Present and future of new systemic therapies for early and intermediate stages of hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is a high mortality neoplasm which usually appears on a cirrhotic liver.The therapeutic arsenal and subsequent prognostic outlook are intrinsically linked to the HCC stage at diagnosis.Notwithstanding the current deployment of treatments with curative intent(liver resection/local ablation and liver transplantation)in early and intermediate stages,a high rate of HCC recurrence persists,underscoring a pivotal clinical challenge.Emergent systemic therapies(ST),particularly immunotherapy,have demonstrate promising outcomes in terms of increase overall survival,but they are currently bound to the advanced stage of HCC.This review provides a comprehensive analysis of the literature,encompassing studies up to March 10,2024,evaluating the impact of novel ST in the early and intermediate HCC stages,specially focusing on the findings of neoadjuvant and adjuvant regimens,aimed at increasing significantly overall survival and recurrence-free survival after a treatment with curative intent.We also investigate the potential role of ST in enhancing the downstaging rate for the intermediate-stage HCC initially deemed ineligible for treatment with curative intent.Finally,we critically discuss about the current relevance of the results of these studies and the encouraging future implications of ST in the treatment schedules of early and intermediate HCC stages.

Pixelated non-volatile programmable photonic integrated circuits with 20-level intermediate states

Multi-level programmable photonic integrated circuits(PICs)and optical metasurfaces have gained widespread attention in many fields,such as neuromorphic photonics,opticalcommunications,and quantum information.In this paper,we propose pixelated programmable Si_(3)N_(4)PICs with record-high 20-level intermediate states at 785 nm wavelength.Such flexibility in phase or amplitude modulation is achieved by a programmable Sb_(2)S_(3)matrix,the footprint of whose elements can be as small as 1.2μm,limited only by the optical diffraction limit of anin-house developed pulsed laser writing system.We believe our work lays the foundation for laser-writing ultra-high-level(20 levels and even more)programmable photonic systems and metasurfaces based on phase change materials,which could catalyze diverse applications such as programmable neuromorphic photonics,biosensing,optical computing,photonic quantum computing,and reconfigurable metasurfaces.

Enhanced anomalous Hall effect in kagome magnet YbMn_(6)Sn_(6)with intermediate-valence ytterbium

We report on the magnetization and anomalous Hall effect(AHE)in the high-quality single crystals of the kagome magnet YbMn_(6)Sn_(6),where the spins of the Mn atoms in the kagome lattice order ferromagnetically and the intermediate-valence Yb atoms are nonmagnetic.The intrinsic mechanism plays a crucial role in the AHE,leading to an enhanced anomalous Hall conductivity(AHC)compared with the other rare-earth RMn_(6)Sn_(6)compounds.Our band structure calculation reveals a strong hybridization between the 4f electrons of Yb and conduction electrons.

Steam reforming of acetic acid over Ni/biochar of low metal-loading:Involvement of biochar in tailoring reaction intermediates renders superior catalytic performance

Biochar is a reactive carrier as it may be partially gasified with steam in steam reforming,which could influence the formation of reaction intermediates and modify catalytic behaviors.Herein,the Ni/biochar as well as two comparative catalysts,Ni/Al_(2)O_(3) and Ni/SiO_(2),with low nickel loading(2%(mass))was conducted to probe involvement of the varied carriers in the steam reforming.The results indicated that the Ni/biochar performed excellent catalytic activity than Ni/SiO_(2) and Ni/Al_(2)O_(3),as the biochar carrier facilitated quick conversion of the -OH from dissociation of steam to gasify the oxygen-rich carbonaceous intermediates like C=O and C-O-C,resulting in low coverage while high exposure of nickel species for maintaining the superior catalytic performance.In converse,strong adsorption of aliphatic intermediates over Ni/Al_(2)O_(3) and Ni/SiO_(2) induced serious coking with polymeric coke as the main type(21.5%and 32.1%,respectively),which was significantly higher than that over Ni/biochar(3.9%).The coke over Ni/biochar was mainly aromatic or catalytic type with nanotube morphology and high crystallinity.The high resistivity of Ni/biochar towards coking was due to the balance between formation of coke and gasification of coke and partially biochar with steam,which created developed mesopores in spent Ni/biochar while the coke blocked pores in Ni/Al_(2)O_(3) and Ni/SiO_(2) catalysts.

