Immunohistochemistry of p53 surrogates mutation as an accurate predictor for early-relapse of surgically resected stage I-III lung adenocarcinoma.

Introduction: is a strong tumor suppressor gene; its deactivation contributes to carcinogenesis and influences clinical outcomes. However, the prognostic influence of p53 deactivation on early relapse in patients with surgically resected non-small cell lung cancer remains unclear.

Materials And Methods: A cohort of 170 patients with primary stage I through III lung adenocarcinoma (LADC) and lung squamous cell carcinoma who underwent complete resection at Tokyo Medical and Dental University was screened for mutations using panel testing, and association studies between mutations and clinical data, including histology and postoperative recurrence, were performed.

The possibility of mutations of RAS signaling genes and/or TP53 in combination as a negative prognostic impact on pathological stage I non-small cell lung cancer.

Background: The recurrence rate of non-small cell lung cancer (NSCLC) is as high as 30%, even in the cancer with pathological stage I disease. Therefore, identifying factors predictive of high-risk pathological recurrence is important. However, few studies have examined the genetic status of these tumors and its relationship to prognosis.

Diversity and Evolution of Highly Repetitive DNA Sequences Constituting Chromosome Site-Specific Heterochromatin in Two Gerbillinae Species.

Constitutive heterochromatin, consisting of repetitive sequences, diverges very rapidly; therefore, its nucleotide sequences and chromosomal distributions are often largely different, even between closely related species. The chromosome C-banding patterns of two Gerbillinae species, Meriones unguiculatus and Gerbillus perpallidus, vary greatly, even though they belong to the same subfamily. To understand the evolution of C-positive heterochromatin in these species, we isolated highly repetitive sequences, determined their nucleotide sequences, and characterized them using chromosomal and filter hybridization.

Identification of a Biallelic Missense Variant in Gasdermin D (c.823G > C, p.Asp275His) in a Patient of Atypical Gorham-Stout Disease in a Consanguineous Family.

Gorham-Stout disease (GSD), also called vanishing bone disease, is a rare osteolytic disease, frequently associated with lymphangiomatous tissue proliferation. The causative genetic background has not been noted except for a case with a somatic mutation in . However, in the present study, we encountered a case of GSD from a consanguineous family member.

Therapeutic applications of local injection of hsa-miR-634 into canine spontaneous malignant melanoma tumors.

Malignant melanoma (MM) is one of the most common tumors in both dogs and humans. As canine MM (CMM) and human MM (HMM) have similar clinical characteristics, CMM appears to be a good clinical model for HMM. We previously demonstrated that the introduction of a synthetic double-strand-microRNA-634 (miR-634) mimic triggered apoptotic cell death by directly targeting the genes associated with cytoprotective processes in various human cancer cell lines, including those of HMM.

Imaging flow cytometry-based multiplex FISH for three IGH translocations in multiple myeloma.

Three types of chromosomal translocations, t(4;14)(p16;q32), t(14;16)(q32;q23), and t(11;14)(q13;q32), are associated with prognosis and the decision making of therapeutic strategy for multiple myeloma (MM). In this study, we developed a new diagnostic modality of the multiplex FISH in immunophenotyped cells in suspension (Immunophenotyped-Suspension-Multiplex (ISM)-FISH). For the ISM-FISH, we first subject cells in suspension to the immunostaining by anti-CD138 antibody and, then, to the hybridization with four different FISH probes for genes of IGH, FGFR3, MAF, and CCND1 tagged by different fluorescence in suspension.

Potential for reversing -mediated cytoprotective processes to improve efficacy of chemotherapy against oral squamous cell carcinoma.

For advanced oral squamous cell carcinoma (OSCC), increasing sensitivity to chemotherapy is a major challenge in improving treatment outcomes, and targeting cytoprotective processes that lead to the chemotherapy resistance of cancer cells may be therapeutically promising. Tumor-suppressive microRNAs (miRNAs) can target multiple cancer-promoting genes concurrently and are thus expected to be useful seeds for cancer therapeutics. We revealed that -mediated targeting of multiple cytoprotective process-related genes, including cellular inhibitor of apoptosis protein 1 (), can effectively increase cisplatin (CDDP)-induced cytotoxicity and overcome CDDP resistance in OSCC cells.

Clinical Utility of Germline Genetic Testing in Japanese Men Undergoing Prostate Biopsy.

Background: Multiple common variants and also rare variants in monogenic risk genes such as and have been reported to be associated with risk of prostate cancer (PCa); however, the clinical setting in which germline genetic testing could be used for PCa diagnosis remains obscure. Herein, we tested the clinical utility of a 16 common variant-based polygenic risk score (PRS) that has been developed previously for Japanese men and also evaluated the frequency of PCa-associated rare variants in a prospective cohort of Japanese men undergoing prostate biopsy.

Methods: A total of 1336 patients undergoing first prostate biopsy were included.

Genomic landscape of a mouse model of diffuse-type gastric adenocarcinoma.

Background: There is a need for a model of diffuse-type gastric cancer that captures the features of the disease, facilitates the study of its mechanisms, and aids the development of potential therapies. One such model may be Cdh1 and Trp53 double conditional knockout (DCKO) mice, which have histopathological features similar to those of human diffuse-type gastric cancer. However, a genomic profile of this mouse model has yet to be completed.

miR-766-5p Targets Super-Enhancers by Downregulating CBP and BRD4.

Super-enhancers (SE) are clusters of transcription enhancers that drive gene expression. SEs are typically characterized by high levels of acetylation of histone H3 lysine 27 (H3K27ac), which is catalyzed by the histone lysine acetyltransferase CREB binding protein (CBP). Cancer cells frequently acquire tumor-specific SEs at key oncogenes, such as , which induce several hallmarks of cancer.

