SnRK1 kinase-mediated phosphorylation of transcription factor bZIP39 regulates sorbitol metabolism in apple.

Sorbitol is a major photosynthate produced in leaves and transported through the phloem of apple (Malus domestica) and other tree fruits in Rosaceae. Sorbitol stimulates its own metabolism, but the underlying molecular mechanism remains unknown. Here, we show that sucrose nonfermenting 1 (SNF1)-related protein kinase 1 (SnRK1) is involved in regulating the sorbitol-responsive expression of both SORBITOL DEHYDROGENASE 1 (SDH1) and ALDOSE-6-PHOSPHATE REDUCTASE (A6PR), encoding 2 key enzymes in sorbitol metabolism. SnRK1 expression is increased by feeding of exogenous sorbitol but decreased by sucrose. SnRK1 interacts with and phosphorylates the basic leucine zipper (bZIP) transcription factor bZIP39. bZIP39 binds to the promoters of both SDH1 and A6PR and activates their expression. Overexpression of SnRK1 in 'Royal Gala' apple increases its protein level and activity, upregulating transcript levels of both SDH1 and A6PR without altering the expression of bZIP39. Of all the sugars tested, sorbitol is the only 1 that stimulates SDH1 and A6PR expression, and this stimulation is blocked by RNA interference (RNAi)-induced repression of either SnRK1 or bZIP39. These findings reveal that sorbitol acts as a signal regulating its own metabolism via SnRK1-mediated phosphorylation of bZIP39, which integrates sorbitol signaling into the SnRK1-mediated sugar signaling network to modulate plant carbohydrate metabolism.

Tumor Microenvironment Responsive RNA Drug Delivery Systems: Intelligent Platforms for Sophisticated Release.

Cancer is a significant health concern, increasingly showing insensitivity to traditional treatments, highlighting the urgent need for safer and more practical treatment options. Ribonucleic acid (RNA) gene therapy drugs have demonstrated promising potential in preclinical and clinical trials for antitumor therapy by regulating tumor-related gene expression. However, RNA's poor membrane permeability and stability restrict its effectiveness in entering and being utilized in cells. An appropriate delivery system is crucial for achieving targeted tumor effects. The tumor microenvironment (TME), characterized by acidity, hypoxia, enzyme overexpression, elevated glutathione (GSH) concentration, and excessive reactive oxygen species (ROS), is essential for tumor survival. Furthermore, these distinctive features can also be harnessed to develop intelligent drug delivery systems. Various nanocarriers that respond to the TME have been designed for RNA drug delivery, showing the advantages of tumor targeting and low toxicity. This Review discusses the abnormal changes of components in TME, therapeutic RNAs' roles, underlying mechanisms, and the latest developments in utilizing vectors that respond to microenvironments for treating tumors. We hope it provides insight into creating and optimizing RNA delivery vectors to improve their effectiveness.

Unveiling the mechanism of source-sink rebalancing in cucumber-pumpkin heterografts: the buffering roles of rootstock cotyledon.

Grafting onto pumpkin rootstock is widely applied in cucumber production to improve growth and yield, as well as to overcome soil-borne diseases and enhance resistance to abiotic stresses. In this study, we constructed the cucumber-pumpkin heterografts with the one-cotyledon grafting method, and examined the effects of heterografting on biomass allocation and sugar partitioning, with cucumber and pumpkin self-grafts used as control. Compared with cucumber self-grafts, heterografting onto pumpkin rootstock promoted photosynthesis in cucumber scion, and led to higher sucrose contents in the 1st true leaf (source) and newly emerged leaf (sink). Thereby, the scion part of heterografts accumulated more biomass than cucumber self-grafts. In contrast, when compared to pumpkin self-grafts, grafting with cucumber scion reduced root vigor and biomass but promoted cotyledon growth in pumpkin rootstock. The roots (sink) of heterografts contained less sucrose and hexoses, and showed reduced sucrose synthase (SuSy) and hexokinase (HXK) activities. However, the rootstock cotyledon (source) contained more sucrose and starch, and showed higher activities of HXK, cell-wall invertase (CWIN), and enzymes for starch synthesis and degradation. Furthermore, removal or shade of rootstock cotyledon led to reduced growth of root and scion. Silencing of CmoMEX1a gene in rootstock cotyledon inhibited maltose export and reduced root growth of heterografts. These results indicated that rootstock cotyledon, especially its starch content, played a buffering role in the growth regulation of cucumber-pumpkin heterografts. Taken together, our results provided a major contribution to our understanding of source-sink sugar partitioning and scion-rootstock growth balancing in cucumber-pumpkin heterografts.

