Identification of novel homozygous nonsense SLC10A7 variant causing short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis and surgical management of spine.

BACKGROUND: Short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis is a rare, autosomal recessive, skeletal disorder first described in 2018. This syndrome starts with pre- and postnatal developmental delay, and gradually presents with variable facial dysmorphisms, a short stature, amelogenesis imperfecta, and progressive skeletal dysplasia affecting the limbs, joints, hands, feet, and spine. CASE PRESENTATION: We identified a homozygous novel nonsense mutation in exon 1 of SLC10A7 (NM_001300842.2: c.100G > T / p.Gly34*) segregating with the typical disease phenotype in a Han Chinese family. We reviewed the 12-year surgical treatment history with seven interventions on spine. CONCLUSION: To date, only 12 cases of the SLC10A7 mutation have been reported, mainly from consanguineous families. Our patient showed a relatively severe and broad clinical phenotype compared with previously reported cases. In this patient, annual check-ups and timely surgeries led to a good outcome.

Pharmacogenetic Approach for the Prevention of Rivaroxaban's ADRs: A Systematic Review and Meta-Analysis.

Introduction: Pharmacogenetics is a potential approach that can be applied to decline the burden of rivaroxaban's ADRs. The current systematic review and meta-analysis aim to identify genetic variants correlated with rivaroxaban exposure and evaluate their importance. Methods: We systematically searched PubMed, Web of Science, and Scopus databases for all observational and interventional studies. The fixed effect method was used to pool the data when the Q-test's p value was higher than 0.1. We used random models when the p value was less than 0.1. Results: Data from ten studies (4721 participants) were analyzed in the current review. Qualitative synthesis from included studies found that two variants of ABCB1 (rs1045642 and rs2032582) and one variant of APOB (rs13306198) are potential contributors to rivaroxaban concentrations. Both wild homozygotes (AA) and heterozygotes (AC) of rs1045642 have significantly lower rivaroxaban concentrations compared to mutated homozygotes (CC) (SMD = 0.516, 95% CI: 0.115 to 0.917; SMD = 0.772, 95% CI: 0.088 to 1.455, respectively). Nevertheless, pooling unadjusted odds ratios did not yield a statistically significant correlation between rivaroxaban ADRs and genetic mutations. Conclusion: This study revealed that being an AC or CC for rs1045642 is attributed to a considerably higher rivaroxaban level in participants using rivaroxaban. That is to say, rs1045642 is a remarkable predictor of rivaroxaban metabolism. We concluded that identifying rs1045642 before drug administration might decrease ADRs although further studies adjusted for potential confounders are strongly suggested.

Specific functions of single pistil S-RNases in S-gene homozygous Pyrus germplasm.

Gametophytic self-incompatibility (SI) is regulated by S-allele recognition; that is, pollen in a style with the same S-genotype will undergo programmed cell death and stop growing so that it is unable to complete double fertilization, ultimately resulting in the SI response. S-RNase is the female determinant of SI in pear (Pyrus). In the Pyrus genome, there are two different S-RNase alleles at the S-locus, which generate two different S-RNase products in the pistil. The extracted S-glycoprotein is actually a protein complex. In this study, artificial self-pollination was conducted at the bud stage to overcome SI in 'Huanghua' (S1S2) pear. Seven plants homozygous for S1-RNase and four homozygous for S2-RNase were selected from the selfed progeny of 'Huanghua' by S-gene molecular identification biotechnology. We investigated the function of single S-RNases isolated from the pistils of S-gene homozygous Pyrus germplasm. The pollen of 'Huanghua' could smoothly pass through the style of the S-gene homozygous germplasm and complete fertilization. S-RNases were extracted from flower styles of different genotypes and used to treat different types of pollen. The S-RNase from 'Huanghua' completely inhibited the growth of S1S2, S1S1, and S2S2 pollen, while the S-RNase from homozygous germplasm allowed some S1S2 pollen and different single genotypes of pollen to continue growing. These results further validate the core events of SI including cytoskeleton depolymerization and programmed cell death. By iTRAQ-based proteomic analysis of style proteins, a total of 13 S-RNase-related proteins were identified. In summary, we have created reliable S-RNase gene homozygous germplasm, which will play a crucial role in further research on SI in pear and in the development of the pear industry.

