Nonpathogenic E. coli engineered to surface display cytokines as a new platform for immunotherapy.

Given the safety, tumor tropism, and ease of genetic manipulation in non-pathogenic Escherichia coli (E. coli), we designed a novel approach to deliver biologics to overcome poor trafficking and exhaustion of immune cells in the tumor microenvironment, via the surface display of key immune-activating cytokines on the outer membrane of E. coli K-12 DH5α. Bacteria expressing murine decoy-resistant IL18 mutein (DR18) induced robust CD8+ T and NK cell-dependent immune responses leading to dramatic tumor control, extending survival, and curing a significant proportion of immune-competent mice with colorectal carcinoma and melanoma. The engineered bacteria demonstrated tumor tropism, while the abscopal and recall responses suggested epitope spreading and induction of immunologic memory. E. coli K-12 DH5α engineered to display human DR18 potently activated mesothelin-targeting CAR NK cells and safely enhanced their trafficking into the tumors, leading to improved control and survival in xenograft mice bearing mesothelioma tumor cells, otherwise resistant to NK cells. Gene expression analysis of the bacteria-primed CAR NK cells showed enhanced TNFα signaling via NFkB and upregulation of multiple activation markers. Our novel live bacteria-based immunotherapeutic platform safely and effectively induces potent anti-tumor responses in otherwise hard-to-treat solid tumors, motivating further evaluation of this approach in the clinic.

EvHandPose: Event-Based 3D Hand Pose Estimation With Sparse Supervision.

Event camera shows great potential in 3D hand pose estimation, especially addressing the challenges of fast motion and high dynamic range in a low-power way. However, due to the asynchronous differential imaging mechanism, it is challenging to design event representation to encode hand motion information especially when the hands are not moving (causing motion ambiguity), and it is infeasible to fully annotate the temporally dense event stream. In this paper, we propose EvHandPose with novel hand flow representations in Event-to-Pose module for accurate hand pose estimation and alleviating the motion ambiguity issue. To solve the problem under sparse annotation, we design contrast maximization and hand-edge constraints in Pose-to-IWE (Image with Warped Events) module and formulate EvHandPose in a weakly-supervision framework. We further build EvRealHands, the first large-scale real-world event-based hand pose dataset on several challenging scenes to bridge the real-synthetic domain gap. Experiments on EvRealHands demonstrate that EvHandPose outperforms previous event-based methods under all evaluation scenes, achieves accurate and stable hand pose estimation with high temporal resolution in fast motion and strong light scenes compared with RGB-based methods, generalizes well to outdoor scenes and another type of event camera, and shows the potential for the hand gesture recognition task.

FAM20A is a golgi-localized Type II transmembrane protein.

Family with sequence similarity 20, member A (FAM20A) is a pseudo-kinase in the secretory pathway and is essential for enamel formation in humans. Here we examine if FAM20A is a membrane-associated protein. We show that the full-length FAM20A can be purified from HEK293 cells transfected with a FAM20A-expresing construct. Further, it is only found in the membrane fraction, but not in the soluble fraction, of cell lysate. Consistently, it is not secreted out of the expressing cells. Moreover, it is co-localized with GM130, a cis-Golgi network marker, and membrane topology analysis indicates that it has its C-terminus oriented towards the lumen of the organelle. Our results support that FAM20A is a Type II transmembrane protein within the secretory compartments.

Enhancing the electric charge output in LiNbO3-based piezoelectric pressure sensors.

Lithium niobate (LiNbO3) single crystals are a kind of ferroelectric material with a high piezoelectric coefficient and Curie temperature, which is suitable for the preparation of piezoelectric pressure sensors. However, there is little research reporting on the use of LiNbO3 single crystals to prepare piezoelectric pressure sensors. Therefore, in this paper, LiNbO3 was used to prepare piezoelectric pressure sensors to study the feasibility of using LiNbO3 single crystals as a sensitive material for piezoelectric pressure sensors. In addition, chemical mechanical polishing (CMP) technology was used to prepare LiNbO3 crystals with different thicknesses to study the influence of these LiNbO3 crystals on the electric charge output of the sensors. The results showed that the sensitivity of a 300 µm sample (0.218 mV kPa-1) was about 1.23 times that of a 500 µm sample (0.160 mV kPa-1). Low-temperature polymer heterogeneous integration and oxygen plasma activation technologies were used to realize the heterogeneous integration of LiNbO3 and silicon to prepare piezoelectric pressure sensors, which could significantly improve the sensitivity of the sensor by approximately 16.06 times (2.569 mV kPa-1) that of the original sample (0.160 mV kPa-1) due to an appropriate residual stress that did not shatter LiNbO3 or silicon, thus providing a possible method for integrating piezoelectric pressure sensors and integrated circuits.

