Lipoxygenases (LOXs) are a family of enzymes that can oxygenate polyunsaturated fatty acids. As a member of the family, 15-lipoxygenase-1 (15-LOX-1) specifically metabolizes arachidonic acid and linoleic acid. 15-LOX-1 can affect physiological and pathophysiological events via regulation of the protein-lipid interactome, alterations in intracellular redox state and production of lipid metabolites that are involved in the induction and resolution of inflammation. Although several studies have shown that 15-LOX-1 has an antitumorigenic role in many different cancer models, including breast cancer, the role of the protein in cancer drug resistance has not been established yet. In this study, we, for the first time, aimed to show the potential role of 15-LOX-1 in acquired doxorubicin (DOX) resistance in MCF7 and HeLa cancer cell lines. Our results show that ALOX15 was transcriptionally downregulated in DOX-resistant cells compared with their drugsensitive counterparts. Moreover, overexpression of ALOX15 in the drug-resistant cells resulted in resensitization of those cells to DOX in a cell-dependent manner. 15-LOX-1 expression could induce apoptosis by activating PPARγ and enhance the accumulation of DOX in drug-resistant MCF7 cells by altering cellular motility properties, and membrane dynamics. However, HeLa DOX cells did not show any of these effects but were susceptible to cell death when treated with 13(S)-HODE. These results underline the role and importance of 15-LOX-1 in cancer drug resistance, and points to novel mechanisms as a therapeutic approach to overcome cancer drug resistance. K E Y W O R D S 15-LOX-1, cancer drug resistance, cell motility, doxorubicin, PPARγ

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Mesomelic dysplasias are a genetically and clinically heterogeneous group of diseases with more than 10 types defined. This article presents an 18-year-old female patient with normal intelligence and a multisystem phenotype including disproportionate short stature, scoliosis, mesomelic limb shortening, radial bowing, short fourth to fifth metacarpals and metatarsals, fusions in the carpal/tarsal bones, operated pes equinovarus, primary amenorrhea, uterine hypoplasia, vesicoureteral reflux, and chronic kidney disease. Whole-exome sequencing revealed a de novo heterozygous c.881T>G (p.Met294Arg) variant in HOXA11 (NM_005523.6) gene. The variant was located in the homeodomain of HOXA11 and predicted to alter DNA-binding ability of the protein. In silico analyses indicated that the variant could promote the alterations in the protein-protein interaction. The possible functional effect of the variant was supposed as dominant-negative. Hoxa11-mutant mice have been reported to exhibit homeotic transformations in the thoracic and sacral vertebrae, zeugopodal phenotype in forelimb and hindlimb, and urogenital abnormalities. Although mice models were reported as mesomelic dysplasia and urogenital abnormalities (MDUGA), this phenotype has not yet been reported in humans. This was the first case with MDUGA putatively related to a de novo variant in HOXA11.

Thauvin‐Robinet‐Faivre syndrome (TROFAS; OMIM #617107) is a rare autosomal recessive overgrowth syndrome characterized by generalized overgrowth, dysmorphic facial features, and delayed psychomotor development caused by biallelic pathogenic variants in the FGF‐1 intracellular binding protein (FIBP) gene. To date, only four patients from two families have been reported. In this report, we present a 4‐year‐old male patient with generalized overgrowth and delayed developmental milestones consistent with this syndrome. In addition, he has unique features that were not reported in previous patients, including drooling, recurrent pulmonary infections, chronic pulmonary disease, hyperextensible elbow joints, hypoplastic nipples, unilateral cryptorchidism, and frequent spontaneous erections. We identified a homozygous, likely pathogenic variant, c.415_416insCAGTTTG (p.Asp139AlafsTer3), which causes a frameshift in the FIBP. Additionally, we identified a homozygous missense variant in the Toll‐like receptor 5(TLR5) gene and a hemizygous missense variant in the chloride voltage‐gated channel 4 (CLCN4) gene, with uncertain significance in either case. In this article, we set out the new observations and also discuss the frequency of the characteristic findings of the syndrome in the patients so far reported.