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peptide science.

B cell-driven refractory hemocytopenia in immune checkpoint inhibitor therapy: a report of two cases.

Transl Lung Cancer Res

Feng Li, Chunyan Wang, Guohua Yao +4 more

The integration of immune checkpoint inhibitors (ICIs) with chemotherapy has revolutionized lung cancer treatment, yet it amplifies the risk of severe hematologic toxicities.

Immune signaling and function in neurodegeneration.

J Clin Invest

Yvonne L Latour, Dorian B McGavern

Neurodegenerative diseases arise from interactions among pathogenic proteins, immune responses, and diverse environmental or age-related stressors that disrupt CNS homeostasis. CNS resident microglia detect self-derived danger signals through pattern recognition receptors, and their activation can promote clearance of aberrant proteins, including amyloid-β, tau, α-synuclein, and TAR DNA-binding protein 43. However, microglial activation may also drive maladaptive states that amplify neuroinflammation. Microglial transitions are further shaped by receptor-mediated signaling and antigen presentation pathways that integrate environmental cues with functional responses. Adaptive immune cells contribute additional layers of regulation, with CD8+ and CD4+ T cells exerting neuroprotective or neurotoxic effects depending on disease context, activation state, and antigen specificity. The identification of granzyme K-expressing CD8+ T cells in several neurodegenerative conditions highlights the growing recognition that distinct T cell subsets may have specialized roles in disease. Aging, repetitive head injury, and viral infection further alter microglial phenotypes, weaken barrier integrity, promote T cell recruitment, and prime the CNS for chronic inflammation. In this review, we synthesize current knowledge of innate and adaptive immune mechanisms in neurodegeneration, examine how external factors influence these responses, and consider how these insights may guide future therapeutic strategies.

Impact of endogenous LH and LH supplementation on clinical outcome following a long GnRH agonist protocol in younger and older patients.

Front Endocrinol (Lausanne)

Jing Chen, Huiliu Fan, Qiuyue Wen +5 more

The optimal luteinizing hormone (LH) concentration on the day of hCG trigger during long-protocol IVF/ICSI remains uncertain. Although some studies associate profound LH suppression with impaired reproductive outcomes, others report no adverse effects. Importantly, most existing evidence does not consider maternal age as a potential effect modifier, despite its well established role in ovarian response and oocyte competence.

Nuclear Translocation of IGF1R Induces Cell Cycle Re-entry via Cyclin D1 Regulation in an Aβ-Driven Alzheimer's Disease Model.

Mol Neurobiol

Priyanka Sengupta, Debashis Mukhopadhyay

Alzheimer's disease (AD) involves progressive neurodegeneration, with abnormal receptor signaling and disrupted cell-cycle activity leading to neuronal loss. Here, we identify a previously unknown mechanism linking β-amyloid (Aβ) exposure to the nuclear translocation of the Insulin-like Growth Factor 1 Receptor (IGF1R) in differentiated SH-SY5Y neuronal cells. The differentiated cholinergic model induced by retinoic acid and BDNF expresses acetylcholinesterase (AChE) and indicates that under amyloidogenic stress, IGF1R may transition from homeostatic membrane and vesicular signaling to a nuclear-centric function. We show that prolonged Aβ treatment causes phosphorylation-dependent nuclear import of IGF1R, confirmed by confocal imaging and biochemical fractionation. IGF1R is conventionally located in the membrane and vesicular membranes; however, under amyloidogenic stress, we show here that it is imported to the nucleus and exerts transcriptional control. The buildup of nuclear IGF1R coincided with increased Cyclin D1 levels and redistribution of neurons into S and G₂ phases, indicating abnormal cell-cycle re-entry. Chromatin immunoprecipitation demonstrated increased IGF1R binding at the CCND1 and JUN promoters after Aβ exposure, suggesting a direct role in gene transcription. Pharmacological blockade of IGF1R phosphorylation by PPP or SUMOylation by Ginkgolic acid significantly reduced Cyclin D1 elevation, implying that both post-translational modifications are involved in receptor nuclear trafficking. Co-immunoprecipitation and confocal imaging identified Nucleophosmin (NPM1) as a putative IGF1R interacting partner, potentially contributing to its nuclear transport and stabilizing receptor-chromatin complexes. These results establish IGF1R as a signaling-transcription connector linking extracellular amyloid stress to nuclear gene regulation, providing a mechanistic explanation for faulty neuronal cell-cycle re-entry in AD. We suggest that abnormal IGF1R-NPM1 interactions contribute to receptor mislocalization and cell-cycle failure, highlighting new targets for therapeutic intervention aimed at receptor trafficking and neuroprotection in Alzheimer's disease.

