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This article defines immunophenotypes of stromal inflammatory and endothelial cells and fibroblasts 3 months after augmentation of the peri-implant soft tissue using a porcine cross-linked collagen matrix (VCMX). Peri-implant soft tissue samples were obtained from 12 patients at the lining mucosa (LM)-masticatory mucosa (MM) junction before (1) and 3 months after (2) augmentation. Immu-nohistochemical stains were performed to identify inflammatory cells (T [CD3] and B [CD20] lymphocytes, plasma cells [CD138]), macrophages (CD68-proinflammatory, CD163-anti-inflammatory/ reparative), endothelial cells (CD31, CD34), and fibroblasts (CD90, TE-7). Differences in the mean positively stained cells pre- and postaugmentation were analyzed by Wilcoxon signed-rank test. CD31+ endothelial cells showed increased mean numbers in MM2 compared to MM1 (P = .025) and in LM2 compared to LM1 (P = .047). CD163+ anti-inflammatory macrophages showed higher mean numbers in MM2 than in MM1 (P = .021) and in LM2 than in LM1 (P = .012). All other cell phenotypes showed nonsignificant changes between pre- and postaugmentation. This molecular study provides novel insight on the frequency of stromal cell phenotypes in the wound healing process at 3 months postaugmentation with VCMX, with anti-inflammatory CD163+ macrophages being predominant. This should be further investigated to help find novel therapeutic approaches to modulate and promote the VCMX-related healing process. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the effect of interleukin-6 (IL-6) inhibitor (tocilizumab) on bacterial infection-associated bone resorption around implants during osseointegration in rabbits. Materials and Methods: At total of 24 male, 9-monthold New Zealand white rabbits were included, and their two mandibular anterior teeth were extracted. Three months after extraction, 24 one-piece Dentium implants (Ø 2.5 mm, intraosseous length of 12 mm) were inserted in the anterior mandible, and the rabbits were divided into four groups (n = 6 per group). Different treatment methods were used in each group: blank control group (BC); only silk ligation (negative control [NC]); silk ligation and injection with minocycline hydrochloride ointment (positive control [PC]); and silk ligation and injection with tocilizumab at 8 mg/kg via the auricle vein (experimental [EP]). Eight weeks later, the animals were sacrificed, and samples were collected and then analyzed using microcomputed tomography (microCT) scanning, immunohistochemical analysis, and histologic analysis. Results: From the microCT measurement, the ratio of the bone volume to the total volume (BV/TV) in the EP group was 67.00% ± 2.72%, which was higher than that in the other three groups (58.85% ± 2.43% in the BC group, 55.72% ± 2.48% in the PC group, and 36.52% ± 3.02% in the NC group). From immunohistochemical analysis, the expression of IL-6 was found to be higher in the NC group than in the BC, PC, and EP groups, but there was no statistical difference between these three groups. Furthermore, the RANKL (receptor activator of nuclear factor-κB ligand) expression was the lowest in the EP group, followed by the BC group, the PC group, and the NC group, which had the highest expression; there was no difference between the NC and PC groups. Upon histologic analysis, significant new bone was found on the implant surfaces in the EP group, sparse and less new bone could be seen in the BC and PC groups, and the most serious bone resorption occurred in the NC group. Conclusions: Tocilizumab, an inhibitor of IL-6, has a certain effect in preventing bone loss around implants caused by bacterial infection during the osseointegration period. [ABSTRACT FROM AUTHOR]

Secretory carcinoma is a malignant salivary gland tumor, which typically presents as an indolent painless mass within the parotid gland. Involvement of the minor gland is reported but less common. Secretory carcinoma was often misclassified as other salivary gland mimics, particularly acinic cell carcinoma, prior to 2010. It was first recognized as a molecularly distinct salivary gland tumor harboring the same fusion gene as well as histologic and cytogenetic features seen in juvenile breast cancer. Secretory carcinoma is generally managed in the same way as other low-grade salivary gland neoplasms and has a favorable prognosis; however, high-grade transformation requiring aggressive therapeutic interventions have been documented. Recent studies of biologic agents targeting products of this fusion gene offer the promise of a novel therapeutic option for treatment of this malignancy. Due to the limited number of reported cases, the spectrum of clinical behavior, best practices for management, and long-term treatment outcomes for secretory carcinoma remain unclear. A long-standing secretory carcinoma involving minor salivary glands of the mucobuccal fold, which was detected years after it was first noted by the patient, is reported. This case brings to light the importance of a thorough clinical exam during dental visits and reviews diagnostic differentiation of this malignancy from other mimics and discusses decision making for its management. [ABSTRACT FROM AUTHOR]

Purpose: To investigate bone regeneration among three different bone graft materials in a rat calvarum model. Materials and Methods: A total of 24 rats had two 5-mm defects placed per calvarial. Rats were divided into four groups: bovine xenograft (XG), demineralized bone matrix (DBM), mineralized bone graft (MBG), and collagen membrane control (CC). Within each group, samples were collected at two time points: 4 weeks (T4) and 8 weeks (T8). Bone regeneration was assessed by microcomputed tomography (micro-CT) imaging and was analyzed using MATLAB software. Additionally, the fixed samples were subsequently demineralized for immunohistochemistry and histomorphometry. Slides were mounted and stained with hematoxylin and eosin (H&E) stain as well as bone morphogenetic protein 2 (BMP-2) and runt-related transcription factor 2 (RUNX2) markers. The numbers of positive cells/area were calculated for each group and analyzed. Results: At 4 weeks, DBM showed low mineral density (7.7%) compared to the control (25.2%), but increased dramatically at 8 weeks (DBM, T8 = 27.6%; CC, T8 = 27.2%). Xenograft material showed an increase in mineral desnity between T4 and T8 (XG, T4 = 25.0%; XG, T8 = 32.3%). MBG remained consistent over the 8-week trial period (MBG, T4 = 30.4%; MBG, T8 = 30.4%). BMP-2 expression was present in cells adherent to all graft materials. RUNX2 expression was also observed in cells adherent to all graft materials, indicating that during the 4- to 8-week healing period, all materials supported osteogenesis. Conclusions: Compared to other materials, the DBM had high osteoinductive properties during the 4- to 8-week time period based on increased mineral content. All materials were associated with immunohistologic evidence of osteogenesis in the rat calvarial defect model. [ABSTRACT FROM AUTHOR]

Purpose: To analyze the process of early oral osseointegration of titanium (Ti) implants in diabetic 129/Sv mice through microCT and histologic and immunohistochemical analysis. Materials and Methods: A group of 30 male 129/Sv mice was equally subdivided into two groups: (1) nondiabetic (ND), in which mice did not undergo systemic alterations and received a standard diet, and (2) diabetic (D), in which mice were provided a high-fat diet from the age of 6 weeks until the conclusion of the study and received two intraperitoneal (IP) injections of streptozotocin (STZ) at a concentration of 100 mg/Kg each. Each mouse underwent extraction of a maxillary first molar, and customized Ti screws (0.50 mm diameter, 1.5 mm length) were placed in the residual alveolar sockets of the palatal roots. At 7 and 21 days after implant placement, the animals were euthanized for maxilla and pancreas collection. Maxillae containing Ti implants were analyzed with microCT, histology, and immunohistochemistry for cells that were positive for F4/80, CD146, runt-related transcription factor 2 (Runx2), and proliferating cell nuclear antigen (PCNA). Pancreata were histologically analyzed. Quantitative data were statistically analyzed with a significance level at 5% (P < .05). Results: ND mice presented successful healing and osseointegration, with a significantly higher fraction of bone volume compared to D mice, both at the alveolar sockets (53.39 ± 5.93 and 46.08 ± 3.18, respectively) and at the implant sites (68.88 ± 7.07 and 44.40 ± 6.98, respectively) 21 days after implant placement. Histologic evaluation revealed that the ND mice showed a significant decrease in inflammatory infiltrate and a significant increase in newly formed bone matrix at 21 days, whereas peri-implant sites in the D mice were predominantly encapsulated by fibrous tissue and chronic inflammatory infiltrate. Immunohistochemical characterization revealed higher Runx2 osteoblast differentiation and higher cell proliferation activity in the ND mice at 7 days, while higher amounts of macrophages were present in D mice at 7 and 21 days. Interestingly, no differences were found in CD146-positive cells when comparing ND and D mice. Conclusions: This study evaluated the effects of immediate dental implant placement in 129/Sv diabetic mice by using specific healing markers to identify changes in cellular events involved in early oral osseointegration. This approach may serve as tool to evaluate new materials and surface coatings to improve osseointegration in diabetic patients. [ABSTRACT FROM AUTHOR]

Objective: To histologically evaluate the effects of a novel human recombinant amelogenin (rAmelX) on periodontal wound healing/regeneration in intrabony defects. Method and mater-ials: Intrabony defects were surgically created in the mandible of three minipigs. Twelve defects were randomly treated with either rAmelX and carrier (test group) or with the carrier only (control group). At 3 months following reconstructive surgery, the animals were euthanized, and the tissues histologically processed. Thereafter, descriptive histology, histometry, and statistical analyses were performed. Results: Postoperative clinical healing was uneventful. At the defect level, no adverse reactions (eg, suppuration, abscess formation, unusual inflammatory reaction) were observed with a good biocompatibility of the tested products. The test group yielded higher values for new cementum formation (4.81 ± 1.17 mm) compared to the control group (4.39 ± 1.71 mm) without reaching statistical significance (P= .937). Moreover, regrowth of new bone was greater in the test compared to the control group (3.51 mm and 2.97 mm, respectively, P = .309). Conclusions: The present results provided for the first-time histologic evidence for periodontal regeneration following the use of rAmelX in intrabony defects, thus pointing to the potential of this novel recombinant amelogenin as a possible alternative to regenerative materials from animal origins. [ABSTRACT FROM AUTHOR]

