The aim was to establish a liver venous deprivation (LVD) model in rats, compare hepatic hypertrophy between LVD and associated liver partition and portal vein ligation for staged hepatectomy (ALPPS), and explore the underlying mechanisms.

The LVD or extended-LVD (e-LVD) group received portal vein ligation (PVL) combined with hepatic vein ligation (HVL). The ALPPS or e-ALPPS group received PVL plus parenchyma ligation. Liver regeneration was assessed by measuring the liver weight and performing pathological analysis. Liver functions and the sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P)/sphingosine-1-phosphate receptor 1 (S1PR1) pathway were also investigated.

All future liver remnants (FLRs) in the ALPPS, e-ALPPS, LVD, and e-LVD groups exhibited significant hypertrophy compared with the control group. The LVD and e-LVD procedures induced similar liver hypertrophy than that in the corresponding ALPPS groups. Furthermore, the LVD and e-LVD methods led to obvious cytolysis in the venous-deprived lobes as well as a noticeable increase in serum transaminase levels, while no necrosis was observed in the ALPPS and e-ALPPS groups. SPHK1/S1P/S1PR1 pathway were distinctly activated after operation, especially in congestive/ischemic livers.

We describe the first rat model of LVD and e-LVD with simultaneously associated HVL and PVL. Compared with the ALPPS technique, the LVD or e-LVD procedure had a comparable overall effect on the hypertrophy response and a stronger effect on liver function. The SPHK1/S1P/S1PR1 pathway was involved in the LVD- or ALPPS-induced liver remodeling.

Currently, scientific interest has focused on fat accumulation outside of subcutaneous adipose tissue. As various imaging modalities are available to quantify fat accumulation in particular organs, fatty pancreas has become an important area of research over the last decade. The pancreas has an essential role in regulating glucose metabolism and insulin secretion by responding to changes in nutrients under various metabolic circumstances. Mounting evidence has revealed that fatty pancreas is linked to impaired β-cell function and affects insulin secretion with metabolic consequences of impaired glucose metabolism, type 2 diabetes, and metabolic syndrome. It has been shown that there is a connection between fatty pancreas and the presence and severity of nonalcoholic fatty liver disease (NAFLD), which has become the predominant cause of chronic liver disease worldwide. Therefore, it is necessary to better understand the pathogenic mechanisms of fat accumulation in the pancreas and its relationship with NAFLD. This review summarizes the epidemiology, diagnosis, risk factors, and metabolic consequences of fatty pancreas and discusses its pathophysiology links to NAFLD.

Hepatic ischemia/reperfusion (I/R) injury has become an inevitable issue during liver transplantation, with no effective treatments available. However, peptide drugs provide promising regimens for the treatment of this injury and peptidomics has gradually attracted increasing attention. This study was designed to analyze the spectrum of peptides in injured livers and explore the potential beneficial peptides involved in I/R injury.

C57BL/6 mice were used to establish a liver I/R injury animal model. Changes in peptide profiles in I/R-injured livers were analyzed by mass spectrometry, and the functions of the identified peptides were predicted by bioinformatics. AML12 cells were used to simulate hepatic I/R injury in vitro. After treatment with candidate liver-derived peptides (LDPs) 1–10, the cells were collected at various reperfusion times for further study.

Our preliminary study demonstrated that 6 h of reperfusion caused the most liver I/R injury. Peptidomic results suggested that 10 down-regulated peptides were most likely to alleviate I/R injury by supporting mitochondrial function. Most importantly, a novel peptide, LDP2, was identified that alleviated I/R injury of AML12 cells. It increased cell viability and reduced the expression of inflammation- and apoptosis-related proteins. In addition, LDP2 inhibited the expression of proteins related to autophagy.

Investigation of changes in the profiles of peptides in I/R-injured livers led to identification of a novel peptide, LDP2 with potential function in liver protection by inhibiting inflammation, apoptosis, and autophagy.

