Case report: Robust response to sintilimab in advanced distal cholangiocarcinoma with PD-L1 expression and DNA damage repair.

Cholangiocarcinoma (CCA) is a highly heterogeneous tumor that occurs in the bile duct epithelium; adenosquamous carcinoma is a rare pathological subtype of CCA. The clinical treatment of patients with metastatic distal CCA poses significant challenges. We report a 53-year-old female diagnosed with a stage III adenosquamous carcinomas of distal CCA. Metastasis occurred 4 months postoperatively and she was diagnosed with stage IV disease. The patient was treated with Gemcitabine + Oxaliplatin (GEMOX) and Capecitabine + Oxaliplatin (CAPEOX), followed by sintilimab monotherapy. After two cycles of treatment, the patient achieved partial response (PR) and the lesion continued to shrink. After 37 months of follow-up, the patient's liver metastasis had almost completely disappeared, and complete response (CR) was achieved. Moreover, she had more than 46 months of disease progression-free survival (PFS). Immunohistochemical testing showed high expression of PD-L1, and next-generation sequencing revealed the presence of mutations in DNA damage repair (DDR) pathway genes. To the best of our knowledge, this is the first reported case of the successful treatment of metastatic distal adenosquamous CCA with sintilimab alone. Remarkably, patients of CCA with high PD-L1 expression and DDR pathway gene mutations may benefit from sintilimab treatment.

Demineralized bone matrix for repair and regeneration of maxillofacial defects: A narrative review.

OBJECTIVES: Demineralized bone matrix (DBM) is a well-established bone graft material widely accepted by dentists and the public for its favorable osteoconductivity and osteoinductive potential. This article aimed to provide a narrative review of the current therapeutic applications and limitations of DBM in maxillofacial bone defects. STUDY SELECTION, DATA, AND SOURCES: Randomized controlled trials, prospective or retrospective clinical studies, case series and reports, and systematic reviews. MEDLINE, PubMed, and Google Scholar were searched using keywords. CONCLUSIONS: Some evidence supported the therapeutic application of DBM in periodontal intrabony defects, maxillary sinus lifts, ridge preservation, ridge augmentation, alveolar cleft repair, orthognathic surgery, and other regional maxillofacial bone defects. However, the limitations of DBM should be considered when using it, including potential low immunogenicity, instability of osteoinductive potential, handling of the graft material, and patient acceptance. CLINICAL SIGNIFICANCE: With the increasing demand for the treatment of maxillofacial bone defects, DBM is likely to play a greater role as a promising bone graft material. Safe and effective combination treatment strategies and how to maintain a stable osteoinductive potential will be the future challenges of DBM research.

X-Site Substituted 2D Cs2 Pb(SCN)2 Br2 Perovskites for X-Ray Detection.

2D Ruddlesden-Popper (RP) perovskites have been intensively investigated due to their superior stability and outstanding optoelectrical properties. However, investigations on 2D RP perovskites are mainly focused on A-site substituted perovskites and few reports are on X-site substituted perovskites especially in X-ray detection field. Here, X-site substituted 2D RP perovskite Cs2 Pb(SCN)2 Br2 polycrystalline wafers are prepared and systematically studied for X-ray detection. The obtained wafers show a large resistivity of 2.0 × 1010 Ω cm, a high ion activation energy of 0.75 eV, a small current drift of 2.39 × 10-6 nA cm-1 s-1 V-1 , and charge carrier mobility-lifetime product under X-ray as high as 1.29 × 10-4 cm2 V-1 . These merits enable Cs2 Pb(SCN)2 Br2 wafer detectors with a sensitivity of 216.3 µC Gyair -1 cm-2 , a limit of detection of 42.4 nGyair s-1 , and good imaging ability with high spatial resolution of 1.08 lp mm-1 . In addition, Cs2 Pb(SCN)2 Br2 wafer detectors demonstrate excellent operational stability under high working field up to 2100 V cm-1 after continuous X-ray irradiation with a total dose of 45.2 Gyair . The promising features such as short octahedral spacing and weak ion migration will open up a new perspective and opportunity for SCN-based 2D perovskites in X-ray detection.

