Direct Tumor Killing and Immunotherapy through Anti-SerpinB9 Therapy.

Cancer therapies kill tumors either directly or indirectly by evoking immune responses and have been combined with varying levels of success. Here, we describe a paradigm to control cancer growth that is based on both direct tumor killing and the triggering of protective immunity. Genetic ablation of serine protease inhibitor SerpinB9 (Sb9) results in the death of tumor cells in a granzyme B (GrB)-dependent manner. Sb9-deficient mice exhibited protective T cell-based host immunity to tumors in association with a decline in GrB-expressing immunosuppressive cells within the tumor microenvironment (TME). Maximal protection against tumor development was observed when the tumor and host were deficient in Sb9. The therapeutic utility of Sb9 inhibition was demonstrated by the control of tumor growth, resulting in increased survival times in mice. Our studies describe a molecular target that permits a combination of tumor ablation, interference within the TME, and immunotherapy in one potential modality.

Recurrent SMARCB1 Mutations Reveal a Nucleosome Acidic Patch Interaction Site That Potentiates mSWI/SNF Complex Chromatin Remodeling.

Mammalian switch/sucrose non-fermentable (mSWI/SNF) complexes are multi-component machines that remodel chromatin architecture. Dissection of the subunit- and domain-specific contributions to complex activities is needed to advance mechanistic understanding. Here, we examine the molecular, structural, and genome-wide regulatory consequences of recurrent, single-residue mutations in the putative coiled-coil C-terminal domain (CTD) of the SMARCB1 (BAF47) subunit, which cause the intellectual disability disorder Coffin-Siris syndrome (CSS), and are recurrently found in cancers. We find that the SMARCB1 CTD contains a basic α helix that binds directly to the nucleosome acidic patch and that all CSS-associated mutations disrupt this binding. Furthermore, these mutations abrogate mSWI/SNF-mediated nucleosome remodeling activity and enhancer DNA accessibility without changes in genome-wide complex localization. Finally, heterozygous CSS-associated SMARCB1 mutations result in dominant gene regulatory and morphologic changes during iPSC-neuronal differentiation. These studies unmask an evolutionarily conserved structural role for the SMARCB1 CTD that is perturbed in human disease.

Spermine enhances antiviral and anticancer responses by stabilizing DNA binding with the DNA sensor cGAS.

Self-nonself discrimination is vital for the immune system to mount responses against pathogens while maintaining tolerance toward the host and innocuous commensals during homeostasis. Here, we investigated how indiscriminate DNA sensors, such as cyclic GMP-AMP synthase (cGAS), make this self-nonself distinction. Screening of a small-molecule library revealed that spermine, a well-known DNA condenser associated with viral DNA, markedly elevates cGAS activation. Mechanistically, spermine condenses DNA to enhance and stabilize cGAS-DNA binding, optimizing cGAS and downstream antiviral signaling. Spermine promotes condensation of viral, but not host nucleosome, DNA. Deletion of viral DNA-associated spermine, by propagating virus in spermine-deficient cells, reduced cGAS activation. Spermine depletion subsequently attenuated cGAS-mediated antiviral and anticancer immunity. Collectively, our results reveal a pathogenic DNA-associated molecular pattern that facilitates nonself recognition, linking metabolism and pathogen recognition.

Chromatin regulation of transcriptional enhancers and cell fate by the Sotos syndrome gene NSD1.

Nuclear receptor-binding SET-domain protein 1 (NSD1), a methyltransferase that catalyzes H3K36me2, is essential for mammalian development and is frequently dysregulated in diseases, including Sotos syndrome. Despite the impacts of H3K36me2 on H3K27me3 and DNA methylation, the direct role of NSD1 in transcriptional regulation remains largely unknown. Here, we show that NSD1 and H3K36me2 are enriched at cis-regulatory elements, particularly enhancers. NSD1 enhancer association is conferred by a tandem quadruple PHD (qPHD)-PWWP module, which recognizes p300-catalyzed H3K18ac. By combining acute NSD1 depletion with time-resolved epigenomic and nascent transcriptomic analyses, we demonstrate that NSD1 promotes enhancer-dependent gene transcription by facilitating RNA polymerase II (RNA Pol II) pause release. Notably, NSD1 can act as a transcriptional coactivator independent of its catalytic activity. Moreover, NSD1 enables the activation of developmental transcriptional programs associated with Sotos syndrome pathophysiology and controls embryonic stem cell (ESC) multilineage differentiation. Collectively, we have identified NSD1 as an enhancer-acting transcriptional coactivator that contributes to cell fate transition and Sotos syndrome development.

