Rare immune-related adverse events in patients with melanoma: incidence, spectrum, and clinical presentations.

Immune-related adverse events (irAEs) are side effects of immune checkpoint inhibitor therapy (ICI). While common irAEs have been well characterized, there are more limited data on rare immune related adverse events (RirAEs) due to low incidence. Lack of characterization of these entities has led to difficulties in accurate diagnosis and management. Here, we conducted a multi-institution analysis of all patients with stage III/IV melanoma who developed RirAEs after being treated with ICIs (anti-PD-1/L1, anti-CTLA-4, and combination PD-1/CTLA-4 blockade) at three institutions (Vanderbilt University Medical Center, Massachusetts General Hospital, and Melanoma Institute of Australia). RirAEs were defined as those occurring in approximately <1% of patients treated with anti-PD-1 or <2% with combination. Of 2834 patients who received ICIs, 82 developed RirAEs and were more common with combination PD-1/CTLA-4 blockade (4.6%) vs. anti-PD-1/L1 agents (2.8%). Overall median time from ICI start to RirAE was 86 days (interquartile range 42-235 days) with significantly earlier onset in combination therapy (p < 0.001). The spectrum of RirAEs spanned across several organ systems. Most RirAEs were grade 2 (57 [41.3%]) and grade 3 (40 [29.0%]) with relatively few grade 4 (11 [8.0%]) or 5 (5 [3.6%]) events. Steroid re-escalation (21.4%) or additional immunosuppression (13.8%) were commonly required. RirAE recurrence occurred in 22.6% with ICI rechallenge; 37.1% had new irAEs with rechallenge. In conclusion, RirAEs associated with ICIs in melanoma patients occurred, in aggregate, in 2-5% of patients treated with anti-PD-1-based therapy. Steroid re-escalation and alternative immunosuppression use were frequently required but fatal irAEs were fairly uncommon.

Hypoglycemic oligostilbenes from the stems of Caragana sinica.

Six new oligostilbenes, carastilphenols A-E (1-5) and (-)-hopeachinol B (6), with three reported oligostilbenes were obtained from the stems of Caragana sinica. The structures of compounds 1-6 were determined by comprehensive spectroscopy analysis, and their absolute configurations were determined by electronic circular dichroism calculations. Thus, natural tetrastilbenes were determined as absolute configuration for the first time. Also, we did several pharmacological essays. In the antiviral tests, compounds 2, 4 and 6 showed moderate anti-coxsackie virus B3 type (CVB3) effect on Vero cells activities in vitro with IC50 values of 19.2 âˆ¼ 69.3 µM; and compounds 3 and 4 showed different levels of anti-respiratory syncytial virus (RSV) effect on Hep2 cells activities in vitro with IC50 values of 23.1 and 33.3 µM, respectively. As for hypoglycemic activity, compounds 6-9 (10 µM) showed the inhibition of α-glucosidase in vitro with IC50 values of 0.1 âˆ¼ 0.4 µM; and compound 7 showed significant inhibition (88.8%, 10 µM) of protein tyrosine phosphatase 1B (PTP1B) with IC50 value of 1.1 µM in vitro.

An overview of the structure and function of the flagellar hook FlgE protein.

The flagellum is an important organelle for the survival of bacteria and consists of a basal body, hook, and filament. The FlgE protein is the subunit of the hook that connects the basal body and the filament and determines the motility of bacteria. Also, flgE gene plays an essential role in flagellar biosynthesis, swimming ability and biofilm formation. Although the intact flagella and the major component filament have been extensively studied, so far, little is known about the comprehensive understanding of flagellar hook and FlgE. Here in this review, we summarize the structures of flagellar hook and its subunit FlgE in various species and physiological functions of FlgE, including the hook assembly, the structural characteristics of flagellar hook, the mechanical properties of hook, and the similarities and differences between FlgE (hook) and FlgG (distal rod), with special attention on the interaction of FlgE with other molecules, the antigenicity and pro-inflammatory effect of FlgE, and cross-linking of FlgE in spirochetes. We hope our summary of this review could provide a better understanding of the FlgE protein and provide some useful information for developing new effective antibacterial drugs in the future work.

Depression Scores following Ventral Intermediate Nucleus Deep Brain Stimulation for Essential Tremor: A Meta-Analysis.

