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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]

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]

Objective: To investigate the mechanism of induction of ferroptosis by brazilin in breast cancer cells. Methods: Breast cancer 4T1 cells were divided into 6 groups: control, brazilin 1/2 half maximal inhibitory concentration (IC50), IC50, 2×IC50, erastin (10 µg/mL) and capecitabine (10 µg/mL) groups. The effect of brazilin on the proliferation of 4T1 cells was detected by cell counting kit-8 assay, and the treatment dose of brazilin was screened. The effect of brazilin on the mitochondrial morphology of 4T1 cells, and the mitochondrial damage was evaluated under electron microscopy. The levels of Fe2+, reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH) and glutathione peroxidase 4 (GPX4) were estimated using various detection kits. The invasion and migration abilities of 4T1 cells were detected by scratch assay and transwell assay. The expressions levels of tumor protein p53, solute carrier family 7 member 11 (SLC7A11), GPX4 and acyl-CoA synthetase long-chain family member 4 (ACSL4) proteins were quantified by Western blot assay. Results: Compared to the control group, the 10 (1/2 IC50), 20 (IC50) and 40 (2×IC50) µg/mL brazilin, erastin, and capecitabine groups showed a significant decrease in the cell survival rate, invasion and migration abilities, GSH, SLC7A11 and GPX4 protein expression levels, and mitochondrial volume and ridge (P<0.05), and a significant increase in the mitochondria membrane density, Fe2+, ROS and MDA levels, and p53 and ACSL4 protein expression levels (P<0.05). Conclusions: Brazilin actuated ferroptosis in breast cancer cells, and the underlying mechanism is mainly associated with the p53/SLC7A11/GPX4 signaling pathway. [ABSTRACT FROM AUTHOR]

The Cd40l –/– mouse is a well-established model of X-linked hyper-immunoglobulin M (IgM) syndrome, an immunodeficiency disorder of human beings characterized by the lack of expression of the CD40 ligand (CD40L) on activated T-cells, predisposing to infections with opportunistic pathogens like Pneumocystis jirovecii. The aim of our study was to describe the pulmonary lesions in Cd40l –/– mice experimentally infected with Pneumocystis murina, in comparison with naturally infected severe combined immunodeficient (SCID) mice. Formalin-fixed paraffin-embedded lungs from 26 Cd40l –/–, 11 SCID, and 5 uninfected Cd40l –/– mice were examined by histology and immunohistochemistry for the presence of the pathogen and for leukocyte populations (CD3, CD4, CD45R/B220, CD8a, Iba-1, Ly-6G, CD206, MHC II, and NKp46/NCR1). Infection was confirmed by immunohistochemistry in 18/26 (69%) Cd40l –/– mice and in 11/11 (100%) SCID mice. Fourteen out of 26 (54%) Cd40l –/– mice had interstitial pneumonia. Twenty-three out of 26 (88%) Cd40l –/– mice had peribronchiolar/perivascular lymphoplasmacytic infiltrates, rich in B-cells and Mott cells. Acidophilic macrophage pneumonia was additionally found in 20/26 (77%) Cd40l –/– mice. Only 4/11 (36%) SCID mice had interstitial pneumonia, but no peribronchiolar/perivascular infiltrates or acidophilic macrophage pneumonia were observed in this strain. This study represents the first description of pulmonary histopathological lesions in Cd40l –/– mice infected with P. murina. We speculate that the singular characteristics of the inflammatory infiltrates observed in Cd40l –/– mice could be explained by the specific immune phenotype of the model. [ABSTRACT FROM AUTHOR]

High survivin expression has been correlated with poor outcomes in several canine tumors but not in soft tissue tumors (STTs). Survivin is a target gene of the Wnt/β-catenin pathway, which is involved in human STT oncogenesis. Immunohistochemistry for survivin, β-catenin, and Ki-67 was performed on 41 canine perivascular wall tumors (cPWTs), and statistical associations of protein expression and histopathologic and clinical variables with clinical outcomes were investigated. Immunohistochemically, there was nuclear positivity (0.9%–12.2% of tumor cells) for survivin in 41/41 (100%), cytoplasmic positivity (0 to > 75% of tumor cells) for survivin in 31/41 (76%), nuclear positivity (2.9%–67.2% of tumor cells) for β-catenin in 24/41 (59%), and cytoplasmic positivity (0% to > 75% of tumor cells) for β-catenin in 23/41 (56%) of cPWTs. All tumors expressed nuclear Ki-67 (2.2%–23.5%). In univariate analysis and multivariate analysis (UA and MA, respectively), every 1% increase of nuclear survivin was associated with an increase of the instantaneous death risk by a factor of 1.15 [hazard ratio (HR) = 1.15; P =.007]. Higher nuclear survivin was associated with grade II/III neoplasms (P =.043). Expression of cytoplasmic survivin, nuclear and cytoplasmic β-catenin, and nuclear Ki-67 were not significantly associated with prognosis in UA nor MA. Tumor size was a significant prognostic factor for local recurrence in UA [subdistribution HR (SDHR) = 1.19; P =.02] and for reduced overall survival time in MA. According to UA and MA, a unitary increase of mitotic count was associated with an increase of the instantaneous death risk by a factor of 1.05 (HR = 1.05; P =.014). Nuclear survivin, mitotic count, and tumor size seem to be potential prognostic factors for cPWTs. In addition, survivin and β-catenin may represent promising therapeutic targets for cPWTs. [ABSTRACT FROM AUTHOR]

Histologic diagnosis of less well-differentiated cases of canine extramedullary plasmacytomas (CEMPs) may require immunohistochemical confirmation to discriminate these tumors from other round cells tumors including lymphoma, cutaneous histiocytoma, and amelanotic melanomas. CEMPs are characterized by widespread immunoreactivity for multiple myeloma 1 (MUM1) antigen and λ light chains, while the melanocytic marker melan-A has been reported to yield negative results. Here, 33 randomly selected CEMPs, 20 melanocytomas, and 20 malignant melanomas were immunohistochemically tested for MUM1, melan-A, and PNL2. In addition, CEMPs were examined for PAX5, E-cadherin, CD3, CD18, CD20, S100, as well as λ and κ light chain immunoreactivity. All CEMPs were characterized by labeling for MUM1 and λ light chain, as well as variable immunopositivity for the remaining antibodies. Notably, 13 cases of CEMPs (39.4%) exhibited immunolabeling for melan-A. Melanocytic tumors immunolabeled for melan-A (40/40; 100%) and PNL2 (34/40; 85%). An unexpected cytoplasmic immunoreactivity for MUM1 was observed in 2 melanocytic tumors. Summarized, MUM1 or melan-A immunomarkers alone are not sufficient to differentiate between CEMPs and amelanotic melanomas and should be part of a larger immunopanel including λ light chain, CD20, and PNL2. [ABSTRACT FROM AUTHOR]

Cutaneous and subcutaneous mast cell tumors (MCTs) are common canine neoplasms characterized by variable biological behavior. Tumor-associated macrophages (TAMs) and tumor-infiltrating lymphocytes (TILs) can be effective prognostic markers in numerous human neoplasms and are increasingly investigated in dogs. The aim of this study was to characterize immune cells in canine MCTs and their relationship with histological location (cutaneous, subcutaneous) and histologic nodal metastatic status (HN0-3). Thirty-eight MCTs (26 cutaneous, 12 subcutaneous) from 33 dogs with known sentinel lymph node (SLN) metastatic status were immunolabeled for Iba1 (macrophages), CD20 (B cells), CD3 (T cells), and Foxp3 (regulatory T cells). Semiquantitative scoring of interstitial and perivascular CD3+, CD20+, and Foxp3+ cells and morphological evaluation of Iba1+ cells were performed. For each marker, the percent immunopositive area was evaluated by image analysis. All MCTs were diffusely infiltrated by Iba1+ cells and variably infiltrated by CD20+, CD3+, and rare Foxp3+ cells. Stellate/spindle Iba1+ cells were associated with HN2 and HN3 SLNs. Perivascular Foxp3+ cells, CD3+ cells, and percent CD3+ areas were increased in subcutaneous MCTs. Interstitial CD3+ cells were increased in cutaneous MCTs with HN0 SLNs. No differences in CD20+ cells were identified between cutaneous and subcutaneous MCTs and among SLN classes. MCTs were markedly infiltrated by TAMs and variably infiltrated by TILs. Stellate/spindle morphology of TAMs associated with HN2 and HN3 SLNs is suggestive of a pro-tumoral (M2) phenotype. Cutaneous and subcutaneous MCTs have different tumor-immune microenvironments, and T-cell infiltration might contribute to prevention of nodal metastatic spread of cutaneous MCTs. [ABSTRACT FROM AUTHOR]

