Continuous Global Improvement of Human Papillomavirus (HPV) Genotyping Services: The 2022 and 2023 HPV LabNet International Proficiency Studies.

The International Human Papillomavirus (HPV) Reference Center launches annual global HPV genotyping proficiency panels to enhance the precision and international standardization of HPV genotyping services. This study aims to assess the proficiency levels achieved in the global HPV genotyping proficiency panels conducted in 2022 and 2023, and to evaluate trends in performance over time. The proficiency panels comprised 44 blinded samples each, including 40 samples containing various purified plasmids corresponding to HPV types combined with human DNA, plus four control samples (one negative control and three extraction controls). Proficiency required a sensitivity of 50 International Units (IU)/5 µL for HPV 16 and HPV 18 500 IU/5 µL for HPVs 6, 11, 31, 33, 45, 52, and 58 and 500 genome equivalents (GE)/5 µL for other HPV types in both single and multiple infections, while avoiding false positivity. In 2022, 78 laboratories submitted a total of 154 data sets, and in 2023, 81 laboratories contributed 141 data sets. Most data sets (87%, 258/295) utilized commercially available HPV assays. Proficiency was common, with 77% of data sets meeting the proficiency criteria in 2022 and 79% in 2023. False positive results significantly decreased from 22% in 2022 to 13% in 2023. The high proficiency and increasing specificity in HPV genotyping services indicates progress toward more reliable HPV testing. High accuracy is crucial for supporting global efforts in HPV and cervical cancer elimination.

Prevalence of Mycoplasma genitalium and macrolide resistance in rectal and urine samples among men who have sex with men in Sweden.

OBJECTIVES: While Mycoplasma genitalium is reported as a common rectal infection among men who have sex with men (MSM), published data refer predominantly to urethral infections. Currently, most guidelines recommend M. genitalium testing from urine in men with symptomatic, non-gonococcal urethritis. Macrolide resistance-associated mutations (MRMs) among M. genitalium have increased during the last decade especially among MSM. We aim to demonstrate the prevalence and anatomical distribution of M. genitalium infection and MRM in urine and rectal specimens among MSM in Sweden. METHODS: In this cross-sectional study in 2019, paired urine and rectal samples from symptomatic and asymptomatic MSM attending a sexually transmitted infection clinic in the south of Sweden were screened for M. genitalium, presence of MRM, Neisseria gonorrhoeae, Chlamydia trachomatis, HIV and syphilis. RESULTS: The overall prevalence of M. genitalium was 10.5% (64 of 609), rectal samples 7.6% (46 of 609) and urine samples 3.9% (24 of 609) (p=0.007). Among M. genitalium-positive cases, single rectal and single urethral infection was detected in 62.5% (40 of 64) and 28.1% (18 of 64), respectively (p<0.0001). Infection at both sites was seen in 9.4% (6 of 64). The prevalence of MRM was 67.9% (19 of 28). M. genitalium was significantly associated with HIV (OR 2.60, 95% CI 1.14 to 5.88, p=0.02). Among the MSM, 7.4% (45 of 609) were infected with N. gonorrhoeae, 6.7% (41 of 609) with C. trachomatis, 7.1% (43 of 609) with HIV and 0.7% (4 of 609) with syphilis. CONCLUSIONS: In this study, among MSM, most infections with M. genitalium were detected as rectal mono infections. The prevalence of M. genitalium among MSM was almost twofold higher in rectal samples (7.6%) compared with urine samples (3.9%). The prevalence of macrolide resistance was high with no difference between urine and rectal samples.

Comparing visual inspection with acetic acid, with and without Lugol's Iodine for triage of HPV self-sample positive women in Ethiopia: a randomized controlled trial.

