Histiocytosis and adult-onset orbital xanthogranuloma in 2023: a review of the literature and mini case series.

PURPOSE: Within the large umbrella of histiocytosis are a few similar yet heterogenous entities involving the orbit and periocular tissues with or without systemic infiltration, termed adult onset xanthogranuloma or orbital xanthogranuloma. Due to rarity of these conditions, different classifications in use, diverse clinical presentations and still unknown etiology, the aim of this paper was to provide an up-to-date literature review of the actual understanding of histiocytosis and its subgroups involving the orbit and periocular area, diagnostic strategies and therapeutic modalities. METHODS: We present a review of literature and small case series comprising four patients diagnosed and treated in the period from 2001 until 2023 in our hospital. Clinical files of 4 patients with adult-onset xanthogranulomatous disease of the orbit and ocular adnexa (AOXGD) were reviewed retrospectively. Clinical, laboratory, radiological, histopathological, and immunohistochemical findings were reexamined. RESULTS: Reviewing medical records of our patients with AOXGD, we found significant overlap between histiocytosis and different immune disorders. A broad workup should be considered in these patients as they can harbour severe immune disfunctions and hematologic disorders. Preferred treatment modality depends on a histopathologic type of AOXGD, clinical presentation and systemic involvement and should be conducted multidisciplinary. CONCLUSION: The diagnosis is often delayed because of its rarity and diverse clinical findings. Development of molecular genetic tests, detection of BRAF V600E mutation and different types of kinase mutations, mutations in transcriptional regulatory genes as well as tyrosine kinase receptors have shed a new light on the etiopathogenesis and potential targeted treatment of histiocytosis.

Papillary thyroid carcinoma within a mature cystic ovarian teratoma.

Mature cystic ovarian teratoma (dermoid cyst) is the most common germ cell tumor. Malignant tissue alteration in mature cystic teratoma is extremely rare, and malignant proliferation of thyroid tissue has been documented in only a few cases. This article presents a case of incidentally detected papillary microcarcinoma (PTMC) within a mature cystic ovarian teratoma. A 42-year-old patient with an ultrasound-suspected dermoid cyst was indicated for surgical treatment. Laparoscopic adnexectomy was performed, and a cystic-solid tumor 3.5 cm in diameter was removed entirely. Pathohistological analysis confirmed the diagnosis of a mature cystic teratoma with a PTMC 0.3 cm in diameter. Afterward, the patient underwent additional investigations with an oncologic radiotherapist and endocrinologist. Thyroid ultrasound, thyroglobulin serum levels, anti-thyroglobulin antibodies, thyroid scintigraphy, and abdominal positron emission tomography (PET) scan were performed to exclude disease dissemination. All results were with no findings of other disease seed/metastasis, and the patient will be followed up regularly by a gynecologist and endocrinologist.

The Appearance of 4-Hydroxy-2-Nonenal (HNE) in Squamous Cell Carcinoma of the Oropharynx.

Tumor growth is associated with oxidative stress, which causes lipid peroxidation. The most intensively studied product of lipid peroxidation is 4-hydroxy-2-nonenal (HNE), which is considered as a "second messenger of free radicals" that binds to proteins and acts as a growth-regulating signaling factor. The incidence of squamous cell carcinoma of the oropharynx is associated with smoking, alcohol and infection of human papilloma virus (HPV), with increasing incidence world-wide. The aim of this retrospective study involving 102 patients was to determine the immunohistochemical appearance of HNE-protein adducts as a potential biomarker of lipid peroxidation in squamous cell carcinoma of the oropharynx. The HNE-protein adducts were detected in almost all tumor samples and in the surrounding non-tumorous tissue, while we found that HNE is differentially distributed in squamous cell carcinomas in dependence of clinical stage and histological grading of these tumors. Namely, the level of HNE-immunopositivity was increased in comparison to the normal oropharyngeal epithelium in well- and in moderately-differentiated squamous cell carcinoma, while it was decreasing in poorly differentiated carcinomas and in advanced stages of cancer. However, more malignant and advanced cancer was associated with the increase of HNE in surrounding, normal tissue. This study confirmed the onset of lipid peroxidation, generating HNE-protein adducts that can be used as a valuable bioactive marker of carcinogenesis in squamous cell carcinoma of the oropharynx, as well as indicating involvement of HNE in pathophysiological changes of the non-malignant tissue in the vicinity of cancer.