What can be done to protect toddlers from air pollution: Current evidence.

PROBLEM: Toddlers are more prone to exposure to widely distributed air pollution and to health damage from it. However, systematic summaries of evidence on protective behaviors against air pollution for toddlers are lacking. OBJECTIVE: To identify currently available evidence on protective behaviors against air pollution for toddlers. METHODS: The literature retrieval was performed in selected databases, limited from 2002 to 2022. Studies meeting the following criteria were included and praised: 1) clinical practice guideline, systematic review, expert consensus, recommended practice, randomized control test (RCT) or cohort study published in Chinese or English; 2) studies reporting effects of protective behaviors against air pollution on toddlers' health outcomes or providing recommendation on these behaviors. The evidence in the included studies was extracted, synthesized and graded for evidence summary. RESULTS: Studies (N = 19) were used for evidence summary development and 35 pieces of best evidence were synthesized, which were divided into three categories, including "avoiding or reducing air pollution generation", "removing existing air pollution", and "avoiding or reducing exposure to existing air pollution". CONCLUSIONS: More evidence is needed to identify protective measures against outdoor air pollution and tobacco smoke. Research in the future should focus on the safety, effectiveness and feasibility of universal measures implemented in toddlers, and try to develop protective measures specific to toddlers which highlight their special nature. IMPLICATIONS: The results of this study can help pediatric nurses provide individualized advice and assistance for toddlers and their families, and conduct research on the effectiveness of toddler-targeting protective behaviors more efficiently.

Voluntary wheel running prevents formation of membrane attack complexes and myelin degradation after peripheral nerve injury.

Regular aerobic activity is associated with a reduced risk of chronic pain in humans and rodents. Our previous studies in rodents have shown that prior voluntary wheel running can normalize redox signaling at the site of peripheral nerve injury, attenuating subsequent neuropathic pain. However, the full extent of neuroprotection offered by voluntary wheel running after peripheral nerve injury is unknown. Here, we show that six weeks of voluntary wheel running prior to chronic constriction injury (CCI) reduced the terminal complement membrane attack complex (MAC) at the sciatic nerve injury site. This was associated with increased expression of the MAC inhibitor CD59. The levels of upstream complement components (C3) and their inhibitors (CD55, CR1 and CFH) were altered by CCI, but not increased by voluntary wheel running. Since MAC can degrade myelin, which in turn contributes to neuropathic pain, we evaluated myelin integrity at the sciatic nerve injury site. We found that the loss of myelinated fibers and decreased myelin protein which occurs in sedentary rats following CCI was not observed in rats with prior running. Substitution of prior voluntary wheel running with exogenous CD59 also attenuated mechanical allodynia and reduced MAC deposition at the nerve injury site, pointing to CD59 as a critical effector of the neuroprotective and antinociceptive actions of prior voluntary wheel running. This study links attenuation of neuropathic pain by prior voluntary wheel running with inhibition of MAC and preservation of myelin integrity at the sciatic nerve injury site.

