Pelvic packing or endovascular interventions: Which should be given priority in managing hemodynamically unstable pelvic fractures? A systematic review and a meta-analysis.

Background: Pelvic fractures in trauma patients can be associated with substantial massive hemorrhage. Hemostasis interventions mainly consist of pelvic packing (PP) and endovascular intervention (EI), such as angiography-embolization (AE) and resuscitative endovascular balloon occlusion of the aorta (REBOA). Whether PP or EI should be prioritized for the management of hemodynamic unstable patients with pelvic fractures remains under debate. This meta-analysis aimed to establish the evidence-based recommendations for the management of hemodynamic unstable patients. Materials and methods: PubMed, CENTRAL, and EMBASE databases were searched for articles published from January 1, 2000 to January 31, 2023. Eligible studies, such as retrospective cohort studies, propensity score matching studies, prospective cohort studies, observational cohort studies, quasi-randomized clinical trials evaluating PP and EI (AE or REBOA) for the management of patients with hemodynamically unstable pelvic fractures, were included. Mean Difference (MD), relative risk (RR), and 95 % confidence intervals (CI) were calculated using fixed- or random-effects models depending on the heterogeneity of included trials. We compared the effectiveness of the two methods in terms of mortality, unstable fracture pattens, injury severity score (ISS), systolic blood pressure (SBP), lactate (LA), base deficiency (BE), hemoglobin preoperatively, blood transfusion requirement, the time to and of operation, complications. Results: Overall, 15 trials enrolling 1136 patients were analyzed, showing a total mortality rate of 28.4 % (323/1136). No effect of PP preference on the ISS (PP 36.4 ± 10.4 vs. EI 34.5 ± 12.7), SBP (PP 81.1 ± 24.3 mmHg vs. EI 94.2 ± 32.4 mmHg), LA (PP 4.66 ± 2.72 mmol/L vs. 4.85 ± 3.45 mmol/L), BE (PP 8.14 ± 5.64 mmol/L vs. 6.66 ± 5.68 mmol/L), and unstable fracture patterns (RR = 1.10, 95 % CI [0.63, 1.92]) was observed. PP application was associated with lower preoperative hemoglobin level (PP 8.11 ± 2.28 g/dL vs. EI 8.43 ± 2.43 g/dL, p < 0.05), more preoperative transfusion (MD = 2.53, 95 % CI [0.01, 5.06]), less postoperative transfusion within the first 24 h (MD = -1.09, 95 % CI [-1.96, -0.22]), shorter waiting time to intervention (MD = -0.93, 95 % CI [-1.54, -0.31]), and shorter operation time of intervention (MD = -0.41, 95 % CI [-0.52, -0.30]). PP had lower mortality rate owing to uncontrolled hemorrhage in the acute phase (RR = 0.41, 95 % CI [0.22, 0.79]). There was neither difference in mortality due to other complications (RR = 1.60, 95 % CI [0.79, 3.24]), nor in total mortality (RR = 0.92, 95%CI [0.49, 1.74]) (p > 0.05). Conclusions: PP showed advantages of reducing the amount of postoperative transfusion, shortening the time of waiting and operating, and decreasing mortality due to uncontrolled hemorrhage in the acute phase without raising the odds of mortality due to complications. PP, a reliable hemostatic method, should be prioritized for resuscitating most pelvic fractures with hemodynamically unstable, especially in case of bleeding from veins and fracture sites, as well as inadequate EI.

Do we need reshape rTNM staging system for ipsilateral breast tumor recurrence of breast cancer? A population-based, propensity score matched cohort study.

