SENP2 promotes ESCC proliferation through SETDB1 deSUMOylation and enhanced fatty acid metabolism.

Esophageal squamous cell carcinoma (ESCC) has a poor prognosis, and its metabolic reprogramming mechanism remains unclear. Small ubiquitin-like modifier(SUMO) -specific protease(SENP2) is highly related to fatty acids metabolism in some normal tissue. Thus, this study investigates the correlation between SENP2 and ESCC, and the possible mechanism. SENP2 expression was up-regulated in ESCC tissues compared to normal tissues, with high levels associated with poor overall survival rates. Knockdown of SENP2 inhibited ESCC proliferation, fatty acid uptake, and oxidation in vitro. RNA-seq indicated that SENP2 upregulated PPARγ, CPT1A, ACSL1, and CD36, through the deSUMOylation of SETDB1. SENP2 promotes ESCC proliferation and enhances fatty acid uptake and oxidation. High expression of SENP2 may be a poor prognostic biomarker for ESCC patients.

Sample Fabrication of BiOCl Nanosheets with Low Specific Surface Area for Efficient Photocatalytic Degradation of Organic Wastewater.

BiOCl photocatalyst with excellent performance has been prepared by a simple liquid-solid phase transition method. Three BiOCl-x (x = 0.5, 0.75, 1.0) photocatalysts were obtained by changing the amount of HCl in the preparation process. The main dominant crystal planes are (001), (002), and (003). Their forbidden bandwidths are reduced to 2.81, 2.89, and 2.84 eV. The samples were characterized by X-ray diffractometer, high-resolution field emission scanning electron microscopy, transmission electron microscopy, high-resolution transmission electron microscopy, X-ray photoelectron spectroscopy, Fourier infrared spectrometry, UV-vis diffuse reflection spectrometer, and UV-vis spectrophotometer. The degradation mechanism of BiOCl-x on Rhodamine B(RhB) has been investigated by quenching experiments on active materials. ·O2- was the primary degradation agent. When the dosage of HCl was 0.75 mL, the degradation effect of RhB was the best under the same experimental conditions. In visible light, RhB was almost completely degraded within 15 min, demonstrating an excellent photocatalytic degradation efficiency.

Suppressing SENP1 inhibits esophageal squamous carcinoma cell growth via SIRT6 SUMOylation.

PURPOSE: Esophageal squamous cell carcinoma (ESCC) is a prevalent tumor in the gastrointestinal tract, but our understanding of the molecular mechanisms underlying ESCC remains incomplete. Existing studies indicate that SUMO specific peptidase 1 (SENP1) plays a crucial role in the development and progression of various malignant tumors through diverse molecular mechanisms. However, the functional mechanism and clinical implications of SENP1 in the progression of ESCC remain unclear. METHODS: Bulk RNA-Sequencing (RNA-seq) was used to compare potential genes in the esophageal tissues of mice with ESCC to the control group. The up-regulated SENP1 was selected. The protein level of SENP1 in ESCC patient samples was analyzed by immunohistochemistry and western blot. The potential prognostic value of SENP1 on overall survival of ESCC patients was examined using tissue microarray analysis and the Kaplan-Meier method. The biological function was confirmed through in vitro and in vivo knockdown approaches of SENP1. The role of SENP1 in cell cycle progression and apoptosis of ESCC cells was analyzed by flow cytometry and western blot. The downstream signaling pathways regulated by SENP1 were investigated via using RNA-Seq. SENP1-associated proteins were identified through immunoprecipitation. Overexpression of Sirtuin 6 (SIRT6) wildtype and mutant was performed to investigate the regulatory role of SENP1 in ESCC progression in vitro. RESULTS: Our study discovered that SENP1 was upregulated in ESCC tissues and served as a novel prognostic factor. Moreover, SENP1 enhanced cell proliferation and migration of ESCC cell lines in vitro, as well as promoted tumor growth in vivo. Thymidine kinase 1 (TK1), Geminin (GMNN), cyclin dependent kinase 1(CDK1), and cyclin A2 (CCNA2) were identified as downstream genes of SENP1. Mechanistically, SENP1 deSUMOylated SIRT6 and subsequently inhibited SIRT6-mediated histone 3 lysine 56 (H3K56) deacetylation on those downstream genes. SIRT6 SUMOylation mutant (4KR) rescued the growth inhibition upon SENP1 depletion. CONCLUSIONS: SENP1 promotes the malignant progression of ESCC by inhibiting the deacetylase activity of SIRT6 pathway through deSUMOylation. Our findings suggest that SENP1 may serve as a valuable biomarker for prognosis and a target for therapeutic intervention in ESCC.

