Prevalence of oral human papillomavirus infection among the general adult population in Hong Kong.

A cross-sectional study in 2021-23 collected oral rinse gargle samples from an human papillomaviruses (HPV) vaccine-naïve general adult population in Hong Kong. HPV was detected by a PCR using SPF10 primers, and genotyped by a linear array covering 25 genotypes. Epidemiologic information including sociodemographics, medical history, oral health, and sexual behavior were collected by a self-administered questionnaire. Altogether, 2323 subjects aged 18-75 (median 47) years with 50.1% male were recruited. The prevalence for oral HPV infection with all genotypes combined, high-risk, and low-risk genotypes was 1.5%, 0.7%, and 0.7%, respectively; and with no statistically significant difference between participant gender. The prevalence increased with age and was highest in women at 45-54 years (2.7% for all genotypes combined), and highest in men aged >64 years (4.1% for all genotypes combined). HPV52 was the most common genotype among all participants. Univariate analysis suggested more lifetime sexual or oral sexual partners as risk factors, but they did not reach statistical significance upon multivariate analysis; whereas higher educational level had an independent protective effect. To conclude, oral HPV prevalence increased with age in Hong Kong. Strategies to prevent oral HPV infection and the associated cancers are urgently needed.

Economic Burden of Cervical and Head and Neck Cancer in Taiwan from a Societal Perspective.

BACKGROUND: Head and neck cancers (HNC) are increasingly recognized as important human papillomavirus (HPV)-related malignancies in addition to cervical cancer (CC). However, data on the socioeconomic impact of HNC and CC in Taiwan are limited. METHODS: A retrospective cohort study was conducted to estimate the total direct medical cost and indirect productivity loss from CC and HNC between 2014 and 2015. Patient data from the Taiwan National Cancer Registry were analyzed, with matched non-cancer controls from the Taiwan National Healthcare Reimbursement Database. Indirect costs due to premature deaths were calculated using public data from Taiwanese government reports. RESULTS: In the direct cost analysis, 2083 patients with newly diagnosed CC and 11,078 with newly diagnosed HNC (10,036 males) were identified between 2014 and 2015 and followed up through the end of 2016 or until death. The total direct medical costs incurred in 2014 and 2015 due to HNC were 11.54 times higher in males than in females, and 4.55 times higher than CC. Indirect cost analysis showed the total annual productivity loss was New Taiwan Dollar (NTD) $12 billion in 2019, and 79.99% was attributed to male HNC. CONCLUSION: In Taiwan, the socioeconomic burden associated with male HNC is high and greater than that seen with CC. While not all HNCs are attributable to HPV infection, prevention of HNC through HPV vaccination should be considered for both sexes.

m6A demethylase FTO renders radioresistance of nasopharyngeal carcinoma via promoting OTUB1-mediated anti-ferroptosis.

Radiotherapy is a valid treatment for nasopharyngeal carcinoma (NPC), and radioresistance is the main cause of local NPC treatment failure. However, the underlying mechanisms and valuable markers of radioresistance for NPC remain have not been established. In this study, we observed that the m6A mRNA demethylase fat mass and obesity-associated protein (FTO) was significantly upregulated in radioresistant NPC tissues and cells relative to parental radiosensitive NPC tissues and cells. FTO enhances radioresistance by repressing radiation-induced ferroptosis in NPC. Mechanistically, FTO acts as an m6A demethylase to erase the m6A modification of the OTUB1 transcript and promote the expression of OTUB1, thereby inhibiting the ferroptosis of cells induced by radiation and finally triggering the radiotherapy resistance of NPC. Furthermore, our in vivo experiment results showed that the FTO inhibitor, FB23-2, and the ferroptosis activator, erastin, altered tumor responsiveness to radiotherapy in NPC cell lines and patient-derived xenografts. Our findings reveal, for the first time, that FTO enhances NPC radiotherapy resistance by withstanding radiation-induced ferroptosis, suggesting that FTO may serve as a potential therapeutic target and valuable prognostic biomarker in patients with NPC.

BMI-1 promotes breast cancer proliferation and metastasis through different mechanisms in different subtypes.