Viruses inhibit TIR gcADPR signalling to overcome bacterial defence.

The Toll/interleukin-1 receptor (TIR) domain is a key component of immune receptors that identify pathogen invasion in bacteria, plants and animals1-3. In the bacterial antiphage system Thoeris, as well as in plants, recognition of infection stimulates TIR domains to produce an immune signalling molecule whose molecular structure remains elusive. This molecule binds and activates the Thoeris immune effector, which then executes the immune function1. We identified a large family of phage-encoded proteins, denoted here as Thoeris anti-defence 1 (Tad1), that inhibit Thoeris immunity. We found that Tad1 proteins are 'sponges' that bind and sequester the immune signalling molecule produced by TIR-domain proteins, thus decoupling phage sensing from immune effector activation and rendering Thoeris inactive. Tad1 can also efficiently sequester molecules derived from a plant TIR-domain protein, and a high-resolution crystal structure of Tad1 bound to a plant-derived molecule showed a unique chemical structure of 1 ''-2' glycocyclic ADPR (gcADPR). Our data furthermore suggest that Thoeris TIR proteins produce a closely related molecule, 1''-3' gcADPR, which activates ThsA an order of magnitude more efficiently than the plant-derived 1''-2' gcADPR. Our results define the chemical structure of a central immune signalling molecule and show a new mode of action by which pathogens can suppress host immunity.

P3N-PIPO but not P3 is the avirulence determinant in melon carrying the Wmr resistance against watermelon mosaic virus, although they contain a common genetic determinant.

Viruses employ a series of diverse translational strategies to expand their coding capacity, which produces viral proteins with common domains and entangles virus-host interactions. P3N-PIPO, which is a transcriptional slippage product from the P3 cistron, is a potyviral protein dedicated to intercellular movement. Here, we show that P3N-PIPO from watermelon mosaic virus (WMV) triggers cell death when transiently expressed in Cucumis melo accession PI 414723 carrying the Wmr resistance gene. Surprisingly, expression of the P3N domain, shared by both P3N-PIPO and P3, can alone induce cell death, whereas expression of P3 fails to activate cell death in PI 414723. Confocal microscopy analysis revealed that P3N-PIPO targets plasmodesmata (PD) and P3N associates with PD, while P3 localizes in endoplasmic reticulum in melon cells. We also found that mutations in residues L35, L38, P41, and I43 of the P3N domain individually disrupt the cell death induced by P3N-PIPO, but do not affect the PD localization of P3N-PIPO. Furthermore, WMV mutants with L35A or I43A can systemically infect PI 414723 plants. These key residues guide us to discover some WMV isolates potentially breaking the Wmr resistance. Through searching the NCBI database, we discovered some WMV isolates with variations in these key sites, and one naturally occurring I43V variation enables WMV to systemically infect PI 414723 plants. Taken together, these results demonstrate that P3N-PIPO, but not P3, is the avirulence determinant recognized by Wmr, although the shared N terminal P3N domain can alone trigger cell death.IMPORTANCEThis work reveals a novel viral avirulence (Avr) gene recognized by a resistance (R) gene. This novel viral Avr gene is special because it is a transcriptional slippage product from another virus gene, which means that their encoding proteins share the common N-terminal domain but have distinct C-terminal domains. Amazingly, we found that it is the common N-terminal domain that determines the Avr-R recognition, but only one of the viral proteins can be recognized by the R protein to induce cell death. Next, we found that these two viral proteins target different subcellular compartments. In addition, we discovered some virus isolates with variations in the common N-terminal domain and one naturally occurring variation that enables the virus to overcome the resistance. These results show how viral proteins with common domains interact with a host resistance protein and provide new evidence for the arms race between plants and viruses.

Manipulation of the polarization state of the focus based on a slab plasmon waveguide.