BACKGROUND: Essential tremor (ET) patients present with both motor and non-motor symptoms including depression. Although deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM) is used to treat motor symptoms of ET, there is no consensus as to how VIM DBS influences non-motor symptoms, specifically depression. OBJECTIVE: The objective of this study was to conduct a meta-analysis of available studies investigating change in pre- to postoperative depression scores as measured by Beck Depression Inventory (BDI) in ET patients receiving VIM DBS. METHODS: Inclusion criteria were randomized control trials or observational studies of patients undergoing unilateral/bilateral VIM DBS. Non-ET patients, case reports, patients <18 years old, only non-VIM electrode placement, non-English articles, and abstracts were excluded. The primary outcome was change in BDI score from the preoperative time point to the last available follow-up. Pooled estimates of overall effect for BDI standardized mean difference were calculated using random effects models with the inverse variance method. RESULTS: Seven studies divided into eight cohorts for a total of 281 ET patients met inclusion criteria. Pooled preoperative BDI score was 12.44 (95% CI [6.63-18.25]). A statistically significant decrease in depression scores was observed postoperatively (SMD = -0.29, 95% CI [-0.46 to -0.13], p = 0.0006). Pooled postoperative BDI score was 9.18 (95% CI [4.98-13.38]). A supplementary analysis which included an additional study with an estimated standard deviation at last follow-up was conducted. There was also a statistically significant decrease in depression postoperatively (9 cohorts, n = 352, SMD = -0.31, 95% CI [-0.46 to -0.16], p < 0.0001). CONCLUSIONS: Both quantitative and qualitative analyses of the existing literature suggest that VIM DBS improves depression postoperatively among ET patients. These results may guide surgical risk-benefit analysis and counseling for ET patients undergoing VIM DBS.

Echocardiographic Mitral Annular Calcification is Associated With Atrial Fibrillation Recurrence After Catheter Ablation.

There is a significant relation between mitral annular calcification (MAC) and the development of atrial fibrillation (AF) and major adverse cardiovascular events. However, the influence of MAC on the outcome of AF ablation remains unknown. The study cohort included 785 consecutive patients who underwent successful ablation. AF recurrence was monitored 3 months after ablation. Cox proportional hazards models were used to assess the association between MAC and AF recurrence. Kaplan-Meier analysis was performed to calculate the incidence of AF recurrence. Over a follow-up period of 16 ± 10 months, 190 patients (24.2%) experienced AF recurrence after ablation. MAC by echocardiography was identified in 42 patients (22%) with AF recurrence but only 60 without (10%, p <0.001). Patients with MAC were older (p <0.001), more often women (p <0.001), with a higher prevalence of hypertension (p <0.001) and diabetes mellitus (p<0.001), moderate/severe mitral regurgitation (p <0.001), larger left atrial dimension (p <0.001), and higher CHA2DS2-VASc score (p <0.001). Patients with MAC were more likely to develop AF recurrence than those without (36% vs 22%, respectively, p = 0.002). MAC was significantly associated with AF recurrence in the unadjusted analysis (hazard ratio 1.77, 95% confidence interval 1.26 to 2.58, p <0.001) and remained statistically significant after the multivariate adjustment (hazard ratio 1.48, 95% confidence interval 1.13 to 1.95, p = 0.001). In conclusion, echocardiographic MAC is significantly associated with an increased risk of AF recurrence after successful ablation, demonstrating an independent predictive value other than the established risk factors.

USP47 deubiquitylates Groucho/TLE to promote Wnt-ß-catenin signaling.

The Wnt-ß-catenin signal transduction pathway is essential for embryonic development and adult tissue homeostasis. Wnt signaling converts TCF from a transcriptional repressor to an activator in a process facilitated by the E3 ligase XIAP. XIAP-mediated monoubiquitylation of the transcriptional corepressor Groucho (also known as TLE) decreases its affinity for TCF, thereby allowing the transcriptional coactivator ß-catenin to displace it on TCF. Through a genome-scale screen in cultured Drosophila melanogaster cells, we identified the deubiquitylase USP47 as a positive regulator of Wnt signaling. We found that USP47 was required for Wnt signaling during Drosophila and Xenopus laevis development, as well as in human cells, indicating evolutionary conservation. In human cells, knockdown of USP47 inhibited Wnt reporter activity, and USP47 acted downstream of the ß-catenin destruction complex. USP47 interacted with TLE3 and XIAP but did not alter their amounts; however, knockdown of USP47 enhanced XIAP-mediated ubiquitylation of TLE3. USP47 inhibited ubiquitylation of TLE3 by XIAP in vitro in a dose-dependent manner, suggesting that USP47 is the deubiquitylase that counteracts the E3 ligase activity of XIAP on TLE. Our data suggest a mechanism by which regulated ubiquitylation and deubiquitylation of TLE enhance the ability of ß-catenin to cycle on and off TCF, thereby helping to ensure that the expression of Wnt target genes continues only as long as the upstream signal is present.