BACKGROUND: The aim of the study was to explore the role of recurrent TNM (rTNM) staging in predicting prognosis for ipsilateral breast tumor recurrence (IBTR) and determine the optimal treatment strategy for IBTR. METHOD: IBTR cases were identified from the Surveillance, Epidemiology, and End Results (SEER) database spanning the years 2000-2018. Cox proportional hazards analysis was performed to examine factors associated with overall survival (OS) and breast cancer-specific survival (BCSS). Propensity score matching (PSM) was employed to match IBTR with primary early breast cancer (EBC) based on clinicopathological characteristics. Investigations into the impact of different therapies were also included. RESULTS: Of the 4375 IBTR cases included in the study, the 5-year OS was 87.1%, 71.6% and 58.7% in rTNM stages I, II and III, respectively. After PSM, while IBTR patients had worse survival to primary EBC patients, prognosis of IBTR for different rTNM stage always closely aligned with the corresponding stage of primary EBC. Repeat breast-conserving surgery (BCS) with radiation therapy was equivalent to mastectomy with respect to OS and BCSS. Chemotherapy was favorable for OS and BCSS in estrogen receptor (ER)-negative IBTR or IBTR occurring within a 60-month interval. CONCLUSIONS: rTNM staging system has an outstanding prognostic value for survival outcome of patients with IBTR, and IBTR and primary EBC may have potentially analogous features in the context of TNM staging. BCS plus radiation therapy may be an alternative. IBTR cases who have experienced recurrence with short intervals and with ER-negative tumors might benefit from chemotherapy.

Potential rapid intraoperative cancer diagnosis using dynamic full-field optical coherence tomography and deep learning: A prospective cohort study in breast cancer patients.

An intraoperative diagnosis is critical for precise cancer surgery. However, traditional intraoperative assessments based on hematoxylin and eosin (H&E) histology, such as frozen section, are time-, resource-, and labor-intensive, and involve specimen-consuming concerns. Here, we report a near-real-time automated cancer diagnosis workflow for breast cancer that combines dynamic full-field optical coherence tomography (D-FFOCT), a label-free optical imaging method, and deep learning for bedside tumor diagnosis during surgery. To classify the benign and malignant breast tissues, we conducted a prospective cohort trial. In the modeling group (n = 182), D-FFOCT images were captured from April 26 to June 20, 2018, encompassing 48 benign lesions, 114 invasive ductal carcinoma (IDC), 10 invasive lobular carcinoma, 4 ductal carcinoma in situ (DCIS), and 6 rare tumors. Deep learning model was built up and fine-tuned in 10,357 D-FFOCT patches. Subsequently, from June 22 to August 17, 2018, independent tests (n = 42) were conducted on 10 benign lesions, 29 IDC, 1 DCIS, and 2 rare tumors. The model yielded excellent performance, with an accuracy of 97.62%, sensitivity of 96.88% and specificity of 100%; only one IDC was misclassified. Meanwhile, the acquisition of the D-FFOCT images was non-destructive and did not require any tissue preparation or staining procedures. In the simulated intraoperative margin evaluation procedure, the time required for our novel workflow (approximately 3 min) was significantly shorter than that required for traditional procedures (approximately 30 min). These findings indicate that the combination of D-FFOCT and deep learning algorithms can streamline intraoperative cancer diagnosis independently of traditional pathology laboratory procedures.

Mapping of a Major-Effect Quantitative Trait Locus for Seed Dormancy in Wheat.

The excavation and utilization of dormancy loci in breeding are effective endeavors for enhancing the resistance to pre-harvest sprouting (PHS) of wheat varieties. CH1539 is a wheat breeding line with high-level seed dormancy. To clarify the dormant loci carried by CH1539 and obtain linked molecular markers, in this study, a recombinant inbred line (RIL) population derived from the cross of weak dormant SY95-71 and strong dormant CH1539 was genotyped using the Wheat17K single-nucleotide polymorphism (SNP) array, and a high-density genetic map covering 21 chromosomes and consisting of 2437 SNP markers was constructed. Then, the germination percentage (GP) and germination index (GI) of the seeds from each RIL were estimated. Two QTLs for GP on chromosomes 5A and 6B, and four QTLs for GI on chromosomes 5A, 6B, 6D and 7A were identified. Among them, the QTL on chromosomes 6B controlling both GP and GI, temporarily named QGp/Gi.sxau-6B, is a major QTL for seed dormancy with the maximum phenotypic variance explained of 17.66~34.11%. One PCR-based diagnostic marker Ger6B-3 for QGp/Gi.sxau-6B was developed, and the genetic effect of QGp/Gi.sxau-6B on the RIL population and a set of wheat germplasm comprising 97 accessions was successfully confirmed. QGp/Gi.sxau-6B located in the 28.7~30.9 Mbp physical position is different from all the known dormancy loci on chromosomes 6B, and within the interval, there are 30 high-confidence annotated genes. Our results revealed a novel QTL QGp/Gi.sxau-6B whose CH1539 allele had a strong and broad effect on seed dormancy, which will be useful in further PHS-resistant wheat breeding.

