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Infectious bronchitis virus (IBV) strains of genotype GVIII have been emerging in Europe in the last decade, but no biological characterization has been reported so far. This paper reports the extensive genetic and biological characterization of IBV strain D2860 of genotype GVIII which was isolated from a Dutch layer flock that showed a drop in egg production. Whole genome sequencing showed that it has a high similarity (95%) to CK/DE/IB80/2016 (commonly known as IB80). Cross-neutralization tests with antigens and serotype-specific antisera of a panel of different non-GVIII genotypes consistently gave less than 2% antigenic cross-relationship with D2860. Five experiments using specified pathogen-free chickens of 0, 4, 29 and 63 weeks of age showed that D2860 was not able to cause clinical signs, drop in egg production, false layers or renal pathology. There was also a distinct lack of ciliostasis at both 5 and 8 days post-inoculation at any age, despite proof of infection by immunohistochemical (IHC) staining, RT–PCR and serology. IHC showed immunostaining between 5 and 8 days post inoculation in epithelial cells of sinuses and conchae, while only a few birds displayed immunostaining in the trachea. In vitro comparison of replication of D2860 and M41 in chicken embryo kidney cells at 37°C and at 41°C indicated that D2860 might have a degree of temperature sensitivity that might cause it to prefer the colder parts of the respiratory tract. [ABSTRACT FROM AUTHOR]

One of the emerging trends in modern analytical and bioanalytical chemistry involves the substitution of enzyme labels (such as horseradish peroxidase) with nanozymes (nanoparticles possessing enzyme-like catalytic activity). Since enzymes and nanozymes typically operate through different catalytic mechanisms, it is expected that optimal reaction conditions will also differ. The optimization of substrates for nanozymes usually focuses on determining the ideal pH and temperature. However, in some cases, even this step is overlooked, and commercial substrate formulations designed for enzymes are utilized. This paper demonstrates that not only the pH but also the composition of the substrate buffer, including the buffer species and additives, significantly impact the analytical signal generated by nanozymes. The presence of enhancers such as imidazole in commercial substrates diminishes the catalytic activity of nanozymes, which is demonstrated herein through the use of 3,3′-diaminobenzidine (DAB) and Prussian Blue as a model chromogenic substrate and nanozyme. Conversely, a simple modification to the substrate buffer greatly enhances the performance of nanozymes. Specifically, in this paper, it is demonstrated that buffers such as citrate, MES, HEPES, and TRIS, containing 1.5–2 M NaCl or NH4Cl, substantially increase DAB oxidation by Prussian Blue and yield a higher signal compared to commercial DAB formulations. The central message of this paper is that the optimization of substrate composition should be an integral step in the development of nanozyme-based assays. Herein, a step-by-step optimization of the DAB substrate composition for Prussian Blue nanozymes is presented. The optimized substrate outperforms commercial formulations in terms of efficiency. The effectiveness of the optimized DAB substrate is affirmed through its application in several commonly used immunostaining techniques, including tissue staining, Western blotting assays of immunoglobulins, and dot blot assays of antibodies against SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Background: Brain imaging studies suggest that volume reductions and compromised white matter integrity occur in schizophrenia and bipolar disorder (BD). However, the cellular correlates have not yet been identified. To address this issue we assessed oligodendrocyte, astrocyte and microglial populations in postmortem white matter from schizophrenia, BD and nonpsychiatric control samples. Methods: The density, areal fraction and spatial distribution of glial fibrillary acidic protein (GFAP)-expressing astrocytes and ionized calciumbinding adaptor molecule-1 (IBA-1)-expressing microglia as well as the density, nuclear size and spatial distribution of Nissl-stained oligodendrocytes were quantified in postmortem white matter adjacent to the dorsolateral prefrontal cortex (Brodmann area 9) in schizophrenia, BD and control samples (n = 20). In addition, the oligodendrocyte-associated proteins myelin basic protein and 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNPase) were quantified in the same samples by enzyme-linked immunosorbent assay and immunoblotting. Results: Oligodendrocyte density (p = 0.012) and CNPase protein levels (p = 0.038) differed between groups, being increased in BD compared with control samples. The GFAP area fraction (p = 0.05) and astrocyte spatial distribution (p = 0.040) also differed between groups, reflecting decreased area fraction and increased cell clustering in both schizophrenia and BD samples. Limitations: Oligodendrocytes were identified using morphological criteria. Conclusion: This study provides evidence for glial pathology in prefrontal white matter in schizophrenia and BD. Changes in oligodendrocyte and astrocyte populations in white matter in the major psychiatric disorders may reflect disruptions in structural or metabolic support of axons. [ABSTRACT FROM AUTHOR]

BACKGROUND: Although previous study has demonstrated that brain-derived neurotrophic factor (BDNF) is involved in the antidepressant-like effect of oleanolic acid, there is little information regarding the details of the molecular mechanism involved in this effect. METHODS: We used a chronic unpredictable mild stress (CUMS) model to test the antidepressant-like effect of oleanolic acid on depressant-like behaviour, miR-132 expression and synaptic protein expression in the male mouse hippocampus. Furthermore, we explored the possible signalling pathways associated with miR-132 expression that mediate the effect of oleanolic acid on neuronal proliferation. RESULTS: The results demonstrated that a 3-week treatment with oleanolic acid ameliorated CUMS-induced anhedonic and anxiogenic behaviours. Furthermore, we found that oleanolic acid led to the BDNF-related phosphorylation and activation of extracellular signal-regulated kinases (ERK) and cyclic adenosine monophosphate response element binding protein (CREB), which was associated with the upregulation of miR-132 and hippocampal neuronal proliferation. Moreover, experiments with an miR-132 antagomir revealed that targeting miR-132 led to inhibition of neuronal proliferation and the postsynaptic density protein 95, but did not affect presynaptic protein synapsin I. LIMITATIONS: Several other stimuli can also induce CREB phosphorylation in the hippocampus. Thus, regulation of miR-132 may not be restricted to neurotrophic signalling. CONCLUSION: Our results show that oleanolic acid induces the upregulation of miR-132, which serves as an important regulator of neurotrophic actions, mainly through the activation of the hippocampal BDNF-ERK-CREB signalling pathways. [ABSTRACT FROM AUTHOR]

Tumor-to-tumor metastasis (TTM) is a rare phenomenon documented in patients with multiple primary cancers. This condition is defined as a metastasis between two true primary tumors. The most frequently reported recipient tumor is renal cell carcinoma (RCC), and the lung carcinomas are the most common metastatic tumor donors. Therefore, this paper attempts to address the current gap in knowledge about this rare phenomenon. The first part of this review outlines the recently proposed models and mechanisms involved in the TTM process. The second part then summarizes and analyzes previous case reports in the literature. We also present our experience with the case of lung cancer that metastasized into RCC. Given the sporadic incidence of TTM, no specific management guidelines exist. Therefore, considering TTM in patients with multiple primary tumors is important as it could potentially modify the oncological management offered. [ABSTRACT FROM AUTHOR]

Primary bronchial lung cancer, commonly known as lung cancer, is one of the malignant tumors with high morbidity and mortality in the world. In recent years, the incidence of lung cancer in women has increased, and most of them are lung adenocarcinoma. Because the early symptoms of lung cancer are occult, it is often detected when metastasis has already occurred. We report a case of endometrial metastasis of lung adenocarcinoma. The patient presented with abnormal vaginal bleeding, and the pathology after curettage indicated adenocarcinoma. After immunohistochemical examination and imaging examination were combined to exclude the possibility of tumor origin in other sites, the diagnosis was confirmed as lung adenocarcinoma metastasis to the endometrium. Metastasis of lung cancer to the endometrium is extremely rare and is likely to be missed or misdiagnosed. In this paper, the data of a case of endometrial metastasis of lung adenocarcinoma were retrospectively analyzed and the relevant literatures were reviewed in order to enhance the clinical vigilance of endometrial metastasis of lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Breast cancer is the most frequently diagnosed cancer and leading cause of cancer-related deaths worldwide. Timely decision-making that enables implementation of the most appropriate therapy or therapies is essential for achieving the best clinical outcomes in breast cancer. While clinicopathologic characteristics and immunohistochemistry have traditionally been used in decision-making, these clinical and laboratory parameters may be difficult to ascertain or be equivocal due to tumor heterogeneity. Tumor heterogeneity is described as a phenomenon characterized by spatial or temporal phenotypic variations in tumor characteristics. Spatial variations occur within tumor lesions or between lesions at a single time point while temporal variations are seen as tumor lesions evolve with time. Due to limitations associated with immunohistochemistry (which requires invasive biopsies), whole-body molecular imaging tools such as standard-of-care [18F]FDG and [18F]FES PET/CT are indispensable in addressing this conundrum. Despite their proven utility, these standard-of-care imaging methods are often unable to image a myriad of other molecular pathways associated with breast cancer. This has stimulated interest in the development of novel radiopharmaceuticals targeting other molecular pathways and processes. In this review, we discuss validated and potential roles of these standard-of-care and novel molecular approaches. These approaches' relationships with patient clinicopathologic and immunohistochemical characteristics as well as their influence on patient management will be discussed in greater detail. This paper will also introduce and discuss the potential utility of novel PARP inhibitor-based radiopharmaceuticals as non-invasive biomarkers of PARP expression/upregulation. [ABSTRACT FROM AUTHOR]

