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Chromosomal instability (CIN) is a pervasive feature of human cancers involved in tumor initiation and progression and which is found elevated in metastatic stages. CIN can provide survival and adaptation advantages to human cancers. However, too much of a good thing may come at a high cost for tumor cells as excessive degree of CIN-induced chromosomal aberrations can be detrimental for cancer cell survival and proliferation. Thus, aggressive tumors adapt to cope with ongoing CIN and most likely develop unique susceptibilities that can be their Achilles’ heel. Determining the differences between the tumor-promoting and tumor-suppressing effects of CIN at the molecular level has become one of the most exciting and challenging aspects in cancer biology. In this review, we summarized the state of knowledge regarding the mechanisms reported to contribute to the adaptation and perpetuation of aggressive tumor cells carrying CIN. The use of genomics, molecular biology, and imaging techniques is significantly enhancing the understanding of the intricate mechanisms involved in the generation of and adaptation to CIN in experimental models and patients, which were not possible to observe decades ago. The current and future research opportunities provided by these advanced techniques will facilitate the repositioning of CIN exploitation as a feasible therapeutic opportunity and valuable biomarker for several types of human cancers.

Glioblastoma, the most aggressive and lethal form of brain cancer, is defined by profound genomic instability, with Chromosomal Instability (CIN) playing a central role in driving tumor progression, therapy resistance, and poor prognosis. CIN is characterized by numerical and structural alterations, is driven by mechanisms such as mitotic errors, centrosome amplification, spindle assembly checkpoint dysfunction, and defective DNA repair pathways. These aberrations contribute to tumor heterogeneity, leading to the emergence of Glioblastoma Stem Cells (GSCs) with enhanced plasticity, therapy resistance, and metastatic capacity. Chromothripsis, frequently involves specific chromosomes and stems from micronuclei rapture, resulting in chromosomal rearrangement. The immune implications of CIN are also critical, with the Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes (cGAS-STING) pathway toggling between anti-tumor immunity and immune evasion. Therapeutic strategies targeting CIN are explored, including inhibitors of centrosomal clustering, DNA damage response pathways, and spindle assembly components, as well as innovative approaches like Chimeric Antigen Receptor T (CAR-T) cell therapies and nanoparticle-based drug delivery systems. Advances in single-cell sequencing provide transformative insights into CIN-driven glioblastoma heterogeneity and therapeutic vulnerabilities. By integrating mechanistic understanding with translational strategies, this review underscores CIN as both a therapeutic challenge and an opportunity, charting a path toward improving glioblastoma treatment outcomes and patient survival.

Contrast‐induced nephropathy (CIN) is a condition that causes kidney damage in patients receiving angiography with iodine‐based contrast agents. This study investigated the potential protective effects of berberine (BBR) against CIN and its underlying mechanisms. The researchers conducted both in vivo and in vitro experiments to explore BBR's renal protective effects. In the in vivo experiments, SD rats were used to create a CIN model, and different groups were established. The results showed that CIN model group exhibited impaired renal function, severe damage to renal tubular cells and increased apoptosis and ferroptosis. However, BBR treatment group demonstrated improved renal function, decreased apoptosis and ferroptosis. Similar results were observed in the in vitro experiments using HK‐2 cells. BBR reduced ioversol‐induced apoptosis and ferroptosis, and exerted its protective effects through Akt/Foxo3a/Nrf2 signalling pathway. BBR administration increased the expression of Foxo3a and Nrf2 while decreasing the levels of p‐Akt and p‐Foxo3a. In conclusion, this study revealed that BBR effectively inhibited ioversol‐induced apoptosis and ferroptosis in vivo and in vitro. The protective effects of BBR were mediated through the modulation of Akt/Foxo3a/Nrf2 signalling pathway, leading to the alleviation of CIN. These findings suggest that BBR may have therapeutic potential for protecting against CIN in patients undergoing angiography with iodine‐based contrast agents.

Performance and Spanish film is the first book to provide a detailed study of screen acting in Spanish film. With fifteen original essays by leading scholars of Spanish film, the book casts light on the manifold meanings, methods and influences of Spanish screen performance, from the silent era to the present day. In doing so, the book provides bold new readings of the work of significant Spanish actors and filmmakers, from Javier Bardem, Penélope Cruz and Alfredo Landa, to Pedro Almodóvar, Carlos Saura and Alejandro Amenábar. The fine-grained study of acting in each chapter also provides a means of exploring broader questions surrounding Spanish film practices, culture and society.Performance and Spanish film will be essential reading for both students and scholars of Spanish film alike, as well as to those more broadly interested in the history of screen acting.