Breast cancer is among the most common malignant cancers in women. B-cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) is a transcriptional repressor that has been shown to be involved in tumorigenesis, the cell cycle, and stem cell maintenance. In our study, increased expression of BMI-1 was found in both human triple negative breast cancer and luminal A-type breast cancer tissues compared with adjacent tissues. We also found that knockdown of BMI-1 significantly suppressed cell proliferation and migration in vitro and in vivo. Further mechanistic research demonstrated that BMI-1 directly bound to the promoter region of CDKN2D/BRCA1 and inhibited its transcription in MCF-7/MDA-MB-231. More importantly, we discovered that knockdown of CDKN2D/BRCA1 could promote cell proliferation and migration after repression by PTC-209. Our results reveal that BMI-1 transcriptionally suppressed BRCA1 in TNBC cell lines whereas, in luminal A cell lines, CDKN2D was the target gene. This provides a reference for the precise treatment of different types of breast cancer in clinical practice.

The Clinical and Economic Impact of a Nonavalent Versus Bivalent Human Papillomavirus National Vaccination Program in Taiwan.

OBJECTIVES: This study aimed to estimate the epidemiologic and economic impact of a nonavalent human papillomavirus (HPV) vaccination program for 13- to 14-year-old females compared with that of the bivalent vaccine in Taiwan. METHODS: A previously developed dynamic transmission model for the nonavalent HPV vaccine was adapted to the Taiwan setting. The natural history of cervical cancer and genital warts was simulated by the HPV model assuming an 80% vaccination coverage rate in girls aged 13 to 14 years of age with a 2-dose schedule for the nonavalent and bivalent HPV vaccines. A lifetime duration of vaccine protection was assumed for the HPV vaccine types. RESULTS: The model estimated that the nonavalent HPV vaccine would prevent an additional 15 951 cervical cancer cases, 6600 cervical cancer-related deaths, 176 702 grade 2 or grade 3 cervical intraepithelial neoplasia cases, 103 959 grade 1 cervical intraepithelial neoplasia cases, and 1 115 317 genital warts cases compared with the bivalent HPV vaccine. The nonavalent HPV vaccination program was projected to cost an additional New Taiwan dollars (NTD) 675.21 per person and to produce an additional 0.00271 quality-adjusted life-year per person over 100 years compared with the bivalent HPV vaccine. Thus, the incremental cost-effectiveness ratio of the nonavalent HPV vaccine versus the bivalent HPV vaccine was NTD 249 462/quality-adjusted life-year. CONCLUSIONS: A nonavalent HPV vaccination program for 13- to 14-year-old girls would have additional public health and economic impacts and would be highly cost-effective compared with the bivalent HPV vaccine, relative to per capita gross domestic product, which is estimated at NTD 746 526 for Taiwan.

Establishment of a multilevel linear model to analyse the factors affecting piglet litter performance at birth.

This study aimed to establish a feasible model for analysing factors affecting piglet litter performance at birth. Data of 61,984 litters were collected from 16 herds, and general linear model (GLM), multilevel Poisson regression model (MPM) and multilevel linear model (MLM) were established to compare their goodness of fit for these data. Influencing factors of piglet litter performance at birth were analysed using the established optimal model. Results showed the intraclass correlation coefficients of total born piglets (TBP), piglets born alive (PBA), low-birth-weight piglets (LBW), and average birth weight of piglets (ABW) reached 27.89%, 23.88%, 24.66% and 22.27%, respectively (p < .05). Akaike's information criterion and Bayesian information criterion in MLM of TBP, PBA, LBW and ABW were lower than those in GLM. Pearson residuals in MPM increased to nearly 1 after introduction of a discrete scale factor, and the p values in MPM were similar to those in MLM. Analyses of MLM indicated crossbred sows with good management supplemented with oregano essential oil and farrowing at warm season had higher TBA, PBA and ABW, but lower LBW than other sows (p < .05). In conclusion, MLM is superior to GLM and can replace MPM in analysing discrete data with hierarchical structure in pig production. More importantly, other potential influencing factors of litter performance at birth can be analysed using the established MLM in the future.

Serum and Seminal Plasma Element Concentrations in Relation to Semen Quality in Duroc Boars.