Boosting photo-thermal co-catalysis CO2 methanation by tuning interface electron transfer via Mott-Schottky heterojunction effect.

Photo-thermal co-catalytic reduction of CO2 to synthesize value-added chemicals presents a promising approach to addressing environmental issues. Nevertheless, traditional catalysts exhibit low light utilization efficiency, leading to the generation of a reduced number of electron-hole pairs and rapid recombination, thereby limiting catalytic performance enhancement. Herein, a Mott-Schottky heterojunction catalyst was developed by incorporating nitrogen-doped carbon coated TiO2 supported nickel (Ni) nanometallic particles (Ni/x-TiO2@NC). The optimal Ni/0.5-TiO2@NC sample displayed a conversion rate of 71.6 % and a methane (CH4) production rate of 65.3 mmol/(gcat·h) during photo-thermal co-catalytic CO2 methanation under full-spectrum illumination, with a CH4 selectivity exceeding 99.6 %. The catalyst demonstrates good stability as it shows no decay after two reaction cycles. The Mott-Schottky heterojunction catalysts display excellent efficiency in separating photo-generated electron-hole pairs and elevate the catalysts' temperature, thus accelerating the reaction rate. The in-situ experiments revealed that light-induced electron transfer effectively facilitates H2 dissociation and enhances surface defects, thereby promoting CO2 adsorption. This study introduces a novel approach for developing photo-thermal catalysts for CO2 reduction, aiming to enhance solar energy utilization and facilitate interface electron transfer.

Perioperative Outcomes and Survival after Neoadjuvant Immunochemotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma.

OBJECTIVE: This study aimed to compare the difference in perioperative outcomes and prognosis between neoadjuvant immunochemotherapy (nICT) and neoadjuvant chemoradiotherapy (nCRT) for locally advanced esophageal squamous cell carcinoma (LA-ESCC). METHODS: The LA-ESCC patients receiving nICT or nCRT were identified from a prospectively maintained database at Zhongshan Hospital of Fudan University between Jan 2018 and March 2022. Propensity score matching (PSM) was performed to balance the two groups. RESULTS: A total of 124 patient pairs were enrolled in the final analysis. The complete pathological response rate (20.2% vs. 29.0%, p=0.140) was similar in the two groups while the lower major pathological response rate (44.4% vs. 61.3%, p=0.011) was observed in the nICT group. nICT was associated with a lower rate of adverse events (42.7% vs. 55.6%, p=0.047) without additional postoperative complications (38.7% vs. 35.5%, p=0.693). The nICT group had lower distant metastasis (6.5% vs. 16.1%, p=0.027) and overall recurrence (11.3% vs. 23.4%, p=0.019) in the postoperative 1 year. Also, nICT was associated with better progression-free survival (HR=0.50; 95% CI: 0.32-0.77; p=0.002). Cox proportional hazard analysis showed that nICT (univariable: HR=0.55; 95% CI: 0.37-0.82; p=0.003; multivariable: HR=0.44; 95% CI: 0.29-0.65; p<0.001) was one of the independent prognostic factors for progression-free survival. The two groups had similar overall survival (HR=0.62; 95%CI: 0.36-1.09; p=0.094) at the latest follow-up. CONCLUSION: This retrospective study showed that nICT was safe and effective for LA-ESCC patients. Further verification is needed in the randomized controlled trials.

Regulating Spin Density using TEMPOL Molecules for Enhanced CO2-to-Ethylene Conversion by HKUST-1 Framework Derived Electrocatalysts.

