LOXL2-induced PEAR1 Ser891 phosphorylation suppresses CD44 degradation and promotes triple-negative breast cancer metastasis.

CD44 is associated with a high risk of metastasis, recurrence, and drug resistance in various cancers. Here we report that platelet endothelial aggregation receptor 1 (PEAR1) is a CD44 chaperone protein that protected CD44 from endocytosis-mediated degradation and enhances cleavage of the CD44 intracellular domain (CD44-ICD). Furthermore, we found that lysyl oxidase-like protein 2 (LOXL2), an endogenous ligand of PEAR1, bound to the PEAR1-EMI domain and facilitated the interaction between PEAR1 and CD44 by inducing PEAR1 Ser891 phosphorylation in a manner that was independent of its enzyme activity. Levels of PEAR1 protein and PEAR1 phosphorylation at Ser891 were increased in patients with triple-negative breast cancer (TNBC), were positively correlated with expression of LOXL2 and CD44, and were negatively correlated with overall survival. The level of PEAR1 Ser891 phosphorylation was identified as the best independent prognostic factor in TNBC patients. The prognostic efficacy of the combination of PEAR1 phosphorylation at Ser891 and CD44 expression was superior to that of PEAR1 phosphorylation at Ser891 alone. Blocking the interaction between LOXL2 and PEAR1 with monoclonal antibodies significantly inhibited TNBC metastasis, representing a promising therapeutic strategy for TNBC.

Limbal stem cells carried by a four-dimensional -printed chitosan-based scaffold for corneal epithelium injury in diabetic rabbits.

Methods: Herein, we obtained and characterized deltaN p63- and adenosine triphosphate-binding cassette subfamily G member 2-expressing limbal stem cells (LSCs). Chitosan and carboxymethyl chitosan (CTH) were cross-linked to be an in situ thermosensitive hydrogel (ACH), which was printed through four-dimensional (4D) printing to obtain a porous carrier with uniform pore diameter (4D-CTH). Rabbits were injected with alloxan to induce diabetes mellitus (DM). Following this, the LSC-carrying hydrogel was spread on the surface of the cornea of the diabetic rabbits to cure corneal epithelium injury. Results: Compared with the control group (LSCs only), rapid wound healing was observed in rabbits treated with LSC-carrying 4D-CTH. Furthermore, the test group also showed better corneal nerve repair ability. The results indicated the potential of LSC-carrying 4D-CTH in curing corneal epithelium injury. Conclusion: 4D-CTH holds potential as a useful tool for studying regenerative processes occurring during the treatment of various diabetic corneal epithelium pathologies with the use of stem cell-based technologies.

The role of PALLD-STAT3 interaction in megakaryocyte differentiation and thrombocytopenia treatment.

Impaired differentiation of megakaryocytes constitutes the principal etiology of thrombocytopenia. The signal transducer and activator of transcription 3 (STAT3) is a crucial transcription factor in regulating megakaryocyte differentiation, yet the precise mechanism of its activation remains unclear. PALLD, an actin-associated protein, has been increasingly recognized for its essential functions in multiple biological processes. This study revealed that megakaryocyte/plateletspecific knockout of PALLD in mice exhibited thrombocytopenia due to diminished platelet biogenesis. In megakaryocytes, PALLD deficiency led to impaired proplatelet formation and polyploidization, ultimately weakening their differentiation for platelet production. Mechanistic studies demonstrated that PALLD bound to STAT3 and interacted with its DNA-binding domain (DBD) and Src homology 2 (SH2) domain via Immunoglobulin domain 3 (Ig3). Moreover, the absence of PALLD attenuated STAT3 Y705 phosphorylation and impeded STAT3 nuclear translocation. Based on the PALLD-STAT3 binding sequence, we designed a peptide C-P3, which can facilitate megakaryocyte differentiation and accelerate platelet production in vivo. In conclusion, this study highlights the pivotal role of PALLD in megakaryocyte differentiation and proposes a novel approach for treating thrombocytopenia by targeting the PALLD-STAT3 interaction.

Anti-angiogenesis agents plus chemoradiotherapy for locally advanced nasopharyngeal cancer: a systematic review and meta-analysis.