Melanoma is the most aggressive type of skin cancer and can metastasize during primary tumor formation. This research aimed to determine the relationship between the prevention of melanoma development in a mouse model treated with liposomes loaded with soybean lunasin and amaranth unsaponifiable matter (UM + LunLip) and cell cycle arrest. Tumors excised from C57BL/6 mice treated topically or subcutaneously with UM + LunLip were subjected to immunohistochemistry. Markers related to cell cycle inhibition (p16, p21, p27, and p53) and markers involved in cell cycle progression (cyclin-dependent kinase, CDK6, and cyclin D1) were assessed. The results showed that UM + LunLip had antitumor activity in C57BL/6 mice treated either topically or subcutaneously by p16, p21, p27, and p53 overexpression (up to 572-, 134-, 30-, and 57-fold change, FC, respectively) in the tumors of mice treated with 30 mg UM + LunLip/kg body weight compared with the tumor-bearing untreated control. However, CDK6 and cyclin D1 expression was not inhibited (up to 1.37 FC and 2.09 FC, respectively), which is a typical behavior of cyclin D in melanoma. Therefore, melanoma tumor development was prevented by the overexpression of cell cycle inhibitors p16, p21, p27, and p53 due to UM + LunLip treatments. Since the topical application was effective, less invasive, and more practical for the user, this application will be recommended for future steps in in vivo studies. [ABSTRACT FROM AUTHOR]

Background: Medication overuse headache (MOH) is the most common secondary headache disorder, resulting from chronic and excessive use of medication to treat headaches, for example, sumatriptan. In a recent study, we have shown that the peripheral C-C motif ligand 2 (CCL2), C-C motif chemokine receptor 2 (CCR2) and calcitonin-gene-related peptide (CGRP) signaling pathways interact with each other and play critical roles in the development of chronic migraine-related behavioral and cellular sensitization. In the present study, we investigated whether CCL2-CCR2 and CGRP signaling pathways play a role in the development of sumatriptan overuse-induced sensitization, and whether they are involved in its resolution by the low-dose interleukin-2 (LD-IL-2) treatment. Methods: Mice received daily sumatriptan administration for 12 days. MOH-related behavioral sensitization was assessed by measuring changes of periorbital mechanical thresholds for 3 weeks. CCL2-CCR2 and CGRP signaling pathways were inhibited by targeted gene deletion or with an anti-CCL2 antibody. Ca2+-imaging was used to examine whether repetitive sumatriptan treatment enhances CGRP and pituitary adenylate cyclase–activating polypeptide (PACAP) signaling in trigeminal ganglion (TG) neurons. LD-IL-2 treatment was initiated after the establishment of sumatriptan-induced sensitization. Immunohistochemistry and flow cytometry analyses were used to examine whether CCL2-CCR2 signaling controls regulatory T (Treg) cell proliferation and/or trafficking. Results: CCL2, CCR2 and CGRPα global KO mice exhibited robust sumatriptan-induced behavioral sensitization comparable to wild-type controls. Antibody neutralization of peripheral CCL2 did not affect sumatriptan-induced behaviors either. Repeated sumatriptan administration did not enhance the strength of CGRP or PACAP signaling in TG neurons. Nevertheless, LD-IL-2 treatment, which facilitated the resolution of sumatriptan-induced sensitization in wild-type and CGRPα KO mice, was completely ineffective in mice with compromised CCL2-CCR2 signaling. In CCL2 KO mice, we observed normal LD-IL-2-induced Treg expansion in peripheral blood, but the increase of Treg cells in dura and TG tissues was significantly reduced in LD-IL-2-treated CCL2 KO mice relative to wild-type controls. Conclusions: These results indicate that the endogenous CCL2-CCR2 and CGRP signaling pathways are not involved in sumatriptan-induced behavioral sensitization, suggesting that distinct molecular mechanisms underlie chronic migraine and MOH. On the other hand, peripheral CCL2-CCR2 signaling is required for LD-IL-2 to reverse chronic headache-related sensitization. [ABSTRACT FROM AUTHOR]

Introduction: Activated vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs) and c-Kit have been shown to be involved in the growth, invasion and metastasis of non-rhabdomyosarcoma soft tissue sarcoma tumor (NRSTS) with promising results for targeted therapy. Our aim was to assess the expression of these markers among different histological types and correlate with outcomes. Material and methods: This retrospective study included pediatric patients aged ≤ 18 years diagnosed with high-grade NRSTS who were treated at Children Cancer Hospital Egypt 57357 as per the COG NRSTS protocol (ARST0332). Expression of VEGFR2, PDGFRs (α and β) and c-Kit in tumor tissue was assessed by immunohistochemistry and correlated with clinical outcome. Results: Of 113 patients, 96 were eligible for the analysis with a median age of 11 years. Overall, 32.3% demonstrated high expression of PDGFRα, 17.7% for PDGFRβ, 19.8% for VEGFR2 and 8.3% exhibited positive expression for c-kit on the tumor cells. Most cases of synovial sarcoma (45.8%) and 43.7% of patients with undifferentiated sarcoma exhibited high expression of PDGFRα while 41.6% of MPNST showed high expression to PDGFRβ. The 5-year overall survival (OS), event free survival and relapse free survival (RFS) for the whole cohort were 59%, 54% and 60% respectively. In univariate analyses, only PDGFRα had a negative prognostic impact on relapse free survival (RFS) (p =0.03). In multivariate analyses, VEGFR2 was found to have a negative prognostic impact for OS (p = 0.02). Conclusion: Our findings indicated that tyrosine kinase receptors are upregulated in NRSTS and exhibited a distinct expression pattern within various subgroups. High expression of VEGFR2 and PDGFRα significantly correlated with reduced survival and may guide targeted therapy approaches for this poor prognosis group of patients. [ABSTRACT FROM AUTHOR]

Background: Calcitonin gene-related peptide (CGRP) is part of the calcitonin peptide family, which includes calcitonin (CT), amylin (AMY), and adrenomedullin (ADM). CGRP and its receptor are highly present in the trigeminovascular system (TVS). Recent research suggests that other members of the calcitonin family could be feasible therapeutic targets in the treatment of migraine. The present study aims to elucidate the distribution of ADM, AMY, CT, and their receptors in the rat TVS, and to explore potential sex differences in their expression. Methods: Trigeminal ganglia (TG) were dissected from male and female adult rats. Protein and gene expression were assessed through immunohistochemistry and RT-qPCR. Additionally, the dura mater was isolated for further investigation of protein expression and fiber localization using immunohistochemistry. Results: Quantitative gene expression analysis revealed the presence of all genes in male and female TGs, except for calcitonin receptor (CTR). Notably, CGRP mRNA levels in TG were several folds higher than those of other genes. The receptor activity-modifying protein-1 (RAMP1) mRNA levels were significantly higher in female compared to male. No AMY or CT immunoreactivity was observed in the TVS. In contrast, immunoreactivity for ADM, CGRP, RAMP1, CTR, and calcitonin-like receptor (CLR) were observed in the cytoplasm of TG neurons. Immunoreactive Aδ-fibers storing RAMP1, ADM and CLR were also identified. RAMP2 and RAMP3 were expressed in nucleus of TG neurons and in satellite glial cells. Furthermore, RAMP1 and CLR were co-localized with CASPR in the nodes of Ranvier located in Aδ-fibers. Conclusions: This study provides valuable insights into the distribution of the CGRP family of peptides and their receptors in the TVS. CGRP mRNA levels in the TG were markedly higher than those of other genes, demonstrating the key role of CGRP. The co-localization of CLR and RAMP1 on Aδ-fibers with CASPR suggests a potential role for this receptor in modulating trigeminal nerve function and neuronal excitability, with implications for migraine pathophysiology. Additionally, RAMP1 mRNA levels were significantly higher in female TG compared to males, indicating sex-specific differences in gene expression. These findings underscore the need for further research into the functional significance of gender-related variations. [ABSTRACT FROM AUTHOR]

Epigenetic changes accompany the dynamic changes in the cell wall composition during the development of callus cells. H3K4me3 is responsible for active gene expression and reaction to environmental cues. Chromatin immunoprecipitation (ChIP) is a powerful technique for studying the interplay between epigenetic modifications and the DNA regions of interest. In combination with sequencing, it can provide the genome-wide enrichment of the specific epigenetic mark, providing vital information on its involvement in the plethora of cellular processes. Here, we describe the genome-wide distribution of H3K4me3 in morphogenic and non-morphogenic callus of Fagopyrum tataricum. Levels of H3K4me3 were higher around the transcription start site, in agreement with the role of this mark in transcriptional activation. The global levels of methylation were higher in the non-morphogenic callus, which indicated increased gene activation compared to the morphogenic callus. We also employed ChIP to analyse the changes in the enrichment of this epigenetic mark on the cell wall-related genes in both calli types during the course of the passage. Enrichment of H3K4me3 on cell wall genes was specific for callus type, suggesting that the role of this mark in cell-wall remodelling is complex and involved in many processes related to dedifferentiation and redifferentiation. This intricacy of the cell wall composition was supported by the immunohistochemical analysis of the cell wall epitopes' distribution of pectins and extensins. Together, these data give a novel insight into the involvement of H3K4me3 in the regeneration processes in F. tataricum in vitro callus tissue culture. [ABSTRACT FROM AUTHOR]

Background: Intervertebral disc degeneration (IDD) was the most common cause of low back pain. Platelet rich plasma (PRP) has the potential to repair IDD, however, there is still no conclusion on whether Leukocyte-poor platelet rich plasma (Lp-PRP) or Leukocyte-rich platelet rich plasma (Lr-PRP) is better for the treatment of IDD. Methods: First, we conducted an in vitro study to compare the effects of autologous Lp-PRP and Lr-PRP on human degenerated nucleus pulposus (NP) cells. Then we verified the in vivo effects of autologous Lp-PRP and Lr-PRP in treating disc degeneration through a rabbit IDD model. Results: The in vitro study showed both autologous Lp-PRP and Lr-PRP can promote the cell proliferation, the synthesis of COL II and Aggrecan of human degenerated NP cells, while Lp-PRP are better than Lr-PRP (P<0.05). In addition, only Lp-PRP can inhibit the apoptosis of human degenerated NP cells (P<0.05), whereas Lr-PRP activates the catabolism on the contrary (P<0.05). Further, the in vivo study through the rabbit IDD model verified that autologous Lp-PRP has better effects than autologous Lr-PRP in repairing IDD according to X-ray, MRI, histological, and immunohistochemical assessment (P<0.05, respectively). And the caspase-3 IHC results also showed that only autologous Lp-PRP treatment could inhibit apoptosis of NP cells in the rabbit IDD model (P<0.05). Conclusion: Combining in vivo and in vitro studies, the present study confirmed that autologous Lp-PRP has a better effect than autologous Lr-PRP in repairing IDD, which may be due to the inflammatory factors (TNFα, IL-1β, etc.) in Lr-PRP antagonizing part of the repair effects and promoting the catabolism additionally. Therefore, our findings suggest that Lp-PRP may provide better results than Lr-PRP for treating IDD. Further randomized clinical trials will provide evidence to guide practice. [ABSTRACT FROM AUTHOR]