A focusing nanostructure with tailored polarization properties based on a metal-dielectric slab waveguide combined with plasmonic slits and gratings is proposed. The polarization state of the focus light can be controlled with overlapping a transverse magnetic (TM) focus and a transverse electric (TE) focus, which are formed by focusing the waveguide modes into free space via grating coupling, extraordinary transmission, and plasmonic beaming. We demonstrated that it is possible to achieve either multiple foci or a single focal spot of the transmitted light with tailored polarization states by judicious design of the structure parameter and the polarization state of the incident light.

Designing high thermally stable deep red phosphors based on low thermal expansion coefficients for optical applications.

Mn4+-activated oxide phosphors with low cost and unique luminescent properties have been considered as a promising candidate for various optical applications, while the search for high thermal stable red-emitting phosphors is still a huge challenge. In our work, we find and unveil the relationship between luminescence thermal quenching behavior and thermal expansion coefficients (α/10-6 K-1) based on double-perovskite niobate phosphors Ca2LnNbO6:Mn4+ (Ln3+ = Y3+, Gd3+, La3+, or Lu3+). It can be concluded that the phosphors with low thermal expansion coefficients contribute to high thermal stability. Subsequently, Ca2LuNbO6:Mn4+ accomplishes accurate temperature testing and high-CRI white light-emitting diodes. Thus, a thermal expansion coefficient strategy is a new guide to select the appropriate substrate with high thermal stability for an Mn4+-activated emitter.

Luminescence thermometry driven by a support vector machine: a strategy toward precise thermal sensing.

Luminescence thermometry is a promising non-contact temperature measurement technique, but improving the precision and reliability of this method remains a challenge. Herein, we propose a thermal sensing strategy based on a machine learning. By using Gd3Ga5O12: Er3+-Yb3+ as the sensing medium, a support vector machine (SVM) is preliminarily adopted to establish the relationship between temperature and upconversion emission spectra, and the sensing properties are discussed through the comparison with luminescence intensity ratio (LIR) and multiple linear regression (MLR) methods. Within a wide operating temperature range (303-853 K), the maximum and the mean measurement errors actualized by the SVM are just about 0.38 and 0.12 K, respectively, much better than the other two methods (3.75 and 1.37 K for LIR and 1.82 and 0.43 K for MLR). Besides, the luminescence thermometry driven by the SVM presents a high robustness, although the spectral profiles are distorted by the interferences within the testing environment, where, however, LIR and MLR approaches become ineffective. Results demonstrate that the SVM would be a powerful tool to be applied on the luminescence thermometry for achieving a high sensing performance.

Risk Factors for Postoperative Complications of Laparoscopic Right Colectomy: A Post Hoc Analysis of the RELARC Trial.

