Deep mutational scanning reveals sequence to function constraints for SWEET family transporters.

Protein science is entering a transformative phase enabled by deep mutational scans that provide an unbiased view of the residue level interactions that mediate function. However, it has yet to be extensively used to characterize the mutational and evolutionary landscapes of plant proteins. Here, we apply the method to explore sequence-function relationships within the sugar transporter AtSWEET13. DMS results describe how mutational interrogation throughout different regions of the protein affects AtSWEET13 abundance and transport function. Our results identify novel transport-enhancing mutations that are validated using the FRET sensor assays. Extending DMS results to phylogenetic analyses reveal the role of transmembrane helix 4 (TM4) which makes the SWEET family transporters distinct from prokaryotic SemiSWEETs. We show that transmembrane helix 4 is intolerant to motif swapping with other clade-specific SWEET TM4 compositions, despite accommodating single point-mutations towards aromatic and charged polar amino acids. We further show that the transfer learning approaches based on physics and ML based In silico variant prediction tools have limited utility for engineering plant proteins as they were unable to reproduce our experimental results. We conclude that DMS can produce datasets which, when combined with the right predictive computational frameworks, can direct plant engineering efforts through derivative phenotype selection and evolutionary insights.

Aspirin suppresses hepatocellular carcinoma progression by inhibiting platelet activity.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common malignant liver disease in the world. Platelets (PLTs) are known to play a key role in the maintenance of liver homeostasis and the pathophysiological processes of a variety of liver diseases. Aspirin is the most classic antiplatelet agent. However, the molecular mechanism of platelet action and whether aspirin can affect HCC progression by inhibiting platelet activity need further study. AIM: To explore the impact of the antiplatelet effect of aspirin on the development of HCC. METHODS: Platelet-rich plasma, platelet plasma, pure platelet, and platelet lysate were prepared, and a coculture model of PLTs and HCC cells was established. CCK-8 analysis, apoptosis analysis, Transwell analysis, and real-time polymerase chain reaction (RT-PCR) were used to analyze the effects of PLTs on the growth, metastasis, and inflammatory microenvironment of HCC. RT-PCR and Western blot were used to detect the effects of platelet activation on tumor-related signaling pathways. Aspirin was used to block the activation and aggregation of PLTs both in vitro and in vivo, and the effect of PLTs on the progression of HCC was detected. RESULTS: PLTs significantly promoted the growth, invasion, epithelial-mesenchymal transition, and formation of an inflammatory microenvironment in HCC cells. Activated PLTs promoted HCC progression by activating the mitogen-activated protein kinase/protein kinase B/signal transducer and activator of transcription three (MAPK/ AKT/STAT3) signaling axis. Additionally, aspirin inhibited HCC progression in vitro and in vivo by inhibiting platelet activation. CONCLUSION: PLTs play an important role in the pathogenesis of HCC, and aspirin can affect HCC progression by inhibiting platelet activity. These results suggest that antiplatelet therapy has promising application prospects in the treatment and combined treatment of HCC.

Human gut Actinobacteria boost drug absorption by secreting P-glycoprotein ATPase inhibitors.

Drug efflux transporters are a major determinant of drug efficacy and toxicity. A canonical example is P-glycoprotein (P-gp), an efflux transporter that controls the intestinal absorption of diverse compounds. Despite a rich literature on the dietary and pharmaceutical compounds that impact P-gp activity, its sensitivity to gut microbial metabolites remains an open question. Surprisingly, we found that the cardiac drug-metabolizing gut Actinobacterium Eggerthella lenta increases drug absorption in mice. Experiments in cell culture revealed that E. lenta produces a soluble factor that post-translationally inhibits P-gp ATPase efflux activity. P-gp inhibition is conserved in the Eggerthellaceae family but absent in other Actinobacteria. Comparative genomics identified genes associated with P-gp inhibition. Finally, activity-guided biochemical fractionation coupled to metabolomics implicated a group of small polar metabolites with P-gp inhibitory activity. These results highlight the importance of considering the broader relevance of the gut microbiome for drug disposition beyond first-pass metabolism.