Metabolic-associated fatty liver disease (MAFLD) is a new disease definition, and is proposed to replace the previous name, nonalcoholic fatty liver disease (NAFLD). Globally, MAFLD/NAFLD is the most common liver disease, with an incidence rate ranging from 6% to 35% in adult populations. The pathogenesis of MAFLD/NAFLD is closely related to insulin resistance (IR), and the genetic susceptibility to acquired metabolic stress-associated liver injury. Similarly, the gut microbiota in MAFLD/NAFLD is being revaluated by scientists, as the gut and liver influence each other via the gut-liver axis. Ferroptosis is a novel form of programmed cell death caused by iron-dependent lipid peroxidation. Emerging evidence suggests that ferroptosis has a key role in the pathological progression of MAFLD/NAFLD, and inhibition of ferroptosis may become a novel therapeutic strategy for the treatment of NAFLD. This review focuses on the main mechanisms behind the promotion of MAFLD/NAFLD occurrence and development by the intestinal microbiota and ferroptosis. It outlines new strategies to target the intestinal microbiota and ferroptosis to facilitate future MAFLD/NAFLD therapies.

Nonalcoholic fatty liver disease (NAFLD) includes a range of progressive disorders generated by excess lipid accumulation in the liver leading to hepatic steatosis and eventually fibrosis. We aimed to identify by high performance mass spectrometry-based proteomics the main signaling pathways and liver proteome changes induced by hypercholesterolemia in a rabbit atherosclerotic model that induced high accumulation of lipids in the liver.

The effect of combined lipid-lowering drugs (statins and anti-PCSK9 monoclonal antibody) were used after the interruption of the hypercholesterolemic diet to identify also the potential mediators, such as alarmins, responsible for the irreversible NAFLD build up under the hyperlipidemic sustained stress.

Proteomic analysis revealed a number of proteins whose abundance was altered. They were components of metabolic pathways including fatty-acid degradation, glycolysis/gluconeogenesis, and nonalcoholic fatty liver disease. Mitochondrial dysfunction indicated alteration at the mitochondrial respiratory chain level and down-regulation of NADH: ubiquinone oxidoreductase. The expression of a majority of cytochromes (P4502E1, b5, and c) were up-regulated by lipid-lowering treatment. Long-term hyperlipidemic stress, even with a low-fat diet and lipid-lowering treatment, was accompanied by alarmin release (annexins, galectins, HSPs, HMGB1, S100 proteins, calreticulin, and fibronectin) that generated local inflammation and induced liver steatosis and aggressive fibrosis (by high abundance of galectin 3, fibronectin, and calreticulin).

The novel findings of this study were related to the residual effects of hyperlipidemic stress with consistent, combined lipid-lowering treatment with statin and inhibitor of PCSK9.

The model for end-stage liver disease (MELD) was originally developed to predict survival after transjugular intrahepatic portosystemic shunt (TIPS). The MELD-sodium (MELD-Na) score has replaced MELD for organ allocation for liver transplantation. However, there are limited studies to compare the MELD with MELD-Na to predict mortality after TIPS.

We performed a retrospective chart review of patients who underwent TIPS placement between 2006 and 2016 at our institution. The primary outcome was mortality, and the secondary outcomes sought to assess which variables could provide prognostic information for mortality after TIPS placement. We performed receiver operating characteristic (ROC) curve analysis to assess the performance of MELD and MELD-Na.

There were 186 eligible patients in the analysis. The mean pre-TIPS MELD and MELD-Na were 13 and 15, respectively. Overall, mortality after TIPS was 15% at 30 days and 16.7% at 90 days. In a comparison of the areas under the ROCs for MELD and MELD-Na, MELD was superior to MELD-Na for 30-day (0.762 vs. 0.709) and 90-day (0.780 vs. 0.730) mortality after TIPS. The optimal cutoff score for 30-day mortality was 15 (0.676–0.848) for MELD and 17 (0.610–0.808) for MELD-Na, whereas the optimal cutoff score for 90-day mortality was 16 (95% CI: 0.705–0.855) for MELD and 17 (95% CI: 0.643–0.817) for MELD-Na. There were 24 patients with high MELD-Na ≥17, but with low MELD <15, and 90-day mortality in this group was 8.3%.

Although MELD-Na is a superior prognostic tool to MELD for predicting overall mortality in cirrhotic patients, MELD tended to outperform MELD-Na to predict mortality after TIPS.

Emerging evidence suggests that RNA-binding motif (RBM) proteins are involved in hepatocarcinogenesis and act either as oncogenes or tumor suppressors. The objective of this study was to investigate the role of RBM34, an RBM protein, in hepatocellular carcinoma (HCC).