Screening the components in multi-biological samples and the comparative pharmacokinetic study in healthy and depression model rats of Suan-Zao-Ren decoction combined with a network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Suanzaoren Decoction (SZRD) is a classic traditional Chinese prescription, which has been commonly used for treating insomnia, depression and other nerve system diseases for a long time. AIM OF THIS STUDY: The present study aimed to explore the metabolic profiles in multi-biological samples and pharmacokinetic mechanism between healthy and depression model rats combined with a network pharmacology approach after administration of SZRD. MATERIALS AND METHODS: In our study, an ultra-high performance liquid chromatography (UPLC)-Q-Exactive Orbitrap Mass Spectrometry method was firstly used to study the prototype components and metabolites of SZRD in plasma, brain, urine, and feces between healthy and depressed rats. The possible metabolic pathways were also speculated. Then a network pharmacological study was conducted on the components in the plasma of model rats. According to the above components screened by network pharmacology and the other reported representative active components, the comparative pharmacokinetic study was established for the simultaneous determination of mangiferin, spinosin, ferulic acid, liquiritin, formononetin. magnoflorine and isoliquiritin between healthy and depression model rats. Finally, molecular docking was used to validate the binding affinity between key potential targets and active components in pharmacokinetics. RESULTS: A total of 115 components were identified in healthy rats, and 101 components were identified in model rats. The prototype components and metabolites in plasma, brain, urine, and feces were also distinguished. The main metabolic pathways included phase I and phase II metabolic reactions, such as dehydrogenation, oxidation, hydroxylation, gluconaldehyde conjugation, glutathione conjugation and so on. These results provided a basis for the further study of antidepressive pharmacokinetic and pharmacological action in SZRD. Then, according to the degree value of network pharmacological study, it was predicted that 10 components and 10 core targets, which involved in the critical pathways such as neuroactive ligand-receptor interaction, cyclic adenosine monophosphate (cAMP) signaling pathway, serotonergic synapse, phosphatidylinositol-3 kinase (PI3K)-Akt signaling pathway, etc. Finally, the established pharmacokinetic method was successfully applied to compare the pharmacokinetic behavior of these 7 active components in plasma of healthy and depressed rats after oral administration of SZRD. It showed that except magnoflorine, the pharmacokinetic parameters of each component were different between healthy and depressed rats. Molecular docking analysis also indicated that the active compounds in pharmacokinetics could bind tightly to the key targets of network pharmacological study. CONCLUSION: This study may provide important information for studying the action mechanism of SZRD in treating depression.

Short-term Exposure to Air Pollution and the Incidence and Mortality of Stroke: A Meta-Analysis.

BACKGROUND: The relationship between short-term exposure to various air pollutants [particulate matter <10 µm (PM10), particulate matter <2.5 µm (PM2.5), nitrogen dioxide (NO2), sulfur dioxide (SO2), carbon monoxide, and ozone (O3)] and the incidence and mortality of stroke remain unclear. REVIEW SUMMARY: We conducted a comprehensive search across databases, including PubMed, Web of Science, and others. A random-effects model was employed to estimate the odds ratios (OR) and their 95% CIs. Short-term exposure to PM10, PM2.5, NO2, SO2, and O3 was associated with increased stroke incidence [per 10 µg/m3 increase in PM2.5: OR = 1.005 (95% CI: 1.004-1.007), per 10 µg/m3 increase in PM10: OR = 1.006 (95% CI: 1.004-1.009), per 10 µg/m3 increase in SO2: OR = 1.034 (95% CI: 1.020-1.048), per 10 µg/m3 increase in NO2: OR = 1.029 (95% CI: 1.015-1.043), and O3 for per 10 µg/m3 increase: OR: 1.006 (95% CI: 1.004-1.007)]. In addition, short-term exposure to PM2.5, PM10, SO2, and NO2 was correlated with increased mortality from stroke [per 10 µg/m3 increase in PM2.5: OR = 1.010 (95% CI: 1.006-1.013), per 10 µg/m3 increase in PM10: OR = 1.004 (95% CI: 1.003-1.006), per 10 µg/m3 increase in SO2: OR = 1.013 (95% CI: 1.007-1.019) and per 10 µg/m3 increase in NO2: OR = 1.012 (95% CI: 1.008-1.015)]. CONCLUSION: Reducing outdoor air pollutant levels may yield a favorable outcome in reducing the incidence and mortality associated with strokes.

Engineered Bacillus subtilis as oral probiotics to target circulating lactic acid.

Lactic acid or lactate, a key byproduct of anaerobic glycolysis, plays pivotal roles in routine metabolism. An increase in lactic acid is observed in various pathological conditions such as cancer, diabetes, genetic mitochondrial disease, and aging. While several groups have proposed small molecule inhibitors to reduce circulating lactic acid, there are few clinically relevant ways to manage acute or chronic elevations in lactic acid in patients. In addition, recent evidence suggests that lactic acid exchanges between the gut, blood, and peripheral tissues, and professional marathon runners harbor specific gut microbial species that more efficiently metabolize lactic acid. Inspired by these findings, this work sought to engineer probiotic B. subtilis strains to express lactate oxidase that could increase circulating lactic acid catabolism after delivery to the gut. After optimization, oral administration of engineered B. subtilis to the gut of mice reduced the elevation in blood lactic acid levels after exogenous lactic acid challenge without affecting normal gut microbiota composition, inflammation or liver enzymes. Taken together, through the oral delivery of engineered probiotics to the gastrointestinal tract, our proof-of-concept study offers a new opportunity to therapeutically target diseases where blood lactic acid is elevated, and provides a new approach to "knocking down" metabolites to help understand the roles of metabolites in host physiological and pathological processes.