Comparison of One-Level Osteotomy and Two-Level Osteotomy for Thoracolumbar Kyphotic Deformity in Ankylosing Spondylitis: A Systematic Review and Meta-Analysis.

BACKGROUND: One- and two-level osteotomies have been used to treat thoracolumbar kyphosis in patients with ankylosing spondylitis (AS). However, the effectiveness and safety of the 2 methods have not been systematically compared, and few studies have reported on which method might be more suitable for treating AS. METHODS: We performed a systematic literature search. All comparative studies of one- and two-level osteotomy for the treatment of thoracolumbar kyphosis caused by AS were included. Efficacy was determined by the radiographic outcomes, including global kyphosis, sagittal vertical axis, and lumbar lordosis and the Oswestry disability index. The complication rates were used to assess the safety. We analyzed the data using Review Manager software. RESULTS: A total of 10 studies were included and used for the meta-analysis. We pooled the studies according to the type of data they had reported to evaluate the radiographic correction and incidence of complications. We found that two-level osteotomy provided advantages compared with one-level osteotomy for spinal correction, including global kyphosis and lumbar lordosis. However, the correction was dependent on the degree of preoperative kyphosis. In addition, we found no differences between the 2 groups in the correction of the sagittal vertical axis or improvement in the Oswestry disability index. However, we did find differences in the incidence of neural complications, dural tear, and operative site infection. CONCLUSIONS: Our findings have shown that one-level osteotomy is safer than two-level osteotomy. For AS patients with nonsevere kyphosis, one-level osteotomy will be sufficient for spinal sequence correction and maintenance of balance, and two-level osteotomy will not be needed. For AS patients with severe kyphosis, two-level osteotomy can be recommended for better orthopedic effects; however, a careful surgical technique is required.

Excess methane production and operation stability for anaerobic digestion of oily food waste controlled by mixing intensity: Focusing on heterogeneity of long chain fatty acids.

Long chain fatty acids (LCFAs) are the key intermediate of anaerobic digestion of oily food waste, not completely soluble in a water-dominant anaerobic system due to their long hydrocarbon chains with hydrophobic property. Their effective concentration affects release of high methanogenic potential and system stability. A long-term continuous anaerobic digestion of oily food waste demonstrated excess methane production of even more than feedstock in an anaerobic continuous stirred tank reactor (CSTR). Assuming feedstock COD at 100%, approximately 120% of COD as methane could be achieved. Oil floating and crystallization with Ca salt resulting from the distribution heterogeneity of LCFAs in the CSTR were found responsible for the excess methane production. Moreover, slow conversion and accumulation of saturated LCFAs with relatively lower solubility played an important role as well. Compared with unsaturated oleic (C18:1) and linoleic acids (C18:2), around twice slower methane production rate and longer lag time could be observed for those saturated LCFAs. Mixing intensity was proved to be a critical controlling factor for methanogenesis and stability possibly by affecting interaction between oil/LCFAs and anaerobes to change effective lipid loading.

Shared Decision-Making in General Surgery: Prospective Comparison of Telemedicine vs In-Person Visits.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has accelerated a shift toward virtual telemedicine appointments with surgeons. While this form of healthcare delivery has potential benefits for both patients and surgeons, the quality of these interactions remains largely unstudied. We hypothesize that telemedicine visits are associated with lower quality of shared decision-making. STUDY DESIGN: We performed a mixed-methods, prospective, observational cohort trial. All patients presenting for a first-time visit at general surgery clinics between May 2021 and June 2022 were included. Patients were categorized by type of visit: in-person vs telemedicine. The primary outcome was the level of shared decision-making as captured by top box scores of the CollaboRATE measure. Secondary outcomes included quality of shared decision-making as captured by the 9-item Shared Decision-Making Questionnaire and satisfaction with consultation survey. An adjusted analysis was performed accounting for potential confounders. A qualitative analysis of open-ended questions for both patients and practitioners was performed. RESULTS: During a 13-month study period, 387 patients were enrolled, of which 301 (77.8%) underwent in-person visits and 86 (22.2%) underwent telemedicine visits. The groups were similar in age, sex, employment, education, and generic quality-of-life scores. In an adjusted analysis, a visit type of telemedicine was not associated with either the CollaboRATE top box score (odds ratio 1.27; 95% CI 0.74 to 2.20) or 9-item Shared Decision-Making Questionnaire (ß -0.60; p = 0.76). Similarly, there was no difference in other outcomes. Themes from qualitative patient and surgeon responses included physical presence, time investment, appropriateness for visit purpose, technical difficulties, and communication quality. CONCLUSIONS: In this large, prospective study, there does not appear to be a difference in quality of shared decision making in patients undergoing in-person vs telemedicine appointments.