Novel evidence for tirzepatide, a dual GLP-1/GIP receptor agonist, to reduce the motivation for cocaine in rodents.

EBioMedicine

Lori A Knackstedt

[Protective effect and mechanism of TSPAN9-mediated mitocytosis in interleukin-1β-induced rat chondrocyte senescence].

Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi

Quan Chen, Wacili Da, Naijia Luo +1 more

To investigate the regulatory role and molecular mechanisms of TSPAN9-mediated mitocytosis in an interleukin-1β (IL-1β)-induced rat chondrocyte senescence model, and to identify novel therapeutic targets for osteoarthritis (OA).

Delayed-onset central adrenal insufficiency following adjuvant pembrolizumab therapy for renal cell carcinoma.

BMJ Case Rep

Naseem Eisa

This report describes a woman in her early 70s who developed severe central adrenal insufficiency 11 months after completing 1 year of adjuvant pembrolizumab for resected clear cell renal cell carcinoma. She presented with debilitating fatigue, profound weakness, unintentional weight loss and hypotension. Because these symptoms were non-specific and emerged long after immunotherapy discontinuation, the diagnosis was delayed for several months. Laboratory testing showed a markedly suppressed morning cortisol with an inappropriately low adrenocorticotropic hormone (ACTH) level and no response to cosyntropin, confirming central adrenal insufficiency. Other pituitary hormone axes remained intact, consistent with isolated ACTH deficiency. Imaging demonstrated adrenal atrophy, supporting chronic central adrenal insufficiency. The patient improved rapidly after starting hydrocortisone replacement. This case highlights a prolonged interval between checkpoint inhibitor cessation and endocrine toxicity, emphasising the importance of continued surveillance for late-onset immune-related endocrinopathies even after therapy completion.

Extracellular Matrix-Derived Matrikines: Circulating Peptides as Candidate Mediators of Lung-to-Brain Signaling.

Int J Mol Sci

Andis Klegeris

Recent studies support the concept of a bidirectional lung-brain axis. While neural, immune, and microbial pathways are increasingly recognized in lung-to-brain communication, the role of matrikines-bioactive peptides generated by extracellular matrix (ECM) proteolysis during remodeling-in this inter-organ communication remains underexplored. This review highlights matrikines originating from the lung, particularly the collagen-derived tripeptide Pro-Gly-Pro (PGP) and the elastin-derived hexapeptide Val-Gly-Val-Ala-Pro-Gly (VGVAPG), as potential mediators linking pulmonary pathology with neurological outcomes. The lung is rich in ECM proteins, and inflammatory conditions such as chronic obstructive pulmonary disease (COPD) and emphysema trigger proteolytic activity by matrix metalloproteinases (MMPs) and neutrophil elastase, releasing matrikines into circulation. Under conditions of blood-brain barrier (BBB) dysfunction, they may access the central nervous system (CNS), where they influence neurons, microglia, and astrocytes, modulating neuroinflammation, autophagy, and synaptic integrity. While PGP can exhibit context-dependent neuroprotective effects, its acetylated form and VGVAPG are associated with neurotoxicity, Tau hyperphosphorylation, and microglial activation. Additional matrikines, including Gly-His-Lys (GHK) and endorepellin, may further modulate CNS homeostasis. Collectively, these findings support lung-derived matrikines as circulating mediators of lung-to-brain signaling, providing a novel mechanistic framework linking chronic pulmonary inflammation to neuropathologies, such as stroke and neurodegenerative disorders, and highlighting potential targets for therapeutic intervention.

GLP-1 Receptor Agonist Semaglutide and SGLT2 Inhibitors after Acute Coronary Syndrome in Patients with Diabetes: Real-World Comparative Outcomes from an Observational Registry.

