Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy.

RAS oncogenes (collectively NRAS, HRAS and especially KRAS) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 and 611. Small molecule inhibitors of the KRAS(G12C) oncoprotein have demonstrated clinical efficacy in patients with multiple cancer types and have led to regulatory approvals for the treatment of non-small cell lung cancer2,3. Nevertheless, KRASG12C mutations account for only around 15% of KRAS-mutated cancers4,5, and there are no approved KRAS inhibitors for the majority of patients with tumours containing other common KRAS mutations. Here we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad-spectrum activity for the active state of both mutant and wild-type KRAS, NRAS and HRAS variants (a RAS(ON) multi-selective inhibitor). Preclinically, RMC-7977 demonstrated potent activity against RAS-addicted tumours carrying various RAS genotypes, particularly against cancer models with KRAS codon 12 mutations (KRASG12X). Treatment with RMC-7977 led to tumour regression and was well tolerated in diverse RAS-addicted preclinical cancer models. Additionally, RMC-7977 inhibited the growth of KRASG12C cancer models that are resistant to KRAS(G12C) inhibitors owing to restoration of RAS pathway signalling. Thus, RAS(ON) multi-selective inhibitors can target multiple oncogenic and wild-type RAS isoforms and have the potential to treat a wide range of RAS-addicted cancers with high unmet clinical need. A related RAS(ON) multi-selective inhibitor, RMC-6236, is currently under clinical evaluation in patients with KRAS-mutant solid tumours (ClinicalTrials.gov identifier: NCT05379985).

Improving fourth harmonic generation performance by elevating the operation temperature of ADP crystal.

In current inertial confinement fusion (ICF) facilities, potassium dihydrogen phosphate (KH2PO4, KDP) type crystals are the only nonlinear optical (NLO) materials that can satisfy the aperture requirement of the ICF laser driver. Ammonium dihydrogen phosphate (NH4H2PO4, ADP) crystal is a typical isomer of KDP crystal, with a large nonlinear optical coefficient, high ultraviolet transmittance, and large growth sizes, which is an important deep ultraviolet (UV) NLO material. In this paper, we investigated the effect of ADP temperature on its fourth-harmonic-generation (FHG) performance. When the temperature of the ADP crystal was elevated to 48.9 °C, the 90° phase-matched FHG of the 1064 nm laser was realized. Compared with the 79° phase-matched FHG at room temperature (23.0 °C), the output energy at 266 nm, conversion efficiency, angular acceptance, and laser-induced damage threshold (LIDT) increased 113%, 71%, 623%, 19.6%, respectively. It shows that elevating ADP temperature is an efficient method to improve its deep UV frequency conversion properties, which may also be available to other NLO crystals. This discovery provides a very valuable technology for the future development of UV, deep UV lasers in ICF facilities.

7.56-W continuous-wave Pr3+-based green laser via managing thermally induced effects.

Blue-laser-diode-pumped Pr3+-based continuous-wave (CW) green lasers have aroused growing research interest in developing optoelectronic applications and deep ultraviolet laser sources due to their simple and compact structural design. However, the obstacle of thermally induced effects limits the available output power of Pr3+-based green lasers. Herein, combined with the theoretical analysis and experimental feedback, we effectively adjust the heat distribution inside the Pr3+:LiYF4 gain crystal by optimizing the crystal dimension and doping concentration. The excellent mode matching between the pump and green lasers is achieved under the consideration of thermally induced effects, yielding a maximum CW output power of 7.56 W. To the best of our knowledge, this is the largest output power of Pr3+-based CW green lasers so far. Moreover, the obtained green laser demonstrates excellent output stability (RMS = 1.27%) and beam quality (M2 = 1.30 × 1.12) under the lasing operation state with the maximum output power. We hope that this study can provide a feasible paradigm for developing blue-laser-diode-pumped visible lasers, especially for high-power lasers.

Passively Q-switched Nd3+ solid-state lasers with hexakis-[(trimethylsilyl)ethynyl]benzene and graphdiyne as saturable absorbers.

In this paper, two-dimensional Graphdiyne and Hexakis-[(trimethylsilyl)ethynyl]benzene nanosheets were prepared using the liquid-phase exfoliation method and were then successfully applied to 1.06 µm passively Q-Switched all-solid-state lasers. The Hexakis-[(trimethylsilyl)ethynyl]benzene was applied for the first time in passively Q-Switched all-solid-state lasers, as we know. For Graphdiyne, the Q-Switched pulse achieved a narrowest pulse width of 415 ns, a maximum repetition frequency of 244.2 kHz, a maximum pulse energy of 133.53 nJ, and peak power of 321.77 mW was obtained. While, the narrowest pulse width, maximum repetition frequency, maximum pulse energy, and peak power for Hexakis-[(trimethylsilyl)ethynyl]benzene are approximately 398.4 ns, 297.1 kHz, 89.61 nJ, and 220.39 mW respectively. The findings demonstrate the promising potential of both candidates as saturable absorbers for signal modulation in solid-state lasers.

