Preliminary exploration of animal models of congenital choledochal cysts.

BACKGROUND: Various animal models have been used to explore the pathogenesis of choledochal cysts (CCs), but with little convincing results. Current surgical techniques can achieve satisfactory outcomes for treatment of CCs. Consequently, recent studies have focused more on clinical issues rather than basic research. Therefore, we need appropriate animal models to further basic research. AIM: To establish an appropriate animal model that may contribute to the investigation of the pathogenesis of CCs. METHODS: Eighty-four specific pathogen-free female Sprague-Dawley rats were randomly allocated to a surgical group, sham surgical group, or control group. A rat model of CC was established by partial ligation of the bile duct. The reliability of the model was confirmed by measurements of serum biochemical indices, morphology of common bile ducts of the rats as well as molecular biology experiments in rat and human tissues. RESULTS: Dilation classified as mild (diameter, ≥ 1 mm to < 3 mm), moderate (≥ 3 mm to < 10 mm), and severe (≥ 10 mm) was observed in 17, 17, and 2 rats in the surgical group, respectively, while no dilation was observed in the control and sham surgical groups. Serum levels of alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin, and total bile acids were significantly elevated in the surgical group as compared to the control group 7 d after surgery, while direct bilirubin, total bilirubin, and gamma-glutamyltransferase were further increased 14 d after surgery. Most of the biochemical indices gradually decreased to normal ranges 28 d after surgery. The protein expression trend of signal transducer and activator of transcription 3 in rat model was consistent with the human CC tissues. CONCLUSION: The model of partial ligation of the bile duct of juvenile rats could morphologically simulate the cystic or fusiform CC, which may contribute to investigating the pathogenesis of CC.

Tislelizumab plus chemotherapy is an optimal option for second-line treatment for advanced gastroesophageal junction adenocarcinoma.

The development of programmed cell death receptor-1 and its ligand (PD-L1) have offered new treatment options for several cancers, but the clinical benefit of tislelizumab in the gastroesophageal junction (GEJ) adenocarcinoma is still murky. Thus, we aim to investigate the efficacy and safety of tislelizumab combined with chemotherapy in patients with GEJ cancer. In this study, 90 GEJ patients were retrospectively enrolled including 45 patients who received chemotherapy plus tislelizumab while 45 underwent chemotherapy only. Overall response rate (ORR), overall survival (OS), and progression-free survival (PFS) were estimated and safety was assessed by treatment-related adverse events between two arms. The ORR was significantly higher in the tislelizumab group than in patients with chemotherapy alone (71.1 vs. 44.4%). The PFS [54.7% (47.2-62.2) vs. 33.3% (26.3-40.3), P = 0.047] and OS [62.1% (54.5-69.7) vs. 40.0% (32.5-47.5), P = 0.031] were also significantly improved in patients with concomitant use of tislelizumab. When stratified by PD-L1 combined positive score (CPS), patients with PD-L1 CPS ≥ 1 also with significantly higher PFS and OS when taking tislelizumab (P = 0.015 and P = 0.038). The incidence of hematologic toxicity was similar in the combination arm compared to the chemotherapy alone arm and the number of adverse events was not significantly increased by adding tislelizumab (all P > 0.05). Concomitant use of tislelizumab and chemotherapy in GEJ patients may be with optimal therapeutic effect and similar incidence of adverse events than chemotherapy alone. Further studies with larger number of patients are warranted to confirm it.

Axillary vein as an alternative venous access site for VV-ECMO cannulation: a case report.