The discovery of "mismatch repair deficient (MMRd)-crypt foci" in non-neoplastic intestinal mucosa in Lynch syndrome (LS) has significantly enhanced our understanding of how tumors and tumor immunity form and evolve in LS. In this study, we report the frequent presence of "mismatch repair proficient (MMRp)-crypt foci" in both non-neoplastic and neoplastic intestinal mucosa in a patient with constitutional MMR deficiency (CMMRD), who carried a germline MSH6 pathogenic variant (c.3261dupC) in trans with an MSH6 likely pathogenic variant (c.3724_3726del) and whose tissues were otherwise deficient in MMR globally. The MMRp-crypts occurred at a rate of 1.1/100 crypts in non-neoplastic intestinal mucosa and were readily discernible in adenomas > 1 cm. Sequencing analysis revealed normalization of the MSH6c.3261dupC variant in MMRp-adenoma crypts, indicating reverse frameshifting of the exon 5 C8 microsatellite. Interestingly but not surprisingly, the MMRp-adenoma crypts remained microsatellite-instability-high (MSI-H), and shared oncogenic APC mutations with the background MMRd-adenoma. Contrasting with MSH6-CMMRD, no PMS2-CMMRD individuals (0/5) harbored MMRp-crypts. In conclusion, our study documents distinct MMRp-crypts in MSH6-CMMRD, a phenomenon in keeping with MSH6 being a frequent target of MSI-H due to its coding microsatellite and suggesting that MSH6-CMMRD can potentially serve as a unique model system to further our understanding of MSH6's role in MSI-H tumor formation and evolution. Our findings also bear diagnostic implications; when using MMR immunohistochemistry as an ancillary tool in detecting CMMRD, awareness of these MMRp crypts can help avoid diagnostic pitfalls. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer’s disease (AD) is the leading cause of dementia, and currently, no effective treatments are available to reverse or halt its progression in clinical practice. Although a plethora of studies have highlighted the benefits of physical exercise in combating AD, elder individuals often have limited exercise capacity. Therefore, mild physical exercise and nutritional interventions represent potential strategies for preventing and mitigating neurodegenerative diseases. Our research, along with other studies, have demonstrated that platycodin D (PD) or its metabolite, platycodigenin, derived from the medicinal plant Platycodon grandiflorus, exerts neuroprotective effects against amyloid β (Aβ)-induced neuroinflammation. However, the combined effects of PD and physical exercise on alleviating AD have yet to be explored. The current study aimed to investigate whether combined therapy could synergistically ameliorate memory deficits and AD pathology in 5 × FAD mice. Methods: Five-month-old 5 × FAD mice were randomly assigned to four groups, and received either PD (5 mg/kg/day, p.o.), voluntary running, or a combination of both for 47 days. Nest building test, locomotion test, and Morris water maze test were used to evaluate the cognitive function. Immunohistochemical and ELISA analysis was performed to determine Aβ build-up, microglia and astrocytes hyperactivation, and survival neurons in the hippocampus and perirhinal cortex. Real-time quantitative PCR analysis was used to assess the polarization of microglia and astrocytes. HPLC analysis was performed to measure monoamine neurotransmitters in the hippocampus. Results and discussion: The combination of PD and voluntary running synergistically restored nest-building behavior, alleviated recognition and spatial memory deficits, and showed superior effects compared to monotherapy. In addition, the PD and voluntary running combination reduced Aβ build-up, decreased hyperactivation of microglia and astrocytes in the hippocampus and perirhinal cortex, promoted the polarization of inflammatory M1 microglia and reactive astrocytes toward beneficial phenotypes, and lowered systemic circulating pro-inflammatory cytokines while increasing anti-inflammatory cytokines in 5 × FAD mice. Furthermore, combined therapy effectively protected neurons and increased levels of 5-hydroxytryptamine (5-HT) and dopamine (DA) in the hippocampus of 5 × FAD mice. In conclusion, the combination of PD and voluntary running holds great potential as a treatment for AD, offering promise for delaying onset or progression of AD. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation is widely recognized as a key factor in the pathogenesis of Alzheimer’s disease (AD), alongside ß-amyloid deposition and the formation of neurofibrillary tangles. The NLR family pyrin domain containing 3 (NLRP3) inflammasome, part of the innate immune system, has been implicated in the neuropathology of both preclinical amyloid and tau transgenic models. Activation of the NLRP3 pathway involves an initial priming step, which increases the expression of Nlrp3 and interleukin (IL)-1β, followed by the assembly of the NLRP3 inflammasome complex, comprising NLRP3, ASC, and caspase-1. This assembly leads to the proteolytic maturation of the pro-inflammatory cytokines IL-1β and IL-18. Additionally, the NLRP3 inflammasome induces Gasdermin D (GSDMD) cleavage, forming membrane pores through which IL-1β and IL-18 are secreted. Inhibition of NLRP3 has been shown to enhance plaque clearance by modulating microglial activation. Furthermore, blocking NLRP3 in tau transgenic mice has been found to reduce tau phosphorylation by affecting the activity of certain tau kinases and phosphatases. Methods: In this study, organotypic brain slice cultures from P301S transgenic mice were treated with lipopolysaccharide (LPS) plus nigericin as a positive control or exposed to tau seeds (K18) to evaluate NLRP3 inflammasome activation. The effect of tau seeding on NLRP3 activity was further examined using Meso Scale Discovery (MSD) assays to measure IL1β secretion levels in the presence and absence of NLRP3 inhibitors. The role of NLRP3 activity was investigated in fullbody Nlrp3 knockout mice crossbred with the tau transgenic P301S model. Additionally, full-body and microglia-selective Gsdmd knockout mice were crossbred with P301S mice, and tau pathology and neurodegeneration were evaluated at early and late stages of the disease using immunohistochemistry and biochemical assays. Results: Activation of the NLRP3 pathway was observed in the mouse organotypic slice culture (OSC) model following stimulation with LPS and nigericin or exposure to tau seeds. However, Nlrp3 deficiency did not mitigate tauopathy or neurodegeneration in P301S mice in vivo, showing only a minor effect on plasma neurofilament (NF-L) levels. Consistently, Gsdmd deficiency did not alter tau pathology in P301S mice. Furthermore, neither full-body nor microglia-selective Gsdmd deletion had an impact on neuronal pathology or the release of pro-inflammatory cytokines. Conclusion: The absence of key components of the NLRP3 inflammasome pathway did not yield a beneficial effect on tau pathology or neurodegeneration in the preclinical Tau-P301S mouse model of AD. Nonetheless, organotypic slice cultures could serve as a valuable ex vivo mechanistic model for evaluating NLRP3 pathway activation and pharmacological inhibitors. [ABSTRACT FROM AUTHOR]

Objective: In this study, we examined the effectiveness of hyperbaric oxygen (HBO) therapy in ameliorating cognitive deficits in mice with Alzheimer’s disease (AD), while also assessing its impact on the autophagic pathway within the context of AD. Methods: 20 double-transgenic mice expressing the amyloid precursor protein and presenilin 1 (APP/PS1) were purposefully selected and randomly assigned to groups A and B. Concurrently, 20 C57BL/6 mice were chosen and randomly categorized into groups C and D, each consisting of 10 mice. Mice in groups B and D received HBO treatment. The Morris water maze assay was used to assess changes in mouse behavior. Immunohistochemistry techniques were used to quantify the expression levels of amyloid-beta 42 (Aβ42) and microtubuleassociated protein 1A/1B-light chain 3 (LC3) in hippocampal tissues, while western blot analysis was used to investigate the levels of LC3-II, p62, phosphoinositide 3-kinase (PI3K), and mammalian target of rapamycin (mTOR) proteins within hippocampal tissues. Results: Mice allocated to group B exhibited reduced escape latency and prolonged dwell time in the target quadrant compared to other groups. Histological examination revealed conspicuous plaque-like deposits of Aβ42 in the hippocampal tissues of mice in groups A and B. Group B displayed diminished Aβ42-positive reactants and augmented microtubule-associated protein 1A/1B-LC3-positive reactants compared to group A. LC3-positive reactants were also detected in the hippocampal tissues of mice in groups C and D, surpassing the levels observed in groups A and B. Furthermore, group B demonstrated significantly lower expression of mTOR protein and markedly higher expression of LC3-II protein in mouse hippocampal tissues when compared to group A (P < 0.05). Conversely, there were no significant disparities noted in PI3K and p62 protein expression between groups B and A. Notably, no discernible discrepancies were observed in the expression levels of mTOR, PI3K, LC3-II, and p62 proteins between groups C and D within mouse hippocampal tissues. Conclusion: HBO treatment demonstrates efficacy in enhancing cognitive function in mice with AD and holds promise as a potential therapeutic intervention for AD by facilitating the activation of the mTOR pathwaymediated autophagy. [ABSTRACT FROM AUTHOR]

