Melanoma: An update on systemic therapies.

Despite advances in early detection as described in part 1 of this continuing medical education series, melanoma continues to be a large contributor to cutaneous cancer-related mortality. In a subset of patients with unresectable or metastatic disease, surgical clearance is often not possible; therefore, systemic and local therapies are considered. The second article in this series provides dermatologists with an up-to-date working knowledge of the treatment options that may be prescribed by oncologists for patients with unresectable stage III, stage IV, and recurrent melanoma.

Melanoma: How and when to consider clinical diagnostic technologies.

In response to rising rates of melanoma worldwide, novel noninvasive melanoma detection techniques are emerging to facilitate the early detection of melanoma and decrease unnecessary biopsies of benign pigmented lesions. Because they often report similar study findings, it may be difficult to determine how best to incorporate these technologies into clinical practice based on their supporting studies alone. The first article in this continuing medical education series provides practical advice on how and when to use various noninvasive melanoma detection techniques in clinical practice.

Evidence concerning the accusation that melanoma is overdiagnosed.

BACKGROUND: Melanoma is one of the most commonly diagnosed malignancies in the United States and is responsible for the majority of deaths from skin cancer. OBJECTIVE: Since the 1970s, the incidence of melanoma has risen appreciably while melanoma-specific mortality has remained stable. This has raised a debate about potential overdiagnosis of melanoma. Herein, we review temporal trends in melanoma incidence and mortality and explore factors that may contribute to observed trends, including an aging population in the United States, ultraviolet exposure, increased numbers of biopsies by dermatologists and physician extenders, skin cancer screenings, histopathology criteria, and historic underdiagnosis. Additionally, we discuss melanoma overdiagnosis and the extent to which it may contribute to current trends. METHODS: The literature was reviewed. RESULTS: Several factors may contribute to an increased incidence of melanoma, including an aging population, ultraviolet exposure, increased skin biopsies, skin cancer screenings, histopathologic criteria, historic underdiagnosis, and current overdiagnosis. LIMITATIONS: Further studies are required to determine exactly which tumors are being overdiagnosed, and how to improve patient outcomes with adjustment to physician's practice. CONCLUSION: The rise in the incidence of melanoma observed since the 1970s is likely multifactorial.

Multifunctional Periphytic Biofilms: Polyethylene Degradation and Cd2+ and Pb2+ Bioremediation under High Methane Scenario.

Priority pollutants such as polyethylene (PE) microplastic, lead (Pb2+), and cadmium (Cd2+) have attracted the interest of environmentalists due to their ubiquitous nature and toxicity to all forms of life. In this study, periphytic biofilms (epiphyton and epixylon) were used to bioremediate heavy metals (HMs) and to biodegrade PE under high (120,000 ppm) methane (CH4) doses. Both periphytic biofilms were actively involved in methane oxidation, HMs accumulation and PE degradation. Epiphyton and epixylon both completely removed Pb2+ and Cd2+ at concentrations of 2 mg L-1 and 50 mg L-1, respectively, but only partially removed these HMs at a relatively higher concentration (100 mg L-1). Treatment containing 12% 13CH4 proved to be most effective for biodegradation of PE. A synergistic effect of HMs and PE drastically changed microbial biota and methanotrophic communities. High-throughput 16S rRNA gene sequencing revealed that Cyanobacteria was the most abundant class, followed by Gammaproteobacteria and Alphaproteobacteria in all high-methane-dose treatments. DNA stable-isotope probing was used to label 13C in a methanotrophic community. A biomarker for methane-oxidizing bacteria, pmoA gene sequence of a 13C-labeled fraction, revealed that Methylobacter was most abundant in all high-methane-dose treatments compared to near atmospheric methane (NAM) treatment, followed by Methylococcus. Methylomonas, Methylocystis, Methylosinus, and Methylocella were also found to be increased by high doses of methane compared to NAM treatment. Overall, Cd+2 had a more determinantal effect on methanotrophic activity than Pb2+. Epiphyton proved to be more effective than epixylon in HMs removal and PE biodegradation. The findings proved that both epiphyton and epixylon can be used to bioremediate HMs and biodegrade PE as an efficient ecofriendly technique under high methane concentrations.

Seasonal changes in phosphorus competition and allelopathy of a benthic microbial assembly facilitate prevention of cyanobacterial blooms.