Discovery of a Bromodomain and Extra Terminal Domain (BET) Inhibitor with the Selectivity for the Second Bromodomain (BD2) and the Capacity for the Treatment of Inflammatory Diseases.

Selective inhibitors targeting the first bromodomain (BD1) or the second bromodomain (BD2) of the bromodomain and extra terminal domain (BET) proteins have triggered extensive research to produce more specific agents. Herein, we described our efforts to design and synthesize a series of selective BET BD2 inhibitors with novel structures. Among them, compound 45 showed single-digit nanomolar potency against BRD4 BD2 (IC50: 1.6 nM) and a 328-fold selectivity for BRD4 BD2 over BRD4 BD1 (IC50: 524 nM). Besides, 45 possessed potent effects on regulating the differentiation of Th17 cells and reducing the levels of Th17-related cytokines by affecting the activation of STAT3 and NF-κB. Further studies demonstrated that 45 had significant therapeutic efficacy in mouse models of imiquimod (IMQ)-induced psoriasis and dextran sulfate sodium (DSS)-induced inflammatory bowel disease (IBD). This work provides a strong foundation for the development of selective BET BD2 inhibitors and the therapeutic strategy for psoriasis and IBD.

Improving the Performance and High-Field Stability of FAPbBr3 Single Crystals in X-Ray Detection with Chenodeoxycholic Acid Additive.

Organometal halide perovskite single crystals are one of the most promising radiation detection materials due to their unique advantages of high absorption coefficient, long carrier diffusion length, and low defect density. However, the severe ion migration in perovskites deteriorates the X-ray detection performance under longtime and high-field operating conditions. This work reports an effective additive of chenodeoxycholic acid (CDCA), which can suppress the ion migration and improve the performance and the operational stability of FAPbBr3 single crystals (SCs) in X-ray detection significantl. The CDCA molecules in precursors effectively suppress the decomposition of FA ions, resulting in a better crystal orientation and stoichiometry. The trace amounts of CDCA residues in FAPbBr3 SCs improve the thermal stability and effectively suppress the ion migration. The resulting detector shows an impressive X-ray sensitivity up to 21 386.88 µC Gyair -1 cm-2 under -500 V and a detection limit of 15.23 nGyair s-1 . The response current of the detector at 225 V cm-1 field is barely changed under the 7200 s irradiation with a dose rate of 1.949 mGyair s-1 . This work provides insights for the additive selection and improving the operational stability of perovskite single crystals for commercial applications.

Significance of thyroid transcription factor 1 and Napsin A for prompting the status of EGFR mutations in lung adenocarcinoma patients.

Background: To evaluate the prompting value of thyroid transcription factor 1 (TTF-1) and Napsin A for the status of epidermal growth factor receptor (EGFR) mutations in an independent cohort of lung adenocarcinomas (LUADs) when genetic testing is unavailable. Methods: In this study, 976 untreated primary LUADs were retrospectively reviewed. The clinical and pathological data, including age, gender, smoking history, predictive values of TTF-1 and Napsin A, EGFR status, and tumor-node-metastasis (TNM) stage were obtained through medical records available in Shanxi Province Cancer Hospital. All patients were divided into 2 groups, a mutant group (n=362) and wild-type group (n=614), according to their EGFR status. The clinical data and the expression of TTF-1 and Napsin A were compared between the 2 groups. TTF-1 and Napsin A are detected by fully automated IHC.PCR was carried out to detect the EGFR mutation. Univariate and multivariate logistic regression analyses were undertaken to distinguish independent factors of EGFR mutations. Results: A total of 362 cases (37.1%) of EGFR mutations were detected, which were more frequent in females, never smokers, lymphatic metastasis, distant metastasis, and the positive expression of TTF-1 and Napsin A. Multivariate analysis indicated that females [odds ratio (OR), 1.950; 95% confidence interval (CI): 1.2958 to 2.938; P=0.001], never smokers (OR, 2.040; 95% CI: 1.345 to 3.094; P=0.001), and the positive expression of TTF-1 (OR, 2.366; 95% CI: 1.440 to 3.887; P=0.001) and Napsin A (OR, 2.295; 95% CI: 1.448 to 3.638; P<0.001) were effective prompting for EGFR mutations. Conclusions: The positive expression of TTF-1 and Napsin A had the prompting value for EGFR mutations in patients with LUAD, and the indicators could be combined with other clinical characteristics to enhance the prediction of the EGFR status in LUAD.

