TM4SF19 controls GABP-dependent YAP transcription in head and neck cancer under oxidative stress conditions.

Tobacco and alcohol are risk factors for human papillomavirus-negative head and neck squamous cell carcinoma (HPV- HNSCC), which arises from the mucosal epithelium of the upper aerodigestive tract. Notably, despite the mutagenic potential of smoking, HPV- HNSCC exhibits a low mutational load directly attributed to smoking, which implies an undefined role of smoking in HPV- HNSCC. Elevated YAP (Yes-associated protein) mRNA is prevalent in HPV- HNSCC, irrespective of the YAP gene amplification status, and the mechanism behind this upregulation remains elusive. Here, we report that oxidative stress, induced by major risk factors for HPV- HNSCC such as tobacco and alcohol, promotes YAP transcription via TM4SF19 (transmembrane 4 L six family member 19). TM4SF19 modulates YAP transcription by interacting with the GABP (Guanine and adenine-binding protein) transcription factor complex. Mechanistically, oxidative stress induces TM4SF19 dimerization and topology inversion in the endoplasmic reticulum membrane, which in turn protects the GABPß1 subunit from proteasomal degradation. Conversely, depletion of TM4SF19 impairs the survival, proliferation, and migration of HPV- HNSCC cells, highlighting the potential therapeutic relevance of targeting TM4SF19. Our findings reveal the roles of the key risk factors of HPV- HNSCC in tumor development via oxidative stress, offering implications for upcoming therapeutic approaches in HPV- HNSCC.

Weight-bearing activity impairs nuclear membrane and genome integrity via YAP activation in plantar melanoma.

Acral melanoma commonly occurs in areas that are not exposed to much sunlight, such as the sole of the foot. Little is known about risk factors and mutational processes of plantar acral melanoma. Nuclear envelope rupture during interphase contributes to genome instability in cancer. Here, we show that the nuclear and micronuclear membranes of melanoma cells are frequently ruptured by macroscopic mechanical stress on the plantar surface due to weight-bearing activities. The marginal region of plantar melanoma nodules exhibits increased nuclear morphological abnormalities and collagen accumulations, and is more susceptible to mechanical stress than the tumor center. An increase in DNA damage coincides with nuclear membrane rupture in the tumor margin. Nuclear envelope integrity is compromised by the mechanosensitive transcriptional cofactor YAP activated in the tumor margin. Our results suggest a mutagenesis mechanism in melanoma and explain why plantar acral melanoma is frequent at higher mechanical stress points.

The Development of AXL Inhibitors in Lung Cancer: Recent Progress and Challenges.

AXL, along with MER and TYRO3, is a receptor tyrosine kinase from the TAM family. Although AXL itself is not thought to be a potent oncogenic driver, overexpression of AXL is known to trigger tumor cell growth, survival, invasion, metastasis, angiogenesis, epithelial to mesenchymal transition, and immune suppression. Overexpression of AXL is associated with therapy resistance and poor prognosis. Therefore, it is being studied as a marker of prognosis in cancer treatment or as a target in various cancer types. Recently, many preclinical and clinical studies on agents with various mechanisms targeting AXL have been actively conducted. They include small molecule inhibitors, monoclonal antibodies, and antibody-drug conjugates. This article reviewed the fundamental role of AXL in solid tumors, and the development in research of AXL inhibitors in recent years. Emphasis was placed on the function of AXL in acquired therapy resistance in patients with non-small cell lung cancer (NSCLC). Since clinical needs increase in NSCLC patients with acquired resistance after initial therapy, recent research efforts have focused on a combination treatment with AXL inhibitors and tyrosine kinase inhibitors or immunotherapy to overcome resistance. Lastly, we deal with challenges and limitations encountered in the development of AXL inhibitors.

Combining Cancer Vaccines with Immunotherapy: Establishing a New Immunological Approach.

Therapeutic cancer vaccines have become increasingly qualified for use in personalized cancer immunotherapy. A deeper understanding of tumor immunology and novel antigen delivery technologies has assisted in optimizing vaccine design. Therapeutic cancer vaccines aim to establish long-lasting immunological memory against tumor cells, thereby leading to effective tumor regression and minimizing non-specific or adverse events. However, due to several resistance mechanisms, significant challenges remain to be solved in order to achieve these goals. In this review, we describe our current understanding with respect to the use of the antigen repertoire in vaccine platform development. We also summarize various intrinsic and extrinsic resistance mechanisms behind the failure of cancer vaccine development in the past. Finally, we suggest a strategy that combines immune checkpoint inhibitors to enhance the efficacy of cancer vaccines.