Role of ferroptosis in Porphyromonas gingivalis-induced impairment of epithelial junction.

Objectives: This study aims to clarify the effect of ferroptosis by P. gingivalis on periodontal epithelium impairment and potential mechanisms. Materials and methods: The expression of epithelial junction proteins (CDH1, OCLN, ZO-1), FTL and GPX4 in healthy and periodontitis tissues was analyzed using bioinformatics analysis and validated in vivo. An in vitro model was constructed to evaluate ferroptosis by mitochondria morphology, content of iron and GSH, and level of lipid peroxidation, FTL, GPX4 and SLC7A11. The iron concentration was changed with iron chelator DFO and iron supplementation FAC. The epithelial impairment was assessed by protein expression. To investigate the mechanism, si-MYB (a negative transcription factor of SLC7A11) and GPX4 inhibitor RSL3 were employed. Results: CDH1, OCLN, ZO-1 and GPX4 expression was decreased, while FTL expression was elevated in periodontitis tissues. Infected cells showed ferroptosis change of the mitochondria with higher level of lipid peroxidation, iron, FTL and lower level of GPX4, GSH, SLC7A11. FAC augmented ferroptosis and weakened epithelial junction, while DFO exhibited a counteractive effect. Silencing MYB rescued SLC7A11, GPX4 and epithelial junction proteins, which was hindered by RSL3. Conclusions: Our study demonstrated that P. gingivalis weakened the oral epithelial barrier by causing ferroptosis via inhibiting SLC7A11/GSH/GPX4 axis.

Indium Promotes Direct Sulfonamidation of Unactivated Alcohols.

An improved protocol has been developed for the direct sulfonamidation of unactivated alkyl alcohols using In(OTf)3 as a Lewis acid catalyst. Although the established methods using Lewis or Brønsted acids have been well-studied for the direct functionalization of alcohols, their substrate scope mainly focuses on the π-activated alcohols. In this reaction, unactivated aliphatic alcohols were evaluated and afforded the desired sulfonamide products with good to excellent yields.

Cytosolic pH is a direct nexus in linking environmental cues with insulin processing and secretion in pancreatic ß cells.

Pancreatic ß cells actively respond to glucose fluctuations through regulating insulin processing and secretion. However, how this process is elaborately tuned in circumstance of variable microenvironments as well as ß cell-intrinsic states and whether its dysfunction links to metabolic diseases remain largely elusive. Here, we show that the cytosolic pH (pHc) in ß cells is increased upon glucose challenge, which can be sensed by Smad5 via its nucleocytoplasmic shuttling. Lesion of Smad5 in ß cells results in hyperglycemia and glucose intolerance due to insulin processing and secretion deficiency. The role of Smad5 in regulating insulin processing and secretion attributes to its non-canonical function by regulating V-ATPase activity for granule acidification. Genetic mutation of Smad5 or administration of alkaline water to mirror cytosolic alkalization ameliorated glucose intolerance in high-fat diet (HFD)-treated mice. Collectively, our findings suggest that pHc is a direct nexus in linking environmental cues with insulin processing and secretion in ß cells.

Imbalanced EphB4/EphrinB2 Signaling Modulates Bone Resorption in Periodontitis Induced by Porphyromonas gingivalis.