The selectivity of multicarbon products in the CO2 reduction reaction (CO2RR) depends on the spin alignment of neighboring active sites, which requires a spin catalyst that facilitates electron transfer with antiparallel spins for enhanced C-C coupling. Here, we design a radical-contained spin catalyst (TEMPOL@HKUST-1) to enhance CO2-to-ethylene conversion, in which spin-disordered (SDO) and spin-ordered (SO) phases co-exist to construct an asymmetric spin configuration of neighboring active sites. The replacement of axially coordinated H2O molecules with TEMPOL radicals introduces spin-spin interactions among the Cu(II) centers to form localized SO phases within the original H2O-mediated SDO phases. Therefore, TEMPOL@HKUST-1 derived catalyst exhibited an approximately two-fold enhancement in ethylene selectivity during the CO2RR at -1.8 V versus Ag/AgCl compared to pristine HKUST-1. In situ ATR-SEIRAS spectra indicate that the spin configuration at asymmetric SO/SDO sites significantly reduces the kinetic barrier for *CO intermediate dimerization toward the ethylene product. The performance of the spin catalyst is further improved by spin alignment under a magnetic field, resulting in a maximum ethylene selectivity of more than 50 %. The exploration of the spin-polarized kinetics of the CO2RR provides a promising path for the development of novel spin electrocatalysts with superior performance.

Research on comprehensive analysis of patient comfort and complication rate using haemodialysis indwelling needles in AVF puncture in haemodialysis treatment.

Traditional needles for haemodialysis access can cause complications and discomfort. Indwelling needles may have advantages, but their efficacy needs to be investigated. Our study sought to compare the safety and efficacy of indwelling needles to traditional needles for haemodialysis access. A single-center retrospective study at the Pingyang County Hospital of Traditional Chinese Medicine included 70 haemodialysis patients. The intervention group used indwelling needles, whereas the control group used traditional needles. The rate of complications, limb mobility, blood chemistry, puncture success rates, operation times, haemostasis times, pain and comfort scores, and internal fistula failure rates were all compared. Overall, complication rates were slightly higher in the control group, but not statistically significant. Both groups improved their limb mobility and blood chemistry, but there were no significant differences. The intervention group had significantly higher puncture success rates (88.4% vs. 80.0%), shorter operation times (65.4 vs. 72.3 seconds), and faster haemostasis times (23.7 vs. 28.2 seconds) than the control group. Patients in the intervention group experienced less pain (3.7 vs. 4.2) and more comfort (8.1 vs. 7.5). The intervention group had slightly lower internal fistula failure rates (2.9% vs. 5.7%), but the difference was not statistically significant. Indwelling needles appear to improve puncture efficiency and patient comfort during hemodialysis.

K2CO3-Catalyzed (3 + 2) Cycloaddition Reaction of N-2,2,2-Trifluoroethylisatin Ketimines with Azodicarboxylates: Access to Spirooxindoles Containing Trifluoromethyl-1,2,4-triazolines.

Potassium carbonate-catalyzed (3 + 2) cycloaddition reaction between N-2,2,2-trifluoroethylisatin ketimines and azodicarboxylates has been developed, constructing a series of novel N-heterocycle infused spirooxindoles in good to excellent yields (up to 98%) under milder conditions. The presence of both biologically active oxindole and trifluoromethyl-1,2,4-triazoline moieties in these novel spirocyclic compounds would provide new lead structures in the discovery of heterocyclic compounds with potential pharmaceutical activities.

Sirtuin 6 ameliorates bleomycin-induced pulmonary fibrosis via activation of lipid catabolism.

Pulmonary fibrosis is a chronic and serious interstitial lung disease with little effective therapies currently. Our incomplete understanding of its pathogenesis remains obstacles in therapeutic developments. Sirtuin 6 (SIRT6) has been shown to mitigate multiple organic fibrosis. However, the involvement of SIRT6-mediated metabolic regulation in pulmonary fibrosis remains unclear. Here, we demonstrated that SIRT6 was predominantly expressed in alveolar epithelial cells in human lung tissues by using a single-cell sequencing database. We showed that SIRT6 protected against bleomycin-induced injury of alveolar epithelial cells in vitro and pulmonary fibrosis of mice in vivo. High-throughput sequencing revealed enriched lipid catabolism in Sirt6 overexpressed lung tissues. Mechanismly, SIRT6 ameliorates bleomycin-induced ectopic lipotoxicity by enhancing lipid degradation, thereby increasing the energy supply and reducing the levels of lipid peroxides. Furthermore, we found that peroxisome proliferator-activated receptor α (PPARα) was essential for SIRT6-mediated lipid catabolism, anti-inflammatory responses, and antifibrotic signaling. Our data suggest that targeting SIRT6-PPARα-mediated lipid catabolism could be a potential therapeutic strategy for diseases complicated with pulmonary fibrosis.