Element concentrations in serum and seminal plasma were studied in Duroc boars with different semen quality characteristics. Based on the utilization rate of 2174 ejaculates from June to August in 2016, a total of 166 Duroc boars were allocated into three groups: low utilization rate group (LG, 0 to 60% utilization rate), medium utilization rate group (MG, 60 to 80%), and high utilization rate group (HG, 80 to 100%). Serum and seminal plasma samples were collected, and element levels were analyzed using inductively coupled plasma mass spectrometry. The results showed that LG boars had higher concentrations of serum copper and seminal plasma cadmium compared with MG and HG boars (P < 0.05), and serum copper and seminal plasma cadmium were negatively correlated with sperm motility, while positively correlated with the abnormal sperm rate. We observed the abnormal sperm rate increased by approximately 4.53% with serum copper increasing from 1.63 to 2.44 mg/L, while sperm motility decreased by approximately 2.85% with seminal plasma cadmium increasing from 0 to 0.82 µg/L. Moreover, serum iron and manganese levels in the LG group were significantly reduced compared with the HG boars (P < 0.05), and the two elements were negatively correlated with the abnormal sperm rate (P < 0.05). In conclusion, excessive copper and absence of iron and manganese in serum as well as higher seminal plasma cadmium may reduce the utilization rate of semen by impairing sperm motility and morphology, indicating the importance of adding and monitoring microelements in boar diet.

Temperament traits in suicidal and non-suicidal mood disorder patients in Taiwan.

Suicide is a major social and clinical problem in Asia. Although studies have suggested that personality traits are possible risk factors for suicide, no study has been conducted among Chinese to compare the temperament traits of suicidal and non-suicidal mood disorder patients with those of healthy controls. This study compared temperament traits of two patient groups, those with a mood disorder who have attempted suicide (n=204), and those with a mood disorder who have not attempted suicide (n=160), and compared the traits of these patients to those of healthy controls (n=178), assessed by Cloninger's Tridimensional Personality Questionnaire and the Brown-Goodwin Aggression Inventory. Patients with suicidal attempts had significantly higher novelty seeking and aggression scores than healthy controls and patients without suicidal attempts. Two groups of patients with mood disorder had significantly higher harm avoidance scores than the healthy controls. However, patients with suicidal attempts did not have higher harm avoidance scores than patients without suicidal attempts. This study confirms findings that harm avoidance and mood disorder are related, and extends them by suggesting that those with a mood disorder and suicide attempts have higher novelty seeking and lifetime aggression scores than those without suicidal attempt, either patients or healthy controls.

Alterations of melatonin receptors MT1 and MT2 in the hypothalamic suprachiasmatic nucleus during depression.

BACKGROUND: The pineal hormone melatonin regulates circadian rhythms, largely by feedback on the central biological clock of the brain, the hypothalamic suprachiasmatic nucleus (SCN). This feedback is mediated by the melatonin receptors, melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2). The circadian system may play a role in the pathophysiology of mood disorders, and indeed, melatonin-receptor agonists are considered a potential therapy for depression. METHOD: In order to investigate melatonin receptors in the SCN during depression, and their relationship to the major neuropeptides in the SCN, vasopressin (AVP) and vasoactive intestinal peptide (VIP), we studied the SCN in 14 depressed patients (five major depression and nine bipolar disorder) and 14 matched controls by immunocytochemistry. RESULTS: We show here that hypothalamic MT2 receptor immunoreactivity was limited to SCN, the supraoptic nucleus and paraventricular nucleus. We found that numbers of MT1-immunoreactive (MT1-ir) cells and AVP and/or VIP-ir cells were increased in the central SCN in depression, but numbers of MT2-ir cells were not altered. Moreover, the number of MT1-ir cells, but not MT2-ir cells was negatively correlated with age at onset of depression, while positively correlated with disease duration. CONCLUSION AND LIMITATIONS: Although every post-mortem study has limitations, MT1 receptors appeared specifically increased in the SCN of depressed patients, and may increase during the course of the disease. These changes may be involved in the circadian disorders and contribute to the efficacy of MT agonists or melatonin in depression. Moreover, we suggest that melatonin receptor agonists for depression should be targeted towards the MT1 receptor selectively.

[Assessment of BIOMED-2 assays for detection of clonal Ig gene rearrangements in mature B-cell lymphomas].

