Copper-Catalyzed, Intramolecular Amination of Unactivated C(sp3)-H Bonds through Radical Relay.

Although copper-catalyzed amination of activated C(sp3)-H bonds through radical relay has been developed, amination of unactivated C(sp3)-H bonds is rare. Herein, copper-catalyzed intramolecular amination of remote unactivated C(sp3)-H bonds is reported. The reaction is conducted in a mild and effective manner with moderate to good yields, demonstrating broad tolerance toward various functional groups and exhibiting complete regio- and chemoselectivities. This innovation supplies novel synthetic pathways for the construction of saturated nitrogenated heterocycles.

Neo-adjuvant radiation and intratumoral immunotherapy followed by surgery-NARIS trial for extremity soft tissue sarcoma.

Extremity soft tissue sarcoma (ESTS) is a rare malignant nonepithelial disease, calling for combined modality treatments with surgery to further improve local control rates and long-term survival, especially in patients with multiple local recurrences with or without risk of amputation. In this double-arm, open-label, Phase II clinical trial, we will enroll 30 patients with pathologically confirmed ESTS without nodal involvement or distant metastases. Patients are randomly assigned to the combination treatment group or the radiation monotherapy group. Additionally, tumor and biological samples will be obtained directly before and after neoadjuvant therapy, allowing for studies of immune response and primary drug resistance mechanisms.Clinical Trial Registration: ChiCTR2200060659 (http://www.chictr.org.cn) (ClinicalTrials.gov).

[Box: see text].

An Indoor Fingerprint Positioning Algorithm Based on WKNN and Improved XGBoost.

Considering the low indoor positioning accuracy and poor positioning stability of traditional machine-learning algorithms, an indoor-fingerprint-positioning algorithm based on weighted k-nearest neighbors (WKNN) and extreme gradient boosting (XGBoost) was proposed in this study. Firstly, the outliers in the dataset of established fingerprints were removed by Gaussian filtering to enhance the data reliability. Secondly, the sample set was divided into a training set and a test set, followed by modeling using the XGBoost algorithm with the received signal strength data at each access point (AP) in the training set as the feature, and the coordinates as the label. Meanwhile, such parameters as the learning rate in the XGBoost algorithm were dynamically adjusted via the genetic algorithm (GA), and the optimal value was searched based on a fitness function. Then, the nearest neighbor set searched by the WKNN algorithm was introduced into the XGBoost model, and the final predicted coordinates were acquired after weighted fusion. As indicated in the experimental results, the average positioning error of the proposed algorithm is 1.22 m, which is 20.26-45.58% lower than that of traditional indoor positioning algorithms. In addition, the cumulative distribution function (CDF) curve can converge faster, reflecting better positioning performance.

A Portable Microfluidic-Based Electrochemiluminescence Sensor for Trace Detection of Trenbolone in Natural Water.

In this study, a portable electrochemiluminescence sensor chip was designed for trenbolone (TBE) trace detection in environmental water. First, a stable ECL signal was obtained with low-toxicity 3,4,9,10-perylenetetracarboxylic acid (PTCA) as a luminophore and persulfate (S2O82-) as a coreactant. Second, hollow-structured Cu2MoS4 was introduced as a coreaction accelerator to catalyze S2O82- reduction. The reversible conversion of the mixed-valence transition metal ions in Cu2MoS4 (Cu+/Cu2+ and Mo4+/Mo6+) greatly promoted the generation of the sulfate radical (SO4•-). Meanwhile, the special porous structure of Cu2MoS4 possessed a large specific surface area, thus enhancing its catalytic performance. Based on these enhancement mechanisms, a strong ECL signal was acquired, which improved the detection sensitivity of the constructed sensor. Importantly, a microfluidic chip was introduced for sensing detection, thereby improving the practicality of the sensor. The developed sensor chip was miniature and portable, exhibiting high sensitivity for TBE detection with a wide linear range (10 fg/mL-100 ng/mL) and lower detection limit (3.32 fg/mL). This was of great significance for timely and rapid analysis of steroid pollutants in natural water.