We first examined the expression of RBM34 across cancers. The correlation of RBM34 with clinicopathological features and the prognostic value of RBM34 for HCC was then investigated. Functional enrichment analysis of RBM34-related differentially expressed genes (DEGs) was performed to explore its biological function. RNA sequencing (RNA-seq) was applied to identify downstream genes and pathways affected upon RBM34 knockout. The correlation of RBM34 with immune characteristics was also analyzed. The oncogenic function of RBM34 was examined in in vitro and in vivo experiments.

RBM34 was highly expressed in hepatocellular carcinoma and correlated with poor clinicopathological features and prognosis. RBM34 was positively associated with tumor immune cell infiltration, biomarkers of immune cells, and immune checkpoint expression. A positive correlation was also observed between RBM34, T cell exhaustion, and regulatory T cell marker genes. Knockout of RBM34 significantly inhibited cell proliferation, migration, and xenograft tumor growth, and sensitized HCC cells to sorafenib treatment. RBM34 inhibition reduced FGFR2 expression and affected PI3K-AKT pathway activation in HCC cells.

Our study suggests that RBM34 may serve as a new prognostic marker and therapeutic target of HCC.

The pathogenesis of metabolic-associated fatty liver disease (MAFLD) is complex and thought to be dependent on multiple parallel hits on a background of genetic susceptibility. The evidence suggests that MAFLD progression is a dynamic two-way process relating to repetitive bouts of metabolic stress and inflammation interspersed with endogenous anti-inflammatory reparative responses. In MAFLD, excessive hepatic lipid accumulation causes the production of lipotoxins that induce mitochondrial dysfunction, endoplasmic reticular stress, and over production of reactive oxygen species (ROS). Models of MAFLD show marked disruption of mitochondrial function and reduced oxidative capacitance with impact on cellular processes including mitophagy, oxidative phosphorylation, and mitochondrial biogenesis. In excess, ROS modify insulin and innate immune signaling and alter the expression and activity of essential enzymes involved in lipid homeostasis. ROS can also cause direct damage to intracellular structures causing hepatocyte injury and death. In select cases, the use of anti-oxidants and ROS scavengers have been shown to diminish the pro-apoptopic effects of fatty acids. Given this link, endogenous anti-oxidant pathways have been a target of interest, with Nrf2 activation showing a reduction in oxidative stress and inflammation in models of MAFLD. Thyroid hormone receptor β (THRβ) agonists and nuclear peroxisome proliferation-activated receptor (PPAR) family have also gained interest in reducing hepatic lipotoxicity and restoring hepatic function in models of MAFLD. Unfortunately, the true interplay between the clinical and molecular components of MAFLD progression remain only partly understood. Most recently, multiomics-based strategies are being adopted for hypothesis-free analysis of the molecular changes in MAFLD. Transcriptome profiling maps the unique genotype-phenotype associations in MAFLD and with various single-cell transcriptome-based projects underway, there is hope of novel physiological insights to MAFLD progression and uncover therapeutic targets.

Abiotic environmental stress causes plants and animals to produce excessive superoxide radicals that are extremely toxic and reactive, thereby causing injury to tissue resulting in the occurrence of several disorders. Antioxidants can counteract free radicals by preventing non-communicable diseases. There are natural and synthetic antioxidants. Natural antioxidants in fruits, vegetables, and spices can be consumed, while synthetic antioxidants are produced in laboratories via chemical processes. This review focused on the sources, pharmacological properties, applications, and prospects of natural and synthetic antioxidants, as well as exogenous and endogenous antioxidants. A literature search was done using different search engines like Google Books, Science.gov, Microsoft Academic, Worldwide Science, ResearchGate, Bielefeld Academic Search Engine (BASE), Medline, and PubMed Central. Different keywords, such as antioxidants, free radicals, oxidative stress, superoxide radicals, and oxygen radicals, were used. The relevant literature was collected and used in this review. Antioxidants inhibit oxidation and help to prevent non-communicable diseases, such as aging and inflammatory processes, tumors, kidney and liver diseases, coronary heart disease, cataracts, renal toxicity, and neurological diseases. It was found that antioxidants in the diet have the capacity to prevent oxidative anxiety-related disorders.

