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Autonomous vehicles (AVs) have been made possible by advances in sensing and computing technologies. However, the high cost of AVs makes privatization take longer. Therefore, companies with autonomous vehicles can develop shared autonomous vehicle (SAV) projects. AVs with a high level of automation require high upgrade and use costs. In order to meet the needs of more customers and reduce the investment cost of the company, SAVs with different levels of automation may coexist for a long time. Faced with multiple travel modes (autonomous cars with different levels of automation, private cars, and buses), travelers’ travel mode choices are worth studying. To further differentiate the types of travelers, this paper defines high-income travelers and low-income travelers. The difference between these two types of travelers is whether they have a private car. The differences in time value and willingness to pay of the two types of travelers are considered. Based on the above considerations, this paper establishes a multi-modal selection model with the goal of maximizing the total utility of all travelers and uses the imperial competition algorithm to solve it. The results show that low-income travelers are more likely to choose buses and autonomous vehicles with lower levels of automation, while high-income travelers tend to choose higher levels of automation due to their high value of travel time.

Background: Acute myeloid leukaemia (AML) with t (8;21) or inv (16), called core binding factor (CBF) AML, has a favourable prognosis. However, some CBF-AML patients have persistent measurable residual disease (MRD) and are more likely to relapse after standard chemotherapy treatment. The CAG regimen, composed of cytarabine, aclarubicin and granulocyte colony-stimulating factor, has been proven to be effective and safe in treating refractory AML patients. Method: We performed a retrospective study to evaluate the efficacy of the CAG regimen to eliminate MRD detected by RUNX1::RUNX1T1 and CBFβ::MYH11 transcript levels by quantitative polymerase chain reaction (Q-PCR) among 23 patients. Molecular response was defined as the ratio of fusion transcript after treatment to that before treatment greater than or equal to 0.5. Result: The molecular response rate and median decrease ratio of fusion transcripts at themolecular level of the CAG regimen were 52.5% and 0.53, respectively. Among the 15 patients who had a poor molecular response to the high/intermediate-dose cytarabine regimen, the median decrease ratios of transcripts at the molecular level of high/intermediate-dose cytarabine and CAG were 1.55 and 0.53 (P=0.028), respectively, and 6 of 15 patients achieved amolecular response to CAG (40%). The median disease-free survival was 18 months, and the overall survival rate at three years among all patients was 72.7%±10.7%. The common treatment-related adverse events were nausea (100%), thrombocytopenia (39%) and neutropenia (37.5%). Conclusion: The CAG regimen may have activity in CBF-AML patients and could provide a new option for patients who have a poor molecular response to high/intermediate-dose cytarabine.

The use of alkyl amines and ethers as traceless hydride donors in [1,5]-hydride transfer cascade reactions represents a promising strategy that greatly enriches redox-neutral hydride transfer chemistry. This review summarizes the remarkable progress made in this field, and focuses on (1) alkyl amines as traceless hydride donors in cascade [1,5]-hydride transfer/elimination reactions and (2) alkyl ethers as traceless hydride donors in [1,5]-hydride transfer cascade reactions. The reaction mechanisms, features, scope, limitations, and synthetic applications are included, where appropriate. Importantly, its powerful ability in allene synthesis and the combination with [Re]-vinylidene and carbocation chemistries render this strategy attractive enough to inspire chemists to develop colorful reactions for building molecular complexity.

Understanding the biological and clinical impact of copy number aberrations (CNAs) on the development of precision therapies in cancer remains an unmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNA conferring an adverse prognosis in several types of cancer, including in the blood cancer multiple myeloma (MM). Although several genes across chromosome 1 (chr1q) portend high-risk MM disease, the underpinning molecular etiology remains elusive. Here, with reference to the 3-dimensional (3D) chromatin structure, we integrate multi-omics data sets from patients with MM with genetic variables to obtain an associated clinical risk map across chr1q and to identify 103 adverse prognosis genes in chr1q-amp MM. Prominent among these genes, the transcription factor PBX1 is ectopically expressed by genetic amplification and epigenetic activation of its own preserved 3D regulatory domain. By binding to reprogrammed superenhancers, PBX1 directly regulates critical oncogenic pathways and a FOXM1-dependent transcriptional program. Together, PBX1 and FOXM1 activate a proliferative gene signature that predicts adverse prognosis across multiple types of cancer. Notably, pharmacological disruption of the PBX1-FOXM1 axis with existing agents (thiostrepton) and a novel PBX1 small molecule inhibitor (T417) is selectively toxic against chr1q-amp myeloma and solid tumor cells. Overall, our systems medicine approach successfully identifies CNA-driven oncogenic circuitries, links them to clinical phenotypes, and proposes novel CNA-targeted therapy strategies in MM and other types of cancer.