High performance 1.9†µm passively Q-switched bulk laser with germanene as a saturable absorber.

Germanene is an analog of graphene, and its independent novel low-bending honeycomb structure gives outstanding advantages such as environmental stability and significant low-frequency optical absorbance. In this paper, the few-layer germanene was successfully prepared by the liquid phase exfoliation method. The saturable absorption characteristics of germanene in the infrared waveband were detected by the open-aperture Z-scan method. With germanene as a saturable absorber, a high-performance passively Q-switched bulk laser was realized at 1.9 µm. The shortest pulse width of 60.5 ns was obtained from continuous-wave pumping, corresponding to a single pulse energy of 6.7 µJ and peak power of 110 W. By utilizing the pulse pumping style with a repletion rate of 10 Hz, the single pulse energy and peak power increased to 45.8 µJ and 328 W, respectively, which exceeded all two-dimensional SA materials reported before. This research manifests that germanene is an excellent SA material for mid-infrared solid-state lasers.

Selective inhibitors of mTORC1 activate 4EBP1 and suppress tumor growth.

The clinical benefits of pan-mTOR active-site inhibitors are limited by toxicity and relief of feedback inhibition of receptor expression. To address these limitations, we designed a series of compounds that selectively inhibit mTORC1 and not mTORC2. These 'bi-steric inhibitors' comprise a rapamycin-like core moiety covalently linked to an mTOR active-site inhibitor. Structural modification of these components modulated their affinities for their binding sites on mTOR and the selectivity of the bi-steric compound. mTORC1-selective compounds potently inhibited 4EBP1 phosphorylation and caused regressions of breast cancer xenografts. Inhibition of 4EBP1 phosphorylation was sufficient to block cancer cell growth and was necessary for maximal antitumor activity. At mTORC1-selective doses, these compounds do not alter glucose tolerance, nor do they relieve AKT-dependent feedback inhibition of HER3. Thus, in preclinical models, selective inhibitors of mTORC1 potently inhibit tumor growth while causing less toxicity and receptor reactivation as compared to pan-mTOR inhibitors.

Identification and expression analysis of C2H2-zinc finger protein genes reveals their role in stress tolerance in Brassica napus.

C2H2-zinc finger (C2H2-ZF) genes are involved in various biological processes in plants including stress response; however, they lack characterization in Brassica napus. We identified 267 C2H2-ZF genes in B. napus and deciphered their physiological properties, subcellular localization, structure, synteny, and phylogeny and investigated the expression of 20 genes in response to different stresses and phytohormone treatments. The 267 genes were distributed on 19 chromosomes; phylogenetic analysis categorized them into five clades. They varied from 0.41 to 9.2 kb in length, had stress-responsive cis-acting elements in promoter regions, and their protein length varied from 9 to 1366 amino acids. About 42% of the genes had one exon, and 88% genes had orthologs in Arabidopsis thaliana. About 97% of the genes were located in nucleus and 3% in cytoplasmic organelles. qRT-PCR analysis showed a different expression pattern of these genes in response to biotic stresses (Plasmodiophora brassicae and Sclerotinia sclerotiorum) and abiotic stresses (cold, drought, and salinity) and hormonal treatments. Differential expression of the same gene was observed under multiple stress conditions, and a few genes showed similar expression in response to more than one phytohormones. Our results suggest that the C2H2-ZF genes can be targeted for the improvement of stress tolerance in canola.

Resection of intracardiac leiomyoma originating from the inferior vena cava through a single median sternotomy incision using a silk suture snare technique: a case report.

BACKGROUND: Intracardiac leiomyoma is a rare benign right heart tumor that usually extends from the intravenous system. The patient often has a history of uterine leiomyoma. CASE PRESENTATION: We report a 46-year-old female patient who presented to us with exertional dyspnea, chest tightness, and shortness of breath for two weeks and had a history of uterine leiomyoma resection. Echocardiography showed a pedunculated solid mass in the right heart with the pedicle attached to the inferior vena cava. The surgery was performed under cardiopulmonary bypass established through the femoral artery and vein with a probable diagnosis of leiomyoma. The tumor was removed by ingenious surgical technique: a snare made of silk suture in which the tumor's pedicle was trapped, and the tumor with its pedicle was carefully removed with the help of a scalpel along the silk suture. The histopathology report confirmed the diagnosis of intravenous leiomyoma. The postoperative course was uneventful and the patient was discharged a week later. CONCLUSION: Intracardiac leiomyoma is a rare benign smooth muscle tumor. Surgery is the mainstay of treatment with different surgical approaches available. It is possible to completely remove cardiac leiomyomas through sternotomy without the need for an abdominal incision if the leiomyoma is originated in the inferior vena cava not far from the right atrium.

