Mitophagy in intracerebral hemorrhage:a new target for therapeutic intervention

Intracerebral hemorrhage is a life-threatening condition with a high fatality rate and severe sequelae.However,there is currently no treatment available for intracerebral hemorrhage,unlike for other stroke subtypes.Recent studies have indicated that mitochondrial dysfunction and mitophagy likely relate to the pathophysiology of intracerebral hemorrhage.Mitophagy,or selective autophagy of mitochondria,is an essential pathway to preserve mitochondrial homeostasis by clearing up damaged mitochondria.Mitophagy markedly contributes to the reduction of secondary brain injury caused by mitochondrial dysfunction after intracerebral hemorrhage.This review provides an overview of the mitochondrial dysfunction that occurs after intracerebral hemorrhage and the underlying mechanisms regarding how mitophagy regulates it,and discusses the new direction of therapeutic strategies targeting mitophagy for intracerebral hemorrhage,aiming to determine the close connection between mitophagy and intracerebral hemorrhage and identify new therapies to modulate mitophagy after intracerebral hemorrhage.In conclusion,although only a small number of drugs modulating mitophagy in intracerebral hemorrhage have been found thus far,most of which are in the preclinical stage and require further investigation,mitophagy is still a very valid and promising therapeutic target for intracerebral hemorrhage in the long run.

Ecological-Based Mining:A Coal-Water-Thermal Collaborative Paradigm in Ecologically Fragile Areas in Western China

A substantial reduction in groundwater level,exacerbated by coal mining activities,is intensifying water scarcity in western China’s ecologically fragile coal mining areas.China’s national strategic goal of achieving a carbon peak and carbon neutrality has made eco-friendly mining that prioritizes the protection and efficient use of water resources essential.Based on the resource characteristics of mine water and heat hazards,an intensive coal-water-thermal collaborative co-mining paradigm for the duration of the mining process is proposed.An integrated system for the production,supply,and storage of mining companion resources is achieved through technologies such as roof water inrush prevention and control,hydrothermal quality improvement,and deep-injection geological storage.An active preventive and control system achieved by adjusting the mining technology and a passive system centered on multiobjective drainage and grouting treatment are suggested,in accordance with the original geological characteristics and dynamic process of water inrush.By implementing advanced multi-objective drainage,specifically designed to address the“skylight-type”water inrush mode in the Yulin mining area of Shaanxi Province,a substantial reduction of 50%in water drillings and inflow was achieved,leading to stabilized water conditions that effectively ensure subsequent safe coal mining.An integrated-energy complementary model that incorporates the clean production concept of heat utilization is also proposed.The findings indicate a potential saving of 8419 t of standard coal by using water and air heat as an alternative heating source for the Xiaojihan coalmine,resulting in an impressive energy conservation of 50.2%and a notable 24.2%reduction in carbon emissions.The ultra-deep sustained water injection of 100 m^(3)·h^(-1)in a single well would not rupture the formation or cause water leakage,and 7.87×10^(5)t of mine water could be effectively stored in the Liujiagou Formation,presenting a viable method for mine-water management in the Ordos Basin and providing insights for green and low-carbon mining.

Mitochondrial targeting sequence of magnetoreceptor MagR:More than just targeting

Iron-sulfur clusters(ISC)are essential cofactors for proteins involved in various biological processes,such as electron transport,biosynthetic reactions,DNA repair,and gene expression regulation.ISC assembly protein IscA1(or MagR)is found within the mitochondria of most eukaryotes.Magnetoreceptor(MagR)is a highly conserved A-type iron and iron-sulfur cluster-binding protein,characterized by two distinct types of iron-sulfur clusters,[2Fe-2S]and[3Fe-4S],each conferring unique magnetic properties.MagR forms a rod-like polymer structure in complex with photoreceptive cryptochrome(Cry)and serves as a putative magnetoreceptor for retrieving geomagnetic information in animal navigation.Although the N-terminal sequences of MagR vary among species,their specific function remains unknown.In the present study,we found that the N-terminal sequences of pigeon MagR,previously thought to serve as a mitochondrial targeting signal(MTS),were not cleaved following mitochondrial entry but instead modulated the efficiency with which iron-sulfur clusters and irons are bound.Moreover,the N-terminal region of MagR was required for the formation of a stable MagR/Cry complex.Thus,the N-terminal sequences in pigeon MagR fulfil more important functional roles than just mitochondrial targeting.These results further extend our understanding of the function of MagR and provide new insights into the origin of magnetoreception from an evolutionary perspective.

