Three-dimensional structure of lymphatics in rabbit stomach

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Mechanisms of phototherapy of Alzheimer’s disease during sleep and wakefulness:the role of the meningeal lymphatics

With the increase in the aging population,the global number of people with Alzheimer’s disease(AD)progressively increased worldwide.The situation is aggravated by the fact that there is no the efective pharmacological therapy of AD.Photobiomodulation(PBM)is non-pharmacological approach that has shown very promising results in the therapy of AD in pilot clinical and animal studies.However,the mechanisms of therapeutic efects of PBM for AD are poorly understood.In this study on mice,we demonstrate that photodynamic efects of 5-aminolevulenic acid and laser 635 nm cause reduction of network of the meningeal lymphatic vessels(MLVs)leading to suppression of lymphatic removal of beta-amyloid(Aβ)from the right lateral ventricle and the hippocampus.Using the original protocol of PBM under electroencephalographic monitoring of wakefulness and sleep stages in non-anesthetized mice,we discover that the 7-day course of PBM during deep sleep vs.wakefulness provides better restoration of clearance of Aβfrom the ventricular system of the brain and the hippocampus.Our results shed light on the mechanism of PBM and show the stimulating efects of PBM on the brain lymphatic drainage that promotes transport of Aβvia the lymphatic pathway.The efects of PBM on the brain lymphatics in sleeping brain open a new niche in the study of restorative functions of sleep as well as it is an important informative platform for the development of innovative smart sleep technologies for the therapy of AD.

Meningeal lymphatic vessel crosstalk with central nervous system immune cells in aging and neurodegenerative diseases

Meningeal lymphatic vessels form a relationship between the nervous system and periphery, which is relevant in both health and disease. Meningeal lymphatic vessels not only play a key role in the drainage of brain metabolites but also contribute to antigen delivery and immune cell activation. The advent of novel genomic technologies has enabled rapid progress in the characterization of myeloid and lymphoid cells and their interactions with meningeal lymphatic vessels within the central nervous system. In this review, we provide an overview of the multifaceted roles of meningeal lymphatic vessels within the context of the central nervous system immune network, highlighting recent discoveries on the immunological niche provided by meningeal lymphatic vessels. Furthermore, we delve into the mechanisms of crosstalk between meningeal lymphatic vessels and immune cells in the central nervous system under both homeostatic conditions and neurodegenerative diseases, discussing how these interactions shape the pathological outcomes. Regulation of meningeal lymphatic vessel function and structure can influence lymphatic drainage, cerebrospinal fluid-borne immune modulators, and immune cell populations in aging and neurodegenerative disorders, thereby playing a key role in shaping meningeal and brain parenchyma immunity.

Intestinal lymphangiectasia:Understanding the bigger picture

Intestinal lymphangiectasia(IL)is characterized by the dilation of intestinal lymphatic vessels,which can rupture and cause loss of lymph into the intestine.Due to the high content of proteins,lipoproteins,and lymphocytes in the intestinal lymph,loss of lymph might result in hypoproteinemia,hypoalbuminemia,hypogammaglobulinemia,and lymphocytopenia.In addition,there may be a depletion of minerals,lipids,and fat-soluble vitamins.IL can be primary due to inherent malfunctioning of the lymphatic system,or secondly,a result of various factors that may hinder lymphatic drainage either directly or indirectly.This condition has emerged as a subject of significant clinical interest.Given that the intestinal lymphatic system plays an important role in the body’s fluid homeostasis,adaptive immunity,nutrient and drug absorption,intestinal transport,and systemic metabolism,its dysfunction may have wider implications.Although primary IL is rare,with varied clinical features,complications,treatment response,and outcomes,secondary IL is more common than previously believed.The definitive diagnosis of IL requires endoscopic demonstration of whitish villi(which frequently resemble snowflakes)and histological confirmation of dilated lacteals in the small intestinal mucosa.Treatment of IL is challenging and involves dietary modifications,managing underlying medical conditions,and using medications such as sirolimus and octreotide.Recognizing its prevalence and diverse etiology is crucial for targeted management of this challenging medical condition.This article provides a comprehensive exploration of the clinical implications associated with IL.In addition,it offers valuable insights into critical knowledge gaps in the existing diagnostic and management landscape.