Background: Further research is still needed to fully understand the potential of prostate-specific membrane antigen (PSMA) in breast cancer (BC) and to develop and optimize targeted therapies and imaging modalities. The objective of this study was to present a comprehensive analysis of immunohistochemistry data on PSMA staining in BC and to discuss its potential value in a theranostic approach. Methods: Fifty-eight male and female patients were randomly selected from a retrospective database of patients who underwent surgery for breast cancer between January 2012 and December 2017 and for whom a specimen is available in our tumour library. Immunodetection of PSMA and CD31 was performed on serial slides. The digitized slides were reviewed and analysed by an experienced pathologist. Additionally, the corresponding TIFF images were processed to calculate the percentage of positive neovessels. Results: Eighteen patients (31.6%) had no expression, 29 (50.9%) had PSMA neovascular expression scored as "1", and 10 (17.5%) had neovascular expression scored as "2". Digital immunohistochemistry analysis for this last specific group of patients showed a median proportion of positive neovessels equal to 5% (range: 3–19). A multivariable logistic regression demonstrated that the odds of PSMA positivity were 4.55 times higher in non-luminal tumours and decreased by a factor of 0.12 in lobular subtypes. There was no association between sex or the presence of a germline BRCA1/2 mutation and PSMA expression in tumours. Conclusions: Our study highlights generally low neovascular expression of PSMA in specific histopathological subtypes of breast cancer, which will likely hamper the development of an adequate theranostic strategy. Trial registration: The procedure has been retrospectively registered to the French National Institute for Health Data (N° F20220615153900). [ABSTRACT FROM AUTHOR]

Background: Segregated-nucleus-containing atypical monocytes have recently been identified in mice. Segregated-nucleus-containing atypical monocytes are thought to originate from the bone marrow and induce fibrosis in the drug-injured lung. The Lyc6c− murine monocyte subset is the counterpart to human CD14−CD16++ non-classical monocytes; however, the human counterpart to murine segregated-nucleus-containing atypical monocytes has not yet been identified. Primary myelofibrosis is a well-known disease of progressive marrow fibrosis, and atypical megakaryocytes are thought to be closely related to fibrosis in primary myelofibrosis bone marrow. However, recently, monocytes have been reported to play an important role in marrow fibrosis in primary myelofibrosis. We speculated that, if there is a human counterpart to murine segregated-nucleus-containing atypical monocytes, it would present the same markers as murine segregated-nucleus-containing atypical monocytes, such as CD14−CD16+ macrophage-1 antigen (CD11b/CD18 complex)+, MSR1+, and CEACAM1+, and it might exist in the bone marrow of patients with primary myelofibrosis. Case presentation: A 74-year-old Japanese male visited our hospital for clinical follow-up after total prostatectomy for prostatic cancer. Anemia, thrombocytosis, and elevated lactate dehydrogenase were suddenly observed in a periodic examination. CALR mutation type 2 (p.K385fs*47) was observed. The histological features of the patient's bone marrow were consistent with fibrotic primary myelofibrosis. We immunohistochemically studied the bone marrow in an attempt to identify a human counterpart to murine segregated-nucleus-containing atypical monocytes. We detected a few CD16+MSR1+CEACAM1+ cells, but not CD14+MSR1+CEACAM1+ cells, by triple immunostaining. The patient is in a good condition and does not require treatment for primary myelofibrosis. Conclusion: There is a possibility that human segregated-nucleus-containing atypical monocytes exist in the bone marrow of primary myelofibrosis patients and might be related to marrow fibrosis. [ABSTRACT FROM AUTHOR]

Receptors for activated C kinases (RACKs) have been shown to coordinate PKC-mediated hypertrophic signalling in mice. However, little information is available on its participation in embryonic gene expression. This study investigated the involvement of RACK1 in the expression of embryonic genes in a zebrafish (ZF) ex vivo heart culture model by using phenylephrine (PE) or a growth factors cocktail (GFs) as a prohypertrophic/regeneration stimulus. Blebbistatin (BL) inhibition has also been studied for its ability to block the signal transduction actions of some PEs. qRT‒PCR and immunoblot analyses confirmed the upregulation of RACK1 in the PE- and GFs-treated groups. BL administration counteracted PE-induced hypertrophy and downregulated RACK1 expression. Immunohistochemical analyses of the heart revealed the colocalization of RACK1 and embryonic genes, namely, Gata4, Wt1, and Nfat2, under stimulation, whereas these genes were expressed at lower levels in the BL treatment group. Culturing ZF heart cells activated via GFs treatment increased the expression of RACK1. The overexpression of RACK1 induced by the transfection of recombinant RACK1 cDNA in ZF heart cells increased the expression of embryonic genes, especially after one week of GFs treatment. In summary, these results support the involvement of RACK1 in the induction of embryonic genes during cardiac hypertrophy/GFs stimulation in a fish heart model, which can be used as an alternative study model for mammals. [ABSTRACT FROM AUTHOR]

Background: Shen-Bai-Jie-Du decoction (SBJDD), a traditional Chinese herb formula developed based on evidence-based medicine, is efficacy to reduce the recurrence and carcinogenesis of colorectal adenoma. However, the mechanism of SBJDD to treat colorectal adenoma remains unclear. The present study aims to investigate the efficacy and mechanism of SBJDD on colorectal adenoma carcinogenesis from the aspects of regulating gut microbiota and short-chain fatty acids (SCFAs). Methods: Twenty-one patients diagnosed with colorectal adenoma were recruited in the study and required to take SBJDD for four consecutive weeks. Analysis of gut microbiota was conducted using 16S rRNA gene amplicon sequencing, while levels of SCFAs in fecal and serum samples were determined through HPLC–MS/MS. Additionally, twenty-four Apcmin/+ mice were randomly assigned to normal diet (ND), high-fat diet (HFD), and SBJDD groups. The pharmacological effects and mechanism of SBJDD on colorectal adenoma carcinogenesis were assessed using RT-qPCR, HE staining, IHC staining, Western blot, IF staining, and Flow cytometry assays. Results: Our clinical study has shown that SBJDD can regulate the gut microbiota composition and enhance SCFAs production in patients with colorectal adenoma. SBJDD alleviated colorectal adenoma formation and carcinogenesis, as well as protected the integrity of the intestinal barrier in the Apcmin/+ mice model compared to the HFD group. Additionally, SBJDD was found to regulate gut microbiota capable of producing SCFAs. G protein-coupled receptors GPR43, GPR41, and GPR109a were effectively activated in the SBJDD group, while HDAC1 and HDAC3 were inhibited. Furthermore, decreased expression levels of interleukin 1 beta (IL-1β) and interleukin 6 (IL-6), along with elevated expression level of interleukin 10 (IL-10), were observed in the colorectal tissue of the SBJDD group. Finally, SBJDD exhibited the ability to reduce the proportion of M1-type macrophages while increasing the proportion of M2-type macrophages. Conclusions: Our study objectively demonstrated the pharmacological effects of SBJDD in inhibiting the progression of colorectal adenoma and investigated its mechanisms in terms of regulating gut microbiota, increasing SCFAs, and reducing colorectal inflammation. [ABSTRACT FROM AUTHOR]

The amygdala and raphe nuclei, which play crucial roles in mood regulation, are influenced by serotonergic neurotransmission. Alterations in this neurotransmission are associated with mood disorders. Therefore, using immunohistochemistry and quantitative methods this study was designed to evaluate potential alterations in the expression of serotoninergic markers in the amygdala and raphe nuclei of mice with oestrogen receptor β (ERβ) knock out which exhibit increased anxiety as evidenced by reduced locomotion and increased thigmotaxis. These alterations could either contribute to heightened anxiety or serve as a compensatory strategy for reducing it. The results show that in ERβ knock‐out mice, 5‐HT1B expression is significantly increased in the amygdala, while 5‐HTT expression is significantly decreased in both the amygdala and raphe nuclei. Furthermore, ERβ deficiency does not affect TPH2. In conclusion, serotonin signalling is altered in the amygdala and raphe nuclei of ERβ knock‐out females. It seems that an increase in 5‐HTT levels has been associated with reduced anxiety, whereas a decrease in 5‐HT1B receptors may encourage fear. However, further studies are required to determine the exact role of ERβ in anxiety‐related behaviour. [ABSTRACT FROM AUTHOR]

Trypanosoma cruzi, the causative agent of Chagas disease, can be congenitally transmitted by crossing the placental barrier. This study investigates the role of T. cruzi-derived exovesicles (TcEVs) in facilitating parasite infection and the consequent tissue damage and apoptotic cell death in human placental explants (HPEs). Our findings demonstrate that TcEVs significantly enhance the parasite load and induce tissue damage in HPEs, both in the presence and absence of the parasite. Through histopathological and immunohistochemical analyses, we show that TcEVs alone can disrupt the placental barrier, affecting the basal membrane and villous stroma. The induction of apoptotic cell death is evidenced by DNA fragmentation, caspase 8 and 3, and p18 fragment immunodetection. This damage is exacerbated when TcEVs are combined with T. cruzi infection. These findings suggest that TcEVs play a critical role in the pathogenesis of congenital Chagas disease by disrupting the placental barrier and facilitating parasite transmission to the fetus. This study provides new insights into the mechanisms of transplacental transmission of T. cruzi and highlights the potential of targeting TcEVs as a therapeutic strategy against congenital Chagas disease. [ABSTRACT FROM AUTHOR]