BACKGROUND: There is concern regarding the possibility of postoperative complications for laparoscopic right colectomy. OBJECTIVE: To evaluate the risk factors for postoperative complications for patients undergoing laparoscopic right colectomy. DESIGN: This was an observational study. SETTINGS: This was a post hoc analysis of a prospective, multicenter, randomized controlled trial (RELARC trial, NCT02619942). PATIENTS: Patients included in the modified intention-to-treat analysis in the RELARC trial were all enrolled in this study. MAIN OUTCOME MEASURES: Risk factors for postoperative complications were identified using univariate and multivariable logistic regression analysis. RESULTS: Of 995 patients, 206 (20.7%) had postoperative complications. Comorbidity ( p = 0.02; OR: 1.544; 95% CI, 1.077-2.212) and operative time >180 minutes ( p = 0.03; OR: 1.453; 95% CI, 1.032-2.044) were independent risk factors for postoperative complications, whereas female sex ( p = 0.04; OR: 0.704; 95% CI, 0.506-0.980) and extracorporeal anastomosis ( p < 0.001; OR: 0.251; 95% CI, 0.166-0.378) were protective factors. Eighty patients (8.0%) had overall surgical site infection, 53 (5.3%) had incisional surgical site infection, and 33 (3.3%) had organ/space surgical site infection. Side-to-side anastomosis was a risk factor for overall surgical site infection ( p < 0.001; OR: 1.912; 95% CI, 1.118-3.268) and organ/space surgical site infection ( p = 0.005; OR: 3.579; 95% CI, 1.455-8.805). The extracorporeal anastomosis was associated with a reduced risk of overall surgical site infection ( p < 0.001; OR: 0.239; 95% CI, 0.138-0.413), organ/space surgical site infection ( p = 0.002; OR: 0.296; 95% CI, 0.136-0.646), and incisional surgical site infection ( p < 0.001; OR: 0.179; 95% CI, 0.099-0.322). Diabetes ( p = 0.039; OR: 2.090; 95% CI, 1.039-4.205) and conversion to open surgery ( p = 0.013; OR: 5.403; 95% CI, 1.437-20.319) were risk factors for incisional surgical site infection. LIMITATIONS: Due to the retrospective nature, the key limitation is the lack of prospective documentation and standardization regarding the perioperative management of these patients, such as preoperative optimization, bowel preparation regimens, and antibiotic regimens, which may be confounder factors of complications. All surgeries were performed by experienced surgeons, and the patients enrolled were relatively young, generally healthy, and without obesity. It is unclear whether the results will be generalizable to obese and other populations worldwide. CONCLUSIONS: Male sex, comorbidity, prolonged operative time, and intracorporeal anastomosis were independent risk factors for postoperative complications of laparoscopic right colectomy. Side-to-side anastomosis was associated with an increased risk of organ/space surgical site infection. Extracorporeal anastomosis could reduce the incidence of overall surgical site infection. Diabetes and conversion to open surgery were associated with an increased risk of incisional surgical site infection. See Video Abstract . CLINICALTRIALSGOV IDENTIFIER: NCT02619942. FACTORES DE RIESGO DE COMPLICACIONES POSOPERATORIAS EN COLECTOMA DERECHA LAPAROSCPICA UN ANLISIS POST HOC DEL ENSAYO RELARC: ANTECEDENTES:Existe preocupación con respecto a la posibilidad de complicaciones postoperatorias en colectomía derecha laparoscópica.OBJETIVO:Evaluar los factores de riesgo de complicaciones postoperatorias en pacientes sometidos a colectomía derecha laparoscópica.DISEÑO:Este fue un estudio observacional.ENTORNO CLINICO:Este fue un análisis post hoc de un ensayo controlado aleatorio, multicéntrico y prospectivo: ensayo RELARC (NCT02619942).PACIENTES:Todos los pacientes incluidos en el análisis de intención de tratar modificado en el ensayo RELARC fueron inscritos en este estudio.PRINCIPALES MEDIDAS DE RESULTADO:Los factores de riesgo de complicaciones posoperatorias se identificaron mediante análisis de regresión logística univariante y multivariable.RESULTADOS:De 995 pacientes, 206 (20,7%) tuvieron complicaciones postoperatorias. La comorbilidad ( p = 0,02, OR: 1,544, IC 95%: 1,077-2,212) y el tiempo operatorio >180 min ( p = 0,03, OR: 1,453, IC 95%: 1,032-2,044) fueron factores de riesgo independientes de complicaciones postoperatorias. Mientras que el sexo femenino ( p = 0,04, OR: 0,704, IC 95%: 0,506-0,980) y la anastomosis extracorpórea ( p < 0,001, OR: 0,251, IC 95%: 0,166-0,378) fueron factores protectores. 80 (8,0%) tenían infección general del sitio quirúrgico (ISQ), 53 (5,3%) tenían ISQ incisional y 33 (3,3%) tenían ISQ de órgano/espacio. Anastomosis latero-lateral fue un factor de riesgo para la ISQ general ( p < 0,001, OR: 1,912, IC 95%: 1,118-3,268) y ISQ órgano/espacio ( p = 0,005, OR: 3,579, IC 95%: 1,455-8.805). La anastomosis extracorpórea se asoció con un riesgo reducido de ISQ general ( p < 0,001, OR: 0,239, IC 95%: 0,138-0,413), ISQ órgano/espacio ( p = 0,002, OR: 0,296, IC 95%: 0,136-0,646), e ISQ incisional ( p < 0,001, OR: 0,179, IC 95%: 0,099-0,322). Diabetes ( p = 0,039, OR: 2,090, IC 95%: 1,039-4,205) y la conversión a cirugía abierta ( p = 0,013, OR: 5,403, IC 95%: 1,437-20,319) fueron factores de riesgo para ISQ incisional.LIMITACIONES:Debido a la naturaleza retrospectiva, la limitación clave es la falta de documentación prospectiva y estandarización sobre el manejo perioperatorio de estos pacientes, como la optimización preoperatoria, los regímenes de preparación intestinal y los regímenes de antibióticos, que pueden ser factores de confusión de las complicaciones. Todas las cirugías fueron realizadas por cirujanos experimentados y los pacientes inscritos eran relativamente jóvenes, generalmente sanos y no obesos. No está claro si los resultados serán generalizables a las poblaciones obesas y de otro tipo en todo el mundo.CONCLUSIONES:Sexo masculino, comorbilidad, el tiempo operatorio prolongado y anastomosis intracorpórea fueron factores de riesgo independientes de complicaciones postoperatorias de la colectomía derecha laparoscópica. Anastomosis latero-lateral se asoció con un mayor riesgo de SSI de órgano/espacio. La anastomosis extracorpórea podría reducir la incidencia de ISQ general. La diabetes y la conversión a cirugía abierta se asociaron con un mayor riesgo de ISQ incisional. (Traducción- Dr. Francisco M. Abarca-Rendon ).

