Search

Dowling-Degos disease (DDD) is a rare genodermatosis, which was first described by Dowling and Freudenthal in 1938 and then by Degos and Ossipowski in 1954. GLO:DF2/01dec19:ced13914-fig-0001.jpg PHOTO (COLOR): (a) Dowling-Degos disease of the mother's vulva: multiple hyperpigmented brownish macules showing dark brown to black macules in both solitary and confluent patterns. GLO:DF2/01dec19:ced13914-fig-0002.jpg PHOTO (COLOR): (a) Dowling-Degos disease of the daughter's vulva: the macules were lighter in colour (light brown) and fewer in number than in the mother. [Extracted from the article]

Fluorescence fish embryo, will be 2.15 Fish embryo Fluorescence Fluorescence blood smear, will be 2.16 Blood Smear Fluorescence (17) In legend figure 5, it says 52 h post fertilization, it should be 52 h post fertilization. [Extracted from the article]

• Structure-based calculations on the nucleosome surface interaction shows that NBPeps induce specific atomic fluctuations of the nucleosome structure. • In vitro studies shows that NBPeps may affect the stability of the nucleosome structure. • Cell-based assays shows that the NBPeps may penetrate the cell and localizes at the nuclear environment. • Fish embryo toxicity (FET) test shows that the NBPeps can cause tissue modifications, such as defects in pigmentation and induction of earlier hatching. • H4 peptide shows to be highly specific for targeting the nucleosome, with important effects on the final nucleosome structure and robust in vivo effects. Chromatin state is highly dependent on the nucleosome binding proteins. Herein, we used a multipronged approach employing biophysical and in vivo experiments to characterize the effects of Nucleosome Binding Peptides (NBPeps) on nucleosome and cell activity. We performed a series of structure-based calculations on the nucleosome surface interaction with GMIP1 (a novel NBPep generated in silico), and HMGN2 (nucleosome binding motif of HMGN2), which contains sites that bind DNA and the acid patch, and also LANA and H4pep (nucleosome binding motif of H4 histone tail) that only bind to the acidic patch. Biochemical assays shows that H4pep, but not HMGN2, GMIP1 and LANA, is highly specific for targeting the nucleosome, with important effects on the final nucleosome structure and robust in vivo effects. These findings suggest that NBPeps might have important therapeutic implications and relevance as tools for chromatin investigation. [ABSTRACT FROM AUTHOR]

