MARCH2, a Novel Oncogene-regulated SNAIL E3 Ligase, Suppresses Triple-negative Breast Cancer Metastases.

Epithelial-mesenchymal transition (EMT) in cancer promotes metastasis and chemotherapy resistance. A subset of triple-negative breast cancer (TNBC) exhibits a mesenchymal gene signature that is associated with poor patient outcomes. We previously identified PTK6 tyrosine kinase as an oncogenic driver of EMT in a subset of TNBC. PTK6 induces EMT by stabilizing SNAIL, a key EMT-initiating transcriptional factor. Inhibition of PTK6 activity reverses mesenchymal features of TNBC cells and suppresses their metastases by promoting SNAIL degradation via a novel mechanism. In the current study, we identify membrane-associated RING-CH2 (MARCH2) as a novel PTK6-regulated E3 ligase that promotes the ubiquitination and degradation of SNAIL protein. The MARCH2 RING domain is critical for SNAIL ubiquitination and subsequent degradation. PTK6 inhibition promotes the interaction of MARCH2 with SNAIL. Overexpression of MARCH2 exhibits tumor suppressive properties and phenocopies the effects of SNAIL downregulation and PTK6 inhibition in TNBC cells, such as inhibition of migration, anoikis resistance, and metastasis. Consistent with this, higher levels of MARCH2 expression in breast and other cancers are associated with better prognosis. We have identified MARCH2 as a novel SNAIL E3 ligase that regulates EMT and metastases of mesenchymal TNBC. SIGNIFICANCE: EMT is a process directly linked to drug resistance and metastasis of cancer cells. We identified MARCH2 as a novel regulator of SNAIL, a key EMT driver, that promotes SNAIL ubiquitination and degradation in TNBC cells. MARCH2 is oncogene regulated and inhibits growth and metastasis of TNBC. These insights could contribute to novel strategies to therapeutically target TNBC.

Clinical Outcomes of Common Femoral Thromboendarterectomy with Bovine Pericardium Patch Angioplasty.

BACKGROUND: The purpose of the study is to evaluate the efficacy of thromboendarterectomy (TEA) for common femoral occlusive disease using bovine pericardium patch angioplasty. METHODS: The subjects were patients who underwent TEA for common femoral occlusive disease with bovine pericardium patch angioplasty from October 2020 to August 2021. The study had a prospective, multicenter, and observational design. The primary end point was primary patency (freedom from restenosis). The secondary end points were secondary patency, amputation-free survival (AFS), postoperative wound complication, hospital death within 30 days, and major adverse cardiovascular events (MACE) within 30 days. RESULTS: Forty-seven TEA procedures with a bovine patch were performed in 42 patients (34 males; median age, 78 years; diabetes mellitus, 57%; end-stage renal disease with hemodialysis, 19%). Clinical presentations were intermittent claudication (68%) and critical limb-threatening ischemia (32%). Sixteen (34%) limbs underwent TEA alone and 31 (66%) underwent a combined procedure. Surgical site infection (SSI) occurred in 4 limbs (9%) and lymphatic fistulas in 3 limbs (6%). One limb with SSI required surgical debridement 19 days after the procedure, and 1 limb (2%) without postoperative wound complications required additional treatment due to acute bleeding. Hospital death within 30 days occurred in 1 case due to panperitonitis. There was no MACE within 30 days. Claudication was improved in all cases. Postoperative ABI of 0.92 [0.72-1.00] was significantly higher than the preoperative value (P < 0.001). The median follow-up period was 10 months [9-13 months]. One limb (2%) required additional endovascular therapy due to stenosis at the endarterectomy site at 5 months postoperatively. Primary and secondary patencies were 98% and 100% at 12 months, respectively, and the AFS rate was 90% at 12 months. CONCLUSIONS: Common femoral TEA with bovine pericardium patch angioplasty has satisfactory clinical outcomes.

Catalytic Behavior of K-doped Fe/MgO Catalysts for Ammonia Synthesis Under Mild Reaction Conditions.