Prophylactic human papillomavirus (HPV) vaccination programs constitute major public health initiatives worldwide. We assessed the global effect of quadrivalent HPV (4vHPV) vaccination on HPV infection and disease. PubMed and Embase were systematically searched for peer-reviewed articles from January 2007 through February 2016 to identify observational studies reporting the impact or effectiveness of 4vHPV vaccination on infection, anogenital warts, and cervical cancer or precancerous lesions. Over the last decade, the impact of HPV vaccination in real-world settings has become increasingly evident, especially among girls vaccinated before HPV exposure in countries with high vaccine uptake. Maximal reductions of approximately 90% for HPV 6/11/16/18 infection, approximately 90% for genital warts, approximately 45% for low-grade cytological cervical abnormalities, and approximately 85% for high-grade histologically proven cervical abnormalities have been reported. The full public health potential of HPV vaccination is not yet realized. HPV-related disease remains a significant source of morbidity and mortality in developing and developed nations, underscoring the need for HPV vaccination programs with high population coverage.

Background Persistent infection by oncogenic human papillomavirus (HPV) is necessary although not sufficient for development of cervical cancer. Behavioural, environmental, or comorbid exposures may promote or protect against malignant transformation. Randomised evidence is limited and the validity of observational studies describing these associations remains unclear. Methods In this umbrella review, we searched electronic databases to identify meta-analyses of observational studies that evaluated risk or protective factors and the incidence of HPV infection, cervical intra-epithelial neoplasia (CIN), cervical cancer incidence and mortality. Following re-analysis, evidence was classified and graded based on a pre-defined set of statistical criteria. Quality was assessed with AMSTAR-2. For all associations graded as weak evidence or above, with available genetic instruments, we also performed Mendelian randomisation to examine the potential causal effect of modifiable exposures with risk of cervical cancer. The protocol for this study was registered on PROSPERO (CRD42020189995). Results We included 171 meta-analyses of different exposure contrasts from 50 studies. Systemic immunosuppression including HIV infection (RR = 2.20 (95% CI = 1.89–2.54)) and immunosuppressive medications for inflammatory bowel disease (RR = 1.33 (95% CI = 1.27–1.39)), as well as an altered vaginal microbiome (RR = 1.59 (95% CI = 1.40–1.81)), were supported by strong and highly suggestive evidence for an association with HPV persistence, CIN or cervical cancer. Smoking, number of sexual partners and young age at first pregnancy were supported by highly suggestive evidence and confirmed by Mendelian randomisation. Conclusions Our main analysis supported the association of systemic (HIV infection, immunosuppressive medications) and local immunosuppression (altered vaginal microbiota) with increased risk for worse HPV and cervical disease outcomes. Mendelian randomisation confirmed the link for genetically predicted lifetime smoking index, and young age at first pregnancy with cervical cancer, highlighting also that observational evidence can hide different inherent biases. This evidence strengthens the need for more frequent HPV screening in people with immunosuppression, further investigation of the vaginal microbiome and access to sexual health services.

Post-treatment follow-up in women with CIN3 is mandatory due to relapse in up to 15% of patients within 2 years. Standard follow-up care based on hrHPV-DNA/cytology co-testing has high sensitivity but limited specificity. The aim of our proof-of-concept case-control study was to evaluate the performance of the methylation test GynTect® for the detection of recurrent CIN2/3 during follow-up. Residual clinical material from a recent, prospective, multicenter, observational study was available for further analysis. We studied a sample of 17 cases with recurrent CIN2/3 diagnosed within 24 months of follow-up and 31 controls without recurrence. DNA from cervical scrapes at baseline (immediately before CIN3 surgery) and up to three follow-up visits were analyzed for hrHPV and GynTect® methylation status. Cytology data were available from the previous study. Overall, 12 cases and 21 controls were GynTect-positive at baseline. In these subgroups, single test sensitivity at first follow-up was 67% (95% CI 39–87%) for GynTect® compared to 83% (95% CI 55–96%) for hrHPV (p = 0.50). Single test specificity was significantly higher for GynTect® (90%, 95% CI 71–98% vs. 62%, 95% CI 40–80%) (p = 0.03). In a co-testing setting, both hrHPV/cytology and GynTect®/cytology detected all recurrences. Specificity for GynTect®/cytology was higher than for hrHPV/cytology, but this difference was not statistically significant. In conclusion, for initially GynTect-positive patients, both hrHPV and GynTect® tests detected recurrent disease with similar sensitivity, but the GynTect® assay has a higher specificity. Incident hrHPV infection and/or persisting multifocal hrHPV infections without clinical disease are most likely responsible for the poorer specificity of the hrHPV test. A future prospective validation study will have to show whether GynTect®/cytology co-testing can outperform hrHPV/cytology co-testing in post-treatment surveillance.