Simple Summary: TP is a widely utilized anticancer medication, particularly effective in treating HCC. Thorough investigation into TP's molecular mechanism in HCC treatment is crucial for precise and combination therapy. In this paper, we have unveiled a novel mechanism of TP in HCC treatment, where it inhibits tumor growth by reducing lipid accumulation. While the inhibition of P53 gene activity is commonly thought to be the reason for TP's effectiveness in treating HCC, this new mechanism serves as a significant complement to the current understanding, paving the way for innovative approaches to HCC treatment. Hepatocellular carcinoma (HCC), which is the third leading cause of cancer-related mortality in the world, presents a significant medical challenge. Triptolide (TP) has been identified as an effective therapeutic drug for HCC. However, its precise therapeutic mechanism is still unknown. Understanding the mechanism of action of TP against HCC is crucial for its implementation in the field of HCC treatment. We hypothesize that the anti-HCC actions of TP might be related to its modulation of HCC lipid metabolism given the crucial role that lipid metabolism plays in promoting the progression of HCC. In this work, we first demonstrate that, both in vitro and in vivo, TP significantly reduces lipid accumulation in HCC cells. Additionally, we notice that lipoprotein lipase (LPL) expression is markedly upregulated in HCC, and that its levels are positively connected with the disease's progression. It is interesting to note that TP dramatically reduces LPL activity, which in turn prevents HCC growth and reduces lipid accumulation. Additionally, the effect of TP on LPL is a direct correlation. These results definitely demonstrate that TP protects hepatocytes against abnormal accumulation of lipids by transcriptionally suppressing LPL, which reduces the development of HCC. This newly identified pathway provides insight into the process through which TP exerts its anti-HCC actions. [ABSTRACT FROM AUTHOR]

Wound age estimation is a significant issue in forensic pathology. Although various methods have been evaluated, no gold standard system or model has been proposed, and accurate injury time estimation is still challenging. The distinction between vital skin wounds—i.e., ante-mortem lesions—and skin alterations that occur after death is a crucial goal in forensic pathology. Once the vitality of the wound has been confirmed, the assessment of the post-trauma interval (PTI) is also fundamental in establishing the causal relationship between the traumatic event and death. The most frequently used techniques in research studies are biochemistry, molecular biology, and immunohistochemistry (IHC). Biochemical methods take advantage of the chemical and physical techniques. A systematic literature search of studies started on 18 February 2023. The search was conducted in the main databases for biomedical literature, i.e., PubMed and Scopus, for papers published between 1973 and 2022, focusing on different techniques of immunohistochemistry and immunofluorescence (IF) for estimating the PTI of skin wounds. The present study involves a comprehensive and structured analysis of the existing literature to provide a detailed and comprehensive overview of the different IHC techniques used to date skin lesions, synthesize the available evidence, critically evaluate the methodologies, and eventually draw meaningful conclusions about the reliability and effectiveness of the different markers that have been discovered and used in wound age estimation. [ABSTRACT FROM AUTHOR]

Angiolymphoid Hyperplasia with Eosinophilia (ALHE) is a benign vascular proliferative disorder with uncertain etiology and pathogenesis. The aim of this paper is to report a case of ALHE in the temporal artery and discuss the general aspects of this pathology. A 29-year-old female black patient sought the Vascular Surgery Outpatient Service, complaining of bulging in the right temporal region, associated with pain and local discomfort. Physical examination revealed pulsatile bulging in the right temporal region measuring approximately 2.5 × 1.5 cm. Nuclear Magnetic Resonance showed an expansive fusiform lesion in the superficial soft parts of the right temporal region, measuring 2.9 cm in the longest longitudinal axis. Surgical excision proved to be the best therapeutic option for the patient in this case. Histopathological sections showed the proliferation of vessels of different sizes, covered by swollen endothelium, prominent inflammatory infiltrate composed of lymphocytes, plasma cells, eosinophils, and scarce histiocytes. Immunohistochemical analysis of the lesion showed positivity for CD31, corroborating the diagnosis of ALHE. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The aim of our work was to determine the presence of GPx8, the latest discovered member of glutathione peroxidase family, in rat male genital organs. BACKGROUND: The oxidative stress is considered as one of the most important causalities of male infertility. To defend itself, the organism comprises many different antioxidants. METHODS: We assessed the GPx8 presence in tissues of genital organs from adult rat Sprague-Dawley males by mRNA expression, Western Blot analysis, and immunohistochemistry. RESULTS: The highest mRNA and protein levels were detected in the testis, followed by seminal vesicle. Within testis the enzyme was observed predominantly in the Leydig and Sertoli cells, residual and Hermes bodies. In other organs, such as epididymis, seminal vesicle and prostate gland, the GPx8 was seen in the cytoplasm of epithelial cells. The enzyme was also observed in the muscular layer of hollow organs, in blood plasma and extracellular matrix. CONCLUSIONS: The antioxidant enzyme GPx8 was detected in all examined male genital organs. The fact, that the enzyme was released into lumen of genital organs probably means, that GPx8 is also a component of the semen. To our knowledge, this is the first paper describing GPx8 presence in male genital organs of mammals (Fig. 8, Ref. 63). [ABSTRACT FROM AUTHOR]

Nothobranchius furzeri is emerging as an exciting vertebrate organism in the field of biomedicine, developmental biology and ecotoxicology research. Its short generation time, compressed lifespan and accelerated ageing make it a versatile model for longitudinal studies with high traceability. Although in recent years the use of this model has increased enormously, there is still little information on the anatomy, morphology and histology of its main organs. In this paper, we present a description of the digestive system of N. furzeri, with emphasis on the intestine. We note that the general architecture of the intestinal tissue is shared with other vertebrates, and includes a folding mucosa, an outer muscle layer and a myenteric plexus. By immunohistochemical analysis, we reveal that the mucosa harbours the same type of epithelial cells observed in mammals, including enterocytes, goblet cells and enteroendocrine cells, and that the myenteric neurons express neurotransmitters common to other species, such as serotonin, substance P and tyrosine hydroxylase. In addition, we detect the presence of a proliferative compartment at the base of the intestinal folds. The description of the normal intestinal morphology provided here constitutes a baseline information to contrast with tissue alterations in future lines of research assessing pathologies, ageing-related diseases or damage caused by toxic agents. [ABSTRACT FROM AUTHOR]

Simple Summary: Skin cancers are common and sometimes difficult to diagnose malignancies that occur worldwide. Most skin cancers are diagnosed by visual assessment of patient samples obtained through biopsy. However, due to the lack of well-defined malignancy features, the diagnosis and classification of skin cancer lesions remain difficult in some cases. To overcome this issue, researchers have attempted to use molecular information such as genes and proteins and imaging data to improve skin cancer diagnosis and classification. Therefore, this paper reviews the recent advancements in large-scale molecular profiling approaches and appraises their limitations and potential for reliable and reproducible classification and stratification of skin cancers. Skin cancers are common and heterogenous malignancies affecting up to two in three Australians before age 70. Despite recent developments in diagnosis and therapeutic strategies, the mortality rate and costs associated with managing patients with skin cancers remain high. The lack of well-defined clinical and histopathological features makes their diagnosis and classification difficult in some cases and the prognostication difficult in most skin cancers. Recent advancements in large-scale "omics" studies, including genomics, transcriptomics, proteomics, metabolomics and imaging-omics, have provided invaluable information about the molecular and visual landscape of skin cancers. On many occasions, it has refined tumor classification and has improved prognostication and therapeutic stratification, leading to improved patient outcomes. Therefore, this paper reviews the recent advancements in omics approaches and appraises their limitations and potential for better classification and stratification of skin cancers. [ABSTRACT FROM AUTHOR]