Interactions among microbes determine the prevalence of harmful algal blooms that threaten water quality. These interactions can be indirectly mediated by shared resources or consumers, or through interference by the production of allelochemicals. Allelopathic interactions and resource competition have been shown to occur among algae and associated microbes. However, little work has considered seasonal influences on ecosystem structure and function. Here, we report results of our investigations on seasonal changes in the interactions between benthic microbial assemblies and the bloom forming cyanobacterium Microcystis aeruginosa. We show that phosphorus (P) competition and allelopathy by the microbial assembly vary seasonally and inhibit growth of M. aeruginosa. The interactions per unit biomass of the microbial assembly are stronger under winter than summer conditions and inhibit the recruitment of the cyanobacteria, thereby preventing the reoccurrence of cyanobacterial blooms in the following summer. The seasonality of these interactions correlates with changes in composition, metabolic activity and functional diversity of the microbial assembly. Our findings highlight the importance of competitive and allelopathic interactions in regulating the occurrence of harmful algal blooms. Our results also imply that seasonal variation of competition and allelopathy of the microbial assembly might be beneficial to adjust aquatic ecosystem structure and function.

Sustained High Nutrient Supply As an Allelopathic Trigger between Periphytic Biofilm and Microcystis aeruginosa.

Allelopathy among aquatic organisms, especially microorganisms, has received growing attention in recent years for its role in shaping interactions with bloom-forming algae. Many studies have shown that allelopathy occurs and increases under nutrient limiting conditions. However, to date there is no reported direct evidence to indicate that allelopathy occurs under the condition of constant high nutrient supply. Here we report the allelopathic action of periphytic biofilm on bloom-forming cyanobacteria (Microcystis aeruginosa), which was triggered by the stress of high nutrient conditions, and continues while nutrients are maintained at high levels (trophic state index at 159 and 171). The experimental evidence indicates that the electron transport from photosystem II (PS II) to photosystem I (PS I) in M. aeruginosa is interrupted by the identified allelochemicals, (9Z)-Octadec-9-enoic acid and (9Z)-Hexadec-9-enoic acid, leading to the failure of photosynthesis and the subsequent death of M. aeruginosa. Our findings indicate that the nutrient stress of constant high nutrient supply may be a newly recognized trigger causing allelopathy between microbial competitors, and therefore opening a new direction for the better management of ecological processes in cyanobacteria-dominated and hyper-eutrophic waters.

Responses of Periphyton to Fe2O3 Nanoparticles: A Physiological and Ecological Basis for Defending Nanotoxicity.

The toxic effects of nanoparticles on individual organisms have been widely investigated, while few studies have investigated the effects of nanoparticles on ubiquitous multicommunity microbial aggregates. Here, periphyton as a model of microbial aggregates, was employed to investigate the responses of microbial aggregates exposed continuously to Fe2O3 nanoparticles (5.0 mg L-1) for 30 days. The exposure to Fe2O3 nanoparticles results in the chlorophyll (a, b, and c) contents of periphyton increasing and the total antioxidant capacity decreasing. The composition of the periphyton markedly changes in the presence of Fe2O3 nanoparticles and the species diversity significantly increases. The changes in the periphyton composition and diversity were due to allelochemicals, such as 3-methylpentane, released by members of the periphyton which inhibit their competitors. The functions of the periphyton represented by metabolic capability and contaminant (organic matter, nitrogen, phosphorus and copper) removal were able to acclimate to the Fe2O3 nanoparticles exposure via self-regulation of morphology, species composition and diversity. These findings highlight the importance of both physiological and ecological factors in evaluating the long-term responses of microbial aggregates exposed to nanoparticles.

Olive (Olea europaea L.) Biophenols: A Nutriceutical against Oxidative Stress in SH-SY5Y Cells.