Periodontitis, a chronic infectious disease in periodontal tissues, is characterized by an imbalance of alveolar bone resorption and remodeling, which eventually results in tooth loosening and even tooth loss. The etiology of periodontitis is polymicrobial synergy and dysbiosis, in which Porphyromonas gingivalis (P. gingivalis) is one of the primary pathogens responsible for periodontitis progression. The interplay of EphrinB2/EphB4 is crucial for osteoblast-osteoclast communication during bone remodeling and healing. This study investigates the mechanism of EphB4/EphrinB2 transduction modulating osteogenesis inhibition and bone resorption in periodontitis induced by P. gingivalis. An in vivo model of chronic periodontitis provoked by P. gingivalis was constructed, the inflammation and bone resorption were evaluated. The expression of EphB4 and EphrinB2 proteins in periodontal tissues was detected, which was also evaluated, respectively, in osteoblasts and osteoclasts infected with P. gingivalis in vitro. Then, a simulated coculture model of osteoblasts and osteoclasts was established to activate the forward and reverse pathways of EphB4/EphrinB2 with P. gingivalis infection. This study showed that P. gingivalis infection promoted alveolar bone resorption in rats and enhanced EphB4 and EphrinB2 expression in periodontal tissues. EphB4 and molecules associated with osteogenesis in osteoblasts infected with P. gingivalis were inhibited, while EphrinB2 and osteoclast differentiation-related markers in osteoclasts were activated. In conclusion, this study suggested that EphB4/EphrinB2 proteins were involved in alveolar bone remodeling in the process of periodontitis induced by P. gingivalis infection. Moreover, attenuated EphB4/EphrinB2 with P. gingivalis infection weakened osteoblast activity and enhanced osteoclast activity.

Comparative transcriptome and metabolome profiles of the leaf and fruits of a Xianjinfeng litchi budding mutant and its mother plant.

Background: Litchi (Litchi chinensis) is an important sub-tropical fruit in the horticulture market in China. Breeding for improved fruit characteristics is needed for satisfying consumer demands. Budding is a sustainable method for its propagation. During our ongoing breeding program, we observed a litchi mutant with flat leaves and sharp fruit peel cracking in comparison to the curled leaves and blunt fruit peel cracking fruits of the mother plant. Methods: To understand the possible molecular pathways involved, we performed a combined metabolome and transcriptome analysis. Results: We identified 1,060 metabolites in litchi leaves and fruits, of which 106 and 101 were differentially accumulated between the leaves and fruits, respectively. The mutant leaves were richer in carbohydrates, nucleotides, and phenolic acids, while the mother plant was rich in most of the amino acids and derivatives, flavonoids, lipids and organic acids and derivatives, and vitamins. Contrastingly, mutant fruits had higher levels of amino acids and derivatives, carbohydrates and derivatives, and organic acids and derivatives. However, the mother plant's fruits contained higher levels of flavonoids, scopoletin, amines, some amino acids and derivatives, benzamidine, carbohydrates and derivatives, and some organic acids and derivatives. The number of differentially expressed genes was consistent with the metabolome profiles. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway-enriched gene expressions showed consistent profiles as of metabolome analysis. Conclusion: These results provide the groundwork for breeding litchi for fruit and leaf traits that are useful for its taste and yield.

The SOC1 gene plays an important role in regulating litchi flowering time.

Litchi (Litchi chinensis Sonn.) is a valuable subtropical fruit tree with high-quality fruit. However, its economic benefits and sustainable development are restrained by a number of challenges. One major challenge is the lack of extremely early and late maturing high-quality varieties due to limited availability of varieties suitable for commercial cultivation and outdated breeding methods, resulting in an imbalanced supply and low price of litchi. Flowering time is a crucial genetic factor influencing the maturation period of litchi. Our previous research has highlighted the pivotal role of the LcFT1 gene in regulating the flowering time of litchi and identified a gene associated with LcFT1 (named as LcSOC1) based on RNA-Seq and weight gene co-expression network (WGCNA) analysis. This study further investigated the function of LcSOC1. Subcellular localization analysis revealed that LcSOC1 is primarily localized in the nucleus, where it acts as a transcription factor. LcSOC1 overexpression in Nicotiana tabacum and Arabidopsis thaliana resulted in significant early flowering. Furthermore, LcSOC1 was found to be expressed in various tissues, with the highest expression in mature leaves. Analysis of spatial and temporal expression patterns of LcSOC1 in litchi varieties with different flowering time under low temperature treatment and across an annual cycle demonstrated that LcSOC1 is responsive to low temperature induction. Interestingly, early maturing varieties exhibited higher sensitivity to low temperature, with significantly premature induction of LcSOC1 expression relative to late maturing varieties. Activation of LcSOC1 triggered the transition of litchi into the flowering phase. These findings demonstrate that LcSOC1 plays a pivotal role in regulating the flowering process and determining the flowering time in litchi. Overall, this study provides theoretical guidance and important target genes for molecular breeding to regulate litchi production period.

Deep Learning Algorithm Based on Molecular Fingerprint for Prediction of Drug-Induced Liver Injury.

