Routine Karyotyping Reveals Frequent Mosaic Reciprocal Chromosome Translocations in Swine: Prevalence, Pedigree, and Litter Size.

In the routine commercial karyotype analysis on 5,481 boars, we identified 32 carriers of mosaic reciprocal translocations, half of which were carrying a specific recurrent translocation, mos t(7;9). An additional 7 mosaic translocations were identified through lymphocyte karyotype analysis from parents and relatives of mosaic carriers (n = 45), a control group of non-carrier boars (n = 73), and a mitogen assessment study (n = 20), bringing the total number of mosaic carriers to 39 cases. Mosaic translocations in all carriers were recognized to be confined to hematopoietic cells as no translocations were identified in fibroblasts cells of the carriers. In addition, negative impact on reproduction was not observed as the fertility of the carriers and their relatives were comparable to breed averages, and cryptic mosaicism was not detected in the family tree. This paper presents the first study of mosaic reciprocal translocations identified in swine through routine screening practices on reproductively unproven breeding boars while presenting evidence that these type of chromosome abnormalities are not associated with any affected phenotype on the carrier animals. In addition, the detection of recurrent mosaic translocations in this study may emphasize the non-random nature of mosaic rearrangements in swine and the potential role of genomic elements in their formation.

Potential application of lutetium-177-labeled prostate-specific membrane antigen-617 radioligand therapy for metastatic castration-resistant prostate cancer in a limited resource environment: Initial clinical experience after 2 years.

In recent years, lutetium-177 (177Lu)-labeled prostate-specific membrane antigen (PSMA)-617 has become a promising new therapeutic agent in patients with metastatic castration-resistant prostate cancer (mCRPC). In this study, we report on an early experience of 177Lu-PSMA therapy with an evaluation of its efficacy and safety in mCRPC patients. Twenty-one mCRPC patients with a mean age of 70.3 ± 9.6 (54-88)-year-old were treated with one to four therapy cycles (median two cycles) and administered activity of 3.7-29.6 GBq (mean of 15.4 GBq). A prostate-specific antigen (PSA) decline ≥ 50% was considered to be a biochemical response (BCR). To evaluate the clinical response, the Eastern Cooperative Oncology Group (ECOG) status was used. Within 2 weeks before and 1 and 2 months after each therapy cycle, hematology, renal function, liver status, alkaline phosphatase, and PSA were checked. The Common Terminology Criteria for Adverse Events was used for grading adverse events induced by 177Lu-PSMA. Furthermore, overall survival (OS) was calculated and analyzed. During the treatment, a BCR was seen in 62% of patients; 19% of patients showed progression and 19% of patients showed stable disease. ECOG status was improved after treatment, and OS was 62.7 weeks. After the treatment, two patients showed Grade II toxicity of white blood cells, Grade I thrombocytopenia was observed in two patients, one patient showed Grade II toxicity in serum creatinine and transient Grade I toxicity in creatinine was seen in two patients. In total, our initial experience demonstrates that 177Lu-PSMA therapy has the potential to positively affect the development and maturation of radioligand practices in selected mCRPC patients, even in resource limited, developing country environments. However, some challenges, such as practitioner training, poor initial acceptance by colleagues and financial concerns, particularly in developing nations, still exist.

Non-Random Distribution of Reciprocal Translocation Breakpoints in the Pig Genome.

Balanced chromosome rearrangements are one of the main etiological factors contributing to hypoprolificacy in the domestic pig. Amongst domestic animals, the pig is considered to have the highest prevalence of chromosome rearrangements. To date over 200 unique chromosome rearrangements have been identified. The factors predisposing pigs to chromosome rearrangements, however, remain poorly understood. Nevertheless, here we provide empirical evidence which sustains the notion that there is a non-random distribution of chromosomal rearrangement breakpoints in the pig genome. We sought to establish if there are structural chromosome factors near which rearrangement breakpoints preferentially occur. The distribution of rearrangement breakpoints was analyzed across three level, chromosomes, chromosome arms, and cytogenetic GTG-bands (G-banding using trypsin and giemsa). The frequency of illegitimate exchanges (e.g., reciprocal translocations) between individual chromosomes and chromosome arms appeared to be independent of chromosome length and centromere position. Meanwhile chromosome breakpoints were overrepresented on some specific G-bands, defining chromosome hotspots for ectopic exchanges. Cytogenetic band level factors, such as the length of bands, chromatin density, and presence of fragile sites, were associated with the presence of translocation breakpoints. The characteristics of these bands were largely similar to that of hotspots in the human genome. Therefore, those hotspots are proposed as a starting point for future molecular analyses into the genomic landscape of porcine chromosome rearrangements.