Stochastic processes drive the soil fungal communities in a developing mid-channel bar.

Intricate associations between rhizosphere microbial communities and plants play a critical role in developing and maintaining of soil ecological functioning. Therefore, understanding the assembly patterns of rhizosphere microbes in different plants and their responses to environmental changes is of great ecological implications for dynamic habitats. In this study, a developing mid-channel bar was employed in the Yangtze River to explore the assembly processes of rhizosphere fungal communities among various plant species using high-throughput sequencing-based null model analysis. The results showed a rare significant variation in the composition and alpha diversity of the rhizosphere fungal community among various plant species. Additionally, the soil properties were found to be the primary drivers instead of plant species types. The null model analysis revealed that the rhizosphere fungal communities were primarily driven by stochastic processes (i.e., undominated processes of ecological drift), and the predominance varied with various plant species. Moreover, the assembly processes of rhizosphere fungal communities were significantly related to the changes in soil properties (i.e., soil total carbon, total nitrogen, organic matter, and pH). The co-occurrence network analysis revealed that many keystone species belonged to unclassified fungi. Notably, five network hubs were almost unaffected by the measured soil properties and aboveground plant traits, indicating the effect of stochastic processes on the rhizosphere fungal community assembly. Overall, these results will provide insights into the underlying mechanisms of fungal community assembly in the rhizosphere soils, which are significant for maintaining the functional stability of a developing ecosystem.

Variability in Organ Procurement Organization Performance by Individual Hospital in the United States.

Importance: Availability of organs inadequately addresses the need of patients waiting for a transplant. Objective: To estimate the true number of donor patients in the United States and identify inefficiencies in the donation process as a way to guide system improvement. Design, Setting, and Participants: A retrospective cross-sectional analysis was performed of organ donation across 13 different hospitals in 2 donor service areas covered by 2 organ procurement organizations (OPOs) in 2017 and 2018 to compare donor potential to actual donors. More than 2000 complete medical records for decedents were reviewed as a sample of nearly 9000 deaths. Data were analyzed from January 1, 2017, to December 31, 2018. Exposure: Deaths of causes consistent with donation according to medical record review, ventilated patient referrals, center acceptance practices, and actual deceased donors. Main Outcomes and Measures: Potential donors by medical record review vs actual donors and OPO performance at specific hospitals. Results: Compared with 242 actual donors, 931 potential donors were identified at these hospitals. This suggests a deceased donor potential of 3.85 times (95% CI, 4.23-5.32) the actual number of donors recovered. There was a surprisingly wide variability in conversion of potential donor patients into actual donors among the hospitals studied, from 0% to 51.0%. One OPO recovered 18.8% of the potential donors, whereas the second recovered 48.2%. The performance of the OPOs was moderately related to referrals of ventilated patients and not related to center acceptance practices. Conclusions and Relevance: In this cross-sectional study of hospitals served by 2 OPOs, wide variation was found in the performance of the OPOs, especially at individual hospitals. Addressing this opportunity could greatly increase the organ supply, affirming the importance of recent efforts from the federal government to increase OPO accountability and transparency.

Inflammatory invasion on human vaginal mucosa correlated with combined drug treatment and recurrence in recurrent vulvovaginal candidiasis.