Many clinicians recommend that patients diagnosed with HPV-related gynecologic cancers receive prophylactic HPV vaccination at the time of cancer diagnosis or after cancer treatment. In view of the large use of such practice, we aimed to assess the literature evidence supporting the use of prophylactic HPV vaccines after diagnosis or treatment of HPV-related gynecologic cancers. Women who develop HPV-related cervical, vaginal, and vulvar cancers represent a subgroup of patients who may be particularly sensitive to HPV infection and re-acquire infections. The rationale that the use of prophylactic HPV vaccination at the time or after treatment for cervical, vaginal, and vulvar cancers might reduce the risk of future HPV-related diseases might be explained by the data coming from the use of HPV vaccination after treatment of pre-invasive disease; however, the evidence on the use of HPV vaccination in the setting of HPV-related gynecologic cancers is currently absent. In this context, observational and experimental studies document an important drop in effectiveness of HPV vaccination by age. Physicians should be aware of catch-up programs in their countries and should be ready to counsel patients about prophylactic HPV vaccine efficacy according to their age. In general, no evidence exists supporting the use of prophylactic HPV vaccine in patients diagnosed with HPV-related gynecologic cancers; therefore, the European Society of Gynecological Oncology (ESGO) prevention committee opinion is to counsel these patients as any HPV-related non-gynecologic cancer (such as anal or oropharyngeal cancer) and non-cancer patient, suggesting vaccination according to patient's age and prognosis, knowing there is a decrease of efficacy with increasing age. Studies on the use of prophylactic HPV vaccine in patients diagnosed with HPV-related gynecologic cancers are strongly needed., (© 2024 The Author(s). International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Purpose: This study explores the performance of MRI in detecting residual disease after platinum-based neoadjuvant chemotherapy (NACT) in pregnant cervical cancer (CC) patients, which would serve as a surrogate of treatment response., Methods: In this retrospective single-centre study, consecutive pregnant cervical cancer patients treated with NACT and undergoing MRI examination before and at the end of the therapeutic protocol between 2010 and 2021 were included. Tumour maximum diameter and nodal status were evaluated in MRI at staging and after NACT. Patients exhibiting increased tumor burden post-NACT were excluded. On post-NACT the presence or absence of residual disease was recorded and the MRI diagnostic performance for assessing residual disease was calculated using histopathology at radical hysterectomy as the reference standard., Results: The study included 12 pregnant patients (median age 36 years, 27-42). At post-NACT MRI, residual disease was absent in 2/12 patients (16.7 %) while present in 10/12 (83.3 %). Histopathology was concordant in all patients without MRI residual disease and in 9/10 patients with MRI residual disease, while discordant in 1/10. MRI sensitivity, specificity, positive predictive value, negative predictive and accuracy for detecting residual disease were 100.0 % (95 %CI: 1.00, 1.00), 66.7 % (95 %CI: 0.13, 1.00), 90 % (95 %CI: 0.71, 1.00), 100 % (95 %CI: 1.00, 1.00), and 91.7 % (95 %CI: 0.76, 1.00) respectively (p = 0.045)., Conclusions: This study suggests that MRI has good diagnostic performance to detect residual disease after NACT in pregnant CC patients, and potentially assess response to treatment in this setting., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Very high-power short-duration (vHPSD) temperature-controlled radiofrequency ablation (vHPSD) may reduce ablation times and improve patient tolerability, permitting pulmonary vein (PV) isolation under mild conscious sedation. We evaluated of the anesthetic drugs use and patients' pain experience during vHPSD PV isolation., Methods: Fifty-eight patients, with paroxysmal and persistent atrial fibrillation (AF), treated with QDot Micro catheter and vHPSD (90 w for 4 s) (vHPSD group), were compared with the last 33 patients treated with a surround flow contact force-sensing catheter guided by the ablation index (450 anteriorly at 50 W, 330 posteriorly at 40 W) (AI group). Anesthetic drugs use was compared as well as pain experience, measured using a 0-10 scale., Results: All PVs were acutely isolated. Procedural time (78 ± 10 min vs 84 ± 12 min, p = 0.012), fluoroscopy time (369 ± 139 s vs 441 ± 172 s, p = 0.03), and RF time in the vHPSD group (8.3 ± 2.1 min) were shorter than in the AI group (25 ± 11 min, p < 0.001). Only 4 patients experienced an access site-related vascular complication (groin hematoma). Midazolam was required in 36 (62%) vHPSD group patients vs 31 (94%) AI group patients (p < 0.001). Fentanyl was required in 4 (7%) vHPSD group patients vs 25 (76%) AI group patients (p < 0.001). No patients required general anesthesia. Twenty-two (38%) vHPSD group patients underwent PV isolation without any anesthetic drug. Pain experience was significantly lower in vHPSD group (4.9 ± 2 vs 6.6 ± 1.8, p < 0.001)., Conclusions: vHPSD radiofrequency ablation for PVI can be performed under conscious sedation using only benzodiazepine in most of patients without compromising patient pain experience., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To date, no data supports the execution of vaccination after hysterectomy for high-grade cervical intraepithelial neoplasia (CIN2+) and early-stage cervical cancer. We aim to evaluate the potential effect of vaccination after hysterectomy for high-grade cervical intraepithelial neoplasia and early-stage cervical cancer., Methods: This is a multi-center retrospective study evaluating data of women who develop lower genital tract dysplasia (including anal, vulvar and vaginal intra-epithelial neoplasia) after having hysterectomy for CIN2+ and FIGO stage IA1- IB1 cervical cancer., Results: Overall, charts for 77 patients who developed lower genital tract dysplasia were collected. The study population included 62 (80.5%) and 15 (19.5%) patients with CIN2+ and early-stage cervical cancer, respectively. The median (range) time between hysterectomy and diagnosis of develop lower genital tract dysplasia was 38 (range, 14-62) months. HPV types covered by the nonavalent HPV vaccination would potentially cover 94.8% of the development of lower genital tract dysplasia. Restricting the analysis to the 18 patients with available HPV data at the time of hysterectomy, the beneficial effect of nonvalent vaccination was 89%. However, considering that patients with persistent HPV types (with the same HPV types at the time of hysterectomy and who developed lower genital tract dysplasia) would not benefit from vaccination, we estimated the potential protective effect of vaccination to be 67% (12 out of 18 patients; four patients had a persistent infection for the same HPV type(s))., Conclusions: Our retrospective analysis supported the adoption of HPV vaccination in patients having treatment for HPV-related disease. Even in the absence of the uterine cervix, HPV vaccination would protect against develop lower genital tract dysplasia. Further prospective studies have to confirm our preliminary research., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: The present study aimed to assess long-term follow-up outcomes in women with in situ/microinvasive adenocarcinoma (AC) of the uterine cervix treated conservatively., Methods: Retrospective multi-institutional study including women with early glandular lesions and 5-year follow-up undergoing fertility-sparing treatment. Independent variables associated with recurrence were evaluated. Logistic regression analysis and Kaplan-Meier survival analysis with Logrank test were performed., Results: Of 269 women diagnosed with in situ/microinvasive AC, 127 participants underwent conservative treatment. During follow-up, recurrences were found in nine women (7.1%). The only factor associated with recurrence during follow-up was positive high-risk Human Papillomavirus (hr-HPV) testing (odds ratio 6.21, confidence interval 1.47-26.08, p = 0.012). HPV positivity in follow-up showed a recurrence rate of 21.7% against 3.8% in patients who were HPV-negative ( p = 0.002, Logrank test). Among women with negative high-risk HPV tests in follow-up, recurrences occurred in 20.0% of non-usual-type histology vs. 2.1% of usual-type cases ( p = 0.005)., Conclusion: HPV testing in follow-up is of pivotal importance in women with early glandular lesions undergoing conservative treatment, given its recurrence predictive value. However, women who are high-risk HPV-negative in follow-up with non-usual-type histopathology may represent a sub-population at increased risk of recurrences. Further studies should confirm these findings.

