Cellular Variant Research Articles

Diagnosis and differential diagnosis of dermatofibrosarcoma protuberans: Utility of high-resolution dynamic contrast-enhanced (DCE) MRI.

Dermatofibrosarcoma protuberans (DFSP) is a kind of low-grade malignant spindle cell neoplasm, the diagnosis, and treatment, which have markedly attracted clinicians' attention for its repeated recurrence. High-resolution magnetic resonance imaging (HR-MRI) has shown unique capabilities in diagnosis of various cutaneous tumors. Data of 29 patients with clinically suspected DFSPs and undergoing dynamic contrast-enhanced (DCE) HR-MRI preoperatively were prospectively collected. The HR-MRI qualitative features were evaluated and compared. The DCE-associated quantitative parameters and the time-signal intensity curve (TIC) types were provided using DCE sequences. A total of 7 DFSPs, nine dermatofibromas (DF, including four cases of cellular variant [CDF]), 12 keloids, and one nodular fasciitis were enrolled. DFSP showed the largest major diameter and the deepest depth. Five DFSPs (71.4%) showed ill-defined margins as well as infiltration of peripheral adipose. All DFSPs showed irregular shape. Most DFSPs presented hyperintensity on T2 WI (71.4%) and iso-intensity on T1 WI (85.7%). Six cases (85.7%) had significant enhancement, and six cases (85.7%) had homogeneous enhancement. There were significant differences of Ktrans , Kep , Ve and iAUC values among DFSPs, DFs, and keloids, and DFSP had the highest values for these parameters. Six DFSPs (85.7%) and four CDFs (100%) showed type-III TICs, while the other lesions showed type-Ⅰor type-Ⅱ TICs. DCE-HR-MRI could show the growth characteristics of DFSPs, which was of great value for the diagnosis and differential diagnosis of DFSPs and was helpful for the determination of treatment options, thereby to improve the prognosis of patients.

Malignant progression of cerebellopontine angle solitary fibrous tumors following radiation: illustrative case.

BACKGROUNDIntracranial solitary fibrous tumors (ISFTs) are rare mesenchymal tumors originating in the meninges and constitute a heterogeneous group of clinical and biological behavior. Benign histotypes, such as hemangiopericytomas are now considered as a cellular phenotypic variant of this heterogenous group of rare spindle-cell tumors. IFSTs are poorly recognized and remain a diagnostic challenge due to rarity and resemblance to other brain tumors. Previously, IFSTs were thought to pursue a slow, indolent, and nonaggressive course, however, a growing body of literature based on longer follow-up demonstrates an unpredictable clinical course and an uncertain diagnosis.OBSERVATIONSA rare case report of malignant transformation of IFST following radiation therapy is reported. In this case a 60-year-old female who underwent gross total resection of the cerebellopontine angle tumor with histopathology consistent with solitary fibrous tumor followed by salvage stereotactic radiosurgery, presented with another recurrence after 2 years of surgery. The authors performed complete removal of the tumor with pathology now consistent with malignant solitary fibrous tumor. A recent follow-up magnetic resonance imaging did not show any recurrence or residual tumor, and the patient reports a generalized well-being.LESSONSThis report will help to understand the natural history and unusual clinical behavior of these intracranial tumors.

Cellular variant of kaposiform lymphangiomatosis: a report of three cases, expanding the morphologic and molecular genetic spectrum of this rare entity