Background: The growth of secondary hair follicles (SHFs) in cashmere goats has periodic changes, including telogen, anagen, and catagen, during which proteins play important roles as the executor of life activities. Results: In this study, the skin tissues of cashmere goats at three different growth stages of SHFs were collected for proteome sequencing and validation experiments. Through protein differential expression analysis and time series analysis, FKBP prolyl isomerase 10 (FKBP10) and fibrillin 2 (FBN2) were screened as the key proteins for SHF cycle growth of cashmere goats, and albumin (ALB), collagen type I alpha 1 chain (COL1A1) and elastin (ELN) were predicted to be their interacting proteins. The results of quantitative real-time PCR (qRT- PCR), western blot, and immunohistochemistry experiments showed that the mRNA and protein expression levels of FKBP10, FBN2, COL1A1, ELN and ALB were higher in anagen and lower in telogen. They were all highly expressed in the outer root sheath of SHFs in anagen. Conclusion: FKBP10, FBN2, COL1A1, ELN, and ALB can promote the growth of SHFs in cashmere goats. This study lays the foundation for analyzing the growth cycle regulatory mechanism of SHFs in cashmere goats, and provides new ideas for further improving cashmere yield and quality. [ABSTRACT FROM AUTHOR]

Purpose: MYB has been shown to play a central role in oncogenesis in a majority of adenoid cystic carcinomas (ACC). Testing for MYB expression via immunohistochemistry (IHC) or testing for the MYB gene fusion by next-generation sequencing (NGS) have become useful tools for the diagnosis of ACC. In addition, detection of MYB expression may have implications for patient management. Methods: A cohort of 35 ACC cases was identified from the archival pathology files of the Massachusetts General Hospital. Cases were tested for MYB expression using a panel of 4 different commercially available MYB antibodies and scored using a modified Allred system. RNA-based NGS for MYB gene fusion detection was also performed. Results: Among 4 different MYB antibodies, the sensitivity for MYB detection ranged from 26 to 97%. When a 30% threshold for determination of MYB immunohistochemical positivity was used, the AB_10900735 IHC clone showed the maximum sensitivity (97%). RNA sequencing revealed 19 (54%) cases positive for MYB fusions, and expression analysis derived from the sequencing data confirmed a significant association between MYB expression and fusion status (p = 0.036). Although less sensitive, the AB_778878 MYB clone showed a significant positive association between IHC staining and MYB RNA expression (R2 = 0.15, p = 0.023). Conclusion: The detection of MYB expression using immunohistochemistry varies significantly depending on the antibody used. Comparison with MYB fusion and transcription levels, as determined by NGS, reveals that MYB has a complex relationship between genetic alterations, transcript levels, and protein abundance. [ABSTRACT FROM AUTHOR]

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Background: Screening for anaplastic lymphoma kinase (ALK) rearranged non‐small cell lung cancer (NSCLC) is crucial for identifying patients eligible for targeted therapy. The FDA‐approved ALK (D5F3) immunohistochemistry (IHC) assay, used with the OptiView Amplification Kit, demonstrates excellent sensitivity and specificity in detecting these patients. However, the clinical significance of resulting focal positivity remains unclear, and ALK (D5F3) expression unrelated to ALK fusion is observed in some cases of neuroendocrine differentiation. This study aims to validate these findings with molecular testing and contribute to the accurate interpretation of ALK (D5F3) IHC results. Methods: A total of 1619 patients diagnosed with NSCLC and neuroendocrine carcinoma were evaluated using ALK (D5F3) IHC. For cases with strong but focal expression and those with diffuse strong positivity in neuroendocrine differentiation, ALK fluorescence in situ hybridization (FISH) and/or next‐generation sequencing (NGS) tests were performed. Results: Seven out of 1109 adenocarcinomas (0.6%) and six out of 289 squamous cell carcinomas (2.1%) exhibited strong focal ALK (D5F3) expression. Nine out of 209 neuroendocrine carcinomas (4.3%) showed homogeneously strong ALK (D5F3) expression. All these cases, including adenocarcinoma with neuroendocrine differentiation and combined small cell carcinoma, were negative for ALK fusions by FISH and/or NGS. Conclusion: This study demonstrates that strong but focal ALK (D5F3) immunostaining and strong expression in neuroendocrine differentiation may not indicate ALK fusion. By considering these findings, we can improve the accuracy of patient selection for targeted therapy by minimizing false‐positive interpretations of ALK (D5F3) staining. [ABSTRACT FROM AUTHOR]

Background: Reticuloendotheliosis virus (REV) is an oncogenic immunosuppressive retrovirus that infects different kinds of avian species; posing significant economic losses to the poultry industry worldwide. Methods: In Egypt, there is an unidentified disease associated with the runting-stunting syndrome with neoplasia, suspected to be REV, that has been continuously monitored in several breeder flocks. To diagnose and analyze REV by cell cultures, enzyme-linked immunosorbent assay (ELISA), histopathological investigation, the polymerase chain reaction (PCR) test, and sequencing analysis, 200 blood samples, and 50 tissue specimens were collected. The current study targets the occurrence and genetic characteristics of a viral neoplastic disease, resembling REV infection, circulating in breeder flocks from 2022 to 2023 in the Ismailia, El-Sharqia, and El-Dakahliya governorates. Result: Here, REV was isolated on chicken embryo fibroblast cell culture; exhibiting cell aggregation, rounding, and cell detachments. Collectively, only 70 serum samples were positive for anti‐REV antibodies with seroprevalence rates of 35% based on the ELISA test. The histopathological observation demonstrated lymphoreticular tumors in the liver, spleen, and other examined organs. The immunohistochemical staining method confirmed the REV-positive signals in all examined organs (liver, kidney, spleen, bursa, ovaries) except for the heart. The PCR assay of the LTR gene assessed 370 base pairs with only 5 positive samples with a percentage of 16.6%. Three positive samples were further sequenced and submitted to the Genbank under accession numbers (PP763709, PP763710, PP763711). Phylogenetic analysis of the REV-LTR gene showed that our three isolates (Sharquia-1-REV, Ismilia-2-REV, Mansoura-3-REV) are REV subtype III which predominantly circulated in breeders in Egypt. These three isolates are highest similar to American, Chinese, and Taiwanese REV reference strains, and other Egyptian strains with nucleotide identity percentages of 100%, 99%, and 99%; respectively, and on the amino acid identity level were with (99–100%), (98%, 99%), (99%, 100%); respectively. Conclusions: This study established that REV infection was extensively distributed in the breeders and became one of the causes of the clinical outbreaks of tumors, raising awareness of REV as the causative agent of avian oncogenic disease in Egypt. [ABSTRACT FROM AUTHOR]

In this study, we investigated the pathological effect of novel goose parvovirus (NGPV) infection on the skeletal muscle, brain, and intestine of naturally affected ducks suffering from locomotor dysfunction as a new approach for deeper understanding of such clinical form. For this purpose, a total of 97 diseased ducks, representing 24 flocks of different duck breeds (14-75 days old), were clinically examined. 72 tissue pools of intestine, brain, and skeletal muscle samples were submitted for molecular identification. Typical clinical signs among the examined ducks suggested the parvovirus infection. Regarding postmortem examination, all examined ducks showed muscle emaciation (100%) either accompanied by congestion (34%) or paleness (66%). Slight congestion, either in the brain (82.5%) or intestine (75.25%), was predominantly detected. Based on molecular identification, the intestine had the highest percentage of positive detection (91.7%), followed by the skeletal muscle (70.8%), and the brain (20.8%). The main histopathological alterations were myofiber atrophy and degeneration, marked enteritis accompanied by lymphocytic infiltration in the lamina propria and submucosa, while the affected brains showed vasculitis, diffuse gliosis, and Purkinje cell degeneration in the cerebellum. Next generation sequencing further confirmed the presence of a variant strain of goose parvovirus (vGPV) that is globally known as NGPV and closely related to Chinese NGPV isolates. Using immunohistochemistry, the NGPV antigen was positively detected in the muscle fibres, enterocytes, and Purkinje cells in the cerebellum. These findings provided proof of the involvement of virus replication in the locomotor disorders linked to NGPV infection in ducks. [ABSTRACT FROM AUTHOR]

Background: Solid pseudopapillary neoplasm of the pancreas (SPN) is a rare and low-grade malignant tumor. It mainly occurs in women of reproductive age, accounting for approximately 1-3% of all pancreatic tumors. SPN has a low incidence rate and is difficult to diagnose before surgery. Some cases may show local infiltration, but distant metastasis rarely occurs. Currently, there is no standardized treatment protocol for SPN. Patient and methods: We have collected clinical data from 5 patients with solid pseudopapillary neoplasm (SPN) of the pancreas who presented with distant metastasis at our hospital. This study retrospectively analyzes their clinical manifestations, imaging characteristics, pathological findings, and treatment outcomes. The aim is to summarize the clinical features of SPN with distant metastasis, thereby improving the diagnosis, treatment, and prognosis prediction of this disease. This study also reviews relevant literature. Results: The median age of the 5 patients was 32 years old, with a male-tofemale ratio of 1:4. All patients underwent enhanced CT scans and were diagnosed with SPN through biopsy or surgical pathology. All 5 patients had liver metastases, and one patient had clavicular lymph node metastasis. Another patient had both lung and clavicular lymph node metastases. Three patients underwent curative surgery, one patient received chemotherapy combined with targeted immunotherapy and subsequently underwent TACE(Transcatheter arterial chemoembolization) and HAIC (Hepatic artery infusion chemotherapy) treatments due to progression. One patient received internal radiation therapy but experienced multiple relapses and eventually died due to complications. The follow-up period ranged from 7 to 53 months, with 2 patients succumbing to the disease. Conclusion: As a low-grade tumor, SPN has a low rate of distant metastasis, typically occurring in only 5%-15% of cases. These metastases often lack characteristic clinical symptoms. Diagnosis can only be confirmed after exclusion of other lesions through imaging and pathological examination. The primary treatment for metastatic SPN is curative surgery, which can lead to a favorable prognosis. [ABSTRACT FROM AUTHOR]