BACKGROUND: Ultrasound-guided percutaneous axillary vein cannulation can reduce cannulation failure and mechanical complications, is as safe and effective as internal jugular vein cannulation, and is superior to subclavian vein cannulation using landmark technique. As far, reports of venovenous extracorporeal membrane oxygenation (VV-ECMO) with percutaneous axillary vein cannulation are rare. CASE PRESENTATION: A 64-year-old man presenting with dyspnea and chest tightness after aspirating sewage was admitted to the emergency department. Computed tomography (CT) showed diffuse exudation of both lungs and arterial blood gas analysis showed an oxygenation index of 86. He was diagnosed with aspiration pneumonia-induced acute respiratory distress syndrome (ARDS) and intubated for deteriorated oxygenation. Despite the combination therapy of protective mechanical ventilation and prone position, the patient's oxygenation deteriorated further, accompanied with multiple organ dysfunction syndrome, which indicated the requirement of support with VV-ECMO. However, vascular ultrasound detected multiple thrombus within bilateral internal jugular veins. As an alternative, right axillary vein was chosen as the access site of return cannula. Subsequently, femoral-axillary VV-ECMO was successfully implemented under the ultrasound guidance, and the patient's oxygenation was significantly improved. Unfortunately, the patient died of hyperkalemia-induced ventricular fibrillation after 36 h of VV-ECMO running. Despite the poor prognosis, the blood flow during ECMO run was stable, and we observed no bleeding complication, vascular injury, or venous return disorder. CONCLUSIONS: Axillary vein is a feasible alternative access site of return cannula for VV-ECMO if internal jugular vein access were unavailable.

Protopanaxadiol improves lupus nephritis by regulating the PTX3/MAPK/ERK1/2 pathway.

Lupus nephritis (LN) is a kidney disease that occurs after systemic lupus erythematosus (SLE) affects the kidneys. Pentraxin 3 (PTX3) is highly expressed in the serum of patients with LN. Renal PTX3 deposition is directly related to clinical symptoms such as proteinuria and inflammation. The excessive proliferation of mesangial cells (MCs) is one of the representative pathological changes in the progression of LN, which is closely related to its pathogenesis. Protopanaxadiol (PPD) is the main component of ginsenoside metabolism and has not been reported in LN. The aim of this study was to investigate the relationship between PTX3 and mesangial cell proliferation and to evaluate the potential role and mechanism of PPD in improving LN. PTX3 is highly expressed in the kidneys of LN patients and LN mice and is positively correlated with renal pathological indicators, including proteinuria and PCNA. The excessive expression of PTX3 facilitated the proliferation of MCs, facilitated the activation of the MAPK/ERK1/2 signaling pathway, and increased the expression of HIF-1α. Further studies showed that PPD can effectively inhibit the abnormal proliferation of MCs with high expression of PTX3 and significantly improve LN symptoms such as proteinuria in MRL/lpr mice. The mechanism may be related to the inhibition of the PTX3/MAPK/ERK1/2 pathway. In this study, both in vitro, in vivo, and clinical sample results show that PTX3 is involved in the regulation of MCs proliferation and the early occurrence of LN. Natural active compound PPD can improve LN by regulating the PTX3/MAPK/ERK1/2 pathway.

mRNA epitranscriptomics.

Epitranscriptomics refers to chemical changes in RNAs and includes numerous chemical types with varying stoichiometry and functions. RNA modifications are highly diverse in chemistry and respond in cell-type- and cell-state-dependent manners that enable and facilitate the execution of a wide array of biological functions. This includes roles in the regulation of transcription, translation, chromatin maintenance, immune response, and many other processes. This special issue presents the past, present, and future of epitranscriptomics research with a focus on mRNA. It includes perspectives from experts in the field, with the goal of encouraging discussions and debates that will further advance this area of research and enable it to realize its full potential in basic research and applications to human health and disease.

Quantification of tRNA m1A modification by templated-ligation qPCR.

N1-methyladenosine (m1A) is a widespread modification in all eukaryotic, many archaeal, and some bacterial tRNAs. M1A is generally located in the T loop of cytosolic tRNA and between acceptor and D stems of mitochondrial tRNAs, it is involved in tertiary interaction that stabilizes tRNA. Human tRNA m1A levels are dynamically regulated that fine-tune translation and can also serve as biomarkers for infectious disease. Although many methods have been used to measure m1A, a PCR method to assess m1A levels quantitatively in specific tRNAs has been lacking. Here we develop a templated-ligation followed by qPCR method (TL-qPCR) that measures m1A levels in target tRNAs. Our method uses the SplintR ligase that efficiently ligates two tRNA complementary DNA oligonucleotides using tRNA as the template followed by qPCR using the ligation product as the template. M1A interferes with the ligation in specific ways, allowing for the quantitative assessment of m1A levels using sub-nanogram amounts of total RNA. We identify the features of specificity and quantitation for m1A modified model RNAs and apply these to total RNA samples from human cells. Our method enables easy access to study the dynamics and function of this pervasive tRNA modification.