Role of matrix metalloproteinases and their inhibitors in the development of cervical metastases in papillary thyroid cancer.

OBJECTIVE: To investigate the role of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in the development of cervical metastases in papillary thyroid cancer. Our hypothesis is that level of expression of MMPs and TIMPs is associated with the development of cervical metastases and the pattern of metastatic process in papillary thyroid cancer. DESIGN: This research retrospectively investigates the expression of MMP-1, -2 and -9 as well as TIMP-1 and -2 in papillary thyroid carcinoma tissue. Tissue specimens were immunohistochemically treated with primary monoclonal antibodies against MMP-1, MMP-2, MMP-9, TIMP-1 and TIMP-2. SETTING: Single-centre study. PARTICIPANTS: In total, samples of 159 patients were analysed. In all patients, total thyroidectomy was performed, whereas 102 patients underwent selective neck dissection of either central (level VI) or lateral neck (level II-V). Subjects were divided into four groups. MAIN OUTCOME MEASURES: Matrix metalloproteinases and TIMPs expression values were analysed in each group, and groups were compared to each other. RESULTS: Total number of patients was 159, of which 125 were women and 34 men. Comparing expression levels of MMPs and TIMPs in metastatic (study groups) and non-metastatic (control group), papillary thyroid carcinomas yielded significant differences in MMP-1 and TIMP-1 expression levels, where the highest expression values were found in the group with metastasis in lateral neck. Expression levels of MMP-2, MMP-9 and TIMP-2 did not differ statistically significant among the groups. CONCLUSION: Elevated expression of MMP-1 and TIMP-1 in tumour tissue can be considered a predictive factor for the development of metastases.

ORAI1 mutations abolishing store-operated Ca2+ entry cause anhidrotic ectodermal dysplasia with immunodeficiency.

BACKGROUND: Store-operated Ca2+ entry (SOCE) through Ca2+ release-activated Ca2+ channels is an essential signaling pathway in many cell types. Ca2+ release-activated Ca2+ channels are formed by ORAI1, ORAI2, and ORAI3 proteins and activated by stromal interaction molecule (STIM) 1 and STIM2. Mutations in the ORAI1 and STIM1 genes that abolish SOCE cause a combined immunodeficiency (CID) syndrome that is accompanied by autoimmunity and nonimmunologic symptoms. OBJECTIVE: We performed molecular and immunologic analysis of patients with CID, anhidrosis, and ectodermal dysplasia of unknown etiology. METHODS: We performed DNA sequencing of the ORAI1 gene, modeling of mutations on ORAI1 crystal structure, analysis of ORAI1 mRNA and protein expression, SOCE measurements, immunologic analysis of peripheral blood lymphocyte populations by using flow cytometry, and histologic and ultrastructural analysis of patient tissues. RESULTS: We identified 3 novel autosomal recessive mutations in ORAI1 in unrelated kindreds with CID, autoimmunity, ectodermal dysplasia with anhidrosis, and muscular dysplasia. The patients were homozygous for p.V181SfsX8, p.L194P, and p.G98R mutations in the ORAI1 gene that suppressed ORAI1 protein expression and SOCE in the patients' lymphocytes and fibroblasts. In addition to impaired T-cell cytokine production, ORAI1 mutations were associated with strongly reduced numbers of invariant natural killer T and regulatory T (Treg) cells and altered composition of γδ T-cell and natural killer cell subsets. CONCLUSION: ORAI1 null mutations are associated with reduced numbers of invariant natural killer T and Treg cells that likely contribute to the patients' immunodeficiency and autoimmunity. ORAI1-deficient patients have dental enamel defects and anhidrosis, representing a new form of anhidrotic ectodermal dysplasia with immunodeficiency that is distinct from previously reported patients with anhidrotic ectodermal dysplasia with immunodeficiency caused by mutations in the nuclear factor κB signaling pathway (IKBKG and NFKBIA).

Hypermethylation of Secreted Frizzled Related Protein 1 gene promoter in different astrocytoma grades.

