Light-chain amyloidosis with dysphagia as the main symptom: a case report.

BACKGROUND: Immunoglobulin light-chain amyloidosis is a relatively rare condition with a worldwide incidence of 5.1-12.8 cases per million person-years (Baker, 2022). It is characterized by a clonal population of immunoglobulin-secreting cells that produce a monoclonal light chain of κ or λ type as either an intact molecule or a fragment. CASE PRESENTATION: A 69-year-old East Asian (Chinese) male patient who presented with progressive dysphagia visited multiple hospitals repeatedly for more than 2 years and was finally diagnosed with immunoglobulin light-chain amyloidosis. CONCLUSIONS: Otolaryngologists should consider immunoglobulin light-chain amyloidosis when encountering suspicious clinical manifestations and intervene early to avoid misdiagnosis.

Soluble biomarkers for immune checkpoint inhibitor-related encephalitis: A mini-review.

Immune checkpoint inhibitors lead to effective antitumour responses but also to immune-related adverse events (irAEs), which affect the nervous system in 1-5% of patients. Encephalitis is the most frequent central nervous system irAE and is clinically relevant due to its high severity and mortality. Early diagnosis is crucial but is hampered by the broad list of alternative diagnoses, the lack of established diagnostic criteria, and the need of extensive diagnostic procedures (e.g., spinal tap, brain MRI) alongside expert neurological evaluation. Additionally, the response to corticosteroids is inconsistent, and the management of corticosteroid-refractory patients remains poorly defined. This mini-review discusses the role of various soluble biomarkers in the diagnosis, prognostication, and management of ICI-encephalitis. Neural antibodies, which are well-established biomarkers of autoimmune and paraneoplastic encephalitis, are found in only a subset of ICI-encephalitis, in which they can aid to establish the diagnosis. The most prevalent are paraneoplastic neurological syndromes (PNS)-associated antibodies, which are found almost exclusively in focal ICI-encephalitis syndromes and are associated with poor outcomes, possibly due to predominantly cytotoxic T cell involvement leading to irreversible neuronal loss. Beside antibodies, serum brain injury biomarkers such as NfL and S100B are elevated in ICI-encephalitis and, even if non-specific, may be useful as a routine test to quickly identify patients in whom neurological evaluation and second-level diagnostic procedures should be prioritized. Additionally, higher serum and CSF NfL levels have been associated with lack of treatment response in ICI-encephalitis, suggesting they may have a prognostic role. Among cytokines, elevated interleukin 6 (IL6) levels have been observed in serum and/or CSF samples of some patients with ICI-encephalitis, but the role of IL6 as a biomarker for response to IL6-directed therapies requires further investigation. Likewise, the value of other biomarkers, including T cells markers and HLA haplotypes, still needs to be evaluated in large cohorts. Overall, neural antibodies are important diagnostic and prognostic biomarkers in ICI-encephalitis, and other soluble biomarkers, especially NfL, deserve further investigation since they have a promising application in clinical practice.

Fluorescence-activated droplet sequencing (FAD-seq) directly provides sequences of screening hits in antibody discovery.

Droplet microfluidics has become a very powerful tool in high-throughput screening, including antibody discovery. Screens are usually carried out by physically sorting droplets hosting cells of the desired phenotype, breaking them, recovering the encapsulated cells, and sequencing the paired antibody light and heavy chain genes at the single-cell level. This series of multiple consecutive manipulation steps of rare screening hits is complex and challenging, resulting in a significant loss of clones with the desired phenotype or large fractions of cells with incomplete antibody information. Here, we present fluorescence-activated droplet sequencing, in which droplets showing the desired phenotype are selectively picoinjected with reagents for RT-PCR. Subsequently, light and heavy chain genes are natively paired, fused into a single-chain fragment variant format, and amplified before off-chip transfer and downstream nanopore sequencing. This workflow is sufficiently sensitive for obtaining different paired full-length antibody sequences from as little as five droplets, fulfilling the desired phenotype. Replacing physical sorting by specific sequencing overcomes a general bottleneck in droplet microfluidic screening and should be compatible with many more applications.

