Identification of a novel mutation of MTP gene in a patient with abetalipoproteinemia

Abetalipoproteinemia (ABL), or Bassen-Kornzweig syndrome, is a rare autosomal recessive disorder of lipoprotein metabolism, characterized by fat malabsorption, hypocholesterolemia retinitis pigmentosa, progressive neuropathy and acanthocytosis from early infancy. We describe the clinical and molecular characterization of a 6-month-old infant born of consanguineous, apparently healthy parents from Iran. The patient was hospitalized because of failure to thrive, greasy stool and vomiting. The patient's serum lipid profile, the clinical phenotype and the duodenal histology suggested the clinical diagnosis of ABL. The MTP gene analysis by direct sequencing revealed a novel homozygous mutation (c.1586 A > G-H529R). The parents were heterozygotes for the same mutation and interestingly the father showed a lipid profile characterized by a slight reduction of total and LDL-cholesterol plasma levels

Analysis of the gene coding for the BRCA2-Interacting protein PALB2 in hereditary prostate cancer

BACKGROUND The genetic basis of susceptibility to prostate cancer (PRCA) remains elusive. Mutations in BRCA2 have been associated with increased prostate cancer risk and account for around 2% of young onset (<56 years) prostate cancer cases. PALB2 is a recently identified breast cancer susceptibility gene whose protein is closely associated with BRCA2 and is essential for BRCA2 anchorage to nuclear structures. This functional relationship made PALB2 a candidate PRCA susceptibility gene. METHODS We sequenced PALB2 in probands from 95 PRCA families, 77 of which had two or more cases of early onset PRCA (age at diagnosis <55 years), and the remaining 18 had one case of early onset PRCA and five or more total cases of PRCA. RESULTS Two previously unreported variants, K18R and V925L were identified, neither of which is in a known PALB2 functional domain and both of which are unlikely to be pathogenic. No truncating mutations were identified. CONCLUSIONS These results indicate that deleterious PALB2 mutations are unlikely to play a significant role in hereditary prostate cancer. Prostate 68: 675–678, 2008. © 2008 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58069/1/20729_ftp.pd

A novel LiDAR-GNSS-INS Two-Phase Tightly Coupled integration scheme for precise navigation

Recent advances in precise navigation have extensively utilized the integration of Global Navigation Satellite System (GNSS) and Inertial Navigation System (INS), particularly in the domain of intelligent vehicles. However, the efficacy of such navigation systems is considerably compromised by the reflection and multipath disruptions of non-light-of-sight (NLOS) signals. Light Detection and Ranging (LiDAR)-based odometry, an active perception-based sensor known for its precise 3D measurements, has become increasingly prevalent in augmenting navigation systems. Nonetheless, the assimilation of LiDAR odometry with GNSS/INS systems presents substantial challenges. Addressing these challenges, this study introduces a two-phase sensor fusion (TPSF) approach that synergistically combines GNSS positioning, LiDAR odometry, and IMU pre-integration through a dual-stage sensor fusion process. The initial stage employs an Extended Kalman Filter (EKF) to amalgamate the GNSS solution with IMU Mechanization, facilitating the estimation of IMU biases and system initialization. Subsequently, the second stage integrates scan-to-map LiDAR odometry with IMU mechanization to support continuous LiDAR factor estimation. Factor graph optimization (FGO) is then utilized for the comprehensive fusion of LiDAR factors, IMU pre-integration, and GNSS solutions. The efficacy of the proposed methodology is corroborated through rigorous testing on a demanding trajectory from an urbanized open-source dataset, with the system demonstrating a notable enhancement in performance compared to the state-of-the-art algorithms, achieving a translational Standard Deviation (STD) of 1.269 meters

Contribution of the PALB2 c.2323C>T [p.Q775X] founder mutation in well-defined breast and/or ovarian cancer families and unselected ovarian cancer cases of French Canadian descent.

BACKGROUND: The PALB2 c.2323C>T [p.Q775X] mutation has been reported in at least three breast cancer families and breast cancer cases of French Canadian descent and this has been attributed to common ancestors. The number of mutation-positive cases reported varied based on criteria of ascertainment of index cases tested. Although inherited PALB2 mutations are associated with increased risks of developing breast cancer, risk to ovarian cancer has not been fully explored in this demographically unique population. METHODS: We screened the PALB2 p.Q775X variant in 71 families with at least three cases of breast cancer (n=48) or breast and ovarian cancers (n=23) that have previously been found negative for at least the most common BRCA1 and BRCA2 mutations reported in the French Canadian population and in 491 women of French Canadian descent who had invasive ovarian cancer and/or low malignant potential tumors of the major histopathological subtypes. RESULTS: We identified a PALB2 p.Q775X carrier in a breast cancer family, who had invasive ductal breast carcinomas at 39 and 42 years of age. We also identified a PALB2 p.Q775X carrier who had papillary serous ovarian cystadenocarcinoma at age 58 among the 238 serous subtype ovarian cancer cases investigated, who also had breast cancer at age 52. CONCLUSION: Our findings, taken together with previous reports, support adding PALB2 c.2323C>T p.Q775X to the list of cancer susceptibility genes for which founder mutations have been identified in the French Canadian population.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