This paper analyzes the investigation of the distribution of the protein tenascin-C in canine mammary tumors. The method involved immunohistochemistry of tissue slices, performed by the application of an antibody to tenascin-C that specifically can be made visible for microscopic inspection. The first phase of the project is the making of the protocol, the second the deduction of a pattern of tenascin-C distribution in tumors and the third the writing of a paper. Each of the phases is analyzed separately, using the concept of resistance and accommodation. My purpose is to show that in each phase of the process of producing knowledge, the scientist meets resistances which force him to accommodate by changing his conceptual, technical and methodological approaches. In reverse, the details of the non-human agent (protocol, pattern or paper) have to be accommodated to the wishes and expectations of the scientist. Through this interaction a situation of stability of knowledge is reached at the end of each phase. In the protocol phase, resistance is found in the antibody and tissue slices. In the phase of pattern deduction the resistance is in the pathological diagnosis of the tumors and the expectations and hypothesis with which the scientist had entered the project; in the criteria to be used for assigning the slices to a tenascin-C pattern; and in the responses of colleagues and supervisor. In the paper-writing phase the interaction is between the scientist and the scientific community which should take on board the knowledge from the research project. When stabilization of knowledge is obtained in one of the phases, the agents of resistance turn into allies in the next phase, giving support to accommodating the resistances in this later phase. Second, the stabilization of knowledge of the protocol is further enhanced when stabilization of the pattern is achieved; in addition, knowledge of the pattern is more definite when it has become stabilized and closed knowledge within the science community. [Copyright &y& Elsevier]

The article presents abstracts related to colorectal diseases which include the potential use of laparoscopic rectosigmoid resection with transanal specimen extraction to treat patients, the use of laparoscopic coloanal anastomosis to cure patients with rectal cancer, and the utility of microsatellite instability and immunohistochemistry in families with suspected Lynch syndrome.

We reviewed eight cases that were diagnosed before 1995 with B-prolymphocytic leukaemia (B-PLL) harbouring t(11;14)(q13;q32) and/or cyclin D1 staining. Thirteen B-PLL patients without t(11;14) were selected as controls. Peripheral blood, bone marrow and histological sections were re-examined without cytogenetic information. Final diagnosis was made using morphology, cytogenetics, immunophenotype and immunohistochemistry. Clinical characteristics were similar for both groups except for younger age, male predominance and extranodal involvement in cases with t(11;14). CD5 was more frequently positive in the t(11;14)+ group (80%) than in the t(11;14)− group (31%). Surface membrane immunoglobulin was strongly expressed by all t(11;14)+ cases, but only 45% of t(11;14)− cases. Histopathological and cytological review of cases with t(11;14) showed an infiltrate with a mixture of cells, some resembling prolymphocytes and others with mantle cell lymphoma (MCL) morphology. Blood films of cases with t(11;14) showed features suggestive of B-PLL in three, and in others, a mixture of cells resembling MCL and nucleolated ones; none corresponded to the blastoid form of MCL. We suggest that ‘B-PLL’ with t(11;14) may represent a splenomegalic form of MCL evolving with leukaemia. These cases illustrate the importance of tissue diagnosis with cyclin D1 staining and fluorescence in situ hybridization analysis in B-cell leukaemia with prolymphocytic features. [ABSTRACT FROM AUTHOR]

We have investigated whether intracellular signal transduction molecules can be used as immunohistological markers of normal and neoplastic human leucocytes in routine tissue sections. We obtained selective labelling of white cells for eight such molecules (the ‘linker’ molecules SLP-76 and BLNK, the Src family kinases Lyn, Fyn, Syk and Hck, and the phospholipases PLC- γ1 and PLC- γ2). Antibodies to SLP-76 and PLC- γ1 selectively labelled T cells, and antibodies to BLNK, Lyn, Fyn, Syk and PLC- γ2 labelled B cells (although Fyn immunostaining was restricted to mantle zone B cells). Antibodies to the Syk and Hck kinases labelled probable thymocyte precursors at the periphery of the thymic cortex. In addition to lymphoid cells, several other leucocyte types were immunostained (e.g. SLP-76, Lyn, Syk and Hck were found in megakaryocytes, myeloid cells and/or macrophages, and PLC- γ2 was detected in arterial endothelium). SLP-76 and PLC- γ1 were found in most T-cell lymphomas studied, and some B-cell lymphomas were also positive for PLC- γ1 (e.g. diffuse large cell and Burkitt's lymphoma). The five B cell-associated markers were found in most B-cell non-Hodgkin's lymphomas, although some diffuse large B-cell lymphomas were negative (e.g. for Lyn) and anti-Fyn tended not to stain small B-cell neoplasms. The observation that a range of leucocyte signalling molecules can be detected in routine biopsies offers new possibilities for studying normal and neoplastic human white cells in diagnostic tissue samples. [ABSTRACT FROM AUTHOR]

This article reports that the information gained from cloning the bicoid gene was spectacular and the localized mRNA made bicoid a bona fide localized determinant, it was clear that the long-range patterning effects could only be understood once distribution and function of the bicoid protein were revealed. The technology to make antibodies against gene products that are too scarce in their native biological system had just become available through bacterial overexpression vectors. However, to demonstrate the reach of a gradient required the generation of an antibody and use of immunohistology techniques that would provide virtually background-free results, as background would make it difficult to determine where the gradient ends.

In 1992, a paper reported that the melatonin content of the rat duodenum was 24 000 ± 2000 pg/g tissue (range: 4000–100 000 pg/g) while the pineal melatonin content was 580 000 ± 36 000 pg/g. The data has been used for the last 30 years to infer that the gut produces 400 hundred times more melatonin than the pineal gland and that it is the source of plasma melatonin during the daytime. No‐one has ever challenged the statement. In this review, evidence is summarised from the literature that pinealectomy eliminates melatonin from the circulation and that studies to the contrary have relied upon poorly validated immunoassays that overstate the levels. Similarly studies that have reported increases in plasma melatonin following tryptophan administration failed to account for cross reactivity of tryptophan and its metabolites in immunoassays. The most extraordinary observation from the literature is that in those studies that have measured melatonin in the gut since 1992, the tissue content is vastly lower than the original report, even when the methodology used could be overestimating the melatonin content due to cross reactivity. Using the more contemporary results we can calculate that rather than a 400:1 ratio of duodenum: pineal melatonin, a ratio of 0.05–0.19: 1 is likely. The gut is not a major extra‐pineal source of melatonin; indeed it may well not produce any. [ABSTRACT FROM AUTHOR]

Metastatic disease is a complex and sequential process that involves the migration of tumor cells from the primary site to distant areas. This metastatic pathway is not always predictable. Therefore, this paper presents three rare cases of unusual metastases, due to their primary site: two metastases of a clear cell renal cell carcinoma, one gingival, and one nasal, as well as a mandibular metastasis of a hepatocellular carcinoma. In all cases, an incisional biopsy was performed in order to find out the diagnosis. After microscopical examination of morphological Hematoxylin and Eosin-stained slides, for all cases, immunohistochemical reactions were performed to support the primary tumor site. Two cases had a previous histopathological diagnosis of a primary tumor, while for the third case, the metastatic lesion represented the first manifestation of the neoplastic disease, with an unfavorable prognosis. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatoblastoma is a rare childhood liver cancer with poor outcomes for high-risk patients. Better treatments and better ways of identifying patients who respond poorly to treatment are needed. This paper uses new methods for identifying chemicals or metabolites produced in the tumour. By comparing the profiles of these metabolites in tumour tissue versus normal liver tissue taken from the same patient, we demonstrated that some metabolites differ significantly in hepatoblastoma. This correlates with gene expression data, suggesting that we identified the metabolites correctly. We also stained tumour tissues for proteins (enzymes) that regulate transport of fatty acids into the mitochondria, which are the cell's powerhouses. Taken together, our results indicate that tumour cells change the energy sources they use and rewire the cellular systems accordingly. Further work is required to verify this, but these leads could improve our understanding of the disease and lead to the development of novel therapies. Hepatoblastoma (HB) is a rare childhood tumour with an evolving molecular landscape. We present the first comprehensive metabolomic analysis using untargeted and targeted liquid chromatography coupled to high-resolution tandem mass spectrometry (LC-MS/MS) of paired tumour and non-tumour surgical samples in HB patients (n = 8 pairs). This study demonstrates that the metabolomic landscape of HB is distinct from that of non-tumour (NT) liver tissue, with 35 differentially abundant metabolites mapping onto pathways such as fatty acid transport, glycolysis, the tricarboxylic acid (TCA) cycle, branched-chain amino acid degradation and glutathione synthesis. Targeted metabolomics demonstrated reduced short-chain acylcarnitines and a relative accumulation of branched-chain amino acids. Medium- and long-chain acylcarnitines in HB were similar to those in NT. The metabolomic changes reported are consistent with previously reported transcriptomic data from tumour and non-tumour samples (49 out of 54 targets) as well as metabolomic data obtained using other techniques. Gene set enrichment analysis (GSEA) from RNAseq data (n = 32 paired HB and NT samples) demonstrated a downregulation of the carnitine metabolome and immunohistochemistry showed a reduction in CPT1a (n = 15 pairs), which transports fatty acids into the mitochondria, suggesting a lack of utilisation of long-chain fatty acids in HB. Thus, our findings suggest a reduced metabolic flux in HB which is corroborated at the gene expression and protein levels. Further work could yield novel insights and new therapeutic targets. [ABSTRACT FROM AUTHOR]