Kaposiform lymphangiomatosis (KLA) is a very rare form of generalized lymphatic anomaly, consisting of a diffuse proliferation of abnormal, dilated lymphatics, and small fascicles of hemosiderin-laden spindled lymphatic endothelial cells. KLA occurs in children and young adults and may present with multicentric disease, pleural and pericardial effusions, and life-threatening coagulopathy. Genetically, KLA most often harbors somatic activating mutations in NRAS. We recently encountered 3 cases of KLA with cellular features, resembling kaposiform hemangioendothelioma (KHE), and studied their clinicopathologic, radiologic, and molecular genetic features. The patients (1 male, 2 females; aged 2 years, 2 months, 4 years) presented with multicentric disease involving skin, soft tissue, bone, and spleenand thrombocytopenia/coagulopathy. Advanced imaging studies confirmed multicentric disease. Biopsies (skin, soft tissue, bone, and spleen) demonstrated both conventional KLA and much more cellular foci, consisting of sheets, nodules, glomeruloid structures, and sieve-like arrays of lymphatic endothelial cells (positive for CD31 and D2-40). Cellular areas superficially resembled KHE but displayed more epithelioid cytology and lacked surrounding hyaline fibrosis and minute platelet aggregates. Molecular genetic studies demonstrated NRAS c.181C>A p.Q61K (Gln61Lys) in 2 specimens from one patient and HRAS p.A59_Q61delinsGGSIL in another. Two patients were treated with sirolimus; all are currently alive with stable disease. We conclude that cellular morphology in KLA, a previously undescribed feature, does not appear to be associated with clinical features, site of disease, mutation type, response to sirolimus, or outcome. Although cellular KLA may mimic KHE, there are sufficient clinical, morphologic, and genetic differences such that these are likely unrelated diseases.

Interaction between the Hepatitis B Virus and Cellular FLIP Variants in Viral Replication and the Innate Immune System.

During viral evolution and adaptation, many viruses have utilized host cellular factors and machinery as their partners. HBx, as a multifunctional viral protein encoded by the hepatitis B virus (HBV), promotes HBV replication and greatly contributes to the development of HBV-associated hepatocellular carcinoma (HCC). HBx interacts with several host factors in order to regulate HBV replication and evolve carcinogenesis. The cellular FADD-like IL-1β-converting enzyme (FLICE)-like inhibitory protein (c-FLIP) is a major factor that functions in a variety of cellular pathways and specifically in apoptosis. It has been shown that the interaction between HBx and c-FLIP determines HBV fate. In this review, we provide a comprehensive and detailed overview of the interplay between c-FLIP and HBV in various environmental circumstances. We describe strategies adapted by HBV to establish its chronic infection. We also summarize the conventional roles of c-FLIP and highlight the functional outcome of the interaction between c-FLIP and HBV or other viruses in viral replication and the innate immune system.

Castleman Disease: A Wide Spectrum of Thoracic Manifestations

Castleman’s disease is a benign lymphoproliferative disorder affecting both lymph nodes and extranodal loci. Castleman’s disease can occur in practically any part of the body, but it occurs mainly in the thorax (~70%) followed by the abdomen and pelvis, neck and axilla. Clinically, Castleman’s disease can be classified into a unicentric or multicentric form, depending on the number of lymph nodes involved, and histologically into a hyaline vascular variant, plasma cell, mixed cellular or plasmablastic variant. In this mini-review we briefly report and focus on all clinical thoracic manifestations of Castleman’s disease resuming for each of them the possible strategy of treatment.

Molecular Imaging of Human Skeletal Myoblasts (huSKM) in Mouse Post-Infarction Myocardium

Current treatment protocols for myocardial infarction improve the outcome of disease to some extent but do not provide the clue for full regeneration of the heart tissues. An increasing body of evidence has shown that transplantation of cells may lead to some organ recovery. However, the optimal stem cell population has not been yet identified. We would like to propose a novel pro-regenerative treatment for post-infarction heart based on the combination of human skeletal myoblasts (huSkM) and mesenchymal stem cells (MSCs). huSkM native or overexpressing gene coding for Cx43 (huSKMCx43) alone or combined with MSCs were delivered in four cellular therapeutic variants into the healthy and post-infarction heart of mice while using molecular reporter probes. Single-Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) performed right after cell delivery and 24 h later revealed a trend towards an increase in the isotopic uptake in the post-infarction group of animals treated by a combination of huSkMCx43 with MSC. Bioluminescent imaging (BLI) showed the highest increase in firefly luciferase (fluc) signal intensity in post-infarction heart treated with combination of huSkM and MSCs vs. huSkM alone (p < 0.0001). In healthy myocardium, however, nanoluciferase signal (nanoluc) intensity varied markedly between animals treated with stem cell populations either alone or in combinations with the tendency to be simply decreased. Therefore, our observations seem to show that MSCs supported viability, engraftment, and even proliferation of huSkM in the post-infarction heart.