BACKGROUND: Most women who are high-risk human papilloma virus (hrHPV) positive in a cervical cancer screening test will spontaneously heal from their infection. Visual inspection with acetic acid (VIA) is recommended by the World Health Organization as a triage test for cervical screening, however its accuracy as a triage test has been questioned. In this study, we aimed to examine the sensitivity and specificity of VIA with and without Lugol's iodine as a triage test to detect cervical intraepithelial neoplasia (CIN2+) among women who tested positive for hrHPV after self-sampling. METHOD: This two-armed randomized controlled trial (RCT) took place in Adama, Ethiopia. The women who tested positive for vaginal hrHPV (Anyplex ΙΙ, Seegene) after self-sampling were randomized to VIA with or without iodine and appointed to a midwife-led clinic. The result of the triage test was categorized as positive, negative, suspicion of cancer or inconclusive, and treated accordingly. Cervical biopsies were collected from women who were hrHPV positive to serve as a gold standard. RESULTS: 22.4% (197/878) of women tested hrHPV positive. Sensitivity and specificity for VIA to detect CIN2+was 25.0% (95% CI 0.6 to 80.0) and 82.7% (95% CI 69.7 to 91.8), respectively. For VIA with iodine, the sensitivity was 50.0% (95% CI 0.7 to 93.2) and the specificity 86.3% (95% CI 71.4 to 93.0). The difference between the two methods was not statistically significant, p=0.5. The odds of detecting CIN2+ was 5.4 times higher if positive for VIA with iodine compared with a negative result. For VIA without iodine, the odds of detecting CIN2+ was 1.6 compared with a negative result. The odds of detecting CIN2+ was 6.4 times higher if the women were HIV positive than for those who were HIV negative. CONCLUSION: VIA with iodine improved detection of CIN2+ in women who were hrHPV DNA positive but was not significantly better than VIA alone. TRIAL REGISTRATION NUMBER: NCT05125380.

Cervical cancer in Region Skåne, Sweden 2017-2020 after the implementation of primary HPV screening: A quality assurance audit.

INTRODUCTION: Primary human papilloma virus (HPV) screening to detect cervical cancer and dysplastic lesions was implemented in Region Skåne 2017 for women aged 30-70. The aim of this study was to characterize the screening history of women diagnosed with cervical cancer to evaluate the performance of the screening program, as well as to assess the cancer treatments given and shortcomings in the follow-up of women with cervical dysplasia. MATERIAL AND METHODS: We performed a quality assurance audit. The data was collected from the National Cervical Cancer Prevention Registry, Region Skåne Labmedicin database and the Melior Journal system in 2017-2020. RESULTS: We identified 247 women diagnosed with invasive cervical cancer in Region Skåne in 2017-2020. Of these, 35 (14.2%) had a screening history over at least two screening rounds before diagnosis. There were 25 (10.1%) women diagnosed with cervical cancer in between screening intervals, i.e., interval cancer. The most common screening history in women with cervical cancer was irregular screening (143, 57.9%), followed by women being above screening age (44, 17.8%). HPV was detected in 96% of the cases, either in cervical cytology or in the tumor tissue. The screening program detected the disease in 96 (38.9%) of the patients, 149 (60.3%) were diagnosed through symptoms and two (0.80%) as a result of incidental findings. CONCLUSIONS: The most powerful tool in the prevention of cervical cancer is screening program attendance. Prolongation with HPV screening among elderly women will also reduce the incidence of cervical cancer. Today, such cancers are usually discovered when symptoms appear.

Cervix cytology samples revealed increased methylation of the human markers FAM19A4/miR124-2 up to 8 years before adenocarcinoma.

INTRODUCTION: Methylation analysis of the promoter region of tumor-suppressor genes has previously shown high sensitivity for detection of high-grade cervical intraepithelial neoplasia (CIN) and cancer. HPV-testing has a high sensitivity to identify women at risk to develop cancer, and has been implemented in cervical screening programs in several countries. But in most HPV-positive women the infection will clear and they will not develop cancer. Testing for methylation could help to identify women who have potentially progressive cervical disease and need closer follow-up. The goal of the present study was to investigate the potential use of methylation as a triage test of HPV-positive women in the screening program. MATERIAL AND METHODS: A collection of liquid-based cytology (LBC) samples from 106 women, collected between 4 months and 8 years before histologically confirmed cervical cancer or CIN3, was analyzed for hypermethylation of the human genes FAM19A4 and miR124-2. RESULTS: Methylation was detected in 45% (33/73) of normal LBC samples from women who later developed CIN3+, compared with 10% (3/31) of normal LBC samples from women without subsequent dysplasia (P = 0.0006). Overall, methylation was detected in 39% (14/36), 51% (19/37), 61% (14/23) and 70% (7/10) of LBC samples from women who later developed CIN3, adenocarcinoma in situ (AIS), squamous cell carcinoma (SCC) and adenocarcinoma (ADC), respectively. Positive methylation analysis was not significantly more frequent than abnormal cytology of atypical squamous cells of unclear significance or worse (ASCUS+) in LBC samples collected 4 months to 8 years before SCC or AIS; however, prior to the development of ADC, methylation was observed in 7/10 LBC samples, despite normal cytology. Overall, LBC samples collected before invasive cancer (ADC and SCC) were more frequently positive in the methylation analysis than in cytological analysis of ASCUS+ (P = 0.048). For LBC samples collected more than 2 years before the development of AIS, SCC or ADC, methylation analysis showed a higher positivity rate than cytology did. CONCLUSIONS: Testing for methylation of FAM19A4/miR124-2 as a triage for HPV-positive women would be useful to identify women at risk of cancer development, especially adenocarcinoma. Further studies are needed to estimate the cost-effectiveness before introducing methylation testing in the screening program.