Crohn’s disease as the intestinal manifestation of pan-lymphatic dysfunction:An exploratory proposal based on basic and clinical data

Crohn’s disease(CD)is caused by immune,environmental,and genetic factors.It can involve the entire gastrointestinal tract,and although its prevalence is rapidly increasing its etiology remains unclear.Emerging biological and small-molecule drugs have advanced the treatment of CD;however,a considerable proportion of patients are non-responsive to all known drugs.To achieve a breakthrough in this field,innovations that could guide the further development of effective therapies are of utmost urgency.In this review,we first propose the innovative concept of pan-lymphatic dysfunction for the general distribution of lymphatic dysfunction in various diseases,and suggest that CD is the intestinal manifestation of pan-lymphatic dysfunction based on basic and clinical preliminary data.The supporting evidence is fully summarized,including the existence of lymphatic system dysfunction,recognition of the inside-out model,disorders of immune cells,changes in cell plasticity,partial overlap of the underlying mechanisms,and common gut-derived fatty and bile acid metabolism.Another benefit of this novel concept is that it proposes adopting the zebrafish model for studying intestinal diseases,especially CD,as this model is good at presenting and mimicking lymphatic dysfunction.More importantly,the ensuing focus on improving lymphatic function may lead to novel and promising therapeutic strategies for CD.

Promising outcomes 5 weeks after a surgical cervical shunting procedure to unclog cerebral lymphatic systems in a patient with Alzheimer’s disease

Recently,the glymphatic system has been recognised as an important‘waste solutes transport channel’within the brain.1 Studies have shown that blockage of the glymphatic system leads to increased beta-amyloid deposits,accelerating the onset and progression of Alzheimer’s disease(AD).12 Given that cervical lymph nodes receive cerebrospinal fluid from the brain’s glymphatic system,34 we speculated that decompression of the lymphatic trunk and cervical lymphatic-venous anastomosis(LVA)could facilitate the flow of cerebrospinal fluid in the cranial glymphatic system,potentially accelerating the clearance of harmful beta-amyloid and tau proteins.We collaborated with surgeons who specialise in LVA supermicrosurgery for maxillofacial tumours and lymphoedema to develop a procedure to relieve the blockage of the glymphatic system.This surgery employs supermicrosurgery techniques to create LVA connecting the bilateral cervical,deep lymphatic vessels to the veins,resulting in lymphatic trunk decompression,which allows the lymph fluid in the high-pressure lymphatic vessels to flow into the low-pressure venous system.The goal of the minimally invasive surgery is to enhance the removal of proteins,such as beta-amyloid and tau,from the brain’s lymphatic systems to the maxillofacial lymphatic vessels,unclogging protein blockages within the brain.This extracranial procedure is safer than intracranial approaches.

Lymphatic plastic bronchitis and primary chylothorax: A study based on computed tomography lymphangiography