Modulation of alternative splicing during early infection of human primary B lymphocytes with Epstein-Barr virus (EBV): a novel function for the viral EBNA-LP protein.

Epstein-Barr virus (EBV) is a human herpesvirus associated with human cancers worldwide. Ex vivo, the virus efficiently infects resting human B lymphocytes and induces their continuous proliferation. This process is accompanied by a global reprogramming of cellular gene transcription. However, very little is known on the impact of EBV infection on the regulation of alternative splicing, a pivotal mechanism that plays an essential role in cell fate determination and is often deregulated in cancer. In this study, we have developed a systematic time-resolved analysis of cellular mRNA splice variant expression during EBV infection of resting B lymphocytes. Our results reveal that major modifications of alternative splice variant expression appear as early as day 1 post-infection and suggest that splicing regulation provides—besides transcription—an additional mechanism of gene expression regulation at the onset of B cell activation and proliferation. We also report a role for the viral proteins, EBNA2 and EBNA-LP, in the modulation of specific alternative splicing events and reveal a previously unknown function for EBNA-LP—together with the RBM4 splicing factor—in the alternative splicing regulation of two important modulators of cell proliferation and apoptosis respectively, NUMB and BCL-X.

Role of the Histological Variant for the Prognosis and Course of the Focal Segmental Glomerulosclerosis

Abstract The focal segmental glomerulosclerosis is characterized by a morphological heterogeneity, most likely reflecting different pathogenetic mechanisms. The Colombian classification distinguishes five morphological types – non-specific (not otherwise specified or classical), perihilar, cellular, a tubular pole (tip) one and a collapsing one. Eighty-one (81) patients were studied. Their distribution according to the histological variant showed the highest frequency of the non-specific (classical) variant – 70.4%, followed by the perihilar variant – 27.20%, the cellular variant – 1.2% and the collapsing variant – 1.2%. No patients with tip lesions were identified. There were significant differences in the creatinine levels and the glomerular filtration rate (GFR) at the beginning and at the end of the follow-up between patients with the perihilar and the non-specific variants. Patients with the perihilar variant had a better treatment response with a high percentage of patients achieving complete remission – 59.1%. Patients with the non-specific variant had a high chance of treatment failure – 26.3% had no effect from treatment. The results of the study give grounds to assume that the histological variant affects the clinical picture, course and therapeutic response in patients with focal segmental glomerulosclerosis. It could be used as a prognostic marker of disease behavior and guide the clinician in treatment decisions.

WWOX Loses the Ability to Regulate Oncogenic AP-2γ and Synergizes with Tumor Suppressor AP-2α in High-Grade Bladder Cancer.

