Multi-ancestry genome-wide analysis identifies shared genetic effects and common genetic variants for self-reported sleep duration.

Both short (≤6 h per night) and long sleep duration (≥9 h per night) are associated with increased risk of chronic diseases. Despite evidence linking habitual sleep duration and risk of disease, the genetic determinants of sleep duration in the general population are poorly understood, especially outside of European (EUR) populations. Here, we report that a polygenic score of 78 European ancestry sleep duration single-nucleotide polymorphisms (SNPs) is associated with sleep duration in an African (n = 7288; P = 0.003), an East Asian (n = 13 618; P = 6 × 10-4) and a South Asian (n = 7485; P = 0.025) genetic ancestry cohort, but not in a Hispanic/Latino cohort (n = 8726; P = 0.71). Furthermore, in a pan-ancestry (N = 483 235) meta-analysis of genome-wide association studies (GWAS) for habitual sleep duration, 73 loci are associated with genome-wide statistical significance. Follow-up of five loci (near HACD2, COG5, PRR12, SH3RF1 and KCNQ5) identified expression-quantitative trait loci for PRR12 and COG5 in brain tissues and pleiotropic associations with cardiovascular and neuropsychiatric traits. Overall, our results suggest that the genetic basis of sleep duration is at least partially shared across diverse ancestry groups.

Neighbourhood relationships moderate the positive association between family caregiver burden and psychological distress in Japanese adults: a cross-sectional study.

OBJECTIVES: Family caregiver burden is associated with higher psychological distress. However, little is known about the impact of neighbourhood relationships on caregivers' psychological distress. We examined whether neighbourhood relationships of caregivers moderate the association between family caregiver burden and psychological distress. STUDY DESIGN: This was a cross-sectional study. METHODS: We recruited 5321 Japanese adults who participated in the Japan Multi-Institutional Collaborative Cohort Study in the Okazaki area between 2013 and 2017. Participants completed self-reported questionnaires to measure psychological distress (Kessler 6: K6), subjective caregiver burden, and neighbourhood relationships. We performed a multivariable linear regression analysis in which caregiver burden was designated as an independent variable and the K6 score as a dependent variable, adjusting for demographics. The interaction term between caregiver burden and neighbourhood relationships was also included in the analysis. RESULTS: Data from a total of 5069 participants were included (mean age [standard deviation]: 63.1 years [10.3 years]; 2226 [43.9%] female). Caregiver burden was significantly and positively associated with psychological distress (compared with no burden, mild burden: ß = 0.24, P = 0.197; severe burden: ß = 0.60, P < 0.01; P for trend < 0.01). There was a significant negative interaction effect of caregiver burden × neighbourhood relationship on psychological distress (severe burden × good neighbourhood relationship: ß = -3.29, P < 0.01). CONCLUSIONS: A higher caregiver burden was associated with higher psychological distress, and neighbourhood relationships moderated this association. Our findings suggest that good neighbourhood relationships can buffer caregiving-associated psychological distress.

Time-Resolved Measurement of Interatomic Coulombic Decay Induced by Two-Photon Double Excitation of Ne_{2}.

The hitherto unexplored two-photon doubly excited states [Ne^{*}(2p^{-1}3s)]_{2} were experimentally identified using the seeded, fully coherent, intense extreme ultraviolet free-electron laser FERMI. These states undergo ultrafast interatomic Coulombic decay (ICD), which predominantly produces singly ionized dimers. In order to obtain the rate of ICD, the resulting yield of Ne_{2}^{+} ions was recorded as a function of delay between the extreme ultraviolet pump and UV probe laser pulses. The extracted lifetimes of the long-lived doubly excited states, 390(-130/+450) fs, and of the short-lived ones, less than 150 fs, are in good agreement with ab initio quantum mechanical calculations.

Slow Interatomic Coulombic Decay of Multiply Excited Neon Clusters.

Ne clusters (∼5000 atoms) were resonantly excited (2p→3s) by intense free electron laser (FEL) radiation at FERMI. Such multiply excited clusters can decay nonradiatively via energy exchange between at least two neighboring excited atoms. Benefiting from the precise tunability and narrow bandwidth of seeded FEL radiation, specific sites of the Ne clusters were probed. We found that the relaxation of cluster surface atoms proceeds via a sequence of interatomic or intermolecular Coulombic decay (ICD) processes while ICD of bulk atoms is additionally affected by the surrounding excited medium via inelastic electron scattering. For both cases, cluster excitations relax to atomic states prior to ICD, showing that this kind of ICD is rather slow (picosecond range). Controlling the average number of excitations per cluster via the FEL intensity allows a coarse tuning of the ICD rate.