Cardiology

Ivana Jurin, Karlo Gjuras, Dijana Bešić +9 more

Patients with type 2 diabetes (T2D) remain at high cardiovascular risk after acute coronary syndrome (ACS), particularly after myocardial infarction (MI). Evidence on the early post-ACS use of glucagon-like peptide-1 receptor agonists (GLP-1RA), particularly semaglutide, and sodium-glucose cotransporter-2 inhibitors (SGLT2i) is limited.

Comparative Efficacy and Safety of Tirzepatide Versus Dulaglutide in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.

Healthcare (Basel)

Sadia Qazi, Mohammad Dawar Zahid, Eshal Atif +8 more

Background: Tirzepatide, a dual GIP/GLP-1 receptor agonist, demonstrates substantial glycemic and weight benefits versus GLP-1 receptor agonists in indirect comparisons, but direct comparative safety evidence versus dulaglutide remains limited. We evaluated comparative safety (primary outcome: overall adverse events) and efficacy. Methods: Following PRISMA 2020 (prospectively registered: PROSPERO CRD420251276594), we searched MEDLINE, Embase, Scopus, and CENTRAL (inception-31 December 2025) for randomized controlled trials (≥26 weeks) comparing once-weekly tirzepatide with dulaglutide in adults with type 2 diabetes. Three trials (N = 13,590 participants) were included. Dichotomous outcomes were pooled using random-effects models (risk ratios [RRs], 95% confidence intervals [CIs]). GRADE assessed certainty of evidence. Results: Overall adverse event incidence did not differ significantly (RR 1.04 [0.98-1.10]; I2 = 36%; moderate-certainty evidence). Discontinuation due to adverse events was consistently higher with tirzepatide (RR 1.32 [1.20-1.45]; I2 = 0%; high-certainty evidence), representing a 32% increased risk across all populations. Categorical HbA1c target achievement was analyzed in two trials; the third trial reported HbA1c as a continuous outcome only. At the primary threshold (HbA1c < 7.0%), tirzepatide was consistently superior with no heterogeneity (RR 1.48 [1.33-1.64]; I2 = 0%; p < 0.00001). Across all thresholds combined, heterogeneity was extreme (I2 = 92%), limiting confidence in any pooled summary estimate; the greatest instability occurred at the strictest threshold (HbA1c < 5.7%; I2 = 98%; p = 0.40). Tirzepatide showed greater HbA1c target attainment in treatment-naive patients receiving dulaglutide 0.75 mg, whereas the glycemic advantage was smaller in patients with established cardiovascular disease receiving dulaglutide 1.5 mg. Categorical weight-loss outcomes were analyzed in two trials; tirzepatide was associated with greater weight-loss threshold achievement (RR 8.80 [4.04-19.17]; very low-certainty evidence), although interpretation is limited by substantial heterogeneity and restricted generalizability. Serious adverse events were not significantly different (RR 0.82 [0.47-1.43]; I2 = 42%). Conclusions: Overall adverse events were similar between treatments, but tirzepatide consistently increased discontinuation risk, indicating a clinically important tolerability-persistence trade-off. Glycemic efficacy was highly population-dependent: benefits were consistent at the primary HbA1c target (<7.0%; I2 = 0%) in early-stage disease, whereas the advantage was smaller in long-standing disease with established cardiovascular disease. Tirzepatide may be favored when glycemic or weight efficacy is prioritized in earlier-stage disease, provided tolerability is proactively managed. Dulaglutide remains appropriate when persistence is threatened by tolerability concerns or cardiovascular risk reduction is the primary goal.

Disproportionality Analysis of Tirzepatide vs. Semaglutide and Liraglutide: System Organ Class-Level Post-Marketing Reporting Patterns in EudraVigilance.