Immune delineation of laryngeal papilloma reveals enhanced neutrophil associated gene profile.

Laryngeal papilloma (LP) is a rare benign disease, caused by recurrent multisite papillomas that are referred to as recurrent respiratory papillomatosis (RRP). RRP is caused primarily by two types of human papillomavirus (HPV): HPV6 and HPV11. The immune dysregulation within the microenvironment of the lesions has been shown to likely play a role in the development of RRP. The present study aimed at analyzing the transcriptional profile of immune response genes and cancer-related genes in the LP microenvironment. We used the NanoString® nCounter® analysis system to study expression of 730 genes among seven paired samples of LP and healthy laryngeal (HL) tissue. qRT-PCR and flow cytometric analysis was performed to confirm identified transcripts and follow-up scores of infiltrating immune cells, respectively. In total, 113 differentially expressed transcripts were detected of which 37 showed increased expression levels and 76 decreased expression levels in the LP samples compared to the HL samples (fold change ≥ 2). Transcripts with increased expression levels included S100As (A7, A8, and A12), CEACAM1, neutrophil activation associated cytokines (IL8), chemokines (CXCL6), and IL receptors, e.g., IL4R. Transcripts with decreased expression in LP were associated with innate and adaptive immunity. Overall, HPV6 and 11 were present in 67% and 33% of the patients, respectively. There was a significant increase in neutrophils and a significant decrease in CD8+ T cells in LP. LP samples display an immune profile characterized by enhanced expression of neutrophilic markers and significantly reduced T cell-associated markers.

Increased prevalence of human papillomavirus in fresh tissue from penile cancers compared to non-malignant penile samples: a case-control study.

BACKGROUND: HPV has been detected in approximately 50% of invasive penile cancers but with a large span between 24 and 89%, most likely due to different types of tumors and various methods for HPV analysis. Most studies of HPV in penile cancer have been performed using paraffin-embedded tissue, argued to be at risk for contaminated HPV analysis. Viral activity of HPV, by the use of HPV mRNA expression is well studied in cervical cancer, but seldom studied in penile cancer. The aim was to determine prevalence of HPV types in fresh tissue of penile cancers compared to non-malignant age-matched penile controls. Additional aims were to analyze the viral expression and copy numbers of HPV16-positive tumors and 10 mm adjacent to the tumor. METHODS: Fresh tissue from penile cancer cases was biopsied inside the tumor and 10 mm outside the tumor. Controls were males circumcised for non-malignant reasons, biopsied at surgery. PCR and Luminex assays were used for identification of HPV types. HPV16-positive samples were investigated for copy numbers and expression of HPV16-mRNA. RESULTS: Among tumors (n = 135) and age-matched controls (n = 105), HPV was detected in 38.5% (52/135) and 11.4% (12/105), respectively (p < 0.001), adjusted odds ratio 12.8 (95% confidence interval 4.9-33.6). High-risk HPV types were found in 35.6% (48/135) of tumors and 4.8% (5/105) of controls (p < 0.001). Among tumors and controls, HPV16 was present in 27.4% (37/135) and 1% (1/105), respectively (p < 0.001). Among HPV16-positive penile cancers, mean HPV16 viral copy/cell was 74.4 (range 0.00003-725.4) in the tumor and 1.6 (range 0.001-14.4) 10 mm adjacent from the tumor. HPV16-mRNA analysis of the tumors and 10 mm adjacent from the tumors demonstrated viral activity in 86.5% (32/37) and 21.7% (5/23), respectively. CONCLUSIONS: The prevalence of HPV was significantly higher in penile cancer (38.5%) than among age-matched non-malignant penile samples (11.4%). HPV16 predominates (27.4%) in penile tumors. HPV16 expression was more common in penile cancer than in adjacent healthy tissue, strongly suggesting an etiological role for HPV16 in the development of penile cancer.