Regulation of T16H subcellular localization for promoting its catalytic efficiency in yeast cells.

To investigate the effect of subcellular localization on the transformation efficiency of heterologous expressed functional P450s in yeast. Microbial biotransformation offers a promising substitute for the direct extraction of natural products, but its viability in industrial applications depends on achieving high transformation efficiencies. To investigate the influence of subcellular microenvironments on the activity of heterologously expressed P450s, Catharanthus roseus tabersonine 16-hydroxylase (T16H) was chosen, and its subcellular localization was regulated by fusing organelle-localization signals. Interestingly, this manipulation had no effect on the gene expression levels of T16H, but resulted in varying conversion rates from tabersonine to 16-hydroxy tabersonine. Notably, the highest transformation efficiency was observed in yeast cells expressing peroxisome-localized T16H. Given the alkaline pH optimum for P450s, the alkaline peroxisomal lumen could be a suitable compartment for P450s reactions to achieve high transformation efficiency using yeast cells. Different organelle-localization of T16H in yeast cells resulted in varying conversion rates, suggesting that compartmentalizing the expression of target enzymes could be a viable approach to increase transformation efficiency in yeast.

A head-to-head comparison of 18F-FDG PET/CT and 18F-FDG PET/MR in patients with nasopharyngeal carcinoma under different disease settings.

OBJECTIVE: Positron emission tomography/computed tomography (PET/CT) and magnetic resonance imaging (MRI) are complementary in staging of nasopharyngeal carcinoma (NPC). The combination of MRI and functional imaging from PET in PET/MR is promising in NPC management. Diagnostic performance of PET/CT and PET/MR was compared in 46 patients with histologically confirmed NPC under different disease scenarios, including primary non-metastatic cases, primary metastatic cases, recurrence and/or metastasis after treatment, and post-treatment follow-up cases. SUBJECTS AND METHODS: Forty-six patients underwent both PET/CT and PET/MR in the same day. Primary tumor extension into risk-stratified anatomic structures, retropharyngeal and cervical lymph node metastasis, distant metastasis and post-treatment follow-up results, were compared. RESULTS: For high-risk structures, PET/MR detected two more sides of tensor/levator veli palatine muscle involvement, one more case of clivus involvement, and ruled out 12 false-positive sides of prevertebral muscle involvement by PET/CT. For medium-risk structures, PET/MR detected four more sides of medial pterygoid muscle involvement. For low-risk structures, abnormal signal on massa lateralis atlantis was detected by PET/MR. PET/MR detected 14 more positive retropharyngeal lymph nodes and more liver micrometastases than PET/CT. Overall, PET/MR changed two patients' T staging. CONCLUSION: Positron emission tomography/MR outperforms PET/CT in delineating muscle, skull-base bone, and nodal involvement, and identifying liver micrometastases, may serve as a single-step staging modality for NPC.

ABA-responsive AREB1/ABI3-1/ABI5 cascade regulates IAA oxidase gene SlDAO2 to inhibit hypocotyl elongation in tomato.

