Transcriptome-based deep learning analysis identifies drug candidates targeting protein synthesis and autophagy for the treatment of muscle wasting disorder.

Sarcopenia, the progressive decline in skeletal muscle mass and function, is observed in various conditions, including cancer and aging. The complex molecular biology of sarcopenia has posed challenges for the development of FDA-approved medications, which have mainly focused on dietary supplementation. Targeting a single gene may not be sufficient to address the broad range of processes involved in muscle loss. This study analyzed the gene expression signatures associated with cancer formation and 5-FU chemotherapy-induced muscle wasting. Our findings suggest that dimenhydrinate, a combination of 8-chlorotheophylline and diphenhydramine, is a potential therapeutic for sarcopenia. In vitro experiments demonstrated that dimenhydrinate promotes muscle progenitor cell proliferation through the phosphorylation of Nrf2 by 8-chlorotheophylline and promotes myotube formation through diphenhydramine-induced autophagy. Furthermore, in various in vivo sarcopenia models, dimenhydrinate induced rapid muscle tissue regeneration. It improved muscle regeneration in animals with Duchenne muscular dystrophy (DMD) and facilitated muscle and fat recovery in animals with chemotherapy-induced sarcopenia. As an FDA-approved drug, dimenhydrinate could be applied for sarcopenia treatment after a relatively short development period, providing hope for individuals suffering from this debilitating condition.

Changes in subcellular localization of Lysyl-tRNA synthetase and the 67-kDa laminin receptor in epithelial ovarian cancer metastases.

BACKGROUND: Although lysyl-tRNA synthetase (KARS1) is predominantly located in the cytosol, it is also present in the plasma membrane where it stabilizes the 67-kDa laminin receptor (67LR). This physical interaction is strongly increased under metastatic conditions. However, the dynamic interaction of these two proteins and the turnover of KARS1 in the plasma membrane has not previously been investigated. OBJECTIVE: Our objective in this study was to identify the membranous location of KARS1 and 67LR and investigate if this changes with the developmental stage of epithelial ovarian cancer (EOC) and treatment with the inhibitor BC-K01. In addition, we evaluated the therapeutic efficacy of BC-K01 in combination with paclitaxel, as the latter is frequently used to treat patients with EOC. METHODS: Overall survival and prognostic significance were determined in EOC patients according to KARS1 and 67LR expression levels as determined by immunohistochemistry. Changes in the location and expression of KARS1 and 67LR were investigated in vitro after BC-K01 treatment. The effects of this compound on tumor growth and apoptosis were evaluated both in vitro and in vivo. RESULTS: EOC patients with high KARS1 and high 67LR expression had lower progression-free survival rates than those with low expression levels of these two markers. BC-K01 reduced cell viability and increased apoptosis in combination with paclitaxel in EOC cell xenograft mouse models. BC-K01 decreased membranous KARS1 expression, causing a reduction in 67LR membrane expression in EOC cell lines. BC-K01 significantly decreased in vivo tumor weight and number of nodules, especially when used in combination with paclitaxel. CONCLUSIONS: Co-localization of KARS1 and 67LR in the plasma membrane contributes to EOC progression. Inhibition of the KARS1-67LR interaction by BC-K01 suppresses metastasis in EOC.

Non-Invasive Photodynamic Therapy against -Periodontitis-causing Bacteria.

Periodontitis is initiated by causative bacteria in the gingival sulcus. However, as the lesion is often deep and out of circulation system and biofilm is frequently formed on the bacteria cluster, use of antibacterial agents has been limited and the invasive method such as curettage is thought as an only treatment. Here we designed non-invasive photodynamic therapy (PDT), with the ointment which leads a photosensitizer deliverable into gingival sulcus. We assessed whether 650 nm light-emitting-diode (LED) penetrates the 3-mm soft tissue and effectively activates a photosensitizer toluidine-blue-O (TBO) through the thickness to remove Porphyromonas gingivalis and Fusobacterium nucleatum species. The oral ointment formulation was optimized to efficiently deliver the photosensitizer into gingival sulcus and its efficacy of PDT was evaluated in in vitro and in vivo models. Four weeks of TBO-formulation mediated-PDT treatment significantly attenuated periodontitis-induced alveolar bone loss and inflammatory cytokines production in rats. These results confirm that a 650 nm LED indeed penetrates the gingiva and activates our TBO formulation which is sufficiently delivered to, and retained within, the gingival sulcus; thus, it effectively kills the bacteria that reside around the gingival sulcus. Collectively, TBO-mediated PDT using LED irradiation has potential as a safe adjunctive procedure for periodontitis treatment.

Evaluation of pemetrexed and etoposide as therapeutic regimens for human papillomavirus-positive oral and oropharyngeal cancer.

Although human papillomavirus (HPV) positive oral and oropharyngeal cancers have distinct epidemiologic and molecular characteristics compared to HPV-negative cancers, all patients with oral and oropharyngeal cancers received same standard regimen regardless of HPV status. For these reasons, specific regimens for patients with HPV-positive oral and oropharyngeal cancer are needed. Differentially expressed genes (DEG) between HPV-positive and HPV-negative oropharyngeal cancers were re-analyzed and categorized from public database. Then, druggable targets to HPV-positive oral and oropharyngeal cancer were identified and were validated with E6/E7, which is oncogene of HPV, transfected oral and oropharyngeal cancer cell lines and HPV infected cell lines. In DEG analysis, HPV-positive oral and oropharyngeal cancer showed distinct disease entity from HPV-negative cancers. Unlike HPV-negative oral and oropharyngeal cancer, thymidylate synthase (TS) and topoisomerase II (Topo II) were overexpressed in HPV-positive cancers. Transfection of Lenti-virus containing E6/ E7 to HPV-negative oral and oropharyngeal cancer cells induced upregulation of TS and Topo II in those cells. Although cisplatin, which is standard regimen in head and neck cancers, showed more effectiveness in HPV-negative cells, 5-FU and pemetrexed, which are TS inhibitors, or etoposide, which is Topo II inhibitors, worked more effectively in HPV-positive cells. In addition, cisplatin/etoposide and cisplatin/pemetrexed combination regimens showed synergic effects in HPV-positive cells. Pemetrexed or etoposide alone, or in combination with other chemotherapeutic agents such as cisplatin, can be used as novel substitutes in a regimen of concurrent chemoradiotherapy or a palliative regimen for HPV-positive oral and oropharyngeal cancer patients. However, a well-designed clinical trial is needed.

Elective neck dissection versus observation in early stage oral squamous cell carcinoma: recurrence and survival.

OBJECTIVES: To evaluate the results of elective neck dissection versus those of observation in the treatment of early stage oral squamous cell carcinoma and to identify factors related to recurrence and survival. MATERIALS AND METHODS: This was a retrospective study of 52 patients who underwent elective neck dissection and 27 who did not receive neck dissection. RESULTS: In survival analyses, elective neck dissection showed a benefit in overall recurrence (P=0.027), especially in stage I patients (P=0.024). With regard to survival, the benefit was statistically insignificant (P=0.990). In multivariable analysis, overall recurrence was independently related to poor histologic grade (odds ratio [OR]=9.65, P=0.006), and cancer-specific death was independently related to advanced age (OR=6.3, P=0.022), higher clinical T stage (OR=15.2, P=0.01), and poorly differentiated histologic grade (OR=6.6, P=0.025). CONCLUSION: Though there was lower recurrence in the elective neck dissection group, there were no statistically significant results on survival. The characteristics of the tumor itself, such as clinical T stage and poor histologic grade, may be more important in cancer-specific survival.