Advantages of nanocarriers for basic research in the field of traumatic brain injury

A major challenge for the efficient treatment of traumatic brain injury is the need for therapeutic molecules to cross the blood-brain barrier to enter and accumulate in brain tissue.To overcome this problem,researchers have begun to focus on nanocarriers and other brain-targeting drug delivery systems.In this review,we summarize the epidemiology,basic pathophysiology,current clinical treatment,the establishment of models,and the evaluation indicators that are commonly used for traumatic brain injury.We also report the current status of traumatic brain injury when treated with nanocarriers such as liposomes and vesicles.Nanocarriers can overcome a variety of key biological barriers,improve drug bioavailability,increase intracellular penetration and retention time,achieve drug enrichment,control drug release,and achieve brain-targeting drug delivery.However,the application of nanocarriers remains in the basic research stage and has yet to be fully translated to the clinic.

A review of the neurotransmitter system associated with cognitive function of the cerebellum in Parkinson's disease

The dichotomized brain system is a concept that was generalized from the‘dual syndrome hypothesis’to explain the heterogeneity of cognitive impairment,in which anterior and posterior brain systems are independent but partially overlap.The dopaminergic system acts on the anterior brain and is responsible for executive function,working memory,and planning.In contrast,the cholinergic system acts on the posterior brain and is responsible for semantic fluency and visuospatial function.Evidence from dopaminergic/cholinergic imaging or functional neuroimaging has shed significant insight relating to the involvement of the cerebellum in the cognitive process of patients with Parkinson’s disease.Previous research has reported evidence that the cerebellum receives both dopaminergic and cholinergic projections.However,whether these two neurotransmitter systems are associated with cognitive function has yet to be fully elucidated.Furthermore,the precise role of the cerebellum in patients with Parkinson’s disease and cognitive impairment remains unclear.Therefore,in this review,we summarize the cerebellar dopaminergic and cholinergic projections and their relationships with cognition,as reported by previous studies,and investigated the role of the cerebellum in patients with Parkinson’s disease and cognitive impairment,as determined by functional neuroimaging.Our findings will help us to understand the role of the cerebellum in the mechanisms underlying cognitive impairment in Parkinson’s disease.

Appendiceal intussusception complicated by adenocarcinoma of the cecum:A case report

BACKGROUND Appendiceal intussusception is a pathological condition in which the appendix is inverted into the cecum,which may cause symptoms that resemble those of other gastrointestinal disorders and may induce intestinal obstruction.The rarity of this case presentation is the co-occurrence of appendiceal intussusception and cecal adenocarcinoma,a combination that to our knowledge has not previously been reported in the medical literature.This case provides new insights into the complexities of diagnosing and managing overlapping pathologies.CASE SUMMARY A 25-year-old woman presented with persistent periumbilical pain and bloody stools.An initial biopsy showed cecal cancer;however,subsequent colonoscopy and computed tomography findings raised the suspicion of appendiceal intussus-ception,which was later confirmed postoperatively.This unique case was charac-terized by a combination of intussusception and adenocarcinoma of the cecum.The intervention included a laparoscopic right hemicolectomy,which led to the histopathological diagnosis of mucinous adenocarcinoma with appendiceal intussusception.The patient recovered well postoperatively and was advised to initiate adjuvant chemotherapy.This case highlights not only the importance of considering appendiceal intussusception in the differential diagnosis,but also the possibility of appendicitis and the atypical presentation of neoplastic lesions.CONCLUSIONS Physicians should consider the possibility of appendiceal intussusception in cases of atypical appendicitis,particularly when associated with neoplastic presentation.