An important part of realizing a carbon-neutral society using ammonia will be the development of an inexpensive yet efficient catalyst for ammonia synthesis under mild reaction conditions (<400 °C, <10 MPa). Here, we report Fe/K(3)/MgO, fabricated via an impregnation method, as a highly active catalyst for ammonia synthesis under mild reaction conditions (350 °C, 1.0 MPa). At the mentioned conditions, the activity of Fe/K(3)/MgO (17.5 mmol h-1 gcat -1 ) was greater than that of a commercial fused iron catalyst (8.6 mmol h-1 gcat -1 ) currently used in the Haber-Bosch process. K doping was found to increase the ratio of Fe0 on the surface and turnover frequency of Fe in our Fe/K(3)/MgO catalyst. In addition, increasing the pressure to 3.0 MPa at the same temperature led to a significant improvement of the ammonia synthesis rate to 29.6 mmol h-1 gcat -1 , which was higher than that of two more expensive, benchmark Ru-based catalysts, which are also potential alternative catalysts. A kinetics analysis revealed that the addition of K enhanced the ammonia synthesis activity at ≥300 °C by changing the main adsorbed species from NH to N which can accelerate dissociative adsorption of nitrogen as the rate limiting step in ammonia synthesis.

Operando Spectroscopic Study of the Dynamics of Ru Catalyst during Preferential Oxidation of CO and the Prevention of Ammonia Poisoning by Pt.

Hydrogen is a promising clean energy source. In domestic polymer electrolyte fuel cell systems, hydrogen is produced by reforming of natural gas; however, the reformate contains carbon monoxide (CO) as a major impurity. This CO is removed from the reformate by a combination of the water-gas shift reaction and preferential oxidation of CO (PROX). Currently, Ru-based catalysts are the most common type of PROX catalyst; however, their durability against ammonia (NH3) as an impurity produced in situ from trace amounts of nitrogen also contained in the reformate is an important issue. Previously, we found that addition of Pt to an Ru catalyst inhibited deactivation by NH3. Here, we conducted operando XAFS and FT-IR spectroscopic analyses with simultaneous gas analysis to investigate the cause of the deactivation of an Ru-based PROX catalyst (Ru/α-Al2O3) by NH3 and the mechanism of suppression of the deactivation by adding Pt (Pt/Ru/α-Al2O3). We found that nitric oxide (NO) produced by oxidation of NH3 induces oxidation of the Ru nanoparticle surface, which deactivates the catalyst via a three-step process: First, NO directly adsorbs on Ru0 to form NO-Ruδ+, which then induces the formation of O-Ru n+ by oxidation of the surrounding Ru0. Then, O-Ru m+ is formed by oxidation of Ru0 starting from the O-Ru n+ nuclei and spreading across the surface of the nanoparticle. Pt inhibits this process by alloying with Ru and inducing the decomposition of adsorbed NO, which keeps the Ru in a metallic state.

Co Nanoparticle Catalysts Encapsulated by BaO-La2O3 Nanofractions for Efficient Ammonia Synthesis Under Mild Reaction Conditions.

Ruthenium catalysts may allow for realization of renewable energy-based ammonia synthesis processes using mild reaction conditions (<400 °C, <10 MPa). However, ruthenium is relatively rare and therefore expensive. Here, we report a Co nanoparticle catalyst loaded on a basic Ba/La2O3 support and prereduced at 700 °C (Co/Ba/La2O3_700red) that showed higher ammonia synthesis activity at 350 °C and 1.0-3.0 MPa than two benchmark Ru catalysts, Cs+/Ru/MgO and Ru/CeO2. The synthesis rate of the catalyst at 350 °C and 1.0 MPa (19.3 mmol h-1 g-1) was 8.0 times that of Co/Ba/La2O3_500red and 6.9 times that of Co/La2O3_700red. The catalyst showed ammonia synthesis activity at temperatures down to 200 °C. Reduction at the high temperature induced the formation of BaO-La2O3 nanofractions around the Co nanoparticles by decomposition of BaCO3, which increased turnover frequency, inhibited the sintering of Co nanoparticles, and suppressed ammonia poisoning. These strategies may also be applicable to other non-noble metal catalysts, such as nickel.

Deep evolutionary origin of gamete-directed zygote activation by KNOX/BELL transcription factors in green plants.