Engineering Tripartite Gene Editing Machinery for Highly Efficient Non-Viral Targeted Genome Integration.

Non-viral DNA donor template has been widely used for targeted genomic integration by homologous recombination (HR). This process has become more efficient with RNA guided endonuclease editor system such as CRISPR/Cas9. Circular single stranded DNA (cssDNA) has been harnessed previously as a genome engineering catalyst (GATALYST) for efficient and safe targeted gene knock-in. Here we developed enGager, a system with enhanced GATALYST associated genome editor, comprising a set of novel genome editors in which the integration efficiency of a circular single-stranded (css) donor DNA is elevated by directly tethering of the cssDNA to a nuclear-localized Cas9 fused with ssDNA binding peptides. Improvements in site-directed genomic integration and expression of a knocked-in DNA encoding GFP were observed at multiple genomic loci in multiple cell lines. The enhancement of integration efficiency, compared to unfused Cas9 editors, ranges from 1.5- to more than 6-fold, with the enhancement most pronounced for transgenes of > 4Kb in length in primary cells. enGager-enhanced genome integration prefers ssDNA donors which, unlike traditional dsDNA donors, are not concatemerized or rearranged prior to and during integration Using an enGager fused to an optimized cssDNA binding peptide, exceptionally efficient, targeted integration of the chimeric antigen receptor (CAR) transgene was achieved in 33% of primary human T cells. Enhanced anti-tumor function of these CAR-T primary cells demonstrated the functional competence of the transgenes. The 'tripartite editors with ssDNA optimized genome engineering' (TESOGENASE™) systems help address the efficacy needs for therapeutic gene modification while avoiding the safety and payload size limitations of viral vectors currently used for CAR-T engineering.

Correction: Silver complexes with substituted terpyridines as promising anticancer metallodrugs and their crystal structure, photoluminescence, and DNA interactions.

Correction for 'Silver complexes with substituted terpyridines as promising anticancer metallodrugs and their crystal structure, photoluminescence, and DNA interactions' by Jiahe Li et al., Dalton Trans., 2023, 52, 9607-9621, https://doi.org/10.1039/D2DT03463H.

Inverse design of chiral functional films by a robotic AI-guided system.

Artificial chiral materials and nanostructures with strong and tuneable chiroptical activities, including sign, magnitude, and wavelength distribution, are useful owing to their potential applications in chiral sensing, enantioselective catalysis, and chiroptical devices. Thus, the inverse design and customized manufacturing of these materials is highly desirable. Here, we use an artificial intelligence (AI) guided robotic chemist to accurately predict chiroptical activities from the experimental absorption spectra and structure/process parameters, and generate chiral films with targeted chiroptical activities across the full visible spectrum. The robotic AI-chemist carries out the entire process, including chiral film construction, characterization, and testing. A machine learned reverse design model using spectrum embedded descriptors is developed to predict optimal structure/process parameters for any targeted chiroptical property. A series of chiral films with a dissymmetry factor as high as 1.9 (gabs ~ 1.9) are identified out of more than 100 million possible structures, and their feasible application in circular polarization-selective color filters for multiplex laser display and switchable circularly polarized (CP) luminescence is demonstrated. Our findings not only provide chiral films with the highest reported chiroptical activity, but also have great fundamental value for the inverse design of chiroptical materials.

TESOGENASE, An Engineered Nuclease Editor for Enhanced Targeted Genome Integration.

