BACKGROUND: Environmental exposures to toxicants, such as per- and polyfluoroalkyl substances (PFAS), during gestation can disrupt immune development, causing long-term impacts on a child's ability to generate a well-regulated, protective immune response. T-cells coordinate with all immune cell types to orchestrate both cellular and antibody-mediated responses. While there is compelling evidence that PFAS alters immunity in humans, the specific effects of early life PFAS exposure on infant T-cell development are unreported. Because of their central role in immunity, altered T-cell development in infants would have implications on immune responses broadly and long-term. OBJECTIVES: We seek to model longitudinal changes in the frequency of functionally distinct CD4+ T-cell subpopulations from birth through 12 months and their association with in utero PFAS exposure. METHODS: Maternal-infant dyads were recruited as part of the UPSIDE-ECHO cohort during the first trimester between 2015 and 2019 in Rochester, New York; dyads were followed through the infant's first birthday. Maternal PFAS concentrations (PFOS, PFOA, PFNA, PFHXS and PFDA) were quantified in serum during the second trimester using high-performance liquid chromatography and tandem mass spectrometry. Infant lymphocyte frequencies were assessed at birth, 6- and 12-months using mass cytometry and high-dimensional clustering methods. Linear mixed-effects models were employed to analyze the relationship between maternal PFAS concentrations and CD4+ T-cell subpopulations (n = 200). All models included a PFAS and age interaction and were adjusted for parity, infant sex, and prepregnancy body mass index. RESULTS: In utero PFAS exposure correlated with multiple CD4+ T-cell subpopulations in infants. The greatest effect sizes were seen in T follicular helper (Tfh) and T-helper 2 (Th2) cells at 12 months. A log2-unit increase in PFOS was associated with lower Tfh [0.17% (95% CI: -0.30, -0.40)] and greater Th2 [0.27% (95% CI: 0.18, 0.35)] cell percentages at 12 months. Similar trends were observed for PFOA, PFNA, PFHXS, and PFDA. DISCUSSION: Maternal PFAS exposures correlate with cell-specific changes in the infant T-cell compartment, including key CD4+ T-cell subpopulations that play central roles in coordinating well-regulated protective immunity. Future studies into the role of PFAS-associated T-cell distribution and the risk of adverse immune-related health outcomes in children are warranted.
Pediatric repetitive mild traumatic brain injury (rmTBI) is a major public health concern with links to chronic cognitive dysfunction. Neuroinflammation represents a significant maladaptive outcome after rmTBI. Persistent innate and adaptive immune cell responses can lead to neurodegeneration and deficits in brain development. Therefore, a deeper understanding of the early dynamics of peripheral immune cell infiltration after pediatric rmTBI is critical for the development of effective treatment. We hypothesize that pediatric rmTBI alters neuroinflammation through T cell infiltration. We used wild-type (C57BL/6) and T cell knockout (TCRβ-/- δ-/-) mice to test this hypothesis. We developed a pediatric postnatal day 21 rmTBI model, with three consecutive subconcussive impact acceleration injuries separated in time by 1 week. After inducing rmTBI in juvenile mice, we observed a progressive infiltration of macrophages, CD8+, and CD4+ T cells into the brain parenchyma, which increased with repeated injury. Furthermore, neuroinflammation in the white matter was detected when we analyzed the lateral corpus callosum (CC). Since increased infiltration of CD4+ and CD8+ T cells was detected, we utilized TCRβ-/- δ-/- mice to further explore the role of T cells on neuroinflammation after pediatric rmTBI. We observed a reduction in the infiltration of pro-inflammatory macrophages and decreased neuroinflammation in the lateral CC. Overall, our findings highlight the significant role of T cell infiltration in the modulation of neuroinflammation following rmTBI in the developing brain, suggesting that they may serve as potential therapeutic targets for managing neuroinflammation following pediatric brain injuries.
