Search Results (142)

Bovine rotavirus (BRV) poses a major threat to the global cattle industry, driving significant morbidity and mortality in young calves. In Yunnan Province, China, BRV is the primary cause of neonatal calf diarrhea (NCD), yet the molecular epidemiology of circulating strains remains poorly understood. This study aimed to investigate the molecular characteristics of bovine rotavirus strains associated with a severe outbreak of the NCD on a local farm. Fecal samples were collected from 396 calves and screened for BRV by RT-PCR targeting the VP6 gene. Positive samples were subjected to virus isolation in MA104 cells, followed by whole-genome sequencing, phylogenetic analysis, and pathogenicity assessment in suckling mice. Of 396 samples, 85 tested positive for BRV, corresponding to an animal-level prevalence of 21.5% (95% CI: 17.5–25.8%), with four fatalities recorded. A strain designated as BRV-YN1-2021 was successfully isolated, exhibiting characteristic cytopathic effects, specific immunofluorescence, and typical rotavirus morphology by electron microscopy. Genomic analysis revealed the constellation G8-P[¹]-I2-R2-C2-M2-A3-N2-T6-E2-H3, identified as genotype G8P[¹]. BLAST analysis showed that four genomic segments shared the highest identity with deer rotavirus strains, five with human rotavirus strains, and two with bovine rotavirus strains. Phylogenetic analysis demonstrated close relationships with US deer strains, Japanese bovine strains, and human strains circulating in China. Experimental infection in suckling mice induced diarrhea and significant intestinal histopathology, degeneration of villous epithelial cells, goblet cell hyperplasia, and inflammatory infiltration. This study reports the first isolation of a G8P[¹] bovine rotavirus from a diarrhea outbreak in Chinese cattle. The multi-host genetic composition provides evidence of interspecies reassortment events, highlighting the zoonotic potential of BRV and emphasizing the need for continuous molecular surveillance to inform effective control strategies. Full article

Titanium dioxide nanoparticles (TiO₂ NPs), widely used as food additives, frequently coexist with high-fat diets (HD) in modern dietary patterns, yet their combined in vivo toxicity remains poorly understood. This study investigated the multi-organ effects of co-exposure to TiO₂ NPs or food-grade E171 and HD in male C57BL/6J mice. Mice were randomly assigned to six groups and fed regular or high-fat diets containing 1 wt% TiO₂ NPs or E171 for 13 weeks. Histopathology, serum biochemistry, organ coefficients, and open-field behavioral tests were used to assess tissue injury and functional alterations. Co-exposure to TiO₂ NPs and HD markedly exacerbated tissue damage across multiple organs. In the liver, more severe ballooning degeneration, necrosis, and inflammatory infiltration were observed, accompanied by altered liver enzymes and reduced organ coefficients. Intestinal injury was characterized by crypt distortion and increased inflammation, particularly in the HD + TiO₂ group. Testicular tissues showed disorganized seminiferous tubules, loss of spermatogenic cells, and interstitial hyperplasia. In the brain, hippocampal neurons exhibited pyknosis and disarray, with decreased brain coefficients and impaired exploratory behavior. E171 induced similar but milder effects. These findings indicate that HD enhances TiO₂ NPs induced multi-organ toxicity, highlighting the health risks of realistic co-exposure to dietary nanoparticles and high-fat foods. Full article

Background: Calcitonin, a tumor marker primarily used to diagnose medullary thyroid carcinoma (MTC), can also be elevated in other conditions, complicating diagnosis. This study aims to provide a clinical evaluation of the real-world consequences of unexplained calcitonin elevation. Methods: We conducted a retrospective cohort study of patients with elevated basal calcitonin levels who presented at the Department of General, Visceral, and Transplantation Surgery, University Medical Center Mainz, between January 2015 and March 2025. Additionally, we reviewed electronic health records from 2007 onward for patients with ICD codes indicating calcitonin hypersecretion. Patients with confirmed MTC or genetic syndromes were excluded. Results: Of 345 patients with elevated calcitonin levels, 167 (48%) met the inclusion criteria, and 29 additional patients with calcitonin hypersecretion were identified via ICD, resulting in 167 patients analyzed. More than half of the patients were female (52%), had an average age of 53.9 years and a high prevalence of goiter (86%). Calcitonin levels were slightly elevated (<20 pg/mL) in 81% of cases and were above 50 pg/mL in only 10 patients. Surgery was performed in 77% of patients, mainly to exclude malignancy. Postoperatively, calcitonin normalized in 86% of patients but remained elevated in eight patients. Two of these patients were found to have false-positive results due to assay interference. Follow-up data were incomplete for a substantial proportion of patients, with a median follow-up of 4.6 months. The mortality rate was 4%, with causes unrelated to calcitonin levels. Conclusions: Elevated basal calcitonin levels, especially slightly elevated levels (<20 pg/mL), are common in clinical practice and often do not appear to be related to malignant disease, so careful investigation is required. Persistently elevated calcitonin levels justify further examinations, especially if other explanations can be ruled out. Only a few patients attend follow-up appointments, which makes patient follow-up challenging. Full article