KNOX and BELL transcription factors regulate distinct steps of diploid development in plants. In the green alga Chlamydomonas reinhardtii, KNOX and BELL proteins are inherited by gametes of the opposite mating types and heterodimerize in zygotes to activate diploid development. By contrast, in land plants such as Physcomitrium patens and Arabidopsis thaliana, KNOX and BELL proteins function in meristem maintenance and organogenesis during the later stages of diploid development. However, whether the contrasting functions of KNOX and BELL were acquired independently in algae and land plants is currently unknown. Here, we show that in the basal land plant species Marchantia polymorpha, gamete-expressed KNOX and BELL are required to initiate zygotic development by promoting nuclear fusion in a manner strikingly similar to that in C. reinhardtii. Our results indicate that zygote activation is the ancestral role of KNOX/BELL transcription factors, which shifted toward meristem maintenance as land plants evolved.

Simultaneous CK2/TNIK/DYRK1 inhibition by 108600 suppresses triple negative breast cancer stem cells and chemotherapy-resistant disease.

Triple negative breast cancer (TNBC) remains challenging because of heterogeneous responses to chemotherapy. Incomplete response is associated with a greater risk of metastatic progression. Therefore, treatments that target chemotherapy-resistant TNBC and enhance chemosensitivity would improve outcomes for these high-risk patients. Breast cancer stem cell-like cells (BCSCs) have been proposed to represent a chemotherapy-resistant subpopulation responsible for tumor initiation, progression and metastases. Targeting this population could lead to improved TNBC disease control. Here, we describe a novel multi-kinase inhibitor, 108600, that targets the TNBC BCSC population. 108600 treatment suppresses growth, colony and mammosphere forming capacity of BCSCs and induces G2M arrest and apoptosis of TNBC cells. In vivo, 108600 treatment of mice bearing triple negative tumors results in the induction of apoptosis and overcomes chemotherapy resistance. Finally, treatment with 108600 and chemotherapy suppresses growth of pre-established TNBC metastases, providing additional support for the clinical translation of this agent to clinical trials.

Highly Stable and Active Solid-Solution-Alloy Three-Way Catalyst by Utilizing Configurational-Entropy Effect.

Since 1970, people have been making every endeavor to reduce toxic emissions from automobiles. After the development of a three-way catalyst (TWC) that concurrently converts three harmful gases, carbon monoxide (CO), hydrocarbons (HCs), and nitrogen oxides (NOx ), Rh became an essential element in automobile technology because only Rh works efficiently for catalytic NOx reduction. However, due to the sharp price spike in 2007, numerous efforts have been made to replace Rh in TWCs. Nevertheless, Rh remains irreplaceable, and now, the price of Rh is increasing significantly again. Here, it is demonstrated that PdRuM ternary solid-solution alloy nanoparticles (NPs) exhibit highly durable and active TWC performance, which will result in a significant reduction in catalyst cost compared to Rh. This work provides insights into the design of highly durable and efficient functional alloy NPs, guiding how to best take advantage of the configurational entropy in addition to the mixing enthalpy.

Acute aortic dissection combined with cardiac tamponade in an elderly patient saved by pericardial drainage: A case report.

Acute aortic dissection combined with cardiac tamponade is fatal. The radical treatment is an aortic replacement; however, the risk is high. We suggest conservative treatment with pericardial drainage as a treatment option in elderly patients with comorbidities.

Coreduction methodology for immiscible alloys of CuRu solid-solution nanoparticles with high thermal stability and versatile exhaust purification ability.

This study provides a coreduction methodology for solid solution formation in immiscible systems, with an example of a whole-region immiscible Cu-Ru system. Although the binary Cu-Ru alloy system is very unstable in the bulk state, the atomic-level well-mixed CuRu solid solution nanoparticles were found to have high thermal stability up to at least 773 K in a vacuum. The exhaust purification activity of the CuRu solid solution was comparable to that of face-centred cubic Ru nanoparticles. According to in situ infrared measurements, stronger NO adsorption and higher intrinsic reactivity of the Ru site on the CuRu surface than that of a pure Ru surface were found, affected by atomic-level Cu substitution. Furthermore, CuRu solid solution was a versatile catalyst for purification of all exhaust gases at a stoichiometric oxygen concentration.

Chemoselective hydrogenation of heteroarenes and arenes by Pd-Ru-PVP under mild conditions.

Monometallic (Pd, Ru or Rh) and bimetallic (Pd0.5-Ru0.5) alloy NPs catalysts were examined for the hydrogenation of quinoline. Pd-Ru alloy catalyst showed superior catalytic activity to the traditional Rh catalyst. The characterization of Pd0.5-Ru0.5 catalysts, HAADF-EDX mapping and XPS analysis suggested that the alloy state of PdRu catalysts remained unchanged in the recovered catalyst. Furthermore, the catalyst was highly selective for the hydrogenation of different arenes.