AIM: To identify the involvement of Secreted Frizzled Related Protein 1 (SFRP1) promoter hypermethylation in different malignancy grades of astrocytoma and assess its association with beta-catenin, lymphoid-enhancer factor 1, and T-cell factor 1. METHODS: Twenty-six astrocytoma samples were collected from 2008-2015. Promoter hypermethylation was evaluated by methylation-specific polymerase-chain-reaction and protein expression by immunohistochemistry and stereological analysis. The staining intensity was scored by comparing immunoreactivity with normal tissue and by using 10% and 50% cut-offs. RESULTS: SFRP1 promoter methylation was found in 32% of astrocytomas. The number of hypermethylated samples increased in higher astrocytoma grades and was the highest in glioblastoma (P=0.042 compared to other astrocytoma grades). There was 45.8% of samples with the lack of or weak expression of SFRP1 protein and 29.2% with strong expression. Samples with methylated promoter expressed significantly less SFRP1 than samples with unmethylated promoter (P=0.031). Beta-catenin expression levels were elevated. Yet, glioblastomas with unmethylated SFRP1 promoter had significantly less beta-catenin (P=0.033). Strong expression of lymphoid-enhancer factor 1 was associated to higher astrocytoma grades (P=0.006). CONCLUSION: SFRP1 gene was epigenetically silenced in glioblastomas when compared to low astrocytoma grades, which may suggest that the lack of its protein is involved in astrocytoma progression.

SFRP4 protein expression is reduced in high grade astrocytomas which is not caused by the methylation of its promoter.

Introduction: Epigenetics play a vital role in stratifying CNS tumors and gliomas. The importance of studying Secreted frizzled-related protein 4 (SFRP4) in gliomas is to improve diffuse glioma methylation profiling. Here we examined the methylation status of SFRP4 promoter and the level of its protein expression in diffuse gliomas WHO grades 2-4. Methods: SFRP4 expression was detected by immunohistochemistry and evaluated semi-quantitatively. In the tumor hot-spot area, the intensity of protein expression in 200 cells was determined using ImageJ (National Institutes of Health, United States). The assessment of immunopositivity was based on the IRS score (Immunoreactivity Score). Promoter methylation was examined by methylation specific-PCR (MSP) in fifty-one diffuse glioma samples and appropriate controls. Isolated DNA was treated with bisulfite conversion and afterwards used for MSP. Public databases (cBioPortal, COSMIC and LOVD) were searched to corroborate the results. Results and discussion: SFRP4 protein expression in glioblastomas was very weak or non-existent in 86.7% of samples, moderate in 13.3%, while strong expression was not observed. The increase in astrocytoma grade resulted in SFRP4 protein decrease (p = 0.008), indicating the loss of its antagonistic role in Wnt signaling. Promoter methylation of SFRP4 gene was found in 16.3% of cases. Astrocytomas grade 2 had significantly more methylated cases compared to grade 3 astrocytomas (p = 0.004) and glioblastomas (p < 0.001), which may indicate temporal niche of methylation in grade 2. Furthermore, the expression levels of SFRP4 were high in samples with methylated SFRP4 promoter and low or missing in unmethylated cases (Pearson's R = -0.413; p = 0.003). We also investigated the association of SFRP4 changes to key Wnt regulators GSK3ß and DKK3 and established a positive correlation between methylations of SFRP4 and GSK3ß (Pearson's R = 0.323; p = 0.03). Furthermore, SFRP4 expression was correlated to unmethylated DKK3 (Chi square = 7.254; p = 0.027) indication that Wnt signaling antagonist is associated to negative regulator's demethylation. Conclusion: The study contributes to the recognition of the significance of epigenetic changes in diffuse glioma indicating that restoring SFRP4 protein holds potential as therapeutic avenue. Reduced expression of SFRP4 in glioblastomas, not following promoter methylation pattern, suggests another mechanism, possible global methylation, that turns off SFRP4 expression in higher grades.

FANCM Gene Variants in a Male Diagnosed with Sertoli Cell-Only Syndrome and Diffuse Astrocytoma.