Neurofilament light chain as a promising biomarker for depression diagnosis: a systematic review and meta-analysis.

BACKGROUND: Depression is a prevalent and serious mental health disorder that significantly impacts daily life and functioning. Neurofilament Light chain (NfL), associated with axonal neuronal damage, has been identified as a promising biomarker, potentially aiding in early diagnosis of depression, personalized treatment, and tracking disease progression. This study used meta-analysis to evaluate the potential of plasma NfL as a biomarker for depression patients. METHODS: A systematic search following the PRISMA guidelines was conducted across PubMed, Web of Science, Scopus, and Google Scholar databases to find relevant studies on plasma NfL levels in patients with depression. A random effects model meta-analysis was applied to determine its potential as a biomarker for differentiating patients from controls. RESULTS: Our meta-analysis, based on four articles with six datasets, revealed that plasma NfL levels were notably higher in individuals with depression (228 cases) compared to healthy controls (118 individuals). The weighted mean difference (WMD) was 8.78 (95% CI: 5.28, 12.28; P < 0.01), indicating a significant effect size. Given the diverse confounding factors inherent in the included observational studies, the observed variability can be attributed to these influences. Due to the observed heterogeneity (heterogeneity Chi-Square: 54.91, p < 0.05), we performed a subgroup analysis. Subgroup analyses based on depression type and analysis method consistently supported the association between NfL and depression, strengthening the evidence. CONCLUSION: Our meta-analysis demonstrates that elevated NfL levels may serve as a promising biomarker for diagnosing depressive disorders. Further research on diverse subtypes and longitudinal changes is needed to validate its clinical utility.

A Case of Solitary Amyloid Lung Nodule Treated With Surgery.

Primary or light-chain (AL) (lambda) amyloidosis is a rare systemic disorder that is characterized by the misfolding of autologous proteins and the extracellular deposition of abnormally folded proteins composed of immunoglobulin light chains, often caused by plasma cell dyscrasias. We present a unique case of a 57-year-old female with multiple comorbidities, including extensive smoking history and chronic kidney disease, who was incidentally discovered to have a left upper lobe lung nodule on a chest X-ray prompted by complaints of shortness of breath. The patient underwent biopsy of the lung nodule, and by utilizing the gold standard diagnostic technique of a Congo red stain, positive test results confirmed the diagnosis of AL amyloidosis. However, additional investigations, including bone marrow and fat pad biopsies, were negative for plasma cell dyscrasias. The patient subsequently underwent a wedge resection of the nodule, and a follow-up positron emission tomography-computed tomography (PET-CT) scan showed only post-surgical changes in the left upper lobe of the lung without evidence of disease progression or systemic involvement. Given the asymptomatic and multisystem symptomology of most cases, treatment options for AL amyloidosis are individualized. This case discusses pulmonary nodular AL amyloidosis and highlights the diagnostic and treatment options for this disorder.

Periorbital purpura can be the only initial symptom of primary light chain amyloidosis: A case report.

BACKGROUND: Primary light chain amyloidosis is a rare and complex disease with complex clinical features and is highly susceptible to misdiagnosis and underdiagnosis in the early stages. CASE SUMMARY: We report a case of a 47-year-old female patient whose only initial symptom was periorbital purpura, which was not taken seriously enough. As the disease progressed, pleural effusion gradually appeared, and after systematic diagnosis and treatment, she was diagnosed with "primary light chain amyloidosis". She achieved rapid hematological remission after treatment with a daratumumab + bortezomib + cyclophosphamide + dexamethasone regimen. CONCLUSION: Periorbital purpura can be the only initial symptom of primary light chain amyloidosis; we should pay attention to the cases where the initial clinical symptoms are only periorbital purpura.

Carvedilol Activates a Myofilament Signaling Circuitry to Restore Cardiac Contractility in Heart Failure.