Background: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare form of non-Hodgkin lymphoma that primarily affects subcutaneous tissues. Its occurrence in the orofacial region is exceptionally uncommon, presenting diagnostic challenges due to symptom overlap with more prevalent orofacial condition. Case presentation: This report details the case of a 15-year-old male who presented with persistent left-sided facial swelling, initially misdiagnosed as facial cellulitis. Diagnostic complexity arose from the similarity of symptoms to common orofacial diseases. Comprehensive diagnostic approaches, including liquid-based thin-layer cytometry, immunohistochemistry, and advanced imaging, were pivotal in identifying SPTCL. The recurrence of symptoms following the cessation of dexamethasone treatment indicated hormone dependency. Surgical intervention and subsequent histopathological analysis confirmed SPTCL, with immunohistochemical profiling playing a critical role in the definitive diagnosis. The patient's management involved a multidisciplinary approach, leading to a referral to a hematology specialist and subsequent favorable outcomes. Conclusions: This case underscores the diagnostic challenges of orofacial lymphomas such as SPTCL and highlights the necessity for early, accurate pathological diagnosis. It emphasizes the role of advanced diagnostic techniques and the importance of a comprehensive, multidisciplinary approach in the management of such rare cases. This report contributes to the limited but growing body of literature on SPTCL in the orofacial region, providing insights for clinicians in similar future cases. [ABSTRACT FROM AUTHOR]

Ovarian tumors can be divided into epithelial tumors, germ cell tumors, sex cordstromal tumors and metastatic tumors according to histological types. Their biological behaviors are different. Lymphangioma is a rare benign tumor that can occur anywhere in the body. Among them, ovarian lymphangioma is particularly rare. The case we reported is the case of ovarian lymphangioma. The patient was admitted to the hospital one month after the physical examination found the ovarian mass. After the examination, the patient was treated with laparoscopic surgery. The patient recovered well after the operation, and no recurrence was found after the follow-up. [ABSTRACT FROM AUTHOR]

The document is a correction notice for an article titled "PSMD9 promotes the malignant progression of hepatocellular carcinoma by interacting with c-Cbl to activate EGFR signaling and recycling." The correction addresses errors in Figures 1 and 6 of the original article, specifically related to plot type errors and mislabeling of fluorescence markers. The corrected figures provide data on the expression of PSMD9 in HCC tissues and its association with patient prognosis. The article is licensed under a Creative Commons Attribution 4.0 International License. [Extracted from the article]

Neuroendocrine tumors (NETs) are a rare type of neoplasm that originate from neuroendocrine cells and peptide neurons. Primary renal well-differentiated NETs are extremely rare, and only a few cases have been reported worldwide. In this study, we present a new case of primary renal well-differentiated NET at our institution, followed by a literature review. A systematic search was conducted using various search terms to identify relevant literature on primary renal well-differentiated NETs from 2021 to present. The study analyzed the clinical features, age, gender, tumor size, location, gross pathology, light microscopy, and immunohistochemical results of 32 cases of primary renal well-differentiated NETs. The findings suggest that these tumors are rare and have nonspecific clinical and imaging features. The diagnosis heavily relies on immunohistochemical analysis. Primary renal well-differentiated NETs are associated with low malignant potential and a favorable prognosis. Surgical resection is the preferred treatment, and long-term follow-up is necessary to monitor the patient's condition. [ABSTRACT FROM AUTHOR]

Intratumoral heterogeneity poses a significant challenge to the diagnosis and treatment of recurrent glioblastoma. This study addresses the need for non-invasive approaches to map heterogeneous landscape of histopathological alterations throughout the entire lesion for each patient. We developed BioNet, a biologically-informed neural network, to predict regional distributions of two primary tissue-specific gene modules: proliferating tumor (Pro) and reactive/inflammatory cells (Inf). BioNet significantly outperforms existing methods (p < 2e-26). In cross-validation, BioNet achieved AUCs of 0.80 (Pro) and 0.81 (Inf), with accuracies of 80% and 75%, respectively. In blind tests, BioNet achieved AUCs of 0.80 (Pro) and 0.76 (Inf), with accuracies of 81% and 74%. Competing methods had AUCs lower or around 0.6 and accuracies lower or around 70%. BioNet's voxel-level prediction maps reveal intratumoral heterogeneity, potentially improving biopsy targeting and treatment evaluation. This non-invasive approach facilitates regular monitoring and timely therapeutic adjustments, highlighting the role of ML in precision medicine. [ABSTRACT FROM AUTHOR]

Background: Cadonilimab is the first approved dual immune checkpoint inhibitor targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), currently utilized for the treatment of various solid tumors. Oral mucosal adverse reactions, such as oral lichenoid lesions, represent one of the most prevalent immune-related adverse events associated with immune checkpoint antibodies. However, reports detailing oral side effects specifically linked to Cadonilimab are lacking. Documenting these side effects is essential to alert oncologists and stomatologists, facilitating timely intervention for affected patients. Case Presentation: We present a case involving a 35-year-old male patient diagnosed with hepatocellular carcinoma who received Cadonilimab following hepatectomy and subsequently developed extensive oral lichenoid lesions along with mucosal erosion at 13–14 weeks post-treatment initiation. A biopsy was conducted revealing immunohistochemical findings of CD3+, CD4+, CD8+, CD20 + lymphocytes, CD68 + macrophages, and α-SMA + myofibroblasts infiltrating the tissue of the oral lichenoid lesions. The patient's oral lesions improved after administration of systemic and local glucocorticoid therapy alongside cessation of Cadonilimab treatment. Conclusion: This report marks the first documented instance of an oral adverse effect associated with Cadonilimab use. It underscores that administration of this agent may lead to significant lichenoid lesions and erosions within the oral cavity—an issue warranting increased vigilance from both oncologists and stomatologists. [ABSTRACT FROM AUTHOR]

Purpose: Cumulating evidence supports the close association between periodontal diseases, neuroinflammation and neurodegenerative pathologies, except for peri-implantitis (PI). Thus, this study explored the association between experimental PI and neuropathological changes in the rat brain. Materials and methods: After bilateral first molars extraction, experimental PI was induced at titanium implants placed in the maxillae by lipopolysaccharide injections and ligature placement. Following 28-weeks of disease progression, the maxillae and brains were retrieved from 6 rats. Healthy brains from 3 rats were used as control. Brains were analyzed by immunohistochemistry to detect signs of neuroinflammation (interleukin (IL)-6 and tumor necrosis factor (TNF)-α)), microglial activation (IBA-1) and astrogliosis (GFAP). To explore signs of neurodegeneration, hematoxylin/eosin and Nissl stainings were used. Also, four different antibodies against amyloid beta (Aβ 1–42) were tested. Results: Chronic PI lesions showed peri-implant bone resorption accompanied by large inflammatory infiltrates. IL-6+ and TNF-α+ cells were found within the CA1 and Dentate Gyrus regions of the hippocampus of the PI-affected group, while almost no immune-positivity was detected in the control (p < 0.05). Detection of activated GFAP+ microglia and IBA-1+ astrocytes surface were significantly higher at the CA areas, and cerebral cortex of the PI-affected group, in comparison with control (p < 0.05). Shrunk neurons with pyknotic nuclei were inconsistently found among the PI-affected group, and these were almost not detected in control. No positive Aβ reactivity was detected in any of the samples. Conclusion: Chronic experimental PI lesions led to an increased detection of IL-6 and TNF-α, GFAP+ microgliosis and IBA-1+ astrocytosis, and in some cases, neurodegeneration, in the rat brain. [ABSTRACT FROM AUTHOR]