Cervical Spinal Fracture Caused by Untreated Tourette Syndrome: A Case Report.

Cervical myelopathy can occur in Tourette syndrome patients with severe motor tics showing repetitive and violent neck movements. However, motor tics causing spinal fractures have been rarely reported. A 15-year-old girl presented at our clinic, complaining of recent development of motor weakness of all 4 extremities. She had untreated motor tics involving the neck. Computed tomography and magnetic resonance imaging findings suggested cervical spinal fractures and myelopathy. After diagnosing of Tourette syndrome, medical and psychologic therapies were started. Her motor tics were well controlled, and no complications in the patient's daily life were observed later. Cervical radiography taken at a 9-month follow-up showed bony healings of the fractured cervical spines. Uncontrolled severe motor tics may cause spinal fractures. Conservative treatments would suffice for proper control of these tics and stabilize the spine, and considered as initial treatment in patients with Tourette syndrome.

Philadelphia+ Chronic Myeloid Leukemia with CALR Mutation: A Case Report and Literature Review.

Myeloproliferative neoplasms (MPNs) are classified as chronic myeloid leukemia (CML) and Philadelphia chromosome-negative MPN. In MPN cases, the presence of a BCR-ABL1 translocation with a coexisting mutation is exceptionally rare. Herein, we report the first documented patient with CML harboring CALR mutation in Korea. A 33-year-old woman was referred to our hospital in February 2015 with splenomegaly, leukocytosis, and thrombocytosis. She was diagnosed with CML and started receiving nilotinib. In October 2015, a major molecular response was observed, but thrombocytosis persisted. A repeat bone marrow (BM) examination revealed no specific findings. However, as thrombocytosis worsened, we changed nilotinib to dasatinib. In May 2019, owing to persistent thrombocytosis, we repeated the BM examination and found CALR mutation (15.97%) on the MPN-next generation sequencing (NGS) test. We then retrospectively performed repeat MPN-NGS testing using the BM aspirate sample obtained in 2015 and found CALR mutation (10.64%).

Economic evaluation of manual therapy for musculoskeletal diseases: a protocol for a systematic review and narrative synthesis of evidence.

INTRODUCTION: Manual therapy is the non-surgical conservative management of musculoskeletal disorders using the practitioner's hands on the patient's body for diagnosing and treating disease. The aim of this study is to systematically review trial-based economic evaluations of manual therapy relative to other interventions used for the management of musculoskeletal diseases. METHODS AND ANALYSIS: Randomised clinical trials (RCTs) on the economic evaluation of manual therapy for musculoskeletal diseases will be included in the review. The following databases will be searched from their inception: Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Econlit, Mantis, Index to Chiropractic Literature, Science Citation Index, Social Science Citation Index, Allied and Complementary Medicine Database (AMED), Cochrane Database of Systematic Reviews (CDSR), National Health Service Database of Abstracts of Reviews of Effects (NHS DARE), National Health Service Health Technology Assessment Database (NHS HTA), National Health Service Economic Evaluation Database (NHS EED), CENTRAL, five Korean medical databases (Oriental Medicine Advanced Searching Integrated System (OASIS), Research Information Service System (RISS), DBPIA, Korean Traditional Knowledge Portal (KTKP) and KoreaMed) and three Chinese databases (China National Knowledge Infrastructure (CNKI), VIP and Wanfang). The evidence for the cost-effectiveness, cost-utility and cost-benefit of manual therapy for musculoskeletal diseases will be assessed as the primary outcome. Health-related quality of life and adverse effects will be assessed as secondary outcomes. We will critically appraise the included studies using the Cochrane risk of bias tool and the Drummond checklist. Results will be summarised using Slavin's qualitative best-evidence synthesis approach. ETHICS AND DISSEMINATION: The results of the study will be disseminated via a peer-reviewed journal and/or conference presentations. TRIAL REGISTRATION NUMBER: PROSPERO CRD42015026757.