Int J Mol Sci

Ruxandra Cristina Marin, Cosmin Mihai Vesa, Delia Mirela Tit +2 more

Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist, introduces a mechanistically distinct approach within incretin-based therapies. While its efficacy is established, real-world data comparing post-marketing safety with established GLP-1 receptor agonists remain limited. This study assessed System Organ Class (SOC)-level reporting patterns for tirzepatide versus semaglutide and liraglutide using EudraVigilance data. Aggregated individual case safety reports (ICSRs) were analyzed using pairwise disproportionality analyses based on a case/non-case approach. Reporting odds ratios (RORs) with 95% confidence intervals were calculated. False discovery rate (FDR) correction using the Benjamini-Hochberg procedure and sensitivity analyses restricted to serious and healthcare professional-reported cases were performed to assess robustness. After FDR adjustment, 20 SOCs were significant in tirzepatide-semaglutide and 23 in tirzepatide-liraglutide comparisons; eight SOCs remained significant across all analytical conditions. Compared with semaglutide, tirzepatide showed higher reporting for immune (ROR 1.97, 95% CI 1.75-2.21) and hepatobiliary disorders (ROR 1.71, 95% CI 1.61-1.82). Versus liraglutide, higher odds occurred for musculoskeletal (ROR 2.02, 95% CI 1.85-2.21) and psychiatric disorders (ROR 2.14, 95% CI 1.99-2.30), and lower odds for neoplasms (ROR 0.28, 95% CI 0.26-0.31). Tirzepatide shows heterogeneous reporting patterns compared with GLP-1 receptor agonists, with consistent excess reporting for hepatobiliary, immune, and musculoskeletal disorders. These findings are hypothesis-generating and warrant confirmation in exposure-adjusted studies.

Oral Delivery of Liraglutide Formulated with PLGA for Sustained Obesity Management.

Int J Mol Sci

Nipeng Chen, Zhipeng Zeng, Xiaoyu Ji +3 more

Liraglutide (Lira), a glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated substantial efficacy in improving glycemic control and reducing body weight. However, subcutaneous injection is poorly adherent for patients. To improve treatment compliance, we developed a poly(lactic-co-glycolic acid) (PLGA)-based nanovesicle (PLGA-Lira-NV) system for the oral delivery of Lira using a double-emulsion solvent evaporation technique. The optimized formulation yielded a narrow size distribution and high encapsulation efficiency (>95%). In vitro release studies showed that PLGA-Lira-NVs remained relatively stable under acidic conditions (pH 1.2 to 6.8) and exhibited sustained drug release in a neutral environment (pH 7.4), enabling protection of the fragile peptide in the stomach and controlled release after crossing the intestine. Following oral administration to obese mice (10 mg/kg), PLGA-Lira-NVs achieved prolonged glycemic control for up to 72 h. Notably, body weight decreased to 83% of baseline after 12 days, outperforming the subcutaneous injection (free Lira) group (88%). The consistent trend toward weight reduction confirms the sustained-release properties of PLGA nanocarrier for Lira, highlighting its potential to reduce dosing frequency and improve patient compliance. Collectively, these findings underscore the promising potential of PLGA nanovesicles as an oral delivery platform for peptide therapeutics.

GV1001 Reprograms CD47 Immune Checkpoint to Restore Macrophage Antitumor Activity in Oral Squamous Cell Carcinoma.

Int J Mol Sci

Wei Chen, Seojin Kim, Cheyenne Beheshtian +3 more

Cluster of Differentiation 47 (CD47) functions as a key "don't-eat-me" signal that enables cancer cells to evade macrophage-mediated immune clearance. GV1001, a 16-amino-acid peptide derived from human telomerase reverse transcriptase (hTERT), has been reported to exhibit antitumor and anti-inflammatory properties and to downregulate CD47 expression in human cells. In this study, we investigated whether GV1001 modulated CD47 expression and enhanced antitumor immunity in oral squamous cell carcinoma (OSCC). In vitro, GV1001 significantly reduced CD47 expression in both murine and human OSCC cells in dose- and time-dependent manners, resulting in a marked increase in macrophage-mediated phagocytosis. Mechanistically, GV1001 suppressed CD47 promoter activity and inhibited multiple upstream regulator expression in murine and human OSCC cell lines, while exerting minimal effects on normal human keratinocytes and fibroblasts. In vivo, GV1001 significantly inhibited tumor growth, suppressed CD47 expression, increased macrophage infiltration, and induced tumor cell necrosis and apoptosis in both murine OSCC syngeneic graft model and human OSCC xenograft model. GV1001 administered alone or in combination with cisplatin produced antitumor effects. Collectively, these findings demonstrate that GV1001 functions as a potent immunomodulatory anticancer peptide that downregulates CD47 expression and restores macrophage-mediated tumor clearance, highlighting its potential as a therapeutic strategy for OSCC.

