Search Results (651)

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma (NHL) worldwide. Currently, approximately sixty percent of patients are cured with R-CHOP as frontline treatment, while the remaining patients experience primary refractory or relapsed (R/R) disease. Recently, the introduction of Pola-R-CHP as front-line therapy has represented a major advance in the management of DLBCL, resulting in improved outcomes. Prognosis of R/R DLBCL patients is poor, particularly for those eligible neither for chimeric antigen receptor (CAR) T-cell therapy nor autologous stem cell transplantation (ASCT), representing a significant unmet clinical need. The advent of bispecific monoclonal antibodies (BsAbs), such as bispecific T-cell engagers (BiTEs), dual affinity retargeting (DART) molecules and IgG-like bispecific antibodies, offers a novel promising therapeutic approach in the treatment of DLBCL, both as frontline treatment and in the R/R setting. BsAbs simultaneously engage two different antigens, a tumor-associated antigen and an immune cell antigen, redirecting T-cells against malignant cells and enhancing the immune response. Most BsAbs developed for the treatment of NHLs engage T-cells via CD3 and malignant B-cells via CD20, a surface antigen expressed on most lymphomatous cells. Engagement of malignant B-cells by BsAbs activates T-cells, leading to the release of multiple cytokines and potentially to two characteristic adverse events: cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The most extensively studied BsAbs, in both the frontline and relapsed/refractory (R/R) settings, include epcoritamab, glofitamab, mosunetuzumab, and odronextamab. Epcoritamab and glofitamab have received FDA and EMA approval for R/R DLBCL after two or more systemic line of therapies. EMA has also approved glofitamab in combination with gemcitabine and oxaliplatin (GemOx) for patients with R/R DLBCL ineligible for ASCT, whereas this indication has not been approved by FDA. Odronextamab is approved by EMA for R/R DLBCL and FL in patients who have received at least two prior lines of therapy, but it has not been approved by FDA. Mosunetuzumab is approved by both agencies—but only for R/R follicular lymphoma (FL). BsAbs represent a breakthrough therapy in the treatment of DLBCL, especially in R/R diseases. The purpose of this article is to review the landscape of BsAbs in DLBCL. Full article

Genomic studies have provided key insights into the molecular pathogenesis of differentiated thyroid carcinoma (DTC), including the role of genes involved in the homologous recombination (HR) related to DNA repair and genomic stability. This research aimed to investigate the genetic landscape of HR genes in thyroid pathology, associated with recurrence risk and clinical prognosis. The study involved six individuals with thyroid conditions, including two patients diagnosed with papillary thyroid carcinoma (PTC) and four individuals with benign thyroid disease. The research material consisted of tumor samples collected during surgical procedures. Protein interactions were analyzed using the STRING database (string-db.org). Homologous recombination genes were sequenced using the HRR Panel vr1.0 on the MiSeq™ Sequencing System. Bioinformatics analysis revealed a relationship between BRAF mutations and HR gene defects in PTC. Mutations in BRCA1, BRCA2, and FANCA genes, typically associated with thyroid tumors, were identified in the tissue of papillary thyroid cancer (PTC). A statistically significant correlation was found between the FANCA gene mutation (rs7195066) and the recurrent course of the PTC. The preliminary findings suggest a potential role for non-pathogenic BARD1 mutations in follicular adenoma. No significant association was found between genes involved in homologous recombination repair and the incidence of papillary thyroid carcinoma, suggesting that these genes may not play a major role in the development of this type of thyroid cancer. Full article

