hTERT Epigenetics Provides New Perspectives for Diagnosis and Evidence-Based Guidance of Chemotherapy in Cancer.

Strong epigenetic pan-cancer biomarkers are required to meet several current, urgent clinical needs and to further improve the present chemotherapeutic standard. We have concentrated on the investigation of epigenetic alteration of the hTERT gene, which is frequently epigenetically dysregulated in a number of cancers in specific developmental stages. Distinct DNA methylation profiles were identified in our data on early urothelial cancer. An efficient EpihTERT assay could be developed utilizing suitable combinations with sequence-dependent thermodynamic parameters to distinguish between differentially methylated states. We infer from this data set, the epigenetic context, and the related literature that a CpG-rich, 2800 bp region, a prominent CpG island, surrounding the transcription start of the hTERT gene is the crucial epigenetic zone for the development of a potent biomarker. In order to accurately describe this region, we have named it "Acheron" (Ἀχέρων). In Greek mythology, this is the river of woe and misery and the path to the underworld. Exploitation of the DNA methylation profiles focused on this region, e.g., idiolocal normalized Methylation Specific PCR (IDLN-MSP), opens up a wide range of new possibilities for diagnosis, determination of prognosis, follow-up, and detection of residual disease. It may also have broad implications for the choice of chemotherapy.

Skin color reporting in basal cell carcinoma-related randomized controlled trials in top dermatology journals: a systematic review.

OBJECTIVES: To determine the rate skin color is reported in randomized controlled trials (RCTs) involving basal cell carcinoma (BCC) identification and treatment in the top ten dermatology journals. METHODS: A systematic review was conducted of RCTs involving BCC among the top ten dermatology journals, determined by impact factor, from inception to July 11th, 2023. Studies were included if they reviewed the prevention, detection, and treatment of BCC, directly involved patients, and were classified as RCTs. Studies were classified as positive for reporting skin of color (SOC) if the demographic data in the methods or results included any of the following terms: Fitzpatrick scale, race, ethnicity, skin of color, or sunburn tendency. RESULTS: Of the 51 studies identified, only 23 articles reported data pertaining to skin color within the results section (45.1%); whereas 28 articles mentioned skin color somewhere within the text (54.9%). Subgroup analysis was performed, and no statistical significance was found for study location or year of publication. CONCLUSION: Dark skin color can make it more difficult to diagnose skin tumors and it is unknown if race affects response to treatment. Less than 50% of RCTs related to basal cell carcinoma in top international dermatology journals included skin color within the demographic portion of their results section pertaining to study participants. Subgroup analysis demonstrated that studies performed within the United States reported skin color less than half the time (40%). Additionally, there has been no statistically significant difference in reporting over the past 4 decades. Further research is necessary to determine whether low reporting rates of race/skin color in BCC-related RCTS could impact diagnostic or treatment recommendations for patient care in this group.

Navigating Viral Gastroenteritis: Epidemiological Trends, Pathogen Analysis, and Histopathological Findings.

