Asia Oceania Guidelines for the Implementation of Programs for Cervical Cancer Prevention and Control

This paper aims to provide evidence-based recommendations for health professionals, to develop a comprehensive cervical cancer program for a clinic, a community, or a country. Ensuring access to healthcare is the responsibility of all societies, and the Asia Oceania Research Organisation in Genital Infections and Neoplasia (AOGIN) is committed to working collaboratively with governments and health professionals to facilitate prevention programs, to protect girls and women from cervical cancer, a disease that globally affects 500,000 and kills nearly 300,000 women annually, just over half of whom are in the Asia Oceania region. We share the vision that a comprehensive program of vaccination, screening, and treatment should be made accessible to all girls and women in the world. The primary purpose of these guidelines is to provide information on scientific evidence on the different modalities and approaches of cervical cancer prevention programs, for high resource and low resource settings. The secondary purpose is to provide an overview of the current situation of cervical cancer control and prevention in various Asian Oceania countries: their views of an ideal program, identified obstacles, and suggestions to overcome them are discussed

RASSF1A–LATS1 signalling stabilizes replication forks by restricting CDK2-mediated phosphorylation of BRCA2

Genomic instability is a key hallmark of cancer leading to tumour heterogeneity and therapeutic resistance. ​BRCA2 has a fundamental role in error-free DNA repair but also sustains genome integrity by promoting ​RAD51 nucleofilament formation at stalled replication forks. ​CDK2 phosphorylates ​BRCA2 (pS3291-​BRCA2) to limit stabilizing contacts with polymerized ​RAD51; however, how replication stress modulates ​CDK2 activity and whether loss of pS3291-​BRCA2 regulation results in genomic instability of tumours are not known. Here we demonstrate that the Hippo pathway kinase ​LATS1 interacts with ​CDK2 in response to genotoxic stress to constrain pS3291-​BRCA2 and support ​RAD51 nucleofilaments, thereby maintaining genomic fidelity during replication stalling. We also show that ​LATS1 forms part of an ​ATR-mediated response to replication stress that requires the tumour suppressor ​RASSF1A. Importantly, perturbation of the ​ATR–​RASSF1A–​LATS1 signalling axis leads to genomic defects associated with loss of ​BRCA2 function and contributes to genomic instability and ‘BRCA-ness’ in lung cancers

Quantitative High-Speed Laryngoscopic Analysis of Vocal Fold Vibration in Fatigued Voice of Young Karaoke Singers

Summary: Purpose. The present study aimed to determine whether there were physiological differences in the vocal fold vibration between nonfatigued and fatigued voices using high-speed laryngoscopic imaging and quantitative analysis. Methods. Twenty participants aged from 18 to 23 years (mean, 21.2 years; standard deviation, 1.3 years) with normal voice were recruited to participate in an extended singing task. Vocal fatigue was induced using a singing task. Highspeed laryngoscopic image recordings of /i/ phonation were taken before and after the singing task. The laryngoscopic images were semiautomatically analyzed with the quantitative high-speed video processing program to extract indices related to the anteroposterior dimension (length), transverse dimension (width), and the speed of opening and closing. Results. Significant reduction in the glottal length-to-width ratio index was found after vocal fatigue. Physiologically, this indicated either a significantly shorter (anteroposteriorly) or a wider (transversely) glottis after vocal fatigue. Conclusion. The high-speed imaging technique using quantitative analysis has the potential for early identification of vocally fatigued voice

Targeting of Slc25a21 is associated with orofacial defects and otitis media due to disrupted expression of a neighbouring gene.

Homozygosity for Slc25a21(tm1a(KOMP)Wtsi) results in mice exhibiting orofacial abnormalities, alterations in carpal and rugae structures, hearing impairment and inflammation in the middle ear. In humans it has been hypothesised that the 2-oxoadipate mitochondrial carrier coded by SLC25A21 may be involved in the disease 2-oxoadipate acidaemia. Unexpectedly, no 2-oxoadipate acidaemia-like symptoms were observed in animals homozygous for Slc25a21(tm1a(KOMP)Wtsi) despite confirmation that this allele reduces Slc25a21 expression by 71.3%. To study the complete knockout, an allelic series was generated using the loxP and FRT sites typical of a Knockout Mouse Project allele. After removal of the critical exon and neomycin selection cassette, Slc25a21 knockout mice homozygous for the Slc25a21(tm1b(KOMP)Wtsi) and Slc25a21(tm1d(KOMP)Wtsi) alleles were phenotypically indistinguishable from wild-type. This led us to explore the genomic environment of Slc25a21 and to discover that expression of Pax9, located 3' of the target gene, was reduced in homozygous Slc25a21(tm1a(KOMP)Wtsi) mice. We hypothesize that the presence of the selection cassette is the cause of the down regulation of Pax9 observed. The phenotypes we observed in homozygous Slc25a21(tm1a(KOMP)Wtsi) mice were broadly consistent with a hypomorphic Pax9 allele with the exception of otitis media and hearing impairment which may be a novel consequence of Pax9 down regulation. We explore the ramifications associated with this particular targeted mutation and emphasise the need to interpret phenotypes taking into consideration all potential underlying genetic mechanisms