Transcriptomic effects of paternal cocaine-seeking on the reward circuitry of male offspring.

It has been previously established that paternal development of a strong incentive motivation for cocaine can predispose offspring to develop high cocaine-seeking behavior, as opposed to sole exposure to the drug that results in drug resistance in offspring. However, the adaptive changes of the reward circuitry have not been fully elucidated. To infer the key nuclei and possible hub genes that determine susceptibility to addiction in offspring, rats were randomly assigned to three groups, cocaine self-administration (CSA), yoked administration (Yoke), and saline self-administration (SSA), and used to generate F1. We conducted a comprehensive transcriptomic analysis of the male F1 offspring across seven relevant brain regions, both under drug-naïve conditions and after cocaine self-administration. Pairwise differentially expressed gene analysis revealed that the orbitofrontal cortex (OFC) exhibited more pronounced transcriptomic changes in response to cocaine exposure, while the dorsal hippocampus (dHip), dorsal striatum (dStr), and ventral tegmental area (VTA) exhibited changes that were more closely associated with the paternal voluntary cocaine-seeking behavior. Consistently, these nuclei showed decreased dopamine levels, elevated neuronal activation, and elevated between-nuclei correlations, indicating dopamine-centered rewiring of the midbrain circuit in the CSA offspring. To determine if possible regulatory cascades exist that drive the expression changes, we constructed co-expression networks induced by paternal drug addiction and identified three key clusters, primarily driven by transcriptional factors such as MYT1L, POU3F4, and NEUROD6, leading to changes of genes regulating axonogenesis, synapse organization, and membrane potential, respectively. Collectively, our data highlight vulnerable neurocircuitry and novel regulatory candidates with therapeutic potential for disrupting the transgenerational inheritance of vulnerability to cocaine addiction.

Simultaneous nanopore profiling of mRNA m6A and pseudouridine reveals translation coordination.

N6-methyladenosine (m6A) and pseudouridine (Ψ) are the two most abundant modifications in mammalian messenger RNA, but the coordination of their biological functions remains poorly understood. We develop a machine learning-based nanopore direct RNA sequencing method (NanoSPA) that simultaneously analyzes m6A and Ψ in the human transcriptome. Applying NanoSPA to polysome profiling, we reveal opposing transcriptomic co-occurrence of m6A and Ψ and synergistic, hierarchical effects of m6A and Ψ on the polysome.

Neoadjuvant Immunotherapy With Ipilimumab Plus Nivolumab in Mismatch Repair Deficient/Microsatellite Instability-High Colorectal Cancer: A Preliminary Report of Case Series.

BACKGROUND: Although ipilimumab plus nivolumab have significantly improved the survival of metastatic colorectal cancer (CRC) with mismatch repair deficient (dMMR) /microsatellite instability-high (MSI-H), the data on neoadjuvant setting is limited. PATIENTS AND METHODS: We enrolled 11 patients with advanced dMMR/MSI-H CRC. 10 patients were locally advanced and 1 was metastatic. Ten patients were treated with 1 dose of ipilimumab (1 mg/kg) and 2 doses of nivolumab (3 mg/kg), and 1 patient was treated with 1 dose of ipilimumab (1 mg/kg) and 2 doses of nivolumab (3 mg/kg) with 2 cycles. All the patients underwent surgery after immunotherapy. The aim of the study was to evaluate the safety and short-term efficacy of this strategy. RESULTS: Pathologic responses were observed in 11/11 (100%) dMMR/MSI-H tumors, with 9/11 (81.8%) achieving complete responses. Among these 9 cases with complete responses, 1 achieved a radiological noncomplete response after treatment with 1 dose of ipilimumab (1 mg/kg) and 2 doses of nivolumab (3 mg/kg), so another cycle of treatment with 1 dose of ipilimumab (1 mg/kg) and 2 doses of nivolumab (3 mg/kg) was administered, followed by surgery. The postoperative pathological evaluation was a complete response. Seven patients (63.6%) developed grade I/II adverse events. No patients developed grade III/IV adverse events or postoperative complications. CONCLUSION: Neoadjuvant immunotherapy with ipilimumab plus nivolumab induced tumor regression with a major clinical and pathological response in advanced dMMR/MSI-H CRC. Notably, patients do not achieve a complete response to neoadjuvant immunotherapy, additional neoadjuvant immunotherapy may offer benefits. Further research is needed to assess the long-term efficacy of this strategy.