Synthesis of Carboranylated Dihydropyrrolo[1,2-a]quinoxalines and Dihydroindolo[1,2-a]quinoxalines by BF3·OEt2-Catalyzed Heterocyclization of C-Formyl-o-carboranes and Investigation of Their Oxidation Stability.

A BF3·OEt2-catalyzed synthesis of carboranylated dihydropyrrolo[1,2-a]quinoxalines and dihydroindolo[1,2-a]quinoxalines in 30-99% yields is presented through the heterocyclization of various C-modified C-formyl-o-carboranes with 1-(2-aminophenyl)-pyrroles/indoles. A systematic comparative investigation of their oxidation stability in air confirmed that 4-carboranyl-4,5-dihydropyrrolo[1,2-a]quinoxaline had better stability than the 4-phenyl analogue. A cage-deboronation reaction for N-acetyl-substituted carboranylated dihydropyrrolo[1,2-a]quinoxaline produced the corresponding 7,8-nido-carborane cesium salt. A kinetic resolution was also realized to obtain an optically pure carboranylated N-heterocycle scaffold bearing a carborane cage carbon-bonded chiral stereocenter.

A nomogram model for predicting postoperative prognosis in patients with aneurysmal subarachnoid hemorrhage using preoperative biochemical indices.

OBJECTIVE: The nutritional status and inflammatory responses of patients with aneurysmal subarachnoid hemorrhage (aSAH) play a vital prognostic role. We investigated the relationship between preoperative prognostic nutritional index (PNI)、neutrophil/albumin ratio (NAR)、platelet/albumin ratio (PAR) and other factors and the clinical prognosis of patients who underwent clipping for aSAH and its predictive model. METHODS: The clinical data of 212 patients with aSAH who underwent neurosurgery at Nanyang Central Hospital between 2018 and 2023 were retrospectively analyzed. Based on the Glasgow Outcome Scale (GOS) score at 6 months postoperatively, the patients were categorized into two groups: poor (GOSI-III) and good (GOSIV-V) prognosis groups. Multivariate logistic regression analysis was performed to determine the predictive value of preoperative PNI、NAR、PAR、hyperlipidemia and Glasgow Coma Scale (GCS) for prognosis. Furthermore, nomograms and prognostic prediction models were constructed. Receiver operating characteristic curves and area under the curve (AUC) were utilized to determine the predictive values. RESULTS: Multivariate logistic regression analysis revealed that PNI (OR = 1.250, 95%CI 1.060 ~ 1.475, P = 0.008), NAR (OR = 0.000, 95%CI 0.000 ~ 0.004, P = 0.000), PAR(OR = 0.515, 95%CI 0.283 ~ 0.937, P = 0.030), hyperlipidemia (OR = 4.627, 95%CI 1.166 ~ 18.367, P = 0.029), and GCS(OR = 1.446, 95%CI 1.041 ~ 2.008, P = 0.028) are independent risk factors for poor postoperative prognosis. The total score of the nomogram was 200, and the AUC value was 0.972. CONCLUSIONS: PNI and NAR can reflect the nutritional status and inflammatory responses of patients.They are significantly associated with the postoperative prognosis of patients with aSAH. Comprehensively analyzing PNI and NAR combined with other clinical indicators can more effectively guide treatment and help predict prognosis.