Background: Intervertebral disc (IVD) degeneration (IVDD) is one of the main causes of low back pain. One of the most important features of IVDD is the loss of extracellular matrix (ECM) with its structural components. Cartilage intermediate layer proteins (CILPs), minor glycoproteins residing in ECM, have been found to be increased in IVD as degeneration and aging progresses. The aim of the present study was to evaluate the expression of CILP-2 in the IVD of patients with lumbar radiculopathy. Methods: The IVD samples were collected from 25 patients during spinal surgery (interlaminectomy, herniated disc removal). The control IVD samples were obtained from nine patients who underwent lateral corpectomies in the thoracic region. CILP-2 expression was detected by immunohistochemistry. The patients were divided into two groups – aged under or over 50 years. A standardized clinical examination with assessment of radicular signs and deficits was performed. Subjective disability and pain were assessed using the visual analogue scale and Oswestry Disability Index (ODI). The pre-operative MRI was graded for the degree of IVD degeneration by Pfirrmann grading system. IVD samples obtained during operations were subjected to the standardized histopathological analysis applying modified Boos classification. The data were analysed by t-test, Mann-Whitney U-test, and Spearman correlation test. Results: Both histopathology scores and Pfirrmann grades did not differ between patients' groups. Also, no correlations were found between histopathology and Pfirrmann grades, neither were any differences seen when correlating both grades to ODI, back pain or leg pain scores. CILP-2 staining was noted in all studied samples, notably strong staining was seen around large cell clusters. However, no differences in CILP-2 staining were seen between the age groups of patients. No correlations were found between CILP-2 staining and Pfirrmann grades. Grading of CILP-2 immunostaining in nine control patient samples resulted in significantly lower values. The difference is statistically significant (P = 0.002) compared to CILP-2 staining scores of all 25 patients' samples. Conclusion: In this study, we detected increased CILP-2 expression in the human IVD as compared to the control group patients. CILP-2 can be a possible IVDD marker; however, as knowledge about the role of CILP-2 is limited, further studies are required. [ABSTRACT FROM AUTHOR]

Background: Vitamin C plays key roles in cellular homeostasis, functioning as a potent antioxidant and a positive regulator of cell differentiation. In skeletal muscle, the vitamin C/sodium co-transporter SVCT2 is preferentially expressed in oxidative slow fibers. SVCT2 is up-regulated during the early fusion of primary myoblasts and decreases during initial myotube growth, indicating the relevance of vitamin C uptake via SVCT2 for early skeletal muscle differentiation and fiber-type definition. However, our understanding of SVCT2 expression and function in adult skeletal muscles is still limited. Results: In this study, we demonstrate that SVCT2 exhibits an intracellular distribution in chicken slow skeletal muscles, following a highly organized striated pattern. A similar distribution was observed in human muscle samples, chicken cultured myotubes, and isolated mouse myofibers. Immunohistochemical analyses, combined with biochemical cell fractionation experiments, reveal a strong co-localization of SVCT2 with intracellular detergent-soluble membrane fractions at the central sarcomeric M-band, where it co-solubilizes with sarcoplasmic reticulum proteins. Remarkably, electrical stimulation of cultured myofibers induces the redistribution of SVCT2 into a vesicular pattern. Conclusions: Our results provide novel insights into the dynamic roles of SVCT2 in different intracellular compartments in response to functional demands. [ABSTRACT FROM AUTHOR]

Objective: To examine the clinicopathological features, immunohistochemical profiles, and differential diagnosis of sclerosing angiomatiod nodular transformation (SANT). Methods: Three cases of SANT of the spleen, diagnosed between 2014 and 2023 at the Affiliated Hospital of Zunyi Medical University, were analysed. Pathological features were assessed using haematoxylin and eosin staining, followed by immunohistochemistry with the EnVision system. Additionally, a review of relevant literature was conducted. Results: The study included one male and two female patients aged 40–55 years, with a median age of 47.5 years. All lesions were solitary, with tumour diameters ranging from 4 to 7.4 cm (mean 5.7 cm). Gross examination demonstrated that the masses were well-demarcated from the surrounding splenic tissue, with no evident capsule. The cut surfaces of the masses exhibited irregular, porcelain-white nodules that were tough in consistency, with some areas intermingling with splenic tissue. Microscopic examination revealed round or circular nodules comprising multiple slit-like or sinusoidal capillaries, separated by concentric collagen fibres. The nodules exhibited chronic inflammatory cell infiltration, calcification, haemosiderin deposition, and fibrous connective tissue with hyaline or mucoid changes. Immunohistochemical analysis demonstrated differential expression of markers, including cluster of differentiation (CD) 34, CD31, and CD8, within the sinusoidal nodule areas. Periodic acid-Schiff staining was positive for perinodular collagen deposits, while reticulin staining highlighted nodule profiles and intranodular vessels. None of the patients experienced postoperative recurrence or metastasis, and one patient was on aspirin for thrombocytosis. Conclusion: SANT of the spleen is generally considered a rare, benign lesion with angioma-like characteristics. It exhibits exhibiting distinctive histomorphological features within the red pulp. Understanding the differential diagnosis is crucial to prevent missed or incorrect diagnoses. [ABSTRACT FROM AUTHOR]

Background: Identifying distinct mechanisms and biomarkers for painful diabetic peripheral neuropathy (DPN) is required for advancing the treatment of this major global unmet clinical need. We previously provided evidence in calf skin biopsies that disproportion between reduced sensory small nerve fibers and increased blood vessels may distinguish painful from non-painful DPN. We proposed that overexposure of the reduced nerve fibers in DPN to increased hypoxemia-induced vasculature and related algogenic factors, e.g., nerve growth factor (NGF), leads to neuropathic pain. To further investigate this proposed mechanism, we have now studied more proximal thigh skin biopsies, to see if the same disproportion between increased vasculature and decreased nerve fibers generally differentiates painful DPN from painless DPN. Methods: A total of 28 subjects with type 2 diabetes (T2DM) and 13 healthy volunteers (HV) underwent detailed clinical and neurophysiological assessments, based on the neuropathy composite score of the lower limbs [NIS(LL)] plus 7 tests. T2DM subjects were subsequently divided into three groups: painful DPN (n = 15), painless DPN (n = 7), and no DPN (n = 6). All subjects underwent skin punch biopsy from the upper lateral thigh 20 cm below the anterior iliac spine. Results: Skin biopsies showed decreased PGP 9.5-positive intraepidermal nerve fiber (IENF) density in both painful DPN (p < 0.0001) and painless DPN (p = 0.001). Vascular marker von Willebrand Factor (vWF) density was markedly increased in painful DPN vs. other groups, including painless DPN (p = 0.01). There was a resulting significant decrease in the ratio of intraepidermal nerve fiber density to vasculature and PGP9.5 to vWF, in painful DPN vs. painless DPN (p = 0.05). These results were similar in pattern to those observed in these HV and T2DM groups previously in distal calf biopsies; however, the increase in vWF was much higher and nerve fiber density much lower in the calf than thigh for painful DPN. Thigh skin vWF density was significantly correlated with several metabolic (waist/hip ratio, HbA1c), clinical (e.g., pain score), and neurophysiological measures. Conclusion: This study supports our proposal that increased dermal vasculature, and its disproportionate ratio to reduced nociceptors, may help differentiate painful DPN from painless DPN. This disproportion is greater in the distal calf than the proximal thigh skin; hence, neuropathic pain in DPN is length-dependent and first localized to the distal lower limbs, mainly feet. [ABSTRACT FROM AUTHOR]

Cardiorenal fibrosis is a common feature of chronic cardiovascular disease and recent data suggests that cytokines and chemokines may also drive fibrosis. Here we tested the hypothesis that CXCR7, a highly conserved chemokine receptor, contributes to cardiac and renal fibrosis. We generated an anti-mouse CXCR7-specific monoclonal antibody (CXCR7 mAb) and tested its anti-fibrotic actions in cardiorenal fibrosis induced using the deoxycorticosterone acetate/uni-nephrectomy (DOCA-UNX) model. CXCR7 mAb treatment (10 mg/kg, twice weekly for 6 weeks) significantly attenuated the development of cardiac and renal fibrosis, and reduced fibrotic and inflammatory gene expression levels, in the absence of an effect on blood pressure. Immunohistochemical analysis demonstrated an increase in the vascular expression of CXCR7 in DOCA-UNX-treated mice. This study demonstrated that a CXCR7 mediated pathway plays a significant role in cardiac and renal fibrosis induced by DOCA-UNX treatment. Accordingly, antagonism of CXCR7 may provide a therapeutic opportunity to mitigate against fibrosis in the setting of mineralocorticoid excess. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer's disease (AD) is marked by the accumulation of fibrillary aggregates composed of pathological tau protein. Although neuroinflammation is frequently observed in conjunction with tau pathology, current preclinical evidence does not sufficiently establish a direct causal role in tau tangle formation. This study aimed to evaluate whether chronic Toll-like receptor 4 (TLR4) stimulation, induced by a high dose of lipopolysaccharide (LPS, 5 mg/kg), exacerbates neurofibrillary tangle (NFT) pathology in a transgenic mouse model of tauopathy that expresses human truncated 151-391/3R tau, an early feature of sporadic AD. Methods: We utilized a transgenic mouse model of tauopathy subjected to chronic TLR4 stimulation via weekly intraperitoneal injections of LPS over nine consecutive weeks. Neurofibrillary tangle formation, microglial activation, and tau hyperphosphorylation in the brainstem and hippocampus were assessed through immunohistochemistry, immunofluorescence, and detailed morphometric analysis of microglia. Results: Chronic LPS treatment led to a significant increase in the number of Iba-1+ microglia in the LPS-treated group compared to the sham group (p < 0.0001). Notably, there was a 1.5- to 1.7-fold increase in microglia per tangle-bearing neuron in the LPS-treated group. These microglia exhibited a reactive yet exhausted phenotype, characterized by a significant reduction in cell area (p < 0.0001) without significant changes in other morphometric parameters, such as perimeter, circumference, solidity, aspect ratio, or arborization degree. Despite extensive microglial activation, there was no observed reduction in tau hyperphosphorylation or a decrease in tangle formation in the brainstem, where pathology predominantly develops in this model. Discussion: These findings suggest that chronic TLR4 stimulation in tau-transgenic mice results in significant microglial activation but does not influence tau tangle formation. This underscores the complexity of the relationship between neuroinflammation and tau pathology, indicating that additional mechanisms may be required for neuroinflammation to directly contribute to tau tangle formation. [ABSTRACT FROM AUTHOR]