The ovary is among the earliest organs to undergo age-related degeneration, limiting the reproductive potential of elite horses and constraining the growth of the equine industry. Follicular development during estrus is a key determinant of fertility, yet the molecular mechanisms underlying its decline, particularly at the level of specific ovarian cell types, remain poorly understood in equids. Here, we constructed a single-cell transcriptomic atlas to investigate ovarian changes in Kazakh horses. Using single-cell RNA sequencing (scRNA-seq), we profiled 112,861 cells from follicle-containing and follicle-absent ovaries, identifying nine distinct ovarian cell types and their subtypes, each with distinct gene expression signatures. Functional enrichment analyses revealed cell type-specific engagement in biological pathways, including ECM–receptor interaction, PI3K-Akt signaling, and oxytocin signaling. Gene expression patterns indicated tightly regulated processes of ovarian activation and cell differentiation. Notably, stromal cells exhibited high expression of ROBO2, LOC111770199, and TMTC2, while smooth muscle cells (SMCs) were marked by elevated levels of CCL5, KLRD1, and NKG7. Moreover, cell–cell interaction analyses revealed robust signaling interactions among SMCs, endothelial cells, neurons, and proliferating (cycling) cells. Together, these findings provide a comprehensive single-cell transcriptomic map of normal and abnormal ovarian states during estrus in Kazakh horses, offering novel insights into the cellular mechanisms of follicular development and identifying potential diagnostic biomarkers and therapeutic targets for ovarian quiescence in equids. Full article

Ovine gammaherpesvirus 2 (OvGHV2) is a Macavirus and the cause of sheep-associated malignant catarrhal fever (SA-MCF) in susceptible mammalian hosts worldwide. OvGHV2 may produce typical clinical manifestations of SA-MCF or subclinical infections. Additionally, OvGHV2 is associated with cutaneous lesions in ruminants, with few documented reports of this unusual manifestation worldwide. This paper presents the pathological, immunohistochemical (IHC), and molecular findings observed in outbreaks of OvGHV2-related skin infections in dairy cattle from Southern Brazil. Cutaneous scrapings (n = 35) and biopsies (n = 6) were obtained from dairy cows derived from three farms. All cows (n = 35) developed widespread, ulcerative to scaly and erythematous skin lesions, and had no contact with sheep or goats. The biopsies were evaluated for histopathological diagnosis and then used in IHC analyses designed to detect malignant catarrhal fever virus (MCFV) antigens and to evaluate the inflammatory response. All scrapings and biopsies were used in PCR assays to amplify OvGHV2. Additionally, all biopsies were used in PCR assays to detect bovine gammaherpesvirus 6 (BoGHV6), bovine alphaherpesvirus 1 (BoAHV1), and poxvirus. Histopathology revealed chronic folliculitis in all biopsies. IHC detected intralesional, intracytoplasmic MCFV antigens in most (83.3%; 5/6) of the cutaneous lesions with folliculitis. These skin lesions showed a strong T-cell response, macrophage clusters, and caspase-positive follicular keratinocytes. OvGHV2 DNA was detected in 66.7% (4/6) of the cutaneous biopsies that contained MCFV antigens and in 8.6% (3/35) of the cutaneous scrapings. The DNA of BoGHV6, BoAHV1, and Poxvirus was not amplified from any of the cutaneous biopsies. These findings demonstrated that OvGHV2 was associated with the cutaneous lesions in dairy cows at these farms and represent the first description of OvGHV2-related skin disease in ruminants from Brazil and the entire Latin America. A review of previous cases of skin lesions associated with infections by OvGHV2 revealed that most cases had a histological diagnosis of folliculitis, suggesting that folliculitis may be associated with OvGHV2-related skin infections. Additionally, this investigation contrasts all previous reports of OvGHV2-related skin disease in ruminants, since the infected cows herein identified were not reared concomitantly or within proximity of the asymptomatic reservoir host. Furthermore, the possible form of OvGHV2 dissemination to the susceptible cows during this study is discussed. Full article