Introduction: Conformationally stabilized Env trimers have been developed as antigens for the induction of neutralizing antibodies against HIV-1. However, the non-glycosylated immunodominant base of these soluble antigens may compete with the neutralizing antibody response. This has prompted attempts to couple Env trimers to organic or inorganic nanoparticles with the base facing towards the carrier. Such a site-directed coupling could not only occlude the base of the trimer, but also enhance B cell activation by repetitive display., Methods: To explore the effect of an ordered display of HIV-1 Env on microspheres on the activation of Env-specific B cells we used Bind&Bite, a novel covalent coupling approach for conformationally sensitive antigens based on heterodimeric coiled-coil peptides. By engineering a trimeric HIV-1 Env protein with a basic 21-aa peptide (Peptide K) extension at the C-terminus, we were able to covalently biotinylate the antigen in a site-directed fashion using an acidic complementary peptide (Peptide E) bearing a reactive site and a biotin molecule. This allowed us to load our antigen onto streptavidin beads in an oriented manner., Results: Microspheres coated with HIV-1 Env through our Bind&Bite system showed i) enhanced binding by conformational anti-HIV Env broadly neutralizing antibodies (bNAbs), ii) reduced binding activity by antibodies directed towards the base of Env, iii) higher Env-specific B cell activation, and iv) were taken-up more efficiently after opsonization compared to beads presenting HIV-1 Env in an undirected orientation., Discussion: In comparison to site-directed biotinylation via the Avi-tag, Bind&Bite, offers greater flexibility with regard to alternative covalent protein modifications, allowing selective modification of multiple proteins via orthogonal coiled-coil peptide pairs. Thus, the Bind&Bite coupling approach via peptide K and peptide E described in this study offers a valuable tool for nanoparticle vaccine design where surface conjugation of correctly folded antigens is required., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Di Vincenzo, Beutel, Arnold, Wang, Damm, Tannig, Lux, Temchura, Eichler and Überla.)

Background: Fc-fusion proteins have been successfully developed for therapeutic purposes, but are also a promising platform for the fast generation and purification of immunogens capable of inducing strong humoral immune responses in preclinical immunization studies. As the Fc-portion of immunoglobulins fused to an antigen confers functional properties of the parental antibody, such as dimerization, binding to Fc-receptors and complement activation, several studies reported that Fc-fusion proteins elicit stronger antigen-specific antibody responses than the unfused antigen. However, dimerization or half-life extension of an antigen have also been described to enhance immunogenicity., Methods: To explore the role of Fc-effector functions for the immunogenicity of fusions proteins of viral glycoproteins and Fc fragments, the HIV-1 gp120 and the RBD of SARS-CoV-2 were fused to the wild type muIgG2a Fc fragment or mutants with impaired (LALA-PG) or improved (GASDIE) Fc-effector functions., Results: Immunization of BALB/c mice with DNA vaccines encoding gp120 - Fc LALA-PG induced significantly higher antigen-specific antibody responses than gp120 - Fc WT and GASDIE. In contrast, immunization with DNA vaccines encoding the RBD fused to the same Fc mutants, resulted in comparable anti-RBD antibody levels and similar neutralization activity against several SARS-CoV-2 variants., Conclusion: Depending on the antigen, Fc-effector functions either do not modulate or suppress the immunogenicity of DNA vaccines encoding Fc-antigen fusion proteins., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Richel, Wagner, Klessing, Di Vincenzo, Temchura and Überla.)

Ensuring site-selectivity in covalent chemical modification of proteins is one of the major challenges in chemical biology and related biomedical disciplines. Most current strategies either utilize the selectivity of proteases, or are based on reactions involving the thiol groups of cysteine residues. We have modified a pair of heterodimeric coiled-coil peptides to enable the selective covalent stabilization of the dimer without using enzymes or cysteine moieties. Fusion of one peptide to the protein of interest, in combination with linking the desired chemical modification to the complementary peptide, facilitates stable, regio-selective attachment of the chemical moiety to the protein, through the formation of the covalently stabilized coiled-coil. This ligation method, which is based on the formation of isoeptide and squaramide bonds, respectively, between the coiled-coil peptides, was successfully used to selectively modify the HIV-1 envelope glycoprotein. Covalent stabilization of the coiled-coil also facilitated truncation of the peptides by one heptad sequence. Furthermore, selective addressing of individual positions of the peptides enabled the generation of mutually selective coiled-coils. The established method, termed Bind&Bite, can be expected to be beneficial for a range of biotechnological and biomedical applications, in which chemical moieties need to be stably attached to proteins in a site-selective fashion., Competing Interests: J. B. and T. S. are employees of Institut Virion-Serion GmbH. P. T., R. D. V., K. Ü. and J. E. declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Human papillomavirus (HPV) is the most common sexually transmitted infection. The implementation of primary prevention aims to reduce the burden of HPV infection and HPV-related disease. However, HPV-related diseases are still a concern, even in high-income countries. Approximately 570 000 new cervical cancer cases are diagnosed in Italy every year. Prophylactic HPV vaccines have been developed to minimize the spread of HPV. Growing evidence supports the administration of HPV vaccines (even just one dose) in reducing the prevalence of HPV infection and HPV-related disease including cancers. HPV vaccines are characterized by a high level of efficacy (>95%) in women who are naïve to HPV; however, they do not increase clearance in patients with ongoing HPV infection. With more than 200 million doses administered to date, HPV vaccines are considered to be safe and effective at preventing HPV-related infections and cancers. In this review we aim to review the current evidence regarding HPV vaccination and to describe trends in HPV vaccination coverage in Italy. In Italy, vaccination against HPV has been included in the National Immunization Plan (NIP) since 2007-2008. Using data abstracted from the Italian Ministry of Health, we analyzed changes in HPV vaccination coverage. We observed that HPV vaccines are underutilized and coverage rates are decreasing. Looking at the target population (females and males aged 11-12 years) in Italy, a decrease in coverage rates was observed. A call for action, improved HPV awareness, and education are the key elements to enhance the widespread adoption of HPV vaccination., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Triple negative breast cancer (TNBC) is an aggressive clinical tumor, accounting for about 25% of breast cancer (BC) related deaths. Chemotherapy is the only therapeutic option to treat TNBC, hence a detailed understanding of the biology and its categorization is required. To investigate the clinical relevance of BCL11A in TNBC subtype, we focused on gene and protein expression and its mutational status in a large cohort of this molecular subtype., Methods: Gene expression profiling of BCL11A and its isoforms (BCL11A-XL, BCL11A-L and BCL11A-S) has been determined in Luminal A, Luminal B, HER2-enriched and TNBC subtypes. BCL11A protein expression has been analyzed by immunohistochemistry (IHC) and its mutational status by Sanger sequencing., Results: In our study, BCL11A was significantly overexpressed in TNBC both at transcriptional and translational levels compared to other BC molecular subtypes. A total of 404 TNBCs were selected and examined showing a high prevalence of BCL11A-XL (37.3%) and BCL11A-L (31.4%) isoform expression in TNBC, associated with a 26% of BCL11A protein expression levels. BCL11A protein expression predicts scarce LIV (HR = 0.52; 95% CI, 0.29-0.92, P = 0.03) and AR downregulation (HR = 0.37; 95% CI, 0.16-0.88; P = 0.02), as well as a higher proliferative index in TNBC cells. BCL11A-L expression is associated with more aggressive TNBC histological types, such as medullary and metaplastic carcinoma., Conclusion: Our finding showed that BCL11A protein expression acts as an unfavorable prognostic factor in TNBC patients, especially in non luminal TNBCs subgroups. These results may yield a better treatment strategy by providing a new parameter for TNBC classification., (© 2022. The Author(s).)