Validation of the GALS musculoskeletal screening exam for use in primary care: a pilot study

<p>Abstract</p> <p>Background</p> <p>As the proportion of the Canadian population ≥65 grows, so too does the prevalence of musculoskeletal (MSK) conditions. Approximately 20% of visits to family physicians occur as a result of MSK complaints. The GALS (Gait, Arms, Legs, and Spine) screening examination was developed to assist in the detection of MSK abnormalities. Although MSK exams are primarily performed by rheumatologists or other MSK specialists, expanding their use in primary health care may improve the detection of MSK conditions allowing for earlier treatment. The primary goal of this study was to evaluate the use of the GALS locomotor screen in primary care by comparing the results of assessments of family physicians with those of rheumatologists. The secondary goal was to examine the incidence of MSK disorders and assess the frequency with which new diagnoses not previously documented in patients' charts were identified.</p> <p>Methods</p> <p>Patients ≥65 years old recruited from an academic family health centre were examined by a rheumatologist and a family physician who recorded the appearance of each participant's gait and the appearance and movement of the arms, legs and spine by deeming them normal or abnormal. GALS scores were compared between physicians with the proportion of observed (P_obs), positive (P_pos) and negative (P_neg) agreement being the primary outcomes. Kappa statistics were also calculated. Descriptive statistics were used to describe the number of "new" diagnoses by comparing rheumatologists' findings with each patient's family practice chart.</p> <p>Results</p> <p>A total of 99 patients consented to participate (92 with previously diagnosed MSK conditions). Results showed reasonable agreement between family physicians and rheumatologists; P_obs= 0.698, P_pos= 0.614 and P_neg= 0.752. The coefficient of agreement (estimated Kappa) was 0.3675 for the composite GALS score. For individual components of the GALS exam, the highest agreement between family physicians and rheumatologists was in the assessment of gait and arm movement.</p> <p>Conclusion</p> <p>Previously reported increases in undiagnosed signs and symptoms of musculoskeletal conditions have highlighted the need for a simple yet sensitive screening exam for the identification of musculoskeletal abnormalities. Results of this study suggest that family physicians can efficiently use the GALS examination in the assessment of populations with a high proportion of musculoskeletal issues.</p

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A&gt;T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Tumour Suppressive Function and Modulation of Programmed Cell Death 4 (PDCD4) in Ovarian Cancer

Background: Programmed cell death 4 (PDCD4), originally identified as the neoplastic transformation inhibitor, was attenuated in various cancer types. Our previous study demonstrated a continuous down-regulation of PDCD4 expression in the sequence of normal-borderline-malignant ovarian tissue samples and a significant correlation of PDCD4 expression with disease-free survival. The objective of the current study was to further investigate the function and modulation of PDCD4 in ovarian cancer cells. Principal Findings: We demonstrated that ectopic PDCD4 expression significantly inhibited cell proliferation by inducing cell cycle arrest at G1 stage and up-regulation of cell cycle inhibitors of p27 and p21. Cell migration and invasion were also inhibited by PDCD4. PDCD4 over-expressing cells exhibited elevated phosphatase and tensin homolog (PTEN) and inhibited protein kinase B (p-Akt). In addition, the expression of PDCD4 was up-regulated and it was exported to the cytoplasm upon serum withdrawal treatment, but it was rapidly depleted via proteasomal degradation upon serum re-administration. Treatment of a phosphoinositide 3-kinase (PI3K) inhibitor prevented the degradation of PDCD4, indicating the involvement of PI3K-Akt pathway in the modulation of PDCD4. Conclusion: PDCD4 may play a critical function in arresting cell cycle progression at key checkpoint, thus inhibiting cell proliferation, as well as suppressing tumour metastasis. The PI3K-Akt pathway was implied to be involved in the regulatio