PURPOSE: To evaluate literature evidences about the efficacy and safety of anti-angiogenesis agents plus chemoradiotherapy versus chemoradiotherapy in the treatment of locally advanced nasopharyngeal carcinoma. METHODS: The relevant literature was systematically searched from the date of establishment to April 2023 in PubMed, Embase, Web of Science, The Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Biological Medicine, Wanfang and VIP database. Search terms included: Nasopharyngeal Neoplasms, Angiogenesis inhibitors, Endostar, Anlotinib, Apatinib, Bevacizumab, Sunitinib, Pazopanib, Chemoradiotherapy. The literature was strictly screened according to the inclusion and exclusion criteria, and 8 eligible studies were finally included in our meta-analysis (4 randomized controlled trials and 4 retrospective studies). RESULTS: A total of 642 patients were included, with 316 in the anti-angiogenesis agents plus chemoradiotherapy group and 326 in the chemoradiotherapy group. The results of our meta-analysis showed that compared with chemoradiotherapy group, the complete response rate (RR = 1.35, 95% CI 1.05-1.74, P = 0.02), objective response rate (RR = 1.26, 95% CI 1.12-1.43, P = 0.0002) in the anti-angiogenesis agents plus chemoradiotherapy group were significantly improved. In terms of safety, there was a higher incidence of cardiac arrhythmia (RR = 3.63, 95% CI 1.16-11.37, P = 0.03) and hypertension (RR = 1.85, 95% CI 1.04-3.27, P = 0.004) in the anti-angiogenesis agents plus chemoradiotherapy group, while no statistically significant differences were reported in other adverse reactions (all P > 0.05). CONCLUSION: Compared with chemoradiotherapy, anti-angiogenesis agents plus chemoradiotherapy could bring more benefits in terms of short-term efficacy, particularly by notably improving both complete response rate and objective response rate, and overall adverse reactions were acceptable. Anti-angiogenesis agents plus chemoradiotherapy may provide a promising direction for the treatment of locally advanced nasopharyngeal carcinoma. SYSTEMATIC REVIEW REGISTRATION: https://inplasy.com/inplasy-2023-8-0076/ , registration number INPLASY202380076.

Triglyceride-glucose body mass index predicts prognosis in patients with ST-elevation myocardial infarction.

Triglyceride glycemic-body mass index (TyG-BMI) is a simple and reliable surrogate for insulin resistance (IR). However, it is still unclear if TyG-BMI has any predictive value in patients having percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). The purpose of this study was to examine the TyG-BMI index's prognostic significance and predictive power in patients with STEMI. The study comprised a total of 2648 consecutive STEMI patients who underwent PCI. The primary endpoint was the occurrence of major adverse cardiovascular events (MACE), defined as the combination of all-cause death, nonfatal myocardial infarction, nonfatal stroke, and coronary revascularization. The TyG-BMI index was formulated as ln [fasting triglycerides (mg/dL) × fasting plasma glucose (mg/dL)/2] × BMI. 193 patients in all experienced MACE over a median follow-up of 14.7 months. There was a statistically significant difference between the Kaplan-Meier survival curves for the TyG-BMI index tertiles (log-rank test, p = 0.019) for the cumulative incidence of MACE. The adjusted HRs for the incidence of MACE in the middle and highest quartiles of the TyG-BMI index compared with the lowest quartile were 1.37 (95% CI 0.92, 2.03) and 1.53 (95% CI 1.02, 2.29), respectively, in the fully adjusted Cox regression model. At six months, one year, and three years, the TyG-BMI area under the curve (AUC) for predicting MACE was 0.691, 0.666, and 0.637, respectively. Additionally, adding the TyG-BMI index to the risk prediction model enhanced outcome prediction. In STEMI patients undergoing PCI, TyG-BMI was independently linked to MACE. TyG-BMI could be a simple and solid way to assess MACE risk and prognosis.

Utilizing AAV-mediated LEAPER 2.0 for programmable RNA editing in non-human primates and nonsense mutation correction in humanized Hurler syndrome mice.