The aim of this study was to evaluate the effects of Flos lonicerae and Baikal skullcap extracts (PE) on laying performance, antioxidant capacity, immune function, follicular development, estrogen secretion, ovarian metabolomics, and cecal microbiota in aged laying hens. The total number of 70-week-old XinYang Black-Feathered laying hens was 240. These hens were randomly divided into two groups, with each group consisting of six replicates of 20 birds. Control (CON) group was fed a basal diet, whereas the PE group received the same basal diet supplemented with 500 mg/kg of PE. The duration of the experiment was 10 weeks. The findings indicated that the supplementation of PE improved laying performance, antioxidant capacity, and immune function. This was reflected by significant increases (p < 0.05) in laying rate, feed conversion ratio, antioxidant indicators (such as glutathione peroxidase, total antioxidant capacity, and catalase), and immunoglobulin levels. Additionally, there were notable decreases (p < 0.05) in the malondialdehyde levels and pro-inflammatory markers. Moreover, the PE group exhibited a greater number of large yellow and white follicles, as well as higher serum estrogen levels, compared to the CON group (p < 0.05). 16S rRNA sequencing revealed that PE supplementation altered the composition of the cecal microbiota by increasing Ruminococcus_torques_group, Butyricoccus and Christensenellaceae_R-7_group abundances and decreasing Bacteroides, Prevotellaceae_UCG-001 and Megamonas abundances (at genus level), which are primarily associated with short-chain fatty acid production. Ovarian metabolomic analysis showed that the major metabolites altered by PE supplementation were mainly involved in follicular development, estrogen biosynthesis, anti-inflammatory and antioxidant properties. Moreover, changes in both the cecal microbiota (at genus level) and ovarian metabolites were strongly correlated with laying performance, antioxidant status, and immune function. In conclusion, PE supplementation improved laying performance in aged hens by enhancing antioxidant, immune, and ovarian functions, promoting follicular development and estrogen secretion, and modulating the gut microbiota and ovarian metabolites. These findings will offer novel insights into the mechanisms that underlie egg production in the ovaries of aged poultry. Full article

The yak is a large ruminant that lives in the high-altitude and hypoxic environment of the Qinghai–Tibet Plateau in China and typically exhibits limited reproductive capacity, posing a significant challenge to the advancement of animal husbandry in the region. Retinoid X receptors (RXRs), as an important member of the NR superfamily, play a key role in the regulation of reproductive hormone synthesis, follicular development, and embryo implantation. However, there is still a lack of systematic research on the expression characteristics and potential functions of RXRs in the yak’s reproductive system. This study characterized RXR expression in ovarian, uterine, and oviductal tissues from three yaks per reproductive phase (follicular, luteal, and pregnancy). Using Quantitative Real-Time PCR Experiments (RT-qPCR), Western blot (WB), immunohistochemistry (IHC), and immunofluorescence (IF), we analyzed RXR mRNA and protein expression and localization. RXR expression varied significantly (p ≤ 0.05), peaking in ovaries during the follicular phase, oviducts during the luteal phase, and uteri during pregnancy. RXRs were localized in ovarian granulosa and theca cells, oviductal epithelium, and uterine endometrial glands, with dynamic nuclear–cytoplasmic shifts. These findings suggest RXRs regulate key reproductive processes in yaks, offering insights on improving fertility in high-altitude environments. Full article

Background: Primary cicatricial alopecias (PCA) are inflammatory disorders that cause permanent hair loss through follicular destruction and fibrosis. Hair transplantation (HT) may restore coverage in stable or end-stage PCA cases. This review assesses the efficacy of HT in PCA including optimal timing, graft survival rates, and the risk of disease reactivation. Material & Methods: A PubMed literature search identified 33 studies of HT in lichen planopilaris (LPP), frontal fibrosing alopecia (FFA), discoid lupus erythematosus, central centrifugal cicatricial alopecia, pseudopelade of Brocq, morphea en coup de sabre, and folliculitis decalvans from the 1960s to present. Reviews were excluded. Results: Among 147 PCA patients, 87.8% had positive HT outcomes. LPP showed high graft survival (70–90%). In contrast, eyebrow FFA (75%), folliculitis decalvans (25%), and scalp FFA (8.6%) had the highest failure rates. Follicular unit extraction was used slightly more than follicular unit transplantation. Notably, 46 patients developed PCA post-HT for presumed androgenetic alopecia. Discussion: HT in PCA can succeed with careful patient selection and stable disease (ideally ≥12–24 months). Graft survival varies by subtype. LPP has consistently reported successful outcomes post-transplantation, whereas folliculitis decalvans and FFA had the poorest outcomes. Adjuncts like immunosuppressants, PRP, and minoxidil may enhance results. Conclusions: Hair transplantation is viable in quiescent PCA, but outcomes are subtype-dependent. Many surgeons already perform these surgeries, but the published literature is lacking, and more research is needed to establish standardized timing, improve long-term graft survival, and clarify the risk of post-HT PCA onset. Full article