The COVID-19 pandemic is a major threat worldwide. Since it is a contagious disease and there are no established treatment procedures, the situation demands stronger preventive measures. Thus, an effective and reliable prevention method is important. The use of gargles and nasal rinses are well-known ancient Ayurvedic procedures that have been an effective weapon against many infections related to the throat and nasal path. Thus, their role in preventive management of COVID-19 should be investigated. Soaps and detergents are proven to be very effective in destroying the virus outside the body, but can this be useful in the throat? Most of the virus passes to the lungs via the throat and nasal route, so inactivation or flushing out of the virus from the throat and nasal path itself may prevent its entry to the lungs. The use of gargles and nasal rinses consisting of saponins as natural surfactants may provide antiviral action. The virus is said to remain in the throat for 3 to 4 days. Gargling allows these natural surfactants to come directly into contact with the adhering virus in the throat, thereby flushing out or inactivating the virus. Many studies have shown that constituents like glycyrrhizin (liquorice), curcumin (turmeric) and methylglyoxal (manuka honey) etc. have potential activity against life threatening viruses. Thus, a medicated gargle and nasal rinse incorporating these natural surfactants along with potential antiviral drugs may be able to exert an acceptable result in preventive management of SARS-CoV-2.

Chronic hepatitis caused by hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC). We investigated the roles of oncogenic HBV infection-associated long noncoding RNAs in HCC.

Bioinformatics analysis of data from the Cancer Genome Atlas (TCGA) was performed to screen potential oncogenic HBV-related lncRNAs. Next, we assessed their expression in clinical samples and investigated their correlation with clinical characteristics. The detailed oncogenic effects were analyzed by performing in vitro and in vivo studies.

RP11-40C6.2, an HBV infection-related lncRNA, was identified by analysis of the TCGA–Liver Hepatocellular Carcinoma database. Gene Set Enrichment Analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of differentially expressed genes revealed a strong association of RP11-40C6.2 with the Hippo signaling pathway. RP11-40C6.2 was overexpressed in HCC patients with HBV infection compared to those without HBV infection. RP11-40C6.2 transcription showed a positive association with HBV-X protein (HBx), but not HBV core protein (HBc) expression, both of which are carcinogenic proteins. Luciferase gene reporter and ChIP assays revealed that YAP1/TAZ/TEADs complex enhanced RP11-40C6.2 transcription by binding to its promoter area. RP11-40C6.2 showed oncogenic characteristics in HCC cell lines and in animal models that were mediated via activation of YAP1. In vitro ubiquitylation assay revealed that RP11-40C6.2 can promote the stabilization of YAP1 by stopping phosphorylation at its s127 residue and further stopping its degradation through binding to 14-3-3.

RP11-40C6.2 is an HBV infection-related lncRNA that exerts its oncogenic effects by targeting the Hippo signaling pathway.

Nonbiological artificial liver (NBAL) is frequently used as a first-line treatment for hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF). This study aimed to compare the therapeutic efficacy and cost-effectiveness ratio (CER) of comprehensive medical treatment, plasma exchange (PE), and double plasma molecular adsorption system (DPMAS) plus half-dose PE (DPMAS+PE) in patients with HBV-ACLF.

A total of 186 patients with HBV-ACLF randomly received comprehensive medical treatment, PE, or DPMAS+PE and were prospectively evaluated. Patients were divided into four subgroups based on the pretreatment prothrombin activity (PTA): Group I (PTA>40%), group II (PTA 30–40%), group III (PTA 20–30%), and group IV (PTA<20%). The main outcome measures were 28 day effectiveness; 90 day liver transplantation-free survival; change of biochemical parameters; and CER.

DPMAS+PE treatment was associated with significantly higher 28 day effectiveness and 90 day liver transplantation-free survival compared with PE treatment in patients with group I liver failure. Clearance of serum total bilirubin (TBIL), AST, and creatinine (Cr) were significantly higher in the DPMAS+PE group than in the PE group. For subjects with group I liver failure, DPMAS+PE treatment had advantages of lower CER values and better cost-effectiveness.

Compared with comprehensive medical treatment and PE alone, DPMAS with half-dose sequential PE treatment more effectively improved TBIL, AST, and Cr in HBV-ACLF patients, improved 28 day effectiveness and 90 day survival rates in patients with group I liver failure, and was more cost effective. DPMAS+PE is a viable NBAL approach for treatment of HBV-ACLF.

