Cumulative live birth rates and birth outcomes after IVF/ICSI treatment cycles in young POSEIDON patients: A real-world study

ObjectiveThe aim of this study was to describe the cumulative live birth rates (CLBRs) of young women with or without low prognosis according to the POSEIDON criteria after IVF/ICSI cycles and to investigate whether the diagnosis of low prognosis increases the risk of abnormal birth outcomes.DesignRetrospective study.SettingA single reproductive medicine center.PopulationFrom January 2016 to October 2020, there were 17,893 patients (<35 years) involved. After screening, 4,105 women were included in POSEIDON group 1, 1,375 women were included in POSEIDON group 3, and 11,876 women were defined as non-POSEIDON.Intervention(s)Baseline serum AMH level was measured on the D2–D3 of menstrual cycle before IVF/ICSI treatment.Main outcome measure(s)Cumulative live birth rate (CLBR), birth outcomes.Result(s)After four stimulation cycles, the CLBRs in POSEIDON group 1, POSEIDON group 3, and non-POSEIDON group reached 67.9% (95% CI, 66.5%–69.3%), 51.9% (95% CI, 49.2%–54.5%), and 79.6% (95% CI, 78.9%–80.3%), respectively. There was no difference in gestational age, preterm delivery, cesarean delivery, and low birth weight infants between the three groups, but macrosomia was significantly higher in non-POSEIDON group, after adjusting for maternal age and BMI.Conclusion(s)The POSEIDON group shows lower CLBRs than the non-POSEIDON group in young women, while the risk of abnormal birth outcomes in the POSEIDON group will not increase

Synergistic Drug Induction in Immunotherapy for Pediatric Cancer: Ewing Sarcoma

Ewing sarcoma is a pediatric bone and soft tissue tumor that lacks effective therapies beyond cytotoxic chemotherapy, radiation, and surgery. Although immunotherapies are a popular cancer treatment, Ewing sarcoma lacks consistent expression of target antigens. The goal of this project is to discover the critical window for maximum expression of the cancer antigen GD2 on the surface of pediatric tumor cells following the synergistic treatment with two epigenetically targeted drugs, pinometostat (DOT1L inhibitor) and tazemetostat (EZH2 inhibitor). I hypothesize that there is a limited time window in which pinometostat is needed along with tazemetostat for induction of GD2. This study will deepen our lab’s understanding of pinometostat’s role in cooperating with tazemetostat to induce GD2. This knowledge also informs how pinometostat can be used with tazemetostat as an adjunct to pediatric cancer immunotherapy. To address this goal, I will determine the critical time window for pinometostat treatment and understand the gene expression changes in that time frame using RT-qPCR. A total of 3 human cell lines were be used for completing this project. The results and data from this project support my hypothesis that 3 days of pinometostat synergistically with 7 days of tazemetostat produce similar results to 7 days of pinometostat and tazemetostat. These findings narrow the critical time window of pinometostat treatment with tazemetostat in which maximum GD2 expression is shown on the tumor cell surface for CAR-T cell killing. The results give insight into the mechanism of DOT1L inhibition synergizing with EZH2 inhibition. This furthers the use of these combination drugs in clinical trial and may reduce polypharmacy in treatment for pediatric cancer immunotherapy

Kinetic Resolution of β-Alkyl Phenylethylamine Derivatives through Palladium-Catalyzed, Nosylamide-Directed C−H Olefination

Palladium-catalyzed C-H activation reactions have attracted the attention of organic researchers due to their unique high selectivity, broad functional group tolerance, and high efficiency, and they are widely used in natural products and asymmetric synthesis. Here, we report an example of enantioselective C-H alkenylation between β-alkyl phenylethylamine compounds and styrenes with Boc-L-lle-OH as the ligand and nosylamide as the directing group. This reaction is applicable to styrene containing various electron-deficient and electron-donating substitutions and may be utilized for the synthesis of benzoazepine compounds

Metabolomic profiling of plasma reveals potential biomarkers for screening and early diagnosis of gastric cancer and precancerous stages