Strategic regulation of nitrogen-containing intermediates for enhanced nitrate reduction over Co_(3)O_(4)/SiC catalyst having multiple active centers

Regulating the intermediates involved in the electrocatalytic nitrate reduction reaction(NO_(3)RR)is crucial for the enhancement of reaction efficiency.However,it remains a great challenge to regulate the reaction intermediates through active site manipulation on the surface of the catalyst.Here,a family of n%-Co_(3)O_(4)/SiC(n=5,8,12,20)catalysts with a delicate percentage of Co^(2+)and Co^(3+)were prepared for NO_(3)RR.We found that Co^(3+)primarily acts as the active site for NO_(3)^(−)reduction to NO_(2)^(−),while Co^(2+)is responsible for the conversion of NO_(2)^(−)to NH_(3).Moreover,the conversion of these intermediates over the active sites is autonomous and separately controllable.Both processes synergistically accomplish the reduction of nitrate ions to synthesize ammonia.Combining the experimental studies and density functional theory(DFT)calculations,it is discovered the pathway(^(*)NHO→^(*)NHOH→^(*)NH_(2)OH→^(*)NH_(2)→^(*)NH_(3))is more favorable due to the lowerΔG value(0.25 eV)for the rate-limiting step(^(*)NO→^(*)NHO).The NH_(3)yield rate of 8%-Co_(3)O_(4)/SiC reached 1.08 mmol/(cm^(2)h)with a Faradaic efficiency of 96.4%at−0.89 V versus the reversible hydrogen electrode(RHE),surpassing those of most reported non-noble NO_(3)RR catalysts.This strategy not only provides an efficient catalyst for NO_(3)RR but also serves as an illustrative model for the regulation of multi-step reaction intermediates through the design of distinct active sites,thereby presenting a new approach to enhance the efficiency of intricate reactions.

Regulating^(*)COOH intermediate via amino alkylation engineering for exceptionally effective photocatalytic CO_(2) reduction

Photocatalytic reduction of CO_(2) into fuel represents a promising approach for achieving carbon neutrality,while realizing high selectivity in this process is challenging due to uncontrollable reaction intermediate and retarded desorption of target products.Engineering the interface microenvironment of catalysts has been proposed as a strategy to exert a significant influence on reaction outcomes,yet it remains a significant challenge.In this study,amino alkylation was successfully integrated into the melem unit of polymeric carbon nitrides(PCN),which could efficiently drive the photocatalytic CO_(2) reduction.Experimental characterization and theoretical calculations revealed that the introduction of amino alkylation lowers the energy barrier for CO_(2) reduction into^(*)COOH intermediate,transforming the adsorption of^(*)COOH intermediate from the endothermic to an exothermic process.Notably,the as-prepared materials demonstrated outstanding performance in photocatalytic CO_(2) reduction,yielding CO_(2)at a rate of 152.8μmol h^(-1) with a high selectivity of 95.4%and a quantum efficiency of 6.6%.

The study of intelligent algorithm in particle identification of heavy-ion collisions at low and intermediate energies

Traditional particle identification methods face timeconsuming,experience-dependent,and poor repeatability challenges in heavy-ion collisions at low and intermediate energies.Researchers urgently need solutions to the dilemma of traditional particle identification methods.This study explores the possibility of applying intelligent learning algorithms to the particle identification of heavy-ion collisions at low and intermediate energies.Multiple intelligent algorithms,including XgBoost and TabNet,were selected to test datasets from the neutron ion multi-detector for reaction-oriented dynamics(NIMROD-ISiS)and Geant4 simulation.Tree-based machine learning algorithms and deep learning algorithms e.g.TabNet show excellent performance and generalization ability.Adding additional data features besides energy deposition can improve the algorithm’s performance when the data distribution is nonuniform.Intelligent learning algorithms can be applied to solve the particle identification problem in heavy-ion collisions at low and intermediate energies.