This review highlights the encouraging advances in hydride transfer-involved dearomatization reaction during the past decade, the content of which is categorized according to the hydride acceptors, namely vinylogous imines and quinone methides.

The reaction of 2-pyridylacetates and α,β-unsaturated pyrazolamides with DBU as the catalyst has been developed. A range of unexplored multisubstituted 2,3-dihydro-4H-quinolizin-4-ones are obtained with satisfactory yields (up to 94%) and excellent diastereoselectivities (all cases >20 : 1 dr) via a dearomative [3 + 3] annulation process. This practical method also features transition metal free, mild reaction conditions, wide functional group tolerance, easy scale-up synthesis, and versatile further derivatization.

Partial nitritation is necessary for the implementation of the mainstream anammox (anaerobic ammonium oxidation) process in wastewater treatment plants. However, the difficulty in outcompeting nitrite-oxidizing bacteria (NOB) at mainstream conditions hinders the performance of partial nitritation. The present work aimed to develop a high-rate partial nitritation process for low-ammonium wastewater treatment at low temperatures by seeding aerobic granules. Experimental results suggested that both stratified structure of nitrifiers developed in the granules and sufficient residual ammonium concentration (18-35 mg N L-1) in the bulk liquid contributed to efficient NOB repression. With the hydraulic retention time progressively shortened from 1.0 to 0.17 h, the influent nitrogen loading rate of the partial nitritation process reached 6.8 ± 0.4 kg N m-3 d-1 even at 10-15 °C. The high concentration (7.5 gVSS L-1) and activity (0.48 g N g-1 VSS d-1 at 11 °C) of granular sludge made the reactor possess an overcapacity evaluated by the ratio between the actual ammonium oxidation rate of the granules and their maximum potential. The overcapacity helped the reactor to face the adverse effect of decreasing temperatures. Overall, this work indicated the great potential of applying aerobic granules to achieve high-rate partial nitritation at mainstream conditions. Moreover, anammox bacteria with a relative abundance of 2.8% was also identified in the partial nitritation granules at the end of this study, suggesting that the granules provided a habitable niche for anammox bacteria growth. Note that these results cannot fully relate to the treatment of real domestic/municipal wastewater, they are a source of important information increasing the knowledge about low temperature partial nitrification.

The change of bubbles and the position of the tuyere in an oxygen coal combustion melting and separating furnace affect the flow and splash behavior of the molten pool. To analyze this problem further, a three-dimensional numerical simulation method was used to explore the behavior and change of the flow field inside the molten pool during double-row tuyere injection. In addition, the arrangement of the tuyere was changed for a more detailed understanding of the internal phase distribution and splashing in a molten pool. The results indicated that under three-dimensional numerical simulation conditions, bubbles rise after leaving the tuyere and break on the surface of the molten pool, which results in certain fluctuations in the nearby melt. During the injection process of the tuyere, the meteorological accumulation in the middle part of the molten pool formed part of the foam slag because of the influence of surface tension. When the layout of the upper and lower exhaust tuyeres was changed from staggered to symmetrical, or when the spacing of the upper and lower exhaust tuyeres changed, it had an effect on the phase distribution and splash behavior.