Abstract Gastric cancer (GC) faces a great challenge in clinical diagnosis, that it often is detected at advanced stages and there is a loss of optimum time for treatment. Thus, it is necessary to develop effective strategies for diagnosis of GC. In this study, 82 participants were enrolled, including 50 chronic superficial gastritis (CSG) patients, 7 early gastric cancer (EGC), and 25 advanced gastric cancer (AGC) ones. Metabolites profiling on patient plasma was performed. Furthermore, the proposed biomarkers were used to create random forest models, in which discrimination efficiency and accuracy were ascertained by receiver operating characteristic (ROC) curve analysis. l‐carnitine, l‐proline, pyruvaldehyde, phosphatidylcholines (PC) (14:0/18:0), lysophosphatidylcholine (14:0) (LysoPC 14:0), lysinoalanine were defined as the potential biomarker panel for the diagnosis among CSG and EGC patients. Compared with EGC patients, PC(O‐18:0/0:0) and LysoPC(20:4(5Z,8Z,11Z,14Z)) were found to be upregulated in AGC patients, whereasl‐proline, l‐valine, adrenic acid, and pyruvaldehyde downregulated. Pathway analysis revealed several metabolism disorders, involving amino acids and lipid metabolism. ROC analysis demonstrated a high diagnostic performance in disease diagnosis between CSG and GC. The above results indicate that the biomarker panels are sensitive to early diagnosis of GC disease, which is expected to be a promising diagnostic tool for disease stratification studies

Novel Inhibitors of Human DOPA Decarboxylase Extracted from <i>Euonymus glabra</i> Roxb.

Dopamine, a biogenic amine with important biological functions, is produced from l-DOPA by DOPA decarboxylase (DDC). DDC is a potential target to modulate the production of dopamine in several pathological states. Known inhibitors of DDC have been used for treatment of Parkinson’s disease but suffered low specificity and diverse side effects. In the present study, we identified and characterized a novel class of natural-product-based selective inhibitors for DDC from the extract of <i>Euonymus glabra</i> Roxb. by a newly developed high-throughput enzyme assay. The structures of these inhibitors are dimeric diarylpropane, a unique chemical structure containing a divalent dopamine motif. The most effective inhibitors <b>5</b> and <b>6</b> have an IC₅₀ of 11.5 ± 1.6 and 21.6 ± 2.7 μM in an <i>in vitro</i> purified enzyme assay, respectively, but did not inhibit other homologous enzymes. Compound <b>5</b> but not <b>6</b> dose-dependently suppressed the activity of hDDC and dopamine levels at low micromolar concentrations in cells. Furthermore, structure–activity relationship analyses revealed that <i>p</i>-benzoquinone might be a crucial moiety of these inhibitors for inhibiting hDDC. The natural-product-based selective inhibitors of hDDC could serve as a chemical lead for developing improved drugs for dopamine-related disease states

Table1_Chuanzhitongluo capsule ameliorates microcirculatory dysfunction in rats: Efficacy evaluation and metabolic profiles.XLSX

Background: Ischemic stroke is a leading cause of mortality and disability worldwide. Microcirculatory dysfunction is the foremost hindrance for a good clinical prognosis in ischemic stroke patients. Clinical researches show that Chuanzhitongluo capsule (CZTL) has a curative effect during the recovery period of ischemic stroke, which contributes to a good prognosis. However, it is not known whether CZTL treats ischemic stroke by ameliorating microcirculation dysfunction.Objective: In this study, we investigated the influence of CZTL on microcirculation and its underlying mechanism.Methods: A rat model of acute microcirculatory dysfunction was established by stimuli of adrenaline and ice water. The microcirculatory damage in model rats and the efficacy of CZTL were assessed by detecting laser speckle contrast imaging, coagulation function, hemorheology, vasomotor factor and microcirculation function. The potential mechanism of CZTL action was explored by the untargeted metabolomic analysis based on ultra-performance liquid chromatography-quadrupole-time of flight-mass spectrometry.Results: Laser speckle contrast imaging showed that model rats suffered low perfusion in ears, feet and tails, and CZTL treatment increased microcirculatory blood flow. Coagulation function detection results showed that CZTL diminished the reduction of thrombin time, prothrombin time, activated partial thromboplastin time and the elevated fibrinogen level caused by acute microcirculatory dysfunction. Furthermore, CZTL could recover the increased blood viscosity as well as the abnormal vasomotor and microcirculation function in rats with acute microcirculatory dysfunction. Metabolomics analysis indicated that CZTL might regulate sphingolipid metabolism and arachidonic acid metabolism to exert protective effects on microcirculation.Conclusion: These results elucidated that CZTL was highly effective against microcirculatory dysfunction and its potential mechanisms related with the modulation of sphingolipid and arachidonic acid metabolic pathways. The present study provided a new perspective on the clinical application of CZTL, and it contribute to explore novel therapeutic drug against microcirculatory dysfunction.</p

