Chemical Conversion of 5-Fluoromethyl- and 5-Difluoromethyl-Uracil Bases in Oligonucleotides Using Postsynthetic Modification Strategy.

This article describes the postsynthetic modification of oligonucleotides (ONs) containing 2'-deoxy-5-fluoromethyluridine (dU ) and 2'-deoxy-5-difluoromethyluridine (dU ). Reactions of fully protected and controlled pore glass (CPG)-attached ONs containing dU and dU in basic solutions result in deprotection of all protecting groups except for the 4,4'-dimethoxytrityl group, cleavage from CPG, and conversion of the fluoromethyl or difluoromethyl groups to afford the corresponding ONs containing 5-substituted 2'-deoxyuridines. Moreover, the difluoromethyl group can be converted to formyl, oxime, or hydrazone via the postsynthetic conversion of protection- and CPG-free ON containing dU .

Cell migration is impaired in XPA-deficient cells.

Xeroderma pigmentosum (XP) is a hereditary disorder characterized by photosensitivity, predisposition to skin cancers, and neurological abnormalities including microcephaly and progressive neurodegeneration. A lack of nucleotide excision repair (NER) in patients with XP can cause hypersensitivity to the sun, leading to skin cancer, whereas the etiology of the neuronal symptoms of XP remains ambiguous. There are various neurological disorders that perturb neuronal migration, causing mislocalization and disorganization of the cortical lamination.

Severe and delayed-onset acneiform eruptions as an adverse reaction to regorafenib.

Regorafenib is an oral multikinase inhibitor targeting several tyrosine kinase receptors including BRAF and epidermal growth factor receptor (EGFR) and is approved as a third-line treatment for metastatic gastrointestinal stromal tumor (GIST). While acneiform eruptions have been observed in patients receiving other BRAF and EGFR inhibitors, the commonly reported adverse reactions to regorafenib are fatigue and palmar-plantar erythrodysesthesia. Herein, we report, to the best of our knowledge, the first case who presented with a severe acneiform eruption 24 months after beginning regorafenib for the treatment of GIST.

NUMB as a Therapeutic Target for Melanoma.

The upregulation of the adaptor protein NUMB triggers melanocytic differentiation from multipotent skin stem cells, which share many properties with aggressive melanoma cells. Although NUMB acts as a tumor suppressor in various human cancer types, little is known about its role in melanoma. In this study, we investigated the role of NUMB in melanoma progression and its regulatory mechanism.

Induced pluripotent stem cell-derived melanocyte precursor cells undergoing differentiation into melanocytes.

Induced pluripotent stem cell (iPSC) technology offers a novel approach for conversion of human primary fibroblasts into melanocytes. During attempts to explore various protocols for differentiation of iPSCs into melanocytes, we found a distinct and self-renewing cell lineage that could differentiate into melanocytes, named as melanocyte precursor cells (MPCs). The MPCs exhibited a morphology distinctive from that of melanocytes, in lacking either the melanosomal structure or the melanocyte-specific marker genes MITF, TYR, and SOX10.

Inflammation Due to Voriconazole-induced Photosensitivity Enhanced Skin Phototumorigenesis in Xpa-knockout Mice.

Voriconazole is an antifungal agent and used as a prophylactic measure, especially in immunocompromised patients. However, there have been several reports of its adverse reactions, namely photosensitivity with intense inflammatory rashes and subsequent skin cancer development. To assess the effects of photosensitizing drugs voriconazole and hydrochlorothiazide (HCTZ) on the enhancement of UV-induced inflammatory responses and UV-induced tumorigenesis, we utilized Xpa-knockout mice, which is DNA repair-deficient and more susceptible to UV-induced inflammation and tumor development than wild-type mice.

CXCL1 Inhibition Regulates UVB-Induced Skin Inflammation and Tumorigenesis in Xpa-Deficient Mice.

Xeroderma pigmentosum complementation group A is a hereditary disease characterized by early onset of skin cancers and freckle-like pigmented maculae in sun-exposed sites. Although the etiology of the predisposition to UVR-induced skin tumors in xeroderma pigmentosum complementation group A is well investigated as a repair deficiency in UVR-induced DNA damage, the mechanism of exaggerated sunburn in patients with xeroderma pigmentosum complementation group A and whether UVR-induced inflammation relates to a skin tumor-prone phenotype remains to be elucidated. Using gene profiling of xeroderma pigmentosum complementation group A model mice, Xpa-deficient mice, we found that expression of CXCL1 in the skin and blood of Xpa-deficient mice increased significantly after UVB exposure over even a limited area compared with that of wild-type mice.