Primary paragangliomas (PGs) are extra-adrenal neuroendocrine tumours that are extremely rare. Multiple lesions in the central nervous system raise suspicion of a metastatic process. Lack of consensus on their management warrants the categorization of existing literature to evaluate management options. A systematic review of the medical literature on paraganglioma within the cranial vault was completed in accordance with PRISMA guidelines using the Medline database. Tumour physical measures, management parameters, and immunohistochemistry of all documented cases of primary and secondary paraganglioma within the cranial vault were descriptively compared. This review was augmented by comparison with our centre's case of a 48-year-old man diagnosed with metastatic PG originating in the cauda equina and seeding in the cerebellum. Histological parameters within the literature was also established. The systematic literature review yielded published 52 papers. Most prevalent primary intracranial PGs (n = 37) were in the sellar region (78%, n = 23) and the cerebellum (21%, n = 6). The highest progression free survival was seen in primary sellar PGs (87.5% by 34.5 months) and cerebellar PGs (100% by 35.7 months) when treated with adjuvant radiotherapy with subtotal resection or gross total resection, respectively. Contrasting, the most frequent intracranial PGs metastases (n = 15) occurred in the cerebellum (36%, n = 6), and the cerebral parenchyma (29%, n = 4). Their recurrence rate was between 4 and 10% and these metastasized PG in the cerebellum are slow growing (8.9 years, range: 3–22 years). Adjuvant radiotherapy with Gross Total Resection resulted in the optimum progression-free survival (100% up to 48 months) for the patient with PGs metastasis to the cerebellum. Metastatic PGs tend to be slow-growing and are clinically silent tumours. Diagnosed patients should undergo regular surveillance neuroradiological assessment, regardless of symptomatology, for metastases along the complete neural axis. We recommend operative management with GTR and adjunct RT in these patients. [ABSTRACT FROM AUTHOR]

Temporomandibular disorders (TMD) are a group of internal derangements encompassing dysfunction, displacement, degeneration of the temporomandibular joints and surroundings muscles of mastication, often accompanied by pain. Relationships between TMD and various chemical biomarkers have been examined throughout the years. This paper aims to gather evidence from the literature regarding other biomarkers and presenting them as one systematic review to investigate the potential links between TMD and different biochemical activity. To identify relevant papers, a comprehensive literature search was carried out in MEDLINE/PubMED, EMBASE, Web of Science and a manual search was performed in the International Journal of Oral and Maxillofacial Surgery, Journal of Oral and Maxillofacial surgery, and Journal of Cranio-Maxillo-Facial Surgery. The literature review produced extensive results relating to the biochemical and immunohistochemical markers of TMD. Many enzymes, inflammatory markers, proteoglycans, and hormones were identified and organized in tables, along with a brief description, study design, and conclusion of each study. Through this review, recurring evidence provides confidence in suggesting involvement of certain biomarkers that may be involved in this complex pathogenesis, in addition to pointing to differences in gender prevalence of TMD. However, more organized research on large human samples needs to be conducted to delve deeper into the understanding of how this disease develops and progresses. [ABSTRACT FROM AUTHOR]

Background: Lewis serologic reagents frequently give inaccurate phenotyping results. Furthermore these serologic reagents are often used in nonserologic assays such as inhibition and immunohistochemistry. In both scenarios knowledge of the fine specificity and cross-reactivity of these reagents will improve the quality of results obtained.Study Design and Methods: A range of contemporary and historical workshop and developmental Lewis reagents including mouse monoclonal (MoAb) and human and goat polyclonal (PoAb) reagents were evaluated. All were evaluated both against Lewis kodecytes expressing only single Le(a) , Le(b) , ALe(b) , BLe(b) , Le(x) , Le(y) , ALe(y) , or BLe(y) antigens and against the same antigens inkjet printed on a paper-based microplate and analyzed by enzyme immunoassay. Nine clinical samples were also evaluated. A kodecyte antigen dilution sensitivity assay was used to establish the ratio of Le(b) antigen between group A1 /A2 and O RBCs.Results: A continuum of cross-reactivity from Le(x) through to H was observed with MoAbs. All PoAb and few MoAb anti-Le(a) samples and reagents cross-reacted to some degree with Le(b) antigen. Some PoAb and MoAb anti-Le(b) did not cross-react with Le(a) . All polyclonal goat anti-Le(b) reagents showed substantial activity against ALe(b) and BLe(b) , while no MoAb reagent had this activity. A1 RBCs had less than half the Le(b) antigen of A2 /O RBCs.Conclusions: Substantial cross-reactivity of both MoAbs and PoAbs with related antigens highlights the risks of using serologic reagents in nonserologic assays or against synthetic antigens. The lack of ALe(b) activity in anti-Le(b) MoAbs explains their poor performance against blood group A1 Le(a-b+) phenotypes. [ABSTRACT FROM AUTHOR]

Simple Summary: The prevalence of certain cancers is high in the diabetic population. Dipeptidyl peptidase (DPP)-4, a therapeutic target for type 2 diabetes mellitus, is also involved in autophagic flux and cancer biology. In this paper, we reported that DPP-4 inhibition promotes breast cancer cell survival via induction of autophagy by the C-X-C motif chemokine 12/C-X-C receptor 4/mammalian target of rapamycin/hypoxia-inducible factor-1α axis. Metformin counteracts such an undesirable influence of DPP-4 inhibition on cancer biology. Our findings suggest that DPP-4 inhibitor, one of the most prescribed anti-diabetic drugs, could harm patients with certain cancers. The combination with metformin use could provide some clues to the use of DPP-4 inhibitors via the modulation of cancer autophagy-dependent survival signaling. Autophagy plays a complex role in breast cancer cell survival, metastasis, and chemotherapeutic resistance. Dipeptidyl peptidase (DPP)-4, a therapeutic target for type 2 diabetes mellitus, is also involved in autophagic flux. The potential influence of DPP-4 suppression on cancer biology remains unknown. Here, we report that DPP-4 deficiency promotes breast cancer cell survival via the induction of autophagy by the C-X-C motif chemokine 12 (CXCL12)/C-X-C receptor 4 (CXCR4)/mammalian target of rapamycin (mTOR)/hypoxia inducible factor (HIF)-1α axis. DPP-4 knockdown and DPP-4 inhibitor KR62436 (KR) treatment both increased the levels of LC3II and HIF-1α in cultured human breast and mouse mammary cancer cells. The KR-induced autophagic phenotype in cancer cells was inhibited by treatment with the CXCR4 inhibitor AMD3100 and rapamycin. HIF-1α knockdown also suppressed breast cancer autophagy induced by KR. The autophagy inhibitor 3-methyladenine significantly blocked the KR-mediated suppression of cleaved caspase-3 levels and apoptosis in breast cancer cell lines. Finally, we found that the metformin-induced apoptosis of DPP-4-deficient 4T1 mammary cancer cells was associated with the suppression of autophagy. Our findings identify a novel role for DPP-4 inhibition in the promotion of breast cancer survival by inducing CXCL12/CXCR4/mTOR/HIF-1α axis-dependent autophagy. Metformin is a potential drug that counteracts the breast cancer cell survival system. [ABSTRACT FROM AUTHOR]

Simple Summary: The aim of our study is to provide a wide perspective on the available literature data on the immune landscape of breast cancers, focusing on TILs and PD-L1 expression across different breast cancer subtypes. Moreover, treatment options such as immunotherapy and chemotherapy in adjuvant and neoadjuvant settings are discussed, along with the most relevant cut-offs and scores for TILs and PD-L1 pathological assessment. With the rise of novel immunotherapies able to stimulate the antitumor immune response, increasing literature concerning the immunogenicity of breast cancer has been published in recent years. Numerous clinical studies have been conducted in order to identify novel biomarkers that could reflect the immunogenicity of BC and predict response to immunotherapy. In this regard, TILs have emerged as an important immunological biomarker related to the antitumor immune response in BC. TILs are more frequently observed in triple-negative breast cancer and HER2+ subtypes, where increased TIL levels have been linked to a better response to neoadjuvant chemotherapy and improved survival. PD-L1 is a type 1 transmembrane protein ligand expressed on T lymphocytes, B lymphocytes, and antigen-presenting cells and is considered a key inhibitory checkpoint involved in cancer immune regulation. PD-L1 immunohistochemical expression in breast cancer is observed in about 10–30% of cases and is extremely variable based on tumor stage and molecular subtypes. Briefly, TNBC shows the highest percentage of PD-L1 positivity, followed by HER2+ tumors. On the other hand, PD-L1 is rarely expressed (0–10% of cases) in hormone-receptor-positive BC. The prognostic role of PD-L1 expression in BC is still controversial since different immunohistochemistry (IHC) clones, cut-off points, and scoring systems have been utilized across published studies. In the present paper, an extensive review of the current knowledge of the immune landscape of BC is provided. TILS and PD-L1 expression across different BC subtypes are discussed, providing a guide for their pathological assessment and reporting. [ABSTRACT FROM AUTHOR]