Plant biophenols have been shown to be effective in the modulation of Alzheimer's disease (AD) pathology resulting from free radical-induced oxidative stress and imbalance of the redox chemistry of transition metal ions (e.g., iron and copper). On the basis of earlier reported pharmacological activities, olive biophenols would also be expected to have anti-Alzheimer's activity. In the present study, the antioxidant activity of individual olive biophenols (viz. caffeic acid, hydroxytyrosol, oleuropein, verbascoside, quercetin, rutin and luteolin) were evaluated using superoxide radical scavenging activity (SOR), hydrogen peroxide (H2O2) scavenging activity, and ferric reducing ability of plasma (FRAP) assays. The identification and antioxidant activities in four commercial olive extracts-Olive leaf extractTM (OLE), Olive fruit extractTM (OFE), Hydroxytyrosol ExtremeTM (HTE), and Olivenol plusTM (OLP)-were evaluated using an on-line HPLC-ABTS•+ assay, and HPLC-DAD-MS analysis. Oleuropein and hydroxytyrosol were the predominant biophenols in all the extracts. Among the single compounds examined, quercetin (EC50: 93.97 µM) and verbascoside (EC50: 0.66 mM) were the most potent SOR and H2O2 scavengers respectively. However, OLE and HTE were the highest SOR (EC50: 1.89 µg/mL) and H2O2 (EC50: 115.8 µg/mL) scavengers among the biophenol extracts. The neuroprotection of the biophenols was evaluated against H2O2-induced oxidative stress and copper (Cu)-induced toxicity in neuroblastoma (SH-SY5Y) cells. The highest neuroprotection values (98% and 92%) against H2O2-induced and Cu-induced toxicities were shown by the commercial extract HTETM. These were followed by the individual biophenols, caffeic acid (77% and 64%) and verbascoside (71% and 72%). Our results suggest that olive biophenols potentially serve as agents for the prevention of neurodegenerative diseases such as AD, and other neurodegenerative ailments that are caused by oxidative stress.

Evaluation and management of benign tumors of the eye and eyelid.

Benign tumors of the eye and eyelid are common in children and adults, and they rarely undergo malignant transformation. Their workup and management have evolved over the years with increasing advancements in surgical and laser therapies. This contribution focuses on describing the following benign eye and eyelid tumors and their diagnostic and treatment approaches: congenital and acquired melanocytic nevi; nevus of Ota (Hori nevus); conjunctival papilloma; seborrheic keratosis; epidermoid cyst; dermoid cyst; milium; xanthelasma; hemangioma (cherry angioma and pyogenic granuloma); neurofibroma; neurilemmoma (schwannoma); and fibroepithelial polyp. Surgical removal is the primary treatment approach for many of these benign tumors. With advancements in laser technologies, there are now several laser types that can be used in the treatment of these benign eye and eyelid tumors. Other treatment modalities include cryosurgery, electrosurgery, and topical or intralesional medications. We hope this review will provide a reference to dermatologists and ophthalmologists in their approach to evaluation and management of benign eye and eyelid tumors.

Ethical Implications of Mentor Influence on Career Choices in Dermatology.

Mentorship is a critical aspect of personal and professional development throughout anyone's life. Unlike many other fields, a medical career is a long multistep process that can begin in high school and continue throughout a physician's career. When considering competitive specialties such as dermatology, mentors are increasingly crucial in helping students successfully match to programs of their choice, but the variability and extent of mentorship can raise ethical concerns. We discuss the evolution of mentorship in dermatology and the potential ethical issues involved. We propose possible solutions to the ethical conflict between mentor and mentee.

Insights into seed coats of nine cultivars of Australian lupin: Unravelling LC-QTOF MS-based biochemical profiles, nutritional, functional, antioxidant, and antidiabetic properties together with rationalizing antidiabetic mechanism by in silico approaches.

Lupins, and other legumes, have attained international interest due to their reported remarkable health benefits. Currently, the seed coats are discarded as waste or animal feed. The research presented here summarizes the potential for incorporating the seed coats into 'whole grain' foods. We aimed to identify metabolites found in the seed coats of nine commercial Australian cultivars of lupin (Lupinus angustifolius and L. albus species), and to evaluate and compare their functional, nutritional, antioxidant, and antidiabetic properties, along with in silico exploration of mechanisms of action for selected identified secondary metabolites. The seed coats were found to contain 79 to 90% dietary fibers and substantial quantity of essential macrometals. LC-QTOF MS-based, untargeted bioactive metabolite profiling explored a total of 673 chemical entities, and identified 63 bioactive secondary metabolites including: biophenols, unsaturated fatty acids, triterpenoids, alkaloids, and dietary prebiotics (insoluble fibers). The seed coats from these nine cultivars show substantial antioxidant activity. The cultivars of L. angustifolius inhibit α-amylase and α-glucosidase significantly in vitro. Moreover, in silico docking and dynamic simulation along with ADME/T analysis suggest that quercetin 3-methyl ether and 8-C-methylquercetin 3-methyl ether as molecules, novel in lupin seed coats, are responsible for the α-amylase and α-glucosidase inhibition. The findings indicated that lupin seed coats might be beneficial food components, rather than be discarded as 'mill waste'.