Surface hopping simulations on charge photogeneration in conjugated polymers.

The mechanism of charge photogeneration in neat conjugated polymers has long been controversial and a unified explanation has not been achieved so far. In this paper, we use a surface hopping method to simulate the excited-state dynamics of a system composed of five π-stacked polymer chains. In this system, polaron pairs (PPs) with large electron-hole distance can be seen as free charges. The surface hopping method is based on the Pariser-Parr-Pople (PPP) Hamiltonian and the excited states of the system are calculated with configuration interaction singles (CIS) formalism. During the simulations, the yields of PPs and free charges are calculated using a statistical method. By comparison, it is found that impurity and excess energy have significant effects on the yields of PPs and free charges. Free charges are difficult to be generated in neat systems with small excess energy. Free charges come from direct dissociation of high-energy excitons.

Concentration-resistance relationship and PK/PD evaluation of danofloxacin against emergence of resistant Pasteurella multocida in an in vitro dynamic model.

AIMS: This study aimed to assess the pharmacokinetic/pharmacodynamic (PK/PD) targets of danofloxacin to minimize the risk of selecting resistant Pasteurella multocida mutants and to identify the mechanisms underlying their resistance in an in vitro dynamic model, attaining the optimum dosing regimen of danofloxacin to improve its clinical efficacy based on the mutant selection window (MSW) hypothesis. METHODS AND RESULTS: Danofloxacin at seven dosing regimens and 5 days of treatment were simulated to quantify the bactericidal kinetics and enrichment of resistant mutants upon continuous antibiotic exposure. The magnitudes of PK/PD targets associated with different efficacies were determined in the model. The 24 h area under the concentration-time curve (AUC) to minimum inhibitory concentration (MIC) ratios (AUC24h/MIC) of danofloxacin associated with bacteriostatic, bactericidal and eradication effects against P. multocida were 34, 52, and 64 h. This translates to average danofloxacin concentrations (Cav) over 24 h being 1.42, 2.17, and 2.67 times the MIC, respectively. An AUC/MIC-dependent antibacterial efficacy and AUC/mutant prevention concentration (MPC)-dependent enrichment of P. multocida mutants in which maximum losses in danofloxacin susceptibility occurred at a simulated AUC24h/MIC ratio of 72 h (i.e. Cav of three times the MIC). The overexpression of efflux pumps (acrAB-tolC) and their regulatory genes (marA, soxS, and ramA) was associated with reduced susceptibility in danofloxacin-exposed P. multocida. The AUC24h/MPC ratio of 19 h (i.e. Cav of 0.8 times the MPC) was determined to be the minimum mutant prevention target value for the selection of resistant P. multocida mutants. CONCLUSIONS: The emergence of P. multocida resistance to danofloxacin exhibited a concentration-dependent pattern and was consistent with the MSW hypothesis. The current clinical dosing regimen of danofloxacin (2.5 mg kg-1) may have a risk of treatment failure due to inducible fluoroquinolone resistance.

Cyclic GMP-AMP synthase recognizes the physical features of DNA.

Cyclic GMP-AMP synthase (cGAS) is a major cytosolic DNA sensor that plays a significant role in innate immunity. Upon binding to double stranded DNA (dsDNA), cGAS utilizes GTP and ATP to synthesize the second messenger cyclic GMP-AMP (cGAMP). The cGAMP then binds to the adapter protein stimulator of interferon genes (STING) in the endoplasmic reticulum, resulting in the activation of the transcription factor interferon regulatory factor 3 (IRF3) and subsequent induction of type I interferon. An important question is how cGAS distinguishes between self and non-self DNA. While cGAS binds to the phosphate backbone of DNA without discrimination, its activation is influenced by physical features such as DNA length, inter-DNA distance, and mechanical flexibility. This suggests that the recognition of DNA by cGAS may depend on these physical features. In this article we summarize the recent progress in research on cGAS-STING pathway involved in antiviral defense, cellular senescence and anti-tumor response, and focus on DNA recognition mechanisms based on the physical features.