Incidence of penile intraepithelial neoplasia and treatment strategies in Sweden 2000-2019.

OBJECTIVES: To analyse the incidence, treatment strategies and complications associated with penile intraepithelial neoplasia (PeIN) in Sweden over a period of 20 years. MATERIALS AND METHODS: Data on PeIN from the Swedish National Penile Cancer Register were analysed regarding treatment in relation to age, size of the PeIN lesion, localization of the PeIN lesion and complications using chi-squared tests and logistic regression. The incidence of PeIN was calculated and age-standardized according to the European Standard population. RESULTS: Between 2000 and 2019 a total of 1113 PeIN cases were reported. The age-standardized incidence of PeIN was 1.40 per 100 000 men (95% confidence interval [CI] 1.32-1.49). An increase in incidence over time was seen, with a standardized incidence rate of 2.37 (95% CI 1.56-3.70) in 2019 compared to the baseline year, 2000. Surgical or topical treatments were given in 75.0% and 14.6% of cases, respectively. The complication rate was higher in laser surgery (12.1%, 7/58) compared to local surgery (4.6%, 16/348; P = 0.03) with an age-adjusted odds ratio (OR) of 2.82 (95% CI 1.10-7.19; P = 0.03). Local surgery was more common than laser surgery in the last 5 years compared to the first 5 years of the study period: OR 5.75 (95% CI 2.94-11.27). Treatments with imiquimod and topical 5-fluorouracil (5-FU) were more common than destructive methods such as photodynamic therapy, cryotherapy, curettage and electrocautery in the last 5 years compared to the first 5 years: OR 9.48 (95% CI 2.29-39.24). CONCLUSIONS: A twofold increase in the age-standardized incidence of PeIN was seen in Sweden over 20 years. Complications were three times more common in laser surgery compared to local surgery. Changes in treatment showed an increase of treatment strategies such as local surgery and treatment with imiquimod and topical 5-FU over time.

Co-testing in cervical screening among 40- to 42-year-old women is unreasonable.

INTRODUCTION: The screening program for cervical cancer in Sweden recommends the use of primary human papillomavirus (HPV) screening for women aged ≥30 to 65 years. Co-testing with both HPV analysis and cytology is recommended at the first screening after the age of 40 years. To fulfil co-testing, all screened women aged 40-42 years within the region of Skåne were co-tested. The aim of the audit was to investigate the proportion of severe dysplasia as diagnosed by cytology and histological follow-up among women with Aptima HPV-negative tests. We also calculated the cost of adding the cytology to the HPV primary screening program. MATERIAL AND METHODS: The local cytology registry was used to identify women aged 40-42 years who attended screening and were co-tested during the 4 years from January 2017 to December 2020. The Aptima HPV messenger RNA assay detects 14 HPV types. For Aptima HPV-negative women with high-grade cytology or histological high-grade squamous intraepithelial lesions (HSILs), we performed extended HPV typing for 40 HPV types with polymerase chain reaction using modified GP5+/6+ primers followed by a Luminex assay. To estimate the added cost of using cytology to identify each histologically confirmed cervical HSIL case among Aptima HPV-negative women, we used the current cost of €21.2 per cytology evaluation at our laboratory. RESULTS: Of 19 599 women, 5.8% (1137/19 599) had abnormal cytology. Among Aptima HPV-negative women, 0.11‰ (2/18 132) had histologically confirmed HSIL. One of the women was infected with HPV18 and the other with HPV73 at the diagnosis of HSIL. The calculated cost to find one HSIL, by adding cytology to HPV-negative cases, was approximately €200 000. CONCLUSIONS: The clinical benefit of a single cytology co-test added to an HPV-based screening program in women aged 40-42 years appears doubtful and economically unreasonable.