Simple SummaryA prognostic factor of bladder cancer which can benefit from research on molecular markers is the histologic grade. WWOX, AP-2α and AP-2γ are known to have a grade-dependent effect but have not been investigated in that aspect in bladder cancer. Depending on the specific collaboration, their role was found to promote or inhibit grade 2 bladder cancer. As further research is needed on higher grades, the aim of the present study was to examine the functionality of WWOX and two AP-2 factors in grade 3 and grade 4 bladder cancer. It was found that WWOX, AP-2α and their combination mainly demonstrated anti-cancer properties; in contrast, AP-2γ promoted cancer development, which was not inhibited by WWOX in their combined variant. Next-generation sequencing was performed to identify the genes worth investigating as biomarkers. To conclude, WWOX and AP-2α demonstrate tumor suppressor synergism in high-grade bladder cancer, similar to intermediate grade. However, WWOX does not appear to guide oncogenic AP-2γ, which was the case in the lower grade. The cause of such a change in molecule superiority, as well as proposed bladder cancer-related genes, should be further investigated.The cytogenic locus of the WWOX gene overlaps with the second most active fragile site, FRA16D, which is present at a higher frequency in bladder cancer (BLCA) patients with smoking habit, a known risk factor of this tumor. Recently, we demonstrated the relevance of the role of WWOX in grade 2 BLCA in collaboration with two AP-2 transcription factors whose molecular actions supported or opposed pro-cancerous events, suggesting a distinct character. As further research is needed on higher grades, the aim of the present study was to examine WWOX-AP-2 functionality in grade 3 and 4 BLCA using equivalent in vitro methodology with additional transcriptome profiling of cellular variants. WWOX and AP-2α demonstrated similar anti-cancer functionality in most biological processes with subtle differences in MMP-2/9 regulation; this contradicted that of AP-2γ, whose actions potentiated cancer progression. Simultaneous overexpression of WWOX and AP-2α/AP-2γ revealed that single discrepancies appear in WWOX-AP-2α collaboration but only at the highest BLCA grade; WWOX-AP-2α collaboration was considered anti-cancer. However, WWOX only appeared to have residual activity against oncogenic AP-2γ in grade 3 and 4: variants with either AP-2γ overexpression alone or combined WWOX and AP-2γ overexpression demonstrated similar pro-tumoral behavior. Transcriptome profiling with further gene ontology certified biological processes investigated in vitro and indicated groups of genes consisting of AP-2 targets and molecules worth investigation as biomarkers. In conclusion, tumor suppressor synergism between WWOX and AP-2α is unimpaired in high-grade BLCA compared to intermediate grade, yet the ability of WWOX to guide oncogenic AP-2γ is almost completely lost.

MO294COMPARISON OF TIP AND CELLULAR VARIANT OF PRIMARY FOCAL SEGMENTAL GLOMERULOSCLEROSIS

Abstract Background and Aims After membranous nephropathy, focal segmental glomerulosclerosis (FSGS) is the most common cause of nephrotic syndrome in European population. According to Columbia classification, there are five histological variants of FSGS defined on light microscopy (tip, cellular, perihilar, collapsing and not otherwise specified - NOS) and this classification has a prognostic significance. The aim is to compare features and outcomes of tip and cellular variant of primary FSGS. Method All patients with FSGS were identified by a retrospective review of the Registry of kidney biopsies at the Department of Nephrology and Dialysis, Dubrava University Hospital, Zagreb, from 2003 until 2020. Each kidney specimen was analyzed by light, immunofluorescent and electron microscopy and Columbia classification was applied by experienced nephropathologist. Patients with primary FSGS met following criteria: full nephrotic syndrome and diffuse podocyte foot process effacement in absence of secondary causes of FSGS. Laboratory findings were obtained for every patient at the time of biopsy and following outpatient visits. Complete remission was defined as proteinuria &amp;lt; 0.3 g/day with normal kidney function and partial remission as proteinuria 0.3 - 3.5 g/day. Variables are expressed as median ± IQR (interquartile range) and frequencies. Statistical comparison between groups of patients with tip and cellular variant of primary FSGS and disease outcome analysis were done. Results Out of 200 patients with FSGS, 59 (29.5 %) had primary form of disease. Tip variant was the most common form of primary FSGS (22 patients, 37 %) followed by NOS (20, 34 %), cellular (13, 22 %), perihilar (2, 3.5 %) and collapsing (2, 3.5 %) variant. Demographic and clinical features with initial laboratory findings are shown in Table 1. There were no significant differences between two groups in all analyzed variables in Figure 1. All patients were treated by anti-RAAS agents and steroids. Median follow-up was 55 months (range 1 – 196 months), and followup data were unavailable for three patients. Figure 2 shows treatment regimens in both patient grouos with treatment outcomes. Remission rate was significantly higher in tip variant (90 % vs. 41 %, p = 0.002). There was no difference in relapse rate between the two groups (p = 0.717). Conclusion There were no significant differences in clinical features and laboratory findings at the time of clinical presentation between tip and cellular variant of primary FSGS. Patients with tip variant had significantly higher remission rate than patients with cellular variant.