BACKGROUND This study presents an evaluation of the computed tomography lymphangio-graphy(CTL)features of lymphatic plastic bronchitis(PB)and primary chylotho-rax to improve the diagnostic accuracy for these two diseases.AIM To improve the diagnosis of lymphatic PB or primary chylothorax,a retrospective analysis of the clinical features and CTL characteristics of 71 patients diagnosed with lymphatic PB or primary chylothorax was performed.METHODS The clinical and CTL data of 71 patients(20 with lymphatic PB,41 with primary chylothorax,and 10 with lymphatic PB with primary chylothorax)were collected retrospectively.CTL was performed in all patients.The clinical manifestations,CTL findings,and conventional chest CT findings of the three groups of patients were compared.The chi-square test or Fisher's exact test was used to compare the differences among the three groups.A difference was considered to be statistically significant when P<0.05.RESULTS(1)The percentages of abnormal contrast medium deposits on CTL in the three groups were as follows:Thoracic duct outlet in 14(70.0%),33(80.5%)and 8(80.0%)patients;peritracheal region in 18(90.0%),15(36.6%)and 8(80.0%)patients;pleura in 6(30.0%),33(80.5%)and 9(90.0%)patients;pericardium in 6(30.0%),6(14.6%)and 4(40.0%)patients;and hilum in 16(80.0%),11(26.8%)and 7(70.0%)patients;and(2)the abnormalities on conven-tional chest CT in the three groups were as follows:Ground-glass opacity in 19(95.0%),18(43.9%)and 8(80.0%)patients;atelectasis in 4(20.0%),26(63.4%)and 7(70.0%)patients;interlobular septal thickening in 12(60.0%),11(26.8%)and 3(30.0%)patients;bronchovascular bundle thickening in 14(70.0%),6(14.6%)and 4(40.0%)patients;localized mediastinal changes in 14(70.0%),14(34.1%),and 7(70.0%)patients;diffuse mediastinal changes in 6(30.0%),5(12.2%),and 3(30.0%)patients;cystic lesions in the axilla in 2(10.0%),6(14.6%),and 2(20.0%)patients;and cystic lesions in the chest wall in 0(0%),2(4.9%),and 2(4.9%)patients.CONCLUSION CTL is well suited to clarify the characteristics of lymphatic PB and primary chylothorax.This method is an excellent tool for diagnosing these two diseases.

Roles of cancer-associated fibroblast functional heterogeneity in shaping the lymphatic metastatic landscape:new insights and therapeutic strategies

Lymph node (LN) metastasis is a process in which cancer cells travel from primary tumors to LNs via the lymphatic system,then proliferate and spread within the LNs. In most cancers,LN metastasis is a major mode of cancer dissemination,and a critical indicator of cancer progression and worsening prognosis1. The occurrence of LN metastasis indicates that the tumor has invaded the lymphatic system.

Enhancement of anti-PD-L1 antibody plus anlotinib efficacy due to downregulation of PD-L1 in the micro-conduit endothelium within the tumor:a randomized double-blind trial

Objective:The possible enhancing effect of anlotinib on programmed death receptor ligand(PD-L1)antibody and the efficacy-predicting power of PD-L1 in micro-conduit endothelium,including lymphatic endothelial cells(LECs)and blood endothelial cells(BECs),were determined to identify patients who would benefit from this treatment.Methods:PD-L1 positivity in LECs,BECs,and tumor cells(TCs)was assessed using paraffin sections with multicolor immunofluorescence in an investigator’s brochure clinical trial of TQB2450(PD-L1 antibody)alone or in combination with anlotinib in patients with non-small cell lung cancer.Progression-free survival(PFS)with different levels of PD-L1 expression was compared between the two groups.Results:Among 75 patients,the median PFS(mPFS)was longer in patients who received TQB2450 with anlotinib[10 and 12 mg(161 and 194 days,respectively)]than patients receiving TQB2450 alone(61 days)[hazard ratio(HR)_(10 mg)=0.390(95%confidence interval{CI},0.201–0.756),P=0.005;HR_(12 mg)=0.397(0.208–0.756),P=0.005].The results were similar among 58 patients with high PD-L1 expression in LECs and TCs[159 and 209 vs.82 days,HR_(10 mg)=0.445(0.210–0.939),P=0.034;HR_(12 mg)=0.369(0.174–0.784),P=0.009],and 53 patients with high PD-L1 expression in BECs and TCs[161 and 209 vs.41 days,HR_(10 mg)=0.340(0.156–0.742),P=0.007;HR_(12 mg)=0.340(0.159–0.727),P=0.005].No differences were detected in the mPFS between the TQB2450 and combination therapy groups in 13 low/no LEC-expressing and 18 low/no BEC-expressing PD-L1 cases.Conclusions:Mono-immunotherapy is not effective in patients with high PD-L1 expression in LECs and/or BECs.Anlotinib may increase efficacy by downregulating PD-L1 expression in LECs and/or BECs,which is presumed to be a feasible marker for screening the optimal immune patient population undergoing anti-angiogenic therapy.