Drug-induced liver injury (DILI) is one the rare adverse drug reaction (ADR) and multifactorial endpoints. Current preclinical animal models struggle to anticipate it, and in silico methods have emerged as a way with significant potential for doing so. In this study, a high-quality dataset of 1573 compounds was assembled. The 48 classification models, which depended on six different molecular fingerprints, were built via deep neural network (DNN) and seven machine learning algorithms. Comparing the results of the DNN and machine learning models, the optional performing model was found as the one developed based on the DNN with ECFP_6 as input, which achieved the area under the receiver operating characteristic curve (AUC) of 0.713, balanced accuracy (BA) of 0.680, and F1 of 0.753. In addition, we used the SHapley Additive exPlanations (SHAP) algorithm to interpret the models, identified the crucial structural fragments related to DILI risk, and selected the top ten substructures with the highest contribution rankings to serve as warning indicators for subsequent drug hepatotoxicity screening studies. The study demonstrates that the DNN models developed based on molecular fingerprints can be a trustworthy and efficient tool for determining the risk of DILI during the pre-development of novel medications.

Concurrent inhibition of pBADS99 synergistically improves MEK inhibitor efficacy in KRASG12D-mutant pancreatic ductal adenocarcinoma.

Therapeutic targeting of KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) has remained a significant challenge in clinical oncology. Direct targeting of KRAS has proven difficult, and inhibition of the KRAS effectors have shown limited success due to compensatory activation of survival pathways. Being a core downstream effector of the KRAS-driven p44/42 MAPK and PI3K/AKT pathways governing intrinsic apoptosis, BAD phosphorylation emerges as a promising therapeutic target. Herein, a positive association of the pBADS99/BAD ratio with higher disease stage and worse overall survival of PDAC was observed. Homology-directed repair of BAD to BADS99A or small molecule inhibition of BADS99 phosphorylation by NCK significantly reduced PDAC cell viability by promoting cell cycle arrest and apoptosis. NCK also abrogated the growth of preformed colonies of PDAC cells in 3D culture. Furthermore, high-throughput screening with an oncology drug library to identify potential combinations revealed a strong synergistic effect between NCK and MEK inhibitors in PDAC cells harboring either wild-type or mutant-KRAS. Mechanistically, both mutant-KRAS and MEK inhibition increased the phosphorylation of BADS99 in PDAC cells, an effect abrogated by NCK. Combined pBADS99-MEK inhibition demonstrated strong synergy in reducing cell viability, enhancing apoptosis, and achieving xenograft stasis in KRAS-mutant PDAC. In conclusion, the inhibition of BADS99 phosphorylation enhances the efficacy of MEK inhibition, and their combined inhibition represents a mechanistically based and potentially effective therapeutic strategy for the treatment of KRAS-mutant PDAC.

Single-Electron Reduction of "Push-Pull" C-C Single Bond and Decyanation Using Tertiary Amines as the Organic Electron Donor.

Using commercially available tertiary amines as an organic electron donor (OED), the reduction of "push-pull" C-C single bond and reductive decyanation of tetrahydroisoquinolines were realized. These reactions exhibited higher reaction efficiency and better functional group tolerance compared with those of metallic reductants, and the mechanistic study indicated that a radical intermediate was involved in the reduction of the C-C single bond, which provides a new way to the OED-enabled mild reduction.

A novel post-percutaneous nephrolithotomy sepsis prediction model using machine learning.

OBJECTIVES: To establish a predictive model for sepsis after percutaneous nephrolithotomy (PCNL) using machine learning to identify high-risk patients and enable early diagnosis and intervention by urologists. METHODS: A retrospective study including 694 patients who underwent PCNL was performed. A predictive model for sepsis using machine learning was constructed based on 22 preoperative and intraoperative parameters. RESULTS: Sepsis occurred in 45 of 694 patients, including 16 males (35.6%) and 29 females (64.4%). Data were randomly segregated into an 80% training set and a 20% validation set via 100-fold Monte Carlo cross-validation. The variables included in this study were highly independent. The model achieved good predictive power for postoperative sepsis (AUC = 0.89, 87.8% sensitivity, 86.9% specificity, and 87.4% accuracy). The top 10 variables that contributed to the model prediction were preoperative midstream urine bacterial culture, sex, days of preoperative antibiotic use, urinary nitrite, preoperative blood white blood cell (WBC), renal pyogenesis, staghorn stones, history of ipsilateral urologic surgery, cumulative stone diameters, and renal anatomic malformation. CONCLUSION: Our predictive model is suitable for sepsis estimation after PCNL and could effectively reduce the incidence of sepsis through early intervention.

