and to analyse the learning curve for the procedure. METHODS: A total of 100 mitral valve replacements were performed using the RAMT approach from June 2011 to April 2013 by a single surgeon with no prior experience of this technique. Patients were divided into five blocks according to the operation date. The perioperative data were collected prospectively and analysed using descriptive statistics and CUSUM failure analysis. RESULTS: No significant differences in the background factors among the five periods were observed, except for a small increase in patient age from periods 1 to 5 (p=0.004). The surgeon's performance improved with time; a decrease in the cross-clamp time, operative time, and blood loss was observed (p<0.001). However, no significant difference in the number of failed cases was observed among the periods. All failure cases were evaluated by the CUSUM failure analysis and the CUSUM curve reflected a learning curve associated with this new procedure. The surgeon crossed the lower 80% boundary after about 33 operations, which indicates that better results can be obtained after this point. CONCLUSIONS: Minimally invasive mitral valve surgery using the RAMT approach can be performed by a new surgeon. Furthermore, CUSUM curve analysis is a simple statistical method to implement continuous individual performance monitoring.

Overexpression of CDCA7 predicts poor prognosis and induces EZH2-mediated progression of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with high proliferative and metastatic phenotypes. CDCA7, a new member of the cell division cycle associated family of genes, is involved in embryonic development and dysregulated in various types of human cancer. However, the biological role and molecular mechanism of CDCA7 in TNBC have not been defined. Herein, we found that CDCA7 was preferentially and markedly expressed in TNBC cell lines and tissues. High expression of CDCA7 was associated with metastatic relapse status and predicted poorer disease-free survival in patients with TNBC. We observed that CDCA7 silencing in TNBC cell lines effectively impaired cell proliferation, invasion and migration in vitro. Importantly, depletion of CDCA7 strongly reduced the tumorigenicity and distant colonization capacities of TNBC cells in vivo. Furthermore, CDCA7 increased the expression of EZH2, a marker of aggressive breast cancer that is involved in tumor progression, by enhancing the transcriptional activity of its promoter. This increase in EZH2 expression was essential for the CDCA7-mediated effects on TNBC progression. Finally, our immunohistochemical analysis revealed that the CDCA7/EZH2 axis was clinical relevant. These findings suggest CDCA7 plays a crucial role in TNBC progression by transcriptionally upregulating EZH2 and might be a potential prognostic factor and therapeutic target in TNBC.