HPV73 in cervical cancer and distribution of HPV73 variants in cervical dysplasia.

HPV73 is classified as possibly oncogenic and is not recognized by most commercial primary HPV screening platforms. The aim was to determine the prevalence of HPV73 among invasive cervical cancers, formalin-fixed paraffin embedded (FFPE) samples (N = 69), from southern Sweden during 2009 to 2010. Another aim was to determine proportions of HPV73 among Aptima HPV assay negative cervical cancers (N = 9, out of 206 cancers) and of high-grade cytological cervical diagnosis (N = 75, out of 5807 high grade lesions) in liquid-based cytology (LBC) samples collected between 2016 and 2019. We also investigated the distribution of HPV73 variants A1, A2 and B among HPV73-positive cases. HPV73 was detected by multiplex MGP-PCR and Luminex, and HPV73 variants were identified by sequencing PCR amplicons. HPV73 was detected in 2.9% (2/69, 95% CI: 0.18-9.9) of the FFPE cervical cancer series. Among the Aptima HPV-negative LBC samples, HPV73 was present in 55.5% (5/9) of the cancers and 29.3% (22/75) of the different grades of cervical diagnosis. The A1, A2 and B variants were present in 6.9% (2/29), 82.7% (24/29) and 10.3% (3/29) of the HPV73-positive women, respectively. Among the seven HPV73 cancer cases (two FFPE samples and five LBC samples), six A2 and one A1 isolate were detected. In summary, the A2 variant of HPV73 was most common in our region. In addition, the observed prevalence of HPV73 (2.9%) in cervical cancers and its relative high occurrence (55.5%) among Aptima HPV-negative cancers urge that detection of HPV73 should be included in future primary HPV screening programs.

Penile intraepithelial neoplasia, penile cancer precursors and human papillomavirus prevalence in symptomatic preputium: a cross-sectional study of 351 circumcised men in Sweden.

OBJECTIVES: To investigate the prevalence of pathological disease and spectrum of human papillomavirus (HPV) types among symptomatic foreskin tissue. PATIENTS AND METHODS: Consecutively excised symptomatic foreskins from 351 men were sent for histopathological evaluation. During the surgical procedure, a fresh biopsy was taken for HPV analysis by modified general primer polymerase chain reaction. A medical questionnaire regarding medication, smoking habits, number of lifetime sexual partners, former diseases and surgery performed on penis was completed by all participants. RESULTS: The most common clinical diagnosis and cause for circumcision was phimosis, seen in 85.2%. Histopathologically inflammatory dermatological conditions were present in 87% of the men. The most common histopathological diagnosis was lichen sclerosus (LS) observed among 58.7%. Notably, penile intraepithelial neoplasia (PeIN) was present in 2% without former clinical suspicion. Overall, HPV was detected in 17.1% of the men and 28 different HPV types were found. High-risk (HR) HPV types were identified in 9.1% and HPV16 was present in 2.3%. Current smoking increased the risk of HPV (crude odds ratio [OR] 2.8, confidence interval [CI] 1.4-5.6; P = 0.005). Having >15 lifetime sexual partners increased the risk of HPV (crude OR 2.6, 95% CI 1.4-5.1; P = 0.003) and when adjusted for current smoking the OR was substantially increased (OR 6.0, 95% CI CI 2.2-16.8; P < 0001). CONCLUSIONS: Histopathological evaluation of circumcised symptomatic foreskin revealed PeIN in 2% of the men without any clinical suspicion of malignancy and that treatable dermatological conditions were present in 87%, LS being the most common. HR-HPV types were present in 9%. Due to risk of malignant development both in PeIN and in inflammatory skin diseases we recommend sending all excised foreskins from patients with symptoms for histopathological evaluation as guidance for further clinical management.

Structural Transition with a Sharp Change in the Electrical Resistivity and Spin-Orbit Mott Insulating State in a Rhenium Oxide, Sr3Re2O9.