Myeloid cells play a key role in cancer-associated immunosuppression because their accumulation and reprogramming inhibit antitumor responses and support tumor growth. To modulate their activity, we targeted Fcγ receptors (FcγRs), which are broadly expressed in myeloid subsets. Since low-affinity Fcγ receptor IIb (FcγRIIb) mediates inhibitory signaling, we designed an immunotherapy active at a low dose to limit binding to FcγRIIb while retaining interaction with higher-affinity FcγRs. We engineered an Fc-based fusion protein, whose activity is potentiated by its ability to engage both FcγRs and a coreceptor, Heparan Sulfate Proteoglycan (HSPGs). This immunotherapy, named Fc-T54, combines an HSPG-ligand, named T54, with human IgG1-Fc. Compared with Fc, Fc-T54 displayed superior binding to Fcγ receptor IIa (FcγRIIa), Fcγ receptor IIIa (FcγRIIIa) and enhanced interactions with human leukocytes, including neutrophils, B-lymphocytes, as well as with monocytes, and dendritic cells (DCs) within peripheral blood mononuclear cells. Functionally, Fc-T54 increased monocyte/macrophage and B-cell numbers, reduced neutrophil abundance, and boosted DC activation in both the human and murine systems. Subcutaneous administration of low-dose Fc-T54 - or its murine surrogate - inhibits tumor growth in immune-deserted and immune-excluded mouse models and synergizes with anti-PD-1 therapy in an immune-inflamed model. Tumor microenvironment analysis in the bladder cancer model revealed that the immunotherapy decreased the proportion of granulocytic myeloid-derived suppressor cells while increasing CD8+ T cells and natural killer cells, promoting a microenvironment more prone to tumor control. This FcγR/HSPG-engaging immunotherapy, administered subcutaneously, offers a novel approach to modulate the myeloid compartment and improve outcomes for ICI-resistant, deserted/excluded tumors, and for inflamed tumors when used in combination regimens.
Ubiquitin-specific protease 15 (USP15) is closely associated with the occurrence and progression of hepatocellular carcinoma (HCC). However, its role in shaping the immune landscape of HCC remains unclear. The expression levels, proportions, and spatial distributions of USP15 and specific immune cell subsets in HCC tissues were evaluated using multiplex immunohistochemistry (mIHC). In the tumor parenchyma of HCC tissues, the infiltration of immune cells, particularly natural killer (NK) cells, was significantly reduced (p<0.05). Further analyses revealed that USP15 expression levels were significantly associated with clinical stage and other clinicopathological parameters (p<0.05). In particular, NK cell infiltration was significantly correlated with N stage, M stage, and overall tumor-node-metastasis (TNM) stage (p<0.05). USP15 contributes to the establishment of an immunosuppressive tumor microenvironment in HCC by inhibiting T cell and NK cell infiltration, facilitating programmed death-ligand 1 (PD-L1)-mediated immune evasion, and enhancing macrophage recruitment. These findings indicate that USP15 may serve as a potential therapeutic target for HCC.
Platinum-based chemotherapy remains the cornerstone of ovarian cancer treatment, yet acquired resistance severely limits efficacy. Because platinum agents can also influence immunogenic cell death and tumor microenvironment (TME) remodeling, clarifying cellular pharmacological mechanisms of sensitivity and resistance within the ovarian cancer tumor ecosystem is important for understanding therapeutic failure. We integrated single-cell RNA-seq from treatment-naïve and post-neoadjuvant chemotherapy ovarian tumors with bulk multi-omics cohorts to map epithelial tumor heterogeneity, transcriptional reprogramming, pathway activation, immune infiltration, and inferred cell-cell communication networks. DUSP5 was identified as a candidate regulator linked to stress-adaptive programs. Functional validation included qPCR, proliferation, migration, colony-formation, carboplatin dose-response, and xenograft assays following stable DUSP5 knockdown. Single-cell analysis revealed chemotherapy-associated epithelial states with enhanced stress, EMT, hypoxia, and inflammatory signatures. Elevated DUSP5 expression correlated with MAPK/JAK-STAT/TGF-β signaling, myeloid/stromal infiltration, and clinical outcome differences in independent cohorts. DUSP5 depletion suppressed proliferation and migration, amplified carboplatin-induced MAPK transcriptional responses and pro-apoptotic signaling (BAX/PUMA upregulation, BCL2 downregulation), reduced IC50 values in both OVCAR8 and SKOV3 cells, and significantly inhibited xenograft tumor growth. DUSP5 may contribute to platinum response and resistance by linking tumor-intrinsic adaptive programs with TME-associated features in ovarian cancer. These findings support DUSP5 as a candidate biomarker and therapeutic target that warrants further mechanistic and clinical validation.