Quality Control (QC) and Quality Assurance (QA) principles are essential for effective cervical cancer prevention. Being a crucial diagnostic step, colposcopy's sensitivity and specificity improvements are strongly advocated worldwide since inter- and intra-observer differences are the main limiting factors. The objective of the present study was the evaluation of colposcopy accuracy through the results of a QC/QA assessment from a survey in Italian tertiary-level academic and teaching hospitals. A web-based, user-friendly platform based on 100 colposcopic digital images was forwarded to colposcopists with different levels of experience. Seventy-three participants were asked to identify colposcopic patterns, provide personal impressions, and indicate the correct clinical practice. The data were correlated with a panel of experts' evaluation and with the clinical/pathological data of the cases. Overall sensitivity and specificity with the threshold of CIN2+ accounted for 73.7% and 87.7%, respectively, with minor differences between senior and junior candidates. Identification and interpretation of colposcopic patterns showed full agreement with the experts' panel, ranging from 50% to 82%, in some instances with better results from junior colposcopists. Colposcopic impressions correlated with a 20% underestimation of CIN2+ lesions, with no differences linked to level of experience. Our results demonstrate the good diagnostic performance of colposcopy and the need for improving accuracy through QC assessments and adhesion to standard requirements and recommendations.

The objective of this work is to assess the 5-year outcomes of patients undergoing conization for high-grade cervical lesions that simultaneously present as risk factors in the persistence of HPV infection and the positivity of surgical resection margins. This is a retrospective study evaluating patients undergoing conization for high-grade cervical lesions. All patients included had both positive surgical margins and experienced HPV persistence at 6 months. Associations were evaluated with Cox proportional hazard regression and summarized using hazard ratio (HR). The charts of 2966 patients undergoing conization were reviewed. Among the whole population, 163 (5.5%) patients met the inclusion criteria, being at high risk due to the presence of positive surgical margins and experiencing HPV persistence. Of 163 patients included, 17 (10.4%) patients developed a CIN2+ recurrence during the 5-year follow-up. Via univariate analyses, diagnosis of CIN3 instead of CIN2 (HR: 4.88 (95%CI: 1.10, 12.41); p = 0.035) and positive endocervical instead of ectocervical margins (HR: 6.44 (95%CI: 2.80, 9.65); p < 0.001) were associated with increased risk of persistence/recurrence. Via multivariate analyses, only positive endocervical instead of ectocervical margins (HR: 4.56 (95%CI: 1.23, 7.95); p = 0.021) were associated with worse outcomes. In this high-risk group, positive endocervical margins is the main risk factor predicting 5-year recurrence.

Objective: To evaluate the impact of healthcare reorganization during the severe acute respiratory syndrome coronavirus 2 pandemic on Italian colposcopy clinic activities, focusing on cervical excision procedures, follow-ups for conservative management of low-grade lesions, and follow-ups post cervical excision., Methods: Retrospective study conducted in 14 Italian colposcopy clinics. The number and clinical characteristics of cervical excisions, follow-ups for conservative management of low-grade lesions, and follow-ups after cervical excision were compared between the period March 1, 2019 to February 29, 2020 (pre-pandemic) and March 1, 2020 to February 28, 2021 (pandemic) with a Poisson regression analysis., Results: In the pandemic period, the number of cervical excisions was reduced by 8.8% (95% confidence interval [CI]=-15.6% to -2%; p=0.011). Excisions were less frequently performed in the operating room (-35.1%; 95% CI=-47.6% to -22.6%; p<0.001), the number of patients from spontaneous screening was reduced by -14.0% (95% CI=-23.4% to -4.6%; p=0.003), and the CO2-laser technique was used less frequently (-30%; 95% CI=-45.1% to -15.0%; p<0.001). As compared to the pre-pandemic period, the number of follow-ups for conservative management of low-grade lesions was reduced by -26.7% (95% CI=-39.0% to -14.4%; p<0.001), and the follow-up appointments after cervical excision were reduced by -51.0% (95% CI=-58.1% to -43.9%; p<0.001)., Conclusion: The most significant impact of the healthcare reorganization during the coronavirus disease 2019 pandemic was on follow-ups after cervical excision. The resumption of disrupted activities should follow a risk-based prioritization, starting from women in follow-up after cervical excision. It is advisable that the trend of performing cervical excision as an outpatient procedure is maintained in the post-pandemic period., Competing Interests: No potential conflict of interest relevant to this article was reported., (© 2023. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Background: To date, little and discordant data still exists on the management of cervical cancer (CC) during pregnancy. In this paper, we report our experience of the treatment of these patients analyzing the oncologic, obstetric, and neonatal outcomes., Methods: Between January 2010 and December 2021, 13 patients were diagnosed with CC during pregnancy. All patients underwent platinum-based neoadjuvant chemotherapy (NACT) and 11/13 patients underwent a cesarean radical hysterectomy (CRH)., Results: All 13 patients were diagnosed with squamous-cell carcinoma, FIGO-2018 stage between IB2-IIIC1. The majority of patients had a partial (61.5%) or complete (15.4%) response to NACT. Most patients had a regular course of pregnancy and the obstetric complications observed were gestational diabetes mellitus in 23.1% and IUGR in 15.4% of cases. CRH was performed in the absence of major complications. Only 2 patients (15.4%) had disease recurrence and only 1 patient (7.7%) died of disease. All children are currently healthy. At birth, we observed mainly prematurity-related complications (38.5% respiratory distress syndrome and 7.7% neonatal jaundice) and only a case of congenital malformation (hypospadias). In our pediatric population, we reported a case of malignancy (acute myeloid leukemia)., Conclusion: NACT seems to be safe and efficacious in controlling tumor burden during pregnancy. CRH following NACT appears to be feasible, avoiding repeated surgery and treatment delays. This approach is also reasonably safe from a maternal, obstetric, and neonatal point of view.