Background: Bullous pemphigoid (BP) is a rare, life-threatening autoimmune blistering disease with pruritus and tension blisters/bullous as the main clinical manifestations. Glucocorticosteroids are the main therapeutic agents for it, but their efficacy is poor in some patients. Tofacitinib, a small molecule agent that inhibits JAK1/3, has shown incredible efficacy in a wide range of autoimmune diseases and maybe a new valuable treatment option for refractory BP. Objective: To report a case of refractory BP successfully treated with tofacitinib, then explore the underlying mechanism behind the treatment, and finally review similarities to other cases reported in the literature. Methods: Case report and literature review of published cases of successful BP treatment with JAK inhibitors. The case report describes a 73-year-old male with refractory BP that was successfully managed with the combination therapy of tofacitinib and low-dose glucocorticoids for 28 weeks. Immunohistochemistry and RNA sequencing were performed to analyze the underlying mechanism of tofacitinib therapy. A systematic literature search was conducted to identify other cases of treatment with JAK inhibitors. Results: Throughout the 28-week treatment period, the patient experienced clinical, autoantibody and histologic resolution. Immunohistochemical analysis showed tofacitinib significantly decreased the pSTAT3 and pSTAT6 levels in the skin lesions of this patient. RNA sequencing and immunohistochemical testing of lesion samples from other BP patients identified activation of the JAK-STAT signaling pathway. Literature review revealed 17 previously reported cases of BP treated with four kinds of JAK inhibitors successfully, including tofacitinib (10), baricitinib (1), upadacitinib (3) and abrocitinib (3). Conclusions: Our findings support the potential of tofacitinib as a safe and effective treatment option for BP. Larger studies are underway to better understand this efficacy and safety. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to investigate the therapeutic effects and mechanisms of PRP-exos combined with cyclic peptide-modified β-TCP scaffold in the treatment of rabbit knee cartilage defect. Methods: PRP-exos were extracted and characterized by TEM, NTA and WB. The therapeutic effects were evaluated by ICRS score, HE staining, Immunohistochemistry, qRT-PCR and ELISA. The repair mechanism of PRP-exos was estimated and predicted by miRNA sequencing analysis and protein–protein interaction network analysis. Results: The results showed that PRP-exos had a reasonable size distribution and exhibited typical exosome morphology. The combination of PRP-exos and cyclic peptide-modified β-TCP scaffold improved ICRS score and the expression level of COL-2, RUNX2, and SOX9. Moreover, this combination therapy reduced the level of MMP-3, TNF-α, IL-1β, and IL-6, while increasing the level of TIMP-1. In PRP-exos miRNA sequencing analysis, the total number of known miRNAs aligned across all samples was 252, and a total of 91 differentially expressed miRNAs were detected. The results of KEGG enrichment analysis and the protein–protein interaction network analysis indicated that the PI3K/AKT signaling pathway could impact the function of chondrocytes by regulating key transcription factors to repair cartilage defect. Conclusion: PRP-exos combined with cyclic peptide-modified β-TCP scaffold effectively promoted cartilage repair and improved chondrocyte function in rabbit knee cartilage defect. Based on the analysis and prediction of PRP-exos miRNAs sequencing, PI3K/AKT signaling pathway may contribute to the therapeutic effect. These findings provide experimental evidence for the application of PRP-exos in the treatment of cartilage defect. [ABSTRACT FROM AUTHOR]

Thyroid transcription factor 1 (TTF-1) immunohistochemistry (IHC) is routinely used for the distinction of primary pulmonary adenocarcinomas. However, TTF-1 can also occur in other malignancies. A tissue microarray containing 17,772 samples from 152 different tumor types was analyzed. Napsin-A, CK20, SATB2, FABP1, and Villin-1 IHC data were available from previous studies. TTF-1 staining was seen in 82 of 152 tumor categories including thyroidal cancers (19–100%), adenocarcinomas (94%), neuroendocrine tumors (67%) of the lung, small cell neuroendocrine carcinomas (71–80%), mesenchymal tumors (up to 42%), and thymomas (39%). Comparative analysis of TTF-1 and Napsin-A revealed a sensitivity/specificity of 94%/86% (TTF-1), 87%/98% (Napsin-A), and 85%/99.1% (TTF-1 and Napsin-A) for the distinction of pulmonary adenocarcinomas. Combined analysis of TTF-1 and enteric markers revealed a positivity for TTF-1 and at least one enteric marker in 22% of pulmonary adenocarcinomas but also a TTF-1 positivity in 6% of colorectal, 2% of pancreatic, and 3% of gastric adenocarcinomas. TTF-1 is a marker of high sensitivity but insufficient specificity for pulmonary adenocarcinomas. A small fraction of TTF-1-positive gastrointestinal adenocarcinomas represents a pitfall mimicking enteric-type pulmonary adenocarcinoma. Combined analysis of TTF-1 and Napsin-A improves the specificity of pulmonary adenocarcinoma diagnosis. [ABSTRACT FROM AUTHOR]

Introduction: This study explores clinicians' diagnostic practices and perceptions in the context of granulomatous-lymphocytic interstitial lung disease (GLILD), a pulmonary manifestation of common variable immunodeficiency disorder. The aim was to gain valuable insights into key aspects, such as the utilization of radiological features for diagnostic purposes, indications for lung biopsy, preferred biopsy techniques, and the relative importance of different histopathological findings in confirming GLILD. Method: A survey targeting expert clinicians was conducted, focusing on their experiences, practices, and attitudes towards lung biopsy in suspected GLILD cases. Results: The survey revealed that the majority of respondents accepted high-resolution computed tomography as a sufficient alternative to biopsy for making a probable GLILD diagnosis in most patients. There was a consensus among most respondents that the presence of extrapulmonary granulomatous disease is adequate for making a diagnosis of GLILD where the chest imaging and clinical picture are consistent. When a biopsy was recommended, there was notable variation in the preferred initial biopsy technique, with 35% favouring transbronchial biopsy. Conclusion: Our findings underscore the complexity of diagnosing GLILD, indicating varied clinician opinions on the necessity and efficacy of lung biopsies. They highlight the need for further research and the development of consistent diagnostic criteria and management protocols, ultimately aiming to enhance the accuracy and safety of GLILD diagnosis and treatment strategies. [ABSTRACT FROM AUTHOR]

Introduction: Reactive oxygen species modulator 1 (Romo1) is a novel protein that is critically involved in the intracellular production of reactive oxygen species. Evidence has revealed that Romo1 is associated with treatment outcomes of various human malignancies, including lung cancer. However, the clinical implications of this protein in surgically resected lung cancers harboring epidermal growth factor receptor (EGFR) mutations have not been investigated. Methods: Data were collected from patients who underwent curative resection of EGFR-mutant lung adenocarcinoma. Romo1 protein expression levels were measured in the tumor tissue using immunohistochemical staining and evaluated semi-quantitatively using the histochemical score. Univariate and multivariate analyses were performed to identify the clinicopathological parameters that may be associated with clinical outcomes. Results: A total of 98 samples were analyzed. Using the cutoff H score of 200, the population was classified into low (n = 73) and high (n = 25) Romo1 groups. Romo1 expression was significantly higher in smokers, patients with stage III disease, and patients who experienced recurrence after surgery (all p < 0.05). Multivariate analyses showed that advanced-stage and poorly differentiated cancers were associated with shorter disease-free survival (DFS). In addition, high Romo1 expression was independently associated with poor DFS (hazard ratio = 2.18, 95% confidence interval: 1.10–4.32, p = 0.0261). Conclusions: Our data showed that Romo1 overexpression was significantly associated with early recurrence in patients with resected EGFR-mutant lung adenocarcinoma. Although large-scale studies are required, Romo1 may play a prognostic role in this patient population. [ABSTRACT FROM AUTHOR]

Background/Objectives: Metastatic colorectal cancer remains a fatal disease, with a 5-year survival rate lower than 15%. The most common metastatic sites are the lungs and the liver, while skin metastases are very rare and often indicate a poor prognosis with a lower survival rate. Methods. Herein, we present the clinical case of a 62-year-old female patient with rectal cancer metastases to the skin of the anogenital and abdominal regions, diagnosed 2 years after completion of treatment of the underlying disease. Results: Histological examination of the skin lesions revealed adenocarcinoma, and expression of the same immunohistochemical markers was also found in the primary tumor and in the cutaneous metastases. However, next-generation sequencing demonstrated differences in the mutational profiles of the primary tumor and metastasis to the skin. Somatic mutations in the APC, TP53, and PTPN11 genes were revealed in primary rectal adenocarcinoma, but another pathogenic TP53 mutation and a frameshift variant in the DYNC1I1 gene were found in cutaneous metastases. The patient underwent several courses of FOLFOX6 chemotherapy in combination with bevacizumab, but the treatment was unsuccessful. An analysis of 50 clinical cases from the literature concerning various manifestations of cutaneous metastases of rectal cancer showed a median survival of 8.5 months from the time of detection of the skin lesions. Conclusions: In this regard, careful skin examination of patients with rectal cancer and timely detection of cutaneous metastases are essential steps in the follow-up of patients who have undergone treatment of the primary tumor. [ABSTRACT FROM AUTHOR]

Ganglioneuroblastoma is a rare peripheral neuroblastic tumor located anywhere in the sympathetic nervous system but rarely in the retropharyngeal space. Diagnosis can often be difficult based on imaging alone. We describe one case of a child presenting with snoring. The lesion was located in the rare retropharyngeal space, and its histology finally revealed ganglioneuroblastoma. Therefore, clinicians should be aware of pediatric patients with respiratory symptoms indicating cervical ganglioneuroblastoma. To make a definite diagnosis as soon as possible, a core needle biopsy or even immunohistochemistry may need to be performed before surgery. [ABSTRACT FROM AUTHOR]