Cellular Microenvironment Triggered Ferroptosis and Photodynamic Therapy for Selective Senescent Cell Clearance.

ACS Appl Mater Interfaces

Hang Wang, Yuli Kang, Qiqiang Zhang +7 more

Biomedical strategies based on the cellular microenvironment often lead to significant improvements in diagnosis and therapy. In this study, based on the elevated reactive oxygen species (ROS) microenvironment of senescent cells, we designed Fe3+ coordinated nitrogen doped graphene quantum dots (Fe@N-GQDs) with both photodynamic and ferroptotic activity. The results demonstrated that Fe3+ modulated the electronic structure of nitrogen doped graphene quantum dots (N-GQDs) and enhanced their photodynamic activity. Meanwhile, the high ROS levels in endoplasmic reticulum and mitochondria enabled accumulated Fe@N-GQDs to synergistically amplify oxidative stress through the Fe3+/Fe2+ redox cycle and activate the ferroptosis related process. Under the synergistic photodynamic and ferroptosis effects, the clearance efficiency of senescent cells reached 98%. More importantly, leveraging the senescent cell microenvironment, Fe@N-GQDs showed minimal impact on healthy cells without targeting modifications, significantly improving therapeutic safety.

Clearance of Senescent Cells by BCLXL-PROTAC: A Novel Approach to Treat COPD?

Aging Cell

Justine V Devulder, Peter S Fenwick, Ewa Kolosionek +9 more

Ageing and cellular senescence significantly contribute to the progression of age-related diseases, particularly chronic obstructive pulmonary disease (COPD). Cellular senescence refers to the cessation of cell division in response to stress and damage. While senescent cells remain metabolically active, they secrete pro-inflammatory factors that drive disease progression. Senolytic therapies aim to selectively target and eliminate these senescent cells by inducing their apoptosis. This study examines the senolytic potential of BCLXL-PROTAC, a novel proteolysis-targeting chimera designed to degrade BCLXL, in small airway epithelial cells and fibroblasts from patients with COPD. Treatment of COPD small airway epithelial cells and fibroblasts with BCLXL-PROTAC led to their apoptosis through the activation of caspase 3, along with a reduction in senescence markers such as p21CIP1, p16INK4a and senescence-associated β-galactosidase. The effects of BCLXL-PROTAC were selective for senescent cells and did not affect non-COPD cells. The clearance of COPD small airway epithelial cells and fibroblasts by BCLXL-PROTAC was associated with an increase in the proliferation marker Ki67 and enhanced cell proliferation. Additionally, in precision-cut lung slices obtained from COPD patients, BCLXL-PROTAC significantly reduced p21CIP1 expression in the airway epithelium, validating its effectiveness in a more complex tissue environment. These findings demonstrate that BCLXL-PROTAC is a potent and selective senolytic agent that may promote lung cell rejuvenation, supporting its potential as a novel therapeutic strategy for age-related diseases, including COPD.

Growth Differentiation Factor 15 as a Biomarker of Cardiovascular Burden and Mortality in a Population-Based Cohort.