Dynamic behavior of DNA molecules in microchannels: exploring deflective, elliptical, and spin motions induced by Saffman and Magnus forces.

Precise manipulation of individual DNA molecules entering and leaving the channel ports, as well as their smooth passage across the channel, is essential for the detection and screening of DNA molecules using nano-/micro-fluidic technologies. In this paper, by combining single-molecule fluorescence imaging and numerical simulations, the motion states of DNA molecules translocating through a microfluidic channel under the action of the applied electric field are monitored and analyzed in detail. It is found that, under certain conditions of the applied electric field DNA molecules exhibit various motion states, including translation crossing, deflection outflow, reverse outflow, reciprocal movement, and elliptical movement. Simulations indicate that, under the action of Saffman force, DNA molecules can only undergo deflective motion when they experience a velocity gradient in the microchannel flow field; and they can only undergo elliptical motion when their deflective motion is accompanied by a spin motion. In this case, the Magnus force also plays an important role. The detailed study and elucidation of the movement states, dynamic characteristics and mechanisms of DNA molecules such as the deflective and elliptical motions under the actions of Saffman and Magnus forces have helpful implications for the development of related DNA/gene nano-/microfluidic chips, and for the separation, screening and detection of DNA molecules.

Tamm-cavity terahertz detector.

Efficiently fabricating a cavity that can achieve strong interactions between terahertz waves and matter would allow researchers to exploit the intrinsic properties due to the long wavelength in the terahertz waveband. Here we show a terahertz detector embedded in a Tamm cavity with a record Q value of 1017 and a bandwidth of only 469 MHz for direct detection. The Tamm-cavity detector is formed by embedding a substrate with an Nb5N6 microbolometer detector between an Si/air distributed Bragg reflector (DBR) and a metal reflector. The resonant frequency can be controlled by adjusting the thickness of the substrate layer. The detector and DBR are fabricated separately, and a large pixel-array detector can be realized by a very simple assembly process. This versatile cavity structure can be used as a platform for preparing high-performance terahertz devices and opening up the study of the strong interactions between terahertz waves and matter.

Association between oxidative balance score and risk of gout: The NHANES cross-sectional study, 2007-2018.

BACKGROUND: The Oxidative Balance Score (OBS) is a systematic tool to assess the effects of diet and lifestyle in relation to oxidative stress. The association between OBS and gout has not been reported previously. We conducted a cross-sectional study to investigate the complex association between OBS and gout in US adults. METHODS: In all, 10 492 participants were included in this study. The exposure variable was OBS, which was scored by 16 dietary and four lifestyle factors. Multivariate logistic regression, subgroup analysis, and restricted cubic spline (RCS) regression were used to analyze the association between OBS and gout. RESULTS: Compared with the lowest OBS quartile group (Q1), the multivariate corrected odds ratio (OR) (95% confidence interval [C]) for the highest quartile of OBS (Q4) was 0.72 (0.52-1.00) (p = .13 for trend); furthermore, the RCS showed a negative linear relationship between OBS and gout (p-nonlinear = .606). CONCLUSION: In conclusion, the risk of gout is higher with high OBS. The prevalence of gout decreased with higher OBS. Diabetes may alter this negative correlation.

Exosomal microRNAs in lung cancer: a narrative review.