Azoospermia is a form of male infertility characterized by a complete lack of spermatozoa in the ejaculate. Sertoli cell-only syndrome (SCOS) is the most severe form of azoospermia, where no germ cells are found in the tubules. Recently, FANCM gene variants were reported as novel genetic causes of spermatogenic failure. At the same time, FANCM variants are known to be associated with cancer predisposition. We performed whole-exome sequencing on a male patient diagnosed with SCOS and a healthy father. Two compound heterozygous missense mutations in the FANCM gene were found in the patient, both being inherited from his parents. After the infertility assessment, the patient was diagnosed with diffuse astrocytoma. Immunohistochemical analyses in the testicular and tumor tissues of the patient and adequate controls showed, for the first time, not only the existence of a cytoplasmic and not nuclear pattern of FANCM in astrocytoma but also in non-mitotic neurons. In the testicular tissue of the SCOS patient, cytoplasmic anti-FANCM staining intensity appeared lower than in the control. Our case report raises a novel possibility that the infertile carriers of FANCM gene missense variants could also be prone to cancer development.

Transcriptomic Profiling for Prognostic Biomarkers in Early-Stage Squamous Cell Lung Cancer (SqCLC).

Squamous cell lung carcinoma (SqCLC) is associated with high mortality and limited treatment options. Identification of therapeutic targets and prognostic biomarkers is still lacking. This research aims to analyze the transcriptomic profile of SqCLC samples and identify the key genes associated with tumorigenesis, overall survival (OS), and a profile of the tumor-infiltrating immune cells. Differential gene expression analysis, pathway enrichment analysis, and Gene Ontology analysis on RNA-seq data obtained from FFPE tumor samples (N = 23) and healthy tissues (N = 3) were performed (experimental cohort). Validation of the results was conducted on publicly available gene expression data using TCGA LUSC (N = 225) and GTEx healthy donors' cohorts (N = 288). We identified 1133 upregulated and 644 downregulated genes, common for both cohorts. The most prominent upregulated genes were involved in cell cycle and proliferation regulation pathways (MAGEA9B, MAGED4, KRT, MMT11/13), while downregulated genes predominately belonged to immune-related pathways (DEFA1B, DEFA1, DEFA3). Results of the survival analysis, conducted on the validation cohort and commonly deregulated genes, indicated that overexpression of HOXC4 (p < 0.001), LLGL1 (p = 0.0015), and SLC4A3 (p = 0.0034) is associated with worse OS in early-stage SqCLC patients. In contrast, overexpression of GSTZ1 (p = 0.0029) and LILRA5 (p = 0.0086) was protective, i.e., associated with better OS. By applying a single-sample gene-set enrichment analysis (ssGSEA), we identified four distinct immune subtypes. Immune cell distribution suggests that the memory T cells (central and effector) and follicular helper T cells could serve as important stratification parameters.

Intraneural Nodular Fasciitis of the Dorsal Scapular Nerve: Case Report and Review of the Literature.

BACKGROUND: Nodular fasciitis is a benign neoplasm occurring predominantly in the subcutaneous tissue. There have been nine intraneural occurrences described in the literature. CASE REPORT: A 37-year-old woman presented with numbness and tenderness in her left shoulder and scapula and a slightly dropped left shoulder, without history of trauma. A magnetic resonance imaging (MRI) of the cervical spine showed a well-circumscribed oval mass deep to the levator scapula muscle. Due to persisting symptoms and an unknown nature of the process, surgical excision was performed, and histopathologic analysis confirmed diagnosis of a benign fibroblastic/myofibroblastic neoplasm, nodular fasciitis. The postoperative course was uneventful and the patient was without symptoms at 4 months of follow-up. METHODS: We reviewed the available literature (PubMed, Google Scholar), with nine published cases of intraneural nodular fasciitis. The reported clinical, radiologic, and histopathologic parameters were evaluated and compared. DISCUSSION: Most of the cases reported in the literature were symptomatic, with tenderness and palpability being the main symptoms. Six of the reported cases occurred in the forearm, whereas three were in the leg. To the best of our knowledge, ours is the first reported case of nodular fasciitis occurring in the trunk. Ours is the only case to display desmin positivity, which supports the reactive hypothesis of nodular fasciitis. CONCLUSION: Intraneural nodular fasciitis is an extremely rare diagnosis. Due to its benign natural course, a multidisciplinary approach with this extremely rare diagnosis in mind is needed to avoid overtreatment.

HPV16 Impacts NHERF2 Expression in Oropharyngeal Cancers.