Background: The emergence of chemoresistance markedly compromised the treatment efficiency of human cancer, including non‐small cell lung cancer (NSCLC). In the present study, we aimed to explore the effects of ubiquitin‐specific peptidase 22 (USP22) and murine double minute 2 (MDM2) in gefitinib resistance in NSCLC. Methods: Immunohistochemistry (IHC) assay, quantitative real‐time polymerase chain reaction (qRT‐PCR) assay and western blot assay were carried out to determine the expression of USP22 and MDM2. Transwell assay and flow cytometry analysis were performed to evaluate cell migration and apoptosis. Cell Counting Kit‐8 (CCK‐8) assay was employed to assess gefitinib resistance. The phenomenon of ferroptosis was estimated by related commercial kits. The oxidized C11‐BODIPY fluorescence intensity by C11‐BODIPY staining. The relation between USP22 and MDM2 was analyzed by ubiquitination assay and co‐immunoprecipitation (Co‐IP) assay. Results: USP22 was abnormally upregulated in NSCLC tissues and cells, and USP22 silencing markedly repressed NSCLC cell migration and facilitated apoptosis and ferroptosis. Moreover, our results indicated that ferroptosis could enhance the suppressive effect of gefitinib on NSCLC cells. Besides, USP22 overexpression enhanced gefitinib resistance and ferroptosis protection in NSCLC cells. Mechanically, USP22 stabilized MDM2 and regulated MDM2 expression through deubiquitination of MDM2. MDM2 deficiency partially restored the effects of USP22 on gefitinib resistance and ferroptosis in NSCLC cells. Of note, we validated the promotional effect of USP22 on gefitinib resistance in NSCLC in vivo through establishing the murine xenograft model. Conclusion: USP22/MDM2 promoted gefitinib resistance and inhibited ferroptosis in NSCLC, which might offer a novel strategy for overcoming gefitinib resistance in NSCLC. [ABSTRACT FROM AUTHOR]

This is the first case report of a non‐small‐cell lung cancer (NSCLC) patient harboring HIP1‐ALK (H28:A20) and CTNNB1 p.S45del treated with first‐line alectinib. Approximately 5% of NSCLC patients are reported to have anaplastic lymphoma kinase (ALK) rearrangements, and among these EML4‐ALK is the most frequent fusion variant. However, in recent years the use of next‐generation sequencing (NGS) in clinical laboratories has become increasingly widespread, identifying a lot of new ALK fusion partners as well as a large quantity of co‐occurring genomic alterations. Unfortunately, the growing number of genomic alterations detected by NGS does not always correspond to adequate knowledge of their clinical significance, often resulting in an empiric treatment of patients harboring uncommon mutations. [ABSTRACT FROM AUTHOR]

Introduction: The bone marrow examination is an essential investigation in the diagnosis and management of many haematological disorders. The integration of all investigations, including peripheral blood analysis, bone marrow aspirate, and trephine biopsy findings, along with supplementary tests such as immunophenotyping, cytogenetic analysis, and molecular genetic studies, is crucial for arriving at a final diagnosis. Aim: To assess the presence of reticulin fibres in bone marrow biopsy sections in haematological malignancies, to evaluate the grade of BMF associated with haematological malignancies and to assess the role of angiogenesis using IHC markers in various haematological malignancies. Materials and Methods: A cross-sectional study was conducted in the Department of Pathology at the National Institute of Pathology, Safdarjung Hospital, New Delhi, India in 2009 for a duration of 18 months. Thirty-eight patients with a diagnosis of Acute Myeloid Leukaemia (AML), Acute Lymphoblastic Leukaemia (ALL), Chronic Myeloid Leukaemia (CML), and Chronic Lymphoproliferative Disorder (CLPD) were studied. Bone marrow biopsies were taken, fixed in 10% formalin, and decalcified in 10% Ethylene Diamine Tetraacetic Acid (EDTA). Routine paraffin embedding was performed, and serial sections of 4 µm were obtained on poly-L-lysine-coated slides for Immunohistochemistry (IHC) {Vimentin, Vascular Endothelial Growth Factor (VEGF), CD-34, Smooth Muscle Actin (SMA)}. The presence of reticulin fibres in the bone marrow biopsy sections was assessed using two special stains: Gomori's Silver Impregnation and Masson's Trichrome. Fibrosis was quantified according to the Baurmeister 0-4 grading system of Bone Marrow Fibrosis (BMF). Results: The results of the present study suggest that Endothelial to Mesenchymal Transition (EndMT) may play a role in the pathogenesis of BMF. Various grades of fibrosis were observed, with 15 cases (39.47%) in Grade 3, followed by 11 cases (28.95%) in Grade 2, 8 cases (21.05%) in Grade 1, and 4 cases (10.53%) in Grade 4. Conclusion: BMF was a significant finding even in the early stages of the majority of the lesions studied and was closely linked with angiogenesis. This study showed that angiogenesis plays an important role in the pathogenesis of haematological neoplasms and that VEGF is a prominent stimulus in the majority of these disorders. Additionally, this study suggests that EndMT has a possible role in the pathogenesis of BMF. [ABSTRACT FROM AUTHOR]

Objectives The incidence of pituitary neuroendocrine tumors has been reported high at autopsy. This study aimed to detect many tumors in both anterior and posterior lobes to prove tumor histogenesis. Methods In total, 150 pituitary glands were studied from the University of Kansas Medical Center from 1995 to 2000. The pituitary gland was sagittally sliced from anterior to posterior into 6 to 8 sections. When H&E-stained sections revealed tumors, the tumors were immunohistochemically stained for 6 pituitary hormones. Results Among 150 autopsy cases, 38 (25.3%) harbored microadenomas, including 4 cases with double tumors. Twenty-three (54.7%) cases were negative to all pituitary hormones. Of the remaining 19 tumors, 13 (30.9%) were lactotrophs, with 4 cases being concomitantly somatotrophs and gonadotrophs, and 2 cases were corticotropes. More than 85% of pituitary neuroendocrine tumors were adjacent to the capsule. Thirteen (8.7%) granular cell pituicytomas were found in the posterior lobe. There were pituicytes transforming into granular cell tumors. Conclusions The incidence was 25.3% for pituitary neuroendocrine tumors and 8.7% for granular cell pituicytomas. Since most pituitary neuroendocrine tumors were adjacent to the pituitary capsule, the capsule appeared to be the germinal center. Both pituitary tumors belonged to the 2 different transcription factor lineages. [ABSTRACT FROM AUTHOR]

ABSTRACT: Background and Aims: Outcome analysis of patients with Wilms' tumors (WT) is presented. Materials and Methods: A retrospective analysis of 23 children having WT managed by a single surgeon over 3 years (2021–2024) using the International Society of Paediatric Oncology Umbrella protocol was done. Results: The median age at presentation was 36 months; 32 months and 24 months for the unilateral WT (uWT) (n = 19) and bilateral WT (bWT) (n = 4), respectively. M: F ratio was 2.3: 1. WTs were localized in 19 (uWT-16; bWT-3) and metastatic in 4 (uWT-3; bWT-1) patients. Core-needle biopsy was done in 22 patients (26 renal units). Pre-therapy contrast-enhanced computed tomography volumetry (n = 20) showed a median tumor volume of 1023 ml (range: 47–2680 ml). Post-neoadjuvant chemotherapy (NACT) median tumor burden (n = 19) was 612 ml (range 59–3775 ml). Post-NACT, tumor volume decreased in 11/18 patients but increased in seven patients. NACT was avoided in one neonate. Nephroureterectomy (including one with excision of bladder cuff) and nephron-sparing surgery were done in 17 and 10 renal units including 3 with multifocal WT, respectively. Risk stratification was intermediate in 21 and High in 2. Overall staging in 19 uWT included Stage I-7, Stage II-5, Stage III-4, and Stage IV-3 (local staging-stage I in 1 and stage II in 2). Local staging in 8 renal units with bWT was Stage I in 7 and II in 1. One stage IV uWT had bilateral pulmonary metastatectomy. Adjuvant chemotherapy has been completed in 18 patients; two patients are still on adjuvant chemotherapy; flank radiation was administered in six patients. Three patients with synchronous bWT died; two due to acute kidney injury in the immediate postoperative period and one with metastatic disease who had abandoned adjuvant chemotherapy after the 1st cycle. Another patient died of a huge metachronous tumor in the contralateral kidney after a year of completion of therapy. One patient had successful multimodality treatment of local relapse with liver metastasis. 1-year overall and event-free survivals are 84% and 76%, respectively. Conclusions: Excellent short-term results for localized uWT from a center in a low-middle-income country are reported. [ABSTRACT FROM AUTHOR]

Background TROP2 (TACSTD2) expression is associated with decreased overall survival (OS) in some solid tumors, and the TROP2-targeting antibody-drug conjugate (ADC) sacituzumab govitecan has been approved in breast and urothelial carcinomas. We aimed to explore the multi-omic landscape associated with TACSTD2 gene expression in various solid tumors to identify patients most likely to benefit from this approach. Methods Breast (N  = 11 246), colorectal (N  = 15 425), hepatocellular (N  = 433), pancreatic (N  = 5488), and urothelial (N  = 4125) tumors were stratified into quartiles by TACSTD2 gene expression, analyzed by next-generation DNA sequencing, whole transcriptome sequencing, and immunohistochemistry at Caris Life Sciences (Phoenix, AZ). Survival data were obtained from insurance claims, and Kaplan-Meier estimates were calculated for molecularly defined cohorts. Results Several pathogenic mutations were associated with TACSTD2 -high tumors, including TP53 in breast, colorectal (CRC), pancreatic, and hepatocellular cancers; KRAS in pancreatic and CRC cancers; ARID1A and FGFR3 in urothelial cancer; and CTNNB1 in hepatocellular cancer. TACSTD2-low breast tumors were enriched for copy number amplifications in CCND1 and FGF/R family member genes. TACSTD2 high was generally associated with more immune cell infiltration and greater T-cell inflammation scores. Patients with TACSTD2 -high breast, CRC, and pancreatic cancers demonstrated a significantly shorter OS than TACSTD2 -low tumors. This was restricted to CRC with microsatellite stable tumors and patients with pancreatic cancer with KRAS -mutant tumors. Patients with breast cancer with TACSTD2 -high tumors also experienced significantly worse OS following immune checkpoint inhibitors. Conclusions TACSTD2 expression is associated with key driver alterations and a more active immune microenvironment, suggesting possible combinatorial strategies with TROP2-targeting ADCs plus immunotherapy in various solid tumors. [ABSTRACT FROM AUTHOR]