Background and Objective: Exosomes are nanoscale extracellular vesicles secreted by cells, which can release bioactive macromolecules, such as microRNA (miRNA) to receptor cells. Exosomes can efficiently penetrate various biological barriers which mediate intercellular communication. MiRNA are a class of non-coding RNA that primarily regulate messenger RNA (mRNA) at the post-transcriptional level. MiRNA is abundant in exosomes, which plays an important role by being transported and released through exosomes secreted by lung cancer cells. This review aims to elucidate the roles of exosome-derived miRNAs in lung cancer. Methods: We focused on the roles of exosome-derived miRNAs in cancer occurrence and development, including angiogenesis, cell proliferation, invasion, metastasis, immune escape, drug resistance, and their clinical value as new diagnostic and prognostic markers for lung cancer. Key Content and Findings: Exosomal miRNA can not only affect angiogenesis of lung cancer, induce epithelial-mesenchymal transformation, and promote reprogramming of tumor microenvironment, but also affect immune regulation and drug resistance transmission and participate in regulating lung cancer cell proliferation. Therefore, understanding the regulatory roles of exosomal miRNAs in tumor invasion and metastasis can provide new ideas for the treatment of lung cancer. Conclusions: Exosomal miRNA can provide some unique ideas on how to improve the efficiency of diagnosis and treatment of lung cancer in the future. Targeting tumor-specific exosomal miRNA represents a new strategy for clinical treatment of lung cancer, which can provide potential non-invasive biomarkers in the early diagnosis of lung cancer. Investigation of the involvement of exosomal miRNAs in the occurrence and progression of tumors can yield new opportunities for the clinical diagnosis and treatment of lung cancer.

Multicentre randomized clinical trial on robot-assisted versus video-assisted thoracoscopic oesophagectomy (REVATE trial).

BACKGROUND: Surgery for oesophageal squamous cell carcinoma involves dissecting lymph nodes along the recurrent laryngeal nerve. This is technically challenging and injury to the recurrent laryngeal nerve may lead to vocal cord palsy, which increases the risk of pulmonary complications. The aim of this study was to compare the efficacy and safety of robot-assisted oesophagectomy (RAO) versus video-assisted thoracoscopic oesophagectomy (VAO) for dissection of lymph nodes along the left RLN. METHODS: Patients with oesophageal squamous cell carcinoma who were scheduled for minimally invasive McKeown oesophagectomy were allocated randomly to RAO or VAO, stratified by centre. The primary endpoint was the success rate of left recurrent laryngeal nerve lymph node dissection. Success was defined as the removal of at least one lymph node without causing nerve damage lasting longer than 6 months. Secondary endpoints were perioperative and oncological outcomes. RESULTS: From June 2018 to March 2022, 212 patients from 3 centres in Asia were randomized, and 203 were included in the analysis (RAO group 103; VAO group 100). Successful left recurrent laryngeal nerve lymph node dissection was achieved in 88.3% of the RAO group and 69% of the VAO group (P < 0.001). The rate of removal of at least one lymph node according to pathology was 94.2% for the RAO and 86% for the VAO group (P = 0.051). At 1 week after surgery, the RAO group had a lower incidence of left recurrent laryngeal nerve palsy than the VAO group (20.4 versus 34%; P = 0.029); permanent recurrent laryngeal nerve palsy rates at 6 months were 5.8 and 20% respectively (P = 0.003). More mediastinal lymph nodes were dissected in the RAO group (median 16 (i.q.r. 12-22) versus 14 (10-20); P = 0.035). Postoperative complication rates were comparable between the two groups and there were no in-hospital deaths. CONCLUSION: In patients with oesophageal squamous cell carcinoma, RAO leads to more successful left recurrent laryngeal nerve lymph node dissection than VAO, including a lower rate of short- and long-term recurrent laryngeal nerve injury. Registration number: NCT03713749 (http://www.clinicaltrials.gov).

Oesophageal cancer often requires complex surgery. Recently, minimally invasive techniques like robot- and video-assisted surgery have emerged to improve outcomes. This study compared robot- and video-assisted surgery for oesophageal cancer, focusing on removing lymph nodes near a critical nerve. Patients with a specific oesophageal cancer type were assigned randomly to robot- or video-assisted surgery at three Asian hospitals. Robot-assisted surgery had a higher success rate in removing lymph nodes near the important nerve without permanent damage. It also had shorter operating times, more lymph nodes removed, and faster drain removal after surgery. In summary, for oesophageal cancer surgery, the robotic approach may provide better lymph node removal and less nerve injury than video-assisted techniques.

Synthesis of 4-functionalized pyrazoles via oxidative thio- or selenocyanation mediated by PhICl2 and NH4SCN/KSeCN.

