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Despite the introduction of new therapies for multiple myeloma (MM), many patients are still dying from this disease and novel treatments are urgently needed. We have designed a novel hybrid molecule, called NEO214, that was generated by covalent conjugation of the natural monoterpene perillyl alcohol (POH), an inducer of endoplasmic reticulum (ER) stress, to rolipram (Rp), an inhibitor of phosphodiesterase-4 (PDE4). Its potential anticancer effects were investigated in a panel of MM cell lines. We found that NEO214 effectively killed MM cells in vitro with a potency that was over an order of magnitude stronger than that of its individual components, either alone or in combination. The cytotoxic mechanism of NEO214 involved severe ER stress and prolonged induction of CCAAT/enhancer-binding protein homologous protein (CHOP), a key pro-apoptotic component of the ER stress response. These effects were prevented by salubrinal, a pharmacologic inhibitor of ER stress, and by CHOP gene knockout. Conversely, combination of NEO214 with bortezomib, a drug in clinical use for patients with MM, resulted in synergistic enhancement of MM cell death. Combination with the adenylate cyclase stimulant forskolin did not enhance NEO214 impact, indicating that cyclic adenosine 3',5'-monophosphate (AMP) pathways might play a lesser role. Our study introduces the novel agent NEO214 as a potent inducer of ER stress with significant anti-MM activity in vitro. It should be further investigated as a potential MM therapy aimed at exploiting this tumor's distinct sensitivity to ER stress.

BackgroundMany patients with nasopharyngeal carcinoma (NPC) face poor prognosis. Due to its hidden anatomical location, the tumor is usually diagnosed quite late, and despite initially successful treatment with radiation and cisplatin, many patients will relapse and succumb to the disease. New treatment options are urgently needed. We have performed preclinical studies to evaluate the potential NPC therapeutic activity of a newly developed analog of temozolomide (TMZ), an alkylating agent that is the current chemotherapeutic standard of care for patients with malignant glioma.ResultsTMZ was covalently conjugated to the natural monoterpene perillyl alcohol (POH), creating the novel fusion compound NEO212. Its impact on two NPC cell lines was studied through colony formation assays, cell death ELISA, immunoblots, and in vivo testing in tumor-bearing mice. In vitro, NEO212 effectively triggered tumor cell death, and its potency was significantly greater than that of its individual components, TMZ or POH alone. Intriguingly, merely mixing TMZ with POH also was unable to achieve the superior potency of the conjugated compound NEO212. Treatment of NPC cells with NEO212 inactivated the chemoprotective DNA repair protein MGMT (O6-methylguanine methyltransferase), resulting in significant chemosensitization of cells to a second round of drug treatment. When tested in vivo, NEO212 reduced tumor growth in treated animals.ConclusionOur results demonstrate anticancer activity of NEO212 in preclinical NPC models, suggesting that this novel compound should be evaluated further for the treatment of patients with NPC.

BackgroundMus spretus diverged from Mus musculus over one million years ago. These mice are genetically and phenotypically divergent. Despite the value of utilizing M. musculus and M. spretus for quantitative trait locus (QTL) mapping, relatively little genomic information on M. spretus exists, and most of the available sequence and polymorphic data is for one strain of M. spretus, Spret/Ei. In previous work, we mapped fifteen loci for skin cancer susceptibility using four different M. spretus by M. musculus F1 backcrosses. One locus, skin tumor susceptibility 5 (Skts5) on chromosome 12, shows strong linkage in one cross.ResultsTo identify potential candidate genes for Skts5, we sequenced 65 named and unnamed genes and coding elements mapping to the peak linkage area in outbred spretus, Spret/EiJ, FVB/NJ, and NIH/Ola. We identified polymorphisms in 62 of 65 genes including 122 amino acid substitutions. To look for polymorphisms consistent with the linkage data, we sequenced exons with amino acid polymorphisms in two additional M. spretus strains and one additional M. musculus strain generating 40.1 kb of sequence data. Eight candidate variants were identified that fit with the linkage data. To determine the degree of variation across M. spretus, we conducted phylogenetic analyses. The relatedness of the M. spretus strains at this locus is consistent with the proximity of region of ascertainment of the ancestral mice.ConclusionOur analyses suggest that, if Skts5 on chromosome 12 is representative of other regions in the genome, then published genomic data for Spret/EiJ are likely to be of high utility for genomic studies in other M. spretus strains.