BACKGROUND: Gastroenteritis is a common cause of morbidity and mortality globally. Its cause encompasses a spectrum of agents, including viruses, bacteria, parasites, toxins, and drugs. Viruses account for a considerable portion of gastroenteritis cases across all age groups, typically presenting with symptoms like nausea, vomiting, diarrhea, dehydration, anorexia, and weight loss. While sporadic cases occur, viral gastroenteritis is more frequently observed in outbreaks within closely knit communities such as daycare facilities, nursing homes, and cruise ships. Therefore, it becomes necessary to determine when healthcare providers should consider this condition in their differential diagnosis and to develop the most effective strategy to confirm the diagnosis. METHODS: De-identified data of patients with gastroenteritis were collected over a five-year period utilizing the Patient Cohort Explorer, an electronic health record at the University of Mississippi Medical Center. Confirmatory laboratory tests employed the BioFire® FilmArray® multiplex polymerase chain reaction for gastrointestinal pathogens. Out of the 22 most common agents associated with gastroenteritis, only viral pathogens, specifically adenovirus, astrovirus, norovirus, rotavirus, and sapovirus, were included in the analysis. When available, histopathology was reviewed. RESULTS: Among the various causes of gastroenteritis, both infectious and non-infectious, our findings revealed that 25.46% of the cases were linked to viral pathogens. This included a significantly higher percentage of pediatric patients (72.73%) when compared to adults (27.07%), with a p-value of 0.015. Norovirus genogroups I and II emerged as the most frequently detected viruses across all age groups, with a significant prevalence among adults. No discernible gender-based differences were observed. The histopathological findings included inflammation, ulceration, erosion, architectural distortion, and the pathognomonic viral inclusion bodies associated with adenovirus. CONCLUSION: Our comprehensive analysis of viral gastroenteritis cases highlights the substantial burden of this condition, particularly among pediatric patients. Norovirus emerges as a prevalent culprit which emphasizes the importance of vigilant surveillance and timely diagnosis, especially in settings where outbreaks are common.

Topical clindamycin for acne vulgaris: analysis of gastrointestinal events.

Purpose: Topical clindamycin, a lincosamide antibiotic, is commonly combined with benzoyl peroxide or a retinoid for acne vulgaris (AV) treatment. While oral and topical clindamycin carry warnings/contraindications regarding gastrointestinal (GI) adverse events (AEs), real-world incidence of GI AEs with topical clindamycin is unknown. This review provides background information and an overview of safety data of topical clindamycin for treating AV.Materials and Methods: Available safety data from published literature, previously unpublished worldwide pharmacovigilance data, and two retrospective cohort studies were reviewed.Results and Conclusions: According to pharmacovigilance data, the rate of GI adverse drug reactions with topical clindamycin-containing products was 0.000045% (64/141,084,533). Results from two retrospective medical record studies of patients with AV indicated that physicians prescribe topical clindamycin equally to patients with or without inflammatory bowel disease history, and that rates of pseudomembranous colitis in these patients were low. In 8 published pivotal clinical trials of topical clindamycin for AV, GI AEs were reported in 1.4% of participants. Limitations include under/inaccurate reporting of AEs or prescription data and limited generalizability. This review of published case reports, worldwide pharmacovigilance data, retrospective US prescription data, and clinical trials safety data demonstrates that the incidence of colitis in patients exposed to topical clindamycin is extremely low.

The history of the microscope reflects advances in science and medicine.

Microscopes, more than any other instrument, reflect advances in clinical medicine over the past several hundred years. As the primary tool of the pathologist, they were, and continue to be, a key connector between the bedside and basic sciences. One specific example is the science of clinical dermatology, which relies on clinical-pathologic correlation to make a definitive diagnosis. The microscopes used by pathologists, however, are more than scientific artifacts. Many antique microscopes are hand-crafted works of art. Even while recognizing that light microscopes may soon be obsolete as scanned slides and computer joy-sticks replace optical instruments in patient care and teaching, their significance will not be diminished. The microscope will never be forgotten in the history, art, and science of medicine, for these instruments set the social and cultural stage for modern, scientific patient care.

Skin color reporting in squamous cell carcinoma-related randomized controlled trials in top dermatology journals: a systematic review.

The objectives are to determine the frequency that skin color is reported in randomized controlled trials (RCTs) involving squamous cell carcinoma (SCC) detection and treatment in leading dermatology journals. A systematic review of RCTs involving SCC was conducted among the top ten most impactful dermatology journals from inception to July 10th, 2023. Studies were included if they reviewed the treatment, prevention, or detection of SCC, involved patients directly and were classified as traditional RCTs. Studies were considered positive for reporting SOC if there was any demographic data in the methods or results of the following terms: Fitzpatrick scale, race, ethnicity, sunburn tendency, or skin of color. Of the 39 studies which were identified, 23 reported data related to skin color data (59.0%). White individuals were the most reported in these studies (56.5%). Subgroup analysis was conducted, and no statistical significance was found for study location, year of publication, or funding source. Skin color impacts skin cancer detection, predominant location of tumors, and recurrence. Less than 60% of high-quality RCTs related to SCC in top global dermatology journals included skin color among the demographic traits of study participants. Subgroup analysis demonstrated no improvement in reporting over the past 2 decades. Further research is needed to understand the reason for low skin color reporting rates among SCC-related RCTs and the impact this has on society.