Phosphorylation of myofilament proteins critically regulates beat-to-beat cardiac contraction and is typically altered in heart failure (HF). ß-Adrenergic activation induces phosphorylation in numerous substrates at the myofilament. Nevertheless, how cardiac ß-adrenoceptors (ßARs) signal to the myofilament in healthy and diseased hearts remains poorly understood. The aim of this study was to uncover the spatiotemporal regulation of local ßAR signaling at the myofilament and thus identify a potential therapeutic target for HF. Phosphoproteomic analysis of substrate phosphorylation induced by different ßAR ligands in mouse hearts was performed. Genetically encoded biosensors were used to characterize cyclic adenosine and guanosine monophosphate signaling and the impacts on excitation-contraction coupling induced by ß1AR ligands at both the cardiomyocyte and whole-heart levels. Myofilament signaling circuitry was identified, including protein kinase G1 (PKG1)-dependent phosphorylation of myosin light chain kinase, myosin phosphatase target subunit 1, and myosin light chain at the myofilaments. The increased phosphorylation of myosin light chain enhances cardiac contractility, with a minimal increase in calcium (Ca2+) cycling. This myofilament signaling paradigm is promoted by carvedilol-induced ß1AR-nitric oxide synthetase 3 (NOS3)-dependent cyclic guanosine monophosphate signaling, drawing a parallel to the ß1AR-cyclic adenosine monophosphate-protein kinase A pathway. In patients with HF and a mouse HF model of myocardial infarction, increasing expression and association of NOS3 with ß1AR were observed. Stimulating ß1AR-NOS3-PKG1 signaling increased cardiac contraction in the mouse HF model. This research has characterized myofilament ß1AR-PKG1-dependent signaling circuitry to increase phosphorylation of myosin light chain and enhance cardiac contractility, with a minimal increase in Ca2+ cycling. The present findings raise the possibility of targeting this myofilament signaling circuitry for treatment of patients with HF.

Application of Silk Light Chain on a Graphene Composite Surface: A Molecular Dynamics and Electrochemical Experiment.

The surface functionalization of pristine graphene (PG) with beneficial biocomposites is important for biomedical and tissue engineering. This study introduces silk light chain as novel biocomposites to increase the biocompatibility of PG. We explored the supramolecular structures of the silk heavy and light chains. Through molecular dynamics, we compared and analyzed the structural effects and binding mechanisms of these domains in their interaction with PG. Our results highlighted a significant hydrophobic interaction between the silk light chain and PG, without structural collapse. The supramolecular structure of the silk light chain was identified by analyzing the amino acids bound to PG. Moreover, using the silk light chain, the hydrophobic surface of PG has changed to a hydrophilic surface, and the silk light-chain-PG electron transfer rate was evaluated for the graphene congeners: graphene oxide (GO) and reduced graphene oxide. Therefore, we are confident that the dispersibility and biocompatibility of PG can be increased using silk light chains, which will contribute to broadening the field of application of PG-based materials.

Association between serum neurofilament light chains and depression: A cross-sectional study based on NHANES 2013-2014 database.

BACKGROUND: Serum neurofilament light chain (sNfl), identified as a promising biomarker, is a protein released into the bloodstream post-axonal damage. Studies on its correlation with depression, however, remains scarce. The purpose of this study was to investigate the potential relationship between sNfL levels and risk of depression among a representative segment of the U. S. populace. METHODS: This study included 1,909 participants from the 2013-2014 National Health and Nutrition Examination Survey. The 9-item Patient Health Questionnaire (PHQ-9 scale) assessed depression symptoms, while sNfl concentrations were measured using the Attelica fully automated immunoassay system. The logistic regression, restricted cubic splines (RCS), and subgroup analysis were performed to assess the relationship between sNfL, lnsNfL (log-transformed values of sNfl), and depression. RESULTS: After adjusting for sociodemographic variables, lifestyle, and chronic conditions, sNfl and lnsNfL levels positively correlated with depression. A unit increase in sNfL and lnsNfL levels was linked to a 0.7 % and 33.8 % rise in depression risk, respectively [OR (95 % CI): 1.007 (1.000, 1.014), p = 0.041 for sNfl; 1.338 (1.015, 1.764), p = 0.039 for lnsNfl]. Additionally, a positive linear association was observed between lnsNfl levels and the risk of depression (p for overall = 0.039, p for nonlinear = 0.189 in RCS). No significant differences were observed across subgroups between lnsNfl and depression, with no significant impact on this relationship from subgroups (All p for interaction >0.05). CONCLUSION: The findings of our study suggest a significant positive correlation between sNfl and depression, warranting further investigation into the molecular dynamics linking sNfL to depression and subgroup variability.