AIM: Recurrent vulvovaginal candidiasis (RVVC) is a chronic, difficult to treat vaginal infection, caused by Candida species, which affects women of all ages and ethnic and social background. Most RVVC studies use animal models, and there is still a lack of observation on human tissue samples and effective therapy to reduce recurrence. MATERIALS AND METHODS: We observed CD163+ macrophages and NLRP3 expression by immunohistochemistry, also investigated bacteria and fungi co-invasion by fluorescence in situ hybridization from 144 human vaginal biopsy tissues (48 RVVC, 48 VVC, 48 healthy volunteers), and we also explored the effect of combining metronidazole in the treatment of RVVC. RESULTS: A large number of neutrophils, lymphocytes and plasma cells infiltrated the mucosa, basement membrane and submucosa, accompanied by significantly overexpressed NLRP3 inflammasome. While CD163+ macrophages often infiltrated under the basement membrane in patients with RVVC, 29.2% of cases were found Gardnerella and fungi jointly invaded the vaginal mucosas. RVVC vaginal mucosal histopathology revealed mucosal inflammatory responses dominated by neutrophils, which may involve activation of NLRP3 and immune tolerance of M2 macrophages (CD163+ ). Fluconazole combined with metronidazole can achieve higher efficiency (95.8% vs. 70.8%) and reduce the recurrence rate more (8.3% vs. 37.5%) at 6-month follow-up. CONCLUSION: Inflammatory invasion on human vaginal mucosa correlated with combined drug treatment and recurrence in RVVC. The combined medication will need to further evaluate in future.

Conditional Recurrence-Free Survival After Surgical Resection of Meningioma.

BACKGROUND: Recurrence after meningioma resection warrants serial surveillance imaging, but little evidence guides the optimal time interval between imaging studies/surveillance duration. OBJECTIVES: To describe recurrence-free survival (RFS) after meningioma resection, conditioned to short-term RFS. METHODS: A retrospective cohort study for adults presenting for meningioma resection from 2000 to 2018 was conducted. The primary outcome was postoperative follow-up RFS. Conditional RFS Kaplan-Meier analysis was performed at 1, 2, 3, 5, and 10 years, conditioned to 6-month and 12-month RFS. RFS probabilities conditioned to 6-month RFS were estimated in subgroups, stratified by World Health Organization grade, extent of resection, and need for postoperative radiation. RESULTS: In total, 723 patients were included. Median age at surgery was 57.4 years (IQR = 47.2-67.2). Median follow-up was 23.5 months (IQR = 12.3-47.8). Recurrence was observed in 90 patients (12%), with median time to recurrence of 14.4 months (IQR = 10.3-37.1). Conditioned to 6-month postoperative RFS, patients had 90.3% probability of remaining recurrence-free at 2 years and 69.4% at 10 years. Subgroup analysis conditioned to 6-month RFS demonstrated grade 1 meningiomas undergoing gross total resection (GTR) had 96.0% probability of RFS at 1 year and 82.8% at 5 years, whereas those undergoing non-GTR had 94.5% and 79.9% probability, respectively. RFS probability was 78.8% at 5 years for non-grade 1 meningiomas undergoing GTR, compared with 69.7% for non-grade 1 meningiomas undergoing non-GTR. Patients with non-grade 1 meningiomas undergoing upfront radiation had a 1-year RFS of 90.1% and 5-year RFS of 51.7%. CONCLUSION: Recurrence risk after meningioma resection after an initial recurrence-free period is reported, with high-risk subgroups identified. These results can inform objective shared decision-making for optimal follow-up.

Neogrisemycin, a Trisulfide-Bridged Angucycline, Produced upon Expressing the Thioangucycline Biosynthetic Gene Cluster in Streptomyces albus J1074.

Neogrisemycin (1) was isolated from recombinant Streptomyces albus J1074 strain SB4061 expressing an engineered thioangucycline (TAC) biosynthetic gene cluster (BGC). The structure and absolute configuration of 1 were established by a combination of mass spectrometry, nuclear magnetic resonance, and single-crystal X-ray diffraction analyses. Like the TACs, 1 was also proposed to derive non-enzymatically from the common epoxide (8), the nascent product encoded by the tac BGC, mediated by endogenous hydrogen trisulfide.

Mitochondrial-Targeted Antioxidant MitoQ-Mediated Autophagy: A Novel Strategy for Precise Radiation Protection.