OBJECTIVE: To evaluate the efficiency of the BIOMED-2 PCR assay and its implication in the diagnosis of mature B-cell non-Hodgkin's lymphomas. METHODS: Clinical, morphological and immunohistochemical features of 72 cases of non-Hodgkin's lymphomas were studied, including 25 reactive lymphoid hyperplasia, 37 diffuse large B cell lymphomas (DLBCL) and 35 extranodal marginal zone lymphomas of mucosa associated lymphoid tissues (MALT lymphoma and in addition, 25 cases of reactive lymphoid hyperplasia were used as the controls). DNA was exacted from the paraffin embedded formalin fixed tissue blocks and the quality of DNA was assessed using the BIOMED-2 specimen control reaction. Adequate samples were then analyzed by BIOMED-2 for immunoglobulin heavy and kappa light chain rearrangements. RESULTS: Adequate DNA was obtained in 83 of 97 samples, including 60 mature B cell lymphomas and 23 reactive lymphoid hyperplasia. Clonal B-cell gene rearrangements were detected in 57 of 60 (95%) lymphomas. In contrast, clonal Ig gene rearrangements were not detected in any of the 23 cases of reactive lymphoid hyperplasia. CONCLUSION: BIOMED-2 assay is highly sensitive and specific for the detection of clonal B cell gene rearrangement using routine paraffin embedded formalin fixed specimens.

Diesel pollution biodegradation: synergetic effect of Mycobacterium and filamentous fungi.

OBJECTIVE: To biodegrade the diesel pollution in aqueous solution inoculated with Mycobacterium and filamentous fungi. METHODS: Bacteria sampled from petroleum hydrocarbons contaminated sites in Karamay Oilfield were isolated and identified as Mycobacterium hyalinum (MH) and cladosporium. Spectrophotometry and gas chromatography (GC) were used to analyze of the residual concentrations of diesel oil and its biodegradation products. RESULTS: From the GC data, the values of apparent biodegradation ratio of the bacterial strain MH to diesel oil were close to those obtained in the control experiments. Moreover, the number of MH did not increase with degradation time. However, by using n-octadecane instead of diesel oil, the real biotic degradation ratio increased to 20.9% over 5 days of degradation. Cladosporium strongly biodegraded diesel oil with a real degradation ratio of up to 34% after 5 days treatment. When the two strains were used simultaneously, a significant synergistic effect between them resulted in almost complete degradation of diesel oil, achieving a total diesel removal of 99% over 5 days of treatment, in which one part of about 80% and another part of about 19% were attributed to biotic and abiotic processes, respectively. CONCLUSION: The observed synergistic effect was closely related to the aromatics-degrading ability of Cladosporium, which favored the growth of MH and promoted the bioavailability of diesel oil.

A promoter polymorphism in the monoamine oxidase A gene is associated with the pineal MAOA activity in Alzheimer's disease patients.

BACKGROUND: Monoamine oxidase A (MAOA) is involved in the pathogenesis of mood disorders and Alzheimer's disease (AD). MAOA activity and gene expression have been found to be up-regulated in different brain areas of AD patients, including the pineal gland. Increased pineal MAOA activity might contribute to the reduced pineal melatonin production in AD. A promoter polymorphism of a variable number tandem repeats (VNTR) in the MAOA gene shows to affect MAOA transcriptional activity in vitro. METHODS: Here we examined in 63 aged controls and 44 AD patients the effects of the MAOA-VNTR on MAOA gene expression and activity in the pineal gland as endophenotypes, and on melatonin production. RESULTS: AD patients carrying long MAOA-VNTR genotype (consisting of 3.5- or 4-repeat alleles) showed higher MAOA gene expression and activity than the short-genotyped (i.e., 3-repeat allele) AD patients. Moreover, the AD-related up-regulation of MAOA showed up only among long-genotype bearing subjects. There was no significant effect of the MAOA-VNTR on MAOA activity or gene expression in controls, or on melatonin production in both controls and AD patients. CONCLUSION: Our data suggest that the MAOA-VNTR affects the activity and gene expression of MAOA in the brain of AD patients, and is involved in the changes of monoamine metabolism.