Identification and structural analysis of a selective tropomyosin receptor kinase C (TRKC) inhibitor.

Tropomyosin receptor kinases (TRKs) are a family of TRKA, TRKB and TRKC isoforms. It has been widely reported that TRKs are implicated in a variety of tumors with several Pan-TRK inhibitors currently being used or evaluated in clinical treatment. However, off-target adverse events frequently occur in the clinical use of Pan-TRK inhibitors, which result in poor patient compliance, even drug discontinuation. Although a subtype-selectivity TRK inhibitor may avert the potential off-target adverse events and can act as a more powerful tool compound in the biochemical studies on TRKs, the high sequence similarities of TRKs hinder the development of subtype-selectivity TRK inhibitors. For example, no selective TRKC inhibitor has been reported. Herein, a selective TRKC inhibitor (L13) was disclosed, with potent TRKC inhibitory activity and 107.5-/34.9-fold selectivity over TRKA/B (IC50 TRKA/B/C = 1400 nM, 454 nM, 13 nM, respectively). Extensive molecular dynamics simulations illustrated that key interactions of L13 with the residues and diversely conserved water molecules in the ribose regions of different TRKs may be the structural basis of selectivity. This will provide inspiring insights into the development of subtype-selectivity TRK inhibitors. Moreover, L13 could serve as a tool compound to investigate the distinct biological functions of TRKC and a starting point for further research on drugs specifically targeting TRKC.

Nucleation Engineering in Sprayed MA3Bi2I9 Films for Direct-Conversion X-ray Detectors.

Metal halide perovskite and its derivatives show great promise in X-ray detection. However, large-scale fabrication of high-quality thick perovskite films is still full of challenges due to the complicated crystal nucleation process that always introduces lots of cracks or pinholes in the final perovskite film. Here, a MA3Bi2I9 film was fabricated by the cost-effective, scalable spraying process, and MACl was used as an additive to effectively tune the crystallization process. As a result, a dense MA3Bi2I9 film constituted by large grains was obtained, which has a high carrier mobility of ∼1 cm2 V-1 s-1 and a large activation energy (Ea) for ion migration of 0.91 eV. Thanks to the outstanding optoelectronic characteristics, X-ray detectors with a configuration of ITO/MA3Bi2I9/Au show a sensitivity of 35 µC Gyair-1 cm-2 and a limit of detection (LoD) of 0.14 µGyairs-1, which is outstanding compared with commercial α-Se detectors.

Research progress on oral characterization of Corona Virus Disease 2019 / 口腔疾病防治

@#Corona Virus Disease 2019 (Corona Virus Disease 2019,COVID-19) has become a public health emergency that has attracted global attention because of its large-scale outbreak resulting in numerous human infections and deaths. COVID-19 is a highly contagious respiratory disease caused by novel coronavirus 2019-nCoV. Due to a large number of infections and fast transmission speed, it's significant to diagnose the infected people quickly and detect the asymptomatic infected people as soon as possible. At present, the preliminary screening is judged by the clinical manifestations of the patients, mainly involving the respiratory system, but recent studies have found that the patients infected with COVID-19 have unique oral manifestations, such as taste disturbance, xerostomia, halitosis, inflammation of salivary glands, necrotizing periodontal disease and some of them are earlier than typical symptoms such as dry cough, fever, etc. Paying attention to the oral manifestations of patients can further improve the COVID-19 screening procedure. At present, symptomatic treatment is mainly used for these oral symptoms.