Hypocotyl elongation is dramatically influenced by environmental factors and phytohormones. Indole-3-acetic acid (IAA) plays a prominent role in hypocotyl elongation, whereas abscisic acid (ABA) is regarded as an inhibitor through repressing IAA synthesis and signalling. However, the regulatory role of ABA in local IAA deactivation remains largely uncharacterized. In this study, we confirmed the antagonistic interplay of ABA and IAA during the hypocotyl elongation of tomato (Solanum lycopersicum) seedlings. We identified an IAA oxidase enzyme DIOXYGENASE FOR AUXIN OXIDATION2 (SlDAO2), and its expression was induced by both external and internal ABA signals in tomato hypocotyls. Moreover, the overexpression of SlDAO2 led to a reduced sensitivity to IAA, and the knockout of SlDAO2 alleviated the inhibitory effect of ABA on hypocotyl elongation. Furthermore, an ABA-responsive regulatory SlAREB1/SlABI3-1/SlABI5 cascade was identified to act upstream of SlDAO2 and to precisely control its expression. SlAREB1 directly bound to the ABRE present in the SlDAO2 promoter to activate SlDAO2 expression, and SlABI3-1 enhanced while SlABI5 inhibited the activation ability of SlAREB1 by directly interacting with SlAREB1. Our findings revealed that ABA might induce local IAA oxidation and deactivation via SlDAO2 to modulate IAA homoeostasis and thereby repress hypocotyl elongation in tomato.

Transcriptional repression specifies the central cell for double fertilization.

Double fertilization is a key innovation for the evolutionary success of angiosperms by which the two fertilized female gametes, the egg cell and central cell, generate the embryo and endosperm, respectively. The female gametophyte (embryo sac) enclosed in the sporophyte is derived from a one-celled haploid cell lineage. It undergoes successive events of mitotic divisions, cellularization, and cell specification to give rise to the mature embryo sac, which contains the two female gametes accompanied by two types of accessory cells, namely synergids and antipodals. How the cell fate of the central cell is specified has long been equivocal and is further complicated by the structural diversity of female gametophyte across plant taxa. Here, MADS-box protein AGL80 was verified as a transcriptional repressor that directly suppresses the expression of accessory cell-specific genes to specify the central cell. Further genetic rescue and phylogenetic assay of the AGL80 orthologs revealed a possible conserved mechanism in the Brassicaceae family. Results from this study provide insight into the molecular determination of the second female gamete cell in Brassicaceae.

Two 3D Rubidium Halide Organic-Inorganic Hybrid Perovskite Ferroelectrics Templated by Quasi-Spherical Organic Amine 1,4-Diazabicyclo[3.2.2]nonane.

The emergence of (CH3 NH3 )PbI3 has brought the development of three-dimensional (3D) organic-inorganic hybrid perovskite (OIHP) structures with ABX3 type to a higher level; however, most 3D frameworks are constructed by corner-sharing of BX6 octahedra. Herein, we substituted the spherical molecule 1,4-diazabicyclo[2.2.2]octane (2.2.2-dabco) with 1,4-diazabicyclo[3.2.2]nonane (1,4-3.2.2-dabcn) as a template to react with RbX (X=Br, I) in the corresponding HX acids under the consideration of reducing the molecular symmetry. Two 3D OIHP compounds [1,4-3.2.2-H2 dabcn]RbI3 ⋅H2 O (1) and [1,4-3.2.2-H2 dabcn]RbBr3 (2) crystallized in non-centrosymmetric point group mm2 before the phase transition point were isolated. Among them, the 3D inorganic framework of 1 is constructed by sharing the corner of [RbI6 ] octahedra, while that of 2 is constructed by sharing the corner and face of [RbBr6 ] octahedra to acquire large cavities to accommodate the organic amine cation [1,4-3.2.2-H2 dabcn]2+ ; this 3D framework type is unprecedented in the OIHPs. As expected, compounds 1 and 2 exhibit reversible phase transition, dielectric and second harmonic generation (SHG) and ferroelectric properties, in which the phase transition temperature of 2 at 374 K is much higher than compound 1 at 280 K.

Sex Differences and Temporal Trends in Hospitalization for Catheter Ablation of Nonvalvular Atrial Fibrillation: A Single-Center Experience for 15 Years.

