Fohotodermatoses and Skin Cancer

Preface Skin cancer is one of the most common types of tumors in Western countries. In the United States only, more than one million people are diagnosed with skin cancer each year. Although the absolute number of skin cancer patients is increasing, the death is inversely decreasing, due to the early detection and treatment. Basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma are three major types of skin cancer. BCC and SCC rarely have metastasis; over 95 percent BCC and SCC patients can be cured. Melanoma only accounts for a small percentage of skin cancer, but it causes 75 percent death of this disease. In this book, we invited a number of experts to present their latest accomplishments on skin cancer research. Although the topics are varied, the authors did great work to help readers better understand skin cancer and learn the knowledge to prevent this disease. There are three sections in this book, starting with etiology. Ultraviolet (UV) light exposure is overwhelmingly believed to be the most frequent cause of skin cancer. In this section, the association between UV and photodermatoses, as well as skin cancer is discussed. Desmosomal cadherins are important molecules in tumor cell adhesion and invasion, and their important roles in BCC are also presented in details. In the diagnosis and treatment section, a few new methodologies are described. As known, the outcome of malignant melanoma greatly depends on the thickness of the tumor at the time of treatment. Accurate determination of melanoma lateral and depth of margins using non-invasive imaging technologies is of importance when making sound decisions for treatment and evaluating a five year survival rate. A novel method named differential scanning calorimetry is capable of predicting metastasis of melanoma patients by monitoring the temperature changes of plasma. Electronic miniature X-ray brachytherapy is introduced as a new technology to treat nonmelanoms skin cancer. Although its potential has not yet been fully realized, chemoprevention, in terms of using chemical agents that naturally occur in foods, or are administered as pharmaceuticals to retard or reverse the process of carcinogenesis and progression of cancer, has been recognized to benefit individuals with precancerous lesions or genetic susceptibilities to cancer. In the prevention section, two chapters summarized the most recognized dietary phytochemicals and their potential application in skin cancer. X Preface This book would not have been possible without the contributions of all authors and the support from the publisher. Especially, I will convey my sincere appreciation to Ms. Tajana Jevtic, who has always been available and supportive of me to accomplish this project. Yaguang Xi, M.D., Ph.D. Assistant Professor of Oncologic Sciences, University of South Alabama, US

Probing Lorentz-violating electrodynamics with CMB polarization

We perform a comprehensive study of the signatures of Lorentz violation in electrodynamics on the Cosmic Microwave Background (CMB) anisotropies. In the framework of the minimal Standard Model Extension (SME), we consider effects generated by renormalizable operators, both CPT-odd and CPT-even. These operators are responsible for sourcing, respectively, cosmic birefringence and circular polarization. We propagate jointly the effects of all the relevant Lorentz-violating parameters to CMB observables and provide constraints with the most recent CMB datasets. We bound the CPT-even coefficient to $k_{F,E+B} < 2.31 \times 10^{-31}$ at 95\% CL. This improves previous CMB bounds by one order of magnitude. The limits we obtain on the CPT-odd coefficients, i.e. $|k_{(V)00}^{(3)}| < 1.54 \times 10^{-44} \; {\rm GeV}$ and $|\mathbf{k_{AF}}| < 0.74 \times 10^{-44} \; {\rm GeV}$ at 95\% CL, are respectively one and two orders of magnitude stronger than previous CMB-based limits, superseding also bounds from non-CMB searches. This analysis provides the strongest constraints to date on CPT-violating coefficients in the minimal SME from CMB searches

Galantamine-memantine hybrids for Alzheimer's disease: The influence of linker rigidity in biological activity and pharmacokinetic properties

Neurodegenerative processes characterizing Alzheimer's disease (AD) are strictly related to the impairment of cholinergic and glutamatergic neurotransmitter systems which provoke synaptic loss. These experimental evidences still represent the foundation of the actual standard-of-care treatment for AD, albeit palliative, consisting on the coadministration of an acetylcholinesterase inhibitor and the NMDAR antagonist memantine. In looking for more effective treatments, we previously developed a series of galantamine-memantine hybrids where compound 1 (ARN14140) emerged with the best-balanced action toward the targets of interest paired to neuroprotective efficacy in a murine AD model. Unfortunately, it showed a suboptimal pharmacokinetic profile, which required intracerebroventricular administration for in vivo studies. In this work we designed and synthesized new hybrids with fewer rotatable bonds, which is related to higher brain exposure. Particularly, compound 2, bearing a double bond in the tether, ameliorated the biological profile of compound 1 in invitro studies, increasing cholinesterases inhibitory potencies and selective antagonism toward excitotoxic-related GluN1/2B NMDAR over beneficial GluN1/2A NMDAR. Furthermore, it showed increased plasma stability and comparable microsomal stability in vitro, paired with lower half-life and faster clearance in vivo. Remarkably, pharmacokinetic evaluations of compound 2 showed a promising increase in brain uptake in comparison to compound 1, representing the starting point for further chemical optimizations

Understanding Barriers Impacting upon Patient Wellbeing: A Nationwide Italian Survey and Expert Opinion of Dermatologists Treating Patients with Moderate-to-Severe Psoriasis