Pitfalls in cytological diagnosis of mucinous carcinomas of breast

Mucinous (colloid) carcinoma (MC) of the breast is relatively rare and accounts for 1-6% of all breast cancers. Traditionally, pure mucinous tumors and mixed infiltrating ductal carcinomas with a mucinous component have been described. Pure mucinous carcinoma of the breast has a favorable prognosis than the mixed variety noted in several studies. The common age of presentation is the postmenopausal group. Cytological diagnosis of these tumors is challenging. A retrospective study was conducted at our institute. 22 cases consisting of both mixed and pure mucinous carcinomas diagnosed by cytology and verified on histopathology between January 2007 and November 2015 were included in the study. All cytology and histopathology slides were reviewed. A total of 22 cases were evaluated. The age ranged from 34-78years. The left breast was involved in 12 cases and the right breast in 10cases. 19 cases were diagnosed as mucinous carcinoma on cytology. However 12 of these cases were reported as pure mucinous carcinoma on biopsy. All these cases displayed abundant mucin, small nuclei and/or regular nuclear outlines on cytology. 7 cases turned out to be mixed tumors on histopathology. Sparse mucin, large nuclei, irregular nuclear outlines or the presence of nucleoli were found in mixed mucinous carcinomas but not in pure tumors. Three cases were diagnosed as infiltrating ductal carcinoma (IDC) on cytology. One of these patients had 2 nodules, diagnosed on histopathological examination as IDC and mucinous carcinoma. Out of the other two cases, 1 case was diagnosed as cellular variant of mucinous carcinoma and another case as mixed carcinoma on biopsy. Cellular variant of mucinous carcinoma can mimic low grade ductal carcinoma on cytology. A thorough examination of the slides for mucinous material and few thin capillary fragments provide a valuable diagnostic clue. The distinction between pure and mixed mucinous carcinoma is important, because patients with the former type have a much favorable prognosis, with a low propensity for lymph node and distant metastasis. Cytopathological identification of patients with pure mucinous carcinomas may be performed only in a limited number of cases. The various differential diagnosis should always be kept in mind while dealing with lesions associated with mucin. However the age of presentation, clinical features and radiological findings can help to further categorize the various mucinous lesions.

Dichotomy in Growth and Invasion from Low- to High-Grade Glioma Cellular Variants.

Glial dysfunction outraging CNS plasticity and integrity results in one of the most dangerous cancers, namely glioma, featuring little median survival period and high recurrence. The hallmark properties of proliferation, invasion and angiogenesis with the infiltrated macrophages in glioma are expected to be tightly coupled or cross-linked, but not properly related so far. The present study is aimed to find a relationship between this featured quadrangle from lower to higher grades (HG) of post-operative glioma tissues and their invading subsets. Elevated Ki67-associated proliferation in lower grades (LG) was supported with VEGF dependent angiogenic maintenance which found a decrease unlikely in HG. In contrast, MMP 2 and 9-associated invasions augmented high in HG with the dominant presence of CD204+ M2 polarized macrophages and a general increase in global DNMT1-associated methylation. Marked differences found in ECM invading cellular subsets of HG showing high proliferative capacity indicating rationally for recurrence, contrasting the nature of gross tumor tissue of the same grade. Thus in LG, the neoplastic lesion is more inclined to its growth while in higher grade more disposed towards tissue wreckage in support with cellular environmental milieu whereas the cellular variants and subsets of invaded cells showed different trends. Therefore, some operational dichotomy or coupling among cellular variants in glioma is active in determining its low- to high-grade transition and aggressive progression.

