Targeting BCL9/BCL9L enhances antigen presentation by promoting conventional type 1 dendritic cell(cDC1)activation and tumor infiltration

Conventional type 1 dendritic cells(cDC1)are the essential antigen-presenting DC subset in antitumor immunity.Suppressing B-cell lymphoma 9 and B-cell lymphoma 9-like(BCL9/BCL9L)inhibits tumor growth and boosts immune responses against cancer.However,whether oncogenic BCL9/BCL9L impairs antigen presentation in tumors is still not completely understood.Here,we show that targeting BCL9/BCL9L enhanced antigen presentation by stimulating cDC1 activation and infiltration into tumor.Pharmacological inhibition of BCL9/BCL9L with a novel inhibitor hsBCL9z96 or Bcl9/Bcl9l knockout mice markedly delayed tumor growth and promoted antitumor CD8^(+)T cell responses.Mechanistically,targeting BCL9/BCL9L promoted antigen presentation in tumors.This is due to the increase of cDC1 activation and tumor infiltration by the XCL1-XCR1 axis.Importantly,using single-cell transcriptomics analysis,we found that Bcl9/Bcl9l deficient cDC1 were superior to wild-type(WT)cDC1 at activation and antigen presentation via NF-κB/IRF1 signaling.Together,we demonstrate that targeting BCL9/BCL9L plays a crucial role in cDC1-modulated antigen presentation of tumor-derived antigens,as well as CD8^(+)T cell activation and tumor infiltration.Targeting BCL9/BCL9L to regulate cDC1 function and directly orchestrate a positive feedback loop necessary for optimal antitumor immunity could serve as a potential strategy to counter immune suppression and enhance cancer immunotherapy.

The functions of exosomes targeting astrocytes and astrocyte-derived exosomes targeting other cell types

Astrocytes are the most abundant glial cells in the central nervous system;they participate in crucial biological processes,maintain brain structure,and regulate nervous system function.Exosomes are cell-derived extracellular vesicles containing various bioactive molecules including proteins,peptides,nucleotides,and lipids secreted from their cellular sources.Increasing evidence shows that exosomes participate in a communication network in the nervous system,in which astrocyte-derived exosomes play important roles.In this review,we have summarized the effects of exosomes targeting astrocytes and the astrocyte-derived exosomes targeting other cell types in the central nervous system.We also discuss the potential research directions of the exosome-based communication network in the nervous system.The exosome-based intercellular communication focused on astrocytes is of great significance to the biological and/or pathological processes in different conditions in the brain.New strategies may be developed for the diagnosis and treatment of neurological disorders by focusing on astrocytes as the central cells and utilizing exosomes as communication mediators.

Multi-Scale Approach for Gold Targeting in Côte d’Ivoire Paleoproterozoic Rocks

The aim of this study is to contribute to better targeting of gold prospecting areas using geospatial information. To this end, 3 mining sites were selected for the study. They are: the Sénoufo belt (Barrick Gold mine), the Yaouré complex (Perseus Mining mine) and the South Fetêkro belt (Bonikro, Hiré and Agbaou mines). For this study, a multi-scale approach was carried out at regional, mine and microscopic levels. At the regional scale, a comparative analysis of 1:200,000 scale geological maps revealed that 3 main lithologies are regularly repeated on and around the various mining sites. These are: undifferentiated volcanics, metagranodiorites and metasiltites dominated by meta-arenites. Most of these lithologies are affected by undifferentiated faults generally oriented NE-SW, N-S, ENE-WSW and WNW-ESE. In addition, gold and manganese occurrences are present on all the sites studied. At the mine scale, radarsat-1 images processing indicate that the main mining sites are generally located near or at the intersection of lineaments-oriented NE-SW or N-S on the one hand and E-W or ENE-WSW or WNW-ESE or again NW-SE on the other. These mines are also located at the interface between zones of high and low lineament density. At the microscopic scale, petrographic studies of undifferentiated volcanic samples from the various sites indicate that they consist of andesites, meta-andesites and tuffs.