AB017. NFκB1 regulates FDX1 to facilitate elesclomol-induced cuproptosis against glioblastoma.

BACKGROUND: Ferredoxin 1 (FDX1) plays key roles in promoting elesclomol-induced cuproptosis against cancer, whether it has the potential to be a new therapeutic strategy against glioblastoma has not yet been clarified. METHODS: Glioblastoma cells were treated with elesclomol (20 nM/L) and copper chloride (2 µM/L), and then cell proliferation, migration, and invasion were evaluated by CCK-8, clonogenic and transwell assay. Western blot was performed to detect the expression of cuproptosis-relating proteins FDX1, lipoylated dihydrolipoamide S-acetyltransferase (DLAT), copper transport ATPase (ATP7A), heat shock protein 70 (HSP70), apoptotic markers B cell lymphoma-2 (BCL-2) associated X protein (Bax), and BCL-2, as well as the pan-apoptotic/death markers gasdermin D (GSDMD), solute carrier family 7 member 11 (SLC7A11). The effects of knockdown and overexpression of FDX1 on cell proliferation, migration, and invasion were observed. Bioinformatic analysis was performed to predict the corresponding transcription factors regulating FDX1 expression, and verified by dual luciferase assay. The regulatory relationship between FDX1 and its transcription factors was verified by rescue experiment and further evaluated in vivo. RESULTS: Elesclomol had obvious inhibitory effects on the proliferation, migration, and invasion capacities of tumor cells in a dose-dependent manner. When combined with copper chloride, the inhibitory effects on tumor cells were significantly higher both in vitro and in vivo. FDX1 expression was negatively correlated with overall survival of patients. Nuclear factor κ-light-chain enhancer of activated B cell 1 (NFκB1) was the transcription factor of FDX1 verified by dual luciferase assay. Both FDX1 and NFκB1 were highly expressed in glioblastoma. Knockdown of FDX1 or NFκB1 down-regulated proliferation, migration, and invasion abilities of tumor cells, and increased after FDX1 overexpression. FDX1 expression decreased correspondingly after NFκB1 knockdown. Up-regulation of FDX1 promoted elesclomol-induced cuproptosis against glioblastoma both in vitro and in vivo. FDX1 knockdown can reverse the inhibitory effect of elesclomol on tumor cells. CONCLUSIONS: Elesclomol inhibits glioblastoma development via inducing cuproptosis, regulated by NFκB1/FDX1 axis.

Current and Emerging Immunotherapies for Systemic AL Amyloidosis.

Systemic light-chain (AL) amyloidosis is a rare and complex clonal plasma cell neoplasm characterized by the production of misfolded and unstable immunoglobulin light-chains leading to multisystem amyloid deposition, which progresses to organ dysfunction and eventual failure. The importance and urgency of AL amyloidosis depends on its potential to induce significant organ impairment, progressive course, risk of life-threatening complications, and the limited treatment options available. Treatment options and prognosis depend on the number and severity of organ involvement at the time of diagnosis with cardiac involvement carrying the worst outcomes. The treatments aim to target eliminating the underlying clonal plasma cell neoplasm and prevent the production and deposition of amyloid precursor immunoglobulin light-chain protein in the affected vital organs. Strategies for treating systemic AL amyloidosis have incorporated anti-plasma cell therapies approved in the management of multiple myeloma due to their shared cellular derivation. Quadruplet therapy of cyclophosphamide, bortezomib, dexamethasone and daratumumab (DaraCyborD) is the currently approved first-line induction therapy for systemic AL amyloidosis. Some patients need upfront autologous hematopoietic stem cell transplantation (HSCT) after high-dose melphalan conditioning particularly if DaraCyborD is not able to achieve complete hematologic response (CHR). Additionally, a promising treatment option involves disassembling amyloid deposits from the vital organs using monoclonal antibodies such as CAEL 101 or Birtamimab with the expectation of restoring damaged tissues of the vital organs affected thereby improving or reversing patients' symptoms. Both CAEL 101 and Birtamimab are currently being tested in phase 3 clinical trials for systemic AL amyloidosis patients with advanced cardiac involvement. This comprehensive review provides an up-to-date overview of AL amyloidosis therapy, with a particular focus on recent advances and future directions of immunotherapeutic strategies.