Background: Accurate lymphoma classification is critical for effective treatment and immunohistochemistry is a cost‐effective and time‐saving approach. Although several machine learning algorithms showed effective results, they focused on a specific task of classification but not the whole classification workflow, thus impractical to be applied in clinical settings. Thus, we aim to develop an effective and economic machine learning‐assisted system that can streamline the lymphoma differential diagnostic workflow using EBER in situ hybridization and immunohistochemical markers. Methods: We included pathological reports diagnosed as lymphomas from two cancer centers (Sun Yat‐sen University Cancer Center and Peking University Cancer Hospital & Institute). We proposed a hierarchical approach that mimicked the human diagnostic process and employed simplified panels of markers to perform a series of interpretable classification. The diagnostic accuracy for lymphoma pathological subtypes and the markers saving ratio were investigated in both temporal independent population and external medical center. Results: A total of 14,927 patients and corresponding immunohistochemical results from two cancer centers were included. The proposed system had high discriminative ability for differentiating lymphoma pathological subtypes (measured by mean AUC in three validation cohorts, non‐Hodgkin and Hodgkin lymphoma: 0.959; non‐Hodgkin subtypes: 0.983; B‐lymphoma subtypes: 0.868; T‐lymphoma subtypes: 0.962; DLBCL subtypes: 0.957). In addition, the system's well selected characteristics can contribute to the development of agreement on panels of markers for differential diagnosis and help minimize cost of immunohistochemical marker techniques (measured by marker saving ratio compared to real clinical settings, internal primary‐stage cohort: 16.45% saved, p < 0.001; internal later‐stage cohort: 21.73% saved, p < 0.001; external cohort: 3.67% saved, p < 0.001). Conclusions: Machine learning‐based hierarchical system using EBER in situ hybridization and IHC markers was developed, which could streamline the workflow by sequentially determining each lymphoma pathological subtype. The proposed system proved to be effective and cost‐saving in independent and external validation, thus could be adopted affordably in future clinical practice. [ABSTRACT FROM AUTHOR]

Background and objectives: Histopathological similarities between craniopharyngioma (CP) and ameloblastoma (AB) have long been recognized, particularly the shared features of palisading columnar epithelium and stellate reticulum-like areas. This study aimed to investigate potential odontogenic differentiation in CP akin to AB using immunohistochemical odontogenic markers. Methods: We analyzed AMELX, ODAM, and CK19 expression in 44 cases (20 CP and 24 AB). Results: While AMELX and ODAM showed diffuse strong positive expression in both tumors with no significant statistical differences, CK19 expression was notably higher in CP. Conclusion: The markers AMELX and ODAM associated with odontogenic differentiation exhibited similar profiles in both tumors due to shared similar embryological origins. Notably, CK19, a biomarker of odontogenic epithelium, showed even higher expression, suggesting distinct pathways. These findings offer insights into tumor biology and may aid in diagnostic and therapeutic approaches. [ABSTRACT FROM AUTHOR]

Cancer-associated fibroblasts (CAFs) are a key component of the tumor microenvironment and significantly contribute to the progression of various cancers, including esophageal squamous cell carcinoma (ESCC). Our previous study established a direct co-culture system of human bone marrow-derived mesenchymal stem cells (progenitors of CAFs) and ESCC cell lines, which facilitates the generation of CAF-like cells and enhances malignancy in ESCC cells. In this study, we further elucidated the mechanism by which CAFs promote ESCC progression using cDNA microarray analysis of monocultured ESCC cells and those co-cultured with CAFs. We observed an increase in the expression and secretion of amphiregulin (AREG) and the expression and phosphorylation of its receptor EGFR in co-cultured ESCC cells. Moreover, AREG treatment of ESCC cells enhanced their survival and migration via the EGFR-Erk/p38 MAPK signaling pathway. Immunohistochemical analysis of human ESCC tissues showed a positive correlation between the intensity of AREG expression at the tumor-invasive front and the expression level of the CAF marker FAP. Bioinformatics analysis confirmed significant upregulation of AREG in ESCC compared with normal tissues. These findings suggest that AREG plays a crucial role in CAF-mediated ESCC progression and could be a novel therapeutic target for ESCC. [ABSTRACT FROM AUTHOR]

Simple Summary: The aim of this study was to report on the clinical, pathological, and molecular features of endometrioid endometrial cancer (EEC) with and without microcystic, elongated, and fragmented (MELF) infiltration and to evaluate the latest phase of the Federation of Gynecology and Obstetrics (FIGO) staging, updated in 2023. MELF is a special invasion pattern in EEC and is associated with certain clinicopathological features, such as 2023 FIGO staging, tumor grade, the presence of LVSI, LNM, and mismatch-repair deficiency (MMRd). LVSI, LNM, and MMRd were more frequent in the MELF group than in the no-MELF group, and the differences were statistically significant (p < 0.05). Molecular classification was also applicable to the MELF pattern. The recurrence risk was highest in the copy number—high (CNH) subgroup, followed by the microsatellite instability—high (MSI-H) group, whereas POLE and copy number—low (CNL) were associated with a relatively good prognosis in this cohort. This study is a large-cohort investigation and provides valuable information regarding molecular classification and updated 2023 FIGO staging for MELF, highlighting the importance of integrating molecular and traditional histopathological assessments for risk evaluation. This approach could enhance prognostic accuracy and facilitate tailored therapeutic strategies. Background: Microcystic, elongated, and fragmented (MELF) invasion is a special invasion pattern in endometrioid endometrial cancer (EEC). This study aimed to investigate the clinical, pathological, and molecular features of the MELF pattern and its prognostic value in patients with EEC. Materials and Methods: The clinical and pathological data of 342 patients with EEC were retrospectively collected at Peking University People's Hospital from January 2019 to December 2022. Some key clinicopathological features were evaluated, including the tumor grade, Federation of Gynecology and Obstetrics (FIGO) staging, cervical stromal involvement, lymph node status, and lymphatic vascular space infiltration (LVSI). Immunohistochemical staining and molecular tests were performed, and the relevant literature was reviewed. Results: The MELF pattern was more prevalent in low-grade EEC. A significant correlation was found between the MELF pattern and advanced FIGO staging, LVSI, the depth of myometrial invasion, cervical stromal involvement, and lymph node metastasis (LNM). The incidence of mismatch-repair-deficient (MMRd) proteins was much higher in the MELF group than in the no-MELF group. Molecular testing revealed that, after copy number—low (CNL), microsatellite instability—high (MSI-H) was the second-most frequent subtype in the MELF group. The recurrence risk did not significantly differ between the MELF and no-MELF groups, but the differences among the four molecular subtypes were statistically significant. However, the MELF group experienced a shorter recurrence time. Among the four molecular subtypes, the recurrence risk was the highest in the CNH subgroup, followed by the MSI-H subgroup. Conclusions: MELF is a special invasion pattern in EEC and is associated with distinct clinicopathological and molecular characteristics, including the latest 2023 FIGO staging. Further research is warranted to explore its implications for treatment strategies and patient outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: The aim of this study was to assess the impact of various factors—such as age, age at menarche, age at first childbirth, number of births, body mass index (BMI), living environment (rural vs. urban), and other factors later discussed—on the likelihood of developing breast cancer. This article's original research was based on data gathered from 687 breast biopsies, which were analyzed through comparative analysis and regression analysis to identify possible predictors for malignancy and tumor size. The comparative analysis and regression models in this study provide deeper insights into the roles of various variables, particularly positive hormonal receptor status, in malignancy. Introduction: Breast cancer has become one of the most serious and widespread public health concerns globally, affecting an increasing number of women—and, in rare cases, men—across the world. It is the most common cancer among women across all countries. In this study, we aimed to evaluate the influence of demographic factors, medical and reproductive history, diagnostic techniques, and hormone receptor status on the development and progression of breast cancer. Materials and Methods: A total of 687 female patients from Romania underwent standard breast examination techniques, including clinical breast examination, mammography, ultrasonography, and, ultimately, breast biopsy. Statistical analysis was performed using the R programming language and RStudio software. The study included a comparative analysis and a prediction analysis for malignancy and tumor size (cumulative histological dimension) through logistic and linear regression models. Results: The comparative analysis identified several variables associated with malignancy: older age (p < 0.001), non-vulnerability (p = 0.04), no daily physical activity (p = 0.002), no re-biopsy (p < 0.001), immunohistochemistry use (p < 0.001), use of larger gauge needles (p < 0.001), ultrasound-guided biopsy (p < 0.001), and vacuum biopsy (p < 0.001). The hormone receptor statuses—estrogen receptor (ER), progesterone receptor (PR), and androgen receptor (AR)—showed statistically significant differences in distribution across breast cancer B classifications. Logistic regression analysis identified ER, PR, and age as significant predictors of malignancy. Linear regression analysis revealed histopathological results, living environment, geographical region, vulnerability, prior breast examination, and the number of histological fragments as significant predictors of cumulative histological dimension. Conclusions: Our predictive models demonstrate the impact of demographic factors, medical history, diagnostic techniques, and hormone receptor status on breast cancer development and progression, accounting for a significant portion of the variance in malignancy and cumulative histological dimension. [ABSTRACT FROM AUTHOR]