CBr4 as a Mild Oxidant-Enabled Oxidation of a sp3 C-H Bond: A Facile Synthesis of the Persistent Iminium Salts of Tetrahydroisoquinolines.

Using CBr4 as a mild oxidant, the direct C-H bond oxidation of N-aryltetrahydroisoquinolines was achieved, giving a series of the corresponding iminium salts in high yields under metal- and photo-free reaction conditions. This reaction is superior in high yields and good functional group tolerance, and the late-stage derivatization showed that these iminium salts can readily be applied to the synthesis of the functionalized THIQs.

Vertical pathway inhibition of receptor tyrosine kinases and BAD with synergistic efficacy in triple negative breast cancer.

Aberrant activation of the PI3K/AKT signaling axis along with the sustained phosphorylation of downstream BAD is associated with a poor outcome of TNBC. Herein, the phosphorylated to non-phosphorylated ratio of BAD, an effector of PI3K/AKT promoting cell survival, was observed to be correlated with worse clinicopathologic indicators of outcome, including higher grade, higher proliferative index and lymph node metastasis. The structural optimization of a previously reported inhibitor of BAD-Ser99 phosphorylation was therefore achieved to generate a small molecule inhibiting the phosphorylation of BAD at Ser99 with enhanced potency and improved oral bioavailability. The molecule 2-((4-(2,3-dichlorophenyl)piperazin-1-yl)(pyridin-3-yl)methyl) phenol (NCK) displayed no toxicity at supra-therapeutic doses and was therefore assessed for utility in TNBC. NCK promoted apoptosis and G0/G1 cell cycle arrest of TNBC cell lines in vitro, concordant with gene expression analyses, and reduced in vivo xenograft growth and metastatic burden, demonstrating efficacy as a single agent. Additionally, combinatorial oncology compound library screening demonstrated that NCK synergized with tyrosine kinase inhibitors (TKIs), specifically OSI-930 or Crizotinib in reducing cell viability and promoting apoptosis of TNBC cells. The synergistic effects of NCK and TKIs were also observed in vivo with complete regression of a percentage of TNBC cell line derived xenografts and prevention of metastatic spread. In patient-derived TNBC xenograft models, NCK prolonged survival times of host animals, and in combination with TKIs generated superior survival outcomes to single agent treatment. Hence, this study provides proof of concept to further develop rational and mechanistic based therapeutic strategies to ameliorate the outcome of TNBC.

The association between high-oxygen saturation and prognosis for intracerebral hemorrhage.

BACKGROUND: Concerns about the adverse effects of excessive oxygen have grown over the years. This study investigated the relationship between high oxygen saturation and short-term prognosis of patients with spontaneous intracerebral hemorrhage (sICH) after liberal use of oxygen. METHODS: This retrospective cohort study collected data from the Medical Information Mart for Intensive Care III (MIMIC-III) database (ICU cohort) and a tertiary stroke center (general ward cohort). The data on pulse oximetry-derived oxygen saturation (SpO2) during the first 24 h in ICU and general wards were respectively extracted. RESULTS: Overall, 1117 and 372 patients were included in the ICU and general ward cohort, respectively. Among the patients from the ICU cohort, a spoon-shaped association was observed between minimum SpO2 and the risk of in-hospital mortality (non-linear P<0.0001). In comparison with minimum SpO2 of 93-97%, the minimum SpO2>97% was associated with a significantly higher risk of in-hospital mortality after adjustment for confounders. Sensitivity analysis conducted using propensity score matching did not change this significance. The same spoon-shaped association between minimum SpO2 and the risk of in-hospital mortality was also detected for the general ward cohort. In comparison with the group with 95-97% SpO2, the group with SpO2>97% showed a stronger association with, but non-significant risk for, in-hospital mortality after adjustment for confounders. The time-weighted average SpO2>97% was associated significantly with in-hospital mortality in both cohorts. CONCLUSION: Higher SpO2 (especially a minimum SpO2>97%) was unrewarding after liberal use of oxygen among patients with sICH and might even be potentially detrimental.