Meiotic Synapsis and Gene Expression Altered by a Balanced Y-Autosome Reciprocal Translocation in an Azoospermic Pig.

Meiotic sex chromosome silencing (MSCS) has been argued as a prerequisite for normal meiotic cell division progression during the synaptic prophase I stage. Furthermore, irregular asynapsis of autosomal axes at meiosis may be encompassing the lack of transcriptional activity normally observed for the X and Y sex chromosomes. Therefore, any chromosomal rearrangement compromising the normal mechanism of MSCS and/or the contrary, the normal meiotic transcriptional activity of autosomal chromosomes, may be observed as a meiotic and concomitant spermatogenesis arrest. Previously, we have described a Y-autosome translocation t(Y;13)(p1.3;q3.3) in an azoospermic boar. Its chromosome synapsis behavior by synaptonemal complex immunostaining and FISH analyses is documented here. Histone γH2AX protein foci appeared to be located at unsynapsed chromosomal segments (e.g., X chromosome univalents or unpaired multivalent segments), although interestingly a high proportion of primary spermatocytes showed full paired synaptonemal complex-multivalent configurations which were devoid of a γH2AX focus signal, indicating meiotic chromosome silencing. RT-qPCR analysis of testicular expression showed downregulation of 3 SSC13 genes (MLH1, SOX2, UBE2B) and upregulation of SSCY genes (ZFY, SRY). The irregularity of the normal transcription pattern in case of these genes with proven roles in the testis is in agreement with the cytological observations and could contribute to the observed phenotype.

Azoospermia and Testicular Hypoplasia in a Boar Carrier of a Novel Y-Autosome Translocation.

Few sex-autosome chromosome abnormalities have been documented in domestic animal species. In humans, Y-autosome chromosome abnormalities may occur at a rate of 1/2,000 live births, whereas in the domestic pig only 2 Y-autosome reciprocal translocations have been previously described. During a routine cytogenetic screening of young boars, we identified a new Y-autosome translocation carrier, which after puberty showed semen devoid of sperm and testicular hypoplasia with spermatogenesis arrest. Whole chromosome painting by FISH analysis corroborated the reciprocal nature of the chromosomal exchanges between the Y chromosome and SSC13. The possible causes for the observed meiotic arrest of the carrier are reviewed.

Correlation between the Pulmonary Artery Pressure Measured in Echocardiography and Pulmonary Artery Diameter in the CT-Scan of Patients Suffering from Interstitial Lung Disease.

BACKGROUND: Pulmonary hypertension (PH) is a significant cause of morbidity and mortality in patients suffering from pulmonary parenchymal diseases. Diagnosis of PH has always been a major clinical dilemma due to its non-specific clinical manifestations. However, diagnosing PH and determining its severity are essential for the prognosis and treatment planning in PH patients. This study aimed at evaluating the correlation between the pulmonary artery diameter (PAD) in the CT-scan and pulmonary artery pressure (PAP) in echocardiography of patients. MATERIALS AND METHODS: PAD was evaluated in the CT-scan of 117 patients suffering from interstitial lung disease (ILD) and the correlation between PAD and PAP was studied. A receiver operating characteristic curve (ROC curve) which is indicative of the precision of the diagnostic test was drawn to find the cut off point for the MPAD representing PH. The area under the curve was also calculated in order to define the discriminative power of the test. RESULTS: PAP higher than 25 mmHg was considered as PH. PAD over 29 mm reported in the CT-scan for the diagnosis of PH in ILD patients had sensitivity of 63% and specificity of 41.5%. No significant linear correlation was found between PAD and PAP (P-value = 0.17, r = 0.15). The area under the ROC curve was calculated to be 0.49 in the cutoff point of 29 mm for determining PH (CI 95% = 0.38-0.60, P = 0.89). CONCLUSION: ROC curve showed a weak discriminative power. PAD had low sensitivity and specificity in the CT-scan for the diagnosis of PH. Therefore, we conclude that CT-scan alone is not helpful in finding PH cases and further examinations are required.