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Leptomeningeal metastasis remains a difficult clinical challenge. Some success has been achieved by direct administration of therapeutics into the cerebrospinal fluid (CSF) circumventing limitations imposed by the blood brain barrier. Here we investigated continuous infusion versus bolus injection of therapy into the CSF in a preclinical model of human Group 3 medulloblastoma, the molecular subgroup with the highest incidence of leptomeningeal disease. Initial tests of selected Group 3 human medulloblastoma cell lines in culture showed that D283 Med and D425 Med were resistant to cytosine arabinoside and methotrexate. D283 Med cells were also resistant to topotecan, whereas 1 μM topotecan killed over 99% of D425 Med cells. We therefore introduced D425 Med cells, modified to express firefly luciferase, into the CSF of immunodeficient mice. Mice were then treated with topotecan or saline in five groups: continuous intraventricular (IVT) topotecan via osmotic pump (5.28 μg/day), daily bolus IVT topotecan injections with a similar daily dose (6 μg/day), systemic intraperitoneal injections of a higher daily dose of topotecan (15 μg/day), daily IVT pumped saline and daily intraperitoneal injections of saline. Bioluminescence analyses revealed that both IVT topotecan treatments effectively slowed leptomeningeal tumor growth in the brains. Histological analysis showed that they were associated with localized brain necrosis, possibly due to backtracking of topotecan around the catheter. In the spines, bolus IVT topotecan showed a trend towards slower tumor growth compared to continuous (pump) IVT topotecan, as measured by bioluminescence. Both continuous and bolus topotecan IVT showed longer survival compared to other groups. Thus, both direct IVT topotecan CSF delivery methods produced better anti-medulloblastoma effect compared to systemic therapy at the dosages used here.

Medulloblastomas are the most common malignant pediatric brain tumor and have been divided into four major molecular subgroups. Animal models that mimic the principal molecular aberrations of these subgroups will be important tools for preclinical studies and allow greater understanding of medulloblastoma biology. We report a new transgenic model of medulloblastoma that possesses a unique combination of desirable characteristics including, among others, the ability to incorporate multiple and variable genes of choice and to produce bioluminescent tumors from a limited number of somatic cells within a normal cellular environment. This model, termed BarTeL, utilizes a Barhl1 homeobox gene promoter to target expression of a bicistronic transgene encoding both the avian retroviral receptor TVA and an eGFP-Luciferase fusion protein to neonatal cerebellar granule neuron precursor (cGNP) cells, which are cells of origin for the sonic hedgehog (SHH) subgroup of human medulloblastomas. The Barhl1 promoter-driven transgene is expressed strongly in mammalian cGNPs and weakly or not at all in mature granule neurons. We efficiently induced bioluminescent medulloblastomas expressing eGFP-luciferase in BarTeL mice by infection of a limited number of somatic cGNPs with avian retroviral vectors encoding the active N-terminal fragment of SHH and a stabilized MYCN mutant. Detection and quantification of the increasing bioluminescence of growing tumors in young BarTeL mice was facilitated by the declining bioluminescence of their uninfected maturing cGNPs. Inclusion of eGFP in the transgene allowed enriched sorting of cGNPs from neonatal cerebella. Use of a single bicistronic avian vector simultaneously expressing both Shh and Mycn oncogenes increased the medulloblastoma incidence and aggressiveness compared to mixed virus infections. Bioluminescent tumors could also be produced by ex vivo transduction of neonatal BarTeL cerebellar cells by avian retroviruses and subsequent implantation into nontransgenic cerebella. Thus, BarTeL mice provide a versatile model with opportunities for use in medulloblastoma biology and therapeutics.

Catamenial hemothorax is a rare manifestation of thoracic endometriosis, characterized by blood in the pleural cavity associated with menstrual cycles. We present the case of a 42-year-old woman with recurrent right-sided chest pain and dyspnea coinciding with menstruation. Imaging revealed a large pleural effusion and hemothorax. Diagnostic video-assisted thoracoscopic surgery (VATS) confirmed thoracic endometriosis. The patient received a combination of hormonal therapy and VATS. Follow-ups over 36 months showed significant symptom improvement and resolution of pleural effusion. This case emphasizes the need to consider thoracic endometriosis in women with menstrual-related hemothorax., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Daher et al.)