Foot-and-mouth disease (FMD) is a highly contagious infectious disease caused by foot-and-mouth disease virus (FMDV). FMDV replicates not only in epithelial cells, where it induces vesicular lesions, but also in myocardial and skeletal muscle tissues, leading to myocarditis and even fatal outcomes in infected animals. RIPK3/MLKL-mediated necroptosis is a proinflammatory cell death process that plays a significant role in viral infections. However, whether FMDV infection can trigger necroptosis in host cells remains unclear. We assessed necroptosis induced by FMDV infection through activation of the RIPK3/MLKL pathway in PK-15 and BHK-21 cells. Specific inhibitors GSK'872 (targeting RIPK3 phosphorylation) and NSA (targeting MLKL phosphorylation) were applied to examine the impact of this pathway on viral replication. Additionally, Co-immunoprecipitation (Co-IP) was used to analyze the interactions between FMDV-encoded proteins and RIPK3/MLKL, and AlphaFold3 was used to predict the interaction interface between the 3D protein and the RHIM-containing region of RIPK3. FMDV infection activated the RIPK3/MLKL pathway and induced necroptosis in both PK-15 and BHK-21 cells. Inhibitor assays revealed that blocking RIPK3 or MLKL phosphorylation significantly reduced FMDV VP1 expression and viral titers, indicating that the necroptosis pathway favors FMDV replication. Further investigation revealed that the FMDV non-structural protein 3D is the key protein responsible for activating RIPK3/MLKL pathway. Moreover, we confirmed that the 3D protein interacts and colocalizes with RIPK3. AlphaFold3 structural prediction suggested that 3D can directly associate with the RHIM-containing region of RIPK3, with residues R320, H322, E324, and Y346 of 3D interacting with residues N466, V469, and K471 of RIPK3 at the interface. Our results demonstrate that FMDV infection induces necroptosis in host cells. This finding expands the modes of host cell death caused by FMDV infection, advances the understanding of the role of necroptosis in viral infections, and may help elucidate the pathogenic mechanisms of FMDV.
Pelvic organ prolapse (POP) is a prevalent condition characterized by weakened pelvic floor tissues, significantly impacting women's quality of life. Current treatments, including synthetic meshes and native tissue repair, face challenges of high recurrence rates and complications. This study developed a novel tissue-engineered strategy utilizing a decellularized human amniotic membrane (HAAM) scaffold seeded with autologous adipose-derived mesenchymal stem cells (ADSCs) and vaginal wall fibroblasts (HVFs) to construct a bioactive pelvic ligament equivalent. We first validated the successful preparation of HAAM with preserved extracellular matrix integrity and characterized the phenotypic markers of ADSCs and HVFs. In a rat abdominal wall defect model, the HAAM+ADSCs+HVFs composite demonstrated superior tissue regeneration and integration, reduced fibrosis, and effective modulation of the host immune microenvironment -evidenced by enhanced repair and decreased infiltration of pro-inflammatory cells -compared to all control groups (including HAAM alone and single-cell groups). Transcriptomic analysis revealed that the composite treatment promoted extracellular matrix organization and collagen synthesis while suppressing matrix degradation (MMP2/MMP9) and inflammatory pathways. Most importantly, mechanistic studies identified TGFB2 as the key paracrine mediator through which ADSCs exert their effects: TGFB2 inhibition abolished ADSCs-induced improvements in HVFs proliferation, migration, and anti-apoptosis, while its overexpression replicated these benefits. Western blot confirmed that TGFB2 coordinately upregulates COL1A1/COL3A1 and downregulates MMP2/MMP9 to restore ECM homeostasis. These comprehensive findings demonstrate that the HAAM-based ADSCs-HVFs composite promotes functional tissue regeneration via TGFB2-mediated mechanisms, offering a safe, effective, and regenerative therapeutic strategy with strong translational potential for POP.