ZnO nanorod arrays (NRAs) were fabricated on polyester fabrics (PFs) by a two-step method and modified with Ag by magnetron sputtering. The photogenerated charge transport properties of the Ag/ZnO nanorod heterojunctions were studied by a self-made Kelvin probe system and a surface photovoltage (SPV) test system. The measured work functions (WFs) of the deposited Ag and ZnO nanorod are 4.67 and 5.56 eV, respectively. The SPV spectra indicate that the direction of the inner electric field is from the Ag layer to the inner of the ZnO nanorod. The enhancement of light absorption by the local surface plasma resonance (LSPR) effect of Ag/ZnO NRA was observed by Raman microspectroscopy and UV–vis diffuse reflectance spectroscopy. The photocatalytic activity of the Ag/ZnO NRA-functionalized PFs was evaluated by the photocatalytic degradation of Rhodamine B (RB) solution under visible light. The full photo-oxidation of RB and the outperforming ZnO NRA-coated PFs demonstrate that the enhanced photocatalytic performance of Ag/ZnO NRA-coated PFs results from the cooperation of the inner electric field of the Ag/ZnO nanorod heterojunction and Ag LSPR.

Micro-supercapacitors with high power density and stability promise emerging energy storage devices. However, their relatively low energy density and poor mechanical stability largely restricts their application. Here, we report an all-in-one planar micro-supercapacitor (MSC) using ZnO nanosheets anchored on the porous and 3D laser-induced porous graphene foams (ZnO@LIG) as the electrode materials. Due to the 3D networks, the hybrid electrode exhibits fast charge transfer and diffusion channels. More importantly, the hybrid approach can simultaneously take advantage of double-layer capacitance and faradaic energy storage mechanisms. The ZnO@LIG electrode displays a high specific capacitance of 14.7 F cm−2, remarkable rate capability and cycling stability. Furthermore, the MSC showcases high energy density (10.0 Wh kg−1), high power density (0.5 Wh kg−1), long-term stability, and excellent mechanical stability upon bending. The excellent performance parameters of the MSC make it one of the promising micropower sources for flexible microelectronics.

With the wide application of hydraulic servo technology in control systems, the requirement of hydraulic servo position control performance is greater and greater. In order to solve the problems of slow response, poor precision, and weak anti-interference ability in hydraulic servo position controls, a Kalman genetic optimization PID controller is designed. Firstly, aiming at the nonlinear problems such as internal leakage and oil compressibility in the hydraulic servo system, the mathematical model of the hydraulic servo system is established. By analyzing the working characteristics of the servo valve and hydraulic cylinder in the hydraulic servo system, the parameters in the mathematical model are determined. Secondly, a genetic algorithm is used to search the optimal proportional integral differential (PID) controller gain of the hydraulic servo system to realize the accurate control of valve-controlled hydraulic cylinder displacement in the hydraulic servo system. Under the positioning benchmark of step signal and sine wave signal, the PID algorithm and the genetic optimized PID algorithm are compared in the system simulation model established by Simulink. Finally, to solve the amplitude fluctuations caused by the GA optimized PID and reduce the influence of external disturbances, a Kalman filtering algorithm is added to the hydraulic servo system to reduce the amplitude fluctuations and the influence of external disturbances on the system. The simulation results show that the designed Kalman genetic optimization PID controller can be better applied to the position control of the hydraulic servo system. Compared with the traditional PID control algorithm, the PID algorithm optimized by genetic algorithm improves the system’s response speed and control accuracy; the Kalman filter is a good solution for the amplitude fluctuations caused by GA-optimized PID that reduces the influence of external disturbances on the hydraulic servo system.

