TP63, a member of the p53 gene family gene, encodes the ΔNp63 protein and is one of the most frequently amplified genes in squamous cell carcinomas (SCC) of the head and neck (HNSCC) and lungs (LUSC). Using an epiallelic series of siRNAs with intrinsically different knockdown abilities, we show that the complete loss of ΔNp63 strongly impaired cell proliferation, whereas partial ΔNp63 depletion rendered cells hypersensitive to cisplatin accompanied by an accumulation of DNA damage. Expression profiling revealed wide-spread transcriptional regulation of DNA repair genes and in particular Fanconi anemia (FA) pathway components such as FANCD2 and RAD18 - known to be crucial for the repair of cisplatin-induced interstrand crosslinks. In SCC patients ΔNp63 levels significantly correlate with FANCD2 and RAD18 expression confirming ΔNp63 as a key activator of the FA pathway in vivo Mechanistically, ΔNp63 bound an upstream enhancer of FANCD2 inactive in primary keratinocytes but aberrantly activated by ΔNp63 in SCC. Consistently, depletion of FANCD2 sensitized to cisplatin similar to depletion of ΔNp63. Together, our results demonstrate that ΔNp63 directly activates the FA pathway in SCC and limits the efficacy of cisplatin treatment. Targeting ΔNp63 therefore would not only inhibit SCC proliferation but also sensitize tumors to chemotherapy.
Tissue-resident immune cells have been shown to play an important role in skin health and disease. However, owing to limited access to human skin samples and time-consuming, technically demanding protocols, the characterization of tissue-derived cells remains challenging. For this reason, blood-derived leukocytes are frequently used as a surrogate specimen, although they do not necessarily reflect local immune responses in the skin. Therefore, we aimed to establish a rapid protocol to isolate a sufficient number of viable immune cells from 4-mm skin biopsies that can be directly used for a deeper characterization such as comprehensive phenotyping and functional studies of T cells. In this optimized protocol, only two enzymes, type IV collagenase and DNase I, were used to achieve both the highest possible cellular yield and marker preservation of leukocytes stained for multicolor flow cytometry. We further report that the optimized protocol may be used in the same manner for murine skin and mucosa. In summary, this study allows a rapid acquisition of lymphocytes from human or mouse skin suitable for comprehensive analysis of lymphocyte subpopulations, for disease surveillance, and for identification of potential therapeutic targets or other downstream applications.
The aim of this retrospective cohort study was to analyze the cumulative incidence of breast cancer following gout and to investigate the association between gout and subsequent breast cancer in 67,598 primary care patients in Germany.This study included adult female patients (≥ 18 years) with an initial diagnosis of gout in 1284 general practices in Germany between January 2005 and December 2020. Individuals without gout were matched to gout patients using propensity score matching based on average yearly consultation frequency during the follow-up period, diabetes, obesity, chronic bronchitis/COPD diagnoses, and diuretic therapy. The 10-year cumulative incidence of breast cancer in the cohorts with and without gout was also studied using Kaplan-Meier curves, which were then compared using the log-rank test. Finally, a univariable Cox regression analysis was conducted to assess the association between gout and breast cancer.After up to 10 years of follow-up, 4.5% of gout and 3.7% of non-gout patients were diagnosed with breast cancer. A Cox regression analysis revealed a significant association between gout and subsequent breast cancer in the total population (HR: 1.17; 95% CI: 1.05-1.31). In the age-stratified analyses, gout was only strongly associated with subsequent breast cancer in the age group ≤ 50 (HR: 1.58; 95% CI: 1.10-2.27), but the association was not significant in women over 50 years old.Taken together, the findings of our study provide evidence for the association between gout and subsequent breast cancer diagnosis, particularly in the youngest age group.