The misleading laboratory results: Renal impairment associated with high anti myeloperoxidase titer (anti-MPO) does not always mean ANCA vasculitis

Introduction: Antineutrophil cytoplasmic autoantibodies (ANCAs) are crucial in the pathogenesis of ANCA-associated glomerulonephritis. Although highly specific for this disease, these antibodies can appear in healthy individuals or occur in other settings such as malignance, other inflammatory disease, or drugs. Renal biopsy remains essential for diagnosis and as a prognostic tool. Failing to perform a biopsy risks an incomplete evaluation or misdiagnosis. Clinical case: A 60-year-old male known to have had previous normal kidney function was admitted with generalized pitting edema, nonpruritic erythematous rash, and decreased urine output. He had been recently started on clozapine for depression. Laboratory tests revealed nephrotic syndrome with massive proteinuria (11g/day), hematuria and elevated serum creatinine that reached a maximum of 4.9 mg/dl. The only positive finding was a high titer of myeloperoxidase (MPO) ANCA antibody (111 UI/ml). Clozapine was discontinued, and he was started on conservative management of the nephrotic syndrome. The rash disappeared within one week. Kidney biopsy showed cellular variant focal segmental glomerulosclerosis (FSGS) with mild acute tubular injury. The patient was treated with oral prednisolone with complete remission. Repeat MPO-ANCA was negative after one month. Discussion: We present a challenging case that highlights the importance of kidney biopsy for accurate diagnosis with major impact on treatment and prognosis. This case also underlines the presentation and evolution of FSGS cellular variant, a rare and poorly understood disease. The relationship between skin rash with high MPO titer and the administration of clozapine with clinical remission after its discontinuation favors the hypothesis of drug associated ANCA-vasculitis.

Prenatal diagnosis and postnatal management of congenital mesoblastic nephroma: Experience at a single center in China.

To review the prenatal and postnatal clinical characteristics and pathological subtypes, as well as the surgical outcome for congenital mesoblastic nephroma (CMN) cases. A retrospective review was performed in 11 cases with CMN prenatally diagnosed at a single center between 2015 and 2019. The clinical characteristics, surgical outcome, histopathology, and follow-up were retrospectively obtained and reviewed. The median gestational age at which the sonographic diagnosis was made was 35 weeks. Polyhydramnios was found in four (36.4%) cases, and all resulted in a preterm birth. Nine infants had hypertension. Ten cases underwent radical nephrectomy, and one underwent radical nephrectomy and partial adrenalectomy. The pathological results showed that six tumors were classical variants, four mixed variants, and one was a cellular variant. Three cases presented as a stage I, eight as stage II, and no stage III or IV cases were diagnosed. All patients are alive so far. At a median follow-up of 14 months, no local recurrence, or remote metastases were found. The prognosis of prenatal CMN cases is excellent after early surgery.

Characterization of novel USP6 gene rearrangements in a subset of so-called cellular fibroma of tendon sheath

Fibroma of tendon sheath (FTS) is an uncommon benign fibroblastic/myofibroblastic neoplasm that typically arises in the tenosynovial tissue of the distal extremities. Histologically, it is a well-circumscribed proliferation of spindle cells within collagenous stroma with peripheral slit-like vessels. Most examples are relatively hypocellular and more densely collagenous than nodular fasciitis; however, a cellular variant has been described, which has considerable morphologic overlap with nodular fasciitis and has been shown to harbor USP6 translocations in a subset of cases. The incidence of these rearrangements and the identity of the USP6 fusion partners have not been described in detail. In this study we evaluate 13 cases of cellular fibroma of tendon sheath by anchored multiplex PCR/next generation sequencing in order to detect potential gene fusions. Nucleic acids of adequate quality were obtained in 11 cases, demonstrating gene fusions in 7/11 (64%), all of which involve USP6 with a variety of partners, including PKM, RCC1, ASPN, COL1A1, COL3A1, and MYH9. Some unusual histomorphologic findings were present in a subset of cases including palisading growth pattern, epithelioid cells, and osteoclast-like multinucleated giant cells, particularly in the tumors with PKM and ASPN gene partners. Overall, the findings support a biologic relationship between cellular fibroma of tendon sheath and other lesions within the spectrum of USP6-rearranged neoplasms, particularly nodular fasciitis.

Novel GATA6-FOXO1 fusions in a subset of epithelioid hemangioma.