Int J Mol Sci

Beatriz Martín-Carro, Leticia Nieto-García, Clara Sánchez-Pablo +18 more

Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine strongly associated with aging, multimorbidity, and cardiovascular disease. Although prior studies have established its prognostic value in high-risk populations, its role in the general population remains less defined. The aim of this study was to determine if there is an association between plasma GDF15 levels, heart disease and mortality in a representative population-based cohort. We analyzed 1532 participants (mean age 55 years; 54.6% women) with available baseline plasma GDF15 concentrations. Participants were stratified according to an optimal cutoff of 1081 pg/mL, derived from ROC curve analysis for mortality. Associations with prevalent heart disease were assessed using multivariable logistic regression models adjusted for cardiovascular risk factors and NT-proBNP. Mortality was analyzed using Cox proportional hazards models, with model performance evaluated by C-index and time-dependent ROC curves. Individuals with GDF15 > 1081 pg/mL were older and exhibited a more adverse cardiometabolic profile with higher prevalence of comorbidities. Elevated GDF15 was independently associated with ischemic cardiomyopathy (OR 3.34, 95% CI: 1.38-8.11), particularly in men (OR 4.26, 95% CI: 1.40-12.96), but not in women. No independent associations were observed with arrhythmias, valvulopathy, or heart failure after adjustment for NT-proBNP. During a median follow-up of 6.2 years, 51 deaths occurred. Elevated GDF15 independently predicted all-cause mortality (HR 2.47, 95% CI: 1.19-5.13), though the effect was attenuated after adjustment for NT-proBNP. GDF15 improved model discrimination (ΔC-index = +0.01; LRT p = 0.011) and showed robust time-dependent predictive ability, with AUCs of 0.76, 0.82, and 0.85 at 2, 4, and 6 years, respectively. In this population-based cohort, elevated GDF15 identified individuals with an adverse health profile, was independently associated with ischemic cardiomyopathy in men, and predicted mortality. Although its incremental predictive value over NT-proBNP was modest, GDF15 could provide complementary biological information and may enhance multimarker strategies for cardiovascular risk stratification in the general population.

Novel Small Molecule GLP-1R Agonists Based on 1H-Benzo[d]imidazole-5-Carboxylic Acid Scaffold.

Molecules

Elena V Tolkacheva, Tagir L Salakhov, Alexandr Yu Saliev +7 more

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by intestinal endocrine L cells that activates the GLP-1 receptor (GLP-1R), leading to glucose-dependent insulin secretion and suppression of glucagon release. In recent years, GLP-1R agonists (GLP-1RAs) have become one of the leading therapeutic options for the treatment of type 2 diabetes mellitus; however, for a long time clinically approved GLP-1RAs were limited to peptide drugs unsuitable for oral administration. The discovery of the "first-in-class" small molecule agonist danuglipron in 2018 demonstrated the feasibility of orally available GLP-1RAs and stimulated the development of numerous danuglipron-like compounds, some of which showed increased efficacy over the prototype. In this study, we report the design and synthesis of novel GLP-1RAs based on a regioisomeric danuglipron scaffold, 1H-benzo[d]imidazole-5-carboxylic acid. A series of 35 compounds was synthesized and evaluated in vitro for cytotoxicity and GLP-1R agonistic activity using a cAMP accumulation assay. A potent lead compound 12r (pEC50 = 7.72, pCC50 < 3.60) was found which is a close structural analog of danuglipron with reduced cytotoxicity and excellent selectivity over two other class B GPCRs, including GCGR and GIPR. Despite decreased potency compared to danuglipron, the obtained results hold promise for further optimization and provide valuable structure-activity relationship insights.

Effects of Fan Noise on Growth Performance, Blood Parameters, Feeding Behavior, and Slaughter Performance of Geese Aged 21-70 Days.

Animals (Basel)

Qun Xie, Xiaofeng Huang, Zuolan Liu +10 more

We conducted this experiment with the aim of investigating the effects of different noise levels from ventilation fans on the growth and slaughter performance, meat quality, blood parameters, and feeding behavior of geese from 21 to 70 days of age. A total of 108 male geese (21-day-old) were randomly assigned to one of three conditions: a control group (no additional fan noise), low-noise treatment (65-75 dB), and high-noise treatment (85-95 dB). Each treatment included six replicates, with six geese per replicate. The results showed that neither ventilation fan noise level significantly affected growth performance, feeding behavior, slaughter performance, or major meat quality traits (p > 0.05). Compared with the control group, noise exposure significantly reduced circulating adrenocorticotropic hormone and corticosterone concentrations (p < 0.05), and the low-noise group exhibited significantly reduced cortisol concentrations (p < 0.05), while the high-noise group had increased cortisol concentrations. Under noise exposure conditions, no statistically significant effects were observed on superoxide dismutase, total antioxidant capacity, malondialdehyde concentration, catalase, and glutathione peroxidase activities compared with the control group (p > 0.05). Overall, prolonged noise stimulation (65-75 dB and 85-95 dB) alleviated stress responses in commercial geese aged 21-70 days, without negatively affecting their growth performance, slaughter performance, meat quality, or feeding behavior.