Can We Do Breast-Conserving Surgery Without Intraoperative Frozen Section of Margin?

PURPOSE: This study was a retrospective and nonrandomized study to assess the safety and reliability of identifying the surgical margin in breast cancer breast-conserving surgery (BCS) by using intraoperative ultrasonic location and specimen mammography instead of traditional intraoperative frozen pathological section. METHODS: Among the patients who underwent BCS from May 2019 to October 2021, according to the different methods of evaluating the intraoperative margin, 104 breast cancer patients were included in the frozen edge group, 53 breast cancer patients were included in the freeze-free group, and the surgeon judged whether extended resection was needed based on the results of pathological section or evaluation of intraoperative ultrasound and mammography. The surgical margins of the two groups were judged by postoperative pathological results as the gold standard. RESULTS: The median waiting pathology results time in the frozen edge group was 64 minutes, while the waiting time in the freeze-free group was 30 minutes, and the difference was statistically significant (P < .0001). The postoperative pathological results showed that the positive rate of the surgical margin in the frozen edge group was 0.96%. The coincidence rate of intraoperative frozen and postoperative pathological results was 99.04%. The coincidence rate between intraoperative mammography and postoperative pathological results was 100%. CONCLUSIONS: In BCS, the method of using intraoperative staining markers combined with mammography to evaluate the resection margin is highly accurate, reliable, economical and convenient, and at the same time reduces the waiting time of the operator during the operation. However, this was not a randomized controlled study, and there was patient selection bias, and its safety needs to be confirmed by long-term follow-up. In the future, it is expected to become the mainstream means of evaluating.

Paternal cocaine-seeking motivation defines offspring's vulnerability to addiction by down-regulating GABAergic GABRG3 in the ventral tegmental area.

Epidemiological investigations indicate that parental drug abuse experiences significantly influenced the addiction vulnerability of offspring. Studies using animal models have shown that paternal cocaine use and highly motivated drug-seeking behavior are important determinants of offspring addiction susceptibility. However, the key molecules contributing to offspring addiction susceptibility are currently unclear. The motivation for cocaine-seeking behavior in offspring of male rats was compared between those whose fathers self-administered cocaine (SA) and those who were yoked with them and received non-contingent cocaine administrations (Yoke). We found that paternal experience with cocaine-seeking behavior, but not direct cocaine exposure, could lead to increased lever-pressing behavior in male F1 offspring. This effect was observed without significant changes to the dose-response relationship. The transcriptomes of ventral tegmental area (VTA) in offspring were analyzed under both naive state and after self-administration training. Specific transcriptomic changes in response to paternal cocaine-seeking experiences were found, which mainly affected biological processes such as synaptic connections and receptor signaling pathways. Through joint analysis of these candidate genes and parental drug-seeking motivation scores, we found that gamma-aminobutyric acid receptor subunit gamma-3 (Gabrg3) was in the hub position of the drug-seeking motivation-related module network and highly correlated with parental drug-seeking motivation scores. The downregulation of Gabrg3 expression, caused by paternal motivational cocaine-seeking, mainly occurred in GABAergic neurons in the VTA. Furthermore, down-regulating GABAergic Gabrg3 in VTA resulted in an increase in cocaine-seeking behavior in the Yoke F1 group. This down-regulation also reduced transcriptome differences between the Yoke and SA groups, affecting processes related to synaptic formation and neurotransmitter transmission. Taken together, we propose that paternal cocaine-seeking behavior, rather than direct drug exposure, significantly influences offspring addiction susceptibility through the downregulation of Gabrg3 in GABAergic neurons of the VTA, highlighting the importance of understanding specific molecular pathways in the intergenerational inheritance of addiction vulnerability.

Impaired sensitivity to thyroid hormones is associated with albuminuria in the euthyroid population: results from NHANES.