Background/Objectives: Psoriasis is a chronic, systemic, and multifactorial disease affecting approximately 1–2% of the Caucasian population. It is characterized by distinct histopathological features, including epidermal hyperplasia and infiltration of immune cells into the skin. Despite its high prevalence, the underlying mechanisms driving psoriasis remain incompletely understood. Heat shock proteins (HSPs), particularly HSP70, are known to play key roles in modulating immune responses and inflammation. Although previous studies have examined the involvement of HSPs in dermatological conditions such as psoriasis, current evidence remains inconclusive. In this study, we aimed to elucidate the role of Hsp70 deficiency in the pathogenesis of psoriasis using an in vivo model. Methods: We used male mice that were either genetically normal (Hsp70+/+) or lacked the Hsp70 gene (Hsp70−/−) at 8–12 weeks of age. Psoriasis was induced by applying imiquimod cream daily for 7 days. At the end of this period mice were sacrificed and blood and tissue collected for further analysis. The severity of the psoriasis was evaluated daily using the PASI Score. Results: Hsp70 depletion was accompanied by significantly decreased psoriatic-like skin inflammation, fewer histological abnormalities, and lower PASI scores. Flow cytometry analysis revealed a decrease in LY6C⁺ monocytes and an increase in LY6G⁺ neutrophils infiltration in Hsp70-deficient mice. In addition, HSP60 expression was lower in the absence of HSP70, while HSP90 expression was markedly elevated. Conclusions: These results point to a significant regulatory function of HSP70 in psoriatic inflammation and raise the possibility that it could be a therapeutic target. Full article

Splenic nodules in dogs that were historically classified under the broad term “fibrohistiocytic nodules” are now recognised as distinct entities within likely a biological continuum. These include lymphoid hyperplasia extending to indolent lymphoma and complex hyperplasia to stromal sarcoma. However, the molecular mechanisms underpinning these proposed progressions remain largely unexplored, particularly at the genomic and transcriptomic levels. This study aimed to delineate and compare the transcriptomic landscapes of four distinct canine splenic nodules through differential gene expression profiling. RNA sequencing was performed on twelve formalin-fixed, paraffin-embedded (FFPE) splenic tissue samples obtained from dogs diagnosed with lymphoid hyperplasia, complex hyperplasia, histiocytic sarcoma, and stromal sarcoma, with normal canine spleen serving as a control tissue. Comparative transcriptomic analysis identified 47 differentially expressed genes (DEGs) between splenic nodules and normal spleen, including CSRP1, SLC40A1, C1QA, C1QC, DLA-12, FTL, FXYD6, MPEG1, OAS3, CSF1, and JMJD6. Furthermore, 39 DEGs were significantly altered among the four splenic lesion types, such as MLC1, ERAS, MOV10L1, LOC102152143, COL4A1, COL4A2, COL12A1, NOTCH3, PLOD2, CPXM2, MRC1, GALNT5, TIMP1, and TFPI2. Many of these genes have previously been implicated in tumorigenesis and metastasis in other malignancies. These findings suggest that dysregulated gene expression may contribute to the activation of stromal cells and macrophages within the spleen, facilitating malignant transformation. Overall, these findings deliver novel transcriptomic insights into canine splenic tumorigenesis that may improve diagnostic precision, inform prognostic assessment, and support the development of targeted therapeutic strategies in veterinary oncology. Full article