The genetic hallmark of epithelioid hemangioma (EH) is the presence of recurrent gene fusions involving FOS and FOSB transcription factors, which occur in one third of the cases. Certain clinical, pathologic and genotypic correlations have been described, with FOS-related fusions being more often detected in skeletal and cellular variants of EH, while FOSB gene rearrangements are more commonly associated with atypical histologic features and penile location. These fusions are infrequently detected in the cutaneous or head and neck EH. Overall, two-thirds of EH lack these canonical fusions and remain difficult to classify, especially when associated with atypical features and/or clinical presentations. Triggered by an index case of an intravascular soft tissue EH with a novel GATA6-FOXO1 gene fusion by targeted RNA sequencing (Archer® FusionPlex® Sarcoma Panel), we have investigated 27 additional EH cases negative for FOS and FOSB gene rearrangements for this novel abnormality to determine its recurrent potential and its association with clinical and pathologic features. Four additional EH cases were found to display GATA6-FOXO1 fusions (18 %). There were 3 females and 2 males, with a mean age of 32 years old. Three lesions occurred in the head and neck (dura, nasopharyngeal, cheek), one in the back and one in the leg. Two of these lesions were cutaneous and one was intravascular in the subcutis of the leg. Microscopically, the tumors showed a variegated morphology, with alternating vasoformative and solid components, extravasated red blood cells and mild to moderate cytologic atypia. None showed brisk mitotic activity or necrosis. Tumors were negative for FOS and FOSB by immunohistochemistry. In conclusion, we report a new GATA6-FOXO1 fusion in a subset of EH, with a predilection for skin and head and neck location. The relationship of this novel molecular subset with the more common FOS/FOSB-fusion positive EH remains to be determined.

Clinicopathological and molecular characterisation of USP6-rearranged soft tissue neoplasms: the evidence of genetic relatedness indicates an expanding family with variable bone-forming capacity.

USP6 rearrangement underpins self-limiting fibroblastic/myofibroblastic neoplasms, including nodular fasciitis (NF), myositis ossificans (MO), aneurysmal bone cyst (ABC), and related variants. The aim of this study was to characterise UPS6 and fusion partners in order to delineate the clinicopathological, genetic and bone-forming features in such lesions of soft tissue (ST). Break-apart fluorescence in-situ hybridisation (FISH) validated USP6 rearrangement in 31 of 35 NF [comprising three of three fasciitis ossificans (FO) cases, seven of eight cellular variant of fibroma of tendon sheath (C-FTS), four of six MO, three of three ST-ABC, and two of two fibro-osseous pseudotumours of digits (FOPD)]. As determined with FISH and reverse transcription polymerase chain reaction, MYH9-USP6 was the commonest fusion in four C-FTS and 20 NF, including one intravascular case and two infantile (one retroperitoneal) cases. The presence of MYH9-USP6 confirmed the diagnosis of two NFs>50mm with prominent ischaemic necrosis. COL1A1-USP6 was predominant in ossifying lesions, including all FO, MO, ST-ABC and FOPD with identified partner genes, and was also present in non-ossifying head and neck NF (HN-NF) and C-FTS in two cases each. A cervical NF of a 14-month-old girl harboured the novel COL1A2-USP6. Ossifying lesions showed considerable genetic and morphological overlaps. Sharing COL1A1-USP6, FO and FOPD showed similar central or haphazard bone matrix deposition. Besides zonation of outward bone maturation, four COL1A1-USP6-positive MO had incipient to sieve-like pseudocysts reminiscent of ST-ABC. MYH9-USP6 is present in some C-FTS and most NF, including rare variants, but is unrelated to bone formation. All bone-forming USP6-rearranged lesions adopt COL1A1 as the 5' partner, indicating close genetic kinships. However, COL1A1/COL1A2 also contributes to the pathogenesis of minor subsets of non-ossifying USP6-rearranged HN-NF and C-FTS.