Targeting therapy for hepatocellular carcinoma by delivering microRNAs as exosomal cargo

Exosomes,the smallest extracellular vesicles,have gained significant attention as key mediators in intercellular communication,influencing both physiological and pathological processes,particularly in cancer progression.A recent review article by Wang et al was published in a timely manner to stimulate future research and facilitate practical developments for targeted treatment of hepatocellular carcinoma using exosomes,with a focus on the origin from which exosomes derive.If information about the mechanisms for delivering exosomes to specific cells is incorporated,the concept of targeted therapy for hepatocellular carcinoma using exosomes could be more comprehensively understood.

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.

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.

Degradation of FAK-targeting by proteolytic targeting chimera technology to inhibit the metastasis of hepatocellular carcinoma

Liver cancer is a prevalent malignant cancer,ranking third in terms of mortality rate.Metastasis and recurrence primarily contribute to the high mortality rate of liver cancer.Hepatocellular carcinoma(HCC)has low expression of focal adhesion kinase(FAK),which increases the risk of metastasis and recurrence.Nevertheless,the efficacy of FAK phosphorylation inhibitors is currently limited.Thus,investigating the mechanisms by which FAK affects HCC metastasis to develop targeted therapies for FAK may present a novel strategy to inhibit HCC metastasis.This study examined the correlation between FAK expression and the prognosis of HCC.Additionally,we explored the impact of FAK degradation on HCC metastasis through wound healing experiments,transwell invasion experiments,and a xenograft tumor model.The expression of proteins related to epithelial-mesenchymal transition(EMT)was measured to elucidate the underlying mechanisms.The results showed that FAK PROTAC can degrade FAK,inhibit the migration and invasion of HCC cells in vitro,and notably decrease the lung metastasis of HCC in vivo.Increased expression of E-cadherin and decreased expression of vimentin indicated that EMT was inhibited.Consequently,degradation of FAK through FAK PROTAC effectively suppressed liver cancer metastasis,holding significant clinical implications for treating liver cancer and developing innovative anti-neoplastic drugs.

Targeting triple-negative breast cancer:A clinical perspective

Triple-negative breast cancer(TNBC)is a disease with often an aggressive course and a poor prognosis compared to other subtypes of breast cancer.TNBC accounts for approximately 10%–15%of all diagnosed breast cancer cases and represents a high unmet need in the field.Up to just a few years ago,chemotherapy was the only systemic treatment option for this subtype(1).To date,TNBC is considered a heterogeneous disease.One of the existing classifications is based on the analysis of mRNA expression in 587 TNBC cases,in which Lehman et al.proposed six subtypes of TNBC as follows:two basal-like(BL1 and BL2)subtypes,a mesenchymal(M)subtype,a mesenchymal stem-like(MSL)subtype,an immunomodulatory(IM)subtype,and a luminal androgen receptor(LAR)subtype(2).Later studies have demonstrated that the IM and MSL subtypes do not correlate with independent subtypes but reflect background expression by dense infiltration of tumor-infiltrating lymphocytes(TILs)or stromal cells.According to this finding,the classification of TNBC has been revised into the following four subtypes:basal 1,basal 2,LAR,and mesenchymal subtypes(3).Over the last years,several new strategies have been investigated for the treatment of patients with TNBC.Among them,immunotherapy,antibody drug conjugates,new chemotherapy agents,and targeted therapy have been and are currently being developed.The present article aims to provide an updated overview on the different treatment options that are now available or are still under investigation for patients with TNBC.

Molecular mechanisms targeting drug-resistance and metastasis in colorectal cancer:Updates and beyond

Colorectal cancer(CRC)is the third most diagnosed malignancy and a major leading cause of cancer-related deaths worldwide.Despite advances in therapeutic regimens,the number of patients presenting with metastatic CRC(mCRC)is increasing due to resistance to therapy,conferred by a small population of cancer cells,known as cancer stem cells.Targeted therapies have been highly successful in prolonging the overall survival of patients with mCRC.Agents are being developed to target key molecules involved in drug-resistance and metastasis of CRC,and these include vascular endothelial growth factor,epidermal growth factor receptor,human epidermal growth factor receptor-2,mitogen-activated extracellular signal-regulated kinase,in addition to immune checkpoints.Currently,there are several ongoing clinical trials of newly developed targeted agents,which have shown considerable clinical efficacy and have improved the prognosis of patients who do not benefit from conventional chemotherapy.In this review,we highlight recent developments in the use of existing and novel targeted agents against drug-resistant CRC and mCRC.Furthermore,we discuss limitations and challenges associated with targeted therapy and strategies to combat intrinsic and acquired resistance to these therapies,in addition to the importance of implementing better preclinical models and the application of personalized therapy based on predictive biomarkers for treatment selection.