Diagnostic Utility of ACTH, Cortisol, DHEAS, and Their Derived Ratios in Cushing's Syndrome Subtypes.

J Clin Med

Ekin Yiğit Köroğlu, Abbas Ali Tam, Sevgül Faki +6 more

Background/Objectives: Differentiating Cushing's disease (CD) from adrenocorticotropic hormone (ACTH)-independent Cushing's syndrome (AICS) remains challenging in patients with equivocal ACTH levels. While dynamic testing is frequently required, baseline hormonal measurements may offer a simpler diagnostic approach. We aim to evaluate the diagnostic value of baseline plasma ACTH, cortisol, and dehydroepiandrosterone sulfate (DHEAS) levels and their derived ratios for differentiation between ACTH-dependent and ACTH-independent Cushing's syndrome, and to propose a diagnostic algorithm based on these parameters. Methods: This retrospective single-centre study included adult patients with endogenous Cushing's syndrome aged 18-75 years who were followed at our institution. Patients with ectopic/paraneoplastic Cushing's syndrome were excluded. The AICS group comprised overt adrenal CS and mild autonomous cortisol secretion cases. Morning baseline plasma ACTH (pg/mL), serum cortisol (µg/dL), and serum DHEAS (µg/dL) levels were measured and ratios calculated: cortisol-to-ACTH ratio (CAR), DHEAS-to-cortisol ratio (DCR), and CAR-to-DHEAS ratio (CAR/D). ROC analysis assessed diagnostic performance with age and sex adjustments. Results: A total of 100 patients were included, comprising 43 patients with CD and 57 with AICS. Plasma ACTH demonstrated high diagnostic accuracy for identifying CD with a cut-off of ≥14.65 pg/mL (sensitivity 100%, specificity 98.25%, AUC 0.998). Serum DHEAS showed strong discriminative power with a cut-off of ≥67.15 µg/dL (sensitivity 88.37%, specificity 91.23%, AUC 0.925), achieving high discriminative power after age-sex adjustment at ≥85.59 µg/dL (sensitivity 100%, specificity 100%, AUC 0.999). CAR showed good performance in identifying CD with a cut-off of ≤0.75 µg/dL per pg/mL (sensitivity 93.02%, specificity 98.25%, AUC 0.980). CAR/D demonstrated high diagnostic power with a cut-off of ≤1.54 (sensitivity 95.35%, specificity 98.25%, AUC 0.974), improving after age-sex adjustment to ≤2.36 (sensitivity 97.87%, specificity 96.23%, AUC 0.992). Conclusions: Baseline plasma ACTH, serum cortisol, and serum DHEAS measurements, along with derived ratios-especially CAR and CAR/D-provide highly accurate differentiation between ACTH-dependent and ACTH-independent Cushing's syndrome. These widely available measurements may reduce dependence on dynamic testing and improve diagnostic accuracy in patients with equivocal findings.

Capsule and PspA Cooperatively Confer Resistance of Streptococcus pneumoniae to the Human Defensin HNP-1.

Int J Mol Sci

Maria Eduarda Pereira Mendes, Thalita Bastos de Freitas E Silva, Rebeca Faria +9 more

Streptococcus pneumoniae resists host defenses through multiple surface factors, yet their specific contribution to protection against antimicrobial peptides remains incompletely understood. We examined the role of pneumococcal surface protein A (PspA) and the polysaccharide capsule in protection against the human defensin HNP-1. PspA conferred increased resistance to HNP-1-induced killing, shown by a decreased killing in the presence of purified recombinant PspA and an increased sensitivity when PspA was deficient from the surface of strains of two different genetic backgrounds or when anti-PspA antibody was present. The capsule also conferred protection against HNP-1, which was serotype-dependent, with type 2 protecting better than type 4, and free polysaccharides acted as decoys by sequestering HNP-1. Removal of surface PspA from capsule-deficient mutants revealed additive contributions of both factors to survival. Molecular docking analysis suggests a potential electrostatic interaction between PspA and HNP-1. These findings highlight the independent and complementary roles of PspA and the capsule in pneumococcal resistance to HNP-1 and provide novel insights that may inform future vaccine design and antimicrobial strategies.