A series of 4-thio/seleno-cyanated pyrazoles was conveniently synthesized from 4-unsubstituted pyrazoles using NH4SCN/KSeCN as thio/selenocyanogen sources and PhICl2 as the hypervalent iodine oxidant. This metal-free approach was postulated to involve the in situ generation of reactive thio/selenocyanogen chloride (Cl-SCN/SeCN) from the reaction of PhICl2 and NH4SCN/KSeCN, followed by an electrophilic thio/selenocyanation of the pyrazole skeleton.

Fusion of a rice endogenous N-methylpurine DNA glycosylase to a plant adenine base transition editor ABE8e enables A-to-K base editing in rice plants.

Engineering of a new type of plant base editor for simultaneous adenine transition and transversion within the editing window will greatly expand the scope and potential of base editing in directed evolution and crop improvement. Here, we isolated a rice endogenous hypoxanthine excision protein, N-methylpurine DNA glycosylase (OsMPG), and engineered two plant A-to-K (K = G or T) base editors, rAKBE01 and rAKBE02, for simultaneous adenine transition and transversion base editing in rice by fusing OsMPG or its mutant mOsMPG to a plant adenine transition base editor, ABE8e. We further coupled either OsMPG or mOsMPG with a transactivation factor VP64 to generate rAKBE03 and rAKBE04, respectively. Testing these four rAKBEs, at five endogenous loci in rice protoplasts, indicated that rAKBE03 and rAKBE04 enabled higher levels of A-to-G base transitions when compared to ABE8e and ABE8e-VP64. Furthermore, whereas rAKBE01 only enabled A-to-C/T editing at one endogenous locus, in comparison with rAKBE02 and rAKBE03, rAKBE04 could significantly improve the A-to-C/T base transversion efficiencies by up to 6.57- and 1.75-fold in the rice protoplasts, respectively. Moreover, although no stable lines with A-to-C transversion were induced by rAKBE01 and rAKBE04, rAKBE04 could enable simultaneous A-to-G and A-to-T transition and transversion base editing, at all the five target loci, with the efficiencies of A-to-G transition and A-to-T transversion editing ranging from 70.97 to 92.31% and 1.67 to 4.84% in rice stable lines, respectively. Together, these rAKBEs enable different portfolios of editing products and, thus, now expands the potential of base editing in diverse application scenario for crop improvement. Supplementary Information: The online version contains supplementary material available at 10.1007/s42994-024-00138-8.

In Situ Polymerization of a Self-Healing Polyacrylamide-Based Eutectogel as an Electrolyte for Zinc-Ion Batteries.

Gel electrolytes have attracted extensive attention in flexible batteries. However, the traditional hydrogel electrolyte is not enough to solve the fundamental problems of zinc anodes, such as dendrite growth, side reactions, and freezing failure at temperatures below zero, which seriously restricts the development of zinc-ion batteries. As a flexible energy storage device, the zinc-ion battery inevitably undergoes multiple stretches, bends, folds, or twists in daily use. Here, a self-healing and stretchable eutectogel, designated as deep eutectic solvent-acrylamide eutectic gel (DA-ETG), was developed as a solid-state electrolyte for zinc-ion batteries. This gel was prepared by immobilizing a high-concentration ZnCl2 deep eutectic solvent (DES) into a polyacrylamide matrix through in situ polymerization under ultraviolet light. The eutectogel electrolyte showed exceptional mechanical properties with a maximum fracture strength of 0.6 MPa and a high ionic conductivity of 6.4 × 10-4 S cm-1. The in situ polymerization of the DA-ETG electrolyte in the assembly of a full solid-state zinc-ion battery increased the electrode-electrolyte interface area contact, reduced the ion transport distance between the electrode and electrolyte, minimized the internal resistance, and enhanced the battery's long-term cycling stability. Using the DA-ETG electrolyte, a remarkably high capacity of 580 mAh g-1 at 0.1 A g-1 was achieved by the zinc-ion battery, and a considerable capacity of 234 mAh g-1 was maintained even at 5 A g-1, showing exceptional rate performance. After 2000 cycles at 2 A g-1, the cell with the eutectogel retained a capacity of 85% with a cycling efficiency close to 98%, which demonstrated excellent cycling stability. The self-healing function enabled the prepared soft battery to be reused multiple times, with full contact between the electrode and electrolyte interface, and without device failures.