PURPOSE: The relationship between thyroid hormone sensitivity and albuminuria remains unclear. We aimed to investigate the association between thyroid hormone sensitivity and the risk of albuminuria in a euthyroid population. METHODS: This cross-sectional study included 7634 euthyroid adults collected from the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2012. Central sensitivity to thyroid hormones was evaluated using the thyroid-stimulating hormone index (TSHI), the thyrotrophic thyroxine resistance index (TT4RI), and the thyroid feedback quantile-based index (TFQI). Peripheral sensitivity to thyroid hormones was measured using the free triiodothyronine/free thyroxine (FT3/FT4) ratio. Furthermore, the independent relationship between sensitivity to thyroid hormones and albuminuria was assessed. RESULTS: The proportion of albuminuria increased with a higher interquartile range of TFQI levels (7.31% vs. 7.89% vs. 7.95% vs. 9.89%, P = 0.024). Furthermore, TFQI was found to be independently associated with the risk of albuminuria after adjusting for confounding factors (OR = 1.28, 95% CI 1.01-1.60, P = 0.037). Subgroup analysis revealed a significant relationship between TFQI and albuminuria, especially among individuals over 60. CONCLUSIONS: In euthyroid subjects, impaired central sensitivity to thyroid hormones is associated with albuminuria. TFQI holds significant potential as an epidemiological tool for quantifying the impact of impaired central sensitivity on the risk of albuminuria.

Dynamic arterial elastance as a predictor of arterial pressure response to norepinephrine weaning in mechanically ventilated patients with vasoplegic syndrome-a systematic review and meta-analysis.

Introduction: During the de-escalation phase of circulatory shock, norepinephrine weaning may induce diverse arterial pressure responses in patients with different vasomotor tones. Dynamic arterial elastance (Eadyn) has been extensively studied to predict the arterial pressure response to interventions. We conducted this meta-analysis to systematically assess the predictive performance of Eadyn for the mean arterial pressure (MAP) response to norepinephrine weaning in mechanically ventilated patients with vasoplegic syndrome. Materials and methods: A systematic literature search was conducted on May 29, 2023 (updated on January 21, 2024), to identify relevant studies from electronic databases. The area under the hierarchical summary receiver operating characteristic curve (AUHSROC) was estimated as the primary measure of diagnostic accuracy because of the varied thresholds reported. Additionally, we observed the distribution of the cutoff values of Eadyn, while computing the optimal value and its corresponding 95% confidential interval (CI). Results: A total of 5 prospective studies met eligibility, comprising 183 participants, of whom 67 (37%) were MAP responders. Eadyn possessed an excellent ability to predict the MAP response to norepinephrine weaning in patients with vasoplegic syndrome, with an AUHSROC of 0.93 (95% CI: 0.91-0.95), a pooled sensitivity of 0.94 (95% CI: 0.85-0.98), a pooled specificity of 0.73 (95% CI: 0.65-0.81), and a pooled diagnostic odds ratio of 32.4 (95% CI: 11.7-89.9). The cutoff values of Eadyn presented a nearly conically symmetrical distribution; the mean and median cutoff values were 0.89 (95% CI: 0.80-0.98) and 0.90 (95% CI: not estimable), respectively. Conclusions: This meta-analysis with limited evidences demonstrates that Eadyn may be a reliable predictor of the MAP response to norepinephrine weaning in mechanically ventilated patients with vasoplegic syndrome. Systematic Review Registration: PROSPERO CRD42023430362.

Why does HER2-positive breast cancer metastasize to the brain and what can we do about it?

Breast cancer is the most frequent malignancy in women. However, in the middle and late stages, some people develop distant metastases, which considerably lower the quality of life and life expectancy. The brain is one of the sites where metastasis frequently happens. According to epidemiological research, brain metastases occur at a late stage in 30-50% of patients with HER2-positive breast cancer, resulting in a poor prognosis. Additionally, few treatments are available for HER2-positive brain metastatic breast cancer, and the mortality rate is remarkable owing to the complexity of the brain's anatomical structure and physiological function. In this review, we described the stages of the brain metastasis of breast cancer, the relationship between the microenvironment and metastatic cancer cells, and the unique molecular and cellular mechanisms. It involves cancer cells migrating, invading, and adhering to the brain; penetrating the blood-brain barrier; interacting with brain cells; and activating signal pathways once inside the brain. Finally, we reviewed current clinically used treatment approaches for brain metastasis in HER2-positive breast cancer; summarized the traditional treatment, targeted treatment, immunotherapy, and other treatment modalities; compared the benefits and drawbacks of each approach; discussed treatment challenges; and emphasized the importance of identifying potential targets to improve patient survival rates and comprehend brain metastasis in breast cancer.