Freshening of the Intermediate Waters in the Northern South China Sea over the Past Six Decades

The properties of salinity in the South China Sea(SCS),a significant marginal sea connecting the Pacific and Indian Oceans,are greatly influenced by the transport of fresh water flux between the two oceans.However,the long-term changes in the intermediate water in the SCS have not been thoroughly studied due to limited data,particularly in relation to its thermodynamic variations.This study utilized reanalysis data products to identify a 60-year trend of freshening in the intermediate waters of the northern South China Sea(NSCS),accompanied by an expansion of low-salinity water.The study also constructed salinity budget terms,including advection and entrainment processes,and conducted an analysis of the salinity budget to understand the impacts of external and internal dynamic processes on the freshening trend of the intermediate water in the NSCS.The analysis revealed that the freshening in the northwest Pacific Ocean and the intensification of intrusion through the Luzon Strait at intermediate levels are the primary drivers of the salinity changes in the NSCS.Additionally,a weakened trend in the intensity of vertical entrainment also contributes to the freshening in the NSCS.This study offers new insights into the understanding of regional deep sea changes in response to variations in both thermodynamics and oceanic dynamic processes.

Analyzing the Essay Writing Patterns of Iranian Intermediate-Level Korean Language Learners: A Study Based on the TOPIK Exam

This study examines the writing abilities of Iranian intermediate Korean learners,specifically their performance in the compositional writing section of the Test of Proficiency in Korean(TOPIK).By utilizing the many FACETS-Rasch Model,we meticulously analyzed nine writing samples from the 52nd TOPIK.These samples were evaluated using a modified rubric ranging from 0 to 3 based on predefined criteria for written composition.The results underscored that the sections on“appropriateness of spacing and spelling,”“relevance of vocabulary,”and“content diversity”presented the most significant challenges for the learners.On the other hand,“the quantity of writing”emerged as the least challenging aspect.These findings reveal substantial disparities in various aspects of writing proficiency among learners.The study not only pinpoints issue areas in writing skills,but also underscores the necessity of customized teaching strategies within the TOPIK framework to address these weaknesses.Consequently,it offers valuable insights that could bolster the effectiveness of teaching writing to Korean language learners.The findings of this study are not only significant for the field of language education,but also contribute to a deeper understanding of the challenges faced by intermediate learners and provide a roadmap for improving language instruction.

Changes in the Supply of Public Intermediate Goods,Fixed Wage,and the Relative Price in the Harris-Todaro Model

Since the Harris-Todaro model was proposed in 1970,it has played a crucial role in analyzing various environmental and trade issues in developing countries.This paper analyzes the effects of the amount of public intermediate goods provided by the government,the increase in the fixed wage rate in the urban sector,and the changes in the relative international prices of agricultural and manufacturing goods on labor employment,unemployment,and the economic welfare in the context of a small open economy.It also proposes relevant policies to reduce the unemployment rate while improving national welfare.

Experimental study on failure characteristics of single-sided unloading rock under different intermediate principal stress conditions

Investigation of unloading rock failure under differentσ_(2)facilitates the control mechanism of excavation surrounding rock.This study focused on single-sided unloading tests of granite specimens under true triaxial conditions.The strength and failure characteristics were studied with micro-camera and acoustic emission(AE)monitoring.Furthermore,the choice of test path and the effect ofσ_(2)on fracture of unloading rock were discussed.Results show that the increasedσ_(2)can strengthen the stability of single-sided unloading rock.After unloading,the rock’s free surface underwent five phases,namely,inoculation,particle ejection,buckling rupture,stable failure,and unstable rockburst phases.Moreover,atσ_(2)≤30 MPa,the b value shows the following variation tendency:rising,dropping,significant fluctuation,and dropping,with dispersed damages signal.Atσ_(2)≥40 MPa,the tendency shows:a rise,a decrease,a slight fluctuation,and final drop,with concentrated damages signal.After unloading,AE energy is mainly concentrated in the micro-energy range.With the increasedσ_(2),the micro-energy ratio rises.In contrast,low,medium and large energy ratios drop gradually.The increased tensile fractures and decreased shear fractures indicate that the failure mode of the unloading rock gradually changes from tensile-shear mode to tensile-split one.The fractional dimension of the rock fragments first increases and then decreases with an inflection point at 20 MPa.The distribution of SIF on the planes changes asσ_(2)increases,resulting in strengthening and then weakening of the rock bearing capacity.