Fine-tuning the activation behaviors of ternary modular cabazitaxel prodrugs for efficient and on-target oral anti-cancer therapy

The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances (e.g., ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Fine-tuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)S-TG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bond-based linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy.

Functional aspects of the brain lymphatic drainage system in aging and neurodegenerative diseases

The phenomenon of an aging population is advancing at a precipitous rate.Alzheimer's disease(AD)and Parkinson's disease(PD)are two of the most common age-associated neurodegenerative diseases,both of which are primarily characterized by the accumulation of toxic proteins and the progressive demise of neuronal structures.Recent discoveries about the brain lymphatic drainage system have precipitated a growing body of investigations substantiating its novel roles,including the clearance of macromolecular waste and the trafficking of immune cells.Notably,aquaporin 4-mediated glymphatic transport,crucial for maintaining neural homeostasis,becomes disrupted during the aging process and is further compromised in the pathogenesis of AD and PD.Functional meningeal lymphatic vessels,which facilitate the drainage of cerebrospinal fluid into the deep cervical lymph nodes,are integral in bridging the central nervous system with peripheral immune responses.Dysfunction in these meningeal lymphatic vessels exacerbates pathological trajectory of the age-related neurodegenerative disease.This review explores modulatory influence of the glymphatic system and meningeal lymphatic vessels on the aging brain and its associated neurodegenerative disorders.It also encapsulates the insights of potential mechanisms and prospects of the targeted non-pharmacological interventions.

Clinical approach for pulmonary lymphatic disorders

In this editorial,we discuss the clinical implications of the article“Lymphatic plastic bronchitis and primary chylothorax:A study based on computed tomography lymphangiography”published by Li et al.Pulmonary lymphatic disorders involve abnormalities in the lymphatic tissues within the thoracic cavity.Specifically,pulmonary lymphatic perfusion syndrome describes a condition where the flow of lymphatic fluid in the lungs is redirected towards abnormally widened lymphatic vessels.Clinically,individuals with this syn-drome may experience symptoms such as chyloptysis,plastic bronchitis(PB),chylothorax,chylopericardium,and interstitial lung disease.These disorders can be caused by various factors,including PB,chylothorax,and complex lymphatic malformations.Advancements in lymphatic imaging techniques,such as in-tranodal lymphangiography,computed tomography lymphangiography,and dynamic contrast-enhanced magnetic resonance lymphangiography,have enabled the detection of abnormal lymphatic flow.This has enhanced our understanding of the pathophysiology of these conditions.Additionally,innovative minimally invasive treatments,such as thoracic duct embolization,selective embolization of lymphatic channels,and surgical procedures aim to improve clinical condition of patients and address their dietary needs.

Combination of manual lymphatic drainage and Kinesio taping for treating pigmented villonodular synovitis:A case report

BACKGROUND Pigmented villonodular synovitis(PVNS)is a benign proliferative disorder that affects the synovial joints,bursae,and tendon sheaths.To date,few studies have reported on the treatment of postoperative pain and edema in patients with PVNS.Herein,we present the case of a woman who developed pain and edema in the left lower limb 1 wk after synovectomy and arthroscopic partial meniscectomy and was unable to walk due to limited flexion and extension of the left knee.CASE SUMMARY A 32-year-old woman underwent synovectomy and arthroscopic partial meniscectomy successively and was treated with a combination of manual lymphatic drainage(MLD)and kinesio taping(KT)in our hospital to alleviate postoperative pain and edema.The following parameters were assessed at 2 wk post-treatment and 1 wk post-discharge follow up:suprapatellar circumference,infrapatellar circumference,visual analog scale score,knee range of motion,pittsburgh sleep quality index score,hamilton anxiety rating scale(HAMA)score,and hamilton depression rating scale(HAMD)score.After treatment,the postoperative pain and edema in the patient’s left knee were effectively relieved,resulting in improved sleep quality and remarkably attenuated HAMA and HAMD scores.CONCLUSION Combined MLD and KT may be an effective approach for relieving postoperative pain and edema in patients with PVNS.