Genome-wide search reveals the uniqueness of DNA regions associated with coat color and innate immunity in Hokkaido Native Horse.

Hokkaido Native Horse (HKD) is a horse breed native to Hokkaido in Japan known for the traits such as coat color with no white spots and adaptability to the local cold climate. To examine whether those traits of HKD are conferred at the DNA level, we attempted to identify fixed DNA regions in HKD individuals, that is, the selection signatures of HKD. A comparison of genome-wide single nucleotide polymorphism genotypes in 58 HKD individuals by principal component analysis, and cluster analysis between breeds, including HKD, and within the HKD individuals indicated the genetic independence of HKD as a breed. Tajima's D analysis and runs of homozygosity analysis identified 23 selection signatures unique to HKD (P < 0.05), and following database search found 20 traits that were associated with those selection signatures; among these traits, coat color traits, face and body markings, showed the highest important value (0.50 and 0.46). Enrichment analysis of genes in the selection signatures identified six gene ontology terms (P < 0.05), and a term related to innate immunity (regulation of defense response; GO:0031347) showed the highest positive fold enrichment value (7.13). These results provide the first scientific evidence of a genetic basis for the traits of HKD.

[Status epilepticus in a pregnant patient with a previously unrecognized POLG-associated disease]. / Epilepticheskii status u beremennoi patsientki s vpervye vyyavlennym POLG-assotsiirovannym zabolevaniem.

POLG-associated diseases are rare causes of pharmacoresistant epilepsy and status epilepticus, especially in adult patients. Phenotypic and genotypic variability in these conditions causes the complexity of their diagnosis. In the study, we report a case of a 33-year-old female patient who developed recurrent convulsive status epilepticus with focal clonic onset at the week 22/23 of pregnancy. Intensive anti-seizure therapy was administered, including the use of valproic acid, as well as the treatment of somatic complications. Given the acute onset, the semiology of seizures, the presence of psychopathological symptoms, autoimmune etiology of the disease was initially suspected. A month after the withdrawal of valproic acid, the patient began to show signs of toxic hepatitis, which eventually led to death. According to the results of whole-exome sequencing obtained later, the patient was a carrier of a pathogenic homozygous variant c.2243G>C (p.W748S) in the POLG gene. The presented case highlights the importance of molecular genetic testing and the risk associated with valproic acid hepatotoxicity in patients with cryptogenic epileptic status.

Contribution of BAP1 loss and p16 (CDKN2A) deletion analysis to the definitive diagnosis of mesothelioma in effusion cytology.

OBJECTIVE: The cytological diagnosis of mesothelioma is a controversial issue, and definitive diagnosis often requires ancillary tests. The aim of this study was to investigate the contribution of BRCA1-associated protein (1) (BAP1) loss and p16 (CDKN2A) homozygous deletion (HD) on the early diagnosis of mesothelioma in effusion fluids. MATERIALS AND METHODS: Between 2019-2022, 21 pleural and peritoneal fluid samples diagnosed with atypical mesothelial proliferation in our institution were included in the study. The slides of the cases that underwent BAP1 immunohistochemistry (IHC) were retrieved from the archive and re-examined. Homozygous deletion (HD) of p16 (CDKN2A) was investigated by the fluorescence in situ hybridization (FISH) method in cell blocks of cytology samples. At least 100 atypical mesothelial cells were counted in each case, and the HD threshold value was >10%. RESULTS: The mean age of the cases was 63.47 years (34-90 years), female/male ratio was 3/1. Of the pleural mesothelioma cases, 16 were epithelioid, 2 were biphasic, and 1 were sarcomatoid. Two cases were diagnosed with peritoneal well-differentiated papillary mesothelioma (WDPM). BAP1 loss was observed in 11 (69%) of 16 cases. HD deletion of p16 (CDKN2A) was seen in 11 (58%) patients with FISH. The HD threshold value was 10-20% in 6 of the cases, 30-50% in 3 cases, and above 90% in 2 cases. While HD deletion was observed in p16 (CDKN2A) in all biphasic and sarcomatoid cases (n=3), no deletion was observed in peritoneal WDPM (n=2). Positivity was observed with at least one method in 12 (86%) of 14 pleural mesotheliomas who underwent both BAP1 IHC and p16 (CDKN2A) FISH. Due to technical reasons, the FISH signal could not be obtained in two cell blocks, so no results could be obtained. CONCLUSIONS: Asbestos exposure in areas where mesothelioma is endemic and/or the presence of proliferating mesothelial cells in cytological examination are important clues for diagnosis. In controversial cases, BAP1 IHC should be the first step in an ancillary test. Although the FISH method applied to cell blocks has cytology-specific limitations and difficulties, investigating the p16 (CDKN2A) deletion with FISH in selected cases will contribute to the diagnosis.