Radiotherapy (RT) is one of the most effective cancer treatments. However, successful radiation protection for normal tissue is a clinical challenge. Our previous study observed that MitoQ, a mitochondria-targeted antioxidant, was adsorbed to the inner mitochondrial membrane and remained the cationic moiety in the intermembrane space. The positive charges in MitoQ restrained the activity of respiratory chain complexes and decreased proton production. Therefore, a pseudo-mitochondrial membrane potential (PMMP) was developed via maintenance of exogenous positive charges. This study identified that PMMP constructed by MitoQ could effectively inhibit mitochondrial respiration within normal cells, disrupt energy metabolism, and activate adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling to induce autophagy. As such, it could not lead to starvation-induced autophagy among tumor cells due to the different energy phenotypes between normal and tumor cells (normal cells depend on mitochondrial respiration for energy supply, while tumor cells rely on aerobic glycolysis). Therefore, we successfully protected the normal cells from radiation-induced damage without affecting the tumor-killing efficacy of radiation by utilizing selective autophagy. MitoQ-constructed PMMP provides a new therapeutic strategy for specific radiation protection.

Research Progress on the Action Mechanism of Herbicide Safeners: A Review.

Herbicide safeners are agricultural chemicals that protect crops from herbicide injury and improve the safety of herbicides and the effectiveness of weed control. Safeners induce and enhance the tolerance of crops to herbicides through the synergism of multiple mechanisms. The principal mechanism is that the metabolic rate of the herbicide in the crop is accelerated by safeners, resulting in the damaging concentration at the site of action being reduced. We focused on discussing and summarizing the multiple mechanisms of safeners to protect crops in this review. It is also emphasized how safeners alleviate herbicide phytotoxicity to crops by regulating the detoxification process and conducting perspectives on future research on the action mechanism of safeners at the molecular level.

Trends in respiratory diseases before and after the COVID-19 pandemic in China from 2010 to 2021.

BACKGROUND: The ongoing benefits of coronavirus disease 2019 (COVID-19) nonpharmaceutical interventions (NPIs) for respiratory infectious diseases in China are still unclear. We aimed to explore the changes in seven respiratory infectious diseases before, during, and after COVID-19 in China from 2010 to 2021. METHODS: The monthly case numbers of seven respiratory infectious diseases were extracted to construct autoregressive integrated moving average (ARIMA) models. Eight indicators of NPIs were chosen from the COVID-19 Government Response Tracker system. The monthly case numbers of the respiratory diseases and the eight indicators were used to establish the Multivariable generalized linear model (GLM) to calculate the incidence rate ratios (IRRs). RESULTS: Compared with the year 2019, the percentage changes in 2020 and 2021 were all below 100% ranging from 3.81 to 84.71%. Pertussis and Scarlet fever started to increase in 2021 compared with 2020, with a percentage change of 183.46 and 171.49%. The ARIMA model showed a good fit, and the predicted data fitted well with the actual data from 2010 to 2019, but the predicted data was bigger than the actual number in 2020 and 2021. All eight indicators could negatively affect the incidence of respiratory diseases. The seven respiratory diseases were significantly reduced during the COVID-19 pandemic in 2020 and 2021 compared with 2019, with significant estimated IRRs ranging from 0.06 to 0.85. In the GLM using data for the year 2020 and 2021, the IRRs were not significant after adjusting for the eight indicators in multivariate analysis. CONCLUSION: Our study demonstrated the incidence of the seven respiratory diseases decreased rapidly during the COVID-19 pandemic in 2020 and 2021. At the end of 2021, we did see a rising trend for the seven respiratory diseases compared to the year 2020 when the NPIs relaxed in China, but the rising trend was not significant after adjusting for the NPIs indicators. Our study showed that NPIs have an effect on respiratory diseases, but Relaxation of NPIs might lead to the resurgence of respiratory diseases.

An unusual autocatalysis with an air-stable Pd complex to promote enantioselective synthesis of Si-stereogenic enynes.

Given the powerful potential of chiral-at-silicon chemistry, enantioselective synthesis of Si-stereogenic centers has attracted substantial research interest in recent years. However, the catalytic asymmetric synthesis of Si-stereogenic organosilicon compounds remains an appealing venture and is a challenging subject because of the difficulty in achieving high reactivity and stereoselectivity for "silicon-center" transformations. Herein, we disclose a highly enantioselective palladium-catalyzed hydrosilylation of 1,3-diynes with dihydrosilanes, which enables the facile preparation of Si-stereogenic enynes and an enyne-linked chiral polymer (polyenyne) in good yields and excellent ees (up to >99%) by desymmetrization. The unusual stereoselectivity in this reaction is achieved by precisely controlling the steric hindrance and electronic effect of the newly developed chiral ligands, resulting in a wide range of chiral silanes and a Si-containing polymer bearing a Si-stereogenic center which is otherwise difficult to access. The key to the high enantioselectivity relies on catalyst aggregation-induced non-covalent interaction, which exerts a remarkably positive influence on the Si-H bond activation and enhancement of enantioselectivity, in which the palladium/P-ligand complex was proved to be air-stable and moisture-insensitive in this reaction.