Effects of intermediate stress on deep rock strainbursts under true triaxial stresses

The effect of intermediate stress(in situ tunnel axial)on a strainburst is studied with a threedimensional(3D)bonded block distinct element method(DEM).A series of simulations of strainbursts under true triaxial in situ stress conditions(i.e.high tangential stress,moderate intermediate stress and low radial stress)of near-boundary rock masses are performed.Compared with the experimental results,the DEM model is able to capture the stress-strain response,failure pattern and energy balance of strainbursts.The fracturing processes of strainbursts are also numerically reproduced.Numerical results show that,as the intermediate stress increases:(1)The peak strain of strainbursts increases,the yield stress increases,the rock strength increases linearly,and the ratio of yield stress to rock strength decreases,indicating that the precursory information on strainbursts is enhanced;(2)Tensile and shear cracks increase significantly,and slabbing and bending of rock plates are more pronounced;and(3)The stored elastic strain energy and dissipated energy increase linearly,whereas the kinetic energy of the ejected rock fragments increases approximately exponentially,implying an increase in strainburst intensity.By comparing the experimental and numerical results,the effect of intermediate stress on the rock strength of strainbursts is discussed in order to address three key issues.Then,the Mogi criterion is applied to construct new strength criteria for strainbursts by converting the one-face free true triaxial stress state of a strainburst to its equivalent true triaxial stress state.In summary,the effect of intermediate stress on strainbursts is a double-edged sword that can enhance the rock strength and the precursory information of a strainburst,but also increase its intensity.

Morphology and morphometry of two hybridizing buntings at their hybrid zone in northern Iran reveal intermediate and transgressive morphotypes

The closely related Black-headed Bunting(Emberiza melanocephala,a western Palearctic lineage)and Red-headed Bunting(Emberiza bruniceps,an eastern Palearctic lineage)hybridize and replace each other south of the Caspian Sea.The parental species have distinct phenotypes and therefore morphology is useful for assessing hybridization in the contact zone.In the years of 1940 and 1977,quite a few hybrids were collected and studied morphologically.Since then,the hybrid zone appears to have expanded westwards,but there has been a time gap in the collection of morphological data.Here we reanalyze bunting specimens morphologically and compare the historical data with recent data.Morphometric and phenotypic traits from three time periods(1940,1977 and recent)were studied to assess phenotypic variation of hybrids,pattern of hybridization,and transgressive traits in the hybrid zone.Our results show that most of the birds in the hybrid zone exhibit intermediate phenotypes(both colors and morphometric characters),ranging from the pure phenotype of either of the parental species.However,hybridization has also produced novel phenotypes not seen in any of the parents.Using a canonical discriminant function analysis,the morphometric characters separated each parental species and the hybrids quite well.Our results showed morphometric intermediacy of hybrids in accordance with phenotypes.We observe a time trend in which recent hybrids are more similar to Red-headed Buntings phenotypically compared to historical samples.This pattern is likely a signature of a westward expansion of the Red-headed Bunting into the breeding range of the Black-headed Bunting.

Unveil the Redox Evolution of Ore-forming Fluids using Sulfur Isotope:A Case Study of the Zhengguang Intermediate Sulfidation Epithermal Au-Zn Deposit,NE China

Oxygen fugacity(fO_(2))is a key intensity variable during the entire magmatic-hydrothermal mineralization courses.The redox state and its variations between different stages of the ore-forming fluids of intermediate sulfidation epithermal deposits are rarely deciphered due to the lack of appropriate approaches to determine fO_(2)of the fluids.Here,we reported theδ^(34)S of the sulfides from three different stages(stageⅠ,Ⅱ,Ⅲ)of Zhengguang,an Early Ordovician Au-rich intermediate sulfidation(IS)epithermal deposit,to decipher the redox evolution of the ore-forming fluids.The increasingδ^(34)S values from stageⅠpyrite(pyl,average-2.6‰)through py2(average-1.9‰)to py3(average-0.2‰)indicates a decrease of the oxygen fugacity of the ore-forming fluids.A compilation ofδ^(34)S values of sulfides from two subtypes of IS deposits(Au-rich and Ag-rich)from NE China shows that theδ^(34)S values of sulfides from Au-rich IS deposits are systematically lighter than those of Ag-rich IS Ag-Pb-Zn deposit,indicating the ore-forming fluids of the former are more oxidized than the latter.We highlight that sulfur isotopic composition of hypogene sulfides is an efficacious proxy to fingerprint the oxygen fugacity fluctuations of epithermal deposits and could potentially be used to distinguish the subtypes of IS deposits.