Familial recurrent molar pregnancy: positive for KHDC3L gene mutation.

Recurrent hydatidiform moles are defined by the occurrence of two or more molar pregnancies in the same patient. These can be sporadic or familial where familial recurrent hydatidiform mole is rare and inherited as an autosomal recessive condition. Here, we present a case of four consecutive complete molar pregnancies with similar history in the sisters, who was diagnosed with fourth complete molar pregnancy. She underwent suction and evacuation followed by weekly serum ß-hCG. On genetic analysis, she was found to be homozygous for KHDC3L gene mutation. She was advised for evaluation of her sisters and to consider In vitro fertilization (IVF) with donor ovum or adoption. Prompt suspicion and diagnosis along with counselling of the couple regarding the fertility options available to them are the main aspects of this disease to protect them from repeated physical as well as psychological trauma.

Effects of GHRH Deficiency and GHRH Antagonism on Emotional Disorders in Mice.

Growth hormone (GH)-releasing hormone (GHRH) has been suggested to play a crucial role in brain function. We aimed to further investigate the effects of a novel GHRH antagonist of the Miami (MIA) series, MIA-602, on emotional disorders and explore the relationships between the endocrine system and mood disorders. In this context, the effects induced by MIA-602 were also analyzed in comparison to vehicle-treated mice with GH deficiency due to generalized ablation of the GHRH gene (GHRH knock out (GHRHKO)). We show that the chronic subcutaneous administration of MIA-602 to wild type (+/+) mice, as well as generalized ablation of the GHRH gene, is associated with anxiolytic and antidepressant behavior. Moreover, immunohistochemical and Western blot analyses suggested an evident activation of Nrf2, HO1, and NQO1 in the prefrontal cortex of both +/+ mice treated with MIA-602 (+/+ MIA-602) and homozygous GHRHKO (-/- control) animals. Finally, we also found significantly decreased COX-2, iNOS, NFkB, and TNF-α gene expressions, as well as increased P-AKT and AKT levels in +/+ MIA-602 and -/- control animals compared to +/+ mice treated with vehicle (+/+ control). We hypothesize that the generalized ablation of the GHRH gene leads to a dysregulation of neural pathways, which is mimicked by GHRH antagonist treatment.

Distribution of Runs of Homozygosity and Their Relationship with Candidate Genes for Productivity in Kazakh Meat-Wool Sheep Breed.