A 4‐year‐old white male DSH cat was presented to the Veterinary Hospital on 18 December 2023, with a history of lethargy, loss of appetite, and salivation. During the inspection of the oral cavity, unilateral swelling was observed on the ventral side of the jaw. Before any therapeutic intervention, a cell blood count (CBC) test and FNA cytology were conducted. A five‐day course of adjunctive treatment, including ceftriaxone (5.5 mg/kg via IV) and clindamycin (25 mg/kg via IV), was given due to a suspicion of infection. Pantoprazole, metoclopramide (administered at 1 mg/kg via IV and IM), and duphalyte 500 mL (10 mL/kg IV) were used concurrently to alleviate nausea and stimulate appetite. Following a lack of improvement, a radical excision procedure was performed on tooth number 304 after the 5‐day treatment to excise the mass for histopathology and immunohistochemical analysis. The observation of mitotic bodies, pleomorphism, necrosis, and haemorrhage were consistent with malignancy, and squamous cell carcinoma (SCC) was suspected. Immunohistochemical staining was positive for the vimentin marker, the S‐100 protein, and desmin. This report describes a rare case of oral fibrosarcoma in a DSH cat in Iran. [ABSTRACT FROM AUTHOR]

Simple Summary: Small bowel cancer is considered a rare disease with limited clinical and pathological data but with a rising incidence in recent decades. The imaging, pathological diagnosis, and surgical and oncological treatment, as well as the long-term survival, are variable and related to the pathological type, tumor location, and staging. In our retrospective study, we analyzed a number of patients with primary resectable small bowel cancer who had also presented with exceptional types such as multiple bowel cancers. A total of 46 resectable (R0 resection) small bowel cancer patients were included in this study. Long-term survival depends on tumor aggressivity, invaded lymph node number, and unique or multiple locations. Introduction: Small bowel cancer is very rare; although the incidence of adenocarcinoma and other anatomopathological forms has increased recently, the diagnosis and treatment of this disease are still debatable because of the clinical heterogeneity and the absence of studies including a large number of patients. Materials and Methods: We performed a retrospective study over 10 years in which we analyzed the clinical, imaging, and anatomopathological data of 46 patients hospitalized in a surgery clinic and diagnosed with small bowel cancer (duodenum, jejunum, and ileum). Results: After clinical assessment of these patients, including complications (occlusion, bleeding, and perforation), the CT scan established the diagnosis in over 90% of the cases of the complicated form of the disease. Surgery has a curative role in localized cancers; tumor location, local invasion, the presence of locoregional lymph nodes, and the number of multiple tumors influence the type of surgery. The conventional pathological exam was completed via immunohistochemical staining. Adjuvant oncological treatment was performed after surgery (according to the guidelines); in patients with exceptional histopathological forms, the therapy was personalized. Conclusions: Most small bowel cancers were diagnosed with complications (occlusion and bleeding); the tumor type, location, and presence of multiple bowel cancers significantly influenced its management. Independently of the surgical resection (R0/R1 or R2), the prognosis of the disease depends on the tumor aggressivity, location (single/multiple), and locoregional node invasion. [ABSTRACT FROM AUTHOR]

Simple Summary: The tyrosine kinase TYK2 was assessed in this study using digital image analysis of archived formalin-fixed paraffin-embedded blocks. The immunohistochemical expression of TYK2 was significantly weaker in cancer than in normal control tissues, and its high predictive value allowed its use as a biomarker in the diagnosis of CRC. The obtained results were additionally verified by other molecular methods, which confirmed the presence of a higher protein level of the kinase TYK2 and a higher TYK2 fluorescence intensity in normal colonic mucosa than in CRC tissue. Independently assessed TYK2 immunoreactivity in fresh colonic biopsies from CRC and ulcerative colitis (UC) patients showed that the kinase distribution was greater in UC than in cancer. Background/Objectives: The aim of this study was to examine the expression of TYK2 in colorectal cancer (CRC) and to determine the potential diagnostic and prognostic significance of this kinase. Methods: Digital image analysis was performed to assess immunohistochemical TYK2 reactivity. Results: There were significant differences for all positive pixels between CRC and normal colonic mucosa, with higher TYK2 expression levels observed in surgical margins than in adenocarcinomas (p = 0.0004). Paired t tests showed elevated immunoreactivity for overall TYK2 expression in matched pairs of CRC with adjacent surgical margins (p < 0.0001). Higher percentages of weak (p < 0.0001) and strong pixels (p = 0.0260) were detected in normal colonic mucosa than in cancer tissues. To distinguish cancer from normal intestinal mucosa, the following cutoffs for the TYK2 immune score were found: 29.5% for all cases and 31% for matched pairs. Tumor budding (Bd) was negatively correlated with the percentage of strong pixels for TYK2 (ρ = −0.270, p = 0.0096). The percentage of strong pixels was significantly elevated for the T parameter (p = 0.0428). There was a positive correlation between the number of involved lymph nodes and weak pixels (ρ = 0.239, p = 0.0242). Immunofluorescence staining showed significantly higher signal intensities in colonic mucosa than in CRC. The protein level of TYK2 was significantly higher in controls than in cancer tissues. TEM imaging showed lower levels of TYK2 in cancer than in ulcerative colitis. Conclusions: TYK2 protein expression may bring diagnostic value in patients diagnosed with CRC. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate cancer is the second most common cancer diagnosed in men and yet is the second leading cause of cancer-related deaths worldwide. This is often due to the cancer being misdiagnosed as benign prostatic hyperplasia or missed entirely due to the limited nature of the most popular detection method, prostate-specific antigen levels. The aim of this study was to assess the potential of G-protein-coupled receptor-associated sorting protein 1 (GASP-1) as a valid prostate cancer biomarker. Prostate tissue samples from healthy, benign prostatic hyperplasia, and prostate cancer patients were subjected to anti-GASP-1 polyclonal antibodies in immunohistochemical staining and enzyme-linked immunosorbent assay analyses, showing that GASP-1 levels were significantly greater in prostate cancer patients when compared to benign prostatic hyperplasia and healthy patients. Specifically in prostate cancer patients, there was a positive correlation between GASP-1 overexpression and the severity of the prostate cancer. Background/Objectives: Prostate cancer (PCa) is a prevalent malignancy, necessitating accurate diagnostic methods to distinguish it from benign conditions such as benign prostatic hyperplasia (BPH). Current diagnostic tools, relying primarily on serum prostate-specific antigen (PSA) levels, lack specificity, leading to an over-diagnosis and unnecessary treatment of patients with benign conditions. This study explores G-protein-coupled receptor-associated sorting protein 1 (GASP-1) as a more sensitive biomarker for PCa detection. Methods: Prostate tissue microarrays of healthy, BPH, and prostate cancer patients with different Gleason scores were studied. Polyclonal antibodies targeted against GASP-1 were used for routine immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA) analyses. Results: The results indicated a 5-fold difference in serum GASP-1 levels between BPH and PCa, which was validated through GASP-1 IHC. Furthermore, a novel scoring system, the H-score, assesses GASP-1 granules' intensity and size, revealing a clear distinction between BPH and PCa. An additional analysis of GASP-1 expression between PCa cases with different Gleason scores reveals that GASP-1 overexpression correlates with PCa severity, providing insights into disease progression. Conclusions: The study supports GASP-1′s role as a promising diagnostic marker, supplementing PSA testing, and offering improved risk stratification for PCa. Additionally, an open-source software system is introduced for an efficient GASP-1 granule color analysis, enhancing diagnostic accuracy. [ABSTRACT FROM AUTHOR]

Simple Summary: Somatostatin, a growth hormone-release-inhibiting peptide (SST/SRIF), is a widely distributed multifunctional cyclic peptide that acts by activating G protein-coupled receptors (SSTRs, SST1-5). The diagnostic and prognostic role of these peptides in sporadic CRC remains unclear. The current study showed significant differences in the expression of SST and all SSTRs in the tissue material of sporadic CRC, control colorectal mucosa, and in lymph node metastases from the same patients. A significant dependence of the immunoexpression of SST1-5 on the cellular localization pattern was proved. Differences and/or significant correlations of SRIF system components with clinicopathological data (age, histological subtype of CRC, TNM parameters, Ki-67 antigen, and laboratory tests) were found. Interestingly, only control tissue showed differences in SST1-5 expression depending on the colon segment. The coexpression of all SST1-5 and overexpression of not only SST2 and SST5 in CRC may have applications for future therapy based on the SRIF system in sporadic CRC. Background/Objectives: Colorectal cancer (CRC) is one of the most common human malignancies worldwide. The somatotropin-releasing inhibitory factor/somatostatin (SRIF/SST) acts through activation of five membrane receptors (SSTRs, SST1-5). The diagnostic and prognostic role of these peptides in sporadic CRC remains unclear. This study aimed to determine the role of tissue expression of SST and all SSTRs in the pathogenesis, diagnosis, and prognosis of sporadic CRC. Methods: The expression of SST and all SSTRs was assessed in the tissues of CRC patients, control colorectal mucosa and lymph node metastasis from the same patients using real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). Results: Decreased SST (mRNA and peptide) and higher SST2 and SST5 (mRNA and peptide) expression in CRC vs. control was noted. A negative correlation between SST mRNA expression and patient's age in CRC and control groups were observed. IHC study confirmed the coexpression of SSTRs in all tissue groups and significant dependence on the cellular localization. Immunoexpression of SST2 and SST3 showed the most correlations with clinicopathological data in CRC patients. Interestingly, only control tissue showed differences in SST1-5 expression depending on the colon segment. Conclusions: Reduced SST expression in CRC indicates a weakening in its antitumor effect in this cancer in vivo. Overexpression of SST2 and SST5 in CRC suggests that these receptors play an important role in the pathogenesis of this cancer. Analysis of SST1-5 tissue expression allows for differentiation between the mucinous and nonmucinous CRC subtypes. The coexpression of all SST1-5 and overexpression of not only SST2 and SST5 in CRC may have applications for future therapy based on the SRIF system in sporadic CRC. [ABSTRACT FROM AUTHOR]