The role of hypoxia on Alzheimer’s disease-related APP and Tau mRNA formation

The removal of introns from mRNA precursors (pre-mRNAs) is an essential step in eukaryotic gene expression. The splicing machinery heavily contributes to biological complexity and especially to the ability of cells to adapt to altered cellular conditions. Hypoxia also plays a key role in the pathophysiology of many diseases, including Alzheimer’s disease (AD). In the presented study, we have examined the influence of cellular hypoxia on mRNA splice variant formation from Alzheimer’s disease-related Tau and APP genes in brain cells. We have shown that the hypoxic microenvironment influenced the formation of Tau mRNA splice variants, but had no effect on APP mRNA splice variant formation. Additionally, our presented results indicate that splicing factor SRSF1 but not SRSF5 alters the formation of Tau cellular mRNA splice variants in hypoxic cells. Obtained results have also shown that hypoxic brain cells possess enhanced CLK1-4 kinase mRNA levels. This study underlines that cellular hypoxia can influence disease development through changing pre-mRNA splicing.

Whale optimization and sine–cosine optimization algorithms with cellular topology for parameter identification of chaotic systems and Schottky barrier diode models

This research study aims to enhance the optimization accuracy of the two recently emerged metaheuristics of whale and sine–cosine optimizers by means of the balanced improvements in intensification and diversification phases of the algorithms provided by cellular automata (CA). Stagnation at the early phases of the iterations, which leads to entrapment in local optimum points in the search space, is one of the inherent drawbacks of the metaheuristic algorithms. As a favorable solution alternative to this problem, different types of cellular topologies are implemented into these two algorithms with a view to ameliorating their search mechanisms. Exploitation of the fertile areas in the search domain is maintained by the interaction between the topological neighbors, whereas the improved exploration is resulted from the smooth diffusion of the available population information among the structured neighbors. Numerical experiments have been carried out to assess the optimization performance of the proposed cellular-based algorithms. Optimization benchmark problems comprised of unimodal and multimodal test functions have been applied and numerical results have been compared with those found by some of the state-of-the-art literature optimizers including particle swarm optimization, differential evolution, artificial cooperative search and differential search. Cellular variants have been outperformed by the base algorithms for multimodal benchmark problems of Levy and Penalized1 functions. Then, the proposed cellular algorithms have been applied to two different parameter identification cases in order to test their efficiencies on real-world optimization problems. Extensive performance evaluations on different parameter optimization cases reveal that incorporating the CA concepts on these algorithms not only improves the optimization accuracy but also provides considerable robustness to acquired solutions.

Extraskeletal myxoid chondrosarcoma: combining cytopathology with molecular testing to achieve diagnostic accuracy

Advances in the genetics of soft tissue neoplasia have allowed for the diagnostic recognition of specific tumor types from small biopsy specimens, including those procured using the fine needle aspiration (FNA) biopsy technique. Extraskeletal myxoid chondrosarcoma (EMC) is a malignant mesenchymal neoplasm characterized by NR4A3 and, less specifically, by EWSR1 gene rearrangements. A series of EMC cytologic specimens was examined to demonstrate the diagnostic value of incorporating fluorescence in situ hybridization (FISH) testing in cytologic cases of suspected EMC. A search was made of our cytopathology and surgical pathology databases for cases diagnosed as EMC. FNA biopsy cytology, exfoliative cytology, imprint cytology, and FISH analysis were performed and examined using standard techniques. A total of 16 cases of EMC were retrieved from 15 patients (male/female ratio, 2.8:1; mean age, 62 years). Of the 15 patients, 10 were new patients with primary tumors, 2 had locally recurrent tumors, and 4 had metastases. The sites included the extremities in 10 cases, the trunk in 4, serous effusion in 1, and a mediastinal lymph node in 1 case. The specific cytologic diagnoses were EMC (14 cases; 88%), suspicious for EMC (n = 1), and malignant cells (n = 1). All cases for which FISH testing was successfully used were specifically recognized as EMC. Aspirates and imprint smears consisted of uniformly rounded cells set in an opaque myxoid/chondromyxoid stroma (less abundant and more diaphanous in the effusion sample), sometimes arranged in short anastomosing cords. FNA of 1 case of an EMC cellular variant mimicked a malignant small rounded cell tumor. EMC can be added to the growing list of soft tissue neoplasms that are specifically recognizable using cytopathology, coupled with judicious application of ancillary molecular testing.