The therapeutic potential of phosphodiesterase 9 (PDE9) inhibitors: a patent review (2018-present).

INTRODUCTION: Phosphodiesterase 9 (PDE9) has been demonstrated as a potential target for neurological disorders and cardiovascular diseases, such as Alzheimer's disease and heart failure. For the last few years, a series of PDE9 inhibitors with structural diversities have been developed and patented by researchers and pharmaceutical companies, providing insights into first-in-class therapies of PDE9 drug candidates. AREA COVERED: This review provides an overview of PDE9 inhibitors in patents from 2018 to the present. EXPERT OPINION: Only a few of the current PDE9 inhibitors are highly selective over other PDEs, which limits their application in pharmacological and clinical research. The design and development of highly selective PDE9 inhibitors remain the top priority in future research. The advantages of targeting PDE9 rather than other PDEs in treating neurodegenerative diseases need to be explained thoroughly. Besides, application of PDE9 inhibitor-based combination therapies sheds light on treating diabetes and refractory heart diseases. Finally, PDE9 inhibitors should be further explored in clinical indications beyond neurological disorders and cardiovascular diseases.

Decoding the biochemical dialogue: metabolomic insights into soybean defense strategies against diverse pathogens.

Soybean, a crucial global leguminous crop, confronts persistent threats from diverse pathogens, exerting a profound impact on global yields. While genetic dimensions of soybean-pathogen interactions have garnered attention, the intricate biochemical responses remain poorly elucidated. In this study, we applied targeted and untargeted liquid chromatography coupled to mass spectrometry (LC-MS) metabolite profiling to dissect the complex interplay between soybeans and five distinct pathogens. Our analysis uncovered 627 idMS/MS spectra, leading to the identification of four main modules, encompassing flavonoids, isoflavonoids, triterpenoids, and amino acids and peptides, alongside other compounds such as phenolics. Profound shifts were observed in both primary and secondary metabolism in response to pathogenic infections. Particularly notable were the bidirectional changes in total flavonoids across diverse pathogenic inoculations, while triterpenoids exhibited a general declining trend. Noteworthy among the highly inducible total flavonoids were known representative anti-pathogen compounds (glyceollin I), backbone forms of isoflavonoids (daidzein, genistein, glycitein, formononetin), and newly purified compounds in this study (prunin). Subsequently, we delved into the biological roles of these five compounds, validating their diverse functions against pathogens: prunin significantly inhibited the vegetative growth and virulence of Phytophthora sojae; genistein exhibited a pronounced inhibitory effect on the vegetative growth and virulence of Phomopsis longicolla; daidzein and formononetin displayed significant repressive effects on the virulence of P. longicolla. This study underscores the potent utility of metabolomic tools, providing in-depth insights into plant-pathogen interactions from a biochemical perspective. The findings not only contribute to plant pathology but also offer strategic pathways for bolstering plant resistance against diseases on a broader scale.

High-Performance Tin Oxide Thin-Film Transistors Realized by Codoping and Their Application in Logic Circuits.

Tin oxide is a promising channel material, offering the advantages of being low-cost and environmentally friendly and having a wide band gap. However, despite the high electron mobility of SnO2 in bulk, the corresponding thin-film transistors (TFTs) generally exhibit moderate performance, hindering their widespread application. Herein, we proposed a codoping strategy to improve both the electrical property and the stability of SnO2 TFTs. A comparative analysis between doped and undoped SnO2 was conducted. It is observed that taking advantage of the difference in ionic radii between two dopants (indium and gallium) and the tin ions in the host lattice can effectively reduce impurity-induced strain. Additionally, we investigated the effect of codoping content on SnO2 TFTs. The optimal codoped SnO2 (TIGO) TFTs demonstrate high performance, featuring a field-effect mobility of 15.9 cm2/V·s, a threshold voltage of 0.2 V, a subthreshold swing of 0.5 V/decade, and an on-to-off current ratio of 2.2 × 107. Furthermore, the devices show high stability under both positive and negative bias stress conditions with a small threshold voltage shift of 1.8 and -1.2 V, respectively. Utilizing the TIGO TFTs, we successfully constructed a resistor-loaded unipolar inverter with a high gain of 10.76. This study highlights the potential of codoped SnO2 TFTs for advanced applications in electronic devices.