BACKGROUND: The endogenous adenosine deaminases acting on RNA (ADAR) have been harnessed to facilitate precise adenosine-to-inosine editing on RNAs. However, the practicability of this approach for therapeutic purposes is still ambiguous due to the variable expression of intrinsic ADAR across various tissues and species, as well as the absence of all-encompassing confirmation for delivery methods. RESULTS: In this study, we demonstrate that AAV-mediated delivery of circular ADAR-recruiting RNAs (arRNAs) achieves effective RNA editing in non-human primates at dosages suitable for therapy. Within a time frame of 4 to 13 weeks following infection, the editing efficiency in AAV-infected cells can reach approximately 80%, with no discernible toxicity, even at elevated dosages. In addition, when AAV-delivered circular arRNAs are systematically administered to a humanized mouse model of Hurler syndrome, it rectifies the premature stop codon precisely and restores the functionality of IDUA enzyme encoded by the Hurler causative gene in multiple organs. CONCLUSIONS: These discoveries considerably bolster the prospects of employing AAV-borne circular arRNAs for therapeutic applications and exploratory translational research.

Branched-chain amino acids promote thrombocytopoiesis by activating mTOR signaling.

BACKGROUND: Megakaryocyte differentiation and platelet production disorders are the main causes of thrombocythemia and thrombocytopenia and lead to thrombosis or hemorrhage. Branched-chain amino acids (BCAAs) are essential nutrients that regulate important metabolic signals. BCAA administration could also increase platelet activation and promote the risk of thrombosis. OBJECTIVES: To unveil the role of BCAAs in thrombocytopoiesis. METHODS: BCAA-fed mice and megakaryocyte/platelet-specific branched-chain α-keto acid dehydrogenase E1α subunit-deficient mice were used to study the role of BCAAs in thrombocytopoiesis. RESULTS: In this study, we found that BCAA diet could facilitate megakaryocyte differentiation and platelet production. Meanwhile, megakaryocyte/platelet-specific branched-chain α-keto acid dehydrogenase E1α subunit-deficient mice developed thrombocythemia, which was mainly caused by the excessive differentiation of megakaryocytes and proplatelet biogenesis. Moreover, the use of BT2, the agonist of BCAA catabolism, could affect proplatelet formation (PPF) and megakaryocyte polyploidization, as well as ameliorating the thrombocythemia of BCAA-fed mice. CONCLUSION: We found that deficiency in BCAA catabolism led to the activation of p70S6K/mammalian target of rapamycin (mTOR) signaling, megakaryocyte over differentiation, and the acceleration of PPF. Activating BCAA metabolism with BT2 could inhibit mTOR signaling, reduce PPF, and ameliorate thrombocythemia in BCAA-fed mice. Therefore, this study reveals a novel role of BCAAs in megakaryocyte differentiation and platelet production, suggesting that targeting BCAA-mediated p70S6K/mTOR signaling may be a potential strategy for the treatment of thrombocytopenia or thrombocythemia.

Mode-independent thermo-optic switch based on the total-internal-reflection effect.

A broadband mode-independent thermo-optic (TO) switch using the total-internal-reflection (TIR) effect is proposed and experimentally demonstrated on a polymer waveguide platform. By optimizing geometric parameters of the TIR switch, a mode-independent TO switching function with a large bandwidth and extinction ratio can be realized for E11, E12, and E21 modes. The measurement results show an extinction ratio larger than 18.1 dB with a driving power of 160 mW for each mode over the wavelength range of 1500-1620 nm. The designed structure can also be cascaded to form a 1 × N switch network for mode-division multiplexing (MDM) systems, which greatly improves the network flexibility.

Mitochondrial folate metabolism-mediated α-linolenic acid exhaustion masks liver fibrosis resolution.

Sustainable TGF-ß1 signaling drives organ fibrogenesis. However, the cellular adaptation to maintain TGF-ß1 signaling remains unclear. In this study, we revealed that dietary folate restriction promoted the resolution of liver fibrosis in mice with nonalcoholic steatohepatitis. In activated hepatic stellate cells, folate shifted toward mitochondrial metabolism to sustain TGF-ß1 signaling. Mechanistically, nontargeted metabolomics screening identified that α-linolenic acid (ALA) is exhausted by mitochondrial folate metabolism in activated hepatic stellate cells. Knocking down serine hydroxymethyltransferase 2 increases the bioconversion of ALA to docosahexaenoic acid, which inhibits TGF-ß1 signaling. Finally, blocking mitochondrial folate metabolism promoted liver fibrosis resolution in nonalcoholic steatohepatitis mice. In conclusion, mitochondrial folate metabolism/ALA exhaustion/TGF-ßR1 reproduction is a feedforward signaling to sustain profibrotic TGF-ß1 signaling, and targeting mitochondrial folate metabolism is a promising strategy to enforce liver fibrosis resolution.