Mechanistic insights into the active intermediates of 2,6-diaminopyridine dinitration

Mechanistic understanding of the active intermediates of 2,6-diaminopyridine(DAP) dinitration in the concentrated nitric-sulfuric acid system is of crucial importance for the selectivity control of target product, i.e., 2,6-diamino-3,5-dinitropyridine(DADNP). The active intermediates determining the product selectivity are theoretically studied. The HSO_(4)^(-)-NO_(2)^(+) complex is proposed as the dominant active nitrating intermediate for the first time, which shows low energy barrier(i.e., 10.19 kcal·mol^(-1),1 kcal = 4.186 k J) for direct dinitration of DAP to DADNP. The formed water during the reaction results in not only the formation of less active SO_(4)^(2-)-NO_(2)^(+) complex, but also the occurance of DAP sulfonation(DAP-SO_(3)H intermediate)to facilitate the formation of mononitration byproduct. Meanwhile, the accompanied thermal effects cause the generation of undesirable pyridine-NHNO_(2) intermediate, which is difficult to be rearranged to yield DADNP, inhibiting the reaction and thus giving low DAP conversion. The insights reported here elucidates the importance of thermal effects elimination and water content control, confirmed experimentally in the batch-and micro-reaction systems.

Hydrogen production at intermediate temperatures with proton conducting ceramic cells:Electrocatalytic activity,durability and energy efficiency

Proton conducting ceramic cells(PCCs)are an attractive emerging technology operating in the intermediate temperature range of 500 to 700℃.In this work,we evaluate the production of hydrogen at intermediate temperatures by proton conducting ceramic cell electrolysis(PCCEL).We demonstrate a highperformance steam electrolysis owing to a composite positrode based on BaGd_(0.8)La_(0.2)Co_(2)O_(6-δ)(BGLC1082)and BaZr0.5Ce0.4Y0.1O3-δ(BZCY541).The high reliability of PCCEL is demonstrated for 1680 h at a current density as high as-0.8 A cm^(-2)close to the thermoneutral cell voltage at 600℃.The electrolysis cell showed a specific energy consumption ranging from 54 to 66 kW h kg^(-1)that is comparable to state-of-the-art low temperature electrolysis technologies,while showing hydrogen production rates systematically higher than commercial solid oxide ceramic cells(SOCs).Compared to SOCs,the results verified the higher performances of PCCs at the relevant operating temperatures,due to the lower activation energy for proton transfer comparing with oxygen ion conduction.However,because of the p-type electronic conduction in protonic ceramics,the energy conversion rate of PCCs is relatively lower in steam electrolysis.The faradaic efficiency of the PCC in electrolysis mode can be increased at lower operating temperatures and in endothermic conditions,making PCCEL a technology of choice to valorize high temperature waste heat from industrial processes into hydrogen.To increase the faradaic efficiency by optimizing the materials,the cell design,or the operating strategy is a key challenge to address for future developments of PCCEL in order to achieve even more superior techno-economic merits.

Wave Force on the Crown Wall of Rubble Mound Breakwaters at Intermediate Depths

Rubble mound breakwaters with a crown wall are a common coastal engineering structure.The wave force on crown walls is an important parameter for the practice engineering design.Particularly,the wave force on crown walls under intermediate depths has been studied through physical model tests and numerical simulations.In this study,a three-dimensional numerical wave flume was developed to investigate monochromatic wave interactions in a rubble mound breakwater with a crown wall.Armor blocks were modeled in detail.The Navier-Stokes equations for two-phase incompressible flows,combined with shear stress transport k-ωturbulence model and volume of fluid method for tracking the free surface,were solved.A set of laboratory experiments were performed to validate the adopted model.Subsequently,a series of numerical simulations were implemented to examine the impacts of different hydrodynamic parameters(including wave height,incident wave period,and water depth)and the berm width on the wave force of the crown wall.Finally,a comparison of the experimental results and Martin method shows that the latter method is not suitable for this experimental scope.New empirical formulas are proposed to predict the wave force on crown walls under intermediate depth.The results can provide a basis for the design of crown wall of rubble mound breakwaters at intermediate depths.