Efficient ABEI-Dissolved O2-Ce(III, IV)-MOF Ternary Electrochemiluminescent System Combined with Self-Assembled Microfluidic Chips for Bioanalysis.

A signal-amplified electrochemiluminescent (ECL) sensor chip was developed for sensitive analysis of procalcitonin (PCT). Herein, we first prepared a self-enhanced luminophore, which enhanced ECL responses through intramolecular reactions. Second, Au-Pd bimetallic nanocrystals and mixed-valence Ce-based metal-organic frameworks (MOFs) were introduced as co-reaction promoters to facilitate the reduction of dissolved O2. Based on the synergistic catalysis of Au and Pd, the spontaneous cyclic reaction of Ce(III)/Ce(IV), and the high electrochemical active surface area of Ce(III, IV) MOF, a large number of superoxide anion radicals (O2•-) and hydroxyl radicals (OH•) were produced. Therefore, the luminescence efficiency of N-(aminobutyl)-N-(ethylisoluminol)-dissolved O2 (ABEI-O2) systems were greatly improved, providing a new prospect for the application of dissolved O2 in ECL analysis. In addition, the affinity peptide ligands were used for the directional connection of antibodies to provide protection for the bioactivity of the proposed sensor. Finally, the microfluidic technology was applied to ECL analysis to integrate the three-electrode detection system into the self-assembled microfluidic chip, which realized the automation and portability of the detection process. The developed sensor showed high sensitivity for PCT detection with a detection limit of 3.46 fg/mL, which possessed positive significance for the clinical diagnosis of sepsis.

Ternary Z-Scheme Ag-Embedded TiO2-Ag2S Nanojunction as a Novel Photoelectrochemical Converter for CD44 Detection.

Nanoarrays (NAs) with stable signal output have become the most promising photoelectrochemical (PEC) biosensing substrate. However, a general issue is that interfacial charge-carrier recombination in a single-component semiconductor cannot be easily prevented, resulting in a low photocurrent density. Herein, a biosensor utilizing a Ag-embedded TiO2-Ag2S nanojunction (TiO2-Ag-Ag2S) as a signal converter was developed for the detection of CD44 protein─a transmembrane glycoprotein highly expressed in breast cancer cells. The ternary Z-scheme heterojunction was prepared by a distinctive scheme in which the Ag layer is introduced onto the surface of rutile TiO2 NAs by magnetron sputtering, whereas the Ag2S is rooted in the local sulfuration of Ag. With a sufficient density of oriented nanorods, TiO2-Ag-Ag2S exhibits a smooth photocurrent output and minimal variation among different batches; it is undoubtedly a satisfactory PEC sensing carrier, which enables highly specific identification of target CD44 on the surface of MDA-MB-231 cells due to DNA strand displacement reactions (SDRs) and host-guest recognition between hyaluronic acid (HA) and CD44. The biosensor shows a sensitive PEC response to CD44 over a wide range of 37 to 5.0 × 105 cells/mL. We can conclude that this approach will provide an alternative solution to breast cancer diagnosis.

Mutasynthesis Generates Antibacterial Benzothiophenic-Containing Nosiheptide Analogues.

Nosiheptide is a bicyclic thiopeptide featuring an indole-containing side ring, which is biologically important in maintaining its potent antibacterial activity. By using mutational biosynthesis, the pharmaceutically significant benzothiophene was introduced into the nosiheptide biosynthetic pathway, resulting in the generation of three bioactive nosiheptide analogues with characteristic benzothiophene-containing side rings. Insights were provided into the transformation relationship of these analogues, which effectively improves the yield of S-NOS-1 with favorable activity against Gram-positive pathogens.

High-bioactivity microfluidic immunosensing platform for electrochemiluminescence determination of CYFRA 21-1 with the introduction of Fe3O4@Cu@Cu2O.