Transjugular intrahepatic portosystemic shunt for portal hypertension with chronic portal vein occlusion.

PURPOSE: This study aims to evaluate the long-term patency of transjugular intrahepatic portosystemic shunt (TIPS) and determine the predictors of shunt dysfunction in patients with chronic portal vein occlusion (CPVO). METHOD: This retrospective study was conducted from December 2010 to December 2020 in patients with portal hypertension and CPVO. Patients were followed up from initial TIPS insertion to December 2022 or death. Details of TIPS procedure, adverse events and clinical outcomes were recorded. The cumulative rate of shunt patency was calculated by the Kaplan-Meier method and compared by using the log-rank test. Independent predictors of shunt dysfunction were calculated with the Cox regression model. A nomogram comprising independent variables was developed to enhance the predictive accuracy of shunt patency. RESULTS: One hundred six patients (mean age, 45.3 years ± 13.6; 71 males and 35 females) were enrolled in the study. TIPS procedure was technically successful in 100 of 106 patients (94.3 %). The primary shunt patency rates for all 100 patients were 78.9 %, 74.7 %, 67.2 %, and 62.4 % at 6, 12, 24, and 36 months, respectively, and the overall shunt patency rates were 88.9 %, 86.8 %, 83.6 %, and 81.2 % at 6, 12, 24, and 36 months, respectively. Independent predictor of shunt dysfunction were inadequate inflow from superior mesenteric vein or splenic vein (the maximum diameter < 8 mm) and platelet count ≥ 300 × 109/L. The developed nomogram is a simple tool for accurately predicting shunt patency. CONCLUSIONS: In patients with CPVO, inadequate inflow and high platelet count are important factors for TIPS dysfunction.

Sustainable Electrochemical Benzylic C-H Oxidation Using MeOH as an Oxygen Source.

New methods and strategies for the direct oxidation of benzylic C-H bonds are highly desirable, owing to the importance of ketone motifs in significant organic transformations and the synthesis of valuable molecules, including pharmaceuticals, pesticides, and fine chemicals. Herein, we describe an electrochemical benzylic C-H oxidation strategy for the synthesis of ketones using MeOH as an oxygen source. Inexpensive and safe KBr serves as both an electrolyte and a bromide radical precursor in the reaction. This transformation also offers several advantages such as mild conditions, broad functional group tolerance, and operational simplicity. Mechanistic investigations by control experiments, radical scavenging experiments, electron paramagnetic resonance (EPR), kinetic studies, cyclic voltammetry (CV), and in-situ Fourier transform infrared (FTIR) spectroscopy support a pathway involving the formation and transformation of benzyl methyl ether via hydrogen atom transfer (HAT) and single-electron transfer (SET). The practical application of our strategy is highlighted by the successful synthesis of five pharmaceuticals, namely lenperone, melperone, diphenhydramine, cinnarizine, and flunarizine.

Changeable moving window-standard normal variable transformation for visible-NIR spectroscopic analyses.