1 × 2 mode-independent polymeric thermo-optic switch based on a Mach-Zehnder interferometer with a multimode interferometer.

We present the design and performances of a broadband 1 × 2 mode-independent thermo-optic (TO) switch based on Mach-Zehnder interferometer (MZI) with multimode interferometer (MMI). The MZI adopts a Y-branch structure as the 3-dB power splitter and a MMI as the coupler, which are designed to be insensitive to the guided modes. By optimizing the structural parameters of the waveguides, mode-independent transmission and switching functions for E11 and E12 modes can be implemented in the C + L band, and the mode content of the outputs is the same as the mode content of the inputs. We proved the working principle of our design based on polymer platform, which was fabricated by using ultraviolet lithography and wet-etching methods. The transmission characteristics for E11 and E12 modes were also analyzed. With the driving power of 5.9 mW, the measured extinction ratios of the switch for E11 and E12 modes are larger than 13.3 dB and 13.1 dB, respectively, over a wavelength range of 1530 nm to 1610 nm. The insertion losses of the device are 11.7 dB and 14.2 dB for E11 and E12 modes, respectively, at 1550 nm wavelength. The switching times of the device are less than 840 µs. The presented mode-independent switch can be applied in reconfigurable mode-division multiplexing systems.

Survival and complications after neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy for locally advanced gastric cancer: a systematic review and meta-analysis.

Background: There is increasing evidence that neoadjuvant chemoradiotherapy is superior to neoadjuvant chemotherapy for patients with locally advanced gastric cancer. However, a number of studies have come to the opposite conclusion. Therefore, our meta-analysis is to evaluate the efficacy and safety of neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy in the treatment of locally advanced gastric cancer. Methods: We searched Wanfang Database, China National Knowledge Network database, VIP database, China Biomedical Literature Database, PubMed, Embase and Cochrane Library. The searched terms included'Stomach Neoplasms', 'Neoadjuvant Therapy' and 'Chemoradiotherapy'. The retrieval time was from the establishment of the corresponding database to September 2022, and our meta-analysis was performed using RevMan (version 5.3) and Stata (version 17) software. Results: A total of 17 literatures were included, which involved 7 randomized controlled trials and 10 retrospective studies, with a total of 6831 patients. The results of meta-analysis showed that compared with NACT group, the complete response rate(RR=1.95, 95%CI 1.39-2.73, p=0.0001), the partial response rate(RR=1.44, 95%CI 1.22-1.71, p=0.0001), the objective response rate(RR=1.37, 95%CI 1.27-1.54, p=0.00001), the pathologic complete response rate(RR=3.39, 95%CI 2.17-5.30, p=0.00001), the R0 resection rate(RR=1.18, 95%CI 1.09-1.29, p=0.0001) and 3-year overall survival rate(HR=0.89, 95%CI 0.82-0.96, p=0.002) of neoadjuvant chemoradiotherapy group were significantly improved. The results of subgroup analyses of gastric cancer subgroup and gastroesophageal junction cancer subgroup were consistent with the overall results. Meanwhile, the stable disease(RR=0.59, 95%CI:0.44-0.81, P=0.0010) of neoadjuvant chemoradiotherapy group was lower than that of neoadjuvant chemotherapy group, and there were no statistical significance in the progressive disease rate(RR=0.57, 95%CI:0.31-1.03, P=0.06), five-year overall survival rate(HR=1.03, 95%CI:0.99-1.07, P=0.839), postoperative complications and adverse reactions between the neoadjuvant chemoradiotherapy group and neoadjuvant chemotherapy group. Conclusion: Compared with neoadjuvant chemotherapy, neoadjuvant chemoradiotherapy might bring more survival benefits without significantly increasing adverse reactions. neoadjuvant chemoradiotherapy may be a recommended treatment for patients with locally advanced gastric cancer. Systematic Review Registration: https://inplasy.com/inplasy-2022-12-0068/, identifier INPLASY202212068.