BackgroundDexmedetomidine has been documented to reduce the dose of both intrathecal local anesthetic during cesarean delivery, and the concentration of ropivacaine needed for inducing analgesia during labor. However, few studies have compared adjuvant dexmedetomidine to fentanyl on how they impact the dose of ropivacaine required during labor. The aim of the current study was to evaluate the efficacy of epidural dexmedetomidine at doses of 0.3, 0.4, or 0.5 and 2 μg/ml of fentanyl (the traditional clinical concentration), when added to epidural 0.125% ropivacaine.MethodsThis was a randomized, double-blinded study that comprised one hundred eighty-eight patients, allocated into four groups receiving either epidural fentanyl at 2 μg/ml, or dexmedetomidine at 0.3, 0.4, or 0.5 μg/ml for labor analgesia. The primary outcome was the amount of ropivacaine necessary per hour. Secondary outcomes included visual analogue pain scale (VAS), motor block (Bromage Scale), side effects, patient satisfaction, and neonatal outcomes.ResultsAt the completion of the study, data from 165 participants were analyzed. The mean hourly amount of epidural ropivacaine administered was 16.2 ± 3.3, 14.0 ± 3.1, 13.1 ± 3.7 and 12.1 ± 2.5 ml/h in the 2 μg/ml fentanyl group, and the 0.3, 0.4 and 0.5 μg/ml dexmedetomidine groups, respectively. There was a significant difference among groups in the mean hourly consumption of epidural ropivacaine (P < 0.0001 for 1 way ANOVA). The frequency of PCEA (patient-controlled epidural analgesia) was significantly higher in the fentanyl group than in the three dexmedetomidine groups (P < 0.001), and similar among the dexmedetomidine groups. The mean values of the VAS among all groups were similar over time, P > 0.05. The incidence of pruritus in the fentanyl group was 17.5%, whereas no patient experienced pruritus in any of the dexmedetomidine groups, P < 0.0001.ConclusionThe study demonstrated that epidural dexmedetomidine (0.3 and 0.4 μg/ml) was superior to standard dose epidural fentanyl in reducing the mean hourly amount of ropivacaine administered, and minimizing opioid-related side effects. Further large and multicenter studies would be necessary to confirm the benefits of dexmedetomidine, and potentially serve as an alternative to opioids for routine use in labor analgesia.Clinical trial registration[http://www.chictr.org.cn/showproj.aspx?proj=62846], identifier [ChiCTR2000039067].

Targeting glutamine catabolism has been attracting more research attention on the development of successful cancer therapy. Catalytic enzymes such as glutaminase (GLS) in glutaminolysis, a series of biochemical reactions by which glutamine is converted to glutamate and then alpha-ketoglutarate, an intermediate of the tricarboxylic acid (TCA) cycle, can be targeted by small molecule inhibitors, some of which are undergoing early phase clinical trials and exhibiting promising safety profiles. However, resistance to glutaminolysis targeting treatments has been observed, necessitating the development of treatments to combat this resistance. One option is to use synergy drug combinations, which improve tumor chemotherapy's effectiveness and diminish drug resistance and side effects. This review will focus on studies involving the glutaminolysis pathway and diverse combination therapies with therapeutic implications.

In this letter, a fully transparent AlGaN/GaN HEMT (FT-HEMT) using indium-tin-oxide (ITO) as a transparent electrode is fabricated. The n-ohmic contacts are formed based on a Si-implant process using a deposited ITO rather than the conventional alloyed metal stacks. Following a post-annealing process at 600°C, the field-effect mobility and the maximum current density for an FT-HEMT were 1004 cm2/ $\text{V}{\cdot }\text{s}$ and 179 mA/mm, respectively. Furthermore, the measured transmittance for a fabricated chip in the visible range of 400 - 700 nm was greater than 70%, which is almost the same as an as-grown GaN-on-sapphire substrate. These results show that, by using this approach, an FT-HEMT that has superior electronic properties, such as high mobility and high output current, can be realized, and show great promise for applications in transparent and/or flexible electronics, as well as other optoelectronic devices.

In this study, p-GaN/AlGaN/GaN high electron mobility transistors (HEMTs) with indium–tin–oxide (ITO) gate electrodes are demonstrated. The DC measurements for the devices show a drain current ( $\text{I}_{\mathrm{ D}}$ ) of 438 mA/mm at a $\text{V}_{\mathrm{ D}}$ and a $\text{V}_{\mathrm{ G}}$ of 10 and 8 V, respectively. A maximum ${g} _{\mathrm{ m}}$ of 92.1 mS/mm and a specific ON-resistance ( $\text{R}_{\mathrm{ on}}\cdot {\mathrm{ A}}$ ) of 1.86 $\text{m}\Omega $ cm2 are obtained. Furthermore, the robustness of the ITO gate electrode atop the p-GaN layer under the forward gate bias is studied, indicating stable $\text{I}_{\mathrm{ G}}-{\mathrm{ V}}_{\mathrm{ G}}$ and $\text{I}_{\mathrm{ D}}-{\mathrm{ V}}_{\mathrm{ G}}$ characteristics for a gate voltage of less than 11 V, which is higher than the compared device with Ni/Au Schottky gate contact. Therefore, ITO gate electrodes, which are compatible with the Light-emitting diode (LED) process, are a promising alternative for p-GaN HEMT technologies.