Intimal hyperplasia (IH) at vascular anastomosis sites arises from endothelial injury, thrombin activation, and the subsequent proliferation and phenotypic modulation of vascular smooth muscle cells (VSMCs). Existing clinically used systemic pharmacologic regimens (e.g., antiplatelet/anticoagulant therapy) and reported local material-based strategies in the literature (e.g., drug-eluting sutures, hydrogels, or coatings) largely rely on drug release, which can result in burst kinetics, finite duration, and off-target/systemic exposure. We developed a covalently immobilized, non-releasing biointerface in which mitomycin C (MMC) is stably anchored onto polypropylene sutures via low-pressure, non-thermal acetic-acid plasma (AAP) activation. AAP functionalization introduced reactive oxygen-containing groups on polypropylene, enabling amide-bond immobilization of MMC while preserving suture mechanics. Anchored MMC exhibited potent contact-mediated regulation of VSMC fate, reducing metabolic activity to 81% of control, suppressing G₂/M progression, and inducing a dominant sub-G1 apoptotic population (66.3%), consistent with MMC-induced DNA crosslinking, p21 upregulation, and cyclin B1–CDK1 inhibition. In vivo, in a rat infrarenal aortic anastomosis model (male Wistar rats, 10–12 weeks, 300–350 g), MMC-anchored sutures markedly reduced arterial wall thickening and α-SMA and PCNA accumulation at 4 and 12 weeks, without overt evidence of systemic toxicity. Notably, no measurable MMC release was detected under the tested conditions, supporting that the observed bioactivity is consistent with an interface-confined mechanism rather than bulk diffusion. This work establishes a non-releasing suture-based platform that delivers sustained molecular regulation of vascular healing through interface-confined control of VSMC behavior. Covalent drug anchoring transforms a clinically used suture into an active therapeutic interface, providing a promising strategy to prevent pathological vascular remodeling and anastomotic IH. Full article

Acne vulgaris is a chronic inflammatory dermatosis where conventional therapies often face limitations in efficacy and safety, necessitating the development of microbiome-targeted interventions. This study investigated the immunomodulatory potential of microbiome-derived tryptophan metabolites as a novel therapeutic strategy for Cutibacterium acnes (C. acnes)-induced inflammation, focusing on the aryl hydrocarbon receptor (AHR) pathway. We evaluated indole-3-lactic acid (ILA), indole-3-acrylic acid (IAA), and indole-3-propionic acid (IPA) in comparison to tapinarof, utilizing C. acnes-stimulated human epidermal keratinocytes and a C. acnes-induced acne mouse model. In vitro, ILA and IPA significantly suppressed C. acnes-driven inflammatory mediators, including Tumor Necrosis Factor-alpha (TNF-α), Interleukin (IL)-1β, and Cyclooxygenase-2 (COX2), whereas IAA demonstrated limited efficacy. In vivo, ILA treatment exhibited superior therapeutic activity, markedly reducing inflammatory cell infiltration, epidermal hyperplasia, and IL-1β expression. Transcriptomic analysis confirmed that ILA attenuates inflammatory signaling (e.g., IL-17 and TNF pathways) while upregulating AHR-responsive genes such as Cytochrome (CYP) 1A1 and CYP1B1. Collectively, these findings establish ILA as a potent postbiotic that mitigates cutaneous inflammation through selective activation of the AHR. Future studies should prioritize the clinical translation of ILA-based topical formulations, with rigorous evaluation of their efficacy and safety in well-designed human trials, to support their development as a non-antibiotic therapeutic alternative for acne management. Full article

Sharp declines in temperature pose a significant risk for mass mortality events in the Chinese soft-shelled turtle (Pelodiscus sinensis). To assess the effects of acute cold stress on intestinal health, turtles were exposed to temperatures of 28 °C (control), 14 °C, and 7 °C for 1, 2, 4, 8, and 16 days. The results showed that acute cold stress at 14 °C and 7 °C induced time-dependent alterations in intestinal morphology and histopathology. The damage was more severe at 7 °C, characterized by inflammatory cell infiltration, lymphoid hyperplasia, and extensive detachment and necrosis across the villi, muscle layer, and submucosa. 16S rDNA sequencing revealed significant shifts in intestinal microbiota composition in the 7 °C group, dominated by Helicobacter and Citrobacter. Transcriptomic analysis identified differentially expressed genes (DEGs) that respond to acute cold stress and are involved in the Toll-like receptor signaling pathway (Tlr2, Tlr4, Tlr5, Tlr7, and Tlr8), the NOD-like receptor signaling pathway (Traf6, Traf2, Casr, Rnasel, Pstpip1, Plcb2, Atg5, and Mfn2), apoptosis (Tuba1c, Ctsz, Ctsb, Kras, Hras, Pik3ca, Bcl2l11, Gadd45a, Pmaip1, Ddit3, and Fos), and the p53 signaling pathway (Serpine1, Sesn2, Ccng2, Igf1, Mdm2, Gadd45a, Pmaip1, and Cdkn1a). Metabolomic profiling highlighted differentially expressed metabolites (DEMs) that cope with acute cold stress, such as organic acids (oxoglutaric acid, L-aspartic acid, fumaric acid, DL-malic acid, and citric acid) and amino acids (including L-lysine, L-homoserine, and allysine). The integrated analysis of DEGs and DEMs underscored three key pathways modulated by acute cold stress: linoleic acid metabolism, neuroactive ligand–receptor interaction, and the FoxO signaling pathway. This study provides a comprehensive evaluation of intestinal health in Chinese soft-shelled turtles under acute cold stress and elucidates the underlying mechanisms. Full article