Attenuating Colorectal Cancer Using Nine Cultivars of Australian Lupin Seeds: Apoptosis Induction Triggered by Mitochondrial Reactive Oxygen Species Generation and Caspases-3/7 Activation.

As Australian lupin cultivars are rich sources of polyphenols, dietary fibers, high-quality proteins, and abundant bioactive compounds with significant antioxidant, antidiabetic, and anticancer activities, this research work is aimed at investigating the colon cancer alleviation activity of nine cultivars of lupin seeds on HCT116 and HT29 colon carcinoma cell lines through anti-proliferation assay, measurement of apoptosis, and identification of the mechanism of apoptosis. Nine cultivars were pre-screened for anti-proliferation of HCT116 and HT29 cells along with consideration of the impact of heat processing on cancer cell viability. Mandelup and Jurien showed significant inhibition of HCT116 cells, whereas the highest inhibition of HT29 cell proliferation was attained by Jurien and Mandelup. Processing decreased the anti-proliferation activity drastically. Lupin cultivars Mandelup, Barlock, and Jurien (dose: 300 µg/mL) induced early and late apoptosis of colon cancer cells in Annexin V-FITC assay. The mechanism of apoptosis was explored, which involves boosting of caspases-3/7 activation and intracellular reactive oxygen species (ROS) generation in HCT116 cells (Mandelup and Barlock) and HT29 cells (Jurien and Mandelup). Thus, the findings showed that lupin cultivars arrest cell cycles by inducing apoptosis of colorectal carcinoma cells triggered by elevated ROS generation and caspases-3/7 activation.

In Silico, In Vitro, and In Vivo Evaluation of Caffeine-Coated Nanoparticles as a Promising Therapeutic Avenue for AML through NF-Kappa B and TRAIL Pathways Modulation.

BACKGROUND: Advancements in nanoscience have led to a profound paradigm shift in the therapeutic applications of medicinally important natural drugs. The goal of this research is to develop a nano-natural product for efficient cancer treatment. METHODS AND RESULTS: For this purpose, mesoporous silica nanoparticles (MSNPs) were formulated, characterized, and loaded with caffeine to develop a targeted drug delivery system, i.e., caffeine-coated nanoparticles (CcNPs). In silico docking studies were conducted to examine the binding efficiency of the CcNPs with different apoptotic targets followed by in vitro and in vivo bioassays in respective animal models. Caffeine, administered both as a free drug and in nanomedicine form, along with doxorubicin, was delivered intravenously to a benzene-induced AML model. The anti-leukemic potential was assessed through hematological profiling, enzymatic biomarker analysis, and RT-PCR examination of genetic alterations in leukemia markers. Docking studies show strong inter-molecular interactions between CcNPs and apoptotic markers. In vitro analysis exhibits statistically significant antioxidant activity, whereas in vivo analysis exhibits normalization of the genetic expression of leukemia biomarkers STMN1 and S1009A, accompanied by the restoration of the hematological and morphological traits of leukemic blood cells in nanomedicine-treated rats. Likewise, a substantial improvement in hepatic and renal biomarkers is also observed. In addition to these findings, the nanomedicine successfully normalizes the elevated expression of GAPDH and mTOR induced by exposure to benzene. Further, the nanomedicine downregulates pro-survival components of the NF-kappa B pathway and upregulated P53 expression. Additionally, in the TRAIL pathway, it enhances the expression of pro-apoptotic players TRAIL and DR5 and downregulates the anti-apoptotic protein cFLIP. CONCLUSIONS: Our data suggest that MSNPs loaded with caffeine, i.e., CcNP/nanomedicine, can potentially inhibit transformed cell proliferation and induce pro-apoptotic TRAIL machinery to counter benzene-induced leukemia. These results render our nanomedicine as a potentially excellent therapeutic agent against AML.