Disturbance and strategies for reactivation of the circadian rhythm system in aging and Alzheimer's disease.

Circadian rhythm disturbances, such as sleep disorders, are frequently seen in aging and are even more pronounced in Alzheimer's disease (AD). Alterations in the biological clock, the suprachiasmatic nucleus (SCN), and the pineal gland during aging and AD are considered to be the biological basis for these circadian rhythm disturbances. Recently, our group found that pineal melatonin secretion and pineal clock gene oscillation were disrupted in AD patients, and surprisingly even in non-demented controls with the earliest signs of AD neuropathology (neuropathological Braak stages I-II), in contrast to non-demented controls without AD neuropathology. Furthermore, a functional disruption of the SCN was observed from the earliest AD stages onwards, as shown by decreased vasopressin mRNA, a clock-controlled major output of the SCN. The observed functional disconnection between the SCN and the pineal from the earliest AD stage onwards seems to account for the pineal clock gene and melatonin changes and underlies circadian rhythm disturbances in AD. This paper further discusses potential therapeutic strategies for reactivation of the circadian timing system, including melatonin and bright light therapy. As the presence of melatonin MT1 receptor in the SCN is extremely decreased in late AD patients, supplementary melatonin in the late AD stages may not lead to clear effects on circadian rhythm disorders.

Decreased MT1 melatonin receptor expression in the suprachiasmatic nucleus in aging and Alzheimer's disease.

The pineal hormone melatonin is involved in the regulation of circadian rhythms and feeds back to the central biological clock, the hypothalamic suprachiasmatic nucleus (SCN) via melatonin receptors. Supplementary melatonin is considered to be a potential treatment for aging and Alzheimer's disease (AD)-related circadian disorders. Here we investigated by immunocytochemistry the alterations of the MT1 melatonin receptor, the neuropeptides vasopressin (AVP) and vasoactive intestinal peptide (VIP) in the SCN during aging and AD. We found that the number and density of AVP/VIP-expressing neurons in the SCN did not change, but the number and density of MT1-expressing neurons in the SCN were decreased in aged controls compared to young controls. Furthermore, both MT1-expressing neurons and AVP/VIP-expressing neurons were strongly diminished in the last neuropathological stages of AD (Braak stages V-VI), but not in the earliest stages (Braak stages I-II), compared to aged controls (Braak stage 0). Our study suggests that the MT1-mediated effects of melatonin on the SCN are disturbed during aging and even more so in late stage AD, which may contribute to the clinical circadian disorders and to the efficacy of therapeutic melatonin administration under these conditions.

Distribution of MT1 melatonin receptor immunoreactivity in the human hypothalamus and pituitary gland: colocalization of MT1 with vasopressin, oxytocin, and corticotropin-releasing hormone.

Melatonin is implicated in numerous physiological processes, including circadian rhythms, stress, and reproduction, many of which are mediated by the hypothalamus and pituitary. The physiological actions of melatonin are mainly mediated by melatonin receptors. We here describe the distribution of the melatonin receptor MT1 in the human hypothalamus and pituitary by immunocytochemistry. MT1 immunoreactivity showed a widespread pattern in the hypothalamus. In addition to the area of the suprachiasmatic nucleus (SCN), a number of novel sites, including the paraventricular nucleus (PVN), periventricular nucleus, supraoptic nucleus (SON), sexually dimorphic nucleus, the diagonal band of Broca, the nucleus basalis of Meynert, infundibular nucleus, ventromedial and dorsomedial nucleus, tuberomamillary nucleus, mamillary body, and paraventricular thalamic nucleus were observed to have neuronal MT1 receptor expression. No staining was observed in the nucleus tuberalis lateralis and bed nucleus of the stria terminalis. The MT1 receptor was colocalized with some vasopressin (AVP) neurons in the SCN, colocalized with some parvocellular and magnocellular AVP and oxytocine (OXT) neurons in the PVN and SON, and colocalized with some parvocellular corticotropin-releasing hormone (CRH) neurons in the PVN. In the pituitary, strong MT1 expression was observed in the pars tuberalis, while a weak staining was found in the posterior and anterior pituitary. These findings provide a neurobiological basis for the participation of melatonin in the regulation of various hypothalamic and pituitary functions. The colocalization of MT1 and CRH suggests that melatonin might directly modulate the hypothalamus-pituitary-adrenal axis in the PVN, which may have implications for stress conditions such as depression.