Organic Dye Molecule Intercalated Vanadium Oxygen Hydrate Enables High-Performance Aqueous Zinc-Ion Storage.

Although the layered vanadium oxide-based materials have been considered to be one of the candidates for aqueous Zn-ion batteries (AZIBs), it still faces inevitable challenges of unsatisfactory capacities and sluggish kinetics because of strong electrostatic interactions between Zn-ions and structure lattice. This work addresses the strategy of pre-inserting guest materials to vanadium oxide cathode using different intercalants. To achieve this goal, the small organic dye molecules, methyl orange (MO), and methylene blue (MB) are proposed as the intercalants for vanadium oxygen hydrate (VOH). It has been demonstrated that use of these intercalants can facilitate reaction kinetics between Zn2+ and VOH, leading to an improvement of specific capacity (293 mAh g-1 at 0.3 A g-1 for MO-VOH and 311 mAh g-1 for MB-VOH) compared to VOH, a large enhancement of excellent energy density (237.1 Wh kg-1 for MO-VOH, 232.3 Wh kg-1 for MB-VOH), and a prolong lifespan operation at 3 A g-1 . The mechanism studies suggest that the weakened electrostatic interactions between the Zn-ions and V-O lattice after intercalating organic molecules contribute to boosting the electrochemical performance of AZIBs unveiled by charge density difference and binding energy.

Inhibiting NR5A2 targets stemness in pancreatic cancer by disrupting SOX2/MYC signaling and restoring chemosensitivity.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a profoundly aggressive and fatal cancer. One of the key factors defining its aggressiveness and resilience against chemotherapy is the existence of cancer stem cells (CSCs). The important task of discovering upstream regulators of stemness that are amenable for targeting in PDAC is essential for the advancement of more potent therapeutic approaches. In this study, we sought to elucidate the function of the nuclear receptor subfamily 5, group A, member 2 (NR5A2) in the context of pancreatic CSCs. METHODS: We modeled human PDAC using primary PDAC cells and CSC-enriched sphere cultures. NR5A2 was genetically silenced or inhibited with Cpd3. Assays included RNA-seq, sphere/colony formation, cell viability/toxicity, real-time PCR, western blot, immunofluorescence, ChIP, CUT&Tag, XF Analysis, lactate production, and in vivo tumorigenicity assays. PDAC models from 18 patients were treated with Cpd3-loaded nanocarriers. RESULTS: Our findings demonstrate that NR5A2 plays a dual role in PDAC. In differentiated cancer cells, NR5A2 promotes cell proliferation by inhibiting CDKN1A. On the other hand, in the CSC population, NR5A2 enhances stemness by upregulating SOX2 through direct binding to its promotor/enhancer region. Additionally, NR5A2 suppresses MYC, leading to the activation of the mitochondrial biogenesis factor PPARGC1A and a shift in metabolism towards oxidative phosphorylation, which is a crucial feature of stemness in PDAC. Importantly, our study shows that the specific NR5A2 inhibitor, Cpd3, sensitizes a significant fraction of PDAC models derived from 18 patients to standard chemotherapy. This treatment approach results in durable remissions and long-term survival. Furthermore, we demonstrate that the expression levels of NR5A2/SOX2 can predict the response to treatment. CONCLUSIONS: The findings of our study highlight the cell context-dependent effects of NR5A2 in PDAC. We have identified a novel pharmacological strategy to modulate SOX2 and MYC levels, which disrupts stemness and prevents relapse in this deadly disease. These insights provide valuable information for the development of targeted therapies for PDAC, offering new hope for improved patient outcomes. A Schematic illustration of the role of NR5A2 in cancer stem cells versus differentiated cancer cells, along with the action of the NR5A2 inhibitor Cpd3. B Overall survival of tumor-bearing mice following allocated treatment. A total of 18 PDX models were treated using a 2 x 1 x 1 approach (two animals per model per treatment); n=36 per group (illustration created with biorender.com ).