Dogs play a major role in sustaining the transmission of Leishmania infantum to people, making prevention and treatment of canine leishmaniosis (CanL) public health priorities. However, immune mechanisms underlying progression from subclinical stages to terminal disease in dogs remain ill-defined. To address this gap, we generated a single-cell RNA sequencing map of peripheral immune cells from uninfected and naturally infected dogs across well-defined stages of L. infantum infection. Disease progression was marked by a shift from a lymphoid-to a myeloid-dominated immune landscape. CD4+ T cells transition from naive to effector states, with TH1 cells showing progressive exhaustion signatures paralleling disease progression, while CD8+ T cells exhibited TPEX-like phenotypes with differentiation toward effector and proliferative programs during severe L. infantum infection. Monocytes showed inflammatory remodeling across clinical stages. The LeishDog Atlas provides a framework for understanding immune dysregulation in CanL and a resource for comparative and translational studies of its immunopathology.
High-risk human papillomavirus (HR-HPV) infection is the primary driver of cervical cancer. Emerging evidence indicates that the tumor microenvironment (TME) undergoes severe metabolic rewiring, which may accelerate T cell exhaustion (TEX) and impair immune checkpoint blockade (ICB). However, the molecular mechanisms coupling HPV-driven metabolism to T cell dysfunction remain incompletely elucidated. This review summarizes immunometabolic interactions in the cervical cancer TME. We examined the metabolic alterations induced by HPV oncoproteins (E6/E7) and how they reshape nutrient availability, lactate accumulation, and lipid peroxidation to drive anti-tumor CD8+ T cell exhaustion. HPV-driven aerobic glycolysis and IDO1-mediated tryptophan catabolism establish severe metabolic barriers, causing nutrient deprivation and histone lactylation in infiltrating lymphocytes. These alterations are associated with persistent mitochondrial stress and ferroptosis, accelerating terminal TEX. In preclinical models, natural products (e.g., curcumin, berberine, quercetin, and artemisinin derivatives) can counteract this immunosuppressive rewiring by targeting checkpoints such as HIF-1α, PKM2, and AMPK; however, direct evidence of CD8+ tumor-infiltrating lymphocyte rescue in HPV-specific immune-competent systems remains limited, largely inferred from other tumor types. Nanomedicine delivery may further enhance the bioavailability and targeting of these herbal components. HPV-induced metabolic reprogramming is proposed to act as a fundamental checkpoint driving T cell exhaustion in cervical cancer. Targeting these immunometabolic barriers using natural compounds, particularly via nanomedicine-based delivery strategies, represents a promising but still largely preclinical avenue to synergize with conventional immunotherapies and potentially overcome resistance.