Context.--Neurotrophic receptor tyrosine kinase (NTRK) fusion testing has both diagnostic and therapeutic implications for patient care. With 2 tumor-agnostic US Food and Drug Administration--approved tropomyosin receptor kinase (TRK) inhibitors, testing is increasingly used for therapeutic decision making. However, the testing landscape for NTRK fusions is complex, and optimal testing depends on the clinicopathologic scenario. Objective.--To compare different NTRK testing methods to help pathologists understand test features and performance characteristics and make appropriate selections for NTRK fusion detection for their laboratory and individual patient specimens. Data Sources.--A literature search for NTRK gene fusions and TRK protein was performed, including papers that discussed treatment, testing methodology, and detection or prevalence of fusion-positive cases. Conclusions.--As standard of care in some tumor types, next-generation sequencing (NGS) panel testing is a cost effective and reliable way to detect a broad range of NTRK fusions. The design of the panel and use of DNA or RNA will affect performance characteristics. Pan-TRK immuno-histochemistry may be used as a rapid, less expensive screen in cases that will not undergo routine NGS testing, or on specimens unsuitable for NGS testing. Fluorescence in situ hybridization may be appropriate for low-tumor-content specimens that are unsuitable for NGS testing. Quantitative reverse transcription polymerase chain reaction is best suited for monitoring low-level disease of a specific, previously identified target. This information should help laboratories develop a laboratory-specific NTRK testing algorithm that best suits their practice setting and patients' needs. [ABSTRACT FROM AUTHOR]

Systemically administered steroids are widely utilised for hearing preservation therapies. More recently, steroids have been administered to achieve hearing protection after cochlear implant surgery. Currently there is a lack of understanding as to which administration route offers most therapeutic efficacy, local or systemic administration. Paramount to this are observations in animal studies that systemic administration following implantation offers hearing protection and reduced cochlear fibrosis, despite observations that perilymphatic levels are up to 10-fold higher after local administration in non-implanted cochleae. This paper explores the impact that cochlear implantation and associated acute inflammation has on steroid distribution and uptake following systemic administration of dexamethasone. Eight guinea pigs received systemic dexamethasone 60 min prior to cochlear implantation. Implanted and contralateral non-implanted cochlea were harvested for tissue immunohistochemistry and detection of dexamethasone. Cochleostomy with scala tympani implantation resulted in a significant increase in cochlear dexamethasone signal. This was most notable at the organ of Corti, stria vascularis, and blood product in the scala tympani. This study demonstrates that the inner ear distribution of systemically administered steroids is enhanced following surgery for cochlear implantation and provides rationale for systemic perioperative steroids in hearing preservation surgery. [ABSTRACT FROM AUTHOR]

Introduction: Sebaceous carcinoma is a rare, usually slow-growing, malignant epithelial tumor of the skin. Mostly located on the face and neck, especially on the upper eyelid. It accounts for less than 1% of all skin malignancies. Extraocular sebaceous carcinoma is a very rare variant of this cancer. Case report: This paper presents a case of a 92-year-old man who presented with extensive, rapidly growing ulceration, located on the chest and abdomen. Based on the results of histopathological examinations and specific immunohistochemical staining, advanced sebaceous carcinoma was diagnosed in the thoracic and abdominal region. Conclusions: In patients with rapidly spreading ulcers, sebaceous carcinoma should also be considered in the differential diagnosis, although the course of this tumor is usually slow. [ABSTRACT FROM AUTHOR]

Epithelioid rhabdomyosarcoma is an uncommon tumor. It is found mainly in somatic soft tissues like parotid, urinary bladder, trunk, neck, and limbs. Only two cases of this tumor in gastrointestinal tract (liver and gastro esophageal junction) has been reported to date; thus, we herein reported an unusual site of this tumor in the pylorus part of the stomach. In the present paper, we studied a 67-year-old male subject with complaint of dyspepsia, belching, and reflux for about 4 years. He had also consumed herbal drugs to relieve the pain for several years. In the endoscopy procedure, there was a large tumor at the distal part of the gaster. Furthermore, excisional biopsy was performed and the histological specimens showed tumor necrosis with high mitotic cell counts, large vesicles, eosinophilic cytoplasm of epithelial cells, and round nuclei. Immunohistochemistry staining was positive for Myogenin, Desmin, MyoD1 (30% ratio), and Ki67 (70 % ratio). Computed tomography scan images showed several metastases to peritoneum and lungs. After initiating the treatment, the adverse effects of chemotherapy persuaded us to discontinue the regimen. Finally, the patient died due to pulmonary embolism. To conclude, primary epithelioid rhabdomyosarcoma is a very rare lethal cancer that may be found as gastrointestinal cancers. Hence, it requires further diagnostic investigations in order for the best treatment to be found. [ABSTRACT FROM AUTHOR]

Background: Intravenous lobular capillary hemangioma (IVLCH) of the neck is a kind of rare benign tumor of vein. Purpose: In this paper, we report two female patients who were hospitalized because of neck masses. Results: The tumors in the neck veins of our patients were white oval masses with pedicle, clearly defined and of different sizes. Their immunohistochemical staining results showed CD31 (+), CD34 (+), SMA (+), ERG (+). The pathological diagnosis was intravenous lobular capillary hemangioma. Conclusions: Due to the location, morphology and immunohistochemistry, This lesion needs to be distinguished from other intravascular lesions such as thrombus, hemangiosarcoma and papillary endothelial hyperplasia. [ABSTRACT FROM AUTHOR]

Malignant peritoneal mesothelioma is a rare and extremely malignant tumor. It is difficult for clinicians to diagnose early for its insidious onset and lack of specific clinical manifestations, laboratory indicators and imaging characteristics. At present, the accurate diagnosis dependes on the pathological examination and immunochemistry. In this paper, we report a case of malignant peritoneal mesothelioma found by the laparoscopic surgery due to "hydrofallopian tube". This is a female patient of childbearing age who had primary infertility for 3 years. The patient had no history of asbestos exposure, unclear etiology, atypical clinical manifestations. The diagnosis of malignant peritoneal mesothelioma was very difficult before histopathological examination. We analyze retrospectively the medical records of the patient and review of the previous literature. We explore the etiology, diagnosis and treatment of malignant peritoneal mesothelioma and enhance clinicians′ comprehension. [ABSTRACT FROM AUTHOR]

Background: In recent years, great research interest has been directed to the diagnostic, therapeutic and marker role of Preferentially expressed Antigen in Melanoma (PRAME) in the setting of various human neoplasms. Although it has been extensively studied mainly in the differential diagnosis setting of melanocytic pigmented lesions, still very few papers have analyzed the usefulness or otherwise of PRAME in the context of other non-melanoma skin cancers (NMSC). (2) Methods: In this paper, we report the data of our experience of 21 cases of sebaceous carcinoma (SC) classified in the three WHO grade and collected in the period between January 2005 and 31 October 2022, on which immunostaining for PRAME was performed; Non-parametric Mann–Whitney test for non-normally distributed values was performed. A comparison was made of the means between the three study groups (grade I, II and III). A value of p ≤ 0.05 was set as statistically significant (3) Results: Only seven cases (33.3%) were positive with an immunoscore of 2+/3+ for intensity and 1+/2+ for percentage cells positivity, while 14 cases (66.6%) were totally or nearly totally negative for PRAME with a few of sebaceous-like cells positive with an immunoscore of 1+. Eight cases of SC grade I were immunostaining for PRAME, a level of the cytoplasm of foci of sebaceous differentiation with a significant statical value (p < 0.0001) with respect to ten cases of SC grade II; furthermore, the eight cases of grade I were positive for PRAME in the same areas respect the 3 cases of SC grade III (p = 0.0303). There were no statistical significance between the 10 cases of grade II and 3 cases of grade III (p = 0.2028); (4) Conclusions: PRAME not seems to add particular information in the case of histopathological diagnostics of SC where other markers, including adipophylline, can be quite indicative. It seems, on the other hand, that PRAME can be useful in the subclassification setting of sebaceous carcinoma in grades I–II–III according to the directives of the latest WHO 2018, highlighting the foci of mature sebaceous differentiation most present in grades 1–2 and almost completely absent in grade 3 of the SC. [ABSTRACT FROM AUTHOR]