Solitary fibrous tumors (SFTs) are rare neoplasms that can occur in various locations, including the central nervous system (CNS). We present a case report of a 47-year-old male patient with an intracranial SFT who underwent subtotal resection followed by adjuvant radiotherapy. The patient initially presented with chronic left temporal headache and was diagnosed with an intra-axial double-component mass in the left temporoparietal lobe. Histopathological examination confirmed the diagnosis of SFT, and immunohistochemical staining demonstrated positivity for CD34, Bcl-2, and STAT6. Following the incomplete resection, the patient received adjuvant radiotherapy using volumetric modulated arc therapy (VMAT) technique. During radiotherapy, the patient experienced a spontaneous encephalocele rupture but recovered without complications. One year postradiotherapy, the patient showed no recurrence of symptoms or radiological evidence of tumor recurrence. This case highlights the challenges in the diagnosis and management of CNS SFTs and suggests that subtotal resection followed by adjuvant radiotherapy may be an effective treatment approach in achieving favorable outcomes for these rare neoplasms., (© 2024 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

Multiple primary malignancies (MPMs) present diagnostic and therapeutic challenges, especially given their rarity and the distinct treatment strategies required. We report a case of a 66-year-old postmenopausal woman who presented with synchronous triple-negative breast cancer (TNBC) and cervical cancer, an uncommon and complex clinical scenario. Given the complexity of her condition, a comprehensive multidisciplinary approach was employed. The treatment strategy included neoadjuvant chemotherapy for breast cancer, followed by breast-conserving surgery and axillary lymph node dissection. Simultaneously, cervical cancer was addressed with concurrent chemoradiotherapy and brachytherapy. Remarkably, the patient demonstrated complete pathological responses in both the breast and cervical tumors following treatment. At 26 months of follow-up, she remains free of disease recurrence. This case highlights the challenges of managing synchronous TNBC and cervical cancer. It underscores the necessity for individualized treatment plans and seamless multidisciplinary collaboration to achieve optimal patient outcomes., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Kouhen et al.)

Duodenal metastases from pulmonary adenocarcinoma are rare. Early detection, diagnosis, and treatment are crucial for improving the prognosis of patients with duodenal metastases from primary lung cancer, which often go unnoticed due to their low incidence and diagnostic challenges. Here, we present the case of a 64-year-old man with an unusual occurrence of duodenal metastases from pulmonary adenocarcinoma, admitted with symptoms of cholangitis. Radiological findings revealed a mass in the D2-D3 segments of the duodenum. Endoscopic ultrasound with biopsy was performed, and immunohistochemical analysis confirmed that the mass was a duodenal metastasis of pulmonary adenocarcinoma., (© 2024 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

Primary hepatic leiomyosarcoma (PHL) is a rare malignant tumor, which originates from smooth muscles. The imaging features are nonspecific and the diagnosis is often delayed until the tumor reaches a large size, which leads often to a dismal prognosis. We report a case of a 46-year-old male patient who was complaining about abdominal pain for 2 months. The imaging revealed the presence of a large mass in the liver with adrenal and liver metastasis. Diagnosis of PHL was confirmed by histopathological and immunohistochemical examinations. In this case report, we review the epidemiological, clinical, and paraclinical aspects of the disease, as well as the treatment modalities., (© 2024 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