Mantle cell lymphoma (MCL) remains an incurable B-cell malignancy despite major advances in its therapeutic management. While Bruton tyrosine kinase inhibitors (BTKi) and, more recently, CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy have significantly improved outcomes in relapsed or refractory MCL, relapse after CAR-T therapy is associated with a dismal prognosis and represents a major therapeutic challenge. Here, we report the case of a 43-year-old male diagnosed with stage IV common-type MCL, who achieved long-term complete remission (CR) after treatment with polatuzumab vedotin, rituximab, and bendamustine (Pola-R-Benda) following relapse after CAR-T therapy. The patient had previously received standard first-line immunochemotherapy (R-CHOP alternating with R-DHAP) and autologous stem-cell transplantation, resulting in durable CR, followed by ibrutinib at first relapse in 2017 with sustained remission until 2021. Eleven months after CAR-T therapy with brexucabtagene autoleucel, the patient experienced systemic relapse. Enrollment into a Pola-R-Benda clinical protocol resulted in complete metabolic remission after three cycles, confirmed by positron emission tomography/computer tomography. Treatment was well tolerated except for mild grade 2 diarrhea. The patient remains in ongoing CR >20 months after initiation of Pola-R-Benda. To our knowledge, this is among the first reports of long-term remission with Pola-R-Benda following CAR-T failure in MCL, suggesting that antibody-drug conjugate-based therapy may represent an effective salvage option in this highly refractory clinical setting.
Upper Urinary Tract Small Cell Neuroendocrine Ca are extremely rare carcinomas with less than 40 reported cases in literature. 92 years old male with left flank pain and diagnosed to have an enhancing renal pelvic mass, which on histopathological examination was noted to have a predominant small cell carcinoma component. This case report attempts to shed a light on the patients with small cell neuroendocrine carcinoma of the upper tract with its silent and aggressive nature.
Among preterm infants, bronchopulmonary dysplasia (BPD) is the most prevalent chronic pulmonary disorder. Its pathogenesis involves a complex interplay between prenatal inflammatory exposure and abnormal immune activation. Neutrophil extracellular traps (NETs) are mediators of tissue damage, but whether they bridge intrauterine inflammation and the subsequent development of BPD is not yet clear. We used a prenatal lipopolysaccharide (LPS)-exposed rat model to ask two questions: first, whether excessive NETs drive BPD pathogenesis, and second, whether human umbilical cord mesenchymal stem cell-derived microvesicles (hUCMSC-MVs) can alleviate lung injury by inhibiting this process. We established a BPD model in preterm rats via prenatal LPS exposure and assessed lung morphometry, neutrophil infiltration, and NETs markers. We then compared the therapeutic effects of hUCMSC-MVs with NET extrusion (NETosis) inhibitors in vivo and also examined direct neutrophil effects in vitro. Prenatal LPS exposure led to significantly elevated NET markers in both lung tissue and circulation, which correlated with severe alveolar simplification. Neutrophils in this model exhibited a "primed" phenotype with enhanced potential for NETs release. In vivo, hUCMSC-MVs suppressed NET formation, attenuated neutrophilic inflammation, and restored alveolar structure, matching the efficacy of conventional NETosis inhibitors. In vitro, they were internalized by neutrophils and abrogated LPS-induced NETosis. These findings point to excessive NETosis as a key mechanistic link between prenatal inflammation and postnatal lung impairment. hUCMSC-MVs directly inhibit this pathological process and alleviate BPD-like lung injury. This work advances the mechanistic understanding of BPD and supports hUCMSC-MVs as a promising cell-free therapeutic candidate.
Many tumours show deficiencies in DNA damage response (DDR), not only driving tumorigenesis but also exposing vulnerabilities with therapeutic potential. Assessing which patients might benefit from DDR-targeting therapy requires knowledge of tumour DDR deficiency (DDRd) status, with mutational signatures reportedly better predictors than loss-of-function mutations. Existing DDRd models offer effective prediction for pathways with well-characterized processes and mutational signatures. Nevertheless, development of models for additional DDRd and clinically relevant mechanisms could be hampered by the fact that most mutational signatures have unknown etiology. Using supervised non-negative matrix factorization (SNMF), we integrate mutational signature learning with multiclass DDR-deficiency prediction to enable etiology-guided learning of signatures from cell lines with confirmed gene knockouts. Applied to DDR gene knockout human-induced pluripotent stem cell lines, SNMF identified etiology-aligned representations of deficiency in homologous recombination, mismatch repair, and base excision repair. Even guided by pathway-level labels, SNMF captured gene-specific base excision repair submechanisms, showing the integration offered added granularity. Learned cell line signatures showed high similarity to tumour-derived COSMIC signatures, revealed associations with mutations in DDR genes, and enabled high recall of tumours with DDR deficiencies. We envision that SNMF-like methods could leverage knockout screens to learn etiology-guided signatures for improved DDRd annotation and treatment optimization. SNMF is available at: https://github.com/joanagoncalveslab/SNMF.