Promising use of metformin in treating neurological disorders:biomarker-guided therapies

Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases(Alzheimer’s disease,multiple sclerosis,Parkinson’s disease,Huntington’s disease),cerebrovascular conditions(stroke),and neurodevelopmental disorders(autism spectrum disorder).Although they affect millions of individuals around the world,only a limited number of effective treatment options are available today.Since most neurological disorders express mitochondria-related metabolic perturbations,metformin,a biguanide type II antidiabetic drug,has attracted a lot of attention to be repurposed to treat neurological disorders by correcting their perturbed energy metabolism.However,controversial research emerges regarding the beneficial/detrimental effects of metformin on these neurological disorders.Given that most neurological disorders have complex etiology in their pathophysiology and are influenced by various risk factors such as aging,lifestyle,genetics,and environment,it is important to identify perturbed molecular functions that can be targeted by metformin in these neurological disorders.These molecules can then be used as biomarkers to stratify subpopulations of patients who show distinct molecular/pathological properties and can respond to metformin treatment,ultimately developing targeted therapy.In this review,we will discuss mitochondria-related metabolic perturbations and impaired molecular pathways in these neurological disorders and how these can be used as biomarkers to guide metformin-responsive treatment for the targeted therapy to treat neurological disorders.

Small molecule deoxynyboquinone triggers alkylation and ubiquitination of Keap1 at Cys489 on Kelch domain for Nrf2 activation and inflammatory therapy

Activation of nuclear factor erythroid 2-related factor 2(Nrf2)by Kelch-like ECH-associated protein 1(Keap1)alkylation plays a central role in anti-inflammatory therapy.However,activators of Nrf2 through alkylation of Keap1-Kelch domain have not been identified.Deoxynyboquinone(DNQ)is a natural small molecule discovered from marine actinomycetes.The current study was designed to investigate the anti-inflammatory effects and molecular mechanisms of DNQ via alkylation of Keap1.DNQ exhibited significant anti-inflammatory properties both in vitro and in vivo.The pharmacophore responsible for the anti-inflammatory properties of DNQ was determined to be theα,β-unsaturated amides moieties by a chemical reaction between DNQ and N-acetylcysteine.DNQ exerted anti-inflammatory effects through activation of Nrf2/ARE pathway.Keap1 was demonstrated to be the direct target of DNQ and bound with DNQ through conjugate addition reaction involving alkylation.The specific alkylation site of DNQ on Keap1 for Nrf2 activation was elucidated with a synthesized probe in conjunction with liquid chromatography-tandem mass spectrometry.DNQ triggered the ubiquitination and subsequent degradation of Keap1 by alkylation of the cysteine residue 489(Cys489)on Keap1-Kelch domain,ultimately enabling the activation of Nrf2.Our findings revealed that DNQ exhibited potent anti-inflammatory capacity throughα,β-unsaturated amides moieties active group which specifically activated Nrf2 signal pathway via alkylation/ubiquitination of Keap1-Kelch domain,suggesting the potential values of targeting Cys489 on Keap1-Kelch domain by DNQ-like small molecules in inflammatory therapies.

Lipid metabolism analysis in esophageal cancer and associated drug discovery

Esophageal cancer is an upper gastrointestinal malignancy with a bleak prognosis.It is still being explored in depth due to its complex molecular mechanisms of occurrence and development.Lipids play a crucial role in cells by participating in energy supply,biofilm formation,and signal transduction processes,and lipid metabolic reprogramming also constitutes a significant characteristic of malignant tumors.More and more studies have found esophageal cancer has obvious lipid metabolism abnormalities throughout its beginning,progress,and treatment resistance.The inhibition of tumor growth and the enhancement of antitumor therapy efficacy can be achieved through the regulation of lipid metabolism.Therefore,we reviewed and analyzed the research results and latest findings for lipid metabolism and associated analysis techniques in esophageal cancer,and comprehensively proved the value of lipid metabolic reprogramming in the evolution and treatment resistance of esophageal cancer,as well as its significance in exploring potential therapeutic targets and biomarkers.