Background: There exist sex differences in the clinical profile, management, and outcome of atrial fibrillation (AF). Catheter ablation of AF has become a first-line therapy and has markedly made headway over the recent decades. Little is known about sex differences and temporal trends in hospitalization for catheter ablation of AF in the real-world setting. Methods: We retrospectively retrieved medical records of patients at Beijing Anzhen Hospital between January 2005 and December 2019. The patients undergoing catheter ablation of AF were enrolled. Demographical and clinical data were compared between sexes. The temporal trends of sex differences were evaluated. Results: We identified 13502 male patients (66.8%) and 6713 female patients (33.2%). The number of patients undergoing AF ablation had remarkably increased over time, but no sex differences were observed (p=0.17). The median age of women was five years older than that of men (p < 0.001). The median time of in-hospital stay for the women decreased from 11 days to 4 days and for the men from 9 to 4 days. In-hospital mortality was 0.03% and 0.01% for women and men, respectively, with no significant difference between sexes. The women were more likely to have a comorbid diagnosis of hypertension and heart failure than men (p < 0.001). The CHA2DS2-VA score was higher in women than in men (1.64 vs. 1.28, p < 0.001). The temporal trend in the score increased in women from 1.17 to 1.81 (p < 0.001) and in men from 0.91 to 1.41 (p < 0.001). The percentage of patients with CHA2DS2-VA score ≥2 was higher in women than in men (49.8% vs. 35.8%, p < 0.001), and the temporal trend of this sex gap was nearly doubled (8.0% in 2005-2007 vs. 15.5% in 2017-2019, p=0.03). Conclusions: Safety of catheter ablation for AF was comparable in both sexes. In contrast, the women showed a higher CHA2DS2-VA score than men. The percentage of patients with CHA2DS2-VA score ≥2 increased more quickly in women than in men. Furthermore, sex-specific research is warranted to reduce this sex disparity.

3D Perovskite (1,5-3.2.2-H2dabcn)CsBr3 with Reverse Symmetry Breaking.

Even though hybrid organic-inorganic perovskites (HOIPs) have been studied by many scholars in recent years, there are not many reports on three-dimensional (3D) alkali metal cesium halide perovskites. Here, we report an unprecedented 3D HOIP molecule (1,5-3.2.2-H2dabcn)CsBr3 (1), in which the 3D anionic framework is constructed by corner-sharing CsBr6 octahedra and organic cations [1,5-3.2.2-H2dabcn]2+ are located in the cavities formed by the octahedra. Organic cations interact with an inorganic metal frame via two N-H···Br hydrogen bonds. Compound 1 undergoes a reversible order-disorder phase transition and exhibits switchable dielectric and second-harmonic generation (SHG) properties. Interestingly, product 1 crystallizes in a non-centrosymmetric space group Pmn21 at the low-temperature phase (LTP) and transforms into a centrosymmetric space group P2/m at the high-temperature phase (HTP). The space group Pmn21 in the LTP has a higher symmetry than P2/m in the HTP. This inverted symmetry breaking is very unusual.

A receptor heteromer mediates the male perception of female attractants in plants.

Sexual reproduction requires recognition between the male and female gametes. In flowering plants, the immobile sperms are delivered to the ovule-enclosed female gametophyte by guided pollen tube growth. Although the female gametophyte-secreted peptides have been identified to be the chemotactic attractant to the pollen tube, the male receptor(s) is still unknown. Here we identify a cell-surface receptor heteromer, MDIS1-MIK, on the pollen tube that perceives female attractant LURE1 in Arabidopsis thaliana. MDIS1, MIK1 and MIK2 are plasma-membrane-localized receptor-like kinases with extracellular leucine-rich repeats and an intracellular kinase domain. LURE1 specifically binds the extracellular domains of MDIS1, MIK1 and MIK2, whereas mdis1 and mik1 mik2 mutant pollen tubes respond less sensitively to LURE1. Furthermore, LURE1 triggers dimerization of the receptors and activates the kinase activity of MIK1. Importantly, transformation of AtMDIS1 to the sister species Capsella rubella can partially break down the reproductive isolation barrier. Our findings reveal a new mechanism of the male perception of the female attracting signals.