Model-agnostic counterfactual reasoning for identifying and mitigating answer bias in knowledge tracing.

Knowledge tracing (KT) aims to monitor students' evolving knowledge states through their learning interactions with concept-related questions, and can be indirectly evaluated by predicting how students will perform on future questions. In this paper, we observe that there is a common phenomenon of answer bias, i.e., a highly unbalanced distribution of correct and incorrect answers for each question. Existing models tend to memorize the answer bias as a shortcut for achieving high prediction performance in KT, thereby failing to fully understand students' knowledge states. To address this issue, we approach the KT task from a causality perspective. A causal graph of KT is first established, from which we identify that the impact of answer bias lies in the direct causal effect of questions on students' responses. A novel COunterfactual REasoning (CORE) framework for KT is further proposed, which separately captures the total causal effect and direct causal effect during training, and mitigates answer bias by subtracting the latter from the former in testing. The CORE framework is applicable to various existing KT models, and we implement it based on the prevailing DKT, DKVMN, and AKT models, respectively. Extensive experiments on three benchmark datasets demonstrate the effectiveness of CORE in making the debiased inference for KT. We have released our code at https://github.com/lucky7-code/CORE.

Enhanced Interfacial Electron Transfer in Photocatalyst-Natural Enzyme Coupled Artificial Photosynthesis System: Tuning Strategies and Molecular Simulations.

Laccase is capable of catalyzing a vast array of reactions, but its low redox potential limits its potential applications. The use of photocatalytic materials offers a solution to this problem by converting absorbed visible light into electrons to facilitate enzyme catalysis. Herein, MIL-53(Fe) and NH2-MIL-53(Fe) serve as both light absorbers and enzyme immobilization carriers, and laccase is employed for solar-driven chemical conversion. Electron spin resonance spectroscopy results confirm that visible light irradiation causes rapid transfer of photogenerated electrons from MOF excitation to T1 Cu(II) of laccase, significantly increasing the degradation rate constant of tetracycline (TC) from 0.0062 to 0.0127 min-1. Conversely, there is only minimal or no electron transfer between MOF and laccase in the physical mixture state. Theoretical calculations demonstrate that the immobilization of laccase's active site and its covalent binding to the metal-organic framework surface augment the coupled system's activity, reducing the active site accessible from 27.8 to 18.1 Å. The constructed photo-enzyme coupled system successfully combines enzyme catalysis' selectivity with photocatalysis's high reactivity, providing a promising solution for solar energy use.

Metabolic stress induces a double-positive feedback loop between AMPK and SQSTM1/p62 conferring dual activation of AMPK and NFE2L2/NRF2 to synergize antioxidant defense.