High-speed penetration of ogive-nose projectiles into thick concrete targets:Tests and a projectile nose evolution model

The majority of the projectiles used in the hypersonic penetration study are solid flat-nosed cylindrical projectiles with a diameter of less than 20 mm.This study aims to fill the gap in the experimental and analytical study of the evolution of the nose shape of larger hollow projectiles under hypersonic penetration.In the hypersonic penetration test,eight ogive-nose AerMet100 steel projectiles with a diameter of 40 mm were launched to hit concrete targets with impact velocities that ranged from 1351 to 1877 m/s.Severe erosion of the projectiles was observed during high-speed penetration of heterogeneous targets,and apparent localized mushrooming occurred in the front nose of recovered projectiles.By examining the damage to projectiles,a linear relationship was found between the relative length reduction rate and the initial kinetic energy of projectiles in different penetration tests.Furthermore,microscopic analysis revealed the forming mechanism of the localized mushrooming phenomenon for eroding penetration,i.e.,material spall erosion abrasion mechanism,material flow and redistribution abrasion mechanism and localized radial upsetting deformation mechanism.Finally,a model of highspeed penetration that included erosion was established on the basis of a model of the evolution of the projectile nose that considers radial upsetting;the model was validated by test data from the literature and the present study.Depending upon the impact velocity,v0,the projectile nose may behave as undistorted,radially distorted or hemispherical.Due to the effects of abrasion of the projectile and enhancement of radial upsetting on the duration and amplitude of the secondary rising segment in the pulse shape of projectile deceleration,the predicted DOP had an upper limit.

Natural gas exploration potential and favorable targets of Permian Fengcheng Formation in the western Central Depression of Junggar Basin,NW China

Based on the organic geochemical data and the molecular and stable carbon isotopic compositions of natural gas of the Lower Permian Fengcheng Formation in the western Central Depression of Junggar Basin,combined with sedimentary environment analysis and hydrocarbon-generating simulation,the gas-generating potential of the Fengcheng source rock is evaluated,the distribution of large-scale effective source kitchen is described,the genetic types of natural gas are clarified,and four types of favorable exploration targets are selected.The results show that:(1)The Fengcheng Formation is a set of oil-prone source rocks,and the retained liquid hydrocarbon is conducive to late cracking into gas,with characteristics of high gas-generating potential and late accumulation;(2)The maximum thickness of Fengcheng source rock reaches 900 m.The source rock has entered the main gas-generating stage in Penyijingxi and Shawan sags,and the area with gas-generating intensity greater than 20×10^(8) m^(3)/km^(2) is approximately 6500 km^(2).(3)Around the western Central Depression,highly mature oil-type gas with light carbon isotope composition was identified to be derived from the Fengcheng source rocks mainly,while the rest was coal-derived gas from the Carboniferous source rock;(4)Four types of favorable exploration targets with exploration potential were developed in the western Central Depression which are structural traps neighboring to the source,stratigraphic traps neighboring to the source,shale-gas type within the source,and structural traps within the source.Great attention should be paid to these targets.

Exploring the autophagy-related pathogenesis of active ulcerative colitis

BACKGROUND The pathogenesis of ulcerative colitis(UC)is complex,and recent therapeutic advances remain unable to fully alleviate the condition.AIM To inform the development of novel UC treatments,bioinformatics was used to explore the autophagy-related pathogenesis associated with the active phase of UC.METHODS The GEO database was searched for UC-related datasets that included healthy controls who met the screening criteria.Differential analysis was conducted to obtain differentially expressed genes(DEGs).Au-tophagy-related targets were collected and intersected with the DEGs to identiy differentially expressed autophagy-related genes(DEARGs)associated with active UC.DEARGs were then subjected to KEGG,GO,and DisGeNET disease enrichment analyses using R software.Differential analysis of immune infiltrating cells was performed using the CiberSort algorithm.The least absolute shrinkage and selection operator algorithm and protein-protein interaction network were used to narrow down the DEARGs,and the top five targets in the Dgree ranking were designated as core targets.RESULTS A total of 4822 DEGs were obtained,of which 58 were classified as DEARGs.SERPINA1,BAG3,HSPA5,CASP1,and CX3CL1 were identified as core targets.GO enrichment analysis revealed that DEARGs were primarily enriched in processes related to autophagy regulation and macroautophagy.KEGG enrichment analysis showed that DEARGs were predominantly associated with NOD-like receptor signaling and other signaling pathways.Disease enrichment analysis indicated that DEARGs were significantly linked to diseases such as malignant glioma and middle cerebral artery occlusion.Immune infiltration analysis demonstrated a higher presence of immune cells like activated memory CD4 T cells and follicular helper T cells in active UC patients than in healthy controls.CONCLUSION Autophagy is closely related to the active phase of UC and the potential targets obtained from the analysis in this study may provide new insight into the treatment of active UC patients.