We report the successful synthesis, crystal structure, and electrical properties of Sr3Re2O9, which contains Re6+ with the 5d1 configuration. This compound is isostructural with Ba3Re2O9 and shows a first-order structural phase transition at ∼370 K. The low-temperature (LT) phase crystallizes in a hettotype structure of Ba3Re2O9, which is different from that of the LT phase of Sr3W2O9, suggesting that the electronic state of Re6+ plays an important role in determining the crystal structure of the LT phase. The structural transition is accompanied by a sharp change in the electrical resistivity. This is likely a metal-insulator transition, as suggested by the electronic band calculation and magnetic susceptibility. In the LT phase, the ReO6 octahedra are rotated in a pseudo-a0a0a+ manner in Glazer notation, which corresponds to C-type orbital ordering. Paramagnetic dipole moments were confirmed to exist in the LT phase by muon spin rotation and relaxation measurements. However, the dipole moments shrink greatly because of the strong spin-orbit coupling in the Re ions. Thus, the electronic state of the LT phase corresponds to a Mott insulating state with strong spin-orbit interactions at the Re sites.

Na-ion mobility in P2-type Na0.5MgxNi0.17-xMn0.83O2 (0 ≤ x ≤ 0.07) from electrochemical and muon spin relaxation studies.

Sodium transition metal oxides with a layered structure are one of the most widely studied cathode materials for Na+-ion batteries. Since the mobility of Na+ in such cathode materials is a key factor that governs the performance of material, electrochemical and muon spin rotation and relaxation techniques are here used to reveal the Na+-ion mobility in a P2-type Na0.5MgxNi0.17-xMn0.83O2 (x = 0, 0.02, 0.05 and 0.07) cathode material. Combining electrochemical techniques such as galvanostatic cycling, cyclic voltammetry, and the galvanostatic intermittent titration technique with µ+SR, we have successfully extracted both self-diffusion and chemical-diffusion under a potential gradient, which are essential to understand the electrode material from an atomic-scale viewpoint. The results indicate that a small amount of Mg substitution has strong effects on the cycling performance and the Na+ mobility. Amongst the tested cathode systems, it was found that the composition with a Mg content of x = 0.02 resulted in the best cycling stability and highest Na+ mobility based on electrochemical and µ+SR results. The current study clearly shows that for developing a new generation of sustainable energy-storage devices, it is crucial to study and understand both the structure as well as dynamics of ions in the material on an atomic level.

14-type HPV mRNA test in triage of HPV DNA-positive postmenopausal women with normal cytology.

BACKGROUND: During 2013 and 2016 the region of Skåne, Sweden started to analyse human papillomavirus (HPV) and cytology in postmenopausal women 60-65 years of age. Our aim was to evaluate high-risk (HR) HPV mRNA testing for the triage of HPV DNA-positive postmenopausal women with normal cytology. METHODS: A total of 271 women, 60-65 years of age, underwent liquid-based cytology (LBC) and HPV testing by using the HR-HPV DNA MGP-PCR-Luminex assay. HR-HPV DNA-positive women with normal cytology underwent complimentary HPV mRNA testing (Aptima, Hologic Inc.). Over a period of 49 months (SD 11.0) the women received regular follow-ups at intervals of 12-18 months. Women with abnormal cytology and/or a positive HR-HPV DNA and/or mRNA result at two subsequent visits were scheduled for colposcopy and clinical examination. RESULTS: Over the surveillance period, 3.6% (10/271) of the HR-HPV DNA-positive women developed histologically confirmed high-grade squamous intraepithelial lesions (HSILs) or worse. The cumulative incidence rates (CIR) were 29.7% (CI 24.8-30.1) for HSIL or worse among HPV mRNA-positive women at enrolment (39.5% 107/271) and 0% among HPV mRNA-negative women (60.5%, 164/271), (p = 0.002). CONCLUSIONS: Postmenopausal women with normal cytology testing positive for HR-HPV mRNA are at increased risk for the development of high-grade cervical intraepithelial neoplasia (CIN), in contrast to women with a negative HR-HPV mRNA outcome. The HR-HPV mRNA APTIMA assay detecting 14 HR-HPV types may be a useful triage method among HPV DNA-positive postmenopausal women with normal cytology.

Cation Distributions and Magnetic Properties of Ferrispinel MgFeMnO4.