LncRNA-Airn alleviates acute liver injury by inhibiting hepatocyte apoptosis via the NF-κB signaling pathway.

Acute liver injury is a common and serious syndrome caused by multiple factors and unclear pathogenesis. If the injury persists, liver injury can lead to cirrhosis and liver failure and ultimately results in the development of liver cancer. Emerging evidence has indicated that long noncoding RNAs (lncRNAs) play an important role in the development of liver injury. However, the role of antisense Igf2r RNA (Airn) in acute liver injury and its underlying mechanism remain largely unclear. In this study, we show that Airn is upregulated in liver tissue and primary hepatocytes from an acute liver injury mouse model. Consistently, Airn is also overexpressed in serum samples of patients with acute-on-chronic liver failure and is negatively correlated with the Model for End-Stage Liver Disease (MELD) score. Moreover, gene knockout and rescue assays reveal that Airn alleviates CCl 4-induced liver injury by inhibiting hepatocyte apoptosis and oxidative stress in vivo. Further investigation reveals that Airn decreases H 2O 2-induced hepatocyte apoptosis in vitro. Mechanistically, we reveal that Airn represses CCl 4- and H 2O 2-induced enhancement of phosphorylation of p65 and IκBα, suggesting that Airn inhibits hepatocyte apoptosis by inactivating the NF-κB pathway. In conclusion, our results demonstrate that Airn can alleviate acute liver injury by inhibiting hepatocyte apoptosis via inactivating the NF-κB signaling pathway, and Airn could be a potential biomarker for acute liver injury.

The Role of Fluorine-Substituted Positions on the Phase Transition in Organic-Inorganic Hybrid Perovskite Compounds.

Although research on organic-inorganic hybrid perovskites (OIHPs) has grown exponentially in the past two decades, the high phase transition temperature of OIHP materials is still one of the insurmountable difficulties. Herein, a series of A2BX4 type OIHP materials [(2,n-DFBA)2PbCl4] (n = 3, for 1; n = 4, for 2; n = 5, for 3; n = 6, for 4) have been prepared by reactions of double-substituted difluorobenzylamine (difluorobenzylamine = DFBA) with lead chloride in concentrated HCl aqueous solution. It was found the OIHP compounds 1-3 proceed a switchable phase transition with phase transition temperatures (Tc) at 449 K (1), 462 K (2) and 500 K (3), higher than that of the parent compound [(BA)2PbCl4] (BA = benzylammonium) at 438 K, but compound 4 exhibits no phase transition. A crystal structure analysis elucidated that the organic template ligands DFBA lead in the inorganic part in compounds 1-3 to a two-dimensional (2D) perovskite structure, while that in compound 4 leads to a one-dimensional (1D) chain structure. The different double-substituted positions of fluorine atoms on benzylamine have important influences on the phase transition in compounds 1-4.

Sex differences in the association between green tea consumption and hypertension in elderly Chinese adults.

BACKGROUND: Green tea has been one of the most popular beverages in China since ancient times. Mixed results concerning the effect of green tea consumption on the incidence of hypertension have been published over the past decades. However, no previous studies have focused on longevous individuals in China and the sex differences in the association between habitual green tea intake and hypertension. METHODS: The data extracted from the database of the Chinese Longitudinal Healthy Longevity Survey (CLHLS) in 2018 were used for a secondary analysis. Logistic regression models were employed to examine the odds ratio (OR) of daily green tea consumption on the incidence of hypertension by sex. RESULTS: A total of 9277 individuals were included in the analysis (39.8% were men). The included individuals had a mean age of 80.9 and 84.8 years for those who drank green tea daily and those who had never, respectively (p <  0.001). The incidence of hypertension varied at baseline according to green tea drinking habit and sex. For women who had a habitual green tea intake or had never drunk green tea, the incidence of hypertension was 47.3 and 43.9%, respectively (p = 0.241), whereas it was 51.6 and 39.7% for men (p <  0.001). After adjusting for potential confounders, a 38% increase in the risk of hypertension was observed in men who consumed green tea daily (OR, 1.38; 95% CI, 1.15-1.67; p <  0.001). CONCLUSIONS: Chinese longevous men had a 38% higher risk of developing hypertension when drinking green tea daily. However, no effect of green tea consumption on the incidence of hypertension in women was found. More attention should be paid to the lifestyle of longevous individuals for health promotion, and a sex-specific approach to deliver care for very elderly people is warranted.