Increasing the fertility of sheep remains one of the crucial issues of modern sheep breeding. The Kazakh meat-wool sheep is an excellent breed with high meat and wool productivity and well adapted to harsh conditions. Nowadays, runs of homozygosity (ROHs) are considered a suitable approach for studying the genetic characteristics of farm animals. The aims of the study were to analyze the distribution of ROHs, describe autozygosity, and detect genomic regions with high ROH islands. In this study, we genotyped a total of 281 Kazakh meat-wool sheep using the Illumina iScan® system (EquipNet, Canton, MA, USA) via Ovine SNP50 BeadChip array. As a results, a total of 15,069 ROHs were found in the three Kazakh meat-wool sheep populations. The mean number of ROH per animal across populations varied from 40.3 (POP1) to 42.2 (POP2) in the category 1+ Mb. Furthermore, the number of ROH per animal in ROH1-2 Mb were much higher than ROH2-4 Mb and ROH8-16 Mb in the three sheep populations. Most of individuals had small number of ROH>16 Mb. The highest and lowest genomic inbreeding coefficient values were observed in POP2 and POP3, respectively. The estimated FROH presented the impact that recent inbreeding has had in all sheep populations. Furthermore, a set of interesting candidate genes (BMP2, BMPR2, BMPRIB, CLOCK, KDM2B, TIAM1, TASP1, MYBPC1, MYOM1, and CACNA2D1), which are related to the productive traits, were found. Collectively, these findings will contribute to the breeding and conservation strategies of the Kazakh meat-wool sheep breed.

SNP heterozygosity, relatedness and inbreeding of whole genomes from the isolated population of the Faroe Islands.

BACKGROUND: The population of the Faroe Islands is an isolated population but very little is known about it from whole genome sequencing. The population of about 50000 people has a high incidence of rare diseases e.g., 1:300 for Primary Carnitine Deficiency. A screening programme was implemented, and eleven persons were also whole genome sequenced at x37 coverage for diagnostic purposes of those cases that were not affected by the known mutations. The purpose of our study is to utilize the high coverage data to explore the genomic variation and the ancestral history of the population. We study the SNP heterozygosity, the pairwise relatedness from kinship, the inbreeding from runs of homozygosity ROH, and we find the minor allele frequency distribution. We estimate the population ancestry and the timing of the founding event by using the whole genomes from eight consenting individuals. RESULTS: We find the number of SNPs and the heterozygosity for the eight individual samples, and for merged samples, for which we also study the relatedness. We find close relatedness between the supposedly unrelated individuals. From ROH, we interpret the high relatedness as an ancient property of the isolated population. A bottleneck event is estimated starting between years [Formula: see text] with a maximum consanguineous population in year [Formula: see text] and similarly consanguineous between years [Formula: see text]. The ancestry analysis shows the population descends from founders of [Formula: see text] European and [Formula: see text] Admixed American ancestry. A distinct clustering near the central European and British populations of the 1000 Genome Project is likely the result of the population isolation and genetic drift. The minor allele frequency distribution suggests many rare variants. CONCLUSIONS: The ancestry is mainly European while the inbreeding is higher compared to European populations and population isolates. The Faroese population has inbreeding more like ancient Europeans. We discovered a bottlenecked and consanguineous population event and estimated it starting in the 1st-4th century as compared to the oldest archaeological findings from the 4th-6th century.

Melanocytic tumors with spitzoid morphology: correlation of clinicopathologic features and FISH analysis.