Towards characterization of photo-excited electron transfer and catalysis in natural and artificial systems using XFELs.

The ultra-bright femtosecond X-ray pulses provided by X-ray Free Electron Lasers (XFELs) open capabilities for studying the structure and dynamics of a wide variety of biological and inorganic systems beyond what is possible at synchrotron sources. Although the structure and chemistry at the catalytic sites have been studied intensively in both biological and inorganic systems, a full understanding of the atomic-scale chemistry requires new approaches beyond the steady state X-ray crystallography and X-ray spectroscopy at cryogenic temperatures. Following the dynamic changes in the geometric and electronic structure at ambient conditions, while overcoming X-ray damage to the redox active catalytic center, is key for deriving reaction mechanisms. Such studies become possible by using the intense and ultra-short femtosecond X-ray pulses from an XFEL, where sample is probed before it is damaged. We have developed methodology for simultaneously collecting X-ray diffraction data and X-ray emission spectra, using an energy dispersive spectrometer, at ambient conditions, and used this approach to study the room temperature structure and intermediate states of the photosynthetic water oxidizing metallo-protein, photosystem II. Moreover, we have also used this setup to simultaneously collect the X-ray emission spectra from multiple metals to follow the ultrafast dynamics of light-induced charge transfer between multiple metal sites. A Mn-Ti containing system was studied at an XFEL to demonstrate the efficacy and potential of this method.

Genetic epidemiology of tooth agenesis in Japan: a population- and family-based study.

Tooth agenesis is one of the most common congenital anomalies in humans. However, the etiology of tooth agenesis remains largely unclear, as well as evidence base useful for genetic counseling. Therefore, we estimated the prevalence and sibling recurrence risk, and investigated agenetic patterns systematically. Tooth agenesis was classified into two subtypes: hypodontia (one to five missing teeth) and oligodontia (six or more missing teeth). The prevalence of these two subtypes were 6.8% [95% confidence interval (CI): 6.1-7.7%] and 0.1% (95% CI: 0.04-0.3%), respectively, and sibling recurrence risk of these were 24.5% (95% CI: 13.8-38.3%) and 43.8% (95% CI: 26.4-62.3%), respectively. This result suggests that the severe phenotype, oligodontia, might be mostly transmitted in a dominant fashion. Using a simple statistical modeling approach, our data were found to be consistent with a bilateral symmetry model, meaning that there was equal probability of missing teeth from the right and left sides.

Akt phosphorylation in human chondrocytes is regulated by p53R2 in response to mechanical stress.

OBJECTIVE: The p53 tumor-suppressor protein p53R2 is activated in response to various stressors that act on cell signaling. When DNA is damaged, phosphorylation of p53 at its Ser 15 residue induces p53R2 production. The role of p53R2 in chondrocytes remains poorly understood. In this study, we evaluated in chondrocytes, p53R2 expression and its regulation in response to mechanical stress. Furthermore, we investigated the function of p53R2 in relation to mechanotransduction. METHODS: Osteoarthritis (OA) cartilage obtained from total knee replacements and normal cartilage obtained from femoral neck fractures was used to measure p53R2 expression by using immunohistochemistry, western blotting, and real-time polymerase chain reaction (PCR). The OA chondrocytes were subjected to a high magnitude of cyclical tensile strain by using an FX-2000 Flexercell system. Next, sulfated glycosaminoglycan (sGAG) production was quantified in these cells. Protein expression of p53R2, and phosphorylation of Akt, p38MAPK, ERK1/2, and JNK was also detected using western blotting. Moreover, Akt phosphorylation was detected after transfecting the cells with p53R2-specific small interfering RNA (siRNA). RESULTS: Expression of p53R2 was significantly increased in OA chondrocytes and in chondrocytes after applying 5% tensile strain to the cells. However, Akt phosphorylation was down-regulated in OA chondrocytes after the strain, and was up-regulated after transfection of p53R2. sGAG protein as well as collagen type II and aggrecan mRNA was increased following transfection of p53R2-specific siRNA after 5% tensile strain. CONCLUSIONS: p53R2 could regulate matrix synthesis via Akt phosphorylation during chondrocyte mechanotransduction. Down-regulation of p53R2 may be a new therapeutic approach in OA therapy.