Deployment optimization for target perpetual coverage in energy harvesting wireless sensor network

Energy limitation of traditional Wireless Sensor Networks(WSNs)greatly confines the network lifetime due to generating and processing massive sensing data with a limited battery.The energy harvesting WSN is a novel network architecture to address the limitation of traditional WSN.However,existing coverage and deployment schemes neglect the environmental correlation of sensor nodes and external energy with respect to physical space.Comprehensively considering the spatial correlation of the environment and the uneven distribution of energy in energy harvesting WSN,we investigate how to deploy a collection of sensor nodes to save the deployment cost while ensuring the target perpetual coverage.The Confident Information Coverage(CIC)model is adopted to formulate the CIC Minimum Deployment Cost Target Perpetual Coverage(CICMTP)problem to minimize the deployed sensor nodes.As the CICMTP is NP-hard,we devise two approximation algorithms named Local Greedy Threshold Algorithm based on CIC(LGTA-CIC)and Overall Greedy Search Algorithm based on CIC(OGSA-CIC).The LGTA-CIC has a low time complexity and the OGSA-CIC has a better approximation rate.Extensive simulation results demonstrate that the OGSA-CIC is able to achieve lower deployment cost and the performance of the proposed algorithms outperforms GRNP,TPNP and EENP algorithms.

Hydrocarbon accumulation and orderly distribution of whole petroleum system in marine carbonate rocks of Sichuan Basin,SW China

Based on the situation and progress of marine oil/gas exploration in the Sichuan Basin,SW China,the whole petroleum system is divided for marine carbonate rocks of the basin according to the combinations of hydrocarbon accumulation elements,especially the source rock.The hydrocarbon accumulation characteristics of each whole petroleum system are analyzed,the patterns of integrated conventional and unconventional hydrocarbon accumulation are summarized,and the favorable exploration targets are proposed.Under the control of multiple extensional-convergent tectonic cycles,the marine carbonate rocks of the Sichuan Basin contain three sets of regional source rocks and three sets of regional cap rocks,and can be divided into the Cambrian,Silurian and Permian whole petroleum systems.These whole petroleum systems present mainly independent hydrocarbon accumulation,containing natural gas of affinity individually.Locally,large fault zones run through multiple whole petroleum systems,forming a fault-controlled complex whole petroleum system.The hydrocarbon accumulation sequence of continental shelf facies shale gas accumulation,marginal platform facies-controlled gas reservoirs,and intra-platform fault-and facies-controlled gas reservoirs is common in the whole petroleum system,with a stereoscopic accumulation and orderly distribution pattern.High-quality source rock is fundamental to the formation of large gas fields,and natural gas in a whole petroleum system is generally enriched near and within the source rocks.The development and maintenance of large-scale reservoirs are essential for natural gas enrichment,multiple sources,oil and gas transformation,and dynamic adjustment are the characteristics of marine petroleum accumulation,and good preservation conditions are critical to natural gas accumulation.Large-scale marginal-platform reef-bank facies zones,deep shale gas,and large-scale lithological complexes related to source-connected faults are future marine hydrocarbon exploration targets in the Sichuan Basin.