Monocytes/macrophages are important target cells for HIV-1. Here, we investigated whether HIV-1 induces changes in the macrophage gene expression profile to support viral replication. We observed that the macrophage gene expression profiles dramatically changed upon HIV-1 infection. The majority of the HIV-1 regulated genes were also differentially expressed in M2a macrophages. The biological functions associated with the HIV-1 induced gene expression profile in macrophages were mainly related to inflammatory responses. CD9 and ITGA3 were among the top genes upregulated upon HIV-1 infection. We showed that these genes support viral replication and that downregulation of these genes decreased HIV-1 replication in macrophages. Here we showed that HIV-1 infection of macrophages induces a gene expression profile that may dampen inflammatory responses. CD9 and ITGA3 were among the top genes regulated by HIV-1 and were shown to support viral production most likely at the level of viral budding and release., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The combination of primary and secondary prevention has already influenced the colposcopic practice by reduction in HPV (human papillomavirus) vaccine-type HSIL (HIGH-GRADE SIL), colposcopy referral numbers, colposcopic positive predictive value (PPV) for CIN2+, and by modification of referral pattern, colposcopic performance, and procedures. Different strategies, both isolated and combined, have been proposed in order to maintain the diagnostic accuracy of colposcopy: patient risk stratification based on immediate or future risk of CIN3+ or on HPV genotyping after a positive screening test. Data are needed to support alternative colposcopic strategies based on vaccination status and on the application of artificial intelligence where the patient's risk stratification is implicit in precision medicine which involves the transition from an operator-dependent morphology-based to a less-operator dependent, more biomolecular management. The patient's risk stratification based on any combination of "history" and "test results" to decrease colposcopy workload further reduce colposcopic and histologic morphological approaches, while adding genotyping to the risk stratification paradigm means less cytologic morphologic diagnosis. In Italy, there is a strong colposcopic tradition and there is currently no immediate need to reduce the number of colposcopies. Instead, there is a need for more accredited colposcopists to maintain the diagnostic accuracy of colposcopy in the vaccination era.

Introduction: MRI is very accurate in selecting young women with cervical cancer for fertility-sparing surgery (FSS), in particular radical hysterectomy (RH). In order to improve obstetrical outcomes, neoadjuvant chemotherapy (NACT) followed by cold knife conization (CKC) has been proposed as alternative technique., Objective: To investigate the role of MRI in evaluation of response to treatment after neoadjuvant chemotherapy (NACT), followed by CKC, in patients with cervical cancer FIGO stage IB2-IIA1 with tumor size 2 - 4 cm, desiring to preserve their fertility., Methods: 13 young women (23-36 years old) with cervical cancer stage IB2-IIA1 desiring to preserve their fertility were included. Tumor diameter at baseline and after treatment was detected on 1.5 T MRI. Treatment response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and then compared to histopathology result., Results: MRI correctly assessed 11 out of 13 cases, according to RECIST 1.1, compared to histopathology. Among these 7 patients with partial response (PR), 2 cases of CR, 1 SD and 1 PD with persistence or enlargement of primary tumor., Conclusion: Our pilot study supports the usefulness of MRI in assessment of treatment response after NACT, followed by CKC., Trial Registration Number: ClinicalTrials.gov: NCT02323841., (© 2021. The Author(s).)

Human Papillomavirus (HPV) is the most common sexually transmitted infection. Its progression is related to the development of malignant lesions, particularly cervical intraepithelial neoplasias (CINs). CINs correlate with a higher risk of premature births, and their excisional and ablative treatment further increases this risk in pregnant women. These complications are also correlated with higher healthcare costs for their management. In Italy, more than 26,000 new cases of CINs are estimated to occur yearly and their economic burden is significant. Therefore, the management of these conditions is a public health priority. Since HPV vaccination is associated with a reduced risk of relapse in women surgically treated for HPV-related injuries, we estimated the economic impact of extending HPV vaccination to this target population. This strategy would result in a significant reduction in the general costs of managing these women, resulting in an overall saving for the Italian Health Service of €155,596.38 in 5 years. This lower cost is due not only to the reduced incidence of CINs following vaccination, but also to the lower occurrence of preterm births. Extending HPV vaccination to this target population as part of a care path to be offered to women treated for HPV injuries is therefore desirable.