A Compared Study of Eicosapentaenoic Acid and Docosahexaenoic Acid in Improving Seizure-Induced Cognitive Deficiency in a Pentylenetetrazol-Kindling Young Mice Model.

Epilepsy is a chronic neurological disorder that is more prevalent in children, and recurrent unprovoked seizures can lead to cognitive impairment. Numerous studies have reported the benefits of docosahexaenoic acid (DHA) on neurodevelopment and cognitive ability, while comparatively less attention has been given to eicosapentaenoic acid (EPA). Additionally, little is known about the effects and mechanisms of DHA and EPA in relation to seizure-induced cognitive impairment in the young rodent model. Current research indicates that ferroptosis is involved in epilepsy and cognitive deficiency in children. Further investigation is warranted to determine whether EPA or DHA can mitigate seizure-induced cognitive deficits by inhibiting ferroptosis. Therefore, this study was conducted to compare the effects of DHA and EPA on seizure-induced cognitive deficiency and reveal the underlying mechanisms focused on ferroptosis in a pentylenetetrazol (PTZ)-kindling young mice model. Mice were fed a diet containing DHA-enriched ethyl esters or EPA-enriched ethyl esters for 21 days at the age of 3 weeks and treated with PTZ (35 mg/kg, i.p.) every other day 10 times. The findings indicated that both EPA and DHA exhibited ameliorative effects on seizure-induced cognitive impairment, with EPA demonstrating a superior efficacy. Further mechanism study revealed that supplementation of DHA and EPA significantly increased cerebral DHA and EPA levels, balanced neurotransmitters, and inhibited ferroptosis by modulating iron homeostasis and reducing lipid peroxide accumulation in the hippocampus through activating the Nrf2/Sirt3 signal pathway. Notably, EPA exhibited better an advantage in ameliorating iron dyshomeostasis compared to DHA, owing to its stronger upregulation of Sirt3. These results indicate that DHA and EPA can efficaciously alleviate seizure-induced cognitive deficiency by inhibiting ferroptosis in PTZ-kindled young mice.

Genome-wide identification of biotin carboxyl carrier subunits of acetyl-CoA carboxylase in Brassica and their role in stress tolerance in oilseed Brassica napus.

BACKGROUND: Biotin carboxyl carrier protein (BCCP) is a subunit of Acetyl CoA-carboxylase (ACCase) which catalyzes the conversion of acetyl-CoA to malonyl-CoA in a committed step during the de novo biosynthesis of fatty acids. Lipids, lipid metabolites, lipid-metabolizing and -modifying enzymes are known to play a role in biotic and abiotic stress tolerance in plants. In this regard, an understanding of the Brassica napus BCCP genes will aid in the improvement of biotic and abiotic stress tolerance in canola. RESULTS: In this study, we identified 43 BCCP genes in five Brassica species based on published genome data. Among them, Brassica rapa, Brassica oleracea, Brassica nigra, Brassica napus and Brassica juncea had six, seven, seven, 10 and 13 BCCP homologs, respectively. Phylogenetic analysis categorized them into five classes, each with unique conserved domains. The promoter regions of all BCCP genes contained stress-related cis-acting elements as determined by cis-element analysis. We identified four and three duplicated gene pairs (segmental) in B. napus and B. juncea respectively, indicating the role of segmental duplication in the expansion of this gene family. The Ka/Ks ratios of orthologous gene pairs between Arabidopsis thaliana and five Brassica species were mostly less than 1.0, implying that purifying selection, i.e., selective removal of deleterious alleles, played a role during the evolution of Brassica genomes. Analysis of 10 BnaBCCP genes using qRT-PCR showed a different pattern of expression because of exposure of the plants to biotic stresses, such as clubroot and sclerotinia diseases, and abiotic stresses such as drought, low temperature and salinity stresses. CONCLUSIONS: The identification and functional analysis of the Brassica BCCPs demonstrated that some of these genes might play important roles in biotic and abiotic stress responses. Results from this study could lay the foundation for a better understanding of these genes for the improvement of Brassica crops for stress tolerance.

Broadband second-harmonic-generation in GdCOB crystals.