Difference in Acquired Radioresistance Induction Between Repeated Photon and Particle Irradiation.

In recent years, advanced radiation therapy techniques, including stereotactic body radiotherapy and carbon-ion radiotherapy, have progressed to such an extent that certain types of cancer can be treated with radiotherapy alone. The therapeutic outcomes are particularly promising for early stage lung cancer, with results matching those of surgical resection. Nevertheless, patients may still experience local tumor recurrence, which might be exacerbated by the acquisition of radioresistance after primary radiotherapy. Notwithstanding the risk of tumors acquiring radioresistance, secondary radiotherapy is increasingly used to treat recurrent tumors. In this context, it appears essential to comprehend the radiobiological effects of repeated photon and particle irradiation and their underlying cellular and molecular mechanisms in order to achieve the most favorable therapeutic outcome. However, to date, the mechanisms of acquisition of radioresistance in cancer cells have mainly been studied after repeated in vitro X-ray irradiation. By contrast, other critical aspects of radioresistance remain mostly unexplored, including the response to carbon-ion irradiation of X-ray radioresistant cancer cells, the mechanisms of acquisition of carbon-ion resistance, and the consequences of repeated in vivo X-ray or carbon-ion irradiation. In this review, we discuss the underlying mechanisms of acquisition of X-ray and carbon-ion resistance in cancer cells, as well as the phenotypic differences between X-ray and carbon-ion-resistant cancer cells, the biological implications of repeated in vivo X-ray or carbon-ion irradiation, and the main open questions in the field.

Morphologic Changes of the Femoropopliteal Arterial Segment with Knee Flexion after Endovascular Therapy.

Objective: The purpose of this study is to investigate morphologic changes of the femoropopliteal arterial segment (FPAS) with knee flexion after endovascular therapy (EVT). Methods: From July 2012 to January 2015, EVT was performed on 12 limbs in 12 consecutive patients who had obliterative lesions in the FPAS. After the implantation of nitinol stents, angiography was performed with the knee in both extension and flexion to investigate morphologic changes of the FPAS. Results: On angiography, the distal end of the implanted stent was placed at various distances (5-10 cm in two cases, 10-15 cm in nine cases, and 15-20 cm in one case) above the knee joint line with the knee in extension. In all cases, although the popliteal artery was highly bent with the knee in flexion, the FPAS morphology was highly variable. However, the most proximal bending point of the FPAS was about 10 cm above the knee joint line. In one case, the artery was occluded at the distal part of the stent 16 months later, probably due to EVT. Conclusion: In EVT of the FPAS, it is important to consider the characteristics and position of the stent to prevent complications.

A CO Adsorption Site Change Induced by Copper Substitution in a Ruthenium Catalyst for Enhanced CO Oxidation Activity.

Ru is an important catalyst in many types of reactions. Specifically, Ru is well known as the best monometallic catalyst for oxidation of carbon monoxide (CO) and has been practically used in residential fuel cell systems. However, Ru is a minor metal, and the supply risk often causes violent fluctuations in the price of Ru. Performance-improved and cost-reduced solid-solution alloy nanoparticles of the Cu-Ru system for CO oxidation are now presented. Over the whole composition range, all of the Cux Ru1-x nanoparticles exhibit significantly enhanced CO oxidation activities, even at 70 at % of inexpensive Cu, compared to Ru nanoparticles. Only 5 at % replacement of Ru with Cu provided much better CO oxidation activity, and the maximum activity was achieved by 20 at % replacement of Ru by Cu. The origin of the high catalytic performance was found as CO site change by Cu substitution, which was investigated using in situ Fourier transform infrared spectra and theoretical calculations.

Endovascular Repair of an Aortic Arch Aneurysm in a Patient with a Hypoplastic Left Vertebral Artery Terminating into the Posterior Inferior Cerebellar Artery.

We present a 76-year-old male with an aortic arch aneurysm and a hypoplastic left vertebral artery (VA). Endovascular repair with left subclavian artery (SCA) closure was planned. The right VA was dominant, while the left VA was hypoplastic, barely connected to the basilar artery, and appeared to terminate at the posterior inferior cerebellar artery (PICA). The VA sizes and flow patterns during ultrasonography confirmed these findings. Therefore, we performed endovascular repair with left SCA reconstruction to prevent ischemia of the PICA perfusion area. After the operation, he experienced no difficulty with brain perfusion.