BACKGROUND: A subset of melanocytic tumors with spitzoid morphology may lead to potential inaccurate diagnosis and lack of assessment of malignancy potential. In this study, we aimed to evaluate melanocytic tumors with spitzoid morphology using conventional melanoma FISH (RREB-1, CCND1, MYB and CEP6) and 9p21 FISH (CDKN2A) probes and compare the probe results with clinical and histopathological features. METHODS: This study is a multicentric retrospective study including three centers, Istanbul University-Cerrahpasa, Cerrahpasa School of Medicine, Department of Pathology, Acibadem University, School of Medicine, Department of Pathology and ETA Pathology Laboratory. The pathology reports in archives of these three centers between 2015 and 2017 have been reviewed for cases diagnosed as atypical Spitz tumor or melanoma with Spitzoid features. These cases were selected for the study. We analyzed 39 cases of atypical Spitz tumor (AST), 10 cases of melanomas with spitzoid features for clinicopathological data and chromosomal alterations, targeting RREB-1 (6p25), CCND1 (11q13), MYB (6q23), together with 9p21 (CDKN2A), using FISH methodology. RESULTS: Thirty out of total 49 cases showed chromosomal alterations by 4-probe melanoma FISH assay, 22 (56.4%) cases were ASTs, and 8 (80%) cases were melanomas. Eighteen out of 49 cases showed homozygote deletion by 9p21 FISH assay, 12 (30.8%) cases were ASTs, and 6 (60%) cases were melanomas. When histopathological data were compared with FISH results, a statistically significant correlation was found between 9p21 FISH positivity (homozygous deletion) and presence of deep mitosis (p < 0.05). In addition, epidermal consumption (p = 0.07) and increased mitotic activity (p = 0.05) were more frequent in cases with homozygous 9p21 deletion, but these differences did not reach statistical significance. When the clinical features were considered, there was a statistically significant correlation between 9p21 FISH positivity and the diameter (p < 0.05). There was no statistically significant correlation between melanoma FISH assay and any of the histopathological or clinical data. DISCUSSION: These data suggest that 9p21 FISH positivity correlated with more worrisome histopathologic and clinical features, such as deep mitosis, increased mitotic activity, epidermal consumption, and larger lesion size, so these features are precious, pointing out spitzoid lesions with higher risk. However, there is a need for further studies using FISH or similar techniques in order to provide more accurate prognostic information in lesions Blank morphology.

Genetic alterations that deregulate RB and PDGFRA signaling pathways drive tumor progression in IDH2-mutant astrocytoma.

In IDH-mutant astrocytoma, IDH2 mutation is quite rare and biological mechanisms underlying tumor progression in IDH2-mutant astrocytoma remain elusive. Here, we report a unique case of IDH2 mutant astrocytoma, CNS WHO grade 3 that developed tumor progression. We performed a comprehensive genomic and epigenomic analysis for primary and recurrent tumors and found that both tumors harbored recurrent IDH2R172K and TP53R248W mutation with CDKN2A/B hemizygous deletion. We also found amplifications of CDK4 and MDM2 with PDGFRA gain in the recurrent tumor and upregulated protein expressions of these genes. We further developed, for the first time, a xenograft mouse model of IDH2R172K and TP53R248W mutant astrocytoma from the recurrent tumor, but not from the primary tumor. Consistent with parent recurrent tumor cells, amplifications of CDK4 and MDM2 and PDGFRA gain were found, while CDKN2A/B was identified as homozygous deletion in the xenografts, qualifying for integrated diagnosis of astrocytoma, IDH2-mutant, CNS WHO grade 4. Cell viability assay found that CDK4/6 inhibitor and PDGFR inhibitor potently decreased cell viability in recurrent tumor cells, as compared to primary tumor cells. These findings suggest that gene alterations that activate retinoblastoma (RB) signaling pathways and PDGFR may drive tumor progression and xenograft formation in IDH2-mutant astrocytoma, which is equivalent to progressive IDH1-mutant astrocytoma. Also, our findings suggest that these genomic alterations may represent therapeutic targets in IDH2-mutant astrocytoma.

Associations between polymorphisms in the myostatin gene with calving difficulty and carcass merit in cattle.