Relying on the electrochemiluminescence (ECL) and microfluidic technology, an immunosensor chip with high bioactivity was designed for sensitive determination of cytokeratin 19 fragment 21-1 (CYFRA 21-1). The mesoporous nanomaterial Fe3O4@Cu@Cu2O as the co-reaction accelerator was used to catalyze the S2O82- to produce more SO4•- to achieve the amplification of the ECL signal. In fact, the generating of SO4•- could not only be done with the aid of the reversible cycles of Fe2+ and Fe3+ and Cu+ and Cu2+, but could be achieved also through the catalase-like function of Fe3O4. What is more, it has also been proved that Fe3O4@Cu@Cu2O exhibited better catalytic performance than single Fe3O4, Cu2O, and Cu@Cu2O, which supported its application in this system. In addition, a portable microfluidic immunosensor chip for CYFRA 21-1-sensitive determination was assembled, which showed high selectivity, sensitivity, and strong universality in clinical cancer screening and diagnosis. It should be noted that HWRGWVC (HWR) was introduced as the antibody fixator to improve the incubation and binding efficiency of the antibody, which increased the ECL intensity and improved the sensitivity of the immunosensor. This strategy provided a new idea for cancer identification and diagnosis in clinical medicine.

Nosiheptide analogues as potential antibacterial agents via dehydroalanine region modifications: Semi-synthesis, antimicrobial activity and molecular docking study.

The frequent and inappropriate use of antibiotics aggravate the variation and evolution of multidrug-resistant bacteria, posing a serious threat to public health. Nosiheptide (NOS) has excellent lethality against a variety of Gram-positive bacteria, however the physical and chemical drawbacks hamper its routine application in clinical practice. In this study, by using NOS as the starting material, a total of 15 NOS analogues (2a-4e) were semi-synthesized via its dehydroalanine residue reacting with monosubstituted anilines. In vitro antimicrobial susceptibilities of NOS and its analogues against two methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE) clinical isolates were determined by broth microdilution assay to determine the minimum inhibitory concentration (MIC). Antimicrobial susceptibility testing data shown that most of the NOS analogues had a better antibacterial effect than the parent compound, with compound 3c exhibiting the highest antibacterial activity against VRE (MIC = 0.0078 mg/L) and MRSA (MIC < 0.0039 mg/L). Molecular docking of synthetic compounds was also performed to verify the binding interactions of NOS analogues with the target. Our data indicated that compound 3c possesses stronger and more complex intermolecular force than other analogues, which is consistent with the results of the biological activity evaluation. Overall, this study identified a number of potential antibacterial NOS analogues that could act as potent therapeutic agents for multidrug-resistant bacterial infections.

Mutation Variants and Co-Mutations as Genomic Modifiers of Response to Afatinib in HER2-Mutant Lung Adenocarcinoma.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-mutant lung cancer remains an orphan of specific targeted therapy. The variable responses to anti-HER2 therapies in these patients prompt us to examine impact of HER2 variants and co-mutations on responses to anti-HER2 treatments in lung cancer. PATIENTS AND METHODS: Patients with stage IV/recurrent HER2-mutant lung cancers identified through next-generation sequencings were recruited from seven hospitals. The study comprised a cohort A to establish the patterns of HER2 variants and co-mutations in lung cancer and a cohort B to assess associations between HER2 variants, co-mutations, and clinical outcomes. RESULTS: The study included 118 patients (cohort A, n = 86; cohort B, n = 32). Thirty-one HER2 variants and 35 co-mutations were detected. Predominant variants were A775_G776insYVMA (49/118, 42%), G778_P780dup (11/118, 9%), and G776delinsVC (9/118, 8%). TP53 was the most common co-mutation (61/118, 52%). In cohort B, objective response rates with afatinib were 0% (0/14, 95% confidence interval [CI], 0%-26.8%), 40% (4/10, 14.7%-72.6%), and 13% (1/8, 0.7%-53.3%) in group 1 (A775_G776insYVMA, n = 14), group 2 (G778_P780dup, G776delinsVC, n = 10), and group 3 (missense mutation, n = 8), respectively (p = .018). Median progression-free survival in group 1 (1.2 months; 95% CI, 0-2.4) was shorter than those in group 2 (7.6 months, 4.9-10.4; hazard ratio [HR], 0.009; 95% CI, 0.001-0.079; p < .001) and group 3 (3.6 months, 2.6-4.5; HR, 0.184; 95% CI, 0.062-0.552; p = .003). TP53 co-mutations (6.317; 95% CI, 2.180-18.302; p = .001) and PI3K/AKT/mTOR pathway activations (19.422; 95% CI, 4.098-92.039; p < .001) conferred additional resistance to afatinib. CONCLUSION: G778_P780dup and G776delinsVC derived the greatest benefits from afatinib among HER2 variants. Co-mutation patterns were additional response modifiers. Refining patient population based on patterns of HER2 variants and co-mutations may help improve the efficacy of anti-HER2 treatment in lung cancer. IMPLICATIONS FOR PRACTICE: Human epidermal growth factor receptor 2 (HER2)-mutant lung cancers are a group of heterogenous diseases with up to 31 different variants and 35 concomitant genomic aberrations. Different HER2 variants exhibit divergent sensitivities to anti-HER2 treatments. Certain variants, G778_P780dup and G776delinsVC, derive sustained clinical benefits from afatinib, whereas the predominant variant, A775_G776insYVMA, is resistant to most anti-HER2 treatments. TP53 is the most common co-mutation in HER2-mutant lung cancers. Co-mutations in TP53 and the PI3K/AKT/mTOR pathway confer additional resistance to anti-HER2 treatments in lung cancer. The present data suggest that different HER2 mutations in lung cancer, like its sibling epidermal growth factor receptor, should be analyzed independently in future studies.