Broadband second-harmonic-generation (SHG) in GdCOB crystals was demonstrated for the first time. Theoretical calculation and experiments for the type-I frequency doubling of GdCOB crystal was performed. The result revealed that the spectral retracing point of phase-matching angle was at around 1.65 µm. For broadband fundamental laser source tuning in the range of 1.55-1.7 µm, efficient SHG was realized, the highest conversion efficiency was 56%, and the output bandwidth reached 16 nm.

Spontaneous Raman spectra analysis and efficient nanosecond pulse Raman laser of a BaTeW2O9 crystal.

In this Letter, the spontaneous Raman spectra of a novel, to the best of our knowledge, crystal α-BaTeW2O9 (α-BTW) are characterized and analyzed. The relative Raman gain coefficient of the α-BTW crystal is calculated to be 0.84 times that of YVO4. With a 35-mm-long crystal, the first-order Raman laser of α-BTW operating at 1178 nm is realized. The simple external resonator setup is employed in the first-order Raman laser of α-BTW. The pump source is a lamp-pumped electric-optical Q switched Nd:YAG laser amplifier system operating at 1064 nm with a pulse width of 10 ns. The Raman laser exhibits a threshold of 14.7 MW/cm2. In our experiments, a maximum pulse energy of 21.5 mJ is obtained with an optical-to-optical conversion efficiency and slope efficiency of 43.6%, 57.9%, respectively. Due to its high laser damage threshold, relative high Raman gain coefficient, and excellent thermal properties, the α-BTW crystal is a potential Raman material.

Growth, Optical, and Spectroscopic Properties of Pure and Nd3+-Doped GdSr3(PO4)3 Crystals with Disordered Structure.

Disordered crystals have attracted immense attention for the generation of ultrashort laser pulses due to their good thermomechanical characteristics and wide emission bandwidths. In this work, a Gd-based orthophosphate crystal, GdSr3(PO4)3, (GSP), and a Nd3+-doped GdSr3(PO4)3 crystal, (Nd:GSP), were obtained by the Czochralski method. The crystal structure, optical properties, electronic band structure, laser damage threshold, and hardness of the GSP crystal were comprehensively investigated. It exhibited a disordered structure due to the random distribution of Sr and Gd atoms in the same Wyckoff site, which caused inhomogeneous spectral broadening. Additionally, it exhibited a short UV absorption cutoff edge (<200 nm), a large band gap (5.81 eV), and a high laser damage threshold (∼1850 MW/cm2). The spectral properties and Judd-Ofelt calculations of the Nd:GSP crystals were analyzed. A wide absorption band at 803 nm, with a full width at half-maximum value of 20 nm, makes the Nd:GSP crystal suitable for the efficient pumping of AlGaAs laser diodes. Sub-100-fs pulses could be supported by its 25 nm emission bandwidth. Hence, the GSP crystal could be a promising disordered crystal laser matrix.

Recalibration of the nonlinear optical coefficients of BaGa4Se7 crystal using second-harmonic-generation method.

Nonlinear optical coefficients are important parameters for nonlinear optical crystals. Based on the previously disclosed BaGa4Se7 crystal coefficients, the optimum phase-matching direction with the largest effective nonlinear optical coefficient appears in the second octant (90∘<θ<180∘, 0∘<ϕ<90∘). In this study, a recalibration was performed using the second-harmonic-generation method, and it was confirmed that the optimum phase-matching direction of the BaGa4Se7 crystal is located in its XZ principal plane (ϕ=0∘). Therefore, this study will serve as a good reference for future applications of this excellent crystal.

Kerr-lens mode-locked Tm-doped sesquioxide ceramic laser.

Kerr-lens mode-locked solid-state laser operation at ∼2µm is investigated. Using a Tm3+-doped (Lu,Sc)2O3 "mixed" sesquioxide ceramic as a gain medium, pulses as short as 58 fs are generated at ∼2081nm via soft-aperture Kerr-lens mode locking. The average output power amounts to 220 mW at a pulse repetition rate of 84.8 MHz. The emitted spectrum at the long-wavelength wing extends to >2.2µm which is attributed to vibronic transitions of the Tm3+ ions. The latter is found to be essential for generating pulses with durations in the 50 fs range.

Tm:YAG single-crystal fiber laser.

In this Letter, to the best of our knowledge, we present the first thulium (Tm) single-crystal fiber (SCF) laser with free-space propagation of the laser beam only. The SCF is equipped with diffusion-bonded end caps of undoped YAG for better thermal management and enhancement of pump guiding. By utilizing mode matching and pump guiding in different SCF parts, an output power of 9.1 W is achieved at ∼2.02µm with a slope efficiency of 49.4%. This straightforward approach, which is also simple to realize and is based on combining the advantages of fiber-geometry structure and crystalline properties of Tm:YAG, is expected to be useful for 2 µm amplification stages in different time formats as well.