Infection with human papillomaviruses (HPVs), in particular with HPV type 16, is now considered to be a key risk factor for the development of a subset of oropharyngeal squamous cell carcinomas (OPSCC) that show different epidemiological, clinical, and prognostic characteristics from HPV-negative (HPV-) OPSCCs. So far, extensive research efforts aiming to distinguish these two distinct entities have not identified specific biomarkers, nor led to different therapies. Previous research has shown that HPV16 E6 oncoprotein binds NHERF2, inducing its proteasomal degradation, and consequently increasing cell proliferation; we therefore aimed to investigate how this might be reflected in human histological samples. We analyzed NHERF2 expression patterns in HPV16-positive (HPV16+) and HPV- OPSCC samples, to investigate any potential differences in NHERF2 pattern. Interestingly, we observed a statistically significant decrease in NHERF2 levels in HPV16+ and poorly differentiated HPV- OPSCCs, compared with healthy tissue. Furthermore, we observed a significant reduction in the percentage of NHERF2 immunoreactive cancer cells in HPV16+ tumors, compared with well and moderately differentiated HPV- OPSCCs, suggesting the importance of 16E6's targeting of NHERF2 in HPV-driven oncogenesis in the head and neck area.

Complex Permittivity of Ex-Vivo Human, Bovine and Porcine Brain Tissues in the Microwave Frequency Range.

Accurate knowledge about the dielectric properties of biological tissues in the microwave frequency range may lead to advancement of biomedical applications based on microwave technology. However, the published data are very scarce, especially for human brain tissues. The aim of this work was to measure and report the complex permittivity of brain white matter, grey matter and cerebellum. Complex permittivity was measured on human, bovine and porcine brain tissues in the microwave frequency range from 0.5 to 18 GHz using an open-ended coaxial probe. The results present a valuable addition to the available data on the brain tissue complex permittivity. Some noticeable variations between the results lead to several conclusions. Complex permittivity variation within the same tissue type of the individual species was comparable to interspecies variation. The difference was prominent between human brains obtained from autopsies, while bovine brains obtained from healthy animals showed very similar complex permittivity. We hypothesize that the difference might have been caused by the basic pathologies of the patients, where the associated therapies could have affected the brain water content. We also examined the effect of excised tissue degradation on its complex permittivity over the course of three days, and the results suggest the gradual dehydration of the samples.

Role of Matrix Metalloproteinases and Their Inhibitors in Locally Invasive Papillary Thyroid Cancer.

Locally invasive papillary thyroid carcinoma (PTC) protrudes beyond the thyroid capsule and invades local structures. Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) are implicated in local invasion and metastasis in PTC. The aim of our study was to determine expression levels of MMP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2 in tissue specimens of invasive and non-invasive PTC. Our hypothesis was that expression levels of these biomarkers correlate with the development of locally invasive PTC. In our single-center study we retrospectively investigated MMP and TIMP expression levels in 50 samples of thyroid tissue diagnosed as locally invasive papillary carcinoma (study group) and 30 samples of thyroid tissue diagnosed as non-invasive, non-metastatic papillary carcinoma (control group). Tissue specimens were immunohistochemically stained with primary monoclonal antibodies against MMP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2. When correlating expression levels of MMPs and TIMPs in thyroid tissue, statistically significant differences were found for MMP-1 and TIMP-1 expression (p < 0.001; Mann−Whitney U test) with the highest levels of expression in the invasive PTC group. Although expression of MMP-9 and TIMP-2 was higher in invasive PTC, the differences were not statistically significant. Elevated expression of MMP-1 and TIMP-1 in tumor tissue can predict invasiveness for PTC.

Post-mortem Findings of Inflammatory Cells and the Association of 4-Hydroxynonenal with Systemic Vascular and Oxidative Stress in Lethal COVID-19.

A recent comparison of clinical and inflammatory parameters, together with biomarkers of oxidative stress, in patients who died from aggressive COVID-19 and survivors suggested that the lipid peroxidation product 4-hydroxynonenal (4-HNE) might be detrimental in lethal SARS-CoV-2 infection. The current study further explores the involvement of inflammatory cells, systemic vascular stress, and 4-HNE in lethal COVID-19 using specific immunohistochemical analyses of the inflammatory cells within the vital organs obtained by autopsy of nine patients who died from aggressive SAR-CoV-2 infection. Besides 4-HNE, myeloperoxidase (MPO) and mitochondrial superoxide dismutase (SOD2) were analyzed alongside standard leukocyte biomarkers (CDs). All the immunohistochemical slides were simultaneously prepared for each analyzed biomarker. The results revealed abundant 4-HNE in the vital organs, but the primary origin of 4-HNE was sepsis-like vascular stress, not an oxidative burst of the inflammatory cells. In particular, inflammatory cells were often negative for 4-HNE, while blood vessels were always very strongly immunopositive, as was edematous tissue even in the absence of inflammatory cells. The most affected organs were the lungs with diffuse alveolar damage and the brain with edema and reactive astrocytes, whereas despite acute tubular necrosis, 4-HNE was not abundant in the kidneys, which had prominent SOD2. Although SOD2 in most cases gave strong immunohistochemical positivity similar to 4-HNE, unlike 4-HNE, it was always limited to the cells, as was MPO. Due to their differential expressions in blood vessels, inflammatory cells, and the kidneys, we think that SOD2 could, together with 4-HNE, be a potential link between a malfunctioning immune system, oxidative stress, and vascular stress in lethal COVID-19.