Mutational biosynthesis to generate novel analogs of nosiheptide featuring a fluorinated indolic acid moiety.

Nosiheptide (NOS) is a member of bicyclic thiopeptides possessing a biologically important indolic acid (IA) moiety appended onto the family-characteristic core system. The IA formation relies primarily on NosL, a radical S-adenosylmethionine (SAM) protein that catalyzes a complex rearrangement of the carbon side chain of l-tryptophan, leading to the generation of 3-methyl-2-indolic acid (MIA). Here, we establish an efficient mutational biosynthesis strategy for the structural expansion of the side-ring system of NOS. The nosL-deficient mutant Streptomyces actuosus SL4005 complemented by chemically feeding 6-fluoro-MIA is capable of accumulating two new products. The target product 6'-fluoro-NOS contains an additional fluorine atom at C6 of the IA moiety, in contrast with an unexpected product 6'-fluoro-NOSint that features an open side ring and a bis-dehydroalanine (Dha) tail. The newly obtained 6'-fluoro-NOS displayed equivalent or slightly reduced activities against the tested drug-resistant pathogens compared with NOS, but dramatically decreased water solubility compared with NOS. Our results indicate that the modification of the IA moiety of NOS not only affects its biological activity but also affects its activity which will be key considerations for further modification.

Evaluation of sleep quality in adolescent patients with osteosarcoma using Pittsburgh Sleep Quality Index.

The sleep quality of patients with osteosarcoma (OS) was poorly understood. We aimed to evaluate the prevalence of sleep dysfunction in adolescent patients with OS using the Pittsburgh Sleep Quality Index (PSQI) and to further investigate the psychometric properties of the PSQI in this cohort of patients. Fifty four adolescent patients with OS who underwent chemotherapy treatment in our clinic centre were included. Sleep quality was assessed with the Chinese PSQI. Cronbach's alpha was calculated to evaluate the internal consistency. The confirmatory factor analysis (CFA) was used to determine the fitness of a two-factor structure. Sleep disturbance was observed in 57.4% (31/54) of the patients. Patients with the presence of metastasis or more than 2 cycles of chemotherapy were found to have remarkably higher median global score. The overall Cronbach's alpha was 0.87. The CFA showed an overall comparative fit index of 0.97, a root mean square error of approximation of 0.06 and a standardised root mean square residual of 0.07 respectively. PSQI was a reliable instrument to evaluate the sleep quality of adolescent patients with OS. Over half of the patients may experience sleep disturbance during the treatment. Early psychological interventions were recommended to improve the sleep quality of the patients.

An α/ß-hydrolase fold protein in the biosynthesis of thiostrepton exhibits a dual activity for endopeptidyl hydrolysis and epoxide ring opening/macrocyclization.