The STRAT-PARK initiative aims to provide a platform for stratifying Parkinson's disease (PD) into biological subtypes, using a bottom-up, multidisciplinary biomarker-based and data-driven approach. PD is a heterogeneous entity, exhibiting high interindividual clinicopathological variability. This diversity suggests that PD may encompass multiple distinct biological entities, each driven by different molecular mechanisms. Molecular stratification and identification of disease subtypes is therefore a key priority for understanding and treating PD. STRAT-PARK is a multi-center longitudinal cohort aiming to recruit a total of 2000 individuals with PD and neurologically healthy controls from Norway and Canada, for the purpose of identifying molecular disease subtypes. Clinical assessment is performed annually, whereas biosampling, imaging, and digital and neurophysiological phenotyping occur every second year. The unique feature of STRAT-PARK is the diversity of collected biological material, including muscle biopsies and platelets, tissues particularly useful for mitochondrial biomarker research. Recruitment rate is ∼150 participants per year. By March 2023, 252 participants were included, comprising 204 cases and 48 controls. STRAT-PARK is a powerful stratification initiative anticipated to become a global research resource, contributing to personalized care in PD., Competing Interests: Declaration of Competing Interest none, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Advances in molecular biology have improved understanding of the molecular features of carcinogenesis and progression of colorectal cancer. It is clear that the efficacy of anti-EGFR depends upon the RAS mutational status, since any mutation in RAS is associated with resistance to anti-EGFR therapy. The aim of this study is to report the largest North African description of KRAS and NRAS status in metastatic colorectal cancer and to describe the association of these mutations with clinicopathological characteristics., Methods: This is a prospective study of all consecutive unselected metastatic colorectal cancer samples, collected from the Laboratory of Pathology at the National Institute of Oncology of Rabat, Morocco, from January 1st 2020 to December 31st 2021. The molecular analysis was performed on the Idylla™ platform (fully automated real-time polymerase chain reaction-based assay) for KRAS and NRAS mutations in exons 2, 3 and 4. These mutations were correlated to gender, primary tumor site, histological type and degree of differentiation of tumor using adequate statistical methods., Results: Four hundred fourteen colorectal tumors were screened for KRAS and NRAS mutations. These mutations occurred in 51.7% of tumors for KRAS (mainly in exon 12) and in 3% of tumors for NRAS. There was a significant correlation between NRAS mutation and age of colorectal patients in this study. The low rate of invalid RAS tests (1.7% for KRAS and 3.1% for NRAS) was certainly obtained due to the strict respect of pre-analytical factors such as cold ischemia time and formalin fixation., Conclusion: We report the largest North African analysis of NRAS and KRAS status in colorectal metastatic patients. This study showed the ability in low middle income countries to perform a high rate of valid tests and the unusual trend towards older patients for NRAS mutations., (© 2023. The Author(s).)

Background: Botulinum toxin type A (BoNT-A) therapy for upper-limb tremor has emerged as a promising option. However, it is unclear in real-world practices whether a technology-guided approach can compare with expert clinical assessments (including surface anatomy and palpation) for improving outcomes. This retrospective study aims to review our clinical outcomes of treating essential tremor (ET) and Parkinson's disease (PD) tremor using either clinical- or kinematic-based injection pattern determination methods., Methods: 68 ET and 45 PD patients received at least one injection for their upper-limb tremor (unilateral or bilateral) in the last 7 years. Demographics of patients and BoNT-A injections were collected. A Mann-Whitney U statistical test was used to compare outcome measures between ET and PD cohorts., Results: Mean age (72 ± 9 years), number of injections (5), years receiving therapy (~2 years), clinic- (~57%) or kinematic-based patterns, and self-paying (52%) were similar between both cohorts. BoNT-A as a monotherapy in both upper limbs was received in more ET than PD patients. Double reconstitution of Xeomin ® in the wrist flexors/extensors, supinator, biceps, and triceps were most injected. Discontinuation due to no benefit/weakness was not dependent on the injection pattern determination approach., Conclusions: Kinematic-based BoNT-A injections produced similar treatment outcomes to injections based on the clinical expertise of the expert injector. This suggests that kinematics could be used by a non-expert to attain equivalent efficacy potentially improving access to this treatment.