Preliminary study of the significance of reverberation by IVUS detection for patients with severe calcified lesions.

To explore the potential significance of the reverberation of calcification by comparing both intravascular ultrasound (IVUS) and optical coherence tomography (OCT) measurement post manual coregistration. The reverberation phenomenon is often detected by IVUS for severe calcified lesions post rotational atherectomy (RA), which is thought to be due to the glassy and smooth inner surfaces of calcifications. Because of the poor penetration of IVUS, it is impossible to measure the thickness of calcifications, and the relationship between multiple reverberations and the thickness of calcification lesions has not been reported before. A total of forty-nine patients with severe calcified coronary lesions that were detected by IVUS and OCT simultaneously were enrolled in our retrospective study. If reverberation phenomena were detected by IVUS, intravascular imaging (IVI) data (including distance between the IVUS catheter center and the inner surface of the reverberation signal, the intervals between all adjacent reverberation signals, the number of layers of reverberation in IVUS, and the thickness of the calcification in OCT) were measured at the same position and same direction (each cross-section had 4 mutually perpendicular directions) at 1-mm intervals. The correlation between each reverberation observational value and OCT data was the primary target in this retrospective study, and the correlation between reverberation and calcium crack post predilatation was analyzed in other 15 patients. Four hundred twenty-eight valid observational points were analyzed simultaneously by IVUS and OCT; among them, 300 points had a single layer of reverberation, 83 had double layers of reverberation and 42 had multiple layers (≥ 3 layers) of reverberation by IVUS detection post-RA. Multivariate logistic regression analysis showed that the number of layers of reverberation by IVUS was significantly related to the thickness of calcifications by OCT at the same point and in the same direction (p < 0.001). Single, double, and multiple layers of reverberation in IVUS correspond to median calcification thicknesses (interquartile ranges (IQRs)) of 0.620 mm (0.520-0.720), 0.950 mm (0.840-1.040) and 1.185 mm (1.068-1.373), respectively, by OCT detection. Another 100 points in other 15 patients with integrated IVUS data pre- and post-predilatation showed that only single layer of reverberation was related to calcium crack (p < 0.001). The number of layers of reverberation signal detected by IVUS is positively correlated with the thickness of calcifications measured by OCT post-RA and single layer of reverberation is correlated to calcium crack post-predilatation.

Protocol for 3D screening of lung cancer spheroids using natural products.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and accounts for ∼84% of all lung cancer cases. NSCLC remains one of the leading causes of cancer-associated death, with a 5-year survival rate less than 25%. This type of cancer begins with healthy cells that change and start growing out of control, leading to the formation of lesions or tumors. Understanding the dynamics of how the tumor microenvironment promotes cancer initiation and progression that leads to cancer metastasis is crucial to help identify new molecular therapies. 3D primary cell tumor models have received renewed recognition due to their ability to better mimic the complexity of in vivo tumors and as a potential bridge between traditional 2D culture and in vivo studies. Vast improvements in 3D cell culture technologies make them much more cost effective and efficient largely because of the use of a cell-repellent surfaces and a novel angle plate adaptor technology. To exploit this technology, we accessed the Natural Products Library (NPL) at UF Scripps, which consists of crude extracts, partially purified fractions, and pure natural products (NPs). NPs generally are not very well represented in most drug discovery libraries and thus provide new insights to discover leads that could potentially emerge as novel molecular therapies. Herein we describe how we combined these technologies for 3D screening in 1536 well format using a panel of ten NSCLC cells lines (5 wild type and 5 mutant) against ∼1280 selected members of the NPL. After further evaluation, the selected active hits were prioritized to be screened against all 10 NSCLC cell lines as concentration response curves to determine the efficacy and selectivity of the compounds between wild type and mutant 3D cell models. Here, we demonstrate the methods needed for automated 3D screening using microbial NPs, exemplified by crude extracts, partially purified fractions, and pure NPs, that may lead to future use targeting human cancer.