Early versus delayed removal of the pericardial drain in patients with cardiac tamponade complicating radiofrequency ablation of atrial fibrillation.

INTRODUCTION: Cardiac tamponade is a common life-threatening complication during radiofrequency ablation of atrial fibrillation (RAAF) and is mostly managed by pericardiocentesis. Thus far, the optimal timing for drain removal has not been established. METHODS AND RESULTS: We retrospectively enrolled patients with cardiac tamponade complicating RAAF. The ablation was performed with interrupted novel oral anticoagulants, interrupted warfarin or uninterrupted warfarin protocols. An observation period of at least 30 minutes after the last aspiration via the drain was used to monitor the reaccumulation of pericardial fluid, and then, the patients were divided into an early removal (ER) group in the electrophysiology (EP) laboratory and a delayed removal (DR) group in the ward. A total of 51 patients were included: 25 patients in the ER group and 26 patients in the DR group. There were no significant differences in baseline demographics between the two groups, and no cardiac tamponade reoccurred in either group in the ward. Unlike the DR group, the ER group showed an association with a decreased rate of chest pain (P = .000), fever (P = .001), nausea (P = .000), in-hospital recurrent AF (P = .010), and antibiotic use (P = .012). Anticoagulation was earlier (P = .009), and the median in-hospital stay was shorter (P = .001) in the ER group than in the DR group. CONCLUSIONS: ER of the pericardial drain after no evidence of pericardial bleeding for at least 30 minutes in the EP laboratory is safe and associated with a better early hospital course.

ZBTB7A functioned as an oncogene in colorectal cancer.

BACKGROUND: Despite zinc finger and BTB domain-containing 7A (ZBTB7A) documented importance in multiple tumors, the function and clinical value in Colorectal cancer (CRC) remain elusive. The aim of this study was to evaluate the functional roles and the clinical value of ZBTB7A in CRC progression. METHODS: The level of ZBTB7A was detected in a large cohort of CRC patients (n = 189) by immunohistochemistry (IHC), and we analyzed the diagnostic and prognostic value of the protein. In addition, the functional roles of ZBTB7A on CRC were explored in vitro and in vivo. RESULTS: Survival analyses indicated that patients with high ZBTB7A expression made the prognosis worse (P = 0.024). Functionally, knockdown of ZBTB7A could markedly inhibit tumor proliferation in vitro and in vivo, whereas ZBTB7A overexpression displayed the opposite results. CONCLUSIONS: ZBTB7A was associated with poor survival outcomes and functioned as an oncogene in CRC patients, indicating that it is a potential prognostic biomarker and therapeutic target for CRC patients.

Differential Regulation of Anthocyanin Synthesis in Apple Peel under Different Sunlight Intensities.

Sunlight radiation is a main environmental factor which affects anthocyanin synthesis. To clarify the regulatory mechanism of sunlight on the synthesis of anthocyanin in apple peel, bagged apples were exposed to diverse intensities of sunlight through different shading treatments. Under an increased solar ultraviolet-B (UV-B) light intensity, the concentration of anthocyanin in apple peels was consistent with the Michaelis-Menten equation. Under lower sunlight intensities, diphenyleneiodonium chloride (DPI, an inhibitor of plasma membrane NAD(P)H oxidase) treatment increased both the concentration of cyanidin-3-glycoside and the activity of dihydroflavonol 4-reductase (DFR). However, under higher sunlight intensities, DPI treatment decreased the concentrations of cyanidin-3-glycoside and quercetin-3-glycoside, as well as the activities of DFR and UDP-glycose: flavonoid 3-O-glycosyltransferase (UFGT). These results indicate that, under low sunlight intensity, anthocyanin synthesis in apple peel was limited by the supply of the substrate cyanidin, which was regulated by the DFR activity. Nevertheless, after exposure to high sunlight intensity, the anthocyanin produced in the apple peel was dependent on UFGT activity.