Pt-Co Alloy Nanoparticles on a γ-Al2 O3 Support: The Synergistic Effect between Isolated Electron-Rich Pt and Co for Automotive Exhaust Purification.

Invited for this month's cover is the group of Dr. Katsutoshi Sato and Prof. Dr. Katsutoshi Nagaoka (Kyoto University) and collaborators at Oita and Kyushu Universities. The cover picture shows the proposed mechanism for automotive exhaust purification over a Pt-Co alloy nanoparticle catalyst with an extremely low Pt/Co molar ratio. In the catalyst, the isolated electron-rich Pt atoms are present on the surface of the nanoparticles and play an important role in NOx capture and activation, which are important elementary steps in exhaust purification. Read the full text of the article at 10.1002/cplu.201800542.

Pt-Co Alloy Nanoparticles on a γ-Al2 O3 Support: Synergistic Effect between Isolated Electron-Rich Pt and Co for Automotive Exhaust Purification.

There is interest in minimizing or eliminating the use of Pt in catalysts by replacing it with more widely abundant and cost-effective elements. The alloying of Pt with non-noble metals is a potential strategy for reducing Pt use because interactions between Pt and non-noble metals can modify the catalyst structure and electronic properties. Here, a γ-Al2 O3 -supported bimetallic catalyst [Pt(0.1)Co(1)/Al2 O3 ] was prepared which contained 0.1 wt % Pt and 1 wt % Co and thus featured an extremely low Pt : Co ratio (<1 : 30 mol/mol). The Pt and Co in this catalyst formed alloy nanoparticles in which isolated electron-rich Pt atoms were present on the nanoparticle surface. The activity of this Pt(0.1)Co(1)/Al2 O3 catalyst for the purification of automotive exhaust was comparable to the activities of 0.3 and 0.5 wt % Pt/γ-Al2 O3 catalysts. Electron-rich Pt and metallic Co promoted activation of NOx and oxidization of CO and hydrocarbons, respectively. This strategy of tuning the surrounding structure and electronic state of a noble metal by alloying it with an excess of a non-noble metal will enable reduced noble metal use in catalysts for exhaust purification and other environmentally important reactions.

A Convolutional Neural Network Uses Microscopic Images to Differentiate between Mouse and Human Cell Lines and Their Radioresistant Clones.

: Artificial intelligence (AI) trained with a convolutional neural network (CNN) is a recent technological advancement. Previously, several attempts have been made to train AI using medical images for clinical applications. However, whether AI can distinguish microscopic images of mammalian cells has remained debatable. This study assesses the accuracy of image recognition techniques using the CNN to identify microscopic images. We also attempted to distinguish between mouse and human cells and their radioresistant clones. We used phase-contrast microscopic images of radioresistant clones from two cell lines, mouse squamous cell carcinoma NR-S1, and human cervical carcinoma ME-180. We obtained 10,000 images of each of the parental NR-S1 and ME-180 controls as well as radioresistant clones. We trained the CNN called VGG16 using these images and obtained an accuracy of 96%. Features extracted by the trained CNN were plotted using t-distributed stochastic neighbor embedding, and images of each cell line were well clustered. Overall, these findings suggest the utility of image recognition using AI for predicting minute differences among phase-contrast microscopic images of cancer cells and their radioresistant clones. SIGNIFICANCE: This study demonstrates rapid and accurate identification of radioresistant tumor cells in culture using artifical intelligence; this should have applications in future preclinical cancer research.

Carbon ion beam radioresistant rodent cells are sensitized to trifluorothymidine exposure.

Although charged particle therapy, including carbon ion beam radiation, is a cutting-edge technology in human cancer treatment, the molecular mechanisms underlying cellular resistance to this type of therapy remain unknown. Furthermore, the chemotherapeutic agents that are most effective at overcoming cellular resistance remain unknown. In the present study, carbon ion beam radioresistant rodent cells were developed and their sensitization to trifluorothymidine (FTD), a derivative of deoxythymidine, was studied. The results of the present study demonstrated that carbon ion beam radioresistant cells were more sensitive to FTD compared with X-ray radioresistant cells. The results of the present study suggested that FTD is involved in carbon ion beam radioresistance, encouraging further study of cellular resistance to charged particle therapy for refractory human cancer.