Background: The World Health Organization (WHO) declared COVID-19 as a pandemic on 11 March 2020. Many efforts were performed to contain the virus worldwide. People's knowledge and attitude should be directed toward strict preventive practices to halt the spread of the virus. We aimed to assess the knowledge, attitude, practices, and sources of information (KAPS) used by Qatar University (QU) attendees., Methods: A cross-sectional web-based questionnaire was answered by 500 employees and students in the QU community. It included questions on KAPS toward COVID-19. Information on sociodemographics was collected and analyzed. This study was conducted during the second wave of COVID-18 in the state of Qatar (April-May 2021)., Results: A total of 475 participants aged between 18 and 68 years old consented to complete the survey questionnaire. The study involved 279 (58.7%) non-Qatari nationals and 196 (41.3%) natives, with 254 (53.5%) participants pursuing postgraduate studies and 221 (46.5%) undergraduates. Approximately two-thirds of the sample were employed (64.8%), while one-third were unemployed (35.2%). Knowledge scores on average were 66.4% ( M = 5.31, SD = 1.45, and range: 0-8), with only significant differences were noted between nationalities (natives and non-natives) Participants' average score in practices was 69.72% ( M = 4.18, SD = 1.7, and range 0-6) with a significant difference in safe COVID-19 practice scores based on the educational level. Adherence with COVID-19 policies and rules were 82% ( M = 2.46, SD = 0.7, and range: 0-3) with no differences noted between groups. In addition, the population reported relying on governmental press conferences (76.0%) as their primary source of gaining details concerning COVID-19, followed by social media (64.4%). The least popular resources were information gained from family, relatives, friends, and coworkers (47.4%) and the news channels on TV (46.7%)., Conclusion: Overall, this study provides insights into Qatar's KAPS toward COVID-19 during the quarantine of the second wave of this pandemic. This study, being the first of its kind to be conducted in the state of Qatar, is expected to help the ministry of public health and the government communication office to establish a suitable measurement of response to the spread of COVID-19 and develop the best practices for any future epidemics that might occur., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Alkaabi, Abita, Mahdi, Ouda and Malki.)

The in-line control of pharmaceutical processes has become a necessary tool for the evaluation and follow-up of pharmaceutical dosage forms. In this study, a novel approach to the evaluation of conditions established in a conical fluid bed granulator during the in-situ and spray-on fluid bed melt granulation (FBMG) techniques was developed. The determination of temperature mappings allowed the characterization of the critical zones during the melt granulation and the prediction of the volume of the wetting zone, hence enabling the identification of the areas of optimal granule growth. Two grades of polyethylene glycol (PEG 2000 and 6000) were used as meltable binders in three binder spraying rates and droplet size fractions for spray-on and three binder particle sizes and contents for in-situ. The results showed the presence of intense heat exchange in the bottom of the bed during the in-situ technique and under the spraying nozzle during the spray-on technique, identified as the wetting zone. Isotherm maps enabled the identification of the transition between the wetting, cooling and consolidation zones for the spray-on and the cooling zone for the in-situ technique. The shape and volume of the wetting zone was highly dependent on binder spraying rate and spraying pressure for spray-on and binder particle size and content for in-situ FBMG. Granule size and size distribution were correlated to the volume of the wetting zone and an optimized wetting volume interval was determined for both spray-on and in-situ techniques for the optimal quality attributes of the granules., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Angiosarcoma of the breast is a rare tumor, which may be primary or secondary to breast surgery or irradiation. It is characterized by polymorphic and nonspecific clinical and radiological features. A pathologist plays a key role in positive and differential diagnosis and in establishing the prognosis: only a histological examination can confirm the diagnosis, and the histologic grade is the most important prognostic factor. In fact, angiosarcomas of the breast constitute a very heterogeneous group and they are classified into three grades based on the degree of differentiation. We will illustrate diagnostic challenges through this new case of primary angiosarcoma of the breast. Microscopic findings were initially interpreted as a benign vascular tumor. We will also discuss the relevant medical literature., Case Presentation: A 56-year-old Arabian woman presented with a palpable right breast mass that had been enlarging for 2 months, measuring 5 cm, without axillary lymphadenopathy. She had no personal or family history of breast surgery or breast irradiation. A mammography showed no evidence of spiculation. No suspicious calcifications were seen. A needle core biopsy was performed. Microscopic findings were initially interpreted as a benign vascular tumor. However, as the mass measured 5 cm, the diagnosis of angiosarcoma was more appropriate, and mastectomy without axillary dissection was performed. Microscopic examination found mild to moderately scattered pleomorphic cells, and scattered mitotic figures. It also showed papillary formations, solid foci of spindle cells, and hemorrhagic necrosis. The margins of the tumor were infiltrative. The diagnosis of primary intermediately differentiated angiosarcoma of the breast (grade II) was made. No distant metastases were found. Our patient was lost to follow-up and further treatment after mastectomy until she developed local tumor progression 4 months later., Conclusions: Through this case report, we emphasize the importance of clinicopathological confrontation in angiosarcoma of the breast.