Simple Summary: TRPS1 (trichorhinophalangeal syndrome type 1) is a protein that has become an important marker for diagnosing breast cancer, especially in difficult-to-diagnose cases like triple-negative breast cancer. This review explores the expression of TRPS1 in various cancers beyond breast tissue, such as prostate, lung, and ovarian cancers, and discusses its role as a diagnostic tool. While TRPS1 is a highly sensitive marker for breast cancer, its presence in other tumor types poses challenges for pathologists. Our review aims to raise awareness of these diagnostic pitfalls and emphasizes the importance of using multiple markers to improve accuracy. Understanding the broader expression of TRPS1 can help to improve cancer diagnosis and treatment strategies. Background/Objectives: Immunohistochemical expression of TRPS1 (trichorhinophalangeal syndrome type 1) protein is usually used by pathologists to confirm breast origin for triple-negative breast cancers (TNBC) or metastatic carcinomas of unknown primary. However, recent studies have reported TRPS1 expression in a variety of non-breast lesions. This review aims to provide a comprehensive evaluation of TRPS1 expression across various tumor types, highlighting both its diagnostic utility and potential pitfalls that may arise in clinical practice. Methods: A thorough search of the PubMed database on TRPS1 immunoexpression in tumor pathology was conducted. While the gene itself has been known for several decades, most studies regarding its use in immunohistochemistry emerged in the late 2010s. Particular emphasis was placed on case reports and cohort studies that examined the implications of TRPS1 expression in non-breast tissues, as well as variations in the results between commercially available TRPS1 clones, which may influence the staining intensity and specificity. Results: TRPS1 demonstrated a strong diagnostic utility in identifying primary breast lesions, particularly in TNBC cases. However, its expression in a growing number of non-breast cancers, such as lung adenocarcinoma, prostate adenocarcinoma, urothelial carcinoma, ovarian high-grade serous carcinoma, and endometrial adenocarcinoma, as well as up to 96% of synovial sarcomas with SS18-SSX fusion, emphasizes the need for caution when interpreting TRPS1 positivity and suggests a multi-marker approach in order to increase the diagnostic accuracy. Conclusions: While TRPS1 remains a highly sensible immunohistochemical marker for confirming breast primary lesions, pathologists should be aware of its low specificity and incorporate complementary diagnostic methods in order to ensure accurate clinical management. Further research should focus on elucidating the molecular pathways regulating TRPS1 expression in various tumor types, which may better define its clinical utility. [ABSTRACT FROM AUTHOR]

Glucocorticoid receptor (GR) activation may promote metastasis in oestrogen receptor-negative and triple-negative breast cancer (TNBC). However, the role of the GRβ isoform, which has opposing effects to the main isoform, has not been studied in clinical samples. We aimed to analyse the intracellular localisation of total GR and GRβ in vitro using plasmid constructs and fluorescent immunocytochemistry. Additionally, our goal was to perform immunostaining for total GR and GRβ on two cohorts: (i) on 194 clinical breast cancer samples to compare the expression in different molecular subtypes, and (ii) on 161 TNBC samples to analyse the association of GR with survival. We supplemented our analysis with RNA data from 1097 TNBC cases. We found that in the absence of the ligand, GR resided in the cytoplasm of breast cancer cells, while upon ligand activation, it translocated to the nucleus. A negative correlation was found between cytoplasmic GRtotal and Ki67 in luminal A tumours, while the opposite trend was observed in TNBC samples. Tumours with strong lymphoid infiltration showed higher cytoplasmic GRtotal staining compared to those with weaker infiltration. Patients with high nuclear GRtotal staining had shorter progression-free survival in univariate analysis. High cytoplasmic GRβ was a marker for better overall survival in multivariate analysis (10-year overall survival HR [95% CI]: 0.46 [0.22–0.95], p = 0.036). As a conclusions, this study is the first to investigate GRβ expression in breast tumours. Different expression and cellular localisation of GRtotal and GRβ were observed in the context of molecular subtypes, underscoring the complex role of GR in breast cancer. An inverse association between cytoplasmic GRtotal and the Ki67 proliferation index was observed in luminal A and TNBC. Regarding the impact of GR on outcomes in TNBC patients, while cytoplasmic GRβ was associated with a better prognosis, patients with nuclear GRtotal staining may be at a higher risk of disease progression, as it negatively affects survival. Caution should be exercised when using glucocorticoids in patients with nuclear GR staining, as it may negatively impact survival. [ABSTRACT FROM AUTHOR]

Until the early 2000s, advanced or metastatic non–small cell lung cancer (NSCLC) was treated as a single disease with all histologic subtypes treated alike with standard chemotherapy agents. Over the past two decades, the treatment paradigms for advanced NSCLC have changed dramatically with the discovery of multiple targeted therapies that are now approved for the treatment of NSCLC tumors with specific oncogene drivers or molecular alterations. Molecular testing has become integrated and critical for the clinical management of advanced NSCLC. The discovery and success of these targeted therapies have reshaped the classification of NSCLC on the basis of molecular classification and enabled a personalized approach in thoracic oncology. In this review, we discuss recent developments in the molecular profiling of NSCLC, and approved and emerging targeted therapies for the treatment of NSCLC. In this review, we discuss recent developments in the molecular profiling of non–small cell lung cancer (NSCLC), and approved and emerging targeted therapies for the treatment of NSCLC. [ABSTRACT FROM AUTHOR]

Ovarian serous carcinoma is a gynecological malignancy associated with a high mortality rate, which is commonly diagnosed in the first instance at a late stage and has a propensity to develop resistance to platinum-based chemotherapy. Identifying reliable biomarkers for platinum sensitivity is critical for improving patient outcomes. The present retrospective study included 64 patients with high-grade serous ovarian carcinoma (Federation of Gynecology and Obstetrics stages III or IV). Patients were classified as platinum-sensitive (no relapse within 6 months of the last platinum administration) or platinum-resistant (relapse within 6 months). Immunohistochemical analysis was performed to evaluate Fyn expression in tumor tissues, and Fyn knockdown experiments were performed using the OVSAHO ovarian cancer cell line to assess carboplatin sensitivity. Fyn expression was significantly higher in platinum-resistant patients compared with in platinum-sensitive patients (P<0.01). A weighted Fyn expression score was developed and a cutoff score of 6 was determined to predict platinum sensitivity with a specificity of 65.5% and a sensitivity of 62.9%. Patients with low Fyn expression (score ≤6) exhibited higher platinum sensitivity and longer overall survival (P<0.05). Multivariate analysis identified Fyn expression and postoperative residual tumor size as independent predictors of platinum sensitivity (P=0.033 and P=0.023, respectively). In vitro, Fyn knockdown significantly increased carboplatin sensitivity in ovarian cancer cells (P<0.05). Fyn, a member of the Src family of kinases, serves a crucial role in various cellular functions and has been implicated in chemotherapy resistance. The results demonstrated a notable association between Fyn expression and platinum sensitivity in ovarian serous carcinoma. The findings suggested that Fyn may serve as a predictive biomarker for response to platinum-based chemotherapy, offering the potential for more personalized treatment strategies. To the best of our knowledge, the present study is the first to establish an association between Fyn expression and platinum sensitivity in advanced ovarian serous carcinoma. Prospective studies with larger, multi-center cohorts and comprehensive biomarker analyses are recommended to validate and extend these results, ultimately improving therapeutic strategies and patient prognosis. [ABSTRACT FROM AUTHOR]

Although tumor necrosis factor receptor 2 (TNFR2) may serve a protumor role in several types of tumors, the clinical significance of TNFR2, including the diagnostic and prognostic value in tumor (T) stage 2-3 esophageal squamous cell carcinoma (ESCC), remains unclear. Therefore, the present study aimed to explore the clinical significance of TNFR2 in stage T2-3 ESCC. The present study collected the mRNA expression data of TNFR2 from two databases and confirmed the high expression of TNFR2 in ESCC tissue. TNFR2 expression in stage T2-3 ESCC tissue (n=404) was detected using immunohistochemistry and a stratified analysis was performed. For all patients with stage T2-3 ESCC, TNFR2 expression was associated with clinical stage, invasion depth and metastatic lymph nodes. Stage T3 and low differentiation was associated with an increase in the risk of lymph node metastasis, but older age was associated with a decrease. TNFR2 expression was associated with poor overall survival (OS) of all patients with stage T2-3 ESCC and stratified patients with stage T3 ESCC. Moreover, TNFR2 expression and metastatic lymph nodes were independent prognostic factors for these patients. For stratified patients aged ≤60 years, TNFR2 expression was associated with clinical stage and metastatic lymph nodes. In addition, TNFR2 expression was associated with poor OS in stratified patients with stage T2 ESCC. The presence of metastatic lymph nodes was also an independent prognostic factor for these patients. For stratified patients aged >60 years, TNFR2 expression was associated with invasion depth. TNFR2 expression was also associated with poor OS in all patients with stage T2-3 ESCC and stratified patients with stage T3 ESCC. TNFR2 expression and meta-static lymph nodes were identified as independent prognostic factors for these patients. In conclusion, TNFR2 expression is associated with progression and poor prognosis in patients with stage T2-3 ESCC as an independent prognostic factor, except in the subgroup of patients with stage T2-3 ESCC aged ≤60 years. [ABSTRACT FROM AUTHOR]

Low-grade appendiceal mucinous neoplasm (LAMN) is a tumor that primarily originates from the appendix and belongs to the family of appendiceal mucinous neoplasms (AMNs). In 50% of female patients, AMNs (particularly LAMNs) have a tendency to metastasize to organs in the genital tract, where the neoplasm can mimic the features of primary ovarian mucinous cancer (POMC). The present case report reviewed the difficulties in differentiating between these two types of tumors. In the present case report, a 61-year-old female patient was admitted to the Second Department of Gynecological Surgery and Gynecological Oncology, University Clinical Hospital no. 4 at Lublin Medical University (Lublin, Poland) with the diagnosis of a right ovarian mass. After performing ultrasound and computed tomography (CT) scans and laboratory analysis, the patient underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, appendectomy and resection of the Douglas peritoneum. Notably, the postoperative pathological assessment revealed LAMN with metastases to the right ovary and omentum. Immunohistochemically, cytokeratin 20 and caudal type homeobox 2 both stained positively, whereas paired box gene 8 stained negatively. After surgery, the patient received the recommended hyperthermic intraperitoneal chemotherapy at the Department of Surgical Oncology at Lublin Medical University. After 1 year, a CT scan was performed, which indicated no evidence of recurrent disease. In conclusion, observations from the present case report suggest that gynecologists should be conscious of the possibility of malignancies of gastrointestinal origin in cases of ovarian tumors instead of making direct assumptions of POMC. If the mucinous mass involves the base of the appendix or if there is a suspicion of positive margins, then cytoreductive surgery and right-sided hemicolectomy must be performed. In addition, identifying the origin of mucinous tumors in the right ovary and/or the appendix requires the histopathological examination of a panel of markers using immunohistochemistry. [ABSTRACT FROM AUTHOR]