Pineal clock gene oscillation is disturbed in Alzheimer's disease, due to functional disconnection from the "master clock".

The suprachiasmatic nucleus (SCN) is the "master clock" of the mammalian brain. It coordinates the peripheral clocks in the body, including the pineal clock that receives SCN input via a multisynaptic noradrenergic pathway. Rhythmic pineal melatonin production is disrupted in Alzheimer's disease (AD). Here we show that the clock genes hBmal1, hCry1, and hPer1 were rhythmically expressed in the pineal of controls (Braak 0). Moreover, hPer1 and hbeta1-adrenergic receptor (hbeta1-ADR) mRNA were positively correlated and showed a similar daily pattern. In contrast, in both preclinical (Braak I-II) and clinical AD patients (Braak V-VI), the rhythmic expression of clock genes was lost as well as the correlation between hPer1 and hbeta1-ADR mRNA. Intriguingly, hCry1 mRNA was increased in clinical AD. These changes are probably due to a disruption of the SCN control, as they were mirrored in the rat pineal deprived of SCN control. Indeed, a functional disruption of the SCN was observed from the earliest AD stages onward, as shown by decreased vasopressin mRNA, a clock-controlled major output of the SCN. Thus, a functional disconnection between the SCN and the pineal from the earliest AD stage onward could account for the pineal clock gene changes and underlie the circadian rhythm disturbances in AD.

The human pineal gland and melatonin in aging and Alzheimer's disease.

The pineal gland is a central structure in the circadian system which produces melatonin under the control of the central clock, the suprachiasmatic nucleus (SCN). The SCN and the output of the pineal gland, i.e. melatonin, are synchronized to the 24-hr day by environmental light, received by the retina and transmitted to the SCN via the retinohypothalamic tract. Melatonin not only plays an important role in the regulation of circadian rhythms, but also acts as antioxidant and neuroprotector that may be of importance in aging and Alzheimer's disease (AD). Circadian disorders, such as sleep-wake cycle disturbances, are associated with aging, and even more pronounced in AD. Many studies have reported disrupted melatonin production and rhythms in aging and in AD that, as we showed, are taking place as early as in the very first preclinical AD stages (neuropathological Braak stage I-II). Degeneration of the retina-SCN-pineal axis may underlie these changes. Our recent studies indicate that a dysfunction of the sympathetic regulation of pineal melatonin synthesis by the SCN is responsible for melatonin changes during the early AD stages. Reactivation of the circadian system (retina-SCN-pineal pathway) by means of light therapy and melatonin supplementation, to restore the circadian rhythm and to relieve the clinical circadian disturbances, has shown promising positive results.

Molecular changes underlying reduced pineal melatonin levels in Alzheimer disease: alterations in preclinical and clinical stages.

A disturbed sleep-wake rhythm is common in Alzheimer disease (AD) patients and correlated with decreased melatonin levels and a disrupted circadian melatonin rhythm. Melatonin levels in the cerebrospinal fluid are decreased during the progression of AD neuropathology (as determined by the Braak stages), already in cognitively intact subjects with the earliest AD neuropathology (Braak stages I-II) (preclinical AD). To investigate the molecular mechanisms behind the decreased melatonin levels, we measured monoamines and mRNA levels of enzymes of the melatonin synthesis and its noradrenergic regulation in pineal glands from 18 controls, 33 preclinical AD subjects, and 25 definite AD patients. Pineal melatonin levels were highly correlated with cerebrospinal fluid melatonin levels. The circadian melatonin rhythm disappeared because of decreased nocturnal melatonin levels in both the preclinical AD and AD patients. Also the circadian rhythm of beta(1)-adrenergic receptor mRNA disappeared in both patient groups. The precursor of melatonin, serotonin was stepwise depleted during the course of AD, as indicated by the up-regulated monoamine oxidase A mRNA and activity (5-hydroxyindoleacetic acid:serotonin ratio). We conclude that a dysfunction of noradrenergic regulation and the depletion of serotonin by increased monoamine oxidase A result in the loss of melatonin rhythm already in preclinical AD.