Background: Antihypertensive pharmacological therapy includes diuretics, beta-blockers, ACE inhibitors, calcium channel blockers and angiotensin II receptor blockers. Besides their use in arterial hypertension, these drugs also play a major role in the therapy of portal hypertension, heart failure and coronary artery disease. Systematic analyses on the possible influence of these medications on cancer incidence are lacking. Methods: By utilizing the Disease Analyzer database (IQVIA), 349,210 patients with antihypertensive drug prescriptions between 2010 and 2020 without a diagnosis of cancer prior to or at the date of initial drug prescription were included. Propensity score matching was carried out by 1:1:1:1:1 according to the five antihypertensive treatments. Cox regression analyses were performed to investigate an association between antihypertensive drugs and the incidence of cancer. Results: Patients who were diagnosed with cancer were treated with diuretics in 19.9% of cases, calcium channel blockers in 16.9% of cases, and angiotensin II receptor blockers, ACE inhibitors, or beta-blockers in 13.9%, 13.2% and 12.8% of cases, respectively. Cox regression models revealed that diuretic use positively correlated with liver cancer incidence (HR: 1.31, 95%CI: 1.12–2.63) and lymphoid/haematopoietic tissue cancer incidence (HR: 1.27, 95%CI: 1.10–1.46). Use of diuretics negatively correlated with the incidence of prostate (HR: 0.64, 95%CI: 0.53–0.78) and skin cancer (HR: 0.81, 95%CI: 0.72–0.92). Finally, a positive association was found between angiotensin II receptor inhibitors and prostate cancer incidence (HR: 1.50, 95%CI: 1.28–1.65). Conclusions: These data suggest that diuretic use might be associated with liver cancer and lymphoid/haematopoetic tissue cancer development.
With the recent diffusion of access to publicly available large language models (LLMs), common interest in generative artificial-intelligence-based applications for medical purposes has skyrocketed. The increased use of these models by tech-savvy patients for personal health issues calls for a scientific evaluation of whether LLMs provide a satisfactory level of accuracy for treatment decisions. This observational study compares the concordance of treatment recommendations from the popular LLM ChatGPT 3.5 with those of a multidisciplinary tumor board for breast cancer (MTB). The study design builds on previous findings by combining an extended input model with patient profiles reflecting patho- and immunomorphological diversity of primary breast cancer, including primary metastasis and precancerous tumor stages. Overall concordance between the LLM and MTB is reached for half of the patient profiles, including precancerous lesions. In the assessment of invasive breast cancer profiles, the concordance amounts to 58.8%. Nevertheless, as the LLM makes considerably fraudulent decisions at times, we do not identify the current development status of publicly available LLMs to be adequate as a support tool for tumor boards. Gynecological oncologists should familiarize themselves with the capabilities of LLMs in order to understand and utilize their potential while keeping in mind potential risks and limitations.
The aim of this study was to analyze the persistence of women on tamoxifen (TAM) and aromatase inhibitors (AIs) in Germany, and to investigate possible determinants of non-persistence.The present retrospective cohort study was based on the IQVIA longitudinal prescription database (LRx). The study included women with an initial prescription of TAM or AIs (anastrozole, letrozole, and exemestane) between January 2016 and December 2020 (index date). Kaplan-Meier analyses were performed to show the persistence for TAM and AI, using a therapy gap of 90 or 180 days, respectively. A multivariable Cox proportional hazards regression model was further used to estimate the relationship between non-persistence and drug prescription (AI versus TAM), age, and the specialty of the physician initiating therapy (gynecologist, oncologist, or general practitioner).Up to 5 years after the index date, only 35.1% of AI and 32.5% of TAM patients were continuing therapy when therapy discontinuation was defined as at least 90 days without therapy. Using a 180-day therapy gap, 51.9% of AI and 50.4% of TAM patients remained on therapy after 5 years. Cox regression models reveal that initial therapy with TAM (HR 1.06, 95% CI 1.04-1.07), therapy initiation by oncologists (HR 1.09, 95% CI 1.07-1.11), or general practitioners (HR 1.24, 95% CI 1.21-1.27) and age ≤ 50 (HR 1.08, 95% CI 1.06-1.10) were significantly associated with an increased risk of therapy discontinuation.Overall, the present study indicates that persistence rates are low in all age groups for both TAM and AI treatment. We found several factors (e.g., physician specialty, younger age, and type of endocrine therapy) to be associated with an increased risk for non-persistence.