Non-viral DNA donor template has been widely used for targeted genomic integration by homologous recombination (HR). This process has become more efficient with RNA guided endonuclease editor system such as CRISPR/Cas9. Circular single stranded DNA (cssDNA) has been harnessed previously as a g enome engineering c atalyst (GATALYST) for efficient and safe targeted gene knock-in. However, the engineering efficiency is bottlenecked by the nucleoplasm trafficking and genomic tethering of cssDNA donor, especially for extra-large transgene integration. Here we developed enGager, en hanced G ATALYST a ssociated g enome e ditor system by fusion of nucleus localization signal (NLS) peptide tagged Cas9 with various single stranded DNA binding protein modules through a GFP reporter Knock-in screening. The enGager system assembles an integrative genome integration machinery by forming tripartite complex for engineered nuclease editors, sgRNA and ssDNA donors, thereby facilitate the nucleus trafficking of DNA donors and increase their active local concentration at the targeted genomic site. When applied for genome integration with cssDNA donor templates to diverse genomic loci in various cell types, these enGagers outperform unfused editors. The enhancement of integration efficiency ranges from 1.5- to more than 6-fold, with the effect being more prominent for > 4Kb transgene knock-in in primary cells. We further demonstrated that enGager mediated enhancement for genome integration is ssDNA, but less dsDNA dependent. Using one of the mini-enGagers, we demonstrated large chimeric antigen receptor (CAR) transgene integration in primary T cells with exceptional efficiency and anti-tumor function. These tripartite e ditors with s sDNA o ptimized g enome en gineering system (TESOGENASE TM ) add a set of novel endonuclease editors into the gene-editing toolbox for potential cell and gene therapeutic development based on ssDNA mediated non-viral genome engineering. Highlight: A reporter Knock-in screening establishes enGager system to identify TESOGENASE editor to improving ssDNA mediated genome integrationMini-TESOGENASEs developed by fusing Cas9 nuclease with novel ssDNA binding motifsmRNA mini-TESOGENASEs enhance targeted genome integration via various non-viral delivery approachesEfficient functional CAR-T cell engineering by mini-TESOGENASE.

3D Printing of Interpenetrating Network Flexible Hydrogels with Enhancement of Adhesiveness.

3D printing of hydrogels has been widely explored for the rapid fabrication of complex soft structures and devices. However, using 3D printing to customize hydrogels with both adequate adhesiveness and toughness remains a fundamental challenge. Here, we demonstrate mussel-inspired (polydopamine) PDA hydrogel through the incorporation of a classical double network (2-acrylamido-2-methylpropanesulfonic acid) PAMPS/(polyacrylamide) PAAm to achieve simultaneously tailored adhesiveness, toughness, and biocompatibility and validate the 3D printability of such a hydrogel into customized architectures. The strategy of combining PDA with PAMPS/PAAm hydrogels leads to favorable adhesion on either hydrophilic or hydrophobic surfaces. The hydrogel also shows excellent flexibility, which is attributed to the reversible cross-linking of PDA and PAMPS, together with the long-chain PAAm cross-linking network. Among them, the reversible cross-linking of PDA and PAMPS is capable of dissipating mechanical energy under deformation. Meanwhile, the long-chain PAAm network contributes to maintaining a high deformation capability. We establish a theoretical framework to quantify the contribution of the interpenetrating networks to the overall toughness of the hydrogel, which also provides guidance for the rational design of materials with the desired properties. Our work manifests a new paradigm of printing adhesive, tough, and biocompatible interpenetrating network hydrogels to meet the requirements of broad potential applications in biomedical engineering, soft robotics, and intelligent and superabsorbent devices.

Potential Value of FAPI PET/CT in the Detection and Treatment of Fibrosing Mediastinitis: Preclinical and Pilot Clinical Investigation.

Fibrosing mediastinitis (FM) is a rare proliferative disease within the mediastinum that leads to pulmonary hypertension, which has been regarded as a major cause of death. This study aims to evaluate the potential value of fibroblast activation protein inhibitor (FAPI)-PET/CT in the integration of diagnosis and treatment of FM through targeting FAPI in fibrosis rats and provide a theoretical basis for clinical management of FM patients. By performing a 18F-FAPI PET/CT scan, the presence of FAPI-avid in the fibrotic lesion was determined. Through a fibrosis rat model, 18F-FAPI-74 was used for lesion imaging and 177Lu-FAPI-46 was utilized to investigate the potential therapeutic effect on FM in vivo. In addition, biodistribution analysis and radiation dosimetry were carried out. With the 177Lu-FAPI-46 pharmacokinetic data of rats as the input, the estimated dose for female adults was computed, which can provide some useful information for the safe application of radiolabeled FAPI in the detection and treatment of FM in patients. Then, major findings on the use of FAPI PET/CT and SPECT/CT in FM were presented. 18F-FAPI-74 showed a high-level uptake in FM lesions of patients (SUVmax 7.94 ± 0.26), which was also observed in fibrosis rats (SUVmax 2.11 ± 0.23). Consistently, SPECT/CT imaging of fibrosis rats also revealed that 177Lu-FAPI-46-avid was active for up to 60 h in fibrotic lesions. In addition to this robust diagnostic performance, a possible therapeutic impact was evaluated as well. It turned out that no spontaneous healing of lesions was observed in the control group, whereas there was complete healing on day 9, day 11, and day 14 in the 30, 100, and 300 MBq groups, respectively. With a significant difference in the free of event rate in the Kaplan-Meier curve among four groups (P < 0.001), a dose of 300 MBq displayed the best therapeutic effect, and no obvious damage was observed in the kidney. Furthermore, organ-absorbed doses and an effective dose (0.4320 mSv/MBq) of 177Lu-FAPI-46 presumed for patients were assumed to give a preliminary indication of its safe use in clinical practice. In conclusion, 18F-FAPI-46 PET/CT can be a potentially valuable tool for the diagnosis of FM. Of note, 177Lu-FAPI-46 may be a novel and safe radiolabeled reagent for the integration of diagnosis and treatment of FM.