Extracorporeal membrane oxygenation (ECMO) is increasingly utilized for refractory respiratory failure in sickle cell disease (SCD), yet registry data indicate in-hospital survival of only 40% in adults, with particular concerns regarding hemolysis, thrombosis, and bleeding processes already pathologically amplified in SCD. A targeted hematologic strategy using combined therapeutic plasma exchange (PLEX) and red cell exchange (RCE) may offer an alternative approach, but high-quality outcome data remain limited. We report a 37-year-old male with homozygous SCD (HbSS genotype) and glucose-6-phosphate dehydrogenase (G6PD) deficiency who presented with severe vaso-occlusive crisis that progressed to two cardiac arrests, shock requiring four vasopressors, severe acute respiratory distress syndrome (PaO2/FiO2 56 mm Hg), biventricular failure, and multiorgan dysfunction. Laboratory findings included marked lactate dehydrogenase elevation (7,169 U/L, > 25 × upper limit of normal) and severe thrombocytopenia (platelet count 37 × 103/µL). A multidisciplinary team considered ECMO but elected to pursue combined RCE and daily PLEX as salvage therapy. Seven sessions of daily PLEX combined with intermittent RCE reduced the hemoglobin S fraction from 73% to 18%. Vasopressor requirements decreased within 24 h, with complete independence by day 8. Inflammatory markers declined substantially within 72 h. The patient was extubated on day 10 and discharged from the intensive care unit on day 14 without neurological deficit. This case demonstrates that combined RCE and daily PLEX may represent a viable salvage strategy for post-arrest refractory cardiorespiratory failure in SCD, potentially sparing the need for ECMO in carefully selected patients. Prospective validation is essential.
Oncolytic viruses are therapeutic agents that combine self-amplification, lytic activity, and immunostimulatory properties. However, their systemic administration is limited by inefficient tumor delivery. Although mesenchymal stem cell (MSC)-based carrier systems have been proposed to overcome these barriers, their efficacy is restricted by rapid MSC lysis following viral replication, which limits the time available for tumor homing. Here, we describe a tetracycline operator-regulated oncolytic adenovirus designed to temporally control viral replication within MSC carriers and enhance intratumoral viral delivery. In this system, menstrual blood-derived MSCs (MenSCs) are engineered to stably express the tetracycline repressor, while the adenoviral genome incorporates TetO sites upstream of the E1A promoter, enabling reversible pharmacological control of viral replication through tetracycline or doxycycline administration. TetO incorporation did not compromise viral fitness, and viral replication was effectively repressed in TetR-expressing MenSCs, with restoration upon inducer addition. Importantly, once released within the tumor microenvironment, viral progeny replicated unrestrictedly in TetR-negative cancer cells. In lung adenocarcinoma model, TetO-regulated oncolytic adenoviruses delivered by TetR-MenSCs achieved enhanced intratumoral viral accumulation and improved antitumor efficacy. Overall, these findings establish a controllable MSC-based oncolytic adenovirus delivery strategy that addresses a key limitation of systemic virotherapy and supports its clinical translation across solid tumors.