Robot-assisted radical resection of colorectal cancer using the KangDuo surgical robot versus the da Vinci Xi robotic system: short-term outcomes of a multicentre randomised controlled noninferiority trial.

BACKGROUND: The KangDuo surgical robot (KD-SR-01) was recently developed in China. This study aims to evaluate the short-term outcomes of KD-SR-01 for colorectal cancer surgery. METHODS: This is a multicentre randomised controlled noninferiority trial conducted in three centers in China. Enrolled patients were randomly assigned at a 1:1 ratio to receive surgery using the KD-SR-01 system (KD group) or the da Vinci Xi (DV) robotic system (DV group). The primary endpoint was the success rate of operation. The second endpoints were surgical outcomes, pathological outcomes, and postoperative outcomes. RESULTS: Between July 2022 and May 2023. A total of 100 patients were included in the trial and randomly assigned to the KD group (50 patients) and the DV group (50 patients). All cases were completed successfully without conversion to laparoscopic surgery. The time to flatus and the incidence of postoperative complications of Clavien-Dindo grade II or higher grade were comparable between the two groups. Surgeons reported a high level of comfort with the KD-SR-01 system. In the subgroup analysis of different operative procedures, there were no significant differences in docking time, console time, blood loss, and the length of the incision for extraction between the two groups. There were no differences in pathological outcomes including maximum tumor diameter, circumferential resection margin, distal resection margin, and number of harvested lymph nodes. CONCLUSIONS: The KD-SR-01 system was a viable option for colorectal cancer robotic surgery, with acceptable short-term outcomes comparable to the da Vinci Xi robotic system.

Citrulline facilitates the glycolysis, proliferation, and metastasis of lung cancer cells by regulating RAB3C.

Lung cancer (LC) is one of the major malignant diseases threatening human health. The study aimed to identify the effect of citrulline on the malignant phenotype of LC cells and to further disclose the potential molecular mechanism of citrulline in regulating the development of LC, providing a novel molecular biological basis for the clinical treatment of LC. The effects of citrulline on the viability, proliferation, migration, and invasion of LC cells (A549, H1299) were validated by CCK-8, colony formation, EdU, and transwell assays. The cell glycolysis was assessed via determining the glucose uptake, lactate production, ATP levels, extracellular acidification rate (ECAR), and oxygen consumption rate (OCR). RNA-seq and molecular docking were performed to screen for citrulline-binding target proteins. Western blotting experiments were conducted to examine the expression of related signaling pathway molecules. In addition, the impacts of citrulline on LC growth in vivo were investigated by constructing mouse models. Citrulline augmented the viability of LC cells in a concentration and time-dependent manner. The proliferation, migration, invasion, glycolysis, and EMT processes of LC cells were substantially enhanced after citrulline treatment. Bioinformatics analysis indicated that citrulline could bind to RAB3C protein. Western blotting results indicated that citrulline activated the IL-6/STAT3 pathway by binding to RAB3C. In addition, animal experiments disclosed that citrulline promoted tumor growth in mice. Citrulline accelerated the glycolysis and activated the IL6/STAT3 pathway through the RAB3C protein, consequently facilitating the development of LC.

miR-29b-3p targetedly regulates VEGF to inhibit tumor progression and cisplatin resistance through Nrf2/HO-1 signaling pathway in non-small cell lung cancer.