Leukocyte immunoglobulin-like receptor B2:A promising biomarker for colorectal cancer

According to the latest global cancer statistics,colorectal cancer(CRC)has emerged as the third most prevalent malignant tumor across the globe.In recent decades,the medical field has implemented several levels of CRC screening tests,encompassing fecal tests,endoscopic examinations,radiological examinations and blood tests.Previous studies have shown that leukocyte immunoglobulin-like receptor B2(LILRB2)is involved in inhibiting immune cell function,immune evasion,and promoting tumor progression in acute myeloid leukemia and nonsmall cell lung cancer.However,its interaction with CRC has not been reported yet.Recently,a study published in the World Journal of Gastroenterology revealed that LILRB2 and its ligand,angiopoietin-like protein 2,are markedly overexpressed in CRC.This overexpression is closely linked to tumor progression and is indicative of a poor prognosis.The study highlights the potential of utilizing the concentration of LILRB2 in serum as a promising biomarker for tumors.However,there is still room for discussion regarding the data processing and analysis in this research.

Humanβ-defensin-1 affects the mammalian target of rapamycin pathway and autophagy in colon cancer cells through long noncoding RNA TCONS_00014506

BACKGROUND Colorectal cancer has a low 5-year survival rate and high mortality.Humanβ-defensin-1(hBD-1)may play an integral function in the innate immune system,contributing to the recognition and destruction of cancer cells.Long non-coding RNAs(lncRNAs)are involved in the process of cell differentiation and growth.AIM To investigate the effect of hBD-1 on the mammalian target of rapamycin(mTOR)pathway and autophagy in human colon cancer SW620 cells.METHODS CCK8 assay was utilized for the detection of cell proliferation and determination of the optimal drug concentration.Colony formation assay was employed to assess the effect of hBD-1 on SW620 cell proliferation.Bioinformatics was used to screen potentially biologically significant lncRNAs related to the mTOR pathway.Additionally,p-mTOR(Ser2448),Beclin1,and LC3II/I expression levels in SW620 cells were assessed through Western blot analysis.RESULTS hBD-1 inhibited the proliferative ability of SW620 cells,as evidenced by the reduction in the colony formation capacity of SW620 cells upon exposure to hBD-1.hBD-1 decreased the expression of p-mTOR(Ser2448)protein and increased the expression of Beclin1 and LC3II/I protein.Furthermore,bioinformatics analysis identified seven lncRNAs(2 upregulated and 5 downregulated)related to the mTOR pathway.The lncRNA TCONS_00014506 was ultimately selected.Following the inhibition of the lncRNA TCONS_00014506,exposure to hBD-1 inhibited p-mTOR(Ser2448)and promoted Beclin1 and LC3II/I protein expression.CONCLUSION hBD-1 inhibits the mTOR pathway and promotes autophagy by upregulating the expression of the lncRNA TCONS_00014506 in SW620 cells.

Precision targeting in hepatocellular carcinoma:Exploring ligandreceptor mediated nanotherapy

Hepatocellular carcinoma(HCC)is the most common primary liver cancer and poses a major challenge to global health due to its high morbidity and mortality.Conventional chemotherapy is usually targeted to patients with intermediate to advanced stages,but it is often ineffective and suffers from problems such as multidrug resistance,rapid drug clearance,nonspecific targeting,high side effects,and low drug accumulation in tumor cells.In response to these limitations,recent advances in nanoparticle-mediated targeted drug delivery technologies have emerged as breakthrough approaches for the treatment of HCC.This review focuses on recent advances in nanoparticle-based targeted drug delivery systems,with special attention to various receptors overexpressed on HCC cells.These receptors are key to enhancing the specificity and efficacy of nanoparticle delivery and represent a new paradigm for actively targeting and combating HCC.We comprehensively summarize the current understanding of these receptors,their role in nanoparticle targeting,and the impact of such targeted therapies on HCC.By gaining a deeper understanding of the receptor-mediated mechanisms of these innovative therapies,more effective and precise treatment of HCC can be achieved.