The circadian rhythm regulates many physiological human health and disease processes. The central circadian clock is located in the suprachiasmatic nucleus in the hypothalamus and controls a whole range of circadian clock genes. During bone remodeling, circadian rhythm gene expression was observed in osteoblasts and osteoclasts. Moreover, circadian rhythm genes are an essential part of the circadian network in the osseointegration of titanium implants. Namely, titanium biomaterials significantly affect the expression of the circadian clock gene in the oral cavity and thus regulate the establishment of osseointegration. In addition, vitamin D has potential practical implications for patients with dental implants because sufficient vitamin D levels before surgery improve the osseointegration process. Also, the hormone melatonin, whose production depending on the circadian rhythm, affects bone homeostasis. Therefore, melatonin affects bone formation and could serve as a regenerative agent by increasing the process of osseointegration. This review highlights the impact of dental implants on circadian rhythm and osseointegration.

For the past several decades, markers of cellular proliferation in breast cancer have been postulated to indicate prognosis and predict benefits from antineoplastic therapies. The most common method to measure cellular proliferation by Ki-67 is immunohistochemistry (IHC) based assays. However, analytical issues have hindered the widespread adoption of these measures in patient care. The recent monarch E clinical trial prospectively investigated Ki-67 as a biomarker of cyclin-dependent kinase inhibitor (CDKI), Abemaciclib in the adjuvant setting. It established the benefit of CDKI in high-risk ER-positive breast cancer patients with Ki-67 expression >20%, which promoted the increased clinical demand for routine Ki-67 testing in pathology laboratories. This review summarizes some recent developments and practical issues for Ki-67 evaluation.

Decompensated cirrhotic patients with hepatitis C (HCV) are often under-represented in clinical trials. We aimed to evaluate pooled data on the efficacy and safety of sofosbuvir (SOF)-based regimens in these patients.

We conducted a systemic review and meta-analysis by searching multiple databases for studies published from October 2010 to October 2020. Outcomes of interest were sustained virologic response (SVR) and safety of SOF-based regimens in decompensated HCV patients. Two reviewers independently performed the study selection and data extraction.

We included 33 studies that enrolled 5,302 HCV patients. The pooled SVR rate in decompensated patients with SOF-based regimens was 85.1% (95% CI: 82.8–87.3). Patients on SOF/velpatasvir±ribavirin achieved a significantly higher SVR (91.0%, 95% CI: 87.7–93.9) than that of SOF/ledipasvir±ribavirin [(86.3%, 95% CI: 84.6–87.8); p=0.004)], or on SOF/daclatasvir±ribavirin (82.4%, 95% CI: 78.2–86.2%; p<0.001). Adding ribavirin to SOF-based regimens (pooled SVR 84.9%, 95% CI: 81.7–87.9) did not significantly increase the SVR [(83.8% (95% CI: 76.8–89.8%; p=0.76)] in decompensated patients, which was also true in subgroup analyses for each regimen within the same treatment duration. However, adding ribavirin significantly increased the frequency of adverse events from 52.9% (95% CI: 28.0–77.1) to 89.2% (95% CI: 68.1–99.9) and frequency of severe events. The pooled incidence of hepatocellular carcinoma and case-fatality of decompensated patients were 3.1% (95% CI: 1.5–5.0) and 4.6% (95% CI: 3.1–6.3), respectively. The overall heterogeneity was high. There was no publication bias.

The analysis found that 12 weeks of SOF/velpatasvir without ribavirin is the preferred therapy, with a significantly higher SVR compared with other SOF-based regimens in decompensated HCV patients.