Nodal marginal zone lymphoma (NMZL) is an indolent B-cell lymphoma that may pose diagnostic challenges due to the absence of distinct markers. In rare atypical cases, an overabundance of PD1+ T follicular helper (TFH) cells in tumor tissue may mimic peripheral T-cell lymphoma (PTCL) of TFH origin, further complicating the diagnosis. A 72-year-old woman with progressive lymphadenopathy had a cervical lymph node biopsy showing a disrupted architecture with monomorphic nodules of CD20+/MNDA+ B-cells and a prominent central population of proliferating CD4+/PD1+ T-cells, initially suggestive of a PTCL-TFH. The bone marrow contained aggregates of CD20+ B-cells intermixed with CD3+/CD4+/PD1+ T-cells. Next-generation sequencing (NGS) revealed clonal immunoglobulin heavy-chain rearrangements in the lymph node and bone marrow, with T-cell receptor genes displaying a polyclonal pattern. Targeted NGS showed no PTCL-related alterations but identified NMZL-associated mutations with different distributions across lymph node and bone marrow compartments. NOTCH2 mutations (c.6418C>T; p.Gln2140*) were found in both tissues, while the (c.69+2T>A; p.?) TNFRSF14 gene mutation was only detected in the lymph node. The KMT2D gene displayed a frameshift variant in the lymph node (c.4801_4802delinsT; p.Arg1601Leufs*3) and an in-frame deletion (c.11756_11758del; p.Gln3919del) in the bone marrow. Notably, NGS and digital droplet PCR confirmed a TP53 frameshift mutation (c.902del; p.Pro301Glnfs*44) with a fractional abundance of 0.31% in the lymph node and a (c.742C>T; p.Arg248Trp) mutation (0.309%) in the bone marrow. Results underscore the importance of NGS-based clonality to diagnose NMZL with prominent PD1+ T-cell hyperplasia, and prompt further investigation into tissue-specific mutational signatures in these unusual cases. Full article

This study evaluated hepatic pathological and phenotypic alterations, along with the inflammatory response, following sequential dengue virus (DENV) infection in Callithrix penicillata, a relevant model for human endemic scenarios. Twenty-six animals were initially infected subcutaneously with DENV-3. Thirteen were euthanized between 1 and 7 days post-infection (dpi) to assess the acute phase, and up to 60 dpi for the convalescent phase. The remaining animals received a secondary DENV-2 infection two months later. Liver samples underwent histopathological and immunohistochemical analysis. Viral antigens were identified in hepatocytes, Kupffer cells, and Councilman bodies. Observed liver changes included apoptosis, lytic necrosis, midzonal inflammation, Kupffer cell hyperplasia and hypertrophy, sinusoidal dilation, and hemosiderin deposition. Both primary and secondary infections increased activated macrophages, NK cells, S-100 protein, and B lymphocytes. Primary infection was associated with elevated CD4⁺ T cells, IFN-γ, TGF-β, IL-10, and Fas expression, whereas secondary infection induced higher IFN-γ, TNF-α, IL-8, Fas, and VCAM levels. These findings mirror hepatic alterations in severe human dengue cases and underscore the role of direct viral effects and immune dysregulation in liver injury. The results support C. penicillata as a suitable non-human primate model for studying DENV pathogenesis. Full article

Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by dysregulated immunity, skin barrier dysfunction, and cutaneous microbiome dysbiosis. While current therapies face limitations, Thuja sutchuenensis essential oil (TEO) shows promise due to its multi-target potential. We sought to explore the beneficial effects of TEO and delve into its mechanistic actions in a mouse model of AD. We combined network pharmacology with in vivo validation to evaluate the therapeutic efficacy and mechanisms of TEO in an AD model, and confirmed network-predicted targets in an in vitro inflammatory cell model. In AD mice, TEO alleviated pruritus and epidermal hyperplasia, suppressed systemic IL-4/TNF-α and IgE, and partially normalized serum ALB, LDL-C, and HDL-C. Microbial diversity increased after treatment, although potentially pathogenic taxa (Arthrobacter sp. and Corynebacterium mastitidis) remained enriched. Machine-learning analysis indicated the highest predicted metabolic activity in CK controls, whereas the AD and TEO groups showed elevated pathogenic phenotype scores. Network pharmacology prioritized active compounds [(E)-ligustilide, senkyunolide A, 3-butylisobenzofuran-1(3H)-one, butylated hydroxytoluene, Z-buthlidenephthalide, and β-Myrcene] and core targets (TNF, PTPRC, CCR5, JAK1), implicating T-cell receptor signaling, Staphylococcus aureus infection, and STAT3 pathways. Docking and molecular dynamics supported strong, stable binding of major constituents to JAK1, and Western blotting confirmed TEO-mediated inhibition of the JAK1/STAT3 axis. TEO effectively alleviates atopic dermatitis symptoms by modulating immune responses and enhancing microbial diversity. It targets key signaling pathways, such as JAK1/STAT3, highlighting its potential as a therapeutic option for AD. Full article

With growing concerns over the safety of synthetic substances, the development of plant-derived alternatives with minimal adverse effects has gained significant attention. Carica papaya L. peel contains a rich profile of bioactive compounds, including papain, flavonoids, and vitamin C, which exhibit potent antioxidant and anti-inflammatory properties. This study aimed to evaluate the effects of an ethanol extract of C. papaya peel (EECP) on inflammation and skin barrier dysfunction in a mouse model of contact dermatitis (CD) induced by 1-fluoro-2,4-dinitrofluorobenzene (DNFB). Mice were treated by applying EECP at three different levels (60, 80, and 600 μg) to dorsal skin for six days. Skin lesion severity, skin color, skin barrier function (SBF, as indicated by water content and water-holding capacity (WHC)), histopathological abnormalities, cytokine levels, filaggrin and Intercellular Adhesion Molecule-1 (ICAM-1) expression, and phosphorylation of MAPK (Mitogen-Activated Protein Kinase) signaling molecules were assessed. EECP treatment significantly alleviated the CD-associated dermal symptoms induced by DNFB, including skin fissures, scabbing, roughness, changes in color, water content, and WHC, as well as petechiae. EECP also prevented histopathological abnormalities such as epidermal hyperplasia, spongiotic changes, and immune cell infiltration. In addition, EECP suppressed the production of pro-inflammatory cytokines, viz. TNF-α, IFN-γ, IL-6, and MCP-1. In addition, EECP restored filaggrin expression and inhibited ERK (Extracellular signal-regulated kinases) phosphorylation and ICAM-1 expression in HaCaT cells. In summary, C. papaya peel demonstrated therapeutic potential by effectively suppressing inflammation and restoring SBF. These findings support the potential use of EECP as a safe and effective botanical candidate for the treatment of CD and the promotion of overall skin health Full article

Der p 23 induces a high-frequency sensitization in allergic individuals. However, its allergenic activity and clinical impact are scarce. We aimed to evaluate the ability of rDer p 23 to induce allergic inflammation in a mouse model and to test IgE reactivity in humans. Female Balb/c mice were sensitized and challenged with rDer p 23 and Dermatophagoides pteronyssinus extract. Specific antibodies were determined by ELISA, inflammatory cell infiltration and goblet cells hyperplasia were evaluated by lung histology, and bronchial hyperreactivity (BHR) was assessed by the FinePoint RC System^TM and whole-body plethysmography (WBP). IgE reactivity was evaluated by ELISA, the basophils activation test (BAT) and the skin pick test (SPT) in humans. rDer p 23, produced in Escherichia coli, adopts a random coil structure, predominantly exists in a monomeric state, and exhibits high stability. rDer p 23-treated mice showed a significant increase in lung resistance and bronchial hyperreactivity, as well as in eosinophils, neutrophils, and T cell count in bronchoalveolar lavage fluid (BALF). Cytokine and antibodies profiles were biased to a Type-2 response. No significant difference was observed in group 2 Innate Lymphoid Cells (ILC-2s) in lung and regulatory T cells (Treg) in the spleen. In asthmatic individuals sensitized to D. pteronyssinus, serum IgE reactivity to rDer p 23 was 67.5%. BAT and SPT results were significantly higher in allergic patients. Our findings support the pro-allergenic role of rDer p 23 in the development of the pathological features of asthma. Full article