Intervertebral disc (IVD) degeneration is associated with severe clinical symptoms including chronic back pain. Galectins are a family of carbohydrate-binding proteins, some of which can induce functional disease markers in IVD cells and other musculoskeletal tissues. Galectin-4 and -8 were shown to trigger disease-promoting activity in chondrocytes, but their effects on IVD cells have not been investigated yet. IVD specimens from 36 patients with spondylosis, spondylolisthesis, and scoliosis were assessed immunohistochemically for the presence of galectin-4 and -8. The degrees of radiological (Pfirrmann grade) and histopathological (Rutges score) degeneration of all specimens were correlated with histological galectin scores. To assess galectin functions, separate cell cultures of annulus fibrosus (AF) and nucleus pulposus (NP) (n = 21) were established. Cell cultures were treated with recombinant galectin-4, -8 (24 μg/mL), or Interleukin-1β (IL-1β) (10 ng/mL) and analyzed using RT-qPCR and In-Cell Western (ICW). Potential binding sites for galectins including sialylated N-glycans and LacdiNAc structures were determined in AF and NP cells using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). The immunohistochemical presence of galectin-4 in IVD specimens correlated with histopathological and clinical degeneration scores of patients, whereas galectin-8 did not show significant correlations. Both galectins were detected across IVD compartments except for the endplate. In vitro, both galectins activated the nuclear factor-kB pathway and induced functional disease markers (Interleukin-8 (CXCL8) and matrix metalloproteinase-3 (MMP3) mRNA). NP cells were more responsive to galectins and IL-1β than AF cells, indicating region-specific differences in galectin sensitivity. This study identifies galectin-4 as a novel molecular player in the pathogenesis of IVD degeneration.
Sickle cell disease (SCD) is the most common inherited blood disorder worldwide. Although monogenic, it presents substantial clinical heterogeneity influenced by genetic modifiers, including haplotypes and fetal hemoglobin (HbF) levels. This pilot cross-sectional study aimed to characterize, for the first time, the βS gene haplotype distribution among Moroccan patients with sickle cell anemia and evaluate its impact on hematological parameters, particularly HbF levels. Eight polymorphic sites within the β-globin gene cluster were analyzed using PCR-RFLP in 334 chromosomes from SCD patients in northern Morocco. Associations between haplotypes and HbF levels were evaluated. PCR RFLP showed that the Benin haplotype was the most common (61.1%), followed by Bantu (14.1%), Atypical A1 (11.7%), Senegal (10.5%), and Arab-Indian (2.7%). The most frequent genotypes were Ben/Ben (41.3%), Ben/CAR (15%), and Ben/Sen (10.2%). HbF levels varied significantly across haplotypes (p < 0.005), with Senegal and Arab-Indian showing the highest levels and Benin and Bantu the lowest. This study highlights both the genetic and anthropological diversity of SCD in Morocco, likely reflecting historical African gene flow. Haplotype profiling enhances understanding of genotype-phenotype correlations, offering valuable insights for prognosis and individualized care strategies to improve patients' outcomes.
Pleomorphic giant cell carcinoma (PGCC) of the prostate is an extremely rare and aggressive malignancy with limited treatment options. We present a case report of metastatic PGCC patients treated with 177Lu-PSMA-617 radioligand therapy (Pluvicto) after progression on standard therapies. Both patients had PSMA-avid tumors on imaging. Molecular profiling revealed mutations in hallmark tumor suppressors including TP53, RB1, and PTEN. Both patients initially experienced partial radiographic response, in which one patient achieved stable disease for 9 months posttherapy. These findings suggest that PSMA-radioligand therapy may be a reasonable treatment for PGCC patients, but underscore the need for additional therapeutic options.