SMG-BERT: integrating stereoscopic information and chemical representation for molecular property prediction.

Molecular property prediction is a crucial task in various fields and has recently garnered significant attention. To achieve accurate and fast prediction of molecular properties, machine learning (ML) models have been widely employed due to their superior performance compared to traditional methods by trial and error. However, most of the existing ML models that do not incorporate 3D molecular information are still in need of improvement, as they are mostly poor at differentiating stereoisomers of certain types, particularly chiral ones. Also,routine featurization methods using only incomplete features are hard to obtain explicable molecular representations. In this paper, we propose the Stereo Molecular Graph BERT (SMG-BERT) by integrating the 3D space geometric parameters, 2D topological information, and 1D SMILES string into the self-attention-based BERT model. In addition, nuclear magnetic resonance (NMR) spectroscopy results and bond dissociation energy (BDE) are integrated as extra atomic and bond features to improve the model's performance and interpretability analysis. The comprehensive integration of 1D, 2D, and 3D information could establish a unified and unambiguous molecular characterization system to distinguish conformations, such as chiral molecules. Intuitively integrated chemical information enables the model to possess interpretability that is consistent with chemical logic. Experimental results on 12 benchmark molecular datasets show that SMG-BERT consistently outperforms existing methods. At the same time, the experimental results demonstrate that SMG-BERT is generalizable and reliable.

Prospective Correlation of Magnetic Resonance Tumor Regression Grade With Pathologic Outcomes in Total Neoadjuvant Therapy for Rectal Adenocarcinoma.

PURPOSE: Total neoadjuvant therapy (TNT) is a newly established standard treatment for rectal adenocarcinoma. Current methods to communicate magnitudes of regression during TNT are subjective and imprecise. Magnetic resonance tumor regression grade (MR-TRG) is an existing, but rarely used, regression grading system. Prospective validation of MR-TRG correlation with pathologic response in patients undergoing TNT is lacking. Utility of adding diffusion-weighted imaging to MR-TRG is also unknown. METHODS: We conducted a multi-institutional prospective imaging substudy within NRG-GI002 (ClinicalTrials.gov identifier: NCT02921256) examining the ability of MR-based imaging to predict pathologic complete response (pCR) and correlate MR-TRG with the pathologic neoadjuvant response score (NAR). Serial MRIs were needed from 110 patients. Three radiologists independently, then collectively, reviewed each MRI for complete response (mriCR), which was tested for positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity with pCR. MR-TRG was examined for association with the pathologic NAR score. All team members were blinded to pathologic data. RESULTS: A total of 121 patients from 71 institutions met criteria: 28% were female (n = 34), 84% White (n = 101), and median age was 55 (24-78 years). Kappa scores for T- and N-stage after TNT were 0.38 and 0.88, reflecting fair agreement and near-perfect agreement, respectively. Calling an mriCR resulted in a kappa score of 0.82 after chemotherapy and 0.56 after TNT reflected near-perfect agreement and moderate agreement, respectively. MR-TRG scores were associated with pCR (P < .01) and NAR (P < .0001), PPV for pCR was 40% (95% CI, 26 to 53), and NPV was 84% (95% CI, 75 to 94). CONCLUSION: MRI alone is a poor tool to distinguish pCR in rectal adenocarcinoma undergoing TNT. However, the MR-TRG score presents a now validated method, correlated with pathologic NAR, which can objectively measure regression magnitude during TNT.

Silver complexes with substituted terpyridines as promising anticancer metallodrugs and their crystal structure, photoluminescence, and DNA interactions.