The aim of this study was to conduct a systematic review and meta-analysis to determine the prevalence of ovarian cysts in bitches and queens, to classify cyst subtypes, and to evaluate diagnostic and therapeutic strategies reported in the literature. A comprehensive search of PubMed, Scopus, and Google Scholar identified 4321 articles, of which 13 met the inclusion criteria, providing data on 428 bitches and 273 queens. The pooled prevalence of ovarian cysts was 41.7%, with follicular cysts being the most frequently reported subtype. Dogs were significantly more likely to develop cysts than cats, and animals older than five years had a markedly higher risk. Histopathology and ultrasonography were the predominant diagnostic methods, though only one study assessed diagnostic sensitivity. All included studies reported surgical treatment, while non-surgical options and postoperative outcomes were not evaluated. The studies suitable for analysis were also highly variable in reporting, from large studies with near 100% cyst presence in the sample studied, to small studies with relatively low cyst presence, which limits the ability to compute statistical outcomes in a highly reliable way. These findings highlight the high prevalence of ovarian cysts in small animals, particularly in older queens and bitches, and reveal major gaps in standardized diagnostic criteria, non-invasive biomarkers, and therapeutic research. Future prospective studies are needed to validate diagnostic tools, investigate medical management options, and improve evidence-based clinical decision-making in veterinary practice. Full article

Background/Objectives: Angioimmunoblastic T-cell lymphoma (AITL) is a rare peripheral T-cell lymphoma of follicular helper T-cell (TFH) origin, often associated with immune dysregulation and EBV-positive B-cell proliferation. Kaposi sarcoma (KS) is a vascular neoplasm caused by human herpesvirus 8 (HHV-8), typically arising in immunocompromised individuals. The synchronous occurrence of AITL and KS in HIV-negative patients is exceptionally rare, with only three cases previously reported worldwide. Case Presentation: We describe an 81-year-old HIV-negative Korean woman presenting with progressive generalized edema and dyspnea. Imaging revealed multifocal lymphadenopathy. Excisional biopsy of the inguinal lymph node showed two distinct but adjacent neoplastic processes. The AITL component demonstrated a polymorphous infiltrate of atypical TFH cells expressing CD3, CD4, CD10, PD-1, and Bcl-6, with monoclonal TCR-γ rearrangement and TET2 and RHOA mutations. The KS component comprised spindle cells with slit-like vascular spaces, red blood cell extravasation, and immunoreactivity for HHV-8, CD31, CD34, and ERG. The findings were consistent with a collision tumor. Despite supportive care, the patient’s condition deteriorated, and she was discharged with palliative care. Discussion: The coexistence of AITL and KS in an HIV-negative setting raises important pathogenetic considerations. AITL is characterized by profound immune dysregulation, with depletion of normal T-cell subsets, abnormal B-cell activation, and cytokine milieu changes that may favor latent viral reactivation. This immunologic environment may permit HHV-8 reactivation, thereby facilitating the development of KS even in the absence of overt immunodeficiency due to HIV infection. Our findings support the hypothesis that AITL-related immune dysfunction may create a permissive niche for HHV-8-driven neoplasia. Conclusions: This is the first reported case in Asia and the fourth worldwide of a collision tumor comprising AITL and KS in an HIV-negative patI dient. The case suggests that AITL-associated immune dysregulation may facilitate HHV-8 reactivation and KS development even in the absence of HIV infection. Awareness of this association is critical for accurate diagnosis and optimal patient management. Full article

Beyond well-known genetic drivers, microRNA dysregulation has emerged as a key contributor to thyroid tumorigenesis. Central to this process is Dicer1, a ribonuclease essential for microRNA maturation, whose expression is often reduced in papillary thyroid carcinoma (PTC). Evidence from previous studies suggest Dicer1 functions as a context-dependent haplo-insufficient tumor suppressor gene: partial loss may promote tumor development, whereas complete loss may disrupt essential cellular functions, causing cell death and tumor suppression. However, the effects of partial or complete Dicer1 loss in thyroid cancer remain unclear. To explore this, we genetically inactivated one (heterozygous) or both (homozygous) Dicer1 alleles specifically in thyroid follicular cells of a RET/PTC3 transgenic mouse model using an inducible Cre-Lox system. Our findings deepen the current understanding of the RET/PTC3-driven PTC model by revealing an increased number of vimentin-positive cells and disruption in redox homeostasis. Additionally, whereas heterozygous Dicer1 loss did not alter tumor progression in RET/PTC3 mice, total loss reduced tumor growth and led to accumulated DNA damage and cell death. These findings highlight the crucial role of Dicer1 dosage in thyroid cancer progression and underscore its potential as a therapeutic target for aggressive PTC and other malignancies characterized by aberrant Dicer1 expression. Full article