Telocytes protect against lung tissue fibrosis through hexokinase 2-dependent pathway by secreting hepatocyte growth factor.

Pulmonary fibrosis (PF) is one of the common manifestations of end-stage lung disease. Chronic lung failure after lung transplantation is mainly caused by bronchiolitis obliterans syndrome (BOS) and is mainly characterized by lung tissue fibrosis. Pulmonary epithelial-mesenchymal transformation (EMT) is crucial for pulmonary fibrosis. Telocytes (TCs), a new type of mesenchymal cells, play a protective role in various acute injuries. For exploring the anti-pulmonary fibrosis effect of TCs in the BOS model in vitro and the related mechanism, rat tracheal epithelial (RTE) cells were treated with transforming growth factor-ß (TGF-ß) to simulate lung tissue fibrosis in vitro. The RTE cells were then co-cultured with TCs primarily extracted from rat lung tissue. Western blot, Seahorse XF Analysers and enzyme-linked immunosorbent assay were used to detect the level of EMT and aerobic respiration of RTE cells. Furthermore, anti-hepatocyte growth factor (anti-HGF) antibody was exogenously added to the cultured cells to explore further mechanisms. Moreover, hexokinase 2 (HK2) in RTE cells was knocked down to assess whether it influences the blocking effect of the anti-HGF antibody. TGF-ß could induce lung tissue fibrosis in RTE cells in vitro. Nevertheless, TCs co-culture decreased the level of EMT, glucose metabolic indicators (lactate and ATP) and oxygen levels. Furthermore, TCs released hepatocyte growth factor (HGF). Therefore, the exogenous addition of anti-HGF antibody in the co-culture system blocked the anti-lung tissue fibrosis effect. However, HK2 knockdown attenuated the blocking effect of the anti-HGF antibody. In conclusion, TCs can protect against lung tissue fibrosis by releasing HGF, a process dependent on HK2.

BiOCl Nanosheets with (001), (002), and (003) Dominant Crystal Faces with Excellent Light-Degradation Ability.

Gray bismuth chloride nanosheets with a highly enhanced electric field intensity were prepared by a simple and efficient method. Their energy gap is reduced to 2.35 eV. The prepared nanosheets show high photocatalytic activity for the degradation of rhodamine B under visible light. The resulting samples were characterized by X-ray diffractometry, high-resolution scanning electron microscopy, X-ray photoelectron spectroscopy, infrared spectroscopy, UV-vis diffuse reflectance spectroscopy, specific surface area analysis, electrochemical analysis, electron paramagnetic resonance, and UV-vis spectroscopy. The photocatalytic activity of prepared BiOCl was evaluated by the degradation of RhB. The prepared BiOCl sample (0.5 g/L) could completely degrade RhB (10 mg/L) within 10 min, and its visible photocatalytic activity was 80 times that of the original white BiOCl. Superoxide radicals were the main active substance involved in organic degradation.

Neoadjuvant adebrelimab in locally advanced resectable esophageal squamous cell carcinoma: a phase 1b trial.

Overall survival (OS) benefits of neoadjuvant immunotherapy remain elusive in locally advanced esophageal squamous cell carcinomas (ESCC). Here, we reported the results of a phase 1b trial of neoadjuvant PD-L1 blockade with adebrelimab in resectable ESCC. Patients received two neoadjuvant doses of adebrelimab followed by surgery. The primary endpoints were safety and feasibility; secondary endpoints included pathologic complete response (pCR) and OS. Our data showed the primary endpoints of safety and feasibility had been met. Common treatment-related adverse events were anorexia (32%) and fatigue (16%), without grade 3 or more adverse events. Of the 30 patients enrolled in the trial, 25 underwent successful resection without surgery delay and 24% had major pathologic responses including a pCR rate of 8%. The 2-year OS was 92%. Responsive patients had an immune-enriched tumor microenvironment phenotype, whereas nonresponsive patients had greater infiltration of cancer-associated fibroblasts at baseline. Clonotypic dynamics of pre-existing intratumoral T cells was a hallmark of responsive patients. These findings provide a rational for neoadjuvant anti-PD-L1 monotherapy as a therapeutic strategy for patients with resectable ESCC. ClinicalTrials.gov identifier: NCT04215471 .