Follicular cell derived thyroid carcinomas, including papillary thyroid carcinoma and follicular thyroid carcinoma, are common in daily pathology practice and the incidence of this entity is dramatically increased due to the wide application of more sensitive diagnostic procedures. However, uncommon presentations of thyroid cancers can be seen occasionally and without awareness of those scenarios, traps, and pitfalls that can easily compromise the patient's care. We reviewed the English literature through PubMed search based on three uncommon presentations identified during our routine diagnostic service for patients with or without thyroid nodules: (1) Phosphatase and tensin homolog immunoreactivity loss initially identified on common follicular nodules, and follicular thyroid carcinoma leading to the identification of a phosphatase and tensin homolog hamartoma tumor syndrome, (2) metastatic thyroid carcinoma incidentally identified in the specimens of neck lymph node dissection of head and neck squamous cell carcinoma, and (3) a papillary thyroid carcinoma incidentally identified in the specimen of laterally located thyroglossal duct cyst. We discussed the representative case scenarios, which include clinicopathologic, immunophenotypic, some with genomic features, diagnostic pearls, and patient management. Follicular cell-derived thyroid carcinoma is commonly diagnosed at a younger age than most other adult cancers. The awareness of those pitfalls would significantly improve the diagnostic accuracy leading to better patient outcomes.

Surgical specimens resulting from a spontaneous pneumothorax (SP) are commonly encountered in the general surgical pathology practice. Many of the SP cases are primary pneumothorax with no underlying lung diseases. Specimens with primary pneumothorax show nonspecific pneumothorax-related changes, which are important to recognize to exclude the true underlying lung diseases. A variety of disease entities may lead to diffuse cystic changes in the lungs, causing secondary pneumothorax. Some of the diseases are progressive and can cause irreversible damage to the lungs if not treated timely. Diagnosis of cystic lung diseases causing secondary pneumothorax is important for the treatment of the diseases and the prevention of future episodes of pneumothorax. Lymphangioleiomyomatosis and Langerhans cell histiocytosis are two common conditions causing diffuse cystic changes in the lungs. They are discussed in greater detail in this review, given their overlapping features in patient characteristics, radiological findings, and pathologic findings.

Extracellular vesicles (EVs) are vesicular bodies that bud off from the cell membrane or are secreted virtually by all cell types. Small EVs (sEVs or exosomes) are key mediators of cell-cell communication by delivering their cargo, including proteins, lipids, or RNAs, to the recipient cells where they induce changes in signaling pathways and phenotypic properties. Tangible findings have revealed the pivotal involvement of sEVs in the pathogenesis of various diseases. On the bright side, they are rich sources of biomarkers for diagnosis, prognosis, treatment response, and disease monitoring. sEVs have high stability, biocompatibility, targetability, low toxicity, and are immunogenic in nature. Their intrinsic properties make sEVs an ideal delivery vehicle to be loaded with cargo for therapeutic interventions. Liver diseases are a major global health problem. This review aims to focus on the roles and mechanisms of sEVs in the pathogenesis of liver diseases, liver injury, liver failure, and liver cancer. sEVs are released not only by hepatocytes but also by stromal and immune cells in the microenvironment. Early detection of liver disease determines the chance for curative treatment and high survival of patients. This review focuses on the potential of circulating sEV cargo as specific and sensitive noninvasive biomarkers for the early detection and prognosis of liver diseases. In addition, the therapeutic use of sEVs derived from various cell types is discussed. Although sEVs hold promise for clinical applications, there are still challenges to be overcome by further research to bring utilization of sEVs into clinical practice.

The prevalence of conventional and new pathogenic types of allergies is increasing. For the last few years, new atopic disorders – local allergic rhinitis (LAR), local allergic asthma, “dual” allergic rhinitis, and local allergic conjunctivitis – have been described. In particular, LAR was identified a decade ago, whereas its immunopathogenesis is still unclear. Nevertheless, the network of immune cells and neurons determining the maintenance or breakdown of allergen tolerance has partially been studied. Therefore, this field of research is currently at the cutting edge. However, there is still not any definitive answer as to why local disorders take place. Specifically, the nasal cavity is characterized by the following prevalent neuro molecules: acetylcholine, norepinephrine, substance P, neuromedin U, vasoactive intestinal peptide, and calcitonin-gene-related peptide; some of which are pro-immunogenic and a slightly smaller part is protolerogenic. In the spotlight, the hypothesis of an autonomous breakdown of tolerance to allergens in LAR is presented. The article describes immune tolerance as the antipode of the active immune response, which does not lead to producing effector cells and molecules, and vice versa is based on active immunosuppressive processes. In addition, this article focuses on the mechanisms of the maintenance and breakdown of allergen tolerance, a form of immune tolerance, at the nasal level and throughout the body, and the essential role of various cells and molecules, including neuro molecules, in the pathogenesis of LAR.