As essential skin appendages, hair follicles exhibit complex developmental and regenerative processes shaped by the skin microenvironment. Imbalances in skin microenvironmental homeostasis are often accompanied by follicle miniaturization and even hair loss. In studying the mechanisms of hair follicle development, in addition to focusing on the self-regulation of intrinsic signaling within the follicle, it is also crucial to examine the remodeling of the follicular microenvironment triggered by dynamic changes in the skin microenvironment. Herein, we review the individual and combined roles of various cells, tissues, signaling molecules, and metabolic alterations within the skin microenvironment in hair follicle development. Moreover, we summarize the potential applications of the skin microenvironment in treating hair-related diseases, highlight the existing challenges and limitations in the research field, and provide perspectives on future research directions, aiming to elucidate the critical role of the skin microenvironment in regulating hair follicle development. Full article

Purpose: Androgenetic alopecia (AGA) is a common, chronic, non-cicatricial dermatological condition characterized by progressive miniaturization of hair follicles. Although AGA is a benign disorder, it has a considerable impact on patients’ quality of life and psychological health. The current treatment options often demonstrate limited efficacy and are frequently associated with undesirable side effects. This study aimed to co-mill two natural compounds, quercetin (QT) and glycyrrhizic acid (GL), to develop follicle-targeted nanocrystals (NCs), thereby enhancing local accumulation, improving the pathological follicular microenvironment associated with AGA, and promoting hair regrowth. Methods: QT nanocrystals (QT-NCs) were fabricated using a top–down wet media milling technique with GL as a bioactive stabilizer. The resulting QT-NCs were characterized regarding their particle size, crystallinity, morphology, and stability. The skin permeation properties of the QT-NCs were further evaluated in vitro, and their therapeutic efficacy was assessed in a dihydrotestosterone (DHT)-induced AGA mouse model. Results: The QT-NCs exhibited an irregular structure with a particle size ranging from 200 to 300 nm, demonstrating uniform dimensions and excellent storage stability. In vitro permeation studies revealed a 2.27-fold increase in cumulative penetration and a 2.47-fold enhancement in skin retention compared to raw QT. In the DHT-induced AGA mouse model, QT-NCs significantly reduced local DHT levels while concurrently modulating the follicular microenvironment, resulting in markedly improved therapeutic outcomes. Notably, when co-administered, QT and GL demonstrated synergistic pharmacological effects, suggesting potential combinatory benefits. Conclusions: This study presents the first demonstration of QT-NCs for AGA treatment, establishing a novel therapeutic strategy with substantial potential for clinical translation. Full article

The dynamic balance between proliferation and apoptosis of follicular granulosa cells (GCs) is crucial for follicular development in poultry. microRNAs play important roles in ovarian development and follicular function. Previous transcriptome analyses showed that miR-194-3 was significantly differentially expressed in the ovaries of Zhedong white geese during the laying and brooding stages. Therefore, the aim of this study was to investigate the regulatory role and molecular mechanism of miR-194-3 on the proliferation and apoptosis of follicular GCs in Zhedong white geese. We first screened the target gene CHD4 of miR-194-3 and constructed the miR-194-3 mimic and inhibitor, a small interfering RNA of target gene CHD4. The experimental results showed that the overexpression of miR-194-3 significantly down-regulated the mRNA and protein expression of GC proliferation genes (PCNA, CDK-2, and CCND-1), reduced the proportion of EdU-labeled positive cells, blocked cell cycle progression, simultaneously up-regulated the mRNA and protein expression of Caspase-3 and Caspase-9, and significantly increased the rate of apoptosis. In contrast, the inhibition of miR-194-3 expression promoted the proliferation of goose follicular GCs, accelerated cell cycle progression, and decreased the apoptosis rate. Bioinformatics prediction combined with the results of the dual luciferase reporter assay confirmed that CHD4 was a direct target gene of miR-194-3. The knockdown of CHD4 expression resulted in the down-regulation of PCNA, CDK-2 and CCND-1 expression; blockage of cell cycle progression; attenuation of cell proliferation; an up-regulation of Caspase-3 and Caspase-9 expression and a significant increase in apoptotic cell death. In summary, both miR-194-3 overexpression and CHD4 knockdown produced similar effects on goose follicular GC proliferation and apoptosis, suggesting that CHD4 may partially mediate the regulatory effects of miR-194-3; however, additional targets or pathways cannot be excluded. Full article