Clinical significance of serum growth-regulated oncogene alpha (GROalpha) in patients with gynecological cancer.

PURPOSE OF INVESTIGATION: To assess the clinical relevance of serum growth-regulated oncogene alpha (GROalpha) levels in gynecological cancer, we investigated its concentration in distinguishing patients with cervical cancer, endometrial cancer, ovarian cancer, benign ovarian tumor and control. METHODS: Preoperative serum GROalpha levels were measured in women with cervical cancer (n=46), endometrial cancer (n=39), ovarian cancer (n=124), benign ovarian tumors (n=52), and normal controls (n=38) using an enzyme-linked immunosorbent assay. RESULTS: Statistical analyses showed that the serum GROalpha concentration was significantly elevated in the cervical cancer, endometrial cancer and ovarian cancer patients compared with controls. Using GROalpha levels, the receiver operating characteristic (ROC) of cervical cancer (AUC approximately 0.775), endometrial cancer (AUC approximately 0.799), ovarian cancer (AUC approximately 0.749) and benign ovarian tumors (AUC approximately 0.568) vs. controls were identified. CONCLUSION: Our findings suggest that serum GROalpha measurement as a molecular marker might contribute to detection and diagnosis of gynecological cancer.

DcR3 induces cell proliferation through MAPK signaling in chondrocytes of osteoarthritis.

INTRODUCTION: Decoy receptor 3 (DcR3), a soluble receptor belonging to the tumor necrosis factor (TNF) receptor superfamily, competitively binds and inhibits the TNF family including Fas-ligand (Fas-L), lymphotoxin-like inducible protein that competes with glycoprotein D for binding herpesvirus entry mediator on T-cells (LIGHT) and TNF-like ligand 1A (TL1A). In this study, we investigated the functions of DcR3 on osteoarthritis (OA) chondrocytes. METHODS: Expressions of DcR3 in chondrocytes were measured by realtime Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR). Expression of DcR3 in sera and joint fluids was measured by enzyme-linked immunosorbent assay (ELISA). Chondrocytes were incubated with DcR3-Fc chimera protein (DcR3-Fc) before induction of apoptosis by Fas-L and apoptosis was detected with terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labelling labeling (TUNEL) staining and Western blotting of caspase 8 and poly (ADP-ribose) polymerase (PARP). Chondrocytes were incubated with DcR3-Fc and the proliferation was analyzed by 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate (WST) assay. Phosphorylation of Extracellular Signal-Regulated Kinase (ERK), P38 mitogen-activated protein kinase (MAPK) and Jun N-terminal Kinase (JNK) in chondrocytes was measured by Western blotting after incubation with DcR3-Fc, Mitogen-activated protein kinase kinase (MEK1/2) inhibitor, or P38 MAPK inhibitor. Chondrocytes were treated with DcR3-Fc after pre-incubation with blocking antibody of Fas-L, LIGHT and TL1A, and proliferation or phosphorylation of ERK was analyzed. RESULTS: DcR3 was expressed in OA and normal chondrocytes. DcR3-Fc protects chondrocytes from Fas-induced apoptosis. DcR3-Fc increased chondrocytes proliferation and induced the phosphorylation of ERK specifically. DcR3-induced chondrocytes proliferation was inhibited by pre-incubation of PD098059 or blocking Fas-L antibody. DcR3 increased chondrocytes proliferation in OA chondrocytes, but did not in normal. CONCLUSION: DcR3 regulates the proliferation of OA chondrocytes via ERK signaling and Fas-induced apoptosis.

A primary canine and an impacted permanent canine with infection potentially induced an intracranial abscess.

Intracranial abscess is a rare but life-threatening disease. There have been no reports on intracranial abscess induced by the residual primary tooth and the impacted successive permanent tooth with infection. We report on an interesting case of a 29-year-old man suffering from an epidural abscess, potentially caused by an infection of the residual primary maxillary right canine and the impacted permanent maxillary right canine. The patient recovered completely after prolonged antibiotic treatment and extraction of both of the suspected teeth. Fusobacterium sp. was isolated from the culture of a peripheral blood sample. This case alerts us to realize that the lack of suitable and timely intervention in oral conditions might produce a harmful effect on general health.