Highly efficient copper halide scintillators for high-performance and dynamic X-ray imaging.

Progress towards high performance X-ray detection and dynamic imaging applications, including nondestructive inspection, homeland security, and medical diagnostics, requires scintillators with a high light yield, a reasonable decay time, low cost, and eco-friendliness. Recently, copper halide scintillators have drawn tremendous attention due to their outstanding radioluminescence performance. Here, we first employed ß-Cs3Cu2Cl5 as a high-performance scintillator, with a photoluminescence quantum yield (PLQY) of 94.6%, a radioluminescence light yield of 34 000 ± 4000 photons per MeV, a low detection limit of 81.7 nGyair s-1, and good operational stability under a total X-ray dose of 174.6 Gyair in air. In addition, this scintillator presents a high spatial resolution of 9.6 lp mm-1 at the modulation transfer function of 0.2 and a superb performance at 60 frames per second in our X-ray imaging system. Overall, this highly efficient scintillator demonstrates outstanding comprehensive performance and shows great potential for broad applications in X-ray detection and dynamic imaging.

Differentiating Central Lung Tumors from Atelectasis with Contrast-Enhanced CT-Based Radiomics Features.

OBJECTIVES: To evaluate the utility of radiomics features in differentiating central lung cancers and atelectasis on contrast-enhanced computed tomography (CT) images. This study is retrospective. MATERIALS AND METHODS: In this study, 36 patients with central pulmonary cancer and atelectasis between July 2013 and June 2018 were identified. A total of 1,653 2D and 2,327 3D radiomics features were extracted from segmented lung cancers and atelectasis on contrast-enhanced CT. The refined features were investigated for usefulness in classifying lung cancer and atelectasis according to the information gain, and 10 models were trained based on these features. The classification model is trained and tested at the region level and pixel level, respectively. RESULTS: Among all the extracted features, 334 2D features and 1,507 3D features had an information gain (IG) greater than 0.1. The highest accuracy (AC) of the region classifiers was 0.9375. The best Dice score, Hausdorff distance, and voxel AC were 0.2076, 45.28, and 0.8675, respectively. CONCLUSIONS: Radiomics features derived from contrast-enhanced CT images can differentiate lung cancers and atelectasis at the regional and voxel levels.

Synthesis of Dipeptide, Amide, and Ester without Racemization by Oxalyl Chloride and Catalytic Triphenylphosphine Oxide.

An efficient triphenylphosphine oxide-catalyzed amidation and esterification for the rapid synthesis of a series of dipeptides, amides, and esters is described. This reaction is applicable to challenging couplings of hindered carboxylic acids with weakly nucleophilic amines or alcohols, giving the products in good yields (67-90%) without racemization. This system employs the highly reactive intermediate Ph3PCl2 as the activator of the carboxylate in a catalytic manner and drives the reaction to completion in a short reaction time (less than 10 min).

Discovery of a Potent FLT3 Inhibitor (LT-850-166) with the Capacity of Overcoming a Variety of FLT3 Mutations.