Co-occurring mutations in KEAP1 in STK11/LKB1-mutant NSCLC activate NFE2L2/NRF2 to compensate for the loss of STK11-AMPK activity during metabolic adaptation. Characterizing the regulatory crosstalk between the STK11-AMPK and KEAP1-NFE2L2 pathways during metabolic stress is crucial for understanding the implications of co-occurring mutations. Here, we found that metabolic stress increased the expression and phosphorylation of SQSTM1/p62, which is essential for the activation of NFE2L2 and AMPK, synergizing antioxidant defense and tumor growth. The SQSTM1-driven dual activation of NFE2L2 and AMPK was achieved by inducing macroautophagic/autophagic degradation of KEAP1 and facilitating the AXIN-STK11-AMPK complex formation on the lysosomal membrane, respectively. In contrast, the STK11-AMPK activity was also required for metabolic stress-induced expression and phosphorylation of SQSTM1, suggesting a double-positive feedback loop between AMPK and SQSTM1. Mechanistically, SQSTM1 expression was increased by the PPP2/PP2A-dependent dephosphorylation of TFEB and TFE3, which was induced by the lysosomal deacidification caused by low glucose metabolism and AMPK-dependent proton reduction. Furthermore, SQSTM1 phosphorylation was increased by MAP3K7/TAK1, which was activated by ROS and pH-dependent secretion of lysosomal Ca2+. Importantly, phosphorylation of SQSTM1 at S24 and S226 was critical for the activation of AMPK and NFE2L2. Notably, the effects caused by metabolic stress were abrogated by the protons provided by lactic acid. Collectively, our data reveal a novel double-positive feedback loop between AMPK and SQSTM1 leading to the dual activation of AMPK and NFE2L2, potentially explaining why co-occurring mutations in STK11 and KEAP1 happen and providing promising therapeutic strategies for lung cancer.Abbreviations: AMPK: AMP-activated protein kinase; BAF1: bafilomycin A1; ConA: concanamycin A; DOX: doxycycline; IP: immunoprecipitation; KEAP1: kelch like ECH associated protein 1; LN: low nutrient; MAP3K7/TAK1: mitogen-activated protein kinase kinase kinase 7; MCOLN1/TRPML1: mucolipin TRP cation channel 1; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; NSCLC: non-small cell lung cancer; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; PPP2/PP2A: protein phosphatase 2; ROS: reactive oxygen species; PPP3/calcineurin: protein phosphatase 3; RPS6KB1/p70S6K: ribosomal protein S6 kinase B1; SQSTM1/p62: sequestosome 1; STK11/LKB1: serine/threonine kinase 11; TCL: total cell lysate; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3; V-ATPase: vacuolar-type H+-translocating ATPase.

Corrigendum: Identification of an immune-related gene prognostic index for predicting survival and immunotherapy efficacy in papillary renal cell carcinoma.

[This corrects the article DOI: 10.3389/fgene.2022.970900.].

Neoadjuvant chemotherapy with or without camrelizumab in resectable esophageal squamous cell carcinoma: the randomized phase 3 ESCORT-NEO/NCCES01 trial.

Recent single-arm studies involving neoadjuvant camrelizumab, a PD-1 inhibitor, plus chemotherapy for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC) have shown promising results. This multicenter, randomized, open-label phase 3 trial aimed to further assess the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy followed by adjuvant camrelizumab, compared to neoadjuvant chemotherapy alone. A total of 391 patients with resectable thoracic LA-ESCC (T1b-3N1-3M0 or T3N0M0) were stratified by clinical stage (I/II, III or IVA) and randomized in a 1:1:1 ratio to undergo two cycles of neoadjuvant therapy. Treatments included camrelizumab, albumin-bound paclitaxel and cisplatin (Cam+nab-TP group; n = 132); camrelizumab, paclitaxel and cisplatin (Cam+TP group; n = 130); and paclitaxel with cisplatin (TP group; n = 129), followed by surgical resection. Both the Cam+nab-TP and Cam+TP groups also received adjuvant camrelizumab. The dual primary endpoints were the rate of pathological complete response (pCR), as evaluated by a blind independent review committee, and event-free survival (EFS), as assessed by investigators. This study reports the final analysis of pCR rates. In the intention-to-treat population, the Cam+nab-TP and Cam+TP groups exhibited significantly higher pCR rates of 28.0% and 15.4%, respectively, compared to 4.7% in the TP group (Cam+nab-TP versus TP: difference 23.5%, 95% confidence interval (CI) 15.1-32.0, P < 0.0001; Cam+TP versus TP: difference 10.9%, 95% CI 3.7-18.1, P = 0.0034). The study met its primary endpoint of pCR; however, EFS is not yet mature. The incidence of grade ≥3 treatment-related adverse events during neoadjuvant treatment was 34.1% for the Cam+nab-TP group, 29.2% for the Cam+TP group and 28.8% for the TP group; the postoperative complication rates were 34.2%, 38.8% and 32.0%, respectively. Neoadjuvant camrelizumab plus chemotherapy demonstrated superior pCR rates compared to chemotherapy alone for LA-ESCC, with a tolerable safety profile. Chinese Clinical Trial Registry identifier: ChiCTR2000040034 .