Multifaceted roles of lymphatic and blood endothelial cells in the tumor microenvironment of hepatocellular carcinoma:A comprehensive review

The tumor microenvironment is a complex network of cells,extracellular matrix,and signaling molecules that plays a critical role in tumor progression and metastasis.Lymphatic and blood vessels are major routes for solid tumor metastasis and essential parts of tumor drainage conduits.However,recent studies have shown that lymphatic endothelial cells(LECs)and blood endothelial cells(BECs)also play multifaceted roles in the tumor microenvironment beyond their structural functions,particularly in hepatocellular carcinoma(HCC).This comprehensive review summarizes the diverse roles played by LECs and BECs in HCC,including their involvement in angiogenesis,immune modulation,lymphangiogenesis,and metastasis.By providing a detailed account of the complex interplay between LECs,BECs,and tumor cells,this review aims to shed light on future research directions regarding the immune regulatory function of LECs and potential therapeutic targets for HCC.

Advantages of the intradermal lymphoscintigraphy

Lymphoscintigraphy is a nuclear medicine procedure that uses a small quantity of radioactive particles for visualizing the lymphatic system.Traditionally,the radiotracer was injected subcutaneously,but the quality of lymphatic path imaging was scarce due to high background.Intradermal radiotracer injection is considered the modern-day intralymphatic injection.We propose rest/stress intradermal lymphoscintigraphy for the diagnosis,staging and surgical planning of lymphedema.Major and minor findings were described in primary and secondary lymphedema.Based on the in-depth information of the lymphatic pathways,physiotherapists and microsurgeons can obtain important functional information in patients’selection to treat with physical treatments and/or undergo microsurgery.

The Role of Body Composition Analyzer in the Preoperative Assessment of Breast Cancer Patients

Background: The segmental multi-frequency bioelectrical impedance analysis (SMF-BIA) is a useful method for evaluating physical health and nutritional status in various clinical settings. But less is known about its role in the preoperative assessment of breast cancer patients. Herein, we try to monitor the changes in body composition of preoperative patients by SMF-BIA and figure out its association with clinical features. Methods: The changes in body composition were monitored by SMF-BIA in 563 female patients with breast cancer. Monitor body moisture and collect relevant data on the day before surgery as a prospective study. Retrospective analysis will be conducted based on preoperative data and pathological results after lymph node resection, Spearman’s correlation coefficients were calculated to investigate the correlation among parameters. Results: We found that the body water, extracellular water ratio, and bioelectrical impedance of the affected upper limbs of patients with different tumor stages or different numbers of lymph node metastases were significantly different from those of their healthy upper limbs (P P P P P Conclusion: SMF-BIA can help monitor the changes in body composition of breast cancer patients and provide detailed information for making a personalized treatment plan and individual nursing schedule. However, the value of SMF-BIA in preoperative assessment still needs to be validated in large prospective clinical trials.