Background: Myoepithelioma is a rare benign neoplasm, most commonly derived from salivary glands, but there are limited cases of extra salivary gland involvement too. There is little knowledge on typical investigative findings and, instead, diagnosis relies on immunohistochemistry analysis. To our knowledge, this paper reports the 13th case of sinonasal myoepithelioma in the English literature. Case report: This paper presents a 25-year-old man who complained of chronic nasal obstruction. A sinonasal mass was noted on examination that appeared benign on imaging. Biopsy revealed a grade 2 chondrosarcoma that was endoscopically resected; however, excisional margins were positive. On histopathological review at the multidisciplinary team meeting, the lesion was more in keeping with chondromyxoid fibroma, but immunohistochemistry analysis confirmed a myoepithelioma lesion. In light of this revised diagnosis, quorate opinion was for follow up with active monitoring. Conclusion: Sinonasal tumours require a thorough history, examination and investigation before a treatment plan can be formulated. If there is diagnostic uncertainty, it is important to keep a wide differential list and seek a second specialist opinion where possible. [ABSTRACT FROM AUTHOR]

This article presents information on a gradient of bicoid (bcd) protein in drosophila embryos. According to the concept of positional information, the concentration of a morphogen instructs cells within an embryonic field of their position. The cells then interpret this information by an appropriate program of differentiation. Several models have been proposed that describe the generation of stable gradients of morphogens which could specify subregions of the embryo in a concentration-dependent manner.

Immunohistochemical staining is a common technique to study tissue morphology and in situ protein expression. With the rise of immunotherapy, more and more markers in the tumor microenvironment have been discovered. In this paper, the multiplex immunofluorescence staining method was used to stain paraffin sections of 35 cases of gastric adenocarcinoma tissue and 35 cases of colorectal adenocarcinoma tissue and its adjacent tissue. The infiltration of CD8+ T cells and CD103+CD8+ T cells in the slices was detected by using the slice scanner to form the map and CaseViewer2.0 software analysis. The experimental results in this paper showed that compared with adjacent tissues, the infiltration degree of CD8+ T cells in gastric adenocarcinoma tissue was significantly lower (Z = 2.244 , P = 0.025 , P < 0.05), and the infiltration degree of cells was significantly lower (Z = 2.785 , P = 0.005 , P < 0.05). In gastric adenocarcinoma tissue, the infiltration of CD8+ T cells was correlated with the tumor diameter of gastric adenocarcinoma (P = 0.002). There was a statistically significant difference. The degree of CD103+CD8+ T cell infiltration was related to the survival of patients with gastric adenocarcinoma (P = 0.002) and the degree of tumor differentiation (P = 0.004). The infiltration of CD103+CD8+ T cells in gastric cancer tissue and colorectal cancer tissue is related to the survival of patients. CD103+CD8+ T cells are thought to play a role in the prognosis of gastric adenocarcinoma and colorectal adenocarcinoma. Experiments have shown that the more the CD103+CD8+ T cells, the better the prognosis of gastric adenocarcinoma and colorectal adenocarcinoma, so the prognosis of gastric adenocarcinoma and colorectal adenocarcinoma can be improved by increasing CD103+CD8+ T cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Medullary thyroid carcinoma (MTC) is a rare neoplasm that is responsible for a fair proportion of thyroid carcinoma related deaths. The current diagnostic and therapeutic standards are not always effective and need to be upgraded. The role of biomarkers and immunohistochemistry in the diagnosis of MTC is highlighted. Opportunities for improved diagnostics have been seen with the development of nuclear medicine. Some studies have highlighted the possibility of reducing the number of complications during surgical treatment, which is the basic therapeutic method in patients with MTC. Current pharmacotherapy is imperfect, but there is ongoing research into the use of new, more selective drugs. The following paper discusses recent advances in the diagnosis and treatment of MTC. Medullary thyroid carcinoma (MTC) is a neoplasm originating from parafollicular C cells. MTC is a rare disease, but its prognosis is less favorable than that of well-differentiated thyroid cancers. To improve the prognosis of patients with MTC, early diagnosis and prompt therapeutic management are crucial. In the following paper, recent advances in laboratory and imaging diagnostics and also pharmacological and surgical therapies of MTC are discussed. Currently, a thriving direction of development for laboratory diagnostics is immunohistochemistry. The primary imaging modality in the diagnosis of MTC is the ultrasound, but opportunities for development are seen primarily in nuclear medicine techniques. Surgical management is the primary method of treating MTCs. There are numerous publications concerning the stratification of particular lymph node compartments for removal. With the introduction of more effective methods of intraoperative parathyroid identification, the complication rate of surgical treatment may be reduced. The currently used pharmacotherapy is characterized by high toxicity. Moreover, the main limitation of current pharmacotherapy is the development of drug resistance. Currently, there is ongoing research on the use of tyrosine kinase inhibitors (TKIs), highly specific RET inhibitors, radiotherapy and immunotherapy. These new therapies may improve the prognosis of patients with MTCs. [ABSTRACT FROM AUTHOR]

The subspecies T. pallidum pallidum is the cause of the most infamous sexually and congenitally transmitted disease, syphilis. This disease has an estimated incidence of six million infections every year. Multiple studies have noted that the prevalence of syphilis has been steadily increasing worldwide in recent decades, especially among MSMs and HIV-positive patients. Clinically, syphilis presents in four stages with multiple different clinical manifestations. In this paper, we examine the current literature to determine the history and progression, pathogenesis, clinical features, and testing of secondary syphilis. Secondary syphilis is a stage of the disease with the most exuberant local and systemic clinical manifestations. The basis of the pathogenesis of SS underscores the unique mechanisms by which Treponema pallidum utilizes to escape immune recognition while simultaneously induces inflammation. SS can affect multiple organ systems and become more than just an STD. The most common presentation of secondary syphilis is rash, which manifests as a copper-colored maculopapular lesion on the trunk, palms, and soles. Although the RPR, VDRL, and FTA-ABS tests are perhaps the most commonly used diagnostic tools for syphilis and make up the traditional and reverse algorithms, there are other methods, including morphology and immunohistochemistry. [ABSTRACT FROM AUTHOR]

Simple Summary: Clear cell renal cell carcinoma (ccRCC) is a highly aggressive cancer responsible for about 85% of kidney cancers. The majority of the incidentally detected renal masses are small and confined to the kidney; however, a significant number of patients initially present with progressive metastatic cancer succumb to the disease in a short time frame. High levels of expression of hypoxia-inducible transcription factors (HIF) resulting in the downstream epithelial-mesenchymal transition (EMT) pathway and features of cancer stem cells (CSCs) leads to an aggressive and drug-resistant phenotype in ccRCC. In this paper, using data from in-house collected patient tumours and public domain datasets, we highlight EMT and CSC to be prominent players in ccRCC progression. Using these approaches of analysis, we show the development of multi-marker diagnostic and prognostic signatures, which may stratify high-risk patients likely to progress to metastatic disease. The process of epithelial-mesenchymal transition (EMT) involves the phenotypic transformation of cells from epithelial to mesenchymal status. The cells exhibiting EMT contain features of cancer stem cells (CSC), and the dual processes are responsible for progressive cancers. Activation of hypoxia-inducible factors (HIF) is fundamental to the pathogenesis of clear cell renal cell carcinoma (ccRCC), and their role in promoting EMT and CSCs is crucial for ccRCC tumour cell survival, disease progression, and metastatic spread. In this study, we explored the status of HIF genes and their downstream targets, EMT and CSC markers, by immunohistochemistry on in-house accrued ccRCC biopsies and adjacent non-tumorous tissues from patients undergoing partial or radical nephrectomy. In combination, we comprehensively analysed the expression of HIF genes and its downstream EMT and CSC-associated targets relevant to ccRCC by using publicly available datasets, the cancer genome atlas (TCGA) and the clinical proteome tumour analysis consortium (CPTAC). The aim was to search for novel biological prognostic markers that can stratify high-risk patients likely to experience metastatic disease. Using the above two approaches, we report the development of novel gene signatures that may help to identify patients at a high risk of developing metastatic and progressive disease. [ABSTRACT FROM AUTHOR]