Sex-Biased Associations of Circulating Ferroptosis Inhibitors with Reduced Lipid Peroxidation and Better Neurocognitive Performance in People with HIV.

Ferroptosis is implicated in viral neuropathogenesis and may underlie HIV-associated neurocognitive impairment (NCI). Emerging data also suggest differences in brain iron transport by sex. We hypothesized that circulating ferritins that inhibit ferroptosis associate with neurocognitive function and NCI in people with HIV (PWH) in a sex-biased manner. Serum ferritin heavy-chain-1 (FTH1), ferritin light-chain (FTL), and urinary F2-isoprostanes (uF2-isoPs, specific lipid peroxidation marker) were quantified in 324 PWH (including 61 women) with serial global (NPZ-4) and domain-specific neurocognitive testing. Biomarker associations with neurocognitive test scores and NCIs were evaluated by multivariable regression; correlations with uF2-isoPs were also assessed. Higher FTL and FTH1 levels were associated with less NCI in all PWH (adjusted odds ratios 0.53, 95% confidence interval (95% CI) 0.36-0.79 and 0.66, 95% CI 0.45-0.97, respectively). In women, higher FTL and FTH1 were also associated with better NPZ-4 (FTL adjusted beta (ß) = 0.15, 95% CI 0.02-0.29; FTL-by-sex ßinteraction = 0.32, p = 0.047) and domain-specific neurocognitive test scores. Effects on neurocognitive performance persisted for up to 5 years. Levels of both ferritins correlated inversely with uF2-isoPs in women (FTL: rho = -0.47, p < 0.001). Circulating FTL and FTH1 exert sustained, sex-biased neuroprotective effects in PWH, possibly by protecting against iron-mediated lipid peroxidation (ferroptosis). Larger studies are needed to confirm the observed sex differences and further delineate the underlying mechanisms.

Alzheimer's Disease-Related Cerebrospinal Fluid Biomarkers in Progressive Supranuclear Palsy.

Progressive Supranuclear Palsy (PSP) is the most common four-repeat tauopathy. PSP cases are typically characterized by vertical gaze palsy and postural instability; however, various phenotypes have been reported, making antemortem diagnosis based on clinical symptoms challenging. The development of biomarkers reflecting brain pathology and the ability to diagnose patients based on these biomarkers are essential for developing future intervention strategies, including disease-modifying therapies. However, despite many dedicated efforts, no highly specific fluid biomarker for PSP has yet been established. Conversely, several cerebrospinal fluid (CSF) biomarkers of Alzheimer's Disease (AD) have been established, and an AT(N) classification system has been proposed. Typically, among patients with AD, CSF amyloid ß42 (Aß42), but not Aß40, is decreased, resulting in a reduction in the Aß42/Aß40 ratio, while tau phosphorylated at threonine 181 (p-tau181) and total tau (t-tau) are increased. Interestingly, the core CSF AD biomarkers show unique patterns in patients with PSP. Furthermore, reports have indicated that the CSF levels of both Aß42 and Aß40 are decreased independently of Aß accumulation in PSP. Therefore, the Aß42/Aß40 ratio could potentially be used to differentiate PSP from AD. Additionally, studies have reported that CSF p-tau and t-tau are reduced in PSP, and that the neurofilament light chain is remarkably increased compared to healthy controls and patients with AD, even though PSP is a neurodegenerative disease associated with tau accumulation. These PSP-specific changes in AD-related core biomarkers may reflect the pathology of PSP and contribute to its diagnosis. As such, elucidating the mechanisms underlying the observed decreases in Aß and tau levels could facilitate a better understanding of the pathogenesis of PSP.

An updated AL-Base reveals ranked enrichment of immunoglobulin light chain variable genes in AL amyloidosis.