Ultrasensitive electrochemical biosensor for detection of circulating tumor cells based on a highly efficient enzymatic cascade reaction.

There has been great interest in the enzymatic cascade amplification strategy for the electrochemical detection of circulating tumor cells (CTCs). In this work, we designed a highly efficient enzymatic cascade reaction based on a multiwalled carbon nanotubes-chitosan (MWCNTs-CS) composite for detection of CTCs. A high electrochemical effective surface area was obtained for a MWCNTs-CS-modified glassy carbon electrode (GCE) for loading glucose oxidase (GOD), as well as a high loading rate and high electrical activity of the enzyme. As a 'power source', the MWCNTs-CS composites provided a strong driving power for horseradish peroxidase (HRP) on the surface of polystyrene (PS) microspheres, which acted as probes for capturing CTCs and allowed the reaction to proceed with further facilitation of electron transfer. Aptamer, CTCs, and PS microspheres with HRP and anti-epithelial cell adhesion molecule (anti-EpCAM) antibody were assembled on the MWCNTs-CS/GCE to allow for the modulation of enzyme distance at the micrometer level, and thus ultra-long-range signal transmission was made possible. An ultrasensitive response to CTCs was obtained via this proposed sensing strategy, with a linear range from 10 cell mL-1 to 6 × 106 cell mL-1 and a detection limit of 3 cell mL-1. Moreover, this electrochemical sensor possessed the capability to detect CTCs in serum samples with satisfactory accuracy, which indicated great potential for early diagnosis and clinical analysis of cancer.

SENP3 deletion promotes M2 macrophage polarization and accelerates wound healing through smad6/IκB/p65 signaling pathway.

Macrophages preferentially polarize to the anti-inflammatory M2 subtype in response to alterations in the wound microenvironment. SUMO-specific protease 3 (SENP3), a SUMO-specific protease, has been proven to regulate inflammation in macrophages by deSUMOylating substrate proteins, but its contribution to wound healing is poorly defined. Here, we report that SENP3 deletion promotes M2 macrophage polarization and accelerates wound healing in macrophage-specific SENP3 knockout mice. Notably, it affects wound healing through the suppression of inflammation and promotion of angiogenesis and collagen remodeling. Mechanistically, we identified that SENP3 knockout facilitates M2 polarization through the Smad6/IκB/p65 signaling pathway. SENP3 knockout elevated the expression of Smad6 and IκB. Moreover, Smad6 silencing enhanced the expression of p-p65 and proinflammatory cytokines while inhibiting the level of IκB. Our study revealed the essential role of SENP3 in M2 polarization and wound healing, which offers a theoretical basis for further research and a therapeutic strategy for wound healing.

CdSe@CdS quantum dot-sensitized Au/α-Fe2O3 structure for photoelectrochemical detection of circulating tumor cells.

Circulating tumor cells (CTCs) are the important biomarker for cancer diagnosis and individualized treatment. However, due to the extreme rarity of CTCs (only 1-10 CTCs are found in every milliliter of peripheral blood) high sensitivity and selectivity are urgently needed for CTC detection. Here, a sandwich PEC cytosensor for the ultrasensitive detection of CTCs was developed using the photoactive material Au NP/-Fe2O3 and core-shell CdSe@CdS QD sensitizer. In the proposed  protocol, the CdSe@CdS QD/Au NP/α-Fe2O3-sensitized structure with cascade band-edge levels could evidently promote the photoelectric conversion efficiency due to suitable light absorption and efficient electron-hole pair recombination inhibition. Additionally, a dendritic aptamer-DNA concatemer was constructed for highly efficient capture of MCF-7 cells carrying CdSe@CdS QDs, a sensitive material. The linear range of this proposed signal-on PEC sensing method was 300 cell mL-1 to 6 × 105 cell mL-1 with a detection limit of 3 cell mL-1, and it demonstrated an ultrasensitive response to CTCs. Furthermore, this PEC sensor enabled accurate detection of  CTCs in serum samples. Hence, a promising strategy for CTC detection in clinical diagnosis was developed based on CdSe@CdS QD-sensitized Au NP/α-Fe2O3-based PEC cytosensor with dendritic aptamer-DNA concatemer.