Prognostic Significance of BRAF V600E Mutation and CPSF2 Protein Expression in Papillary Thyroid Cancer.

The early-stage diagnosis of papillary thyroid cancer (PTC) has significantly increased in incidence worldwide without any beneficial impact on survival. In order to improve the risk assessment in PTC, we have conducted a retrospective study in which we analyzed the BRAF V600E mutation and CPSF2 protein expression as prognostic markers on archival tissue samples of 49 patients without (control group) and 97 patients with (study group) PTC metastases in the cervical lymph nodes at the time of initial diagnosis. Our aim was to correlate the BRAF V600E mutation and the expression of CPSF2 protein with the clinical and pathological features of PTC. The expression of CPSF2 protein was evaluated via immunohistochemistry and graded semi-quantitatively. The presence of the BRAF V600E mutation was determined via real-time polymerase chain reac-tion (PCR). CPSF2 protein < 3+ intensity expression was correlated with more frequent recurrences (Fisher-Freeman-Halton exact test; p = 0.010; 95% CI: 1.26−22.03), and patients who presented with the BRAF V600E mutation and CPSF2 protein expression < 3+ intensity had shorter disease-free survival (log-rank test; 105.0 months vs. 146.6 months; p < 0.001; HR 8.32, 95% CI: 2.91−23.83), whereas patients with PTC who had CPSF2 expression 3+ had longer disease-free survival in correlation with other lower intensity expressions of CPSF2 protein (log-rank test; 139.7 months vs. 129.6 months; p = 0.008). The multivariate analysis showed that younger patients with CPSF2 protein expression <3+ and the BRAF V600E mutation are at an increased risk for recurrence and require more intensive monitoring (Cox proportional hazards regression model; X2 = 17.5, df = 10, p = 0.025). Our results correlate the BRAF V600E mutation and CPSF2 protein expression with recurrence and disease-free survival as relevant prognostic factors for PTC.

Lipid peroxidation in brain tumors.

There is a lot of evidence showing that lipid peroxidation plays very important role in development of various diseases, including neurodegenerative diseases and brain tumors. Lipid peroxidation is achieved by two main pathways, by enzymatic or by non-enzymatic oxidation, respectively. In this paper, we focus on non-enzymatic, self-catalyzed chain reaction of poly-unsaturated fatty acid (PUFA) peroxidation generating reactive aldehydes, notably 4-hydroxynonenal (4-HNE), which acts as second messenger of free radicals and as growth regulating factor. It might originate from astrocytes as well as from blood vessels, even within the blood-brain barrier (BBB), which is in case of brain tumors transformed into the blood-brain-tumor barrier (BBTB). The functionality of the BBB is strongly affected by 4-HNE because it forms relatively stable protein adducts thus allowing the persistence and the spread of lipid peroxidation, as revealed by immunohistochemical findings. Because 4-HNE can act as a regulator of vital functions of normal and of malignant cells acting in the cell type- and concentration-dependent manners, the bioactivities of this product of lipid peroxidation be should further studied to reveal if it acts as a co-factor of carcinogenesis or as natural factor of defense against primary brain tumors and metastatic cancer.

Human DLG1 and SCRIB Are Distinctly Regulated Independently of HPV-16 during the Progression of Oropharyngeal Squamous Cell Carcinomas: A Preliminary Analysis.