[Overview of Status of Medical Device Registration and Quality Evaluation Requirements for Clinical Mass Spectrometry].

Mass spectrometry technology is becoming an important tool for clinical analysis due to its high specificity, high sensitivity and high multi-component detection capability. The current applications of this technology are mainly in liquid chromatography-tandem mass spectrometry (LC-MS/MS), matrix-assisted laser desorptionionization time-of-flight mass spectrometry (MALDI-TOF-MS), inductively coupled plasma mass spectrometry (ICP-MS), gas chromatography-mass spectrometry (GC-MS) and the related in vitro diagnostic kits. At present, the number of medical device (MD) based on mass spectrometry technology is growing rapidly, especially the number of LC-MS/MS and MALDI-TOF-MS registered MD products, and the standardization of relevant product quality requirements is also being effectively carried out. In general, clinical mass spectrometry equipment is still mainly imported, and the equipment price is relatively high. The development of mass spectrometry kits is mainly based on imported platforms, and domestic equipment is still in its infancy; the further promotion of clinical application of mass spectrometry also depends on the progress of the automation and standardization of the analysis procedure. To investigate the detection performance of mass spectrometry systems, it is necessary to fully consider the characteristics of mass spectrometry technology itself.

Sympathetic ß2-adrenergic receptor blockade overcomes docetaxel resistance in prostate cancer.

PURPOSE: Due to the limited effective therapies, resistance to docetaxel is ordinarily fatal and remains a critical clinical challenge.ß2-adrenergic receptor(ß2-AR)can promote the metastasis and invasion of prostate cancer, but the role in chemotherapy-resistant prostate cancer remains unclear. METHODS: By downloading the GEO database in NCBI, the expression of ß2-AR in different prostate tissues was analyzed. We constructed docetaxel-resistant prostate cancer cell lines by the method of dose-escalation. LC3B-labeled stable cells and shAtg5 knockdown stable cells were constructed by lentivirus infection. The molecular mechanism of ß2-AR affecting docetaxel sensitivity through apoptosis and autophage were investigated by flow cytometry, mitochondrial membrane potential and western blot. Then we detected the interaction between autophagy and apoptotic by performing immunoprecipitation assay. RESULTS: We show that restraining the activity of ß2-AR sensitized the cell response and reduced the resistance to docetaxel. The mechanism involves the regulation of ß2-AR in the cellular response to docetaxel through apoptosis and autophagy via caspase signaling and Atg5/AMPK/mTOR pathway as well as the effect of ß2-AR on the crosstalk between apoptosis and autophagy via p38 MAPK and JNK/c-Jun/FOXO3a signaling pathways. CONCLUSION: Our data demonstrate that ß2-AR inhibitor-induced autophagy and apoptosis contribute to the effectiveness responses to docetaxel in castration-resistant prostate cancer, and in combination with pharmacological agents of ß2-AR and autophagy inhibitors may provide a potential therapeutic strategy to enhance the limited capacity of docetaxel to control castration-resistant prostate cancer.

Nimotuzumab combined with chemoradiotherapy for the treatment of cervical cancer: A meta-analysis of randomized controlled trials.

Objectives: To assess the clinical efficacy and toxicity of nimotuzumab in combination with chemoradiotherapy or chemoradiotherapy alone in the treatment of cervical cancer. Methods: The PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, China Biomedical Medicine, Wanfang, and VIP databases were systematically searched for relevant literature. Ultimately, six randomised controlled trials (n=393) were included in our meta-analysis. Results: A total of 393 patients were included, of which 197 were in the nimotuzumab combined with chemoradiotherapy group and 196 were in the chemoradiotherapy group. The results of our meta-analysis showed that the complete remission rate (risk ratio [RR] = 1.34, 95% confidence interval [CI]: 1.08-1.65, P = 0.007), objective response rate (RR = 1.30, 95% CI: 1.16-1.44, P < 0.05), and three-year survival rate (RR = 1.27, 95% CI: 1.06-1.51, P = 0.008) in the nimotuzumab combined with chemoradiotherapy group were significantly improved compared with the chemoradiotherapy group. This difference was not statistically significant when comparing the incidence of adverse reactions (such as leukocytopenia, gastrointestinal reaction, radiocystitis, and radioproctitis) between the two groups. Conclusions: Nimotuzumab in combination with chemoradiotherapy has some advantages over chemoradiotherapy alone in the treatment of cervical cancer and does not increase toxicity. Therefore, nimotuzumab has the potential to be an effective treatment for cervical cancer; however, further evidence from large-scale randomised controlled trials is needed.