The crystal structure and magnetic properties of the cubic spinel MgFeMnO4 were studied by using a series of in-house techniques along with large-scale neutron diffraction and muon spin rotation spectroscopy in the temperature range between 1.5 and 500 K. The detailed crystal structure is successfully refined by using a cubic spinel structure described by the space group Fd3̅m. Cations within tetrahedral A and octahedral B sites of the spinel were found to be in a disordered state. The extracted fractional site occupancies confirm the presence of antisite defects, which are of importance for the electrochemical performance of MgFeMnO4 and related battery materials. Neutron diffraction and muon spin spectroscopy reveal a ferrimagnetic order below TC = 394.2 K, having a collinear spin arrangement with antiparallel spins at the A and B sites, respectively. Our findings provide new and improved understanding of the fundamental properties of the ferrispinel materials and of their potential applications within future spintronics and battery devices.

HPV-mRNA and HPV-DNA detection in samples taken up to seven years before severe dysplasia of cervix uteri.

Randomized clinical trials using human papillomavirus (HPV) DNA testing have found increased protection against cervical cancer and HPV-based screening is globally recommended for women ≥30 years of age. HPV-mRNA is a promising alternative target for cervical screening tests, but assessing equivalence requires longitudinal evaluation over at least the length of a screening interval. Our aim is to analyze the longitudinal sensitivity of HPV-mRNA and HPV-DNA in cervical samples taken up to 7 years before severe cervical intraepithelial neoplasia or worse (CIN3+). From a population-based cohort of 95,023 women in Sweden, cervical samples were frozen at -80°C between May 2007 and January 2012. Registry linkages identified that 1,204 of these women had CIN3+ 4 months to 7 years after enrolment. Baseline samples were analyzed for HPV-mRNA (Aptima, Hologic) and for HPV-DNA (Cobas 4800, Roche) and results from both tests obtained for 1,172 women. For both women <30 and ≥ 30 years, HPV-mRNA had similar sensitivity for CIN3+ as HPV-DNA (p = 0.0217 and p = 0.0123 in noninferiority testing for at least 90% relative sensitivity, respectively). Among women ≥30 years, the longitudinal sensitivities for CIN3+ occurring 5-7 years later were comparable [76.3% (95% CI: 65.8%-84.3%) and 82.5% (95% CI: 72.6%-89.4%)] as were the longitudinal negative predictive values for absence of CIN3+ [99.97% (95% CI: 99.95-99.98) and 99.98% (95% CI: 99.96-99.99)], for the HPV-mRNA and HPV-DNA test. In conclusion, HPV-mRNA testing has similar longitudinal sensitivity as HPV-DNA, implying that HPV-mRNA testing can safely be used for cervical screening.

Short half-life of HPV16 E6 and E7 mRNAs sensitizes HPV16-positive tonsillar cancer cell line HN26 to DNA-damaging drugs.

Here we show that treatment of the HPV16-positive tonsillar cancer cell line HN26 with DNA alkylating cancer drug melphalan-induced p53 and activated apoptosis. Melphalan reduced the levels of RNA polymerase II and cellular transcription factor Sp1 that were associated with HPV16 DNA. The resulting inhibition of transcription caused a rapid loss of the HPV16 early mRNAs encoding E6 and E7 as a result of their inherent instability. As a consequence of HPV16 E6 and E7 down-regulation, the DNA damage inflicted on the cells by melphalan caused induction of p53 and activation of apoptosis in the HN26 cells. The BARD1-negative phenotype of the HN26 cells may have contributed to the failure to repair DNA damage caused by melphalan, as well as to the efficient apoptosis induction. Finally, nude mice carrying the HPV16 positive tonsillar cancer cells responded better to melphalan than to cisplatin, the chemotherapeutic drug of choice for tonsillar cancer. We concluded that the short half-life of the HPV16 E6 and E7 mRNAs renders HPV16-driven tonsillar cancer cells particularly sensitive to DNA damaging agents such as melphalan since melphalan both inhibits transcription and causes DNA damage.

A novel human in vitro papillomavirus type 16 positive tonsil cancer cell line with high sensitivity to radiation and cisplatin.