CD133-Dependent Activation of Phosphoinositide 3-Kinase /AKT/Mammalian Target of Rapamycin Signaling in Melanoma Progression and Drug Resistance.

Melanoma frequently harbors genetic alterations in key molecules leading to the aberrant activation of PI3K and its downstream pathways. Although the role of PI3K/AKT/mTOR in melanoma progression and drug resistance is well documented, targeting the PI3K/AKT/mTOR pathway showed less efficiency in clinical trials than might have been expected, since the suppression of the PI3K/mTOR signaling pathway-induced feedback loops is mostly associated with the activation of compensatory pathways such as MAPK/MEK/ERK. Consequently, the development of intrinsic and acquired resistance can occur. As a solid tumor, melanoma is notorious for its heterogeneity. This can be expressed in the form of genetically divergent subpopulations including a small fraction of cancer stem-like cells (CSCs) and non-cancer stem cells (non-CSCs) that make the most of the tumor mass. Like other CSCs, melanoma stem-like cells (MSCs) are characterized by their unique cell surface proteins/stemness markers and aberrant signaling pathways. In addition to its function as a robust marker for stemness properties, CD133 is crucial for the maintenance of stemness properties and drug resistance. Herein, the role of CD133-dependent activation of PI3K/mTOR in the regulation of melanoma progression, drug resistance, and recurrence is reviewed.

Clinical-pathologic correlation: The impact of grossing at the bedside.

The unenlightened clinician may submit a skin specimen to the lab and expect an "answer." The experienced clinician knows that in performing skin biopsies, it is critical to select the most appropriate: 1) anatomic location for the biopsy1,2; 2) type of biopsy1,2; 3) depth and breadth of the biopsy; and 4) medium for hematoxylin and eosin staining (formalin) or direct immunofluorescence (Michel's Transport Medium or normal saline).2 Demographic information, anatomic location, clinical context, and differential diagnosis are all critical components of a properly completed requisition form.3-5 Proper biopsy design and appropriate grossing of the tissue at the bedside should be added to this list. In this article, we review the basics of gross pathologic examination and then provide four examples to demonstrate that optimal clinical-pathologic correlation requires the clinician consider the needs of the pathologist when tissue is presented to the lab.

Mechanisms of Melanoma Progression and Treatment Resistance: Role of Cancer Stem-like Cells.

Melanoma is the third most common type of skin cancer, characterized by its heterogeneity and propensity to metastasize to distant organs. Melanoma is a heterogeneous tumor, composed of genetically divergent subpopulations, including a small fraction of melanoma-initiating cancer stem-like cells (CSCs) and many non-cancer stem cells (non-CSCs). CSCs are characterized by their unique surface proteins associated with aberrant signaling pathways with a causal or consequential relationship with tumor progression, drug resistance, and recurrence. Melanomas also harbor significant alterations in functional genes (BRAF, CDKN2A, NRAS, TP53, and NF1). Of these, the most common are the BRAF and NRAS oncogenes, with 50% of melanomas demonstrating the BRAF mutation (BRAFV600E). While the successful targeting of BRAFV600E does improve overall survival, the long-term efficacy of available therapeutic options is limited due to adverse side effects and reduced clinical efficacy. Additionally, drug resistance develops rapidly via mechanisms involving fast feedback re-activation of MAPK signaling pathways. This article updates information relevant to the mechanisms of melanoma progression and resistance and particularly the mechanistic role of CSCs in melanoma progression, drug resistance, and recurrence.