Thiostrepton (TSR), an archetypal bimacrocyclic thiopeptide antibiotic that arises from complex posttranslational modifications of a genetically encoded precursor peptide, possesses a quinaldic acid (QA) moiety within the side-ring system of a thiopeptide-characteristic framework. Focusing on selective engineering of the QA moiety, i.e., by fluorination or methylation, we have recently designed and biosynthesized biologically more active TSR analogs. Using these analogs as chemical probes, we uncovered an unusual indirect mechanism of TSR-type thiopeptides, which are able to act against intracellular pathogens through host autophagy induction in addition to direct targeting of bacterial ribosome. Herein, we report the accumulation of 6'-fluoro-7', 8'-epoxy-TSR, a key intermediate in the preparation of the analog 6'-fluoro-TSR. This unexpected finding led to unveiling of the TSR maturation process, which involves an unusual dual activity of TsrI, an α/ß-hydrolase fold protein, for cascade C-N bond cleavage and formation during side-ring system construction. These two functions of TsrI rely on the same catalytic triad, Ser72-His200-Asp191, which first mediates endopeptidyl hydrolysis that occurs selectively between the residues Met-1 and Ile1 for removal of the leader peptide and then triggers epoxide ring opening for closure of the QA-containing side-ring system in a regio- and stereo-specific manner. The former reaction likely requires the formation of an acyl-Ser72 enzyme intermediate; in contrast, the latter is independent of Ser72. Consequently, C-6' fluorination of QA lowers the reactivity of the epoxide intermediate and, thereby, allows the dissection of the TsrI-associated enzymatic process that proceeds rapidly and typically is difficult to be realized during TSR biosynthesis.

CEP55 promotes the proliferation and invasion of tumour cells via the AKT signalling pathway in osteosarcoma.

The molecular mechanisms underlying the development of osteosarcoma (OS) are not fully understood. In this study, we investigated for the first time the clinical significance and biological activity of centrosomal protein 55 (CEP55) in OS. We found that CEP55 was overexpressed in OS, and the CEP55 expression level in OS was correlated with metastasis and poor prognosis. Through in vitro experiments, we confirmed that CEP55 knockdown significantly induced cell cycle arrest at G1 phase and suppressed OS cell proliferation, migration and invasion. In addition, CEP55 knockdown suppressed OS tumour growth in nude mice. Global gene expression profiling of CEP55-silenced MNNG/HOS cells showed that the AKT pathway might be involved in the regulation of OS cell activity. Two downstream factors of AKT signalling, CCND1 and FN1, were found to have significantly higher expression in tumour tissues, and their mRNA expression levels were strongly correlated with CEP55 expression. To conclude, our data suggest that CEP55 can be used as a prognostic marker for OS, highlighting the significance of CEP55 signalling as a putative therapeutic target.

Visible Light-Induced Radical Cyclization of Tertiary Bromides with Isonitriles To Construct Trifluoromethylated Quaternary Carbon Center.

The reaction of trifluoromethylated tertiary bromides with isonitriles induced by visible light is reported. Defluorination was avoided in a radical process. This method provides an efficient approach to compounds containing a trifluoromethylated quaternary carbon center, most of which show excellent potential to be agrochemicals. In addition, the bromides were prepared from perfluoroisobutylene, which is a waste from industry, after several steps. This reaction shows a feasible transfer of harmful waste into useful compounds.

Rhodium(III)-Catalyzed C(sp3)-H Bond Aminocarbonylation with Isocyanates.

Rh(III)-catalyzed C(sp3)-H bond aminocarbonylation of 8-methylquinolines and isocyanates has been realized under mild conditions. This approach is applicable to different aryl and alkyl isocyanates, leading to the synthesis of various α-quinolinyl amide compounds in moderate to excellent yields. A plausible mechanism for this transformation is proposed according to the experimental results obtained.

Visible light-promoted difluoromethylthiolation of aryldiazonium salts.

Difluoromethylthiolation of aryldiazonium salts under photocatalytic conditions with a shelf-stable, easily prepared and inexpensive reagent, PhSO2SCF2H was described. A variety of difluoromethylthioethers were obtained utilizing aryldiazonium salts containing different functional groups. Aryldiazonium salts with a heteroarene moiety were tolerated. Fluorescence quenching experiments indicated that both oxidative and reductive quenching cycles occurred during this process.