GITRL impairs the immunosuppressive function of MDSCs via PTEN-mediated signaling pathway in experimental Sjögren syndrome.

BACKGROUND: Recent studies have revealed a role of the ligand for glucocorticoid-induced TNFR family-related protein (GITRL) in mediating functional dysregulations of myeloid-derived suppressor cells (MDSCs) in the pathogenesis of primary Sjögren syndrome (pSS), but the underlying molecular mechanism is largely unclear. In this study, we aimed to elucidate GITRL-mediated signaling pathways in MDSCs during the development of experimental SS (ESS). METHODS: MDSCs were stimulated with recombinant GITRL, the activation of PTEN, AKT and STAT3 in MDSCs was analyzed by Western blot. MDSCs with different treatment were adoptively transferred to ESS mice. ELISA was used to detect the level of autoantibodies. Proportions of Th1 and Th17 cells were examined by flow cytometry. Histological evaluation of glandular destruction was analyzed by hematoxylin and eosin (HE) staining. The interaction of GITR, TRAF3 and PP2A was detected by CoIP. RESULTS: Upon the engagement of GITR on MDSCs, PTEN was activated and led to the inhibition of downstream AKT/STAT3 signaling pathway, therefore, resulting in the impaired immunosuppressive function of MDSCs. In ESS mice, blocking the activity of PTEN could efficiently restore the immunomodulatory effect of MDSCs and alleviate the progression of ESS. Furthermore, TRAF3 was found to bind to GITR, and then recruited PP2A to dephosphorylate PTEN, thus enhancing the activity of PTEN. CONCLUSION: This study elucidated the molecular mechanism underlying the effect of GITRL in regulating the function of MDSCs, which may provide a new therapeutic target for the treatment of pSS.

Mode-selective modulator and switch based on graphene-polymer hybrid waveguides.

The mode-division multiplexing (MDM) is an effective technology with huge development potential to improve the transmission capacity of optical communication system by transmitting multiple modes simultaneously in a few-mode fiber. In traditional MDM technology, the fundamental modes of multiple channels are usually modulated by external individual arranged electro-optic modulators, and then multiplexed into the few-mode fiber or waveguide by a mode multiplexer. However, this is usually limited by large device footprint and high power consumption. Here, we report a mode-selective modulator and switch to individually modulate or switch the TE11, TE12 and TE21 modes in a few-mode waveguide (FMW) to overcome this limitation. Our method is based on the graphene-polymer hybrid platform with four graphene capacitors buried in different locations of the polymer FMW by utilizing the coplanar interaction between the capacitors and spatial modes. The TE11, TE12 and TE21 modes in the FMW can be modulated and switched separately or simultaneously by applying independent gate voltage to different graphene capacitor of the device. Our study is expected to make the selective management of the spatial modes in MDM transmission systems more flexible.

Ultra-Broadband and Compact TM-Pass Polarizer Based on Graphene-Buried Polymer Waveguide.

We report an ultra-broadband and compact TM-pass polarizer based on graphene-buried polymer waveguides. The characteristic parameters of the polarizer were carefully designed and optimized. The standard microfabrication processes were employed to fabricate the device. The presented polarizers exhibit high polarization-dependent transmission imposing a TE mode cutoff while leaving the TM mode almost unaffected. We experimentally demonstrated the polarizer that has an ultra-high extinction ratio of more than 22.9 dB and 41.9 dB for the monolayer graphene film placed on the surface of core layer and buried in the center of core layer, respectively, and as low insertion loss as ~4.0 dB for the TM mode with the bandwidth over 110 nm. The presented polarizer has the advantages of high extinction ratio, ultra-broadband, low cost, and easy integration with other polymer-based planar lightwave devices.

Small molecule targeting CELF1 RNA-binding activity to control HSC activation and liver fibrosis.