高频电凝治疗颌面部脉管性疾病

脉管性疾病(vascular anomalies)包括血管瘤(hemangioma)和脉管畸形(vascular malformation)两大类。血管瘤和血管畸形是临床常见的血管病变,80%好发于头颈部及颌面部[1]。近年有用电化学、射频、电针、中医药治疗的相关报道,但尚未见到广泛使用。

喉癌颈淋巴结转移与微淋巴管密度和血管内皮生长因子D的关系

为探索喉癌颈淋巴结转移与微淋巴管形成的关系,我们采用5＇-核苷酸酶和碱性磷酸酶（5＇-Nase-ALPase）双重组织化学染色方法检测喉癌中微淋巴管密度（lymphatic microvessel density,LMVD）,采用免疫组化法检测血管内皮生长因子-D（endothelial vascular growth factor-D,VEGF-D）的表达。

Lymphangiogenesis contributes to exercise-induced physiological cardiac growth

Background:Promoting cardiac lymphangiogenesis exerts beneficial effects for the heart.Exercise can induce physiological cardiac growth with cardiomyocyte hypertrophy and increased proliferation markers in cardiomyocytes.However,it remains unclear whether and how lymphangiogenesis contributes to exercise-induced physiological cardiac growth.We aimed to investigate the role and mechanism of lymphangiogenesis in exercise-induced physiological cardiac growth.Methods:Adult C57 BL6/J mice were subjected to 3 weeks of swimming exercise to induce physiological cardiac growth.Oral treatment with vascular endothelial growth factor receptor 3(VEGFR3) inhibitor SAR1 3 1 675 was used to investigate whether cardiac lymphangiogenesis was required for exercise-induced physiological cardiac growth by VEGFR3 activation.Furthermore,human dermal lymphatic endothelial cell(LEC)-conditioned medium was collected to culture isolated neonatal rat cardiomyocytes to determine whether and how LECs could influence cardiomyocyte proliferation and hypertrophy.Results:Swimming exercise induced physiological cardiac growth accompanied by a remarkable increase of cardiac lymphangiogenesis as evidenced by increased density of lymphatic vessel endothelial hyaluronic acid receptor 1-positive lymphatic vessels in the heart and upregulated LYVE-1 and Podoplanin expressions levels.VEGFR3 was upregulated in the exercised heart,while VEGFR3 inhibitor SAR131675 attenuated exercise-induced physiological cardiac growth as evidenced by blunted myocardial hypertrophy and reduced proliferation marker Ki67 in cardiomyocytes,which was correlated with reduced lymphatic vessel density and downregulated LYVE-1 and Podoplanin in the heart upon exercise.Furthermore,LEC-conditioned medium promoted both hypertrophy and proliferation of cardiomyocytes and contained higher levels of insulinlike growth factor-1 and the extracellular protein Reelin,while LEC-conditioned medium from LECs treated with SAR131675 blocked these effects.Functional rescue assays further demonstrated that protein kinase B(AKT) activation,as well as reduced CCAAT enhancer-binding protein beta(C/EBPβ) and increased CBP/p300-interacting transactivators with E(glutamic acid)/D(aspartic acid)-rich-carboxylterminal domain 4(CITED4),contributed to the promotive effect of LEC-conditioned medium on cardiomyocyte hypertrophy and proliferation.Conclusion:Our findings reveal that cardiac lymphangiogenesis is required for exercise-induced physiological cardiac growth by VEGFR3 activation,and they indicate that LEC-conditioned medium promotes both physiological hypertrophy and proliferation of cardiomyocytes through AKT activation and the C/EBPβ-CITED4 axis.These results highlight the essential roles of cardiac lymphangiogenesis in exercise-induced physiological cardiac growth.

Extraluminal factors contributing to inflammatory bowel disease

Many identified and yet unknown factors contribute to the pathogenesis of inflammatory bowel disease(IBD).The genome-wide association studies clearly support the earlier developed concept that IBD occurs in genetically predisposed individuals who are exposed to distinct environmental factors,which together result in dysregulation of the mucosal immune system.Thus,the majority of previous studies have focused on the immune response within the intestinal wall.The present review aims to emphasize the contribution of three extraluminal structures to this inflammatory process,namely the mesenteric fat tissue,the lymphatics and the microvasculature.Broadening our view across the intestinal wall will not only facilitate our understanding of the disease,but will also us to identify future therapeutic targets.