Secondary mutations of FLT3 have become the main mechanism of FLT3 inhibitor resistance that presents a significant clinical challenge. Herein, a series of pyrazole-3-amine derivatives were synthesized and optimized to overcome the common secondary resistance mutations of FLT3. The structure-activity relationship and molecular dynamics simulation studies illustrated that the ribose region of FLT3 could be occupied to help address the obstacle of secondary mutations. Among those derivatives, compound 67 exhibited potent and selective inhibitory activities against FLT3-ITD-positive acute myeloid leukemia (AML) cells and possessed equivalent potency against transformed BaF3 cells with a variety of secondary mutations. Besides, cellular mechanism assays demonstrated that 67 strongly inhibited phosphorylation of FLT3 and its downstream signaling factors, as well as induced cell cycle arrest and apoptosis in MV4-11 cells. In the MV4-11 xenograft models, 67 exhibited potent antitumor potency without obvious toxicity. Taken together, these results demonstrated that 67 might be a drug candidate for the treatment of FLT3-ITD-positive AML.

High-Performance Perovskite Betavoltaics Employing High-Crystallinity MAPbBr3 Films.

Long-life and self-powered betavoltaic batteries are extremely attractive for many fields that require a long-term power supply, such as space exploration, polar exploration, and implantable medical technology. Organic lead halide perovskites are great potential candidate materials for betavoltaic batteries due to the large attenuation coefficient and the long carrier diffusion length, which guarantee the scale match between the penetration depth of ß particles and the carrier diffusion length. However, the performance of perovskite betavoltaics is limited by the fabrication process of the thick and high-crystallinity perovskite film. In this work, we demonstrated high-performance perovskite betavoltaic cells using thick, high-quality, and wide-band-gap MAPbBr3 polycrystalline films. The solvent annealing method was adopted to improve the crystallinity and eliminate the pinholes in the MAPbBr3 film. The optimal MAPbBr3 betavoltaic cell achieved a power conversion efficiency (PCE) of 5.35% and a maximum output power of 1.203 µW under radiation of electrons of 15 keV with an equivalent activity of 253 mCi. These results are a nearly 50% improvement from previous reports. Effects of the MAPbBr3 perovskite layer thickness on the device performance were also discussed. The mechanisms of film-growth processes and device physics could provide insights for the research community of perovskites and betavoltaics.

High-sensitivity fiber-optic X-ray detectors employing gadolinium oxysulfide composites.

Radiation detection technologies have been applied in broad fields such as security inspection, medical diagnosis, environment monitoring and scientific analysis. Fiber-optic radiation detectors exhibit unique advantages including miniaturization, resistance to water, remote monitoring, and distributable detection. However, the low sensitivity and the high limit-of-detection limit its practical applications. Herein we demonstrated high-performance fiber-optic X-ray detectors with scintillating composites consisting of UV glue and uniformly distributed gadolinium oxysulfide (GADOX) powders. The impacts of the length, thickness and GADOX weight ratio of the composite coating upon the detector performance, were systematically investigated in terms of the generation and the coupling efficiency of radio-luminescence. Besides the high-performance scintillator, the scattering loss and the geometric factor greatly affected the detector performance. A higher sensitivity and lower limit-of-detection could be achieved by increasing the GADOX weight ratio and decreasing the thickness simultaneously. The optimal detector with the highest GADOX weight ratio (70%), exhibited a linear sensitivity to the X-ray dose rate within 31-1575 µGyair/s, and a low limit-of-detection of ∼0.26 µGyair/s at a tube voltage of 120 kV. The mechanism discussed here will provide insightful guidance for further development of fiber-optic radiation detectors and these promising results demonstrate the potential applications of fiber-optic detectors.

Zero-Dimensional Lead-Free FA3Bi2I9 Single Crystals for High-Performance X-ray Detection.