The major causative agents of head and neck squamous cell carcinomas (HNSCCs) are either environmental factors, such as tobacco and alcohol consumption, or infection with oncogenic human papillomaviruses (HPVs). An important aspect of HPV-induced oncogenesis is the targeting by the E6 oncoprotein of PDZ domain-containing substrates for proteasomal destruction. Tumor suppressors DLG1 and SCRIB are two of the principal PDZ domain-containing E6 targets. Both have been shown to play critical roles in the regulation of cell growth and polarity and in maintaining the structural integrity of the epithelia. We investigated how modifications in the cellular localization and protein expression of DLG1 and SCRIB in HPV16-positive and HPV-negative histologic oropharyngeal squamous cell carcinomas (OPSCC) might reflect disease progression. HPV presence was determined by p16 staining and HPV genotyping. Whilst DLG1 expression levels did not differ markedly between HPV-negative and HPV16-positive OPSCCs, it appeared to be relocated from cell-cell contacts to the cytoplasm in most samples, regardless of HPV16 positivity. This indicates that alterations in DLG1 distribution could contribute to malignant progression in OPSCCs. Interestingly, SCRIB was also relocated from cell-cell contacts to the cytoplasm in the tumor samples in comparison with normal tissue, regardless of HPV16 status, but in addition there was an obvious reduction in SCRIB expression in higher grade tumors. Strikingly, loss of SCRIB was even more pronounced in HPV16-positive OPSCCs. These alterations in SCRIB levels may contribute to transformation and loss of tissue architecture in the process of carcinogenesis and could potentially serve as markers in the development of OPSCCs.

Preliminary Findings on the Association of the Lipid Peroxidation Product 4-Hydroxynonenal with the Lethal Outcome of Aggressive COVID-19.

Major findings of the pilot study involving 21 critically ill patients during the week after admission to the critical care unit specialized for COVID-19 are presented. Fourteen patients have recovered, while seven passed away. There were no differences between them in respect to clinical or laboratory parameters monitored. However, protein adducts of the lipid peroxidation product 4-hydroxynonenal (HNE) were higher in the plasma of the deceased patients, while total antioxidant capacity was below the detection limit for the majority of sera samples in both groups. Moreover, levels of the HNE-protein adducts were constant in the plasma of the deceased patients, while in survivors, they have shown prominent and dynamic variations, suggesting that survivors had active oxidative stress response mechanisms reacting to COVID-19 aggression, which were not efficient in patients who died. Immunohistochemistry revealed the abundant presence of HNE-protein adducts in the lungs of deceased patients indicating that HNE is associated with the lethal outcome. It seems that HNE was spreading from the blood vessels more than being a consequence of pneumonia. Due to the limitations of the relatively small number of patients involved in this study, further research on HNE and antioxidants is needed. This might allow a better understanding of COVID-19 and options for utilizing antioxidants by personalized, integrative biomedicine approach to prevent the onset of HNE-mediated vitious circle of lipid peroxidation in patients with aggressive inflammatory diseases.

Pneumatized Crista Galli: A Histopathologic Study.

OBJECTIVE: This is the first histopathologic study that investigates the incidence of the pneumatized crista galli. STUDY DESIGN: A prospective histopathologic study. SETTING: Tertiary academic medical center. SUBJECTS AND METHODS: A total of 109 specimens of crista galli were obtained postmortem during 2018 from randomly chosen patients who died at the University Hospital Centre Zagreb and had an autopsy at our Department of Pathology and Cytology. Specimens were surgically resected during the autopsy and then fixed, decalcinated, dehydrated, and embedded in paraffin. All slides were cut into 5-µm-thin sections and stained with a standard method (hematoxylin and eosin) for light microscope analysis. Specimens were histopathologically analyzed for the existence of pneumatization inside crista galli. The criterion to declare a specimen pneumatized was the presence of mucosa inside the cavity. RESULTS: Pneumatized crista galli was found in 5 of 109 specimens (4.59%). In 5 of 5 cases (100%) of pneumatized crista galli, there was evidence of chronic inflammation. CONCLUSION: We found that the incidence of pneumatized crista galli is significantly lower in our histopathologic study in comparison with the majority of previous radiologic studies. Our study also found that all 5 specimens with pneumatized crista galli had chronic inflammation in the mucosa, which is a considerably higher incidence than in the previous studies (7.7%-44%). Due to the emerging evidence of pneumatized crista galli being of clinical importance, we suggest that a larger study be conducted before the results are generalized to the general population.