Human amnion contains a novel laminin variant, laminin 7, which like laminin 6, covalently associates with laminin 5 to promote stable epithelial-stromal attachment.

Stable attachment of external epithelia to the basement membrane and underlying stroma is mediated by transmembrane proteins such as the integrin alpha6beta4 and bullous pemphigoid antigen 2 within the hemidesmosomes along the basolateral surface of the epithelial cell and their ligands that include a specialized subfamily of laminins. The laminin 5 molecule (previously termed kalinin/nicein/epiligrin) is a member of this epithelial-specific subfamily. Laminin 5 chains are not only considerably truncated within domains III-VI, but are also extensively proteolytically processed in vitro and in vivo. As a result, the domains expected to be required for the association of laminins with other basement membrane components are lacking in the mature laminin 5 molecule. Therefore, the tight binding of laminin 5 to the basement membrane may occur by a unique mechanism. To examine laminin 5 in tissue, we chose human amnion as the source, because of its availability and the similarity of the amniotic epithelial basement membrane with that of skin. We isolated the laminin 5 contained within the basement membrane of human amnion. In addition to monomeric laminin 5, we find that much of the laminin 5 isolated is covalently adducted with laminin 6 (alpha3beta1gamma1) and a novel laminin isotype we have termed laminin 7 (alpha3beta2gamma1). We propose that the association between laminin 5 and laminins 6 and 7 is a mechanism used in amnion to allow stable association of laminin 5 with the basement membrane. The beta2 chain is seen at the human amniotic epithelial-stromal interface and at the dermal-epidermal junction of fetal and adult bovine skin by immunofluorescence, but is not present, or only weakly present, in neonatal human skin.

Interaction between midazolam and serotonin in spinally mediated antinociception in rats.

PURPOSE: Intrathecal administration of serotonin (5-HT) is antinociceptive through the involvement of spinal cord gamma-aminobutyric acid (GABA) receptors. Therefore, 5-HT would interact with the GABA agonist, midazolam, which is well known to exert spinally mediated antinociception in the spinal cord. The present study investigated the antinociceptive interaction between spinally administered 5-HT and midazolam, using two different rat nociceptive models. METHODS: Sprague-Dawley rats with lumbar intrathecal catheters were tested for their thermal tail withdrawal response and paw flinches induced by formalin injection after the intrathecal administration of midazolam or 5-HT, or the midazolam/ HT combination. The effects of the combination were tested by isobolographic analysis, using the combination of each 1, 1/2, 1/4, 1/8, and 1/16 of the 50% effective dose (ED50). The total fractional dose was calculated. Behavioral side effects were also examined. RESULTS: 5-HT alone and midazolam alone both showed dose-dependent antinociception in both the tail flick test and the formalin test. The ED50 of the combination was not different from the calculated additive value either in the tail flick test or in phase 2 of the formalin test, but it was significantly smaller than the calculated additive value in phase 1 of the formalin test. The total fractional dose value was 0.90 in the tail flick test, 0.093 in phase 1 of the formalin test, and 1.38 in phase 2 of the formalin test. The agitation, allodynia, or motor disturbance observed with either agent alone was not seen with the combination treatment. CONCLUSION: The antinociceptive effects of intrathecal midazolam and 5-HT were additive on thermal acute and inflammatory facilitated stimuli, and synergistic on inflammatory acute stimulation.

Low-Dose-Rate and High-Dose-Rate Brachytherapy for Localized Prostate Cancer in ABO-Incompatible Renal Transplant Recipients.

BACKGROUND: Brachytherapy is one of the standard treatments for localized prostate cancer (CaP). However, the feasibility of brachytherapy for renal transplant recipients (RTRs) is still uncertain. MATERIALS AND METHODS: Between August 2007 and March 2018, all patients who had undergone low-dose-rate (LDR) brachytherapy or high-dose-rate (HDR) brachytherapy for clinically localized CaP at our institution were retrospectively identified (n = 394). Of these patients, 3 had a history of renal transplantation. We reviewed all available clinical data retrospectively. RESULTS: All of the RTRs received ABO-incompatible renal grafts from their spouses and had stable renal graft function before the diagnosis of CaP. The median age at diagnosis of CaP was 65 years (range, 60-67 years). The median time between transplantation and brachytherapy was 7 years (range, 4-10 years). In all of the patients, clinical stage was cT1cN0M0. Two patients received 125I LDR-brachytherapy (dose, 145 Gy) and 1 patient was treated by 192Ir HDR brachytherapy (dose, 19 Gy in 2 fractions) combined with external beam radiation therapy of 39 Gy in 13 fractions. The median follow-up period after brachytherapy was 44 months (range, 34-50 months). During the follow-up period, none of the patients developed disease progression including biochemical recurrence or clinically significant adverse events associated with radiation therapy. CONCLUSIONS: LDR brachytherapy and HDR brachytherapy are safe and technically feasible in RTRs with CaP, and oncological outcomes in RTRs do not appear to be inferior to those of patients who did not receive renal transplant.