Selective ischemic-hemisphere targeting Ginkgolide B liposomes with improved solubility and therapeutic efficacy for cerebral ischemia-reperfusion injury

Cerebral ischemia-reperfusion injury(CI/RI)remains the main cause of disability and death in stroke patients due to lack of effective therapeutic strategies.One of the main issues related to CI/RI treatment is the presence of the blood-brain barrier(BBB),which affects the intracerebral delivery of drugs.Ginkgolide B(GB),a major bioactive component in commercially available products of Ginkgo biloba,has been shown significance in CI/RI treatment by regulating inflammatory pathways,oxidative damage,and metabolic disturbance,and seems to be a candidate for stroke recovery.However,limited by its poor hydrophilicity and lipophilicity,the development of GB preparations with good solubility,stability,and the ability to cross the BBB remains a challenge.Herein,we propose a combinatorial strategy by conjugating GB with highly lipophilic docosahexaenoic acid(DHA)to obtain a covalent complex GB-DHA,which can not only enhance the pharmacological effect of GB,but can also be encapsulated in liposomes stably.The amount of finally constructed Lipo@GB-DHA targeting to ischemic hemisphere was validated 2.2 times that of free solution in middle cerebral artery occlusion(MCAO)rats.Compared to the marketed ginkgolide injection,Lipo@GB-DHA significantly reduced infarct volume with better neurobehavioral recovery in MCAO rats after being intravenously administered both at 2 h and 6 h post-reperfusion.Low levels of reactive oxygen species(ROS)and high neuron survival in vitro was maintained via Lipo@GB-DHA treatment,while microglia in the ischemic brain were polarized from the pro-inflammatory M1 phenotype to the tissue-repairing M2 phenotype,which modulate neuroinflammatory and angiogenesis.In addition,Lipo@GB-DHA inhibited neuronal apoptosis via regulating the apoptotic pathway and maintained homeostasis by activating the autophagy pathway.Thus,transforming GB into a lipophilic complex and loading it into liposomes provides a promising nanomedicine strategy with excellent CI/RI therapeutic efficacy and industrialization prospects.

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.

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.

Colon cancer and their targeting approaches through nanocarriers:A review

Colon cancer is the fifth most common type of cancer in the world.Colon cancer develops when healthy cells in the lining of the colon or rectum alter and grow uncontrollably to form a mass known as a tumor.Despite major medical improvements,colon cancer is still one of the leading causes of cancer-related mortality globally.One of the main issues of chemotherapy is toxicity related to conventional medicines.The targeted delivery systems are considered the safest and most effective by increasing the concentration of a therapeutic substance at the tumor site while decreasing it at other organs.Therefore,these delivery systems required lower doses for high therapeutic value with minimum side effects.The current review focuses on targeting therapeutic substances at the desired site using nanocarriers.Additionally,the diagnostic applications of nanocarriers in colorectal cancer are also discussed.

Color-polarization synergistic target detection method considering shadow interference

Aiming at the problem of shadow interference in UAV's ground reconnaissance,a color and polarization synergistic target detection method is proposed for anti-shadow interference,based on the influence of two physical characteristics(wavelength and polarization)under different illuminations.A valid fusion strategy is proposed via integrating two separate detection results on color and polarization images.Moreover,a local enhancement and recognition module(LER)is introduced to boost the performance.Based on our built dataset,experimental results show that our method achieves mAPof 87.76%,and12.37%higher than that of color image and 14.68%higher than that of polarization image.

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.

