Search

Background Cyclin-Dependent Kinase (CDK) 4/6 inhibitors have significantly improved progression-free survival of Hormone Receptor positive (HR+), Human Epidermal Growth Factor Receptor type 2 negative (HER2-) luminal breast cancers (LBC). Several studies demonstrated that the addition of CDK4/6 inhibitors to endocrine therapy results in a significant prolongation of progression-free survival in patients with endocrine-sensitive or endocrine-resistant LBCs. However, the percentage of patients unresponsive or refractory to these therapies is as high as 40%, and no reliable and reproducible biomarkers able to select a priori responder or resistant patients have been validated till now. The main cause of resistance is the selection of mutant clones in the target oncoprotein. Other mechanisms, like oncogene amplification/overexpression or mutations in other pathways, have been described in several models. Here, we focused on palbociclib, a selective inhibitor of CDK4/6. Methods: We generated and characterized human luminal breast cancer MCF-7 and T47D derived cell lines, able to survive and proliferate at different palbociclib concentrations, which also shows cross-resistance to abemaciclib. The resistant MCF7 cell line was characterized by RNA sequencing. Results: To confirm resistance, we performed cell viability assays in MCF-7 and T47D palbociclib sensitive cells (MCF-7pS and T47pS) versus MCF-7 and T47D palbociclib resistant cells (MCF-7pR5), showing a 10-fold increase of IC50 in MCF-7pR5 compared to parental MCF-7pS cells (16.7 vs 1.8 µM) and a 3-fold increase of IC50 in T47DpR5 vs parental T47DpS. We also confirmed a significant cross resistance using abemaciclib in MCF-7pR5 with an IC50 equal to 6.8 vs 0.35 µM and in T47DpR with an IC50 of 10.72 vs 0.5 µM. RNA sequencing, qRT-qPCR and Western blot results demonstrated a dramatic downregulation of the CDK4 inhibitor CDKN2B in both cell lines and we found upregulation of an miR-31, a putative regulator of CDKN2B. This finding was further validated in a biopsy from a patient progressing on CDK4/6 inhibitor therapy. Conclusions: This study provides new relevant information regarding the mechanism of resistance to CDK4/6 inhibitors and suggests potential new markers to follow up patients during the treatment. Citation Format: Nicoletta Cordani, Luca Mologni, Rocco Piazza, Viola Cogliati, Francesca Pepe, Serena Capici, Camillo Di Bella, Marta Jaconi, Maria Grazia Cerrito, Matteo Villa, Pietro Tettamanti, Guido Cavaletti, Marialuisa Lavitrano, Marina Elena Cazzaniga. Loss of CDKN2B expression as a potential marker of resistance to CDK4/6 inhibitor in Luminal Breast Cancer cells [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-13-21.

Background IL-23 inhibitors are the latest class of biologic drugs approved for moderate-to-severe psoriasis. Objectives to investigate real-life safety and efficacy of tildrakizumab. Methods demographic data, medical history, psoriasis disease history, PASI, DLQI, BSA, NAPSI were recorded at weeks 0, 12, 24, 36. Results PASI, BSA, DLQI and NAPSI all decreased rapidly during the 36 week follow-up period. PASI score reduced from 12.28 to 4.65 by week 12, followed by a further decrease to 1.18 at week 36 Multiple logistic regression showed that smoking, BMI ≥30, ≥3 comorbidities, previous systemic traditional or biologic drugs, psoriatic arthritis nor difficult-to-treat areas influenced the reduction of PASI and NAPSI scores during treatment with tildrakizumab ( P > .05). Conclusions we assessed a good performance of tildrakizumab in patients with multiple comorbidities, multi-failure, elderly patients, and in subjects with psoriatic arthritis.