Plasmin induces degradation and dysfunction of laminin 332 (laminin 5) and impaired assembly of basement membrane at the dermal-epidermal junction.

BACKGROUND: The epidermal basement membrane (BM), located at the dermal-epidermal junction (DEJ), plays important roles not only in adhesion between epidermis and dermis, but also in controlling skin functions. In sun-exposed skin, the BM becomes disrupted and multilayered. In order to explore the impairment of BM assembly, we have used a skin-equivalent (SE) as a model of BM damage and previously clarified the involvement of matrix metalloproteinases (MMPs) in impairment of BM assembly. OBJECTIVES: In this work, we examined the role of urokinase-type plasminogen activator (uPA) and plasmin in impairment of BM assembly at the DEJ by using the SE, as ultraviolet irradiation to the skin increases uPA as well as MMPs. METHODS: SEs were used as a model of formation and damage of BM. Human uPA was detected by enzyme-linked immunosorbent assay and zymography, and gelatinases such as MMP-2 and MMP-9 were detected by zymography. Human plasminogen was added at 0.06 micromol L(-1) (about 3% of plasma level) to increase plasmin to a pathological level. N-terminal peptide sequence analysis of plasmin-treated laminin 332 was carried out to identify alpha3, beta3 and gamma2 chains of laminin 332 and their cleavage sites of each chain. Plasmin-treated laminin 332 was analysed in keratinocyte adhesion activity and binding to type VII collagen. RESULTS: Human uPA was detected in addition to MMP-2 and MMP-9, in conditioned medium of SE. Although the BM was well organized in the presence of an MMP inhibitor alone, the activated plasmin disorganized the BM even in the presence of the inhibitor. The impairment of BM assembly made the epidermis thinner as compared with that of a control cultured in the presence of MMP inhibitor, indicating that the BM affects the polarity and differentiation of the epidermis. The addition of aprotinin, a serine proteinase inhibitor, and tranexamic acid, a uPA-plasmin inhibitor, inhibited the plasmin-induced impairment of BM assembly and facilitated BM reorganization, thereby improving the epidermal structure. N-terminal peptide sequence analysis of plasmin-treated laminin 332 revealed the removal of a 5- or 10-kDa fragment, including the cell adhesion region, from the G3 domain of the alpha3 chain, and the LN domain, which binds to the noncollagenous 1 domain in type VII collagen, from the beta3 chain. Plasmin-treated laminin 332 showed lower keratinocyte adhesion activity and reduced binding to type VII collagen. CONCLUSIONS: These results suggest that uPA and plasmin are involved in the impairment of BM assembly and epidermal differentiation, and that these effects arise at least partly through direct degradation of laminin 332.

Interaction between a NMDA receptor antagonist, AP-5 and an AMPA receptor antagonist, YM 872 in antinociception in the spinal cord.

BACKGROUND: The intrathecal N-methyl-D-aspartate (NMDA) receptor antagonist, AP-5 and the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist, YM 872 showed inhibition on both acute and facilitated nociception in our previous study. The present study was performed to investigate the interaction between intrathecal AP-5 and YM 872 in antinociception for acute and chronic nociception. METHODS: Sprague-Dawley rats with lumbar intrathecal catheters were tested for their thermal tail withdrawal response and for their paw flinches by formalin injection after intrathecal administration of AP-5 or YM 872. The effects of the combination were tested by an isobolographic analysis using 50% effective dose (ED50). Total fractional dose was calculated as (ED50 dose of AP-5 in combination)/(ED50 dose of AP-5 alone)+(ED50 dose of YM 872 in combination)/(ED50 dose of YM 872 alone). RESULTS: Intrathecally administered AP-5, YM 872, and their combination produced dose-dependent increases of the tail-flick latency and decreases in the number of flinches in both phase 1 and 2 of the formalin test. The ED50 values of the combination were significantly lower than the calculated additive values (P<0.01). Total fractional dose value was 0.22 in the tail flick test, 0.12 in the phase 1 and 0.14 in the phase 2 of the formalin test. CONCLUSION: An NMDA receptor antagonist, AP-5 and an AMPA receptor antagonist, YM 872 had synergistic antinociceptive effects on both acute thermal and inflammatory induced acute and facilitated nociception.

rac p21 is involved in insulin-induced membrane ruffling and rho p21 is involved in hepatocyte growth factor- and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced membrane ruffling in KB cells.