Abstract Background There is no prognostic test to ascertain whether cervical intraepithelial neoplasias (CINs) regress or progress. The majority of CINs regress in young women, and treatments increase the risk of adverse pregnancy outcomes. We investigated the ability of a DNA methylation panel (the S5 classifier) to discriminate between outcomes among young women with untreated CIN grade 2 (CIN2). Methods Baseline pyrosequencing methylation and human papillomavirus (HPV) genotyping assays were performed on cervical cells from 149 women with CIN2 in a 2-year cohort study of active surveillance. Results Twenty-five lesions progressed to CIN grade 3 or worse, 88 regressed to less than CIN grade 1, and 36 persisted as CIN1/2. When cytology, HPV16/18 and HPV16/18/31/33 genotyping, and the S5 classifier were compared to outcomes, the S5 classifier was the strongest biomarker associated with regression vs progression. The S5 classifier alone or in combination with HPV16/18/31/33 genotyping also showed significantly increased sensitivity vs cytology when comparing regression vs persistence/progression. With both the S5 classifier and cytology set at a specificity of 38.6% (95% confidence interval [CI], 28.4–49.6), the sensitivity of the S5 classifier was significantly higher (83.6%; 95% CI, 71.9–91.8) than of cytology (62.3%; 95% CI, 49.0–74.4; P = 0.005). The highest area under the curve was 0.735 (95% CI, 0.621–0.849) in comparing regression vs progression with a combination of the S5 classifier and cytology, whereas HPV genotyping did not provide additional information. Conclusions The S5 classifier shows high potential as a prognostic biomarker to identify progressive CIN2. Many cervical intraepithelial neoplasias (CINs) regress spontaneously or persist, but to date there is no method to predict progression. In this study, we show that a DNA methylation classifier can predict progression or regression of untreated CIN grade 2.

Background/Objectives: To evaluate the effectiveness of expectant management on grades 1 and 2 cervical intraepithelial neoplasia (CIN), including factors associated with regression and progression. Methods: This multicenter study included 561 women managed expectantly and 359 who underwent immediate surgery at eight institutes between 2013 and 2023. Results: Over a 4-year period, 63% and 68% of CIN 1 and CIN 2 cases regressed, and 9% and 14% of cases progressed, respectively. The median regression times were 1.5 years for CIN 1 and 1.2 years for CIN 2. High-risk human papillomavirus (HPV) types, especially HPV 58 (adjusted hazard ratio [HR]: 0.61; p = 0.032) and high-grade initial cytology, atypical squamous cells—cannot exclude high-grade squamous intraepithelial lesion (ASC-H) and high-grade squamous intraepithelial lesion (HSIL) (adjusted HR: 0.3, p < 0.001), were associated with a lower likelihood of regression. Also, hematological disorders reduced the likelihood of regression (adjusted HR 0.39, p = 0.045). In a separate analysis of the immediate surgery group, age in the 30s (p = 0.016) and HPV 16 infection (p = 0.005) were associated with pathologic upgrading at surgery. Conclusions: CIN 1 and 2 usually regress, allowing expectant management for up to 1.5 and 1.2 years, respectively. However, HPV 58 infection or high-grade initial cytology, and hematological disorders are indications for careful monitoring. Patients in their 30s or infected with HPV 16 have a higher risk of pathologic upgrading at surgery.

White Cottage, White House examines how Classical Hollywood cinema developed and deployed Irish American masculinities to negotiate, consolidate, and reinforce hegemonic whiteness in midcentury America. Largely confined to discriminatory stereotypes during the silent era, Irish American male characters emerge as a favored identity with the introduction of sound, positioned in a variety of roles as mediators between the marginal and mainstream. The book argues that such characters function to express hegemonic whiteness as ethnicity, a socio-racial framing that kept immigrant origins and normative American values in productive tension. It traces key Irish American male types-the gangster, the priest, the cop, the sports hero, and the returning immigrant-who navigated these tensions in maintenance of an ethnic whiteness that was nonetheless \"at home\" in America, transforming from James Cagney's \"public enemy\" to John Wayne's \"quiet man\" in the process. Whether as figures of Depression-era social disruption, avatars of presidential patriarchy and national manhood, or allegories of postwar white flight and the nuclear family, Irish American masculinities occupied a distinctive and unrivaled visibility and role in popular American film.