Background Cyclin-Dependent Kinase (CDK) 4/6 inhibitors have significantly improved progression-free survival of Hormone Receptor positive (HR+), Human Epidermal Growth Factor Receptor type 2 negative (HER2-) luminal breast cancers (LBC). Several studies demonstrated that the addition of CDK4/6 inhibitors to endocrine therapy results in a significant prolongation of progression-free survival in patients with endocrine-sensitive or endocrine-resistant LBCs. However, the percentage of patients unresponsive or refractory to these therapies is as high as 40%, and no reliable and reproducible biomarkers able to select a priori responder or resistant patients have been validated till now. The main cause of resistance is the selection of mutant clones in the target oncoprotein. Other mechanisms, like oncogene amplification/overexpression or mutations in other pathways, have been described in several models. Here, we focused on palbociclib, a selective inhibitor of CDK4/6. Methods: We generated and characterized human luminal breast cancer MCF-7 and T47D derived cell lines, able to survive and proliferate at different palbociclib concentrations, which also shows cross-resistance to abemaciclib. The resistant MCF7 cell line was characterized by RNA sequencing. Results: To confirm resistance, we performed cell viability assays in MCF-7 and T47D palbociclib sensitive cells (MCF-7pS and T47pS) versus MCF-7 and T47D palbociclib resistant cells (MCF-7pR5), showing a 10-fold increase of IC50 in MCF-7pR5 compared to parental MCF-7pS cells (16.7 vs 1.8 µM) and a 3-fold increase of IC50 in T47DpR5 vs parental T47DpS. We also confirmed a significant cross resistance using abemaciclib in MCF-7pR5 with an IC50 equal to 6.8 vs 0.35 µM and in T47DpR with an IC50 of 10.72 vs 0.5 µM. RNA sequencing, qRT-qPCR and Western blot results demonstrated a dramatic downregulation of the CDK4 inhibitor CDKN2B in both cell lines and we found upregulation of an miR-31, a putative regulator of CDKN2B. This finding was further validated in a biopsy from a patient progressing on CDK4/6 inhibitor therapy. Conclusions: This study provides new relevant information regarding the mechanism of resistance to CDK4/6 inhibitors and suggests potential new markers to follow up patients during the treatment.

We have read with great interest the scientific literature regarding the diagnosis and treatment of skin cancer during COVID-19 pandemic.1-5 The cancellation of routine dermatologic visits could lead to the risk of neglecting cutaneous melanoma (CM), with potential consequences in terms of morbidity and mortality,1,2 even though the specific impact of the pandemic on CM has yet to be estimated.

BACKGROUND Mortality of bullous pemphigoid(BP) is a variable parameter,depending especially on the area where the study was conducted.The 1-year mortality rate and the identification of clinictherapeutic factors with potential prognostic value in patients with BP were evaluated in a cohort from a single referral center. METHODS We have reviewed medical records of patients with BP diagnosed at the Sant'Orsola-Malpighi Hospital in Bologna(Italy) between 2005 and 2019.Data collected included sex,age at diagnosis,laboratory findings,severity of disease,dosage of systemic treatments,age at death and comorbidities.Only patients who had at least 1 year of follow-up were included. RESULTS 85 patients were included; the mortality rate was 7.1%.The mortality rate of patients treated with a moderate dosage of corticosteroids was no higher than that of patients treated with a low dosage.The log-rank test showed a statistically significant correlation between mortality and patients aged≥85,BP230 positive,and CCIS≥4. CONCLUSIONS Compared with similar studies,our results show a lower 1-year mortality rate.Advanced age at diagnosis and CCIS were confirmed as major independent factors associated with poor prognosis in BP.Administration of moderate dosage of oral corticosteroids seems to have an overall positive benefit-risk ratio,providing a good control of the disease and minimizing the risk of hospitalization,possible related complications and the mortality rate.

Basal cell carcinoma (BCC) can sometimes affect the eyelids and in particular the eyelid margin, where it can often be misdiagnosed, mimicking other benign, more common diseases. Dermoscopy may provide additional diagnostic criteria for an earlier diagnosis of eyelid margin BCC, although the dermoscopic features of BCC affecting this anatomical site have seldom been reported. We highlight the peculiar presence of linear vessels perpendicular to the eyelid margin in BCCs of the eyelid margin. Our article represents the first report of these dermoscopic findings in a series of BCCs of the eyelid margin.

Bank of Italy data managers check the market notices published daily by the Italian Stock Exchange (Borsa Italiana) and select those of interest to update the Bank of Italy's Securities Database. This activity is time-consuming and prone to errors should a data manager overlook a relevant notice. In this paper we describe the implementation of a supervised model to automatically select the market notices. The model outperforms the manual approach used by data managers and can therefore be implemented in the regular process to update the Securities Database.

(1) Background: The aim of the work is to identify some imaging parameters in osteogenesis imperfecta to assist the dentist in the diagnosis, planning, and orthodontic treatment of Osteogenesis Imperfecta (OI) using 3D cone beam Computed Tomography (CBCT) and the Double Energy X-ray Absorptiometry (DEXA) technique. (2) Methods: 14 patients (9 males and 5 females, aged mean &plusmn, SD 15 &plusmn, 1.5) with a clinical-radiological diagnosis of OI were analyzed and divided into mild and moderate to severe forms. The patients&rsquo, samples were compared with a control group of 14 patients (8 males and 6 females, 1.7), free from osteoporotic pathologies. (3) Results: The statistical analysis allowed us to collect four datasets: in the first dataset (C1 sick population vs. C1 healthy population), the t-test showed a p-value &lt, 0.0001, in the second dataset (C2 sick population vs. C2 healthy population), the t-test showed a p-value &lt, in the third dataset (parameter X of the sick population vs. parameter X of the healthy population), the t-test showed a p-value &lt, in the fourth dataset the bone mineralometry (BMD) value detected by the DEXA technique compared to the C2 value of the OI affected population only) the Welch&ndash, Satterthwaite test showed a p-value &lt, 0.0001. (4) Conclusions: The research has produced specific imaging parameters that assist the dentist in making diagnostic decisions in OI patients. This study shows that patients with OI have a characteristic chin-bearing symphysis, thinned, and narrowed towards the center, configuring it with a constant &ldquo, hourglass&rdquo, appearance, not reported so far in the literature by any author.