Introduction: Prostate cancer (PC) accounts for around 10% of all cancers worldwide and is the fourth most common neoplasm. Localized PC has high cure rates when diagnosed early, but 35% of patients progress to the metastatic form. The search for new molecular markers, such as microRNAs, is fundamental to improving diagnosis and treatment. The role of miR-10a is controversial between tumor tissues, opening a niche for studies on their role in PC. Objectives: To evaluate the role of miR-10a in metastatic PC cell lines, focusing on the mechanisms of proliferation, migration, and invasion, and to analyze the expression in surgical specimens of localized PC. Methods: Three commercial metastatic PC cell lines were used: LNCaP, DU145 and PC-3. Expression of mimic miR-10a was induced by cell transfection, followed by extraction of miRNA and total RNA. The synthesis of complementary DNA (cDNA) and analysis by real-time PCR enabled the expression of miR-10a and the VEGF, MYC, and HAS3 genes to be assessed. Matrigel, colony formation, invasion, and migration assays were evaluated for the transfected cells. The surgical specimens were used to evaluate the miR-10a expression. Results: Transfected cells with mimic significantly increased the expression of miR-10a in the LNCaP (p = 0.0179), PC-3 (p ≤ 0.001), and DU145 (p ≤ 0.001) cell lines. Transfected cells reduced cell invasion in the PC-3 (p = 0.001) and DU-145 (p = 0.0004) cell lines and decreased cell migration and proliferation. In surgical specimens, miR-10a expression was higher in PC compared to Benign Prostatic Hyperplasia (p = 0.0010). Conclusions: Increased expression of miR-10a affects cell migration, invasion, and proliferation, showing potential as a therapeutic target in treating PC. Full article

Medullary thyroid carcinoma (MTC) is a thyroid tumor with neuroendocrine properties purportedly derived from C-cells. The biochemical activity of medullary thyroid carcinoma includes the production of calcitonin and carcinoembryonic antigen, which are sensitive tumor markers, facilitating diagnosis, follow-up, and prognostication. Calcitonin-negative medullary thyroid carcinoma is a rare, poorly understood primary neuroendocrine carcinoma of the thyroid characterized by classic medullary thyroid carcinoma morphology without raised serum calcitonin and with or without the expression of calcitonin detected by immunohistochemistry. Previous studies reported that C-cells were derived from the neural crest; however, more recently, C-cells have been indisputably shown to be derived from the pharyngeal endoderm and ultimobranchial bodies. Ultimobranchial body (UBB) remnants can persist in the thyroid and express p63, but their function is poorly understood. Some have postulated that ultimobranchial bodies may be the “stem” cell of the thyroid and may be precursors for thyroid tumors, particularly mixed tumors with follicular and medullary components. We present a unique case of calcitonin-negative MTC in a 58-year-old male arising in an inflamed and fibrotic thyroid with numerous scattered ultimobranchial body remnants and concomitant C-cell hyperplasia/medullary microcarcinoma (CCH/MMC). The ultimobranchial body remnants, C-cell hyperplasia, and medullary thyroid carcinoma were MTC classifier positive according to ThyroSeq^®. The areas representing CCH/MMC expressed calcitonin by IHC while the main MTC tumor was negative. An additional unique feature was an area demonstrating a “mixed” C-cell/thyroid follicular epithelial phenotype. In this review we review the possible etiologies of calcitonin-negative MTC, the possibility of a neoplastic sequential progression from ultimobranchial bodies to CCH/MMC to medullary thyroid carcinoma with the individual elements (UBB, CCH/MMC, MTC) demonstrated in this thyroid, and previous postulations that ultimobranchial bodies may be the source of some follicular thyroid cancers, medullary thyroid cancers, and mixed tumors of medullary and follicular epithelial types. Full article