A nationwide cross-sectional online survey was administered to dermatologists managing patients with moderate-to-severe plaque psoriasis across Italy to obtain real-world dermatologists' perspectives on the impact of psoriasis and its treatment on patients' daily lives and quality of life (QoL). A total of 91 dermatologists (aged 39.1 +/- 11.2 years) completed a 31-question survey and workshop sessions were undertaken in order to identify the best management approach to achieve patient wellbeing. Social (4.2 +/- 0.1), physical (4.26 +/- 0.2) and mental components (4.1 +/- 0.3) were rated by dermatologists as contributing to patient wellbeing to similar extents. While a high proportion (85.4%; rating of 4.3 out of 5) of dermatologists felt that they considered the QoL of patients, a lower proportion (69.6%; rating of 3.7 out of 5) felt that patients were satisfied in this regard. The psoriasis area and severity index and body surface area were the instruments most frequently used to assess the physical domain, while interviews/questions and the dermatology life quality index were used to assess social and mental domains, with only 60% of dermatologists following up on these aspects. The importance of investigating the presence of comorbidities was recognized but not always carried out by many dermatologists, (&gt;70%), particularly for obesity and anxiety/depression. This survey identified key components contributing to barriers impacting on the QoL of patients with moderate-to-severe psoriasis from the perspective of the dermatologist

A Systematic Review and International Web-Based Survey of Randomized Controlled Trials in the Perioperative and Critical Care Setting: Interventions Reducing Mortality

The authors aimed to identify interventions documented by randomized controlled trials (RCTs) that reduce mortality in adult critically ill and perioperative patients, followed by a survey of clinicians’ opinions and routine practices to understand the clinicians’ response to such evidence. The authors performed a comprehensive literature review to identify all topics reported to reduce mortality in perioperative and critical care settings according to at least 2 RCTs or to a multicenter RCT or to a single-center RCT plus guidelines. The authors generated position statements that were voted on online by physicians worldwide for agreement, use, and willingness to include in international guidelines. From 262 RCT manuscripts reporting mortality differences in the perioperative and critically ill settings, the authors selected 27 drugs, techniques, and strategies (66 RCTs, most frequently published by the New England Journal of Medicine [13 papers], Lancet [7], and Journal of the American Medical Association [5]) with an agreement ≥67% from over 250 physicians (46 countries). Noninvasive ventilation was the intervention supported by the largest number of RCTs (n = 13). The concordance between agreement and use (a positive answer both to “do you agree” and “do you use”) showed differences between Western and other countries and between anesthesiologists and intensive care unit physicians. The authors identified 27 clinical interventions with randomized evidence of survival benefit and strong clinician support in support of their potential life-saving properties in perioperative and critically ill patients with noninvasive ventilation having the highest level of support. However, clinician views appear affected by specialty and geographical location

Continuous vs Intermittent Meropenem Administration in Critically Ill Patients With Sepsis

Importance: Meropenem is a widely prescribed β-lactam antibiotic. Meropenem exhibits maximum pharmacodynamic efficacy when given by continuous infusion to deliver constant drug levels above the minimal inhibitory concentration. Compared with intermittent administration, continuous administration of meropenem may improve clinical outcomes. Objective: To determine whether continuous administration of meropenem reduces a composite of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria compared with intermittent administration in critically ill patients with sepsis. Design, setting, and participants: A double-blind, randomized clinical trial enrolling critically ill patients with sepsis or septic shock who had been prescribed meropenem by their treating clinicians at 31 intensive care units of 26 hospitals in 4 countries (Croatia, Italy, Kazakhstan, and Russia). Patients were enrolled between June 5, 2018, and August 9, 2022, and the final 90-day follow-up was completed in November 2022. Interventions: Patients were randomized to receive an equal dose of the antibiotic meropenem by either continuous administration (n = 303) or intermittent administration (n = 304). Main outcomes and measures: The primary outcome was a composite of all-cause mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28. There were 4 secondary outcomes, including days alive and free from antibiotics at day 28, days alive and free from the intensive care unit at day 28, and all-cause mortality at day 90. Seizures, allergic reactions, and mortality were recorded as adverse events. Results: All 607 patients (mean age, 64 [SD, 15] years; 203 were women [33%]) were included in the measurement of the 28-day primary outcome and completed the 90-day mortality follow-up. The majority (369 patients, 61%) had septic shock. The median time from hospital admission to randomization was 9 days (IQR, 3-17 days) and the median duration of meropenem therapy was 11 days (IQR, 6-17 days). Only 1 crossover event was recorded. The primary outcome occurred in 142 patients (47%) in the continuous administration group and in 149 patients (49%) in the intermittent administration group (relative risk, 0.96 [95% CI, 0.81-1.13], P = .60). Of the 4 secondary outcomes, none was statistically significant. No adverse events of seizures or allergic reactions related to the study drug were reported. At 90 days, mortality was 42% both in the continuous administration group (127 of 303 patients) and in the intermittent administration group (127 of 304 patients). Conclusions and relevance: In critically ill patients with sepsis, compared with intermittent administration, the continuous administration of meropenem did not improve the composite outcome of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28. Trial registration: ClinicalTrials.gov Identifier: NCT03452839