LIDAR-INERTIAL LOCALIZATION WITH GROUND CONSTRAINT IN A POINT CLOUD MAP

Real-time localization is a crucial task in various applications, such as automatic vehicles (AV), robotics, and smart city. This study proposes a framework for map-aided LiDAR-inertial localization, with the objective of accurately estimating the trajectory in a point clouds map. The proposed framework addresses the localization problem through a factor graph optimization (FGO), enabling the fusion of homogenous measurements for sensor fusion and designed absolute and relative constraints. Specifically, the framework estimates the light detection and ranging (LiDAR) odometry by leveraging inertial measurement unit (IMU) and registering corresponding featured points. To eliminate the accumulative error, this paper employs a ground plane distance and a map matching error to constraint the positioning error along the trajectory. Finally, local odometry and constraints are integrated using a FGO, including LiDAR odometry, IMU pre-integration, and ground constraints, map matching constraints, and loop closure. Experimental results were evaluated on an open-source dataset, UrbanNav, with an overall localization accuracy of 2.29 m (root mean square error, RMSE)

Pituitary blastoma: a pathognomonic feature of germ-line DICER1 mutations.

Individuals harboring germ-line DICER1 mutations are predisposed to a rare cancer syndrome, the DICER1 Syndrome or pleuropulmonary blastoma-familial tumor and dysplasia syndrome [online Mendelian inheritance in man (OMIM) #601200]. In addition, specific somatic mutations in the DICER1 RNase III catalytic domain have been identified in several DICER1-associated tumor types. Pituitary blastoma (PitB) was identified as a distinct entity in 2008, and is a very rare, potentially lethal early childhood tumor of the pituitary gland. Since the discovery by our team of an inherited mutation in DICER1 in a child with PitB in 2011, we have identified 12 additional PitB cases. We aimed to determine the contribution of germ-line and somatic DICER1 mutations to PitB. We hypothesized that PitB is a pathognomonic feature of a germ-line DICER1 mutation and that each PitB will harbor a second somatic mutation in DICER1. Lymphocyte or saliva DNA samples ascertained from ten infants with PitB were screened and nine were found to harbor a heterozygous germ-line DICER1 mutation. We identified additional DICER1 mutations in nine of ten tested PitB tumor samples, eight of which were confirmed to be somatic in origin. Seven of these mutations occurred within the RNase IIIb catalytic domain, a domain essential to the generation of 5p miRNAs from the 5' arm of miRNA-precursors. Germ-line DICER1 mutations are a major contributor to PitB. Second somatic DICER1 "hits" occurring within the RNase IIIb domain also appear to be critical in PitB pathogenesis

Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women

Abstract Background PALB2 has recently been identified as a breast cancer susceptibility gene. PALB2 mutations are rare causes of hereditary breast cancer but may be important in countries such as Finland where a founder mutation is present. We sought to estimate the contribution of PALB2 mutations to the burden of breast cancer in French Canadians from Quebec. Methods We screened all coding exons of PALB2 in a sample of 50 French-Canadian women diagnosed with either early-onset breast cancer or familial breast cancer at a single Montreal hospital. The genetic variants identified in this sample were then studied in 356 additional women with breast cancer diagnosed before age 50 and in 6,448 newborn controls. Results We identified a single protein-truncating mutation in PALB2 (c.2323 C>T, resulting in Q775X) in 1 of the 50 high-risk women. This variant was present in 2 of 356 breast cancer cases and in none of 6,440 newborn French-Canadian controls (P = 0.003). We also identified two novel new non-synonymous single nucleotide polymorphisms in exon 4 of PALB2 (c.5038 A>G [I76V] and c.5156 G>T [G115V]). G115V was found in 1 of 356 cases and in 15 of 6,442 controls (P = 0.6). The I76V variant was not identified in either the extended case series or the controls. Conclusion We have identified a novel truncating mutation in PALB2. The mutation was found in approximately 0.5% of unselected French-Canadian women with early-onset breast cancer and appears to have a single origin. Although mutations are infrequent, PALB2 can be added to the list of breast cancer susceptibility genes for which founder mutations have been identified in the French-Canadian population

Antisense inhibition of methylenetetrahydrofolate reductase reduces survival of methionine-dependent tumour lines