Metallated Graphynes as a New Class of Photofunctional 2D Organometallic Nanosheets.

Two-dimensional (2D) nanomaterials are attracting much attention due to their excellent electronic and optical properties. Here, we report the first experimental preparation of two free-standing mercurated graphyne nanosheets via the interface-assisted bottom-up method, which integrates both the advantages of metal center and graphyne. The continuous large-area nanosheets derived from the chemical growth show the layered molecular structural arrangement, controllable thickness and enhanced π-conjugation, which result in their stable and outstanding broadband nonlinear saturable absorption (SA) properties (at both 532 and 1064 nm). The passively Q-switched (PQS) performances of these two nanosheets as the saturable absorbers are comparable to or higher than those of the state-of-the-art 2D nanomaterials (such as graphene, black phosphorus, MoS2 , γ-graphyne, etc.). Our results illustrate that the two metallated graphynes could act not only as a new class of 2D carbon-rich materials, but also as inexpensive and easily available optoelectronic materials for device fabrication.

Capture and Release of Singlet Oxygen in Coordination-Driven Self-Assembled Organoplatinum(II) Metallacycles.

Singlet oxygen (1O2), as an important active reagent, has found wide applications in photodynamic therapy (PDT), synthetic chemistry, and materials science. Organic conjugated aromatics serving as hosts to capture and release singlet oxygen have been systematically investigated over the last decades. Herein, we present a [6 + 6] organoplatinum(II) metallacycle by using ∼180° dipyridylanthracene donor and ∼120° Pt(II) acceptor as the building blocks, which enables the capture and release of singlet oxygen with relatively high photooxygenation and thermolysis rate constants. The photooxygenation of the metallacycle to the corresponding endoperoxide was performed by sensitized irradiation, and the resulting endoperoxide is stable at room temperature and can be stored under ambient condition over months. Upon simple heating of the neat endoperoxide under inert atmosphere at 120 °C for 4 h, the resulting endoperoxide can be reconverted to the corresponding parent form and singlet oxygen. The photooxygenation and thermolysis products were characterized by NMR spectroscopy and electrospray ionization time-of-flight mass spectrometric analysis. Density functional theory calculations were conducted in order to reveal the frontier molecular orbital interactions and reactivity. This work provides a new material platform for singlet oxygen related promising applications.

COVID-19 patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis.

The aim of this study was to analyze the clinical data, discharge rate, and fatality rate of COVID-19 patients for clinical help. The clinical data of COVID-19 patients from December 2019 to February 2020 were retrieved from four databases. We statistically analyzed the clinical symptoms and laboratory results of COVID-19 patients and explained the discharge rate and fatality rate with a single-arm meta-analysis. The available data of 1994 patients in 10 literatures were included in our study. The main clinical symptoms of COVID-19 patients were fever (88.5%), cough (68.6%), myalgia or fatigue (35.8%), expectoration (28.2%), and dyspnea (21.9%). Minor symptoms include headache or dizziness (12.1%), diarrhea (4.8%), nausea and vomiting (3.9%). The results of the laboratory showed that the lymphocytopenia (64.5%), increase of C-reactive protein (44.3%), increase of lactic dehydrogenase (28.3%), and leukocytopenia (29.4%) were more common. The results of single-arm meta-analysis showed that the male took a larger percentage in the gender distribution of COVID-19 patients 60% (95% CI [0.54, 0.65]), the discharge rate of COVID-19 patients was 52% (95% CI [0.34,0.70]), and the fatality rate was 5% (95% CI [0.01,0.11]).

Remarkable temperature-dependent second-harmonic-generation performance of a YCOB crystal.

For the first time, the temperature stability of second-harmonic-generation (SHG) is reported for the entire space of a YCa4O(BO3)3 (YCOB) crystal for a temperature range of -10 - 520 °C. Both theoretical calculations and experimental data indicate an optimum phase-matching (PM) direction of (θ = 149.2°, ϕ = 0°), which is located in the XZ principle plane (90° < θ < 180°). A special regression phenomenon of the PM angle was found in this direction, which further increased the SHG output at high temperature (> 200 °C). As a result, for SHG of the Nd:YAG laser, the measured temperature bandwidth of a YCOB crystal cut along the optimum PM direction is larger than 490 °C·cm. As demonstrated in this study, among all nonlinear optical crystals, this cut-type is currently the best choice when temperature-insensitive SHG is required.