Based on the assumption of point-by-point local linearity, the changeable moving window-standard normal variable (CMW-SNV) was proposed as a reasonable improvement of the classical SNV. The three examples of quantitative and qualitative visible-near-infrared (Vis-NIR) analysis, quantifications of soil organic matter and corn meal moisture, and discriminant of rice seeds identification, were used to validate the effects of the CMW-SNV, SNV and equal segmentation SNV (ES-SNV) methods. The ES-SNV is another improvement of the SNV, but its algorithm would cause artificial discontinuities of the corrected spectrum. The SNV, ES-SNV and CMW-SNV corrected spectra were used to establish partial least squares (PLS) or partial least squares-discriminant analysis (PLS-DA) models respectively. For soil and corn meal datasets in modeling, the CMW-SNV-PLS models were both significantly better than the global SNV-PLS models; the root mean square errors of prediction in modeling (SEPM) values had the relative decrease of 26.4% and 6.6% respectively. For rice seeds dataset in modeling, the CMW-SNV-PLS-DA model was significantly better than the global SNV-PLS-DA model; the total recognition-accuracy rates in modeling (RARM) value increased by 2.1%. For all three datasets, the CMW-SNV models were better than (or close to) ones of the ES-SNV models. The equidistant combination (EC) and wavelength step-by-step phase-out (WSP) methods were used to perform wavelength selection on the CMW-SNV corrected spectra, determining the optimal EC-WSP-PLS or EC-WSP-PLS-DA models. In independent validation of three datasets, the high precision and high recognition accuracy rates validation results were all obtained. The CMW-SNV was a localized natural improvement of the classic global SNV method, and its correction maintained continuity of the spectra. The number of wavelengths m of the correction window represented the scale of localized SNV, and the algorithm platform of CMW-SNV also included the optimization of parameter m, making the localized CMW-SNV method more reasonable.

Synthesis and anti-tumor activity evaluation of 1H-pyrrolo[2,3-b]pyridine-2-carboxamide derivatives with phenyl sulfonamide groups as potent RSK2 inhibitors.

Ribosome S6 Protein Kinase 2 (RSK2) is involved in many signal pathways such as cell growth, proliferation, survival and migration in tumors. Also, RSK2 can phosphorylate YB-1, which induces the expression of tumor initiating cells, leading to poor prognosis of triple negative breast cancer. Herein, phenyl sulfonamide was introduced to a series of 1H-pyrrolo[2,3-b]pyridine-2-carboxamide derivatives to obtain novel RSK2 inhibitors which were evaluated RSK2 inhibitory activity and proliferation inhibitory activity against MDA-MB-468. The newly introduced sulfonamide group was observed to form a hydrogen bond with target residue LEU-74 which played crucial role in activity. The results showed that most of compounds exhibited RSK2 enzyme inhibitory with IC50 up to 1.7 nM. Compound B1 exhibited the strongest MDA-MB-468 cell anti-proliferation activity (IC50 = 0.13 µM). The in vivo tumor growth inhibitory activities were evaluated with compounds B1-B3 in MDA-MB-468 xenograft model which gave up to 54.6% of TGI.

Endovascular Denervation for the Improvement of Limb Ischemia in Patients with Peripheral Artery Disease: A Randomized Clinical Trial.

BACKGROUND: To evaluate the safety and efficacy of endovascular denervation (EDN) as an adjunct to percutaneous vascular intervention (PVI) for peripheral artery disease (PAD). METHODS: From August 2019 to April 2021, 38 eligible patients with PAD enrolled in this study were randomly and equally assigned into 2 groups: the PVI group and the PVI + EDN group treated with EDN at the iliac and femoral arteries before PVI. The primary endpoint was the improvement in the ankle brachial index at 6 months after the procedure. The secondary endpoints were transcutaneous oxygen pressure (TcPO2), Rutherford category, numerical rating scale score, and safety. RESULTS: The technical success rates of PVI and EDN were 100%, and no device-related or procedure-related major adverse events occurred in either group. Compared with PVI alone, PVI + EDN demonstrated a significant improvement in limb hemodynamics at 6 months (Δ ankle brachial index 0.44 ± 0.31 vs. 0.24 ± 0.15, P = 0.018). Microcirculatory perfusion of PAD was significantly better at 6 months in the PVI + EDN group (ΔTcPO2, 15.68 ± 16.72 vs. 4.95 ± 13.43, P = 0.036). The Rutherford category was significantly improved in the PVI + EDN group in comparison with the PVI group at the 3-month follow-up (100.00% vs. 68.42%, P = 0.02). The decrease in the numerical rating scale score in the PVI + EDN group was greater than that in the PVI group at 1 week following the procedure (3 [2-5] vs. 4 [4-6], P = 0.022). CONCLUSIONS: In this single-center pilot analysis of a heterogeneous cohort of patients with PAD, PVI with EDN demonstrated a significant improvement in limb ischemia at 6 months compared with PVI alone.