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Fulltext Roles of Sema4D and Plexin-B1 in tumor progression

Ch'ng ES, Kumanogoh A

Mol. Cancer, 2010;9:251.
PMID: 20858260 DOI: 10.1186/1476-4598-9-251

Sema4D, also known as CD100, is a protein belonging to class IV semaphorin. Its physiologic roles in the immune and nervous systems have been extensively explored. However, the roles of Sema4D have extended beyond these traditionally studied territories. Via interaction with its high affinity receptor Plexin-B1, Sema4D-Plexin-B1 involvement in tumor progression is strongly implied. Here, we critically review and delineate the Sema4D-Plexin-B1 interaction in many facets of tumor progression: tumor angiogenesis, regulation of tumor-associated macrophages and control of invasive growth. We correlate the in vitro and in vivo experimental data with the clinical study outcomes, and present a molecular mechanistic basis accounting for the intriguingly contradicting results from these recent studies.

Matched MeSH terms: Semaphorins/genetics; Semaphorins/metabolism*
Fulltext SEMA3B but Not CUL1 as Marker for Pre-Eclampsia Progression

Samara TD, Liem IK, Prijanti AR, Andrijono

Malays J Med Sci, 2019 Jan;26(1):66-72.
PMID: 30914894 DOI: 10.21315/mjms2019.26.1.6

Background: An imbalance between pro- and anti-angiogenic factors contributes to impaired trophoblast invasion during pregnancy, leading to failure of uterine spiral artery remodeling, blood vessel ischemia, and pre-eclampsia (PE). Anti-angiogenic semaphorin 3B (SEMA3B) and pro-angiogenic cullin 1 (CUL1) are expressed in both the placenta and maternal blood. The present study investigated correlations between serum and placental SEMA3B as well as CUL1 levels in late-onset PE.
Methods: This cross-sectional study included 50 patients with late-onset (≥ 32 weeks gestation) PE. Maternal serum was obtained before delivery, and placentas were obtained immediately after delivery. SEMA3B and CUL1 levels were evaluated by ELISA. Results were statistically analysed by Spearman correlation test, with a P < 0.05 considered statistically significant.
Results: While elevated serum SEMA3B levels significantly correlated with increased placental SEMA3B levels in late-onset PE (R = 0.620, P = 0.000), alteration of serum CUL1 levels did not correlate with alteration of placental CUL1.
Conclusion: Alteration of circulating maternal SEMA3B, but not CUL1, levels can potentially be used to monitor PE progression during pregnancy.

Matched MeSH terms: Semaphorins
Fulltext De Novo Truncating Variants in the Last Exon of SEMA6B Cause Progressive Myoclonic Epilepsy

Hamanaka K, Imagawa E, Koshimizu E, Miyatake S, Tohyama J, Yamagata T, et al.

Am J Hum Genet, 2020 04 02;106(4):549-558.
PMID: 32169168 DOI: 10.1016/j.ajhg.2020.02.011

De novo variants (DNVs) cause many genetic diseases. When DNVs are examined in the whole coding regions of genes in next-generation sequencing analyses, pathogenic DNVs often cluster in a specific region. One such region is the last exon and the last 50 bp of the penultimate exon, where truncating DNVs cause escape from nonsense-mediated mRNA decay [NMD(-) region]. Such variants can have dominant-negative or gain-of-function effects. Here, we first developed a resource of rates of truncating DNVs in NMD(-) regions under the null model of DNVs. Utilizing this resource, we performed enrichment analysis of truncating DNVs in NMD(-) regions in 346 developmental and epileptic encephalopathy (DEE) trios. We observed statistically significant enrichment of truncating DNVs in semaphorin 6B (SEMA6B) (p value: 2.8 × 10-8; exome-wide threshold: 2.5 × 10-6). The initial analysis of the 346 individuals and additional screening of 1,406 and 4,293 independent individuals affected by DEE and developmental disorders collectively identified four truncating DNVs in the SEMA6B NMD(-) region in five individuals who came from unrelated families (p value: 1.9 × 10-13) and consistently showed progressive myoclonic epilepsy. RNA analysis of lymphoblastoid cells established from an affected individual showed that the mutant allele escaped NMD, indicating stable production of the truncated protein. Importantly, heterozygous truncating variants in the NMD(+) region of SEMA6B are observed in general populations, and SEMA6B is most likely loss-of-function tolerant. Zebrafish expressing truncating variants in the NMD(-) region of SEMA6B orthologs displayed defective development of brain neurons and enhanced pentylenetetrazole-induced seizure behavior. In summary, we show that truncating DNVs in the final exon of SEMA6B cause progressive myoclonic epilepsy.

Matched MeSH terms: Semaphorins/genetics*
Fulltext Human iPS-derived pre-epicardial cells direct cardiomyocyte aggregation expansion and organization in vitro

Tan JJ, Guyette JP, Miki K, Xiao L, Kaur G, Wu T, et al.

Nat Commun, 2021 08 17;12(1):4997.
PMID: 34404774 DOI: 10.1038/s41467-021-24921-z

Epicardial formation is necessary for normal myocardial morphogenesis. Here, we show that differentiating hiPSC-derived lateral plate mesoderm with BMP4, RA and VEGF (BVR) can generate a premature form of epicardial cells (termed pre-epicardial cells, PECs) expressing WT1, TBX18, SEMA3D, and SCX within 7 days. BVR stimulation after Wnt inhibition of LPM demonstrates co-differentiation and spatial organization of PECs and cardiomyocytes (CMs) in a single 2D culture. Co-culture consolidates CMs into dense aggregates, which then form a connected beating syncytium with enhanced contractility and calcium handling; while PECs become more mature with significant upregulation of UPK1B, ITGA4, and ALDH1A2 expressions. Our study also demonstrates that PECs secrete IGF2 and stimulate CM proliferation in co-culture. Three-dimensional PEC-CM spheroid co-cultures form outer smooth muscle cell layers on cardiac micro-tissues with organized internal luminal structures. These characteristics suggest PECs could play a key role in enhancing tissue organization within engineered cardiac constructs in vitro.

Matched MeSH terms: Semaphorins