Integrative genome-wide analyses reveal the transcriptional aberrations in Japanese esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a malignant disease. At present, the genomic profiles of ESCC are known to a considerable extent, and DNA methylation and gene expression profiles have been mainly used for the classification of ESCC subtypes, but integrative genomic, transcriptomic, and epigenomic analyses remain insufficient. Therefore, we performed integrative analyses using whole-exome sequencing, DNA methylation, and RNA sequencing (RNA-seq) analyses of Japanese patients with ESCC.

Concurrent targeting of MAP3K3 and BRD4 by overcomes acquired resistance to BET inhibitors in neuroblastoma cells.

Neuroblastoma (NB) harboring amplification is a refractory disease with a poor prognosis. As BRD4, an epigenetic reader belonging to the bromodomain and extra terminal domain (BET) family, drives transcription of in NB cells, BET inhibitors (BETis) are considered useful for NB therapy. However, clinical trials of BETis suggested that early acquired resistance to BETis limits their therapeutic benefit.

Cancer-associated miRNAs and their therapeutic potential.

MicroRNA (miRNA; miR) is a functionally small non-coding RNA and can negatively regulate gene expression by directly binding to the target gene. Some miRNAs are closely involved in the development and progression of cancer and are abnormally expressed in many cancer types. Therefore, control of the expression of cancer-associated miRNAs is expected as a next-generation drug modality to treat advanced types of cancers with high unmet medical needs.

Augmentation of lenvatinib efficacy by topical treatment of ointment in anaplastic thyroid cancer.

Anaplastic thyroid cancer (ATC) is one of the most lethal types of human tumors. Lenvatinib can improve the disease control and prognosis in patients with ATC. However, there is an unmet need to develop a therapeutically safer and non-invasive strategy that improves the efficacy of lenvatinib for advanced ATC tumors, which grow larger close to the skin.

Identification of PDHX as a metabolic target for esophageal squamous cell carcinoma.

The metabolism in tumors is reprogrammed to meet its energetic and substrate demands. However, this metabolic reprogramming creates metabolic vulnerabilities, providing new opportunities for cancer therapy. Metabolic vulnerability as a therapeutic target in esophageal squamous cell carcinoma (ESCC) has not been adequately clarified.

Isolation and characterisation of lymphatic endothelial cells from lung tissues affected by lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a rare pulmonary disease characterised by the proliferation of smooth muscle-like cells (LAM cells), and an abundance of lymphatic vessels in LAM lesions. Studies reported that vascular endothelial growth factor-D (VEGF-D) secreted by LAM cells contributes to LAM-associated lymphangiogenesis, however, the precise mechanisms of lymphangiogenesis and characteristics of lymphatic endothelial cells (LECs) in LAM lesions have not yet been elucidated. In this study, human primary-cultured LECs were obtained both from LAM-affected lung tissues (LAM-LECs) and normal lung tissues (control LECs) using fluorescence-activated cell sorting (FACS).

A missense variant in NUF2, a component of the kinetochore NDC80 complex, causes impaired chromosome segregation and aneuploidy associated with microcephaly and short stature.

Mutations in proteins involved in cell division and chromosome segregation, such as microtubule-regulating, centrosomal and kinetochore proteins, are associated with microcephaly and/or short stature. In particular, the kinetochore plays an essential role in mitosis and cell division by mediating connections between chromosomal DNA and spindle microtubules. To date, only a few genes encoding proteins of the kinetochore complex have been identified as causes of syndromes that include microcephaly.

Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation.

Reversible modification of proteins with linkage-specific ubiquitin chains is critical for intracellular signaling. Information on physiological roles and underlying mechanisms of particular ubiquitin linkages during human development are limited. Here, relying on genomic constraint scores, we identify 10 patients with multiple congenital anomalies caused by hemizygous variants in , encoding a K48/K63 linkage-specific deubiquitylase.

Suppression of MET Signaling Mediated by Pitavastatin and Capmatinib Inhibits Oral and Esophageal Cancer Cell Growth.

Despite increasing knowledge on oral and esophageal squamous cell carcinoma (OSCC and ESCC), specific medicines against both have not yet been developed. Here, we aimed to find novel anticancer drugs through functional cell-based screening of an FDA-approved drug library against OSCC and ESCC. Pitavastatin, an HMGCR inhibitor, emerged as an anticancer drug that inhibits tumor growth by downregulating AKT and ERK signals in OSCC and ESCC cells.

Improving the Efficacy of EGFR Inhibitors by Topical Treatment of Cutaneous Squamous Cell Carcinoma with Ointment.

For cutaneous squamous cell carcinoma (cSCC), topical treatment is an essential option for patients who are not candidates for, or who refuse, surgery. Epidermal growth factor receptor (EGFR) plays a key role in the development of cSCC, but EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib, have shown only partial clinical benefit in this disease. Thus, there is an unmet need to develop novel strategies for improving the efficacy of TKIs in cSCC.

Clinical efficacy of haematopoietic stem cell transplantation for adult adrenoleukodystrophy.

Accumulated experience supports the efficacy of allogenic haematopoietic stem cell transplantation in arresting the progression of childhood-onset cerebral form of adrenoleukodystrophy in early stages. For adulthood-onset cerebral form of adrenoleukodystrophy, however, there have been only a few reports on haematopoietic stem cell transplantation and the clinical efficacy and safety of that for adulthood-onset cerebral form of adrenoleukodystrophy remain to be established. To evaluate the clinical efficacy and safety of haematopoietic stem cell transplantation, we conducted haematopoietic stem cell transplantation on 12 patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy in a single-institution-based prospective study.