In this study, a novel in-line measurement technique of the air temperature distribution during a granulation process using a conical fluidized bed was designed and built for the purpose of measuring the temperature under the Process Analytical Technology (PAT) and introduced to predict the establishment of temperature profiles. Three sets of thermocouples were used, placed at different positions covering the whole operating range, connected to data acquisition measurement hardware, allowing an in-line acquisition and recording of temperatures every second. The measurements throughout the fluidized bed were performed in a steady state by spraying a solution of PVP onto a lactose monohydrate powder bed in order to make predictions of the temperature distribution and the hydrodynamics of the bed during the granulation process using Artificial Neural Networks (ANNs) and to establish the different temperature profiles for different process conditions through the precise predicted information by the constructed, trained, validated and tested neural network. The model's testing results showed a strong prediction capacity of the effects of process variables. Indeed, the predicted temperature values obtained with the ANN model were in good agreement with the values measured with in-line reference method and hence the method can have an application as a predictive control tool., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Endometrial cancer in patients with uterine congenital malformations is exceptional and there are only a few rare cases published in the literature. We report the case of a 67 years-old patient with an endometrial cancer located in the right cavity of a complete septate uterus.

Selenocysteine tRNA 1 associated protein (Trnau1ap) has been characterized as a tRNA[Ser]Sec-binding protein of 43 kDa, hence initially named SECp43. Previous studies reported its presence in complexes containing tRNA[Ser]Sec implying a role of SECp43 as a co-factor in selenoprotein expression. We generated two conditionally mutant mouse models targeting exons 3+4 and exons 7+8 eliminating parts of the first RNA recognition motif or of the tyrosine-rich domain, respectively. Constitutive inactivation of exons 3+4 of SECp43 apparently did not affect the mice or selenoprotein expression in several organs. Constitutive deletion of exons 7+8 was embryonic lethal. We therefore generated hepatocyte-specific Secp43 knockout mice and characterized selenoprotein expression in livers of mutant mice. We found no significant changes in the levels of 75Se-labelled hepatic proteins, selenoprotein levels as determined by Western blot analysis, enzymatic activity or selenoprotein mRNA abundance. The methylation pattern of tRNA[Ser]Sec remained unchanged. Truncated Secp43 Δ7,8mRNA increased in Secp43-mutant livers suggesting auto-regulation of Secp43 mRNA abundance. We found no signs of liver damage in Secp433-mutant mice, but neuron-specific deletion of exons 7+8 impaired motor performance, while not affecting cerebral selenoprotein expression or cerebellar development. These findings suggest that the targeted domains in the SECp43 protein are not essential for selenoprotein biosynthesis in hepatocytes and neurons. Whether the remaining second RNA recognition motif plays a role in selenoprotein biosynthesis and which other cellular process depends on SECp43 remains to be determined.

Atypical teratoid/rhabdoid tumors are rare and highly malignant central nervous system tumors. They have no specific radiological features and often present several histological components that make a problem in differential diagnosis with medulloblastoma and primitive neuroectodermal tumors. We present the case of a newborn girl complained of a gradual proptosis of the left eye secondary to an expansive lesional process of the optic nerve. The location at the optic nerve, reported only twice in the literature, and an exclusive rhabdoid appearance on biopsy added additional differential diagnosis problems. The proptosis worsened and the infant died few days after two cycles of chemotherapy., Virtual Slides: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2037718783145212 .