Six silver hexafluoroantimonate complexes (1-6) with 4'-(4'-substituted-phenyl)-2,2':6',2''-terpyridine compounds bearing hydrogen (L1), methyl (L2), methylsulfonyl (L3), chloro (L4), bromo (L5) and iodo (L6) were prepared and characterized by 1H NMR, 13C NMR, IR, elemental analysis and single crystal X-ray diffraction. All the compounds exhibit interesting photoluminescence properties in the solid state and solution. In vitro data demonstrate that all of them show higher antiproliferative activities than cisplatin against three human carcinoma cell lines, A549, Eca-109 and MCF-7. Compound 3 exhibits the lowest IC50 value (2.298 µM) against A549 cell lines, which is 2.963 µM for 4 against Eca-109 and 1.830 µM for 1 against MCF-7. For silver halogen-substituted terpyridine compounds, their anticancer activities decrease following the sequence of -Cl, -Br, and -I substituents. The comparison results show that their anticancer activity is significantly higher than that of their free ligands. The DNA interaction was studied by fluorescence titration, circular dichroism spectroscopy and molecular modeling methods. Spectrophotometric results reveal that the compounds have strong affinity binding with DNA as intercalators and molecular docking studies indicate that the binding is contributed by the π-π stacking and hydrogen bonds. The DNA binding ability of the complexes has been correlated with their anticancer activities, which could potentially provide a new rationale for the future design of terpyridine-based metal complexes with antitumor potential.

Targeting Fusobacterium nucleatum through chemical modifications of host-derived transfer RNA fragments.

Host mucosal barriers possess an arsenal of defense molecules to maintain host-microbe homeostasis such as antimicrobial peptides and immunoglobulins. In addition to these well-established defense molecules, we recently reported small RNAs (sRNAs)-mediated interactions between human oral keratinocytes and Fusobacterium nucleatum (Fn), an oral pathobiont with increasing implications in extra-oral diseases. Specifically, upon Fn infection, oral keratinocytes released Fn-targeting tRNA-derived sRNAs (tsRNAs), an emerging class of noncoding sRNAs with gene regulatory functions. To explore potential antimicrobial activities of tsRNAs, we chemically modify the nucleotides of the Fn-targeting tsRNAs and demonstrate that the resultant tsRNA derivatives, termed MOD-tsRNAs, exhibit growth inhibitory effect against various Fn type strains and clinical tumor isolates without any delivery vehicle in the nanomolar concentration range. In contrast, the same MOD-tsRNAs do not inhibit other representative oral bacteria. Further mechanistic studies uncover the ribosome-targeting functions of MOD-tsRNAs in inhibiting Fn. Taken together, our work provides an engineering approach to targeting pathobionts through co-opting host-derived extracellular tsRNAs.

Synthesis, characterization and anticancer properties: A series of highly selective palladium(II) substituted-terpyridine complexes.

Ten new palladium(II) complexes [PdCl(L1-10)]Cl have been synthesized by the reaction of palladium(II) chloride and ten 4'-(substituted-phenyl)-2,2':6',2''-terpyridine ligands bearing hydrogen(L1), p-hydroxyl(L2), m-hydroxyl (L3), o-hydroxyl (L4), methyl (L5), phenyl (L6), fluoro (L7), chloro (L8), bromo (L9), or iodo (L10). Their structures were confirmed by FT-IR, 1H NMR, elemental analysis and/or single crystal X-ray diffraction analysis. Their in vitro anticancer activities were investigated based on five cell lines, including four cancer cell lines (A549, Eca-109, Bel-7402, MCF-7) and one normal cell line (HL-7702). The results show that these complexes possess a strong killing effect on the cancer cells but a weak proliferative inhibition on the normal cells, implying their high inhibitory selectivity for the proliferation of the cancer cell lines. Flow cytometry characterization reveals that these complexes affect cell proliferation mainly in the G0/G1 phase and induce the late apoptotic of the cells. The quantity of palladium(II) ion in extracted DNA was determined by ICP-MS, which proved that these complexes target genomic DNA. And the strong affinity of the complexes with CT-DNA were confirmed by UV-Vis spectrum and circular dichroism (CD). The possible binding modes of the complexes with DNA were further explored by molecular docking. As the concentration of complexes 1-10 gradually increases, the fluorescence intensity of bovine serum albumin (BSA) decreases by a static quenching mechanism.