In this study, p-GaN HEMTs with an indium-tin-oxide (ITO) electrode fabricated on the two different Mg concentration, i.e., $1 \mathbf {\mathrm {\times }} 10 ^{19}$ cm −3 and $8 \mathbf {\mathrm {\times }} 10 ^{19\,\,}$ cm −3,in p-GaN layer are investigated for the first time under the forward gate bias to understand the stability of the forward gate bias breakdown and ${\mathrm {V}}_{TH}$ shift stability. First of all, a Mg concentration in p-GaN layer results in a better Ohmic characteristic between the ITO and p-GaN contact. Furthermore, the fabricated device with a high Mg concentration of p-GaN layer shows a better forward gate breakdown voltage, which can be attributed to the better Ohmic characteristic between p-GaN and ITO electrode. Last, an obvious negative ${\mathrm {V}}_{TH}$ shift is observed, which is most probably related to the hole injections/trapping effects. In sum, the gate breakdown characteristic in p-GaN HEMTs with ITO electrode can be further improved while using high Mg concentration of p-GaN layer while an obvious a negative ${\mathrm {V}}_{TH}$ shift under a forward gate bias is observed, indicating a trade-off between the gate breakdown voltage and ${\mathrm {V}}_{TH}$ instability needs to be carefully considered to optimize the forward gate bias stability in p-GaN HEMTs with an ITO electrode.

In this study, p-GaN HEMTs with an indium-tin-oxide (ITO) electrode fabricated on the two different Mg concentration, i.e., $1 \mathbf {\mathrm {\times }} 10 ^{19}$ cm −3 and $8 \mathbf {\mathrm {\times }} 10 ^{19\,\,}$ cm −3,in p-GaN layer are investigated for the first time under the forward gate bias to understand the stability of the forward gate bias breakdown and ${\mathrm {V}}_{TH}$ shift stability. First of all, a Mg concentration in p-GaN layer results in a better Ohmic characteristic between the ITO and p-GaN contact. Furthermore, the fabricated device with a high Mg concentration of p-GaN layer shows a better forward gate breakdown voltage, which can be attributed to the better Ohmic characteristic between p-GaN and ITO electrode. Last, an obvious negative ${\mathrm {V}}_{TH}$ shift is observed, which is most probably related to the hole injections/trapping effects. In sum, the gate breakdown characteristic in p-GaN HEMTs with ITO electrode can be further improved while using high Mg concentration of p-GaN layer while an obvious a negative ${\mathrm {V}}_{TH}$ shift under a forward gate bias is observed, indicating a trade-off between the gate breakdown voltage and ${\mathrm {V}}_{TH}$ instability needs to be carefully considered to optimize the forward gate bias stability in p-GaN HEMTs with an ITO electrode.

In this study, p-GaN/AlGaN/GaN high electron mobility transistors (HEMTs) with indium–tin–oxide (ITO) gate electrodes are demonstrated. The DC measurements for the devices show a drain current ( $\text{I}_{\mathrm{ D}}$ ) of 438 mA/mm at a $\text{V}_{\mathrm{ D}}$ and a $\text{V}_{\mathrm{ G}}$ of 10 and 8 V, respectively. A maximum ${g} _{\mathrm{ m}}$ of 92.1 mS/mm and a specific ON-resistance ( $\text{R}_{\mathrm{ on}}\cdot {\mathrm{ A}}$ ) of 1.86 $\text{m}\Omega $ cm2 are obtained. Furthermore, the robustness of the ITO gate electrode atop the p-GaN layer under the forward gate bias is studied, indicating stable $\text{I}_{\mathrm{ G}}-{\mathrm{ V}}_{\mathrm{ G}}$ and $\text{I}_{\mathrm{ D}}-{\mathrm{ V}}_{\mathrm{ G}}$ characteristics for a gate voltage of less than 11 V, which is higher than the compared device with Ni/Au Schottky gate contact. Therefore, ITO gate electrodes, which are compatible with the Light-emitting diode (LED) process, are a promising alternative for p-GaN HEMT technologies.