Arabidopsis CBP1 Is a Novel Regulator of Transcription Initiation in Central Cell-Mediated Pollen Tube Guidance.

In flowering plants, sperm cells are delivered to the embryo sac by a pollen tube guided by female signals. Both the gametic and synergid cells contribute to pollen tube attraction. Synergids secrete peptide signals that lure the tube, while the role of the gametic cells is unknown. Previously, we showed that CENTRAL CELL GUIDANCE (CCG) is essential for pollen tube attraction in Arabidopsis thaliana, but the molecular mechanism is unclear. Here, we identified CCG BINDING PROTEIN1 (CBP1) and demonstrated that it interacts with CCG, Mediator subunits, RNA polymerase II (Pol II), and central cell-specific AGAMOUS-like transcription factors. In addition, CCG interacts with TATA-box Binding Protein 1 and Pol II as a TFIIB-like transcription factor. CBP1-knockdown ovules are defective in pollen tube attraction. Expression profiling revealed that cysteine-rich peptide (CRP) transcripts were downregulated in ccg ovules. CCG and CBP1 coregulate a subset of CRPs in the central cell and the synergids, including the attractant LURE1. CBP1 is extensively expressed in multiple vegetative tissues and specifically in the central cell in reproductive growth. We propose that CBP1, via interaction with CCG and the Mediator complex, connects transcription factors and the Pol II machinery to regulate pollen tube attraction.

Cetuximab or nimotuzumab plus intensity-modulated radiotherapy versus cisplatin plus intensity-modulated radiotherapy for stage II-IVb nasopharyngeal carcinoma.

To compare intensity-modulated radiotherapy (IMRT) with cisplatin (CDDP) versus cetuximab (CTX) and nimotuzumab (NTZ) for Stage II-IVb Nasopharyngeal Carcinoma (NPC). A total of 1,837 patients with stage II-IVb NPC who received IMRT plus CTX or NTZ, or CDDP between January 2009 and December 2013 were included in the current analysis. Using propensity scores to adjust for potential prognostic factors, a well-balanced cohort of 715 patients was created by matching each patient who underwent IMRT plus concomitant NTZ/CTX with four patients who underwent IMRT plus concomitant CDDP (1:4). Efficacy and safety were compared between the CTX/NTZ and CDDP groups of this well-balanced cohort. Furthermore, we conducted multivariate analysis and subgroup analysis based on all the 1,837 eligible cases. There was no significant difference between CTX/NTZ group and CDDP group in terms of DFS (3-year, 86.7% vs. 86.2%, p > 0.05), LRRFS (96.2% vs. 96.3%, p > 0.05), DMFS (91.1% vs. 92.3%, p > 0.05) and OS (91.7% vs. 91.9%, p > 0.05). Subgroup analysis demonstrated a significant interaction effect between patients with IMRT plus CTX/NTZ and N3 node stage on LRRFS with the highest risk of loco-regional relapse (HR 8.85, p = 0.001). Significantly increased hematologic toxicities, gastrointestinal reactions were observed in the CDDP group (p < 0.05). Patients of 3.4-4.7% experienced severe hematologic toxicities during the treatment with concomitant CTX and NTZ. Increased rate of CTX related-skin reaction and mucositis was observed in the CTX group. CTX/NTZ used concurrently with IMRT may be comparable to those of the standard CDDP-IMRT combination for maximizing survival for patients with stage II-IVb NPC.