Background: Papillary thyroid carcinoma (PTC) is a common neoplasia with multiple variants. One of these extremely rare and poorly described variants is PTC with fibromatosis-like stroma (PTC-FMS), a peculiar entity distinguished by its predominant mesenchymal component. This paper reviews the literature, discusses the diagnostic challenges, and the clinical and surgical implications of this type of tumor which has fewer than 30 cases reported in the literature. Case presentation: We reported a case of PTC-FMS found in a 41-year-old Italian woman, who came to our Institute with a recent growth in the form of a mass on the neck. Further immunohistochemical examination showed β-catenin aberrant staining both in the nuclei and cytoplasm of the mesenchymal cells. The patient underwent total thyroidectomy and received radioactive iodine (RAI) 2 months after surgery. Conclusion: Given the possibility of recurrence of PTC-FMS and the ineffectiveness of RAI therapy, complete surgical resection represents the main treatment for this type of tumor. Despite the fact that the specific nature of these lesions has yet to be determined, guidelines for classical PTC should be followed. [ABSTRACT FROM AUTHOR]

A 1.5-year-old male Iberian lynx born in captivity presented with a 2.2 cm exophytic nodular alopecic mass at the left tarsus medial aspect, before being released into the wild. The lesion had keratinised material protruding through a 1.2 cm pore, forming a cutaneous horn. Histopathology revealed a cystic dermo-epidermal lesion lined by psoriasiform hyperplasia of the epithelium, thicker at the base of the cyst, together with abrupt to progressive keratinization and keratin pearls. The central cystic cavity was filled with fibrillary keratin and ghost cells. Immunohistochemistry for pan-cytokeratin showed strong positive immunolabeling in the hyperplastic epithelium and a weaker immunolabeling at the content of the cyst. A final diagnosis of a Dilated Pore of Winer was made. This paper is the first reported case of a DPW in a lynx and a wild felid. [ABSTRACT FROM AUTHOR]

Simple Summary: Many clinical trials have shown benefit for adding hyperthermia (heat) treatment to radiotherapy. Despite overall success, some patients do not derive maximum benefit from this combination treatment. Tumor hypoxia (low oxygen concentration) is a major cause for radiotherapy treatment resistance. In this paper, we examine the question of whether hyperthermia reduces hypoxia and, if so, whether reduction in hypoxia is associated with treatment outcome. The review is focused mainly on several clinical trials conducted in humans and companion dogs with cancer treated with hyperthermia and radiotherapy. Detailed measurements of temperature, hypoxia and perfusion were made and compared with treatment outcome. These analyses show that reoxygenation after hyperthermia occurs in patients and is related to treatment outcome. Further, reoxygenation is most likely caused by variable intra-tumoral temperatures that improve perfusion and reduce oxygen consumption rate. Directions for future research on this important issue are indicated. Numerous randomized trials have revealed that hyperthermia (HT) + radiotherapy or chemotherapy improves local tumor control, progression free and overall survival vs. radiotherapy or chemotherapy alone. Despite these successes, however, some individuals fail combination therapy; not every patient will obtain maximal benefit from HT. There are many potential reasons for failure. In this paper, we focus on how HT influences tumor hypoxia, since hypoxia negatively influences radiotherapy and chemotherapy response as well as immune surveillance. Pre-clinically, it is well established that reoxygenation of tumors in response to HT is related to the time and temperature of exposure. In most pre-clinical studies, reoxygenation occurs only during or shortly after a HT treatment. If this were the case clinically, then it would be challenging to take advantage of HT induced reoxygenation. An important question, therefore, is whether HT induced reoxygenation occurs in the clinic that is of radiobiological significance. In this review, we will discuss the influence of thermal history on reoxygenation in both human and canine cancers treated with thermoradiotherapy. Results of several clinical series show that reoxygenation is observed and persists for 24–48 h after HT. Further, reoxygenation is associated with treatment outcome in thermoradiotherapy trials as assessed by: (1) a doubling of pathologic complete response (pCR) in human soft tissue sarcomas, (2) a 14 mmHg increase in pO2 of locally advanced breast cancers achieving a clinical response vs. a 9 mmHg decrease in pO2 of locally advanced breast cancers that did not respond and (3) a significant correlation between extent of reoxygenation (as assessed by pO2 probes and hypoxia marker drug immunohistochemistry) and duration of local tumor control in canine soft tissue sarcomas. The persistence of reoxygenation out to 24–48 h post HT is distinctly different from most reported rodent studies. In these clinical series, comparison of thermal data with physiologic response shows that within the same tumor, temperatures at the higher end of the temperature distribution likely kill cells, resulting in reduced oxygen consumption rate, while lower temperatures in the same tumor improve perfusion. However, reoxygenation does not occur in all subjects, leading to significant uncertainty about the thermal–physiologic relationship. This uncertainty stems from limited knowledge about the spatiotemporal characteristics of temperature and physiologic response. We conclude with recommendations for future research with emphasis on retrieving co-registered thermal and physiologic data before and after HT in order to begin to unravel complex thermophysiologic interactions that appear to occur with thermoradiotherapy. [ABSTRACT FROM AUTHOR]

Accurate quantification of nerves in cancer specimens is important to understand cancer behaviour. Typically, nerves are manually detected and counted in digitised images of thin tissue sections from excised tumours using immunohistochemistry. However the images are of a large size with nerves having substantial variation in morphology that renders accurate and objective quantification difficult using existing manual and automated counting techniques. Manual counting is precise, but time-consuming, susceptible to inconsistency and has a high rate of false negatives. Existing automated techniques using digitised tissue sections and colour filters are sensitive, however, have a high rate of false positives. In this paper we develop a new automated nerve detection approach, based on a deep learning model with an augmented classification structure. This approach involves pre-processing to extract the image patches for the deep learning model, followed by pixel-level nerve detection utilising the proposed deep learning model. Outcomes assessed were a) sensitivity of the model in detecting manually identified nerves (expert annotations), and b) the precision of additional model-detected nerves. The proposed deep learning model based approach results in a sensitivity of 89% and a precision of 75%. The code and pre-trained model are publicly available at https://github.com/IA92/Automated_Nerves_Quantification. Author summary: The study of nerves as a prognostic marker for cancer is becoming increasingly important. However, accurate quantification of nerves in cancer specimens is difficult to achieve due to limitations in the existing manual and automated quantification methods. Manual quantification is time-consuming and subject to bias, whilst automated quantification, in general, has a high rate of false detections that makes it somewhat unreliable. In this paper, we propose an automated nerve quantification approach based on a novel deep learning model structure for objective nerve quantification in immunohistochemistry specimens of thyroid cancer. We evaluate the performance of the proposed approach by comparing it with existing manual and automated quantification methods. We show that our proposed approach is superior to the existing manual and automated quantification methods. The proposed approach is shown to have a high precision as well as being able to detect a significant number of nerves not detected by the experts in manual counting. [ABSTRACT FROM AUTHOR]

Duodenal gangliocytic paragangliomas are rare neuroendocrine tumors primarily localized in the periampullary area. Though mostly asymptomatic, they can present with various symptoms, most often jaundice, anemia and abdominal pain. The present paper is a case series report, describing our personal experience with patients presenting to the Emergency Unit with different symptoms due to duodenal gangliocytic paraganglioma. Endoscopic resection is safe and indicated in most of the cases, being also associated with lower medical costs. EUS plays a central role in the pre-resection management and in surveillance, and immunostaining is decisive to ascertain the tumor histologic origin. In addition to reporting our experience, we researched the literature regarding these rare tumors and performed a comprehensive review. [ABSTRACT FROM AUTHOR]

Simple Summary: BCOR (BCL6 corepressor)-rearranged sarcoma (BRS) is a rare sarcoma entity with a predominantly BCOR-CCNB3 fusion. In this paper, we present an index case of BRS with a novel BCOR-CLGN (calmegin) gene fusion that was first identified by next-generation sequencing and then verified by Sanger sequencing. We also carried out in silico protein analysis to demonstrate the 3D structure of the chimera protein. We concluded that, due to its heterogeneity, molecular ancillary tests serve as powerful tools to discover such unusual variants. The fusion protein used in the in silico analysis is an appropriate approach to understanding the exact pathogenesis of such a rare variant. BCOR (BCL6 corepressor)-rearranged sarcomas (BRSs) are a heterogeneous group of sarcomas previously classified as part of the group of "atypical Ewing" or "Ewing-like" sarcomas, without the prototypical ESWR1 gene translocation. Due to their similar morphology and histopathological features, diagnosis is challenging. The most common genetic aberrations are BCOR-CCNB3 fusion and BCOR internal tandem duplication (ITD). Recently, various new fusion partners of BCOR have been documented, such as MAML3, ZC3H7B, RGAG1, and KMT2D, further increasing the complexity of such tumor entities, although the molecular pathogenetic mechanism remains to be elucidated. Here, we present an index case of intrathoracic BRS that carried a novel BCOR-CLGN (calmegin) gene fusion, exhibited by a 52-year-old female diagnosed initially by immunohistochemistry due to the positivity of a BCOR stain; the fusion was identified by next-generation sequencing and was confirmed by Sanger sequencing. In silico protein analysis was performed to demonstrate the 3D structure of the chimera protein. The physicochemical properties of the fusion protein sequence were calculated using the ProtParam web-server tool. Our finding further broadens the fusion partner gene spectrum of BRS. Due to the heterogeneity, molecular ancillary tests serve as powerful tools to discover these unusual variants, and an in silico analysis of the fusion protein offers an appropriate approach toward understanding the exact pathogenesis of such a rare variant. [ABSTRACT FROM AUTHOR]