BACKGROUND: Streptococcus mutans, the main pathogen associated with tooth decay, forms cariogenic biofilms on tooth surfaces. Therefore, controlling oral biofilm helps prevent dental caries. Hen's egg is a nutrient‐dense food, and egg white is a good source of protein. Ovomucoid is one of the major proteins in egg white, with a 28 kDa molecular weight. The present study aimed to investigate the inhibitory effects of ovomucoid on the biofilm formation of S. mutans by suppressing virulence factors, including bacterial adherence, cellular aggregation and exopolysaccharide (EPS) production. RESULTS: Crystal violet staining showed that biofilm formation by S. mutans was inhibited by ovomucoid at 0.25–1 mg mL−1 levels. Field emission scanning electron microscopy also confirmed this inhibition. In addition, ovomucoid reduced mature biofilm, water‐insoluble EPS synthesis and the metabolic activity of bacterial cells in the biofilm. The bacterial adhesion and aggregation abilities of S. mutans were also decreased in the presence of ovomucoid. Ovomucoid downregulated the expression of comDE and vicR genes involved in the two‐component signal transduction system and gtfA and ftf genes involved in EPS production. CONCLUSION: Ovomucoid has the potential for use as an anti‐biofilm agent for dental caries treatment because of its inhibitory effects on the virulence factors of S. mutans. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Background WT1 is one of the genes commonly reported as mutated in children with steroid-resistant nephrotic syndrome (SRNS). We analyzed genotype-phenotype correlations in pediatric SRNS patients with WT1 mutations. Methods From 2001 to 2015, WT1 mutations were detected in 21 out of 354 children with SRNS by genetic screening (5.9 %). The patients were grouped into missense (n = 11) and KTS splicing (n = 10) mutation groups. Results Nine (82 %) patients with missense mutations presented with congenital/infantile nephrotic syndrome, while 8 (80 %) with KTS splicing mutations presented with childhood-onset SRNS. Progression to end-stage renal disease (ESRD) was noted in all patients with missense mutations (median age, 2.6 months; interquartile range [IQR], 0.8 months to 1.7 years) and in 5 patients with KTS splicing mutations (median, 9.3 years; IQR, 3.3-16.5 years). Disorders of sexual development (DSDs) were noted in all 12 patients with a 46, XY karyotype and in only 1 of the 8 patients with a 46, XX karyotype. One patient developed a Wilms tumor and another developed gonadoblastoma. Three patients had a diaphragmatic defect or hernia. Conclusions WT1 mutations manifest as a wide spectrum of renal and extra-renal phenotypes. Genetic diagnosis is essential for overall management and to predict the genotype-specific risk of DSDs and the development of malignancies., Author(s): Yo Han Ahn[sup.1] [sup.2] , Eu Jin Park[sup.1] , Hee Gyung Kang[sup.1] [sup.3] , Seong Heon Kim[sup.4] , Hee Yeon Cho[sup.5] , Jae Il Shin[sup.6] , Joo Hoon Lee[sup.7] [...]

Background Dent disease, an X-linked recessive renal tubulopathy, is caused by mutations in either CLCN5 (Dent disease 1) or OCRL (Dent disease 2). OCRL mutations can also cause Lowe syndrome. In some cases it is difficult to differentiate Dent disease 1 and 2 on the basis of clinical features only without genetic tests. Several studies have shown differences in serum levels of muscle enzymes between these diseases. The aim of our study was to test the validity of these findings. Methods In total, 23 patients with Dent disease 1 (Group A), five patients with Dent disease 2 (Group B) and 19 patients with Lowe syndrome (Group C) were enrolled in our study. The serum levels of three muscle enzymes [creatine phosphokinase (CPK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST)], were measured. The levels of a hepatic enzyme, alanine aminotransferase (ALT), were also measured as a control. Results One patient in Group B had muscle hypoplasia of both upper extremities. The serum levels of all three muscle enzymes assayed were higher in Group B or C patients than in Group A patients. Serum ALT levels were normal in all three groups of patients. Conclusions The serum levels of muscle enzymes in patients with Dent disease can be used as a biomarker to predict genotypes, even though the patients do not have clinical symptoms of muscle involvement. Keywords CLCN5 gene * Dent disease 1 * Dent disease 2 * Lowe syndrome * Muscle enzyme * OCRL gene, Introduction Dent disease is an X-linked hereditary renal tubular disorder characterized by manifestations of proximal tubule dysfunction, including low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis and progressive renal failure [1]. Dent disease [...]