Real-time Rescue Target Detection Based on UAV Imagery for Flood Emergency Response

Timely acquisition of rescue target information is critical for emergency response after a flood disaster.Unmanned Aerial Vehicles(UAVs)equipped with remote sensing capabilities offer distinct advantages,including high-resolution imagery and exceptional mobility,making them well suited for monitoring flood extent and identifying rescue targets during floods.However,there are some challenges in interpreting rescue information in real time from flood images captured by UAVs,such as the complexity of the scenarios of UAV images,the lack of flood rescue target detection datasets and the limited real-time processing capabilities of the airborne on-board platform.Thus,we propose a real-time rescue target detection method for UAVs that is capable of efficiently delineating flood extent and identifying rescue targets(i.e.,pedestrians and vehicles trapped by floods).The proposed method achieves real-time rescue information extraction for UAV platforms by lightweight processing and fusion of flood extent extraction model and target detection model.The flood inundation range is extracted by the proposed method in real time and detects targets such as people and vehicles to be rescued based on this layer.Our experimental results demonstrate that the Intersection over Union(IoU)for flood water extraction reaches an impressive 80%,and the IoU for real-time flood water extraction stands at a commendable 76.4%.The information on flood stricken targets extracted by this method in real time can be used for flood emergency rescue.

Colorectal cancer:Recent advances in management and treatment

Colorectal cancer(CRC)is the third most common cancer worldwide,and the second most common cause of cancer-related death.In 2020,the estimated number of deaths due to CRC was approximately 930000,accounting for 10%of all cancer deaths worldwide.Accordingly,there is a vast amount of ongoing research aiming to find new and improved treatment modalities for CRC that can potentially increase survival and decrease overall morbidity and mortality.Current management strategies for CRC include surgical procedures for resectable cases,and radiotherapy,chemotherapy,and immunotherapy,in addition to their combination,for non-resectable tumors.Despite these options,CRC remains incurable in 50%of cases.Nonetheless,significant improvements in research techniques have allowed for treatment approaches for CRC to be frequently updated,leading to the availability of new drugs and therapeutic strategies.This review summarizes the most recent therapeutic approaches for CRC,with special emphasis on new strategies that are currently being studied and have great potential to improve the prognosis and lifespan of patients with CRC.

Ex vivo liver resection and auto-transplantation and special systemic therapy in perihilar cholangiocarcinoma treatment

This editorial contains comments on the article“Systematic sequential therapy for ex vivo liver resection and autotransplantation:A case report and review of li-terature”in the recent issue of World Journal of Gastrointestinal Surgery.It points out the actuality and importance of the article and focuses primarily on the role and place of ex vivo liver resection and autotransplantation(ELRAT)and systemic therapy,underlying molecular mechanisms for targeted therapy in perihilar cho-langiocarcinoma(pCCA)management.pCCA is a tough malignancy with a high proportion of advanced disease at the time of diagnosis.The only curative option is radical surgery.Surgical excision and reconstruction become extremely com-plicated and not always could be performed even in localized disease.On the other hand,ELRAT takes its place among surgical options for carefully selected pCCA patients.In advanced disease,systemic therapy becomes a viable option to prolong survival.This editorial describes current possibilities in chemotherapy and reveals underlying mechanisms and projections in targeted therapy with ki-nase inhibitors and immunotherapy in both palliative and adjuvant settings.Fi-broblast grow factor and fibroblast grow factor receptor,human epidermal grow-th factor receptor 2,isocitrate dehydrogenase,and protein kinase cAMP activated catalytic subunit alpha(PRKACA)and beta(PRKACB)pathways have been ac-tively investigated in CCA in last years.Several agents were introduced and approved by the Food and Drug Administration.They all demonstrated mean-ingful activity in CCA patients with no global change in outcomes.That is why every successfully treated patient counts,especially those with advanced disease.In conclusion,pCCA is still hard to treat due to late diagnosis and extremely complicated surgical options.ELRAT also brings some hope,but it could be performed in very carefully selected patients.Advanced disease requires systemic anticancer treatment,which is supposed to be individualized according to the genetic and molecular features of cancer cells.Targeted therapy in combination with chemo-immunotherapy could be effective in susceptible patients.