Introduction: The World Health Organization defines epithelioid angiomyolipoma as a potentially malignant mesenchymal neoplasm characterized by proliferation of predominantly epithelioid cells and as closely related to the triphasic (classic) angiomyolipoma. It can be benign, potentially aggressive or malignant. The pathologist's role is crucial in making a positive diagnosis, providing appropriate patient management and assessing prognosis. In this report, we present a case of a patient with an epithelioid angiomyolipoma and hydatid cyst association. To the best of our knowledge, such an association has not been reported previously in the literature., Case Presentation: A 70-year-old Arabian woman presented to our hospital with a 6-month history of a right lumbago and weight loss. Computed tomography objectified a mid-right renal tumor, several locoregional lymph nodes and four abdominopelvic cystic formations. The patient underwent a right nephroureterectomy and removal of abdominal and pelvic masses. Histologically, the tumor corresponded to a proliferation of large eosinophil cells, polygonal or ovoid, with epithelial appearance, and associated with thickened, hyalinized vessel walls, fat cells and bundles of smooth muscle cells. Mitoses were estimated at 2 per 50 high-power fields. In immunohistochemical study, epithelioid tumor cells expressed S-100 protein and Melan-A. The diagnosis of malignant epithelioid angiomyolipoma was made. The wall of the abdominopelvic cysts was eosinophilic and lamellar, corresponding to the cuticular membrane of hydatid cysts., Conclusion: In our patient, careful histological examination and immunohistochemical study allowed us to make the correct diagnosis of angiomyolipoma in its malignant form. The association with hydatid cysts is what makes our case original.

Verrucous carcinoma (VC) is an unusual, well differentiated, and low-grade type of squamous cell carcinoma, characterized by benign histology and cytology but markedly invasive clinical behavior. They have a predilection for squamous mucosae, particularly those of the head and neck region. Many factors have been associated with its pathogenesis, including the presence of previous skin lesions; VC arising from a prosthesis injury is rare. Here we reported a case of VC of oral cavity a particularly very aggressive, arising from prosthesis injury. Regardless of the treatment modality, given new insights into the possible aggressivity of this tumor, radiotherapy associated to chemotherapy may be a more appropriate primary treatment compared with the significant local morbidity associated with surgery.

Introduction: Soft tissue myoepithelial carcinoma and myoepithelioma are rare entities, part of myoepithelial tumors. They were incorporated into the World Health Organization classification of soft tissue tumors in 2002. Here we present an exceptional case of myoepithelial carcinoma and myoepithelioma association. To the best of our knowledge, such an association has never been reported in the literature., Case Presentation: We report a case of myoepithelial carcinoma combined with myoepithelioma occurring in the soft tissue of the right forearm of an 84-year-old Arabian man. We describe the clinical, radiological and pathological features dominated by histological polymorphism. We will also describe the proposed histological criteria of malignancy and the major role of immunohistochemistry in positive and differential diagnosis. We finally mention the therapeutic arsenal available., Conclusion: Through this work, we report that myoepithelioma of soft tissue can progress to malignant myoepithelioma.