Diffusion Tensor Imaging of Lumbar Vertebras in Female Adolescent Idiopathic Scoliosis: Initial Findings.

OBJECTIVE: The purpose of this study was to characterize diffusion tensor imaging (DTI) features of lumbar vertebras in adolescent idiopathic scoliosis (AIS) patients. METHODS: Fifty-two AIS patients and 20 healthy volunteers underwent 3-T magnetic resonance scanning including DTI sequence. The fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values on the convex and concave sides of lumbar vertebras were obtained and compared. RESULTS: The FA and ADC values differed significantly between the convex and concave side of lumbar vertebras in AIS (P < 0.01). The ADC values in AIS differed significantly with healthy volunteers (P < 0.01). The FA values on the convex side of L1 to L2 were significantly lower than L4 to L5 in AIS. The difference of FA values between the concave and convex sides of the apex vertebra correlated significantly with Cobb angle (r = 0.436, P < 0.01). CONCLUSIONS: The convex and concave sides of lumbar vertebras in AIS patients showed different DTI features.

Effect Evaluation of Modified Uvulopalatopharyngoplasty With Low-Temperature Plasma and Selective Nasal Cavity Vasodilatation With Tongue Volume Reduction in Patients With Obstructive Sleep Apnea Hypopnea Syndrome.

OBJECTIVE: To compare the clinical effects of modified uvulopalatopharyngoplasty (UPPP) with low-temperature plasma with selective nasal cavity vasodilatation with tongue volume reduction for obstructive sleep apnea/hypopnea syndrome (OSAHS). METHODS: A retrospective analysis based on 156 patients with serious OSAHS was used for the evaluation. These patients were divided into 2 groups according to surgery methods according to 1:1.s. The patients in observation group accepted modified UPPP with low-temperature plasma and selective nasal cavity vasodilatation with tongue root volume reduction on the basis of fully preparation for surgery, while the patients in the control group accepted normal treatment. The clinic effects, operative complications, postoperative relapse, and other indexes were compared. RESULT: After 6 months of follow-up visit, the general effective rates of the observation group and control groups were 80.77% and 61.54%, the difference was statistically significant (P < 0.05). Besides, the rate complication occurrence in the observation group was also lower than that in the control group. CONCLUSION: The effect of modified UPPP with low-temperature plasma and selective nasal cavity vasodilatation with tongue volume reduction is satisfactory for patients with moderate and severe OSAHS after enough preparation.

Reconstruction of bone defect with allograft and retrograde intramedullary nail for distal tibia osteosarcoma.

BACKGROUND: To investigate the effectiveness of tibiotalocalcaneal arthrodesis with a retrograde nail and allograft in limb salvage surgery for patients with distal tibia osteosarcoma. METHODS: 5 patients diagnosed as distal tibia osteosarcoma underwent ankle arthrodesis with a retrograde nail in our hospital. During the follow-up, radiographic views of the ankle joint were taken in two planes to assess bone healing and axis alignment. Other measurements of outcomes included procedure-related complications, local recurrence, and metastasis. Functional outcomes were evaluated with the Musculoskeletal Tumor Society (MSTS) scoring system. RESULTS: Postoperative complications occurred in 4 patients, including 4 cases of mild subcutaneous fluid and 1 case of screw breakage. All patients showed stable ankle and could stand or walk with the assistance of crutch before the complete union between allograft and host bone. One patient died due to multiple bone and pulmonary metastasis at 1 year after surgery. As for the other 4 patients, they were followed-up regularly for a mean period of 42 months. No local recurrence or distant metastasis occurred in any of these four patients. All the 4 patients expressed satisfaction with the outcome. According to MSTS scale, the mean postoperative functional score was 74.3%±4.4% (range, 70%-81%). CONCLUSIONS: Intramedullary retrograde nail for distal tibia osteosarcoma could produce a satisfactory outcome in terms of functional results and complications. Excellent stabilization of the ankle joint can be achieved through this technique, as it allows patients to perform much earlier postoperative weight-bearing exercise.