CUGBP Elav-like family member 1 (CELF1), an RNA-binding protein (RBP), plays important roles in the pathogenesis of diseases such as myotonic dystrophy, liver fibrosis and cancers. However, targeting CELF1 is still a challenge, as RBPs are considered largely undruggable. Here, we discovered that compound 27 disrupted CELF1-RNA binding via structure-based virtual screening and biochemical assays. Compound 27 binds directly to CELF1 and competes with RNA for binding to CELF1. Compound 27 promotes IFN-γ secretion and suppresses TGF-ß1-induced hepatic stellate cell (HSC) activation by inhibiting CELF1-mediated IFN-γ mRNA decay. In vivo, compound 27 attenuates CCl4-induced murine liver fibrosis. Furthermore, the structure-activity relationship analysis was performed and compound 841, a derivative of compound 27, was identified as a selective CELF1 inhibitor. In conclusion, targeting CELF1 RNA-binding activity with small molecules was achieved, which provides a novel strategy for treating liver fibrosis and other CELF1-mediated diseases.

Androgen deprivation therapy and radiotherapy in intermediate-risk prostate cancer: A systematic review and meta-analysis.

Objectives: Androgen deprivation therapy combined with radiotherapy for intermediate-risk prostate cancer is still a matter of debate. We conducted a meta-analysis to evaluate the necessity of androgen deprivation therapy combined with radiotherapy for intermediate-risk prostate cancer patients. Methods: A comprehensive literature search of articles was performed in PubMed, Embase, Cochrane library, Web of Science, Chinese National Knowledge Infrastructure, Chinese Biological Medicine, Wanfang, and VIP Databases published between February 1988 and April 2022. Studies comparing the survival of patients diagnosed with intermediate-risk prostate cancer who were treated with androgen deprivation therapy combined with radiotherapy or radiotherapy alone were included. Data were extracted and analyzed with the RevMan software (version 5.3) and the Stata software (version 17). Results: Six randomized controlled trials and nine retrospective studies, including 6853 patients (2948 in androgen deprivation therapy combined with radiotherapy group and 3905 in radiotherapy alone group) were enrolled. Androgen deprivation therapy combined with radiotherapy did not provide an overall survival (HR 1.12, 95% CI 1.01-1.12, p=0.04) or biochemical recurrence-free survival (HR 1.23, 95% CI 1.09-1.39, P=0.001) advantage to intermediate-risk prostate cancer patients. Conclusion: Androgen deprivation therapy combined with radiotherapy did not show some advantages in terms of overall survival and biochemical recurrence-free survival and radiotherapy alone may be the effective therapy for intermediate-risk prostate cancer patients. Systematic review registration: https://inplasy.com/inplasy-2022-8-0095/, identifier 202280095.

SENP3 loss promotes M2 macrophage polarization and breast cancer progression.

Tumor-associated macrophages (TAM) play a crucial role in promoting cancer progression. Upon cytokine stimulation, TAM preferentially polarize to the anti-inflammatory and pro-tumor M2 subtype. The mechanism underlying such preferential polarization remains elusive. Here, we report that macrophage-specific deletion of the SUMO-specific protease Sentrin/SUMO-specific protease 3 promotes macrophage polarization towards M2 in bone marrow-derived macrophage (BMDM) induced by interleukin 4 (IL-4)/IL-13 and in an ex vivo model (murine Py8119 cell line), as well as in a mouse orthotopic tumor model. Notably, Sentrin/SUMO-specific protease 3 (SENP3) loss in macrophages accelerated breast cancer malignancy in ex vivo and in vivo models. Mechanistically, we identified Akt Serine/threonine kinase 1 (Akt1) as the substrate of SENP3 and found that the enhanced Akt1 SUMOylation upon SENP3 loss resulted in Akt1 hyper-phosphorylation and activation, which facilitates M2 polarization. Analysis of clinical data showed that a lower level of SENP3 in TAM has a strong negative correlation with the level of the M2 marker CD206, as well as with a worse clinical outcome. Thus, increased Akt1 SUMOylation as a result of SENP3 deficiency modulates polarization of macrophages to the M2 subtype within a breast cancer microenvironment, which in turn promotes tumor progression.