Oxidants Controlled C-H Bond Functionalization of N-Aryltetrahydroisoquinolines: The Construction of the Quaternary Carbon Center and Cleavage of the C-N Bond.

Initiated by triarylamine radical cation salt (TBPA), the direct C-H bond functionalization of α-N-aryltetrahydroisoquinoline esters was smoothly realized, giving a series of α-hydroxylated derivatives with a quaternary carbon center in good yields. Differently, in the presence of tert-butyl nitrite (TBN), the C-N single bond was cleaved to keto esters. The mechanistic study revealed that these reactions were mediated by a similar mechanism, in which the N-nitrosation might provide a driving force to the C-N bond cleavage.

Small molecule inhibition of TFF3 overcomes tamoxifen resistance and enhances taxane efficacy in ER+ mammary carcinoma.

Even though tamoxifen has significantly improved the survival of estrogen receptor positive (ER+) mammary carcinoma (MC) patients, the development of drug resistance with consequent disease recurrence has limited its therapeutic efficacy. Trefoil factor-3 (TFF3) has been previously reported to mediate anti-estrogen resistance in ER+MC. Herein, the efficacy of a small molecule inhibitor of TFF3 (AMPC) in enhancing sensitivity and mitigating acquired resistance to tamoxifen in ER+MC cells was investigated. AMPC induced apoptosis of tamoxifen-sensitive and resistant ER+MC cells and significantly reduced cell survival in 2D and 3D culture in vitro. In addition, AMPC reduced cancer stem cell (CSC)-like behavior in ER+MC cells in a BCL2-dependent manner. Synergistic effects of AMPC and tamoxifen were demonstrated in ER+MC cells and AMPC was observed to improve tamoxifen efficacy in tamoxifen-sensitive cells and to re-sensitize cells to tamoxifen in tamoxifen-resistant ER+MC in vitro and in vivo. Additionally, tamoxifen-resistant ER+MC cells were concomitantly resistant to anthracycline, platinum and fluoropyrimidine drugs, but not to Taxanes. Taxane treatment of tamoxifen-sensitive and resistant ER+MC cells increased TFF3 expression indicating a combination vulnerability for tamoxifen-resistant ER+MC cells. Taxanes increased CSC-like behavior of tamoxifen-sensitive and resistant ER+MC cells which was reduced by AMPC treatment. Taxanes synergized with AMPC to promote apoptosis and reduce CSC-like behavior in vitro and in vivo. Hence, AMPC restored the sensitivity of tamoxifen and enhanced the efficacy of Taxanes in tamoxifen-resistant ER+MC. In conclusion, pharmacological inhibition of TFF3 may serve as an effective combinatorial therapeutic strategy for the treatment of tamoxifen-resistant ER+MC.

Development of an accurate optical sensor for the in situ real-time determination of the chemical oxygen demand of seawater.

Chemical oxygen demand (COD) is an important indicator for monitoring the quality of seawater. The COD of seawater reflects the levels of organic pollutants in the water. Methods that are commonly used to measure the COD of seawater have high accuracy, good repeatability, and low costs. However, using them for the in situ real-time monitoring of the COD of seawater is unfavorable because they require complex procedures and a long measurement time and may cause pollution to the environment. This paper reports on an optical sensor that accurately determines the COD of seawater in situ. The COD determination is based on the absorption of ultraviolet and visible lights with different wavelengths by organic matter in the water. Single-point LEDs emitting lights with different wavelengths (254, 265, 280, and 546 nm) were used as sources of excitation lights, and photodiodes were used as receiving devices. The optical system, circuit system, and mechanical structure of the sensor were efficiently integrated. The inversion of the COD of seawater was obtained after turbidity correction using the multiple linear regression algorithm. The maximum measurement error, detection limit, and repeatability of the sensor were 5%, 0.05 mg/l, and 0.62%, respectively. Moreover, the R2 values for correlations between COD values and absorbance values measured at three wavelengths (254, 265, and 280 nm) were above 0.99. Overall, the sensor is suitable for the in situ real-time monitoring of the COD of seawater. It requires a short measurement time and generates no pollution.