Transformed cells have been documented to be methionine-dependent, suggesting that inhibition of methionine synthesis might be useful for cancer therapy. Methylenetetrahydrofolate reductase synthesises 5-methyltetrahydrofolate, the methyl donor utilised in methionine synthesis from homocysteine by vitamin B12-dependent methionine synthase. We hypothesised that methylenetetrahydrofolate reductase inhibition would affect cell viability through decreased methionine synthesis. Using medium lacking methionine, but containing homocysteine and vitamin B12 (M-H+), we found that nontransformed human fibroblasts could maintain growth. In contrast, four transformed cell lines (one colon carcinoma, two neuroblastoma and one breast carcinoma) increased proliferation only slightly in the M-H+ medium. To downregulate methylenetetrahydrofolate reductase expression, two phosphorothioate antisense oligonucleotides, EX5 and 677T, were used to target methylenetetrahydrofolate reductase in the colon carcinoma line SW620; 400 nM of each antisense oligonucleotide decreased cell survival by approximately 80% (P<0.01) and 70% (P<0.0001), respectively, compared to cell survival after the respective control mismatched oligonucleotide. Western blotting and enzyme assays confirmed that methylenetetrahydrofolate reductase expression was decreased. Two neuroblastoma and two breast carcinoma lines also demonstrated decreased survival following EX5 treatment whereas nontransformed human fibroblasts were not affected. This study suggests that methylenetetrahydrofolate reductase may be required for tumour cell survival and that methylenetetrahydrofolate reductase inhibition should be considered for anti-tumour therapy

Antisperm Antibody Testing: A Comprehensive Review of Its Role in the Management of Immunological Male Infertility and Results of a Global Survey of Clinical Practices

Antisperm antibodies (ASA), as a cause of male infertility, have been detected in infertile males as early as 1954. Multiple causes of ASA production have been identified, and they are due to an abnormal exposure of mature germ cells to the immune system. ASA testing (with mixed anti-globulin reaction, and immunobead binding test) was described in the WHO manual 5th edition and is most recently listed among the extended semen tests in the WHO manual 6th edition. The relationship between ASA and infertility is somewhat complex. The presence of sperm agglutination, while insufficient to diagnose immunological infertility, may indicate the presence of ASA. However, ASA can also be present in the absence of any sperm agglutination. The andrological management of ASA depends on the etiology and individual practices of clinicians. In this article, we provide a comprehensive review of the causes of ASA production, its role in immunological male infertility, clinical indications of ASA testing, and the available therapeutic options. We also provide the details of laboratory procedures for assessment of ASA together with important measures for quality control. Additionally, laboratory and clinical scenarios are presented to guide the reader in the management of ASA and immunological male infertility. Furthermore, we report the results of a recent worldwide survey, conducted to gather information about clinical practices in the management of immunological male infertility

Post-Vasectomy Semen Analysis: Optimizing Laboratory Procedures and Test Interpretation through a Clinical Audit and Global Survey of Practices

Purpose: The success of vasectomy is determined by the outcome of a post-vasectomy semen analysis (PVSA). This article describes a step-by-step procedure to perform PVSA accurately, report data from patients who underwent post vasectomy semen analysis between 2015 and 2021 experience, along with results from an international online survey on clinical practice. Materials and methods: We present a detailed step-by-step protocol for performing and interpretating PVSA testing, along with recommendations for proficiency testing, competency assessment for performing PVSA, and clinical and laboratory scenarios. Moreover, we conducted an analysis of 1,114 PVSA performed at the Cleveland Clinic's Andrology Laboratory and an online survey to understand clinician responses to the PVSA results in various countries. Results: Results from our clinical experience showed that 92.1% of patients passed PVSA, with 7.9% being further tested. A total of 78 experts from 19 countries participated in the survey, and the majority reported to use time from vasectomy rather than the number of ejaculations as criterion to request PVSA. A high percentage of responders reported permitting unprotected intercourse only if PVSA samples show azoospermia while, in the presence of few non-motile sperm, the majority of responders suggested using alternative contraception, followed by another PVSA. In the presence of motile sperm, the majority of participants asked for further PVSA testing. Repeat vasectomy was mainly recommended if motile sperm were observed after multiple PVSA's. A large percentage reported to recommend a second PVSA due to the possibility of legal actions. Conclusions: Our results highlighted varying clinical practices around the globe, with controversy over the significance of non-motile sperm in the PVSA sample. Our data suggest that less stringent AUA guidelines would help improve test compliance. A large longitudinal multi-center study would clarify various doubts related to timing and interpretation of PVSA and would also help us to understand, and perhaps predict, recanalization and the potential for future failure of a vasectomy