Simple Summary: This article herein presented explores the role of the epigenetic marker H3K27me3 in tumors of the Central Nervous System, highlighting its importance for diagnosis, prognosis, and treatment. H3K27me3 involves the trimethylation of lysine 27 on the histone H3 protein, which is essential for regulating gene activity and maintaining chromatin structure. A reduction in H3K27me3 levels is commonly seen in CNS tumors such as diffuse midline gliomas and meningiomas and is associated with more aggressive tumor behavior and a worse prognosis. This article emphasizes the utility of H3K27me3 loss in tumor diagnosis, prognosis, and the advancement of targeted therapies. Central nervous system (CNS) tumors represent a formidable clinical challenge due to their molecular complexity and varied prognostic outcomes. This review delves into the pivotal role of the epigenetic marker H3K27me3 in the development and treatment of CNS tumors. H3K27me3, specifically the trimethylation of lysine 27 on the histone H3 protein, plays a crucial role in regulating gene expression and maintaining chromatin architecture (e.g., in X-chromosome inactivation). Notably, a reduction in H3K27me3 levels, frequently tied to mutations in the H3 gene family such as H3F3A and HIST1H3B, is evident in diverse brain tumor variants, including the diffuse midline glioma characterized by the H3K27M mutation and certain pediatric high-grade gliomas. The loss of H3K27me3 has been linked to more aggressive behavior in meningiomas, with the trimethylation loss associated with significantly shorter recurrence-free survival (RFS) among grade 2 meningiomas, albeit not within grade 1 tumors. Pediatric posterior fossa ependymomas characterized by a lowered H3K27me3 and DNA hypomethylation exhibit poor prognosis, underscoring the prognostic significance of these epigenetic alterations in CNS tumors. Comprehending the role of H3K27me3 in CNS tumors is vital for advancing diagnostic tools and therapeutic interventions, with the goal of enhancing patient outcomes and quality of life. This review underscores the importance of ongoing investigations into H3K27me to refine and optimize management strategies for CNS tumors, paving the way for improved personalized medicine practices in oncology. [ABSTRACT FROM AUTHOR]

Simple Summary: Neoadjuvant chemotherapy has risen in clinical use for the treatment of pancreatic cancer over the past few decades. Many patients now undergo prior treatment before surgical resection to aid in downstaging the tumor for a potentially improved surgical outcome. Potential targeted therapies such as fluorescence-guided surgery often rely on the upregulated protein expression in the tumor. Therefore, it is important to understand the impact of neoadjuvant therapy on tumor protein expression, as protein expression may be altered by chemotherapy treatment. The aim of our study was to evaluate the expression of Mucin 16 (MUC16) after neoadjuvant chemotherapy in pancreatic ductal adenocarcinoma tissue. This study found that MUC16 expression was retained in the tumor following neoadjuvant chemotherapy treatment regimens. These findings may have a broad impact on the delivery of MUC16-targeted therapies before and after neoadjuvant chemotherapy treatment. Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. Currently, surgical resection is the only potentially curative treatment. Unfortunately, less than 20% of PDAC patients are eligible for surgical resection at diagnosis. In the past few decades, neoadjuvant chemotherapy treatment (NCT) has been investigated as a way to downstage PDAC tumors for surgical resection. Fluorescence-guided surgery (FGS) is a technique that can aid in increasing complete resection rates by enhancing the tumor through passive or active targeting of a contrast agent. In active targeting, a probe (e.g., antibody) binds a protein differentially upregulated in the tumor compared to normal tissue. Mucin 16 (MUC16), a transmembrane glycoprotein, has recently been explored as an FGS target in preclinical tumor models. However, the impact of chemotherapy on MUC16 expression is unknown. Methods: To investigate this issue, immunohistochemistry was performed on PDAC patient samples. Results: We found that MUC16 expression was retained after NCT in patient samples (mean expression = 5.7) with minimal change in expression between the matched diagnostic (mean expression = 3.66) and PDAC NCT patient samples (mean expression = 4.5). Conclusions: This study suggests that MUC16 is a promising target for FGS and other targeted therapies in PDAC patients treated with NCT. [ABSTRACT FROM AUTHOR]

Background: The trophoblast is a significant source of vitamin D synthesis during pregnancy, with the literature suggesting its role in fetal growth. We aim to underline a possible mechanism that would explain negative fetal outcomes in COVID-19-positive mothers by examining the relationship between altered placental structure and function and throphoblast cells' vitamin D receptor levels. Methods: The study included 170 placental samples collected from women who gave birth at term without complications, divided into three groups: COVID-19-positive and unvaccinated, COVID-19-negative and vaccinated, and COVID-19-negative and unvaccinated, with exclusion criteria for any other medical complications. Immunohistochemistry (IHC) was performed to detect vitamin D receptor (VDR) expression, and immediate fetal outcomes (weight and Apgar score) were assessed. Results: We found lower gestational age at birth, lower birth weight, and reduced placental VDR (vitamin D receptor) levels in COVID-19-positive women compared to COVID-19-vaccinated and COVID-19-negative women. Conclusions: The presence of the vitamin D receptor in the placenta is related to fetal and placental growth. Its deficiency may contribute to negative fetal outcomes in COVID-19-positive cases. [ABSTRACT FROM AUTHOR]

We genetically manipulated HaCaT cells, a spontaneously immortalised normal keratinocyte cell line, to stably express two different coloured luciferase reporter genes, driven by interleukin 8 (IL‐8) and ubiquitin‐C (UBC) promoters, respectively. Subsequently, we generated a three‐dimensional (3D) skin‐like in vitro composite (SLIC) utilising these cells, with the objective of monitoring bioluminescence emitted from the SLIC. This SLIC was generated on non‐woven silica fibre membranes in differentiation medium. Immunohistochemical analyses of skin differentiation markers in the SLIC revealed the expression of keratins 2 and 10, filaggrin, and involucrin, indicating mature skin characteristics. This engineered SLIC was employed for real‐time bioluminescence monitoring, allowing the assessment of time‐ and dose‐dependent responses to UV stress, as well as to hydrophilic and hydrophobic chemical loads. Notably, evaluation of responses to hydrophobic substances has been challenging with conventional 2D cell culture methods, suggesting the need for a new approach, which this technology could address. Our observations suggest that engineered SLIC with constitutively expressing reporters driven by selected promoters which are tailored to specific objectives, significantly facilitates assays exploring the physiological functions of skin cells based on genetic response mechanisms. It also highlights new avenues for evaluating the physiological impacts of various compounds designed for topical application to human skin. [ABSTRACT FROM AUTHOR]

Background: During the aging process, the number and functional activity of endothelial progenitor cells (EPCs) are impaired, leading to the unsatisfactory efficacy of transplantation. Previous studies demonstrated that Yiqihuoxue decoction (Ginseng-Sanqi-Chuanxiong, GSC) exerts anti-vascular aging effects. The purpose of this study is to evaluated the effects of GSC on D-galactose (D-gal)induced senescence and the underlying mechanisms. Methods: The levels of cellular senescence-related markers P16, P21, P53, AMPK and p-AMPK were detected by Western blot analysis (WB). SA-β-gal staining was used to evaluate cell senescence. EPCs function was measured by CCK-8, Transwell cell migration and cell adhesion assay. The morphological changes of mitochondria were detected by confocal microscopy. The protein and mRNA expression of mitochondrial fusion fission Drp1, Mff, Fis1, Mfn1, Mfn2 and Opa1 in mitochondria were detect using WB and RT–qPCR. Mitochondrial membrane potential, mtROS and ATP of EPCs were measured using IF. H&E staining was used to observe the pathological changes and IMT of the aorta. The expressions of AGEs, MMP-2 and VEGF in aorta were measured using Immunohistochemical (IHC). The levels of SOD, MDA, NO and ET-1 in serum were detected by SOD, MDA and NO kits. Results: In vitro, GSC ameliorated the senescence of EPCs induced by D-gal and reduced the expression of P16, P21 and P53. The mitochondrial morphology of EPCs was restored, the expression of mitochondrial Drp1, Mff and Fis1 protein was decreased, the levels of mtROS and ATP were decreased, and mitochondrial function was improved. Meanwhile, the expression of AMPK and p-AMPK increased. The improvement effects of GSC on aging and mitochondrial morphology and function were were hindered after adding AMPK inhibitor. In vivo, GSC improved EPCs efficiency, ameliorated aortic structural disorder and decreased IMT in aging mice. The serum SOD level increased and MDA level decreased, indicating the improvement of antioxidant capacity. Increased NO content and ET-1 content suggested improvement of vascular endothelial function. The changes observed in SOD and MMP-2 suggested a reduction in vascular stiffness and the degree of vascular damage. The decreased expression of P21 and P53 indicates the delay of vascular senescence. [ABSTRACT FROM AUTHOR]

Background: Central nervous system hemangioblastomas are the most prevalent manifestation of von Hippel‐Lindau (VHL) disease and remain the main cause of mortality. Surgical resection is the primary treatment strategy, but is not always possible, and should be used as restrictively as possible. There is an unmet need for less invasive treatment strategies, such as targeted therapy. Expression of somatostatin receptor 2A (SSTR2A) in VHL‐related hemangioblastomas has been described earlier, but the extent of expression in a larger population has yet to be determined. The authors hypothesize that a substantial subset of VHL‐related hemangioblastomas show SSTR2A expression, which may serve as a potential new treatment target. Methods: Patients who were surgically treated for a VHL‐related hemangioblastoma from 1990 until 2021 at the UMC Utrecht were included. Clinical data was derived from a clinical database. Tissue samples were histopathologically examined with use of hematoxylin and eosin staining, and immunohistochemical analysis of SSTR2A expression was performed. Results: Forty‐three tissue samples were obtained from 26 patients. Nine showed strong positivity for SSTR2A expression, whereas 13 showed moderate and 15 sparse expression. Three samples showed no expression of SSTR2A. The distribution showed right‐skewedness favoring a strong expression. SSTR2A expression colocalized with endothelial markers and not with stromal cells. Additionally, within‐patient variability for SSTR2A expression was described in 14 patients. Conclusion: SSTR2A is expressed in varying degrees in the majority of VHL‐related hemangioblastomas. Future treatment with somatostatin analogues or even peptide receptor radionuclide treatment may be considered for SSTR2A‐positive cases. There is a variable intrapatient expression of somatostatin receptor type 2A hemangioblastomas. [ABSTRACT FROM AUTHOR]