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Objective: Pigmented villonodular synovitis (PVNS) is a rare benign proliferative disease affecting the soft‐tissue lining the synovial joints and tendons. Its etiology is poorly understood, largely limiting the availability of current therapeutic options. Here, we mapped the synovial gene and protein profiles of patients with PVNS, revealed a link between synovial inflammation and invasion, and elucidated the potential molecular mechanism involved. Methods: The expression of synovial genes from 6 control individuals, 7 patients with osteoarthritis (OA), and 19 patients with PVNS was analyzed via RNA sequencing. Protein profiles from 5 control individuals, 10 patients with OA, and 32 patients with PVNS were analyzed using label‐free proteomics. Microarray and reverse transcription–polymerase chain reaction analyses and immunohistochemical staining were used to evaluate inflammatory cytokine and target gene expression levels in synovial tissue, epithelial cells, and synovial fibroblasts (FLSs) derived from tissue of patients with PVNS. Various signaling pathway inhibitors, small interfering RNAs, and Western blots were used for molecular mechanism studies. Transwell migration and invasion assays were subsequently performed. Results: In total, 522 differentially expressed proteins were identified in the tissues of patients with PVNS. By integrating RNA sequencing and microarray analyses, significant changes in the expression of epithelial–mesenchymal transition (EMT)‐related genes, including transforming growth factor TGF‐b induced, neural cadherin, epithelial cadherin, SNAIL, and TWIST, were confirmed in the tissue of patients with PVNS compared to the control tissue. In vitro, TGFβ induced EMT and increased epithelial cell migration and invasion. Moreover, TGFβ not only promoted interactions between epithelial cells and FLSs but also directly increased the migration and invasion abilities of FLSs by activating the classical Smad2/3 and nonclassical JNK/AKT signaling pathways. Conclusion: This study provides overall protein and gene profiles of PVNS and identifies the crucial role of TGFβ in synovial invasion pathology. Exploring the related molecular mechanism may also reveal a new strategy or target for PVNS therapy. [ABSTRACT FROM AUTHOR]

The article discusses the novel role of MDM2 in the diagnosis and treatment of dedifferentiated liposarcoma, a subtype of liposarcoma that often occurs in the retroperitoneum. It highlights the importance of MRI, histopathology, and treatment strategies in managing this condition. The study emphasizes the significance of MDM2 and CDK4 in immunohistochemistry and fluorescence in situ hybridization for accurate diagnosis and potential therapeutic targets. The research provides insights into the clinical features, diagnostic challenges, and treatment options for dedifferentiated liposarcoma, contributing to advancements in the field of oncology. [Extracted from the article]

Background: Psoriasis is an immune‐mediated inflammatory skin disorder with a multifaceted pathogenesis. Immune dysregulation and immune cell dysfunction are among the mechanisms involved. TEA domain family member 4 (TEAD4) is suggested to play a role in psoriasis development. TEAD4 expression in keratinocytes may have a chemotactic effect and could disturb the function of FOXP3‐positive T lymphocytes. This study aimed to evaluate the expressions of TEAD4 and FOXP3 in lesional, nonlesional psoriatic, and healthy skin and assess the clinical impact of their expression. Methods: This case–control study included 32 cases with psoriasis vulgaris and 32 control groups. Hematoxylin and eosin‐stained slides were examined to evaluate the histopathological findings. Moreover, other sections were immunohistochemically stained with FOXP3 and TEAD4. Results: FOXP3 was expressed in inflammatory cells in 56.5, 37.5, and 12.5% of lesional, nonlesional, and healthy skin, whereas it was entirely negative in the keratinocytes. TEAD4 was expressed in keratinocytes in 93.7 and 46.9% of lesional and nonlesional skin, while negative in healthy skin. Significant differences were observed between their lesional, nonlesional, and healthy skin expressions. Furthermore, FOXP3 expression in lesional skin was significantly associated with early onset (P = 0.016), low PASI score (P = 0.002), mild psoriasis (P = 0.007), and axial affection (P = 0.022), while TEAD4 expression was associated with progressive course (P = 0.032), high PASI score (P = 0.002), severe psoriasis (P = 0.001), severe inflammation (P = 0.001), and progressive course (P = 0.017). Conclusion: TEAD4 expression was higher in lesional than nonlesional skin and absent in healthy skin, suggesting a role in psoriasis development. TEAD4 expression was also associated with severe and progressive psoriasis. This may be mediated by the downregulation of FOXP3 and dysfunction of Treg cells. TEAD4 could serve as a promising therapeutic target in psoriasis. [ABSTRACT FROM AUTHOR]

Environmental antineoplastics such as sorafenib may pose a risk to humans through water recycling, and the increased risk of cardiotoxicity is a clinical issue in sorafenib users. Thus, developing strategies to prevent sorafenib cardiotoxicity is an urgent work. Empagliflozin, as a sodium‐glucose co‐transporter‐2 (SGLT2) inhibitor for type 2 diabetes control, has been approved for heart failure therapy. Still, its cardioprotective effect in the experimental model of sorafenib cardiotoxicity has not yet been reported. Real‐time quantitative RT‐PCR (qRT‐PCR), immunoblot, and immunohistochemical analyses were applied to study the effect of sorafenib exposure on cardiac SGLT2 expression. The impact of empagliflozin on cell viability was investigated in the sorafenib‐treated cardiomyocytes using Alamar blue assay. Immunoblot analysis was employed to delineate the effect of sorafenib and empagliflozin on ferroptosis/proinflammatory signaling in cardiomyocytes. Ferroptosis/DNA damage/fibrosis/inflammation of myocardial tissues was studied in mice with a 28‐day sorafenib ± empagliflozin treatment using histological analyses. Sorafenib exposure significantly promoted SGLT2 upregulation in cardiomyocytes and mouse hearts. Empagliflozin treatment significantly attenuated the sorafenib‐induced cytotoxicity/DNA damage/fibrosis in cardiomyocytes and mouse hearts. Moreover, GPX4/xCT‐dependent ferroptosis as an inducer for releasing high mobility group box 1 (HMGB1) was also blocked by empagliflozin administration in the sorafenib‐treated cardiomyocytes and myocardial tissues. Furthermore, empagliflozin treatment significantly inhibited the sorafenib‐promoted NFκB/HMGB1 axis in cardiomyocytes and myocardial tissues, and sorafenib‐stimulated proinflammatory signaling (TNF‐α/IL‐1β/IL‐6) was repressed by empagliflozin administration. Finally, empagliflozin treatment significantly attenuated the sorafenib‐promoted macrophage recruitments in mouse hearts. In conclusion, empagliflozin may act as a cardioprotective agent for humans under sorafenib exposure by modulating ferroptosis/DNA damage/fibrosis/inflammation. However, further clinical evidence is required to support this preclinical finding. [ABSTRACT FROM AUTHOR]

Objective: Diagnosing lesions with unusual clinical presentation can be challenging, mostly for cases in which the inclusion of oral metastasis in the differential diagnosis is necessary. Materials and Methods: A 55‐year‐old man complaining of a large mass in the oral cavity was referred to the Hospital Dentistry Service. The patient reported bleeding episodes and pain, with a 5‐month evolution. Intraoral examination revealed a 5 cm tumour with purplish‐red and ulcerated focal areas at the right buccal mucosa. Differential diagnosis included malignant mesenchymal tumours, lymphoproliferative lesions, and metastasis of an occult primary lesion. Two biopsies were conducted, with the first one presenting an intense haemorrhage, and the second performed under general anaesthesia and difficult bleeding control. Results: Histologic and immunohistochemical analysis diagnosed a clear cell carcinoma infiltration. A whole‐body CT scan reveals a renal tumour with multiple metastasis sites in the abdomen and bones. Metastatic clear cell renal cell carcinoma was finally confirmed, and the patient was followed with palliative care for 4 months. Conclusion: A challenging diagnosis of a rare metastatic lesion in the oral cavity was conducted after two procedures under difficult bleeding conditions. [ABSTRACT FROM AUTHOR]

Introduction: Focal myositis (FM) is an uncommon, localized inflammatory process that affects a single muscle, with unknown aetiology. In the head and neck region, involvement of perioral musculature, floor of the mouth, and sternocleidomastoid muscle have been reported. FM affecting the tongue is very rare, with only four cases previously published to date. Aim: This report describes five additional cases of tongue FM. Case Report: Three patients were male and two were female (mean age, 56 years), and three had symptomatic short‐term nodular swelling. Results: By immunohistochemistry, M2 macrophages and CD4+ T cells were predominant. Focally, CD15+ granulocytes and CD20+ B cells were visualized. Polyclonal CD138+ plasma cells, with a predominance of IgG+ cells (rarely IgG4+), were detected. All patients evolved with complete resolution after biopsy and no signs of clinical or systemic progression were observed during the follow‐up. Conclusions: FM should be considered in the differential diagnosis of rapidly growing nodular lingual lesions. By immunohistochemistry, a predominance of M2 macrophages and CD4+ T cells is typical, and it can help in the differential diagnosis with myositis of other origins. [ABSTRACT FROM AUTHOR]

Objective: Actinic cheilitis (AC) is a chronic lesion that usually precedes the onset of squamous cell carcinoma of the lip. Microscopically, AC may exhibit epithelial dysplasia (ED). Twist is a transcription factor that regulates the mesenchymal phenotype through negative E‐cadherin regulation. This study evaluated Twist and E‐cadherin immunoexpression in AC with different ED degrees. Materials and Methods: Twist and E‐cadherin immunoexpression was evaluated semiquantitatively in the epithelium of 86 cases of AC with different ED degrees. Data obtained were submitted to the Mann–Whitney test and Spearman's correlation test. Results: Immunohistochemical analysis revealed nuclear and cytoplasmic Twist immunoreactivity in all epithelial layers except the cornified layer. In contrast, the membrane and cytoplasmic E‐cadherin immunoreactivity was observed in all epithelial layers except the cornified layer. No significance was observed between the scores of these proteins and the ED degree. It was observed a correlation between total Twist and total (p = 0.030) and membrane (p = 0.014) E‐cadherin and between nuclear Twist and cytoplasmic E‐cadherin (p = 0.030). Conclusions: The results suggest that the high immunoexpression of Twist is an early lip carcinogenesis event. However, it appears not to influence the progression of ED in AC. [ABSTRACT FROM AUTHOR]