Wound healing protects against chemotherapy-induced alopecia in young rats via up-regulating interleukin-1ß-mediated signaling.

Wound healing is a complex process regulated by various cell types and a plethora of mediators. While interactions between wounded skin and the hair follicles (HFs) could induce HF neogenesis or promote wound healing, it remains unknown whether the wound healing-associated signaling milieu can be manipulated to protect against alopecia, such as chemotherapy-induced alopecia (CIA). Utilizing a well-established neonatal rat model of CIA, we show here that skin wounding protects from alopecia caused by several clinically relevant chemotherapeutic regimens, and that protection is dependent on the time of wounding and hair cycle stage. Gene expression profiling unveiled a significant increase in interleukin-1 beta (IL-1ß) mediated signaling by skin wounding. Subsequently, we showed that IL-1ß is sufficient and indispensable for mediating the CIA-protective effect. Administration of IL-1ß alone to unwounded rats exhibited local CIA protection while IL-1ß neutralization abrogated CIA protection by wounding. Mechanistically, IL-1ß retarded postnatal HF morphogenesis, making HFs at the wound sites or IL-1ß treated areas damage-resistant while the rats developed total alopecia elsewhere. We conclude that wound healing switches the cutaneous cytokine milieu to an IL-1ß-dominated state thus retarding HF growth progression and rendering the HFs resistant to chemotherapy agents. In the future, manipulation of HF progression through interfering with the IL-1ß signaling milieu may provide therapeutic benefits to a variety of conditions, from prevention of CIA to inhibition of hair growth and treatment of hirsutism.

Interstitial nephritis in melanoma patients secondary to PD-1 checkpoint inhibitor.

BACKGROUND: Immune checkpoint inhibitors have become the first line therapy in melanoma treatment and their use is extending to other malignancies. However, we are still learning about immune side effects produced by these drugs and their severity especially in patients with history of inflammatory diseases. CASE PRESENTATION: We present two cases of metastatic melanoma treated with nivolumab and pembrolizumab (anti PD-1). Both patients developed acute interstitial nephritis during immune checkpoint therapy. We emphasize the causal association between immune checkpoint inhibitors and the nephritis. The timing of drug administration and appearance of nephritis is suggestive of a causal relation between the checkpoint inhibitor therapy and this adverse event. CONCLUSIONS: Although uncommon, some side effects from checkpoint inhibitors can be severe and may need to be addressed with immunosuppression. Given the increasing frequency of immunotherapy use, awareness should be raised in regards to immune side effects and their appropriate management.

Aneuploidy and Tetraploidy as Distinct Patterns During Melanomagenesis.

Melanoma is characterized by a high degree of chromosome instability (CIN), the loss or gain of entire chromosomes or pieces of chromosomes. Also, CIN is likely to drive the progression of benign melanocytic lesions to malignant tumors, although very little is known about the acquisition of the mechanisms that promote CIN along this progression. Here, we describe the development of a model system to study the progression of melanomagenesis starting with normal human melanocytes followed by inactivation of the p53 and pRb tumor suppressors by addition of the E6/E7 proteins. The cells were then transduced with a growth-promoting, constitutionally-active mutant NRAS. The addition of E6/E7 and E6/E7 NRAS was found to give a growth advantage to the cells compared to normal melanocytes and a statistically significant gain of aneuploidy; aneuploidy was 24.7% in primary melanocytes, 33.8% in E6/E7 melanocytes, and 70.5% in E6/E7 NRAS melanocytes. Further, we found an increase in tetraploid cells in the cell model which was statistically significant between primary melanocytes and E6/E7, NRAS melanocytes. We also observed an increase in aneuploid cells between three population doublings in primary melanocytes, whereas this increase was not seen in the E6/E7 melanocytes. Together, these data demonstrate that this model system utilizing stepwise addition of genetic mutations driving melanomagenesis is a useful tool to study CIN and could even be used to study the mechanisms responsible for these alterations in genetic makeup.

Isolation of Mouse Hair Follicle Bulge Stem Cells and Their Functional Analysis in a Reconstitution Assay.

The hair follicle (HF) is a dynamic structure readily accessible within the skin, and contains various pools of stem cells that have a broad regenerative potential during normal homeostasis and in response to injury. Recent discoveries demonstrating the multipotent capabilities of hair follicle stem cells and the easy access to skin tissue make the HF an attractive source for isolating stem cells and their subsequent application in tissue engineering and regenerative medicine. Here, we describe the isolation and purification of hair follicle bulge stem cells from mouse skin, and hair reconstitution assays that allows the functional analysis of multipotent stem cells.

Adalimumab treatment leads to reduction of tissue tumor necrosis factor-alpha correlated with venous leg ulcer improvement: a pilot study.

Venous leg ulcers (VLUs) have higher tumor necrosis factor-α (TNF-α) levels compared with normal skin. Refractory VLUs of long duration have higher TNF-α levels compared with VLUs of shorter duration. As up to 75% of VLUs fail to heal with standard care, we sought to evaluate the role of anti-TNF-α therapy for patients with refractory VLUs. Evaluable data were obtained in four of five subjects with recalcitrant VLUs treated with 80 mg of subcutaneous adalimumab at week 0 and with 40 mg at week 2 along with compression therapy and were followed-up for 6 weeks. Wound biopsies taken at weeks 0 and 4 were stained with anti-TNF-α antibodies. Average 4-week percent wound size reduction was 20.5% ± 6.4%. Two patients had wound size reduction more than 25%, and their percent wound size reduction correlated to percent TNF-α staining score reductions (P = 0.02, R(2) = 0.999). VLU TNF-α level decrease 4 weeks post-adalimumab treatment correlated with wound healing.

Potential role of meiosis proteins in melanoma chromosomal instability.

Melanomas demonstrate chromosomal instability (CIN). In fact, CIN can be used to differentiate melanoma from benign nevi. The exact molecular mechanisms that drive CIN in melanoma have yet to be fully elucidated. Cancer/testis antigens are a unique group of germ cell proteins that are found to be primarily expressed in melanoma as compared to benign nevi. The abnormal expression of these germ cell proteins, normally expected only in the testis and ovaries, in somatic cells may lead to interference with normal cellular pathways. Germ cell proteins that may be particularly critical in CIN are meiosis proteins. Here, we review pathways unique to meiosis with a focus on how the aberrant expression of meiosis proteins in normal mitotic cells "meiomitosis" could impact chromosomal instability in melanoma and other cancers.

Quality assessment of tissue specimens for studies of diabetic foot ulcers.

Diabetic foot ulcers (DFUs) represent an important clinical problem resulting in significant morbidity and mortality. Ongoing translational research studies strive to better understand