Background: Each monoclonal antibody light chain associated with AL amyloidosis has a unique sequence. Defining how these sequences lead to amyloid deposition could facilitate faster diagnosis and lead to new treatments. Methods: Light chain sequences are collected in the Boston University AL-Base repository. Monoclonal sequences from AL amyloidosis, multiple myeloma and the healthy polyclonal immune repertoire were compared to identify differences in precursor gene use, mutation frequency and physicochemical properties. Results: AL-Base now contains 2,193 monoclonal light chain sequences from plasma cell dyscrasias. Sixteen germline precursor genes were enriched in AL amyloidosis, relative to multiple myeloma and the polyclonal repertoire. Two genes, IGKV1-16 and IGLV1-36, were infrequently observed but highly enriched in AL amyloidosis. The number of mutations varied widely between light chains. AL-associated κ light chains harbored significantly more mutations compared to multiple myeloma and polyclonal sequences, whereas AL-associated λ light chains had fewer mutations. Machine learning tools designed to predict amyloid propensity were less accurate for new sequences than their original training data. Conclusions: Rarely-observed light chain variable genes may carry a high risk of AL amyloidosis. New approaches are needed to define sequence-associated risk factors for AL amyloidosis. AL-Base is a foundational resource for such studies.

Lambda light chain - restricted non - crystalline proximal tubulopathy with cast nephropathy in multiple myeloma: a case report and literature review.

BACKGROUND: Multiple myeloma (MM) often causes renal tubular damage, such as the light chain cast nephropathy (LCCN) and the light chain proximal tubulopathy (LCPT). The excessive light chains deposited in the proximal and distal tubules usually manifest with different characteristics, leading to a rare coexistence of the two pathological conditions. Here we report a unique case of a patient with multiple myeloma (MM) who presented with acute kidney injury (AKI) due to dual conditions of λ light chain-restricted non-crystalline LCPT and LCCN. This report reviews the clinical presentation and histological findings, comparing them with previously published cases. CASE PRESENTATION: A 49-year-old male patient was admitted with a chief complaint of "fatigue, loss of appetite for 40 days and elevated blood creatinine for 10 days." In serum and urine, the λ light chain level and the ratio of κ to λ free light chain were 1235 mg/dl and 93.25 mg/dl, 0.0022 and 0.0316, respectively. Additionally, serum protein electrophoresis showed an M-spike with monoclonal IgD-λ. Bone marrow puncture revealed 30.5% primitive naive plasma cells, indicative of IgD-λ MM. Light microscopy of kidney biopsy specimen showed periodic acid-Schiff (PAS)-negative cytoplasm in some proximal tubules and PAS-negative casts with a rigid appearance in some distal tubule lumens. On immunofluorescence, these proximal tubular epithelial cells cytoplasm and casts stained exclusively with λ-light chains. Electron microscopy did not reveal any crystalline inclusions. Given the clinical and bone marrow puncture findings, the overall pathological presentation was LCPT with LCCN secondary to IgD-λ MM. After chemotherapy and dialysis, the patient's condition was improved and he was tracked in follow-ups. CONCLUSION: In some tubular renal injuries caused by MM, the morphological changes are subtle and often overlooked. In this paper, we present a rare case of LCPT with LCCN showing λ restriction in patient with MM. Through the clinicopathological analysis of patients, the understanding of the disease can be deepened and the diagnosis rate improved.

Imaging modalities in cardiac amyloidosis.

Cardiac amyloidosis (CA) is an infiltrative restrictive cardiomyopathy caused by the deposition of amyloid fibrils in the myocardium, presenting primarily as transthyretin cardiac amyloidosis (ATTR) and immunoglobulin light chain cardiac amyloidosis (AL). ATTR is further classified into wild-type (ATTRwt) and hereditary (ATTRv) based on transthyretin gene mutation. The disease is increasingly recognized as a significant cause of heart failure. Advances in diagnostic modalities, including electrocardiography, echocardiography, cardiac magnetic resonance imaging, and technetium pyrophosphate scintigraphy, have revolutionized the non-invasive diagnosis of CA. While ATTR can often be diagnosed with scintigraphy, AL typically requires histological confirmation. This review explores these diagnostic tools, emphasizing their role in early detection and quantification of disease burden, which are crucial for timely treatment and prognostication. This comprehensive overview aims to aid clinicians in efficiently diagnosing CA, ultimately improving patient outcomes.