Sustainability is a globally targeted concept widely debated in the literature, but still seeking a commonly agreed operationalization within applicable standards. The role of standard setter is commonly played by multi-stakeholder international organizations aiming at offering sound solutions for all kind of organizations, while what could be the role of a local government (LG) as sustainability standard setter and how this could impact on the definitions, rubrics, and measurement of sustainability is currently under-investigated. The case of an Italian LG already acting as standard setter allows to understand the reasons for, the strengths and the weaknesses of territorially bounded standards.

not available

Traffic accidents have increased in the last decade, pedestrians being the most affected group. At autopsy, it is evident that the most common cause of pedestrian death is central nervous system injury, followed by skull base fractures, internal bleeding, lower limb haemorrhage, skull vault fractures, cervical spinal cord injury and airway compromise. The attribution of accident responsibility can be realised through reconstruction of road accident dynamics, investigation of the scene, survey of the vehicle involved and examination of the victim(s). A case study concerning a car accident where both humans and pets were involved is reported here. Investigation and reconstruction of the crime scene were conducted by a team consisting of forensic pathologists and forensic veterinarians. At the scene investigation, the pedestrian and his dog were recovered on the side of the road. An autopsy and a necropsy were conducted on the man and the dog, respectively. In addition, a complete inspection of the sports utility vehicle (SUV) implicated in the road accident was conducted. The results of the autopsy and necropsy were compared and the information was used to reconstruct the collision. This unusual case was solved through the collaboration between forensic pathology and veterinary forensic medicine, emphasising the importance of this kind of co-operation to solve a crime scene concerning both humans and animals.

Collaboration is still being debated in public management studies. As specific way of creating public value, the collaborative working is mainly encouraged by the austerity, that implies putting resources together, not only the financial ones. Hence, new forms of service integration are asked in order to improve public service delivery in a more efficient and effectiveness way. Even if public administrations have embraced this trend, the focus adopted is mainly oriented to the planning and the programming approach rather than to the evaluation phase. What is the outcome of public service delivered through a collaborative approach? What is the outcome evaluation of the collaborative process? These kinds of outcome are evaluated? This study aims at investigating which kind of outcome is outlined by the Italian Strategic Cities in their collaborative strategic planning for cultural services delivery. As a main finding, the research extends the knowledge on the outcome evaluation of the collaboration in terms of process and in terms of impact of public services delivered.

This article analyses consolidated annual accounts in the public sector in six countries (Sweden, the UK, the USA, Canada, New Zealand and Australia) highlighting the differences and similarities in approaches. The authors also examine international trends and take an in-depth look at the International Public Sector Accounting Standards Board (IPSASB).

Human activities involving water may result in a crime scene. Typically, death may be due to natural causes, homicide, or mass disasters. Decomposition in water is a complex process where many factors may interplay. Human remains in water are subject to many potential interactions, depending upon the remains themselves, the type of water and the characteristics of the water. A number of studies are focused on the decomposition process of the corpse in water, on the identification of the post mortem submersion interval (PMSI) and on the diagnosis of drowning, but very few studies consider the fate of floating remains in any aquatic environment. The following case describes a corpse found on a shore of the Tyrrhenian Sea (South West of Italy, Calabria Region). The corpse and the soles of his shoes were colonized by the barnacle Lepas anatifera L. (Crustacea: Cirripedia: Pedunculata). The analyses of the barnacles present on the corpse aided in the evaluation of the floating time of the corpse which assisted in estimating the minimum time since death.

Ingesting caustic substances represents a common event which may result in serious injuries of the gastrointestinal system. Severity of injury depends on the type of ingested substance: Caustic burns are more frequently associated with acid ingestion and their severity depends on type, concentration, time of exposure, and amount of the ingested substance. We report a case of phosphoric acid ingestion leading to death in a patient with depressive disorder. While reports ingestion of other acids and organophosphates can be found in the literature, there are no reports detailing a death due to phosphoric acid ingestion. We hope that presenting the findings in this case can aid death investigators in future cases that may involve ingestion of such a substance. After autopsy pH, phosphate and calcium ions concentration in the blood were analyzed. The cause of death was due to systemic effects: metabolic acidosis, hypophosphatemia, hypocalcemia, and hyperkalemia.