BACKGROUNDS: Non-small cell lung carcinoma (NSCLC) is a common type of lung cancer. Prior investigations have elucidated the pivotal role of miR-29b-3p in restraining tumor growth and metastasis. Nonetheless, it remains to be determined whether miR-29b-3p can effectively suppress NSCLC progression and enhance the sensitivity of NSCLC cells to cisplatin. This investigation sought to determine the mechanism by which miR-29b-3p inhibited the advancement of NSCLC and mitigated resistance to cisplatin. METHODS: We initially assessed miR-29b-3p and VEGF levels in NSCLC tissues and cell lines. Next, miR-29b-3p expression was elevated in NSCLC cell lines H1975 and A549 by overexpression plasmid transfection. Following this, a sequence of molecular biology experiments was conducted to evaluate the impact of miR-29b-3p on the biological behaviors of NSCLC cells and their resistance to cisplatin. Additionally, we predicted VEGF was a target gene of miR-29b-3p by bioinformatics analysis. We next employed western blot to evaluate the protein expression of Nrf2 and HO-1 in NSCLC cells. Finally, we elucidated the effects of VEGF and Nrf2/HO-1pathway on NSCLC progression and cisplatin resistance by in vitro assays. RESULTS: In comparison to paracancerous tissues and human normal lung epithelial cells, the expression of miR-29b-3p was notably reduced and VEGF expression was clearly elevated in NSCLC tissues and cells. Moreover, miR-29b-3p upregulated obviously suppressed the biological activities of NSCLC cells and increased their sensitivity to cisplatin. Furthermore, in NSCLC cells, miR-29b-3p bound to VEGF and negatively regulate its transcription. Additionally, miR-29b-3p overexpression also inhibited the Nrf2/HO-1 signaling pathway. Finally, the overexpression of VEGF and the activation of the Nrf2/HO-1 pathway reversed miR-29b-3p-mediated inhibitory effect on biological behaviors of NSCLC cells and increased the cisplatin resistance. CONCLUSION: Our findings indicate that miR-29b-3p impedes NSCLC cells' biological behaviors and augments their sensitivity to cisplatin by targeting VEGF to modulate the Nfr2/HO-1 signaling pathway.

Multi-Sensor-Assisted Low-Cost Indoor Non-Visual Semantic Map Construction and Localization for Modern Vehicles.

With the transformation and development of the automotive industry, low-cost and seamless indoor and outdoor positioning has become a research hotspot for modern vehicles equipped with in-vehicle infotainment systems, Internet of Vehicles, or other intelligent systems (such as Telematics Box, Autopilot, etc.). This paper analyzes modern vehicles in different configurations and proposes a low-cost, versatile indoor non-visual semantic mapping and localization solution based on low-cost sensors. Firstly, the sliding window-based semantic landmark detection method is designed to identify non-visual semantic landmarks (e.g., entrance/exit, ramp entrance/exit, road node). Then, we construct an indoor non-visual semantic map that includes the vehicle trajectory waypoints, non-visual semantic landmarks, and Wi-Fi fingerprints of RSS features. Furthermore, to estimate the position of modern vehicles in the constructed semantic maps, we proposed a graph-optimized localization method based on landmark matching that exploits the correlation between non-visual semantic landmarks. Finally, field experiments are conducted in two shopping mall scenes with different underground parking layouts to verify the proposed non-visual semantic mapping and localization method. The results show that the proposed method achieves a high accuracy of 98.1% in non-visual semantic landmark detection and a low localization error of 1.31 m.

Exploring the therapeutic mechanisms of resveratrol for treating arecoline-induced malignant transformation in oral epithelial cells: insights into hub targets.

BACKGROUND: Betel nut chewing is a significant risk factor for oral cancer due to arecoline, its primary active component. Resveratrol, a non-flavonoid polyphenol, possesses anti-cancer properties. It has been shown to inhibit arecoline-induced oral malignant cells in preliminary experiments but the underlying mechanism remains unclear. This research therefore aimed to explore the potential therapeutic targets of resveratrol in treating arecoline-induced oral cancer. METHODS: Data mining identified common targets and hub targets of resveratrol in arecoline-induced oral cancer. Gene set variation analysis (GSVA) was used to score and validate the expression and clinical significance of these hub targets in head and neck cancer (HNC) tissues. Molecular docking analysis was conducted on the hub targets. The effect of resveratrol intervention on hub targets was verified by experiments. RESULTS: Sixty-one common targets and 15 hub targets were identified. Hub targets were highly expressed in HNC and were associated with unfavorable prognoses. They played a role in HNC metastasis, epithelial-mesenchymal transition, and invasion. Their expression also affected immune cell infiltration and correlated negatively with sensitivity to chemotherapeutic agents such as bleomycin and docetaxel. Experiments demonstrated that resveratrol down-regulated the expression of the hub targets, inhibited their proliferation and invasion, and induced apoptosis. CONCLUSION: Resveratrol inhibits the arecoline-induced malignant phenotype of oral epithelial cells by regulating the expression of some target genes, suggesting that resveratrol may be used not only as an adjuvant treatment for oral cancer, but also as an adjuvant for oral cancer prevention due to its low toxicity and high efficacy. © 2024 Society of Chemical Industry.