Aims: The selenocysteine insertion sequence (SECIS)-binding protein 2 (Secisbp2) binds to SECIS elements located in the 3'-untranslated region of eukaryotic selenoprotein mRNAs. Selenoproteins contain the rare amino acid selenocysteine (Sec). Mutations in SECISBP2 in humans lead to reduced selenoprotein expression thereby affecting thyroid hormone-dependent growth and differentiation processes. The most severe cases also display myopathy, hearing impairment, male infertility, increased photosensitivity, mental retardation, and ataxia. Mouse models are needed to understand selenoprotein-dependent processes underlying the patients' pleiotropic phenotypes., Results: Unlike tRNA[Ser]Sec-deficient embryos, homozygous Secisbp2-deleted embryos implant, but fail before gastrulation. Heterozygous inactivation of Secisbp2 reduced the amount of selenoprotein expressed, but did not affect the thyroid hormone axis or growth. Conditional deletion of Secisbp2 in hepatocytes significantly decreased selenoprotein expression. Unexpectedly, the loss of Secisbp2 reduced the abundance of many, but not all, selenoprotein mRNAs. Transcript-specific and gender-selective effects on selenoprotein mRNA abundance were greater in Secisbp2-deficient hepatocytes than in tRNA[Ser]Sec-deficient cells. Despite the massive reduction of Dio1 and Sepp1 mRNAs, significantly more corresponding protein was detected in primary hepatocytes lacking Secisbp2 than in cells lacking tRNA[Ser]Sec. Regarding selenoprotein expression, compensatory nuclear factor, erythroid-derived, like 2 (Nrf2)-dependent gene expression, or embryonic development, phenotypes were always milder in Secisbp2-deficient than in tRNA[Ser]Sec-deficient mice., Innovation: We report the first Secisbp2 mutant mouse models. The conditional mutants provide a model for analyzing Secisbp2 function in organs not accessible in patients., Conclusion: In hepatocyte-specific conditional mouse models, Secisbp2 gene inactivation is less detrimental than tRNA[Ser]Sec inactivation. A role of Secisbp2 in stabilizing selenoprotein mRNAs in vivo was uncovered.

Secisbp2 [SECIS (selenocysteine insertion sequence)-binding protein 2] binds to SECIS elements located in the 3'-UTR region of eukaryotic selenoprotein mRNAs. It facilitates the incorporation of the rare amino acid selenocysteine in response to UGA codons. Inactivation of Secisbp2 in hepatocytes greatly reduced selenoprotein levels. Neuron-specific inactivation of Secisbp2 (CamK-Cre; Secisbp2fl/fl) reduced cerebral expression of selenoproteins to a lesser extent than inactivation of tRNA[Ser]Sec. This allowed us to study the development of cortical PV (parvalbumin)+ interneurons, which are completely lost in tRNA[Ser]Sec mutants. PV+ interneuron density was reduced in the somatosensory cortex, hippocampus and striatum. In situ hybridization for Gad67 (glutamic acid decarboxylase 67) confirmed the reduction of GABAergic (where GABA is γ-aminobutyric acid) interneurons. Because of the obvious movement phenotype involving a broad dystonic gait, we suspected basal ganglia dysfunction. Tyrosine hydroxylase expression was normal in substantia nigra neurons and their striatal terminals. However the densities of striatal PV+ and Gad67+ neurons were decreased by 65% and 49% respectively. Likewise, the density of striatal cholinergic neurons was reduced by 68%. Our observations demonstrate that several classes of striatal interneurons depend on selenoprotein expression. These findings may offer an explanation for the movement phenotype of selenoprotein P-deficient mice and the movement disorder and mental retardation described in a patient carrying SECISBP2 mutations.

Selenoproteins are defined as proteins containing the 21st proteinogenic amino acid, selenocysteine (Sec). Sec is encoded by UGA (STOP) codons which are re-coded to Sec by the presence of a selenocysteine insertion sequence (SECIS) element in the 3'-untranslated region of selenoprotein mRNAs. The SECIS element is bound by several proteins, including SECIS-binding protein 2 (SBP2). Translation of selenoproteins critically depends on the integrity of the SECIS element - SBP2 interaction. Mutations in a SECIS element can abrogate expression of the respective selenoprotein. Mutations in SBP2 impinge on biosynthesis of a subset of selenoproteins and lead to a syndrome including hormonal, neurological, immunological symptoms as well as myopathy. Several other RNA-binding proteins are involved in selenoprotein translation and mediate the hierarchical response of selenoproteins to selenium deficiency. Global inhibition of selenoprotein translation is lethal in the mouse and hypomorphic mutations in selenocysteine synthase in humans leads to Progressive Cerebello Cerebral Atrophy, a neurodevelopmental and neurodegenerative disease in pediatric patients.