Direct X-ray detectors based on metal halide perovskites and their derivatives exhibit high sensitivity and low limit of detection (LoD). Compared with three-dimensional (3D) hybrid lead halide perovskites, low-dimensional A3Bi2I9 perovskite derivatives (A = Cs, Rb, NH4, CH3NH3(MA)) present better stability, greater environmental friendliness, and comparable X-ray detection performance. Here, we report FA3Bi2I9 (FA= CH(NH2)2) single crystals (SCs) as a new member of the A3Bi2I9 series for X-ray detection, which were prepared by the nucleation-controlled secondary solution constant temperature evaporation (SSCE) method. Centimeter-sized FA3Bi2I9 SCs show a full width at half-maximum (fwhm) of 0.0096°, which is superior to that of recently reported Cs3Bi2I9 (0.058°) and MA3Bi2I9 SCs (0.024°) obtained by inverse temperature crystallization (ITC). The as-grown FA3Bi2I9 SC shows a large resistivity of 7.8 × 1010 Ω cm and a high ion migration activation energy (Ea) of 0.56 eV, which can guarantee a low noise level and good operational stability under a large external bias. The FA3Bi2I9 SC detector exhibits a LoD of 0.2 µGyair s-1, a sensitivity of 598.1 µC Gyair -1 cm -2, and an X-ray detection efficiency of 33.5%, which are much better than those of the commercialized amorphous selenium detector. Results presented here will provide a new lead-free perovskite-type material to achieve green, sensitive, and stable X-ray detectors.

l-Pyroglutamic Acid-Modified CdSe/ZnS Quantum Dots: A New Fluorescence-Responsive Chiral Sensing Platform for Stereospecific Molecular Recognition.

Stereoselective recognition of amino acids is extremely important due to its high chirality-dependent interactions and physiological activities in life activities. We herein report a novel functionalized chiral fluorescent nanosensor prepared from surface modification of CdSe/ZnS quantum dots (QDs) with pyroglutamic acid derivatives, which could serve as a chiral recognition module for fluorescence detection of chiral molecules. The sensor exhibited a unique stereoselective fluorescence response to histidine (His), glutamate (Glu), and dihydroxyphenylalanine (Dopa) and had preferable response performance to l-enantiomers. The enantiomeric fluorescence difference ratios of His, Glu, and Dopa enantiomers were 3.90, 3.40, and 2.49, respectively. The mechanism for the enantiomeric fluorescence recognition was systematically studied through a fluorescence spectrum, fluorescence life, and density functional theory (DFT) calculation. Presumably, the different hydrogen bonding capacity of the chiral recognition module with two enantiomers mainly contributed to the difference in fluorescence signals. As a result, a broader application of the pyroglutamic acid derivative-coated QDs as a fluorescence-responsive chiral sensing platform for enantiomeric detection would be expected.

A One-Pot Ring-Opening/Ring-Closure Sequence for the Synthesis of Polycyclic Spirooxindoles.

One-pot ring-opening/ring-closure process of combining methyleneindolinone with 3-aminooxindole has been developed in this work. Novel polycyclic spirooxindoles were efficiently assembled under mild conditions in high yields (up to 95 %) with moderate to good diastereoselectivities (up to >95:5 d.r.) through simple filtration.

Organocatalytic, Enantioselective, Polarity-Matched Ring-Reorganization Domino Sequence Based on the 3-Oxindole Scaffold.

A one-pot squaramide-catalyzed enantioselective ring-reorganization domino sequence (Michael addition/intramolecular ring-opening/lactamization) of 3-hydroxyoxindole and methyleneindolinone, which can be readily derived from 3-oxindole, has been established in this work. As a result, novel polycyclic quinolinone-spirooxindoles bearing three contiguous chiral centers were efficiently and step-economically assembled under mild conditions in high yields (up to 97%) with excellent enantioselectivities (up to >99% ee) and moderate to good diastereoselectivities (up to >95:5 dr).

Photocatalytic reductive radical-radical coupling of N,N'-cyclicazomethine imines with difluorobromo derivatives.

A visible-light-induced difluoroalkylation of N,N'-cyclicazomethine imine was successfully realized through a novel photoredox radical-radical cross-coupling reaction. This developed protocol exhibits high functional group tolerance and affords a variety of difluorinated 3-pyrazolidinone scaffolds. Extensive mechanistic investigations have been undertaken, well revealing the involvement of a reductive radical-radical coupling pathway.