A fully functional myostatin gene inhibits muscle fiber growth. The objective of the present study was to quantify the association between 21 known myostatin mutations with both calving and carcass traits in 12 cattle breeds. The myostatin genotypes of 32,770 dam-progeny combinations were used in the association analysis of calving dystocia, with the genotypes of 129,803 animals used in the mixed model association analyses of carcass weight, conformation, and fat score. The mixed model included additive genetic, maternal, and permanent environmental effects where appropriate. The mutant genotypes of nt821, Q204X, and F94L were all associated (P < 0.01) with more calving difficulty when present in either the dam or the progeny. The nt821 deletion had the greatest association with calving difficulty when the homozygous deletion was present in either the calf (0.37 points greater calving difficulty score relative to calves carrying no copies of the deletion based on a one to four scale) or the dam (1.30 points greater calving difficulty score relative to dams carrying no copies of the deletion), although the association between the calf's nt821 genotype and calving difficulty differed depending on the nt821 genotype of the dam. With the exception of nt748_78, nt414, and nt374_51, all other seven segregating myostatin variants were associated (range of allele substitution effect size relative to animals with no copies of the mutant allele) with carcass weight (2.36 kg lighter to 15.56 kg heavier), all 10 segregating variants with conformation (0.15 units less conformed to 2.24 units more conformed assessed on a scale of 1 to 15), and all segregating variants other than E226X with carcass fat (0.23 units less carcass fat cover to 3.85 units more carcass fat cover assessed on a scale of 1 to 15). Of these, the F94L, Q204X, and nt821 mutations generally had the greatest association with all three carcass traits, giving rise to heavier and more conformed carcasses. Despite the antagonistic genetic relationship between calving difficulty and carcass traits, the nt374_51, F94L, and E226X mutations were all associated with improved carcass merit while having minimal expected consequences on calving difficulty. Thus, animals carrying these mutation(s) may have favorable genetic merit for calving difficulty and carcass merit. Furthermore, depending on the dam genotype, a bull with two copies of the nt821 mutation can produce progeny with improved carcass merit while minimizing calving problems.

The objective of the present study was to quantify the association between 21 known myostatin mutations with calving difficulty, carcass fat, carcass conformation, and carcass weight in 12 prominent cattle breeds. Out of all segregating myostatin variants, the nt821 deletion had the greatest observed association with calving difficulty when the homozygous deletion was carried by either the calf or the dam. However, the association between the calf's nt821 genotype and calving difficulty varied depending on the nt821 genotype of the dam. The F94L, Q204X, and nt821 mutations generally had the greatest association with all three carcass traits, resulting in heavier and more conformed carcasses. The nt374_51, F94L, and E226X mutations were all associated with improved carcass merit while having minimal expected consequences on calving difficulty; therefore, animals carrying these mutations could potentially have desirable genetic merit for both calving difficulty and carcass merit. Similarly, depending on the genotype of the dam, a bull carrying two copies of the nt821 deletion could give rise to progeny that have improved carcass merit while minimizing the associated risk of calving difficulty.

Head and neck INI1-deficient carcinoma without primary: a case report.

BACKGROUND: SMARCB1, also known as INI1, is a member of a large protein complex involved in chromatin remodeling and thus the regulation of gene expression. It is located on chromosome 22q11.2. SMARCB1 tumors have been found in various locations, including the sinonasal region, gastrointestinal tract, central nervous system (in atypical teratoid and rhabdoid tumors), and perirenal region (in malignant rhabdoid tumors) in both adults and children. CASE PRESENTATION: We describe here the first case in the literature of an INI1-deficient neck carcinoma without a primary tumor managed with surgical therapy and neck dissection in a young Caucasian woman of 29 years old, followed by chemotherapy before radiotherapy, with regional control after 18 months of follow-up. Histologic analysis showed an undifferentiated carcinoma without glandular or epidermoid differentiation. Biomolecular analysis of the tumor revealed a homozygous deletion of the SMARCB1 gene on RNA sequencing. CONCLUSION: Research of INI1 deletion should be performed for undifferentiated carcinoma of young patients because of possibilities of molecular therapies such as autophagy inhibitors or proteasome inhibitors could be used in clinical trials.

Characterization of BRCA2 R3052Q variant in mice supports its functional impact as a low-risk variant.