Table2_Chuanzhitongluo capsule ameliorates microcirculatory dysfunction in rats: Efficacy evaluation and metabolic profiles.XLSX

Background: Ischemic stroke is a leading cause of mortality and disability worldwide. Microcirculatory dysfunction is the foremost hindrance for a good clinical prognosis in ischemic stroke patients. Clinical researches show that Chuanzhitongluo capsule (CZTL) has a curative effect during the recovery period of ischemic stroke, which contributes to a good prognosis. However, it is not known whether CZTL treats ischemic stroke by ameliorating microcirculation dysfunction.Objective: In this study, we investigated the influence of CZTL on microcirculation and its underlying mechanism.Methods: A rat model of acute microcirculatory dysfunction was established by stimuli of adrenaline and ice water. The microcirculatory damage in model rats and the efficacy of CZTL were assessed by detecting laser speckle contrast imaging, coagulation function, hemorheology, vasomotor factor and microcirculation function. The potential mechanism of CZTL action was explored by the untargeted metabolomic analysis based on ultra-performance liquid chromatography-quadrupole-time of flight-mass spectrometry.Results: Laser speckle contrast imaging showed that model rats suffered low perfusion in ears, feet and tails, and CZTL treatment increased microcirculatory blood flow. Coagulation function detection results showed that CZTL diminished the reduction of thrombin time, prothrombin time, activated partial thromboplastin time and the elevated fibrinogen level caused by acute microcirculatory dysfunction. Furthermore, CZTL could recover the increased blood viscosity as well as the abnormal vasomotor and microcirculation function in rats with acute microcirculatory dysfunction. Metabolomics analysis indicated that CZTL might regulate sphingolipid metabolism and arachidonic acid metabolism to exert protective effects on microcirculation.Conclusion: These results elucidated that CZTL was highly effective against microcirculatory dysfunction and its potential mechanisms related with the modulation of sphingolipid and arachidonic acid metabolic pathways. The present study provided a new perspective on the clinical application of CZTL, and it contribute to explore novel therapeutic drug against microcirculatory dysfunction.</p

Astragaloside IV Attenuates Glutamate-Induced Neurotoxicity in PC12 Cells through Raf-MEK-ERK Pathway.

Astragaloside IV (AGS-IV) is a main active ingredient of Astragalus membranaceus Bunge, a medicinal herb prescribed as an immunostimulant, hepatoprotective, antiperspirant, a diuretic or a tonic as documented in Chinese Materia Medica. In the present study, we employed a high-throughput comparative proteomic approach based on 2D-nano-LC-MS/MS to investigate the possible mechanism of action involved in the neuroprotective effect of AGS-IV against glutamate-induced neurotoxicity in PC12 cells. Differential proteins were identified, among which 13 proteins survived the stringent filter criteria and were further included for functional discussion. Two proteins (vimentin and Gap43) were randomly selected, and their expression levels were further confirmed by western blots analysis. The results matched well with those of proteomics. Furthermore, network analysis of protein-protein interactions (PPI) and pathways enrichment with AGS-IV associated proteins were carried out to illustrate its underlying molecular mechanism. Proteins associated with signal transduction, immune system, signaling molecules and interaction, and energy metabolism play important roles in neuroprotective effect of AGS-IV and Raf-MEK-ERK pathway was involved in the neuroprotective effect of AGS-IV against glutamate-induced neurotoxicity in PC12 cells. This study demonstrates that comparative proteomics based on shotgun approach is a valuable tool for molecular mechanism studies, since it allows the simultaneously evaluate the global proteins alterations