Background: Effusion-based lymphoma (EBL) is a rare and aggressive large B-cell lymphoma. It presents as a body cavity effusion without a solid mass, lacks HHV-8 association, and typically expresses CD20. Objectives: To better understand the biology of this entity, we performed transcriptomic profiling of eight EBL cases. Methods: We analyzed the cases with the NanoString PanCancer Immune Profiling Panel and compared the results with publicly available datasets representing follicular lymphoma (FL), mantle cell lymphoma (MCL), and large B-cell lymphoma (LBCL) subtypes. Results: Unsupervised clustering and differential expression analysis revealed that EBL cases cluster transcriptionally with the LBCL group. Lymphoma-specific signaling pathway enrichment (SignatureDB) predominantly identified non-germinal center (activated B-cell-type) pathways. In addition, KEGG pathway analyses revealed enrichment in specific inflammatory and immune response pathways that are associated with B-cell lymphoma development in the setting of chronic inflammation, including those linked to Toll-like receptor and NF-κB signaling. Conclusions: These findings support a post-germinal center origin for EBL, which arises in a background of chronic inflammation and persistent antigen stimulation. Full article

Homeostasis must be maintained for the healthy living of an organism. In addition to physiological and anatomical homeostasis, the maintenance of the immune system, called immune homeostasis or immunohomeostasis, is critical for overall well-being and general homeostasis. CD8⁺ cytotoxic T cells/lymphocytes (CTLs) are crucial components of the adaptive immune systems of all vertebrates with a thymus. Hence, the thymus is an essential primary lymphoid organ (PLO) for developing T cell-mediated immunity (TCMI) that comprises CD4⁺ helper T cells (Th) cells and their subtypes, such as Th0 (naïve helper T cells), Th1 (pro-inflammatory Th cells that secrete IFN-γ), Th2 (secrete type 2 cytokines, such as IL-4, IL-5, IL-6, IL-10, and IL-13), Th9 (secrete IL-9), Th17 (secrete IL-17), Th22 (secrete IL-22), follicular Th cells (T_fhs, secrete IL-21), regulatory T cells (T_regs), and CD8⁺CTLs. The current article explores the critical role of CD8⁺CTLs in the maintenance of immune homeostasis. The role of the thymus (PLO) in generating and regulating CD8⁺CTLs, as well as mobilizing them to distant lymph nodes (LNs) and the spleen, which are referred to as secondary lymphoid organs (SLOs) and target organs, is discussed in section two of the article. The subsequent third section discusses the role of CD8⁺CTLs’ cytotoxic and immunoregulatory action to maintain immune homeostasis during infection and other inflammatory conditions. Moreover, they mask themselves to different cell types, like Th cells, such as Tc2s, Tc9s, Tc17s, and Tc22s, to maintain immune homeostasis. CD8⁺CTLs also behave as T_regs to exert their immunoregulatory functions. In addition to conventional CD8⁺CTLs, granzyme K (GzmK)⁺CD8⁺CTLs and CD4⁺CTLs with their cytotoxic action to maintain immune homeostasis have also been discussed. The next section discusses cell–cell (APC–CD8⁺CTL) interactions that not only increase the cytotoxic functions of CD8⁺CTLs but also program APCs to support their cytotoxic functions. These CD8⁺CTLs secrete different cytokines (IFN-γ and IL-10) and cytotoxic molecules (perforin and Gzms), which exert immunoregulatory actions to maintain immune homeostasis. The article concludes with a future perspective and a conclusion section, highlighting the critical need to understand CD8⁺CTLs’ cytotoxic and immunoregulatory functions in maintaining immune homeostasis across various diseases, including those with newly identified roles for CD8⁺CTLs. Full article