Design, synthesis and biological evaluation of pyrrolopyrimidine derivatives as novel and selective positive modulator of the small conductance Ca2+-activated K+ channels.

The type 2 small conductance Ca2+-activated K+ channels (SK2) have been considered as one of the most promising therapeutic targets for spinocerebellar ataxias type 2 (SCA2) by playing a critical role in the control of normal purkinje cells (PCs) pacemaking. Herein, a novel series of pyrrolopyrimidine derivatives were designed and synthesized from the lead compound NS13001 as subtype-selective modulators of SK channels. Among them, the halogen-substituted compound 12b (EC50 = 0.34 ± 0.044 µM) was identified with a ∼5.4-fold higher potency on potentiating SK2-a channels at submicromolar concentrations as compared to NS13001 (EC50 = 1.83 ± 0.50 µM). Furthermore, compound 12b exhibited selectivity on SK2-a/SK3 subtype by displaying 93.33 ± 3.26% efficacies on SK2-a channels, and 84.54% ± 7.49% on SK3 channels. In addition, compound 12b demonstrated the potential to cross the blood-brain barrier (BBB) with suitable pharmacokinetic properties and low cytotoxicity. Molecular docking study also unveiled the binding interactions of compound 12b with SK2-CaM protein complex. Overall, the novel pyrrolopyrimidines provide an insightful guidance for future structural optimization of SK channel agonists.

Neoadjuvant therapy with immunoagent (nivolumab) or placebo plus chemotherapy followed by surgery and adjuvant treatment in subjects with resectable esophageal squamous cell carcinoma: study protocol of a randomized, multicenter, double blind, phase II trial (NATION-2203 trial).

Background: Neoadjuvant chemotherapy (nCT) has been the recommended treatment for locally advanced esophageal squamous cell carcinoma (ESCC). The addition of programmed cell death protein 1 (PD-1) inhibitor to nCT may improve oncologic outcome and survival. However, high-level evidence of neoadjuvant immunotherapy (nIT) combined with nCT in locally advanced resectable ESCC patients are still lacking. Hence, we describe this randomized controlled trial in order to assess the efficacy and safety of neoadjuvant nivolumab in combination with chemotherapy for locally advanced (stage II-III) ESCC patients. Methods: This prospective, randomized, multicenter phase II trial aims to enroll 90 locally advanced (stage II-III) ESCC patients who will undergo nivolumab or placebo plus chemotherapy followed by surgery. Patients will be 2:1 randomized to nivolumab/chemo and placebo/chemo group by method of stratified randomization. In both arms, patients who have not achieved complete pathological complete response (pCR) will be administered with adjuvant nivolumab for up to 1 year. The primary endpoint is pCR rate and secondary endpoints include event-free survival (EFS), R0 resection rate, and adverse events (AEs). The safety will be evaluated by AEs, grading by Common Terminology Criteria for Adverse Events (CTCAE) 5.0 classifications. The double-blind will be maintained between subjects and investigators until the final unblinding process. Discussion: This protocol has been reviewed and approved by the Ethics Committee of Zhongshan Hospital (B2022-004R). This is the first prospective, multicenter, randomized controlled trial to compare the combination of immunotherapy and chemotherapy with standard chemotherapy in neoadjuvant treatment for ESCC, also to explore whether adjuvant immunotherapy offers additional benefit in non-pCR patients after nCT with/without immunotherapy and R0 resection. We hypothesize that the pCR rate, R0 resection rate, EFS and OS of the study group (nivolumab/chemo) is significantly better than those of control group. Registration: ClinicalTrial.gov: NCT05213312.