Petrogenesis of the Borjuri diorite pluton in the Mikir Massif of Northeast India:implications for post-collisional intermediate magmatism during the Pan-African orogeny

The Assam-Meghalaya Gneissic Complex(AMGC)of northeast India contains numerous Pan-African granitic bodies that have been attributed to post-collisional rift-related magmatism.The present study is concerned with the first appraisal of intermediate magmatism(diorite,monzonite,and monzodiorite)found in the Borjuri Pluton of Mikir Massif,which is the eastern extension of AMGC.The diorites are strongly metaluminous and exhibit enriched LREE([La/Yb]N=1.63–7.37)with respect to HREE([Gd/Yb]N=1.95–2.27).The studied rocks do not show any mineralogical or textural indication of metamorphism.Tectonic discrimination diagrams indicate that these rocks originated in a within-plate tectonic setting.The lower Mg#(33.49–38.69),low Cr(below detection limit),and Ni(27–41 ppm)contents along with elemental ratios such as Rb/Sr(0.32–0.95),La/Nb(0.49–4.21),and Nb/Ce(0.11–0.64)suggest a crustal source for the diorites.Discrimination diagrams coupled with elemental ratios suggest that these rocks originated due to partial melting of mafic components in the crust with possible contribution from mantle materials.The P–T conditions of diorite emplacement(7.4 kbar,688℃)were calculated using the amphibole-plagioclase geothermobarometer.Geochemical and geochronological data of the Pan-African felsic plutons reported from the AMGC indicate that these rocks were emplaced in a post-collisional extensional regime.The Borjuri Pluton is in close proximity with the Kathalguri Pluton,which has been reported as a product of PanAfrican magmatism.In view of the numerous extensional Pan-African felsic magmatism reported from the AMGC and based on the close vicinity of the Borjuri diorites with the Kathalguri granites,we speculate that the Borjuri diorites are products of the Pan-African post-collisional magmatism.

Intermediate hyperglycemia in early pregnancy:A South Asian perspective

“Intermediate hyperglycemia in early pregnancy(IHEP)”refers to mild hyperglycemia detected before 24 gestational weeks(GW),satisfying the criteria for the diagnosis of gestational diabetes mellitus.Many professional bodies recommend routine screening for“overt diabetes”in early pregnancy,which identifies a significant number of women with mild hyperglycemia of undetermined significance.A literature search revealed that one-third of GDM women in South Asian countries are diagnosed before the conventional screening period of 24 GW to 28 GW;hence,they belong in the IHEP category.Most hospitals in this region diagnose IHEP by oral glucose tolerance test(OGTT)using the same criteria used for GDM diagnosis after 24 GW.There is some evidence to suggest that South Asian women with IHEP are more prone to adverse pregnancy events than women with a diagnosis of GDM after 24 GW,but this observation needs to be proven by randomized control trials.Fasting plasma glucose is a reliable screening test for GDM that can obviate the need for OGTT for GDM diagnosis among 50%of South Asian pregnant women.HbA1c in the first trimester predicts GDM in later pregnancy,but it is not a reliable test for IHEP diagnosis.There is evidence to suggest that HbA1c in the first trimester is an independent risk factor for several adverse pregnancy events.Further research to identify the pathogenetic mechanisms behind the fetal and maternal effects of IHEP is strongly recommended.

A novel three-step implicit iteration process for threeΦ-hemicontractive mapping in the intermediate sense

In this paper,we introduce a three-step composite implicit iteration process for approximating the common fixed point of three uniformly continuous and asymptotically generalizedΦ-hemicontractive mappings in the intermediate sense.We prove that our proposed iteration process converges to the common fixed point of three finite family of asymptotically generalizedΦ-hemicontractive mappings in the intermediate sense.Our results extends,improves and complements several known results in literature.