Pathogenic variants in BRCA2 are known to significantly increase the lifetime risk of developing breast and ovarian cancers. Sequencing-based genetic testing has resulted in the identification of thousands of BRCA2 variants that are considered to be variants of uncertain significance (VUS) because the disease risk associated with them is unknown. One such variant is p.Arg3052Gln, which has conflicting interpretations of pathogenicity in the ClinVar variant database. Arginine at position 3052 in BRCA2 plays an important role in stabilizing its C-terminal DNA binding domain. We have generated a knock-in mouse model expressing this variant to examine its role on growth and survival in vivo. Homozygous as well as hemizygous mutant mice are viable, fertile and exhibit no overt phenotype. While we did not observe any hematopoietic defects in adults, we did observe a marked reduction in the in vitro proliferative ability of fetal liver cells that were also hypersensitive to PARP inhibitor, olaparib. In vitro studies performed on embryonic and adult fibroblasts derived from the mutant mice showed significant reduction in radiation induced RAD51 foci formation as well as increased genomic instability after mitomycin C treatment. We observed mis-localization of a fraction of R3052Q BRCA2 protein to the cytoplasm which may explain the observed in vitro phenotypes. Our findings suggest that BRCA2 R3052Q should be considered as a hypomorphic variant.

Sarcomatoid mesothelioma diagnosed in a patient with mesothelioma in situ: a case report on morphologic differences after 9-month interval with details analysis of cytology in early-stage mesothelioma.

BACKGROUND: Overlapping morphological features of mesothelial cells have been rendered it difficult to distinguish between reactive and malignant conditions. The development of methods based on detecting genomic abnormalities using immunohistochemistry and fluorescence in situ hybridization have contributed markedly to solving this problem. It is important to identify bland mesothelioma cells on cytological screening, perform efficient genomic-based testing, and diagnose mesothelioma, because the first clinical manifestation of pleural mesothelioma is pleural effusion, which is the first sample available for pathological diagnosis. However, certain diagnostic aspects remain challenging even for experts. CASE PRESENTATION: This report describes a case of a 72-year-old man with a history of asbestos exposure who presented with pleural effusion as the first symptom and was eventually diagnosed as mesothelioma. Mesothelioma was suspected owing to prominent cell-in-cell engulfment in mesothelial cells on the first cytological sample, and the diagnosis of mesothelioma in situ was confirmed by histology. Unexpectedly, sarcomatoid morphology of mesothelioma was found in the second pathology samples 9 months after the first pathological examination. Both the mesothelioma in situ and invasive lesion showed immunohistochemical loss of methylthioadenosine phosphorylase (MTAP) and homozygous deletion of cyclin dependent kinase inhibitor 2A (CDKN2A) on fluorescence in situ hybridization. The patient received medication therapy but died of disease progression 12 months after the diagnosis of the sarcomatoid morphology of mesothelioma. CONCLUSION: Our case suggests that cell-in-cell engulfment can be conspicuous in early-stage mesothelioma with inconspicuous nuclear atypia and few multinucleated cells. In addition, the presence of MTAP loss and CDKN2A homozygous deletion are suspected to be involved in early formation to invasive lesions and/or sarcomatoid morphology. We believe that it is important to consider genetic abnormalities when deciding on individual patient management. Furthermore, cases of mesothelioma, even those of an in situ lesion, with MTAP loss and/or CDKN2A deletion should be carefully followed up or subjected to early treatment.

The role of inbreeding depression on productive performance in the Italian Holstein breed.

Inbreeding depression has become an urgent issue in cosmopolitan breeds where the massive genetic progress achieved in the latest generations is counterbalanced by a dramatic loss of genetic diversity causing increased health issues. Thus, the aim of this study was to estimate inbreeding depression on productive traits in Holstein dairy cattle. More precisely, we aimed to i) determine the level of inbreeding in 27,735 Italian Holstein dairy cows using pedigree and genotype data, ii) quantify the effect of inbreeding on 305-d in milk yield (MY; kg), fat yield (FY; kg), and protein yield (PY; kg) based on different statistical approaches, iii) determine if recent inbreeding has a more harmful impact than ancestral ones, and iv) quantify chromosomal homozygosity effect on productive traits. Quality control was performed on the autosomal chromosomes resulting in a final dataset of 84,443 single nucleotide polymorphisms. Four statistical models were used to evaluate the presence of inbreeding depression, which included linear regression analysis and division of FPED and FROH into percentile classes. Moreover, FROH was partitioned into i) length classes to assess the role of recent and ancestral inbreeding and ii) chromosome-specific contributions (FROH-CHR). Results evidenced that inbreeding negatively impacted the productive performance of Italian Holstein Friesian cows. However, differences between the estimated FPED and FROH coefficients resulted in different estimates of inbreeding depression. For instance, a 1% increase in FPED and FROH was associated with a decrease in MY of about 44 and 61 kg (P < 0.01). Further, when considering the extreme inbreeding percentile classes moving from the 5th lowest to the 95th highest, there was a reduction of -263 kg and -561 kg per lactation for FPED and FROH. Increased inbreeding, estimated by FPED and FROH, had also a negative effect on PY and FY, either fit as a regressor or percentile classes. When evaluating the impact of inbreeding based on runs of homozygosity (ROH) length classes, longer ROH (over 8 Mb) had a negative effect in all traits, indicating that recent inbreeding might be more harmful than the ancestral one. Finally, results within chromosome homozygosity highlighted specific chromosomes with a more deleterious effect on productive traits.