Aims: Ulcerative colitis‐associated neoplasia (UCAN) is characterised by multifocal tumourigenesis. A wide range of metachronous lesions have been reported to occur after endoscopic treatment of UCAN, which suggests the development of sporadic tumours in lesions treated as UCAN. Therefore, we aimed to evaluate differences of immunohistochemistry (IHC) in features and clinicopathological characteristics of intramucosal lesions in patients with ulcerative colitis (UC). Methods and results: We examined 35 intramucosal lesions resected for carcinoma or dysplasia by total colectomy from patients with UC and 71 sporadic adenomas (SAs) endoscopically resected from patients without UC. UC lesions were divided into the conventional UCAN group, defined as p53 mutant pattern and normal expression of β‐catenin, and the non‐conventional UCAN group, defined as the rest. Ki‐67 distribution, α‐methylacyl‐CoA racemase (AMACR) expression and mucin phenotypes were compared using IHC, and clinicopathological characteristics were investigated. Conventional and non‐conventional UCAN lesions were located in the left colon and rectum. Relative to the SA lesions, UCAN lesions occurred in much younger patients and exhibited more frequent basal distribution of Ki‐67 in tumour crypts. Conventional UCAN lesions tended to be non‐polyploid and exhibited a higher frequency of normal AMACR expression than SA lesions. UC lesions were heterogeneous—only two of the eight patients with multiple lesions had lesions (both non‐conventional UCAN lesions) exhibiting concordant IHC staining features. Conclusions: The basal pattern of Ki‐67 distribution, normal expression of AMACR and a non‐intestinal mucin phenotype were determined as characteristic features suggestive of UCAN. Non‐polypoid growth was another a key feature of UCAN. [ABSTRACT FROM AUTHOR]

Aims: Decreased oestrogen receptor (ER) expression is a marker of poor prognosis in endometrial carcinomas (EC) of no specific molecular profile (NSMP), but the optimal cut‐off to separate high‐risk 'low ER' versus low‐risk 'high ER' expression has not been defined. Here we characterised the distribution of ER staining in a cohort of ECs. Methods and results: Biopsy specimens from 120 cases of NSMP EC were stained for ER and assigned an Allred score. In 66 additional cases ER staining of matched biopsy and hysterectomy were compared. Twelve of 120 tumours had an Allred score of 0–3, including three endometrioid carcinomas (EEA) (one G1, two G3), four clear cell carcinomas (CCC), two mesonephric‐like adenocarcinoma (MLA) and one each of: gastric‐type adenocarcinoma, carcinosarcoma and endometrial carcinoma NOS. Three had Allred scores of 4–5: two MLA and one high‐grade carcinoma with yolk sac differentiation. Five had Allred scores of 6: four EEA (one G1, one G2, two G3) and one mixed clear cell and endometrioid carcinoma. The remaining 100 tumours with Allred scores ≥ 7 were all EEA (66 G1, 28 G2, five G3 and one grade unknown). Comparing the biopsy versus hysterectomy ER staining (n = 66), the results were within a single Allred score point, except two cases with strong diffuse expression in the biopsy (Allred 8) and moderate expression in the hysterectomy (Allred 5). Conclusions: Most NSMP ECs (> 80%) show high ER expression (Allred score ≥ 7). All non‐endometrioid carcinomas and a few endometrioid carcinomas had lower ER expression (Allred score ≤ 6) or were completely negative. [ABSTRACT FROM AUTHOR]

Aims: The majority of dermatofibrosarcoma protuberans (DFSP) harbour PDGFB or PDGFD rearrangements. We encountered ALK expression/rearrangement in a PDGFB/D‐negative CD34‐positive spindle cell neoplasm with features similar to DFSP, prompting evaluation of ALK‐rearrangements in DFSP and plaque‐like CD34‐positive dermal fibroma (P‐LDF). Methods and Results: We searched the archives of academic institutions for cases previously coded as DFSP and P‐LDF. NGS‐naïve or PDGFB‐negative DFSP were screened for ALK (clone D5F3) expression by immunohistochemistry. NGS or ALK FISH was performed on ALK‐positive cases. Methylome profiling studies were performed and compared with conventional DFSP. One case of "DFSP" and two "P‐LDF" with ALK expression were identified from the archives, while four cases were detected prospectively. These seven cases (6F:1M; 8 months to 76 years) arose in the dermis of the arm (two), scalp, eyelid, thigh, abdomen, and shoulder and ranged from 0.4 to 4.2 cm. Tumours were composed of spindled cells and displayed a storiform growth pattern. Cytologic atypia was absent, and mitotic figures were scarce (0–2/10 HPFs, high power fields). The lesional cells were diffusely positive for CD34 and ALK and negative for S100 protein. By NGS (n = 5), ALK fusion partners included DCTN1 (2), PLEKHH2, and CLIP2 in DFSP‐like cases and FLNA in P‐LDF‐like lesions. ALK FISH was positive in one (of two) cases previously labelled P‐LDF. Methylome profiling of two (of three) ALK‐rearranged DFSP‐like tumours showed clustering with conventional DFSP in the UMAP dimension reduction plot. To date, no tumour has recurred (n = 2; 26, 27 months). Conclusion: We describe a cohort of novel ALK‐rearranged tumours with morphologic features similar to DFSP. [ABSTRACT FROM AUTHOR]

Aims: Areas of gland crowding that do not fulfil diagnostic criteria of endometrioid intra‐epithelial neoplasia (EIN) are often encountered in endometrial biopsies. In this study, we document the prevalence of neoplastic outcome in patients with these subdiagnostic lesions (SL) and assess the utility of morphological features and a three‐marker immunohistochemistry panel (PAX2, PTEN, beta‐catenin) to predict outcome. Methods and results: Of 430 women with SL on endometrial sampling at Brigham and Women's Hospital between 2001 and 2021 with available follow‐up biopsy, 72 (17%) had a neoplastic outcome (EIN or endometrioid carcinoma). Multilayered epithelium and mitoses in SL were statistically associated with a neoplastic outcome. Abnormal three‐marker staining was observed in 93% (53 of 57) of SL with neoplastic outcome and 60% (37 of 62) of a control group with benign outcome. Among the 72 patients with neoplastic outcome, EIN/carcinoma tissue was available in 33; of these, 30 (91%) showed abnormal staining for one or more markers. Remarkably, in 84% of these cases the EIN/carcinoma had the aberrant expression seen in the preceding SL. Based on a prevalence of 17%, the positive and negative predictive values of abnormal staining in one or more markers were 24 and 97%, respectively. Conclusions: The presence of SL warrants clinical surveillance and repeat sampling because it is followed by endometrioid neoplasia in a significant subset of patients. Normal three‐marker staining identifies women with a very low risk of neoplastic outcome. Conversely, abnormal staining is frequent in SL with benign outcome leading to poor specificity and positive predictive value. [ABSTRACT FROM AUTHOR]

Our previous research revealed a close association between the acetylation of peroxisome proliferator-activated receptor γ (PPARγ) histone H3K27 and the adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). We preliminarily explored the epigenetic mechanism of steroid-induced avascular necrosis of the femoral head (SANFH) development, but the specific histone deacetylase (HDAC) involved in this regulatory process remains unknown. In this study, we combined cell, animal, and clinical specimen experiments to screen for specific HDAC genes that could regulate BMSC adipogenic differentiation and to explore their roles. The results showed that dexamethasone (DEX) significantly exacerbated the imbalance between the adipogenic and osteogenic differentiation of BMSCs, and there were differences in HDAC expression in the adipogenic differentiation cell models, with histone deacetylase 10 (HDAC10) showing the most significant decrease in expression. Subsequent use of a chromatin immunoprecipitation assay kit and quantitative polymerase chain reaction (ChIP‒qPCR) revealed a decrease in HDAC10 expression at predicted potential sites within the PPARγ promoter, indicating a significant decrease in HDAC10 enrichment in the PPARγ promoter region of BMSCs, thereby promoting sustained PPARγ expression. Additionally, immunohistochemistry of samples collected from mice and humans with SANFH and normal femoral heads revealed an imbalance between adipogenic and osteogenic differentiation in the necrotic area of femoral heads, with a significant decrease in the relative expression of HDAC10 in the necrotic area of femoral heads with SANFH. In summary, we speculate that HDAC10 affects the progression of SANFH by regulating BMSC adipogenic differentiation, a process possibly related to PPARγ histone acetylation. These findings provide a promising direction for the treatment of SANFH. [ABSTRACT FROM AUTHOR]