Evaluating the Impact of Formal Dermatopathology Fellowship Training on Practice Patterns and Characteristics Among Dermatologists Submitting Claims for Medicare Pathology Examinations in 2017.

Objective: Dermatopathology training is incorporated into dermatology residency programs, yet some individuals choose to pursue additional fellowship training in dermatopathology. We sought to characterize the impact of dermatopathology training on practice patterns of dermatologists performing pathology exams in the Medicare population. Methods: We conducted a cross-sectional review of the 2017 Medicare Public Use File to identify all residency-trained dermatologists performing microscopic pathology exams in 2017. Formal dermatopathology fellowship training was identified through the American Board of Medical Specialties website. Results: There were 2,150 dermatologists performing pathology examinations in 2017; of these, 592 (27.5%) had formal dermatopathology fellowship training. Fellowship training was associated with a higher mean annual pathology exam volume. Those without fellowship training were more likely to practice in the West, in non-academic settings, and in non-metropolitan counties. Limitations: Residency-trained pathologists are not included in the sample. Additionally, some dermatopathology labs may submit claims as an entire organization, rather than at the level of each physician. Conclusion: Fellowship-trained dermatopathologists perform pathology exams at a higher rate than their non-fellowship-trained colleagues and are concentrated in academic practice settings. The findings support the important role of fellowship-trained dermatopathologists in evaluating a wide array of skin pathologies.

Gentians, natural remedies for future of visceral pain control; an ethnopharmacological review with an in silico approach.

Different gentian preparations are used as traditional remedies for internal pain control in: Persian traditional medicine (PTM), Chinese traditional medicine (CTM) and Ancient Greek medicine (AGM) from the time of the Roman Empire. Objective: To present a survey of the ethnopharmacological applications of gentians recorded as being used in Eastern and Western traditional medical systems (PTM, CTM and AGM) and their pharmacological effects, chemical composition as well as an in silico investigation of the possible active component/s for the alleviation of internal pain via molecular docking studies. Major traditional medicine literature (PTM, CTM and AGM, 50 AD- 1770) and ethnobotanical studies for the application of gentians were reviewed. Nine European species representing 5 of the 13 sections currently attributed to Gentiana were selected. Chemical compounds and pharmacological activity data of these species were gathered from different databases including Google Scholar, PubChem, PubMed and Web of Science (between 1972 and 2020). The possible active constituents of gentians on visceral pain receptors were investigated, in silico. In all investigated literature, traditional uses of gentian were indicated to have anti-nociceptive effects on visceral pain and possess diuretic action. According to our computational study, acylated flavonoid glycosides, viz. trans-feruloyl-2"-isovitexin (33), trans-feruloyl-2"-isovitexin-4'-O-ß-D-glucoside (34), iso-orientin-4'-O-glucoside (38), trans-caffeoyl-2"-iso-orientin-4'-O-ß-D-glucoside (39), iso-orientin-2"-O-ß-D-glucoside (40) and isoscoparin (41), might be responsible for visceral pain reduction by interacting with the purinergic receptor (P2X3) and vanilloid receptor 1 (TrpV1). This finding shows a good correlation with different traditional gentian uses in Persian, Chinese and European ethnomedicine for visceral pain control.

A novel biotechnology based on periphytic biofilms with N-acyl-homoserine-lactones stimulation and lanthanum loading for phosphorus recovery.

This study presents an approach for developing periphytic biofilm with N-acyl-homoserine-lactones (AHLs) stimulation and lanthanum (La, a rare earth element) loading, to achieve highly efficient and stable phosphorus (P) recovery from wastewater. AHLs stimulated biofilm growth and formation, also improved stable P entrapment by enhancing extracellular polymeric substance (EPS) production and optimizing P-entrapment bacterial communities. Periphytic biofilms loading La is based on ligand exchanges, and La loading achieved initial rapid P entrapment by surface adsorption. The combination of AHLs stimulation and La loading achieved 99.0% P entrapment. Interestingly, the enhanced EPS production stimulated by AHLs protected biofilms against La. Moreover, a method for P and La separately recovery from biofilms was developed, achieving 89-96% of P and 88-93% of La recovery. This study offers a promising biotechnology to reuse La from La-rich wastewater and recover P by biofilm doped with La, which results in a win-win situation for resource sustainability.