Inbreeding depression is a reduction in performance or health due to the mating of closely related individuals. The overall aim of this study was to investigate the level of inbreeding in the Italian Holstein dairy cow breed and quantify its negative effect on productive performances. The level of inbreeding was estimated by pedigree (FPED) and genomic data by looking at stretches of homozygosity (FROH). Both methods revealed a reduction in milk yield, fat yield, and protein yield when inbreeding increased. Moreover, the study demonstrated that FROH was able to capture more inbreeding depression compared to FPED. In addition, the more recent inbreeding had a stronger negative impact on productive performances compared to ancestral ones. Then, since the amount of runs of homozygosity can vary across the chromosomes of an individual, the effect of each chromosomal homozygosity region on productive traits was also evaluated. The chromosome-level results might be included in breeding programs to limit the accumulation of homozygosity in particular regions that appear to have a more detrimental effect on productive traits. Overall, this study highlights the importance of avoiding inbreeding in animal breeding programs to keep productive animals in the long term.

Circadian disruption does not alter tumorigenesis in a mouse model of lymphoma.

Background: Disruption of natural light cycles, as experienced by shift workers, is linked to enhanced cancer incidence. Several mouse models of cancer develop more severe disease when exposed to irregular light/dark cycles, supporting the connection between circadian disruption and increased cancer risk. Cryptochrome 2 (CRY2), a repressive component of the molecular circadian clock, facilitates turnover of the oncoprotein c-MYC, one mechanism that may link the molecular clock to tumorigenesis. In Eµ-MYC mice, which express transgenic c-MYC in B cells and develop aggressive lymphomas and leukemia, global Cry2 deletion reduces survival and enhances tumor formation. Lighting conditions that mimic the disruption experienced by shift workers dampen Cry2 transcripts in peripheral tissues of C57BL/6J mice. Although it is milder than homozygous deletion of Cry2, we hypothesized that reduced Cry2 rhythmicity could alter MYC protein accumulation and contribute to enhanced cancer risk caused by circadian disruption. We tested this hypothesis in MYC-driven lymphoma. Methods: We housed Eµ-MYC mice in light-tight boxes set to either control (continuous cycles of 12-hours of light followed by 12-hours of dark, LD12:12) or chronic jetlag (eight-hour light phase advances every two to three days, CJL) lighting conditions and assessed the impact of disrupted light cycles on survival and tumor formation in Eµ-MYC mice. Results: Environmental disruption of circadian rhythms did not alter tumor location, tumor growth, or survival in Eµ-MYC mice. Conclusions: Dampened rhythms of Cry2 following disruption of circadian light exposures is milder than deletion of Cry2. The lack of phenotype caused by altered circadian gene expression in contrast to enhanced tumorigenesis caused by homozygous deletion of Cry2 suggests that CRY2 dosage impacts this model. Importantly, these findings indicate that increased cancer risk associated with circadian disruption arises from one or more mechanisms that are not recapitulated here, and may be different in distinct tumor types.