In this study, AlGaN/GaN light-emitting HEMTs (LE-HEMT) with a single quantum well inserted in different locations in the epitaxy layers are fabricated and analyzed. For both structures, light-emitting originated from electrons in the 2DEG and holes from the p-GaN for radiative recombination is located in the quantum well. To investigate the importance of the location of single quantum well, optical characteristics are compared by simulation and experimental results. The experimental results show that the main light-emitting wavelength is shifted from 365 nm in the UV range to 525 nm in the visible range when the radiative recombination is confined in the quantum well and dominates among other mechanisms. Epi B, which has a quantum well above the AlGaN barrier layer in contrast to Epi A which has a quantum well underneath the barrier, shows better intensity and uniformity in light-emitting. According to the simulation results showing the radiative distribution and electron concentrations for both structures, the lower quantum efficiency is due to the diverse current paths in Epi A. On the other hand, Epi B shows better quantum confinement and therefore better luminescence in the same bias condition, which is consistent with experimental observations. These findings are critical for advancing the performance of LE-HEMTs.

Amplification and overexpression of the MYC oncogene in tumor cells, including ovarian cancer cells, correlates with poor responses to chemotherapy. As MYC is not directly targetable, we have analyzed molecular pathways downstream of MYC to identify potential therapeutic targets. Here we report that ovarian cancer cells overexpressing glutaminase (GLS), a target of MYC and a key enzyme in glutaminolysis, are intrinsically resistant to platinum-based chemotherapy and are enriched with intracellular antioxidant glutathione. Deprivation of glutamine by glutamine-withdrawal, GLS knockdown, or exposure to the GLS inhibitor CB-839 resulted in robust induction of reactive oxygen species in high GLS-expressing but not in low GLS-expressing ovarian cancer cells. Treatment with CB-839 rendered GLShigh cells vulnerable to the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, and prolonged survival in tumor-bearing mice. These findings suggest consideration of applying a combined therapy of GLS inhibitor and PARP inhibitor to treat chemoresistant ovarian cancers, especially those with high GLS expression. Significance: Targeting glutaminase disturbs redox homeostasis and nucleotide synthesis and causes replication stress in cancer cells, representing an exploitable vulnerability for the development of effective therapeutics.

The process of cancer development and progression is driven by distinct subsets of cancer stem cells (CSCs) that contribute the self-renewal capacity as the major impetus to the metastatic dissemination and main impediments in cancer treatment. Given that CSCs are so scarce in the tumor mass, there are debatable points on the metabolic signatures of CSCs. As opposed to differentiated tumor progenies, CSCs display exquisite patterns of metabolism that, depending on the type of cancer, predominately rely on glycolysis, oxidative metabolism of glutamine, fatty acids, or amino acids for ATP production. Metabolic heterogeneity of CSCs, which attributes to differences in type and microenvironment of tumors, confers CSCs to have the plasticity to cope with the endogenous mitochondrial stress and exogenous microenvironment. In essence, CSCs and normal stem cells are like mirror images of each other in terms of metabolism. To achieve reprogramming, CSCs not only need to upregulate their metabolic engine for self-renewal and defense mechanism, but also expedite the antioxidant defense to sustain the redox homeostasis. In the context of these pathways, this review portrays the connection between the metabolic features of CSCs and cancer stemness. Identification of the metabolic features in conferring resistance to anticancer treatment dictated by CSCs can enhance the opportunity to open up a new therapeutic dimension, which might not only improve the effectiveness of cancer therapies but also annihilate the whole tumor without recurrence. Henceforth, we highlight current findings of potential therapeutic targets for the design of alternative strategies to compromise the growth, drug resistance, and metastasis of CSCs by altering their metabolic phenotypes. Perturbing the versatile skills of CSCs by barricading metabolic signaling might bring about plentiful approaches to discover novel therapeutic targets for clinical application in cancer treatments.Impact statementThis minireview highlights the current evidence on the mechanisms of pivotal metabolic pathways that attribute to cancer stem cells (CSCs) with a special focus on developing metabolic strategies of anticancer treatment that can be exploited in preclinical and clinical settings. Specific metabolic inhibitors that can overwhelm the properties of CSCs may impede tumor recurrence and metastasis, and potentially achieve a permanent cure of cancer patients.

Hexafluoroisopropanol has been demonstrated as the versatile promoter for redox-neutral α-C(sp3)–H functionalization of cyclic amines via the cascade [1,5]-hydride transfer/cyclization strategy. A ...