Placental dysfunction and immune dysregulation are central to disorders such as fetal growth restriction (FGR) and preeclampsia (PE). Although aberrant placental glycosylation has been implicated in various pregnancy complications, the specific expression patterns of glycosylation-related genes (GRGs) associated with placental pathology and their potential role in driving immune imbalance at the maternal-fetal interface remain poorly understood. First, differentially expressed gene (DEG) identification and gene set enrichment analysis based on two GEO datasets (GSE114691 and GSE203507) revealed disease-associated pathways. Weighted gene co-expression network analysis (WGCNA) further identified glycosylation-related gene modules significantly associated with disease status. Three machine learning algorithms (LASSO, random forest, and support vector machine) were employed to screen diagnostic key genes, and a predictive nomogram was constructed. The efficacy of the diagnostic model was evaluated using receiver operating characteristic curves, calibration curves, and decision curve analysis. CIBERSORT was used to assess immune cell infiltration characteristics in the placenta and decidua of FGR, PE, and PE+FGR. Furthermore, single-cell RNA sequencing validated the expression patterns of key diagnostic genes across different trophoblast subsets, and cell-cell communication networks were analyzed using CellChat. In addition, this study validated the diagnostic efficacy of key genes in real-world samples. Following batch correction and integration of two datasets, 104 samples were analyzed, including controls (n=26), PE (n=28), FGR (n=23), and PE+FGR (n=27). Glycosylation-related pathways were enriched in disease groups. Intersection of WGCNA modules with glycosylation genes yielded 97 overlapping genes, from which five core genes were identified using three machine learning algorithms. A diagnostic model based on these genes showed good predictive performance across disease groups. Immune infiltration analysis implicated multiple immune cell types in disease pathogenesis. Real-world validation of expression of B3GNT2 and ST6GAL1 differed significantly between normal and PE/FGR groups. Five candidate hub genes (B3GNT2, ST6GAL1, GALNT11, GCNT4, and LARGE2) were identified and a nomogram was constructed for FGR, PE, and PE+FGR diagnosis. Protein-level validation confirmed significant downregulation of B3GNT2 and ST6GAL1 in placental tissues from FGR and PE patients; mRNA-level validation of GALNT11, GCNT4, and LARGE2 is provided in independent clinical samples. These hub genes were associated with key immune cell types at both the placenta and decidua.
Epidermal growth factor receptor (EGFR) mutation status plays a critical role in guiding targeted therapy for non-small cell lung cancer (NSCLC). However, molecular testing in patients with stage IA NSCLC may be limited by insufficient tissue availability, procedural invasiveness, and resource constraints. Therefore, developing a non-invasive approach for EGFR mutation prediction is of substantial clinical interest. This study aimed to develop a computed tomography (CT) radiomics based model integrating clinical variables for non-invasive prediction of EGFR mutation status in stage IA NSCLC patients. A total of 375 patients with stage IA NSCLC who underwent pre-treatment chest CT and EGFR mutation testing were retrospectively enrolled. Tumor volumes of interest (VOIs) were manually segmented on CT images, and radiomic features were extracted using the pyradiomics package. Clinical and radiomic features were selected through a feature selection pipeline, and multiple machine learning algorithms were evaluated for EGFR mutation prediction. Model performance was assessed using the Area Under Curve (AUC). Predictive performance varied across feature selection strategies and machine learning algorithms. Among all evaluated combinations, the Linear Regression (LR) model built using the Least Absolute Shrinkage and Selection Operator (LASSO)-30 feature set achieved the best performance, with a test-set AUC of 0.745. In this model, CT radiomic features served as the primary predictive component, while selected clinical variables provided complementary information and modestly improved predictive performance. These findings support the value of integrating radiomic and clinical features for non-invasive EGFR mutation prediction in early-stage NSCLC. A CT radiomics based model demonstrated only moderate performance for the non-invasive prediction of EGFR mutation status in patients with stage IA NSCLC. When clinical variables were incorporated, predictive performance improved, suggesting that clinical features provide complementary information beyond radiomics alone. The combined model highlights the added value of integrating CT-derived radiomics with clinical data for more accurate individualized molecular assessment, particularly when tissue-based genotyping is unavailable or limited.