Insulin and hepatocyte growth factor (HGF) induced morphologically different membrane rufflings in KB cells. Insulin-induced membrane ruffling was inhibited by microinjection of rho GDI, an inhibitory GDP/GTP exchange regulator for both rho p21 and rac p21 small GTP-binding proteins, but not inhibited by microinjection of botulinum exoenzyme C3, known to selectively ADP-ribosylate rho p21 and to impair its function. This rho GDI action was prevented by comicroinjection with guanosine 5'-(3-O-thio)triphosphate (GTP gamma S)-bound rac1 p21. In contrast, HGF-induced membrane ruffling was inhibited by microinjection of rho GDI or C3. This rho GDI action was prevented by comicroinjection with GTP gamma S-bound rhoA p21, and this C3 action was prevented by comicroinjection with GTP gamma S-bound rhoAIle-41 p21, which is resistant to C3. Microinjection of either GTP gamma S-bound rac1 p21 or rhoA p21 alone induced membrane ruffling in the absence of the growth factors. The rac1 p21-induced membrane ruffling was morphologically similar to the insulin-induced kind, whereas rhoA p21-induced ruffling was apparently different from both the insulin- and HGF-induced kinds. Membrane ruffling was also induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), a protein kinase C-activating phorbol ester, but not by Ca2+ ionophore or microinjection of a dominant active Ki-ras p21 mutant (Ki-rasVal-12 p21). The phorbol ester-induced membrane ruffling was morphologically similar to the rhoA p21-induced kind and inhibited by microinjection of rho GDI or C3. These results indicate that rac p21 and rho GDI are involved in insulin-induced membrane ruffling and that rho p21 and rho GDI are involved in HGF- and phorbol ester-induced membrane rufflings.

Importance of the intracrine metabolism of adrenal androgens in androgen-dependent prostate cancer.

The metabolic pathways of androgens and processes by which androgens induce re-growth after androgen deprivation therapy in prostate cancer have not been fully elucidated. In this study, finasteride decreased PSA secretion in medium containing testosterone, androstenedione, androstenediol and dehydroepiandrosterone, whereas dihydrotestosterone (DHT)- and hydroxy-flutamide-induced PSA production was not inhibited by finasteride in LNCaP-FGC cells. The present data show that adrenal androgen precursors do not directly interact with androgen receptors (ARs) but are converted to DHT via the intraprostatic metabolic pathways, resulting in the induction of LNCaP activity. This is the first report confirming this mechanism experimentally and also suggest the use of combined therapies that target ARs and prevent the formation of DHT within prostate cancer cells to achieve optimal therapeutic efficacy.

APOBEC3A associates with human papillomavirus genome integration in oropharyngeal cancers.

The prevalence of human papillomavirus (HPV)-related oropharyngeal cancers has been increasing in developed countries. We recently demonstrated that members of the apolipoprotein B mRNA-editing catalytic polypeptide 3 (APOBEC3, A3) family, which are antiviral factors, can induce hypermutation of HPV DNA in vitro. In the present study, we found numerous C-to-T and G-to-A hypermutations in the HPV16 genome in oropharyngeal cancer (OPC) biopsy samples using differential DNA denaturation PCR and next-generation sequencing. A3s were more abundantly expressed in HPV16-positive OPCs than in HPV-negative, as assessed using immunohistochemistry and reverse transcription quantitative PCR. In addition, interferons upregulated A3s in an HPV16-positive OPC cell line. Furthermore, quantitative PCR analysis of HPV DNA suggests that APOBEC3A (A3A) expression is strongly correlated with the integration of HPV DNA. These results suggest that HPV16 infection may upregulate A3A expression, thereby increasing the chance of viral DNA integration. The role of A3A in HPV-induced carcinogenesis is discussed.