Described herein is an unprecedented N-alkylation-initiated redox-neutral [5 + 2] annulation of 3-alkylindoles with o-aminobenzaldehydes via a cascade N-alkylation/dehydration/[1,5]-hydride transfer/Friedel-Crafts alkylation sequence. A series of indole-1,2-fused 1,4-benzodiazepines are facilely constructed in moderate to good yields in one step. This protocol features excellent regioselectivity, metal-free conditions, high step economy, and wide substrate scope.

Herein, we report the first redox-neutral and transition-metal-free β-C(sp3)–H functionalization of cyclic amines via a consecutive intermolecular hydride transfer process. A series of N-aryl pyrro...

Understanding the biological and clinical impact of copy number aberrations (CNA) in cancer remains an unmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNA conferring adverse prognosis in several cancers, including the blood cancer, multiple myeloma (MM). Although several chr1q genes portend high-risk MM disease, the underpinning molecular aetiology remains elusive. Here we integrate patient multi-omics datasets with genetic variables to identify 103 adverse prognosis genes in chr1q-amp MM. Amongst these, the transcription factor PBX1 is ectopically expressed by genetic amplification and epigenetic activation of its own preserved 3D regulatory domain. By binding to reprogrammed super-enhancers, PBX1 directly regulates critical oncogenic pathways, whilst in co-operation with FOXM1, activates a proliferative gene signature which predicts adverse prognosis across multiple cancers. Notably, pharmacological disruption of the PBX1-FOXM1 axis, including with a novel PBX1 inhibitor is selectively toxic against chr1q-amp cancer cells. Overall, our systems medicine approach successfully identifies CNA-driven oncogenic circuitries, links them to clinical phenotypes and proposes novel CNA-targeted therapy strategies in cancer.SignificanceWe provide a comprehensive systems medicine strategy to unveil oncogenic circuitries and inform novel precision therapy decisions against CNA in cancer. This first clinical multi-omic analysis of chr1q-amp in MM identifies a central PBX1-FOXM1 regulatory axis driving high-risk prognosis, as a novel therapeutic target against chr1q-amp in cancer.

Purpose: Studies involving mouse models and human uterine smooth muscle cells have shown that phenylephrine inhibits uterine contractions in non-pregnant mice and human in vitro cell via cyclic adenosine monophosphate (cAMP) signaling. However, there has been no limited exploration to date of the effect of phenylephrine on uterine contractions in clinical practice. This study aimed to compare the dose requirement of oxytocin with or without the infusion of prophylactic phenylephrine to prevent post spinal hypotension during cesarean delivery under combined spinal and epidural anesthesia.Methods: This was a double-blinded, single-center, randomized, control study. One hundred and sixty pregnant patients provided informed consent and were randomly allocated to the phenylephrine (phenylephrine infusion) and control (saline infusion) groups. Patients randomized to the phenylephrine group received an intravenous prophylactic phenylephrine infusion at a fixed rate of 0.5 μg/kg/min. The control group received a saline placebo at the same rate and used the same apparatus for delivery. After neonatal delivery and clamping of the umbilical cord, patients received a standard institutional oxytocin protocol. The primary outcome measure was the total dose of oxytocin administered during CD. Secondary outcomes including the proportion (%) of patients requiring a secondary uterotonic agent and estimated blood loss (EBL) in the first 24 h after surgery.Results: The median oxytocin dose administered was significantly higher in the phenylephrine group than in the control group [6.9 ± 2.5 international standardized units (IU) vs. 5.4 ± 2.4 IU, p = 0.0004]. The number of patients that required a secondary uterotonic agent was significantly higher in the phenylephrine group than in the control group (24.2% vs. 9.1%; p = 0.034). The EBL in the first 24-h postoperatively was similar between the two groups (467 ± 47 ml vs. 392 ± 38 ml; p = 0.22).Conclusions: Prophylactic infusion of phenylephrine used to prevent post-spinal hypotension during CD was associated with a higher dose of oxytocin. This has important clinical implications, as the suboptimal use of oxytocin is associated with an increased risk of postpartum hemorrhage and increased maternal morbidity and mortality. Further studies are now needed to confirm these findings.