Diagnostic value of six plasma biomarkers in progressive supranuclear palsy, multiple system atrophy, and Parkinson's disease.

OBJECTIVES: This study aimed to evaluate the diagnostic ability of six plasma biomarkers in progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and different subtypes of Parkinson's disease (PD). METHODS: Neurofilament light chain (NfL), phosphorylated tau-181, glial fibrillary acidic protein (GFAP), amyloid-ß 42 (Aß42), and amyloid-ß 40 (Aß40) levels were measured using the single-molecule array (Simoa) technique in a cohort of patients with PSP, MSA, different subtypes of PD, and healthy controls (HCs). RESULTS: Plasma NfL and GFAP levels were beneficial in discriminating between the disease groups and HCs. Plasma NfL, Aß42, and Aß40 could distinguish atypical Parkinsonian syndrome (APS) from PD and its subtypes. GFAP could discriminate APS from tremor dominant PD but could not discriminate APS from postural instability and gait disorder dominant PD. The efficacy of differentiation improved when a combination of multiple plasma biomarkers was applied. CONCLUSIONS: In this study, the plasma biomarkers NfL, GFAP, Aß42, and Aß40 exhibited high discriminatory diagnostic value in PD and APS, and could be used as clinically potential diagnostic biomarkers. Plasma biomarker combinations could improve the differential diagnostic efficacy in the comparisons of PD and APS.

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OBJECTIVES: The expression of serum free light chain (FLC) is abnormal in various diseases, but its role in lung cancer remains unclear. This study aims to investigate the expression and diagnostic value of serum FLC in lung cancer. METHODS: A total of 80 lung cancer patients treated at Xiangdong Hospital, Hunan Normal University from January to December 2021 were selected as the lung cancer group. Another 80 healthy individuals undergoing routine physical examinations during the same period were chosen as the control group. General information and serum κFLC and λFLC levels were collected for all subjects. Clinical indicators such as serum carcinoembryonic antigen (CEA), cytokeratin fragment antigen 21-1 (CYFRA21-1) levels, tumor diameter, histological type, TNM stage, and lymph node metastasis status were recorded for lung cancer patients. The expression levels of serum FLC [κFLC, λFLC, and FLC (κ+λ)] were compared between the lung cancer group and the control group. Lung cancer patients were grouped based on gender, age, smoking history, tumor diameter, TNM stage, histological type, and lymph node metastasis to compare differences in serum κFLC and λFLC levels. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic value of serum FLC alone and in combination with other indicators in lung cancer. RESULTS: The expression levels of serum FLC (κ+λ) and κFLC were significantly higher in the lung cancer group than those in the control group (both P<0.001), while there was no significant difference in serum λFLC levels between the 2 groups (P>0.05). There were no significant differences in serum κFLC levels among lung cancer patients with different tumor diameters, histological types, or TNM stages (all P>0.05); however, serum κFLC levels were higher in lung cancer patients with lymph node metastasis than in those without, with statistical significance (P=0.033). There were no significant differences in serum λFLC levels based on tumor diameter or histological type (both P>0.05), but serum λFLC levels were higher in stage III+IV and lymph node metastatic lung cancer patients compared to stage I+II and non-metastatic patients, with statistical significance (P=0.033 and P=0.019, respectively). The area under the curve (AUC) for κFLC and CEA in diagnosing lung cancer showed no significant difference (P=0.333). The combination of κFLC+CYFRA21-1 had the highest diagnostic efficacy (AUC=0.875) and sensitivity (71.3%). The AUC for the combined diagnosis of κFLC+λFLC+CEA+CYFRA21-1 was 0.915 (95% CI 0.860 to 0.953, P<0.001). CONCLUSIONS: Serum FLC is highly expressed in lung cancer and is associated with its invasion and metastasis. Serum FLC, particularly κFLC, has diagnostic value for lung cancer, and the combined detection of FLC, CEA, and CYFRA21-1 offers the best diagnostic efficacy.