Simple Summary: p16 IHC is the HPV detection method suggested by the current version of the TNM (AJCC 8th edition) for oropharyngeal squamocellular carcinoma. However, its reliability has been extensively discussed, and its applicability in every context, especially the enrollment of patients in de-intensification protocols, is debatable. Here, we discuss its limits, especially in populations with a low prevalence of HPV-driven oropharyngeal squamocellular carcinoma, and suggest the possible actions to be taken to overcome such limitations. High-risk human papillomavirus (HPV) infection is a defined etiopathogenetic factor in oropharyngeal carcinogenesis with a clear prognostic value. The P16 IHC (immunohistochemistry) is a widely accepted marker for HPV-driven carcinogenesis in oropharyngeal squamous cell carcinoma (OPSCC); in the present paper, we discuss its reliability as a standalone marker in different populations. The literature suggests that rates of p16 IHC false positive results are inversely correlated with the prevalence of HPV-driven carcinogenesis in a population. We propose a formula that can calculate such a false positive rate while knowing the real prevalence of HPV-driven OPSCCs in a given population. As it has been demonstrated that p16 positive/HPV negative cases (i.e., false positives at p16 IHC) have the same prognosis as p16 negative OPSCC, we conclude that despite the valuable prognostic value of p16 IHC, relying only on a p16 IHC positive result to recommend treatment de-intensification could be risky. For this aim, confirmation with an HPV nucleic acid detection system, especially in areas with a low prevalence of HPV-related OPSCCs, should be pursued. [ABSTRACT FROM AUTHOR]

Background: Lymphoma neoplasms originate from the lymphocytes. Anatomically, these tumors can be classified into multicentric, digestive, mediastinal, and cutaneous forms. The etiology of cutaneous lymphoma remains unclear; however, it has been associated with chronic skin inflammation. The definitive diagnosis is based on histological analysis and immunohistochemistry, although fine-needle aspiration cytology has shown good results. The aim of this paper is to describe the clinicopathological aspects of a case of cutaneous epitheliotropic T cell lymphoma, classified as mycosis fungoides, in a Lhasa Apso dog. Case: A 8-year-old bitch Lhasa Apso with multiple non-pruritic skin nodules and history of 10-day evolution was referred to the Veterinary Hospital of the Centro Universitário do Espírito Santo (UNESC), Colatina, ES, Brazil. The nodules were erythematous, exophytic, firm, circumscribed, and measured 0.2-4 cm in diameter in locations throughout the animal's body. An incisional biopsy was performed with an 8-mm punch and sent for histopathological examination. An infiltrative, poorly demarcated, non-encapsulated, densely cellular neoplasm, which was replacing the dermal collagen and displacing the adnexa, was observed in the dermis. The tumor was composed of a population of round cells, with generally distinct cell borders and a small-to-moderate amount of eosinophilic cytoplasm. The nuclei were irregularly rounded and occasionally edentulous, with vesicular chromatin, a visible nucleus, and 11 mitotic figures in an area of 2.37 mm2. The immunohistochemical test, which was positive for the CD3 marker, confirmed the diagnosis of T cell lymphoma. On an ultrasound to identify metastasis, the liver showed heterogeneous parenchyma, heterogeneous expansive formation, areas of cavitary appearance, and cytology compatible with lymphoma. Antineoplastic chemotherapy was administered using the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone). However, the animal died after 45 days. Discussion: A diagnosis of the mycosis fungoides type of cutaneous epitheliotropic T cell lymphoma was established based on clinical, laboratory, anatomopathological, and immunohistochemical findings. Pruritus is a common clinical condition in animals with mycosis fungoides, particularly in those with the erythrodermic form of the disease. Epitheliotropic lymphomas have no sexual or racial predilections and usually affect dogs over 9 years of age. The Cocker Spaniel, English Bulldog, Boxer, Golden Retriever, Scottish Terrier, Briard, English Springer Spaniel, Beagle, German Shepherd, and English Cocker Spaniel breeds are frequently affected by these lymphomas. These neoplasms can have a primary skin origin, or they can be secondary and associated with lymphoma found elsewhere in the body. Chemotherapy is the treatment of choice, especially in cases with multifocal distribution. Protocol preference varies with disease stage, patient clinical and laboratory conditions, and the degree of toxicity. Commonly used chemotherapy regimens include L-CHOP (vincristine, cyclophosphamide, doxorubicin, L-asparaginase, and prednisolone), CHOP, COP (cyclophosphamide, vincristine, and prednisone), LAP (lomustine, L-asparaginase, and prednisolone), LOPP (lomustine, vincristine, procarbazine, prednisolone), chlorambucil, and prednisolone. The prognosis of canine epitheliotropic cutaneous lymphoma is unfavorable, with a survival time ranging from a few months to 2 years. The animal in this study survived for 105 days. In addition, epitheliotropic cutaneous T cell lymphoma is aggressive, which may result in a shorter survival time in animals affected by this type of tumor. [ABSTRACT FROM AUTHOR]

Cytoglobin (Cygb), a hemoprotein of the globin family, is expressed in the supportive tissue cells of the fibroblast lineage and in distinct neuronal cell populations. The expression pattern and regulatory parameters of fibroblasts and related cells were studied in organs such as the kidney and liver in a variety of animal models. In contrast, knowledge about cytoglobin-expressing neurons is sparse. Only a few papers described the distribution in the brain as ubiquitous with a restricted number of neurons in focal regions. Although there is evidence for cytoglobin involvement in neuronal hypoxia tolerance, its presence in the auditory system was not studied despite high metabolism rates and oxygen demands of the cochlea and related brainstem centers. In a continuation of a previous study demonstrating Cygb-neurons in, inter alia, auditory regions of the mouse brain, we concentrated on the superior olivary complex (SOC) in the present study. We sought to investigate the distribution, projection pattern and neurochemistry of Cygb-neurons in the SOC. We conducted immunohistochemistry using a Cygb antibody and found that this brainstem region, functionally competent for bilateral hearing and providing cochlear hair cell innervation, contains a considerable number of Cygb-expressing neurons (averaging 2067 ± 211 making up 10 ±1% percent of total neuron number) in rats, and 514 ± 138 (6 ± 1%) in mice. They were observed in all regions of the SOC. Retrograde neuronal tract tracing with Fluorogold injected into the cochlea demonstrated that 1243 ± 100 (6 ± 1% of total neuron number in rat SOC)) were olivocochlear neurons. Approximately 56% of total Cygb neurons were retrogradely labelled, while the majority of olivocochlear neurons of both lateral and medial systems were Cygb-immunoreactive. We also conducted double immunofluorescence staining for Cygb and neuronal nitric oxide synthase (nNOS), the enzyme responsible for nitric oxide production, and observed that cytoglobin in the SOC frequently co-localized with nNOS. Our findings suggest that cytoglobin plays an important physiologic role in the oxygen homeostasis of the peripheral and central auditory nervous system. Further studies, also including transgenic animal models, are required to shed more light on the function(s) of Cygb in neurons, in particular of the auditory system. [ABSTRACT FROM AUTHOR]

Introduction: Parathyroid cancers are rare and difficult to distinguish from benign parathyroid tumours. Prediction of malignancy often relies on intraoperative assessment of invasion. Standard histology is also inadequate; especially in the absence of local invasion, lymph nodal disease and metastasis. The aim of this project was to systematically review published literature on potential bio-markers used for the diagnosis of parathyroid cancer.Methods: Pubmed, Web of Science and Medline databases were searched. Inclusion criteria included English language papers published after 1985 and reporting on biomarkers in human studies of parathyroid cancer and benign disease.Results: 118 relevant papers were appraised; all were observational studies. At least 2 papers studied 8 serum, 4 urine and 27 tissue biomarkers on the diagnosis of parathyroid cancer. Of these, 5 serum and 13 tissue markers have been demonstrated in at least one study to be statistically different in benign and malignant disease. We present a synthesis of data for each biomarker and measures of diagnostic accuracy where possible.Conclusions: Consideration should be given to the use of a panel of biomarkers to review patients with suspected parathyroid cancer. A profile including serum calcium and PTH levels and tissue expression of APC, Parafibromin, PGP9.5, Galectin 3 and Ki67 is proposed. Systematic Review Registration Number - CRD42019127833. [ABSTRACT FROM AUTHOR]