BACKGROUND: Human papillomavirus (HPV) is an established risk factor for oropharyngeal squamous cell carcinoma (OSCC). The aim was to establish cell lines from HPV-positive tonsil carcinomas to be used for treatment development. METHODS: Fresh samples from 23 HPV-positive tonsil carcinomas were cultivated in vitro. The established cell line was analyzed for viral characteristics, cell karyotype, TP53 status, and growth capabilities in nude mice. In vitro studies of sensitivities to radiation, cisplatin and cetuximab were performed. RESULTS: After 19 months (eight passages), one cell line, LU-HNSCC-26, was established in vitro and also grew as xenografts. The tumor was from a 48 year old non-smoking man with non-keratinizing, p16 positive tonsil OSCC, stage T2N0M0 with HPV16. It contained 19.5 (CV% 3.7) HPV16 copies/cell (passage 8). The complete HPV16 genome sequence was obtained. Episomal HPV16 was present with an E2/E7 ratio of 1.1 (CV% 2.6). In addition, HPV16 mRNA specific for the intact E2 gene was detected. The viral expression manifested 1.0 (CV% 0.1) E7 mRNA copies per HPV16 genome. The karyotype was determined and the cell line demonstrated wild type TP53. The ID50 for radiation was 0.90 Gy and the IC50 for cisplatin was 0.99 µmol/L. The cell line was inhibited to a maximum of 18% by cetuximab. CONCLUSIONS: We established an in vitro tonsil carcinoma cell line containing episomal HPV16. This is an important step towards efficient treatment development.

Population-based primary HPV mRNA cervical screening compared with cytology screening.

Primary HPV screening for cervical cancer by HPV mRNA testing (Aptima) was implemented in January 2017, for women ≥30 through 70 years, in the Region of Skåne, Sweden. HPV positive samples underwent cytology assessment, and women with any degree of abnormal cytology were referred for colposcopy. The aim was to audit the primary HPV screening program, by comparing the cytology results to those of corresponding women (aged ≥30 through 65 years) screened with conventional cytology during 2016. Overall, HPV was detected among 7.0% (4433/63,055) of the women ≥30-70 years in the primary HPV screening program. Among a co-tested (cytology and HPV) subgroup aged 40-42 years (N = 5039), HPV was detected in 100% (28/28) of high-grade squamous intraepithelial lesions (HSIL) and atypical squamous cells of undetermined significance (ASCUS) where HSIL could not be excluded (ASCH) (9/9), and in 80% (4/5) of cases of atypical glandular cells (AGC). Among women ≥30-65 years, the proportion ASCUS or worse (ASCUS+) was similar with cytology (3.52% [2016]) and primary HPV screening (3.70% [2017]). Only the proportion of ASC-H changed by the use of primary HPV screening, from 0.13% (2016) to 0.23% (2017) (p < 0.001). The colposcopy referral rate increased by 54% (3.70 vs 2.41%), when primary HPV screening was introduced. In conclusion, the implemented primary HPV screening approach demonstrated similar prevalence of ASCUS+ cytology as conventional screening. In addition, primary HPV screening decreased cytology assessments by 86% in our screening population of women 30 through 70 years taken into account the co-tested women.

Linear Trimer Formation with Antiferromagnetic Ordering in 1T-CrSe2 Originating from Peierls-like Instabilities and Interlayer Se-Se Interactions.

Anomalous successive structural transitions in layered 1T-CrSe2 with an unusual Cr4+ valency were investigated by synchrotron X-ray diffraction. 1T-CrSe2 exhibits dramatic structural changes in in-plane Cr-Cr and interlayer Se-Se distances, which originate from two interactions: (i) in-plane Cr-Cr interactions derived from Peierls-like trimerization instabilities on the orbitally assisted one-dimensional chains and (ii) interlayer Se-Se interactions through p-p hybridization. As a result, 1T-CrSe2 has the unexpected ground state of an antiferromagnetic metal with multiple Cr linear trimers with three-center-two-electron σ bonds. Interestingly, partial substitution of Se for S atoms in 1T-CrSe2 changes the ground state from an antiferromagnetic metal to an insulator without long-range magnetic ordering, which is due to the weakening of interlayer interactions between anions. The unique low-temperature structures and electronic states of this system are determined by the competition and cooperation of in-plane Cr-Cr and interlayer Se-Se interactions.