A pilot clinical study of developing an External Assist Targeting Device for rapid and precise renal calyx access during percutaneous nephrolithotomy

Objective:To design a device to increase the accuracy of the targeting process and reduce the radiation exposure to both the patients and the medical staff.Methods:We analyzed the inherent problem and designed the External Assist Targeting Device(EATD)to assist in the alignment of needle targeting on the desired renal calyx under fluoroscopic guidance.The EATD was designed to allow rapid and precise access to calyces at all angles,with a simple two-step puncture protocol developed for puncturing a target renal calyx.We then tested the device in a pilot human trial with four patients.Results:In experiments with phantom models,the time for successful targeting was reduced by 31%using the device.The mean fluoroscopic time was reduced by 40%.In initial human trial,the puncture time was shortened by 66%and the radiation dose was decreased by 65%compared to free-hand technique.No complication was observed during the trial.Conclusion:The EATD was found to be cost effective,portable,simple to set up,and safe to operate for assisting in the percutaneous nephrolithotomy procedures.Our preliminary tests showed high degree of accuracy in gaining precise access to a targeted renal calyx with much shorter time and lesser radiation dose.The EATD also has the potential to be used to access other organs with precision under fluoroscopic guidance.

Targeting endoplasmic reticulum stress signaling in ovarian cancer therapy

The endoplasmic reticulum(ER),an organelle present in various eukaryotic cells,is responsible for intracellular protein synthesis,post-translational modification,and folding and transport,as well as the regulation of lipid and steroid metabolism and Ca2+homeostasis.Hypoxia,nutrient deficiency,and a low pH tumor microenvironment lead to the accumulation of misfolded or unfolded proteins in the ER,thus activating ER stress(ERS)and the unfolded protein response,and resulting in either restoration of cellular homeostasis or cell death.ERS plays a crucial role in cancer oncogenesis,progression,and response to therapies.This article reviews current studies relating ERS to ovarian cancer,the most lethal gynecologic malignancy among women globally,and discusses pharmacological agents and possible targets for therapeutic intervention.

Therapeutic challenge for immunotherapy targeting cold colorectal cancer: A narrative review

Cold colorectal tumors are not likely to trigger a robust immune response and tend to suppress the immune response.There may be three reasons.First,the complex tumor microenvironment of cold colorectal cancer(CRC)leads to tolerance and clearance of immunotherapy.Second,the modification and concealment of tumor-specific targets in cold CRC cause immune escape and immune response interruption.Finally,the difference in number and function of immune cell subsets in patients with cold CRC makes them respond poorly to immunotherapy.Therefore,we can only overcome the challenges in immunotherapy of cold CRC through in-depth research and understanding the changes and mechanisms in the above three aspects of cold CRC.

Potentials of ribosomopathy gene as pharmaceutical targets for cancer treatment

Ribosomopathies encompass a spectrum of disorders arising from impaired ribosome biogenesis and reduced functionality.Mutation or dysexpression of the genes that disturb any finely regulated steps of ribosome biogenesis can result in different types of ribosomopathies in clinic,collectively known as ribosomopathy genes.Emerging data suggest that ribosomopathy patients exhibit a significantly heightened susceptibility to cancer.Abnormal ribosome biogenesis and dysregulation of some ribosomopathy genes have also been found to be intimately associated with cancer development.The correlation between ribosome biogenesis or ribosomopathy and the development of malignancies has been well established.This work aims to review the recent advances in the research of ribosomopathy genes among human cancers and meanwhile,to excavate the potential role of these genes,which have not or rarely been reported in cancer,in the disease development across cancers.We plan to establish a theoretical framework between the ribosomopathy gene and cancer development,to further facilitate the potential of these genes as diagnostic biomarker as well as pharmaceutical targets for cancer treatment.

Target acquisition performance in the presence of JPEG image compression

This paper presents an investigation on the effect of JPEG compression on the similarity between the target image and the background,where the similarity is further used to determine the degree of clutter in the image.Four new clutter metrics based on image quality assessment are introduced,among which the Haar wavelet-based perceptual similarity index,known as HaarPSI,provides the best target acquisition prediction results.It is shown that the similarity between the target and the background at the boundary between visually lossless and visually lossy compression does not change significantly compared to the case when an uncompressed image is used.In future work,through subjective tests,it is necessary to check whether this presence of compression at the threshold of just noticeable differences will affect the human target acquisition performance.Similarity values are compared with the results of subjective tests of the well-known target Search_2 database,where the degree of agreement between objective and subjective scores,measured through linear correlation,reached a value of 90%.