Purpose: The purpose of this study was to assess the prognostic role and the perioperative outcomes of conization performed before radical hysterectomy in early-stage cervical carcinoma., Methods: This multicenter, retrospective observational cohort study included patients with FIGO 2009 stage IB1 cervical carcinoma treated with radical hysterectomy between June 2004 and June 2019. Patients were divided into two groups according to conization before radical surgery. One-to-one case-control matching was used to adjust the baseline characteristics., Results: A total of 332 patients were included after propensity matching (166, 50% in each group). Twenty-four of 166 (14.4%) and 142 of 166 (85.6%) conization patients had negative and positive surgical margins on the conization specimen, respectively. No difference in intra- and postoperative complications was noted between the two groups (p = 0.542 and p = 0.180, respectively). Patients undergoing conization before radical hysterectomy received less adjuvant treatment (p < 0.001) and had a better 5-year disease-free survival (DFS) than patients who did not receive conization (89.8% vs. 80.0%, respectively; p = 0.010). No difference in 5-year overall survival (OS) (97.1% vs. 91.4%, respectively; p = 0.114) or recurrence pattern (p = 0.115) was reported between the two groups. Factors independently related to higher risk of recurrence were pathologic tumor diameter >20 mm and no conization before radical hysterectomy (p = 0.011 and p = 0.018, respectively). The only independent variable influencing OS was pathologic tumor diameter >20 mm (p = 0.020)., Conclusions: Conization before radical hysterectomy was associated with improved DFS and lower probability of receiving adjuvant treatment. No difference in perioperative complications and OS was evident. Tumor diameter >20 mm was found to be the only independent risk factor affecting OS in both groups.

Background : This study evaluates the possible effect of 9-valent (9vHPV) vaccination on the results of HPV and cytological tests in a cohort of adult women. Methods : This study is a retrospective, single-cohort, monocentric study. Sexually active women aged 14-70 years, who underwent 9vHPV vaccination, were enrolled. Dose administration dates, side effects and data on Pap smears and HPV tests performed before and after the first vaccine dose were collected. Subjects were considered "unexposed" to the vaccine for all time intervals before the first dose administration, and "exposed" to the first, second and third vaccine doses in all time intervals following each specific dose. Results : A total of 512 women underwent the first 9vHPV dose administration and were enrolled in the study. Median age at vaccination was 30.5 (14-70). Log-rank tests and Cox regression analyses showed a highly statistically significant ( p < 0.0001) difference in the time to negativization after the exposure to the third vaccine dose in the 207 women starting with a Pap+ smear (HR (95% C.I.), 2.66 (1.83-3.86)) and in the 198 women starting with an HPV HR+ test (HR (95% C.I.), 7.80 (4.83-12.60)). Conclusions : 9vHPV vaccination may play a role in shortening the clearance time of HPV HR+ or Pap positivity in sexually active adult women.

Objective: To evaluate the outcomes of high-risk (HR) HPV-positive and -negative women affected by high-grade cervical dysplasia., Methods: This is a retrospective multi-institutional study. Medical records of consecutive patients with high-grade cervical dysplasia undergoing conization between 2010 and 2014 were retrieved. All patients included had at least 5 years of follow-up. A propensity-score matching was adopted in order to reduce the presence of confounding factors between groups. Kaplan-Meir and Cox hazard models were used to estimate 5-year outcomes., Results: Overall, data of 2966 women, affected by high-grade cervical dysplasia were reviewed. The study population included 1478 (85%) and 260 (15%) women affected by HR-HPV-positive and HR-HPV-negative high-grade cervical dysplasia. The prevalence of CIN2 and CIN3 among the HR-HPV-positive and -negative cohort was similar (p = 0.315). Patients with HR-HPV-positive high-grade cervical dysplasia were at higher risk of 5-year recurrence (after primary conization) that HR-HPV-negative patients (p < 0.001, log-rank test). Via multivariate analysis, HR-HPV-negative women were at low risk of recurrence (HR: 1.69 (95%CI: 1.05, 4.80); p = 0.018, Cox Hazard model). A propensity-score matched comparison was carried out in order to reduce biases that are related to the retrospective study design. In comparison to HR-HPV-negative patients, thosewith HR-HPV-positive CIN3 was associate with a 8-fold increase in the risk of recurrence (p < 0.001, log-rank test)., Conclusions: HR-HPV-negative high-grade cervical dysplasia is not uncommon, accounting for 15% of our study population. Those patients experience more favorable outcomes than patients with documented HR-HPV infection(s). Further prospective studies are needed to corroborate our data., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The regulation of chromatin biology ultimately depends on the manipulation of its smallest subunit, the nucleosome. The proteins that bind and operate on the nucleosome do so, while their substrate is part of a polymer embedded in the dense nuclear environment. Their molecular interactions must in some way be tuned to deal with this complexity. Due to the rapid increase in the number of high-resolution structures of nucleosome-protein complexes and the increasing understanding of the cellular chromatin structure, it is starting to become clearer how chromatin factors operate in this complex environment. In this review, we analyze the current literature on the interplay between nucleosome-protein interactions and higher-order chromatin structure. We examine in what way nucleosomes-protein interactions can affect and can be affected by chromatin organization at the oligonucleosomal level. In addition, we review the characteristics of nucleosome-protein interactions that can cause phase separation of chromatin. Throughout, we hope to illustrate the exciting challenges in characterizing nucleosome-protein interactions beyond the nucleosome., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To evaluate feasibility of neoadjuvant chemotherapy (NACT) followed by cold-knife conization (CKC) in patients with 2018 FIGO stage IB2-IIA1 cervical cancer who desired to maintain fertility., Design: Pilot study of conization after chemotherapy in stage IB2-IIA1 >2 cm cervical cancer., Setting: University hospital., Patient(s): From 2014 to 2018, 25 patients, <40 years of age, were enrolled., Interventions(s): After laparoscopic pelvic lymph-node assessment, NACT with cisplatin/paclitaxel q21 was administered to eligible patients. Responsive patients were treated with CKC., Main Outcome Measure(s): Obstetrical outcome: pregnancy rate. Oncologic outcome., Result(s): Thirteen out of 25 patients were eligible for fertility-sparing treatment. Oncologic outcome: The clinical overall response rate was 84.5% (11 out of 13 patients). One patient achieved stable disease, was managed by radical surgery, and is still alive; another one experienced progression of disease and died after 15 months. The optimal pathologic response was 69.1%. In the setting of fertility preservation patients, the median follow-up was 37 months (range 18-76). In this group we registered one distant recurrence, 12 months after CKC, in the liver; the patient is still alive and without evidence of disease. Obstetrical outcome: Among the nine patients amenable, three tried to conceive, and two spontaneous pregnancy occurred a few months after the end of treatment, for a pregnancy rate of 66.7%., Conclusion(s): This pilot study supports the feasibility of CKC after NACT as conservative treatment in stage IB2-IIA1 cervical cancer, with oncologic outcomes similar to those reported for trachelectomy in the same stage and with potential benefits in terms of obstetrical outcomes., Clinical Trial Registration Number: NCT02323841., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: Conization aims to remove pre-neoplastic lesions of the uterine cervix. Several techniques for conization have been compared, but evidence regarding the most effective therapeutic option is scant. Here, we aimed to compare the recurrence rate following laser conization and loop electrosurgical excision procedure (LEEP) in patients with high-grade cervical dysplasia (HSIL/CIN2+)., Methods: This is a retrospective multi-institutional study. Medical records of consecutive patients with HSIL/CIN2+ undergoing conization between 2010 and 2014 were retrieved. A propensity-score matching (PSM) was applied in order to reduce allocation bias. The risk of developing recurrence was estimated using Kaplan-Meir and Cox hazard models., Results: Overall, 2966 patients had conization over the study period, including 567 (20%) and 2399 (80%) patients having laser conization and LEEP, respectively. Looking at predictors of recurrence, diagnosis of CIN3 (HR:3.80 (95%CI:2.01,7.21); p < 0.001) and HPV persistence (HR:1.81 (95%CI:1.11,2.96); p < 0.001) correlated with an increased risk of recurrence. After applying a PSM we selected 500 patients undergoing laser conization and 1000 undergoing LEEP. Patients undergoing LEEP were at higher risk of having positive surgical margins in comparison to patients undergoing laser conization (11.2% vs. 4.2%). The risk of having persistence of HPV was similar between the two groups (15.0% vs. 11.6%;p = 0.256). Five-year recurrence rate was 8.1% and 4% after LEEP and laser conization, respectively (p = 0.023). HPV persistence was the only factor associated with [5-]year recurrence after both laser conization (p = 0.003) and LEEP (p = 0.001)., Conclusions: HPV persistence is the only factor associated with an increased risk of recurrence after either laser conization or LEEP. Owing to the lack of data regarding obstetrical outcomes, we are not able to assess the best therapeutic option for women with cervical dysplasia., (Copyright © 2020. Published by Elsevier Inc.)

Background and Aims: Several add-on devices have been developed to increase rates of colon adenoma detection. We aimed to compare the endocuff-assisted colonoscopy with cap-assisted colonoscopy through a pairwise meta-analysis of randomized trials., Methods: We searched the PubMed/Medline and Embase database through March 2020 and identified 6 randomized controlled trials (comprising 2,027 patients). The primary outcome was adenoma detection rate; secondary outcomes included sessile serrated adenoma detection rate, mean adenoma per colonoscopy, cecal intubation rate and time to reach cecum. Safety data were also analyzed. We performed pairwise meta-analysis through a random effects model and expressed data as risk ratio and 95% confidence interval., Results: Overall, pooled adenoma detection rate was 48.1% (39.3-56.8%) with endocuff and 40.5% (30.4- 50.6%; risk ratio 1.14, 0.96-1.35) with cap. Proximal adenoma detection rate was 45.7% (36.8-54.7%) and 24% (17-45.1%) with endocuff and cap, respectively (risk ratio 2.04, 0.93-4.49), whereas endocuff outperformed cap-assisted colonoscopy in detecting diminutive (≤ 5 mm) adenomas (risk ratio 2.74, 1.53-4.90) and in terms of mean adenoma per colonoscopy (mean difference 0.31, 0.05 -0.57; p=0.02). Sessile serrated adenoma detection rate (risk ratio 1.36, 0.72-2.59), cecal intubation rate (risk ratio 0.99, 0.98-1.00), and time to reach cecum (6.87 min versus 6.87 min) were similar between the two groups. No serious adverse event was observed., Conclusion: Endocuff-assisted colonoscopy seems to provide a higher adenoma detection rate as compared to cap-assisted colonoscopy, in particular concerning smaller diminutive polyps.

Human papillomavirus (HPV) related cervical cancer represents an issue of public health priority. The World Health Organization recommended the introduction of HPV vaccination in all national public programs. In Europe, vaccines against HPV have been available since 2006. In Italy, vaccination is recommended and has been freely offered to all young girls aged 11 years since 2008. Three prophylactic HPV vaccines are available against high- and low-risk genotypes. The quadrivalent vaccine contains protein antigens for HPV 6, 11, 16, and 18. The bivalent vaccine includes antigens for HPV 16 and 18. The nonavalent vaccine was introduced in 2014, and it targets HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. Clinical trials demonstrated the effectiveness of the three vaccines in healthy young women. Likewise, all vaccines showed an excellent safety profile. The bivalent vaccine provides two doses in subjects aged between 9 and 14 years and three doses in subjects over 14 years of age. The quadrivalent vaccine provides two doses in individuals from 9 to 13 years and three doses in individuals aged 14 years and over. The nonavalent vaccine schedule provides two doses in individuals from 9 to 14 years of age and three doses in individuals aged 15 years and over at the time of the first administration. Preliminary results suggest that the HPV vaccine is effective in the prevention of cervical squamous intraepithelial lesions even after local treatment. Given these outcomes, in general, it is imperative to expand the vaccinated target population. Some interventions to improve the HPV vaccine's uptake include patient reminders, physicians-focused interventions, school-based vaccinations programs, and social marketing strategies. The Italian Society of Colposcopy and Cervico-Vaginal Pathology (SICPCV) is committed to supporting vaccination programs for children and adolescents with a catch-up program for young adults. The SICPCV also helps clinical and information initiatives in developing countries to decrease the incidence of cervico-vaginal and vulvar pathology.

In the context of the COVID-19 pandemic, patients need to be evaluated within 2-4 weeks in the following cases: cytology result of "squamous cell carcinoma," "atypical glandular cells, favor neoplastic," "endocervical adenocarcinoma in situ," or "adenocarcinoma"; histopathological diagnosis of suspected invasion from cervical/vaginal biopsy, or invasive disease after a cervical excision procedure, vaginal excision, or vulvar biopsy/excision; sudden onset of strongly suggestive symptoms for malignancy. Digital imaging technologies represent an important opportunity during the COVID-19 pandemic to share colposcopic images with reference centers, with the aim of avoiding any concentration of patients. All patients must undergo screening for COVID-19 exposure and should wear a surgical mask. A high-efficiency filter smoke evacuation system is mandatory to remove surgical smoke. Electrosurgical instruments should be set at the lowest possible power and not be used for long continuous periods to reduce the amount of surgical smoke. The following personal protective equipment should be used: sterile fluid-repellant surgical gloves, an underlying pair of gloves, eye protection, FFP3 mask, surgical cap, and gown. The colposcope should be protected by a disposable transparent cover. A protective lens that must be disinfected after each use should be applied. The use of a video colposcope should be preferred., (© 2020 International Federation of Gynecology and Obstetrics.)

The incidence of abdominal and pelvic cancer in pregnancy is low, but it is rising as the population of pregnant women gets older. Depending on disease stage, gestational age and patient's preference, active surveillance as well as surgery and chemotherapy are feasible options during pregnancy. Correct diagnosis and staging of the tumor is crucial for choosing the best therapeutic approach. Moreover, a reproducible modality to assess the treatment response is requested. Magnetic resonance imaging (MRI) is commonly used with good results for the local staging and treatment response evaluation of most abdominal and pelvic cancers in nonpregnant patients, and it is considered relatively safe during pregnancy. The purpose of this article is to analyze the most relevant topics regarding the use of MRI in pregnant women with abdominal and pelvic cancer. We discuss MRI safety during pregnancy, including the use of gadolinium-based contrast agents (GBCAs), how to prepare the patient for the exam and MRI technique. This will be followed by a brief review on the most common malignancies diagnosed during pregnancy and their MRI appearance.

Nucleosomes are a crucial platform for the recruitment and assembly of protein complexes that process the DNA. Mechanistic and structural in vitro studies typically rely on recombinant nucleosomes that are reconstituted using artificial, strong-positioning DNA sequences. To facilitate such studies on native, genomic nucleosomes, there is a need for methods to produce any desired DNA sequence in an efficient manner. The current methods either do not offer much flexibility in choice of sequence or are less efficient in yield and labor. Here, we show that ramified rolling circle amplification (RCA) can be used to produce milligram amounts of a genomic nucleosomal DNA fragment in a scalable, one-pot reaction overnight. The protocol is efficient and flexible in choice of DNA sequence. It yields 10-fold more product than PCR, and rivals production using plasmids. We demonstrate the approach by producing the genomic DNA from the human LIN28B locus and show that it forms functional nucleosomes capable of binding pioneer transcription factor Oct4., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Therapeutic strategies for Inflammatory Bowel Diseases (IBD: Crohn's disease and Ulcerative Colitis) have improved but the risk for HPV infection in patients under immunomodulatory/biologic treatment is unclear. Objective of the study is to identify the attitude of patients and caregivers to cervical screening. To determine the prevalence of HPV and cervical lesions in IBD patients receiving immunomodulatory/biological treatment., Patients and Methods: IBD patients treated with immunomodulators were enrolled from November 2016 to September 2017, thanks to a multidisciplinary cooperation. A survey was administered to enrolled patients as well as to a selected network of IBD expert physicians. Patients who consented underwent gynecological examination, smear, HPV DNA test, colposcopy, vaginal and cervical microbiological swabs., Results: 294 patients from AMICI Onlus Association, 119 patients from the hospital clinic, 30 doctors from national IBD centers participated to the survey. 19 patients from the IBD clinic underwent cervical screening. More than 90% of doctors consider their patients at risk of cervical cancer. A low prevalence of high-risk genotypes and related HPV lesions and an increased prevalence of bacterial vaginosis emerged in the studied population., Conclusions: Biological drugs could lead to a positive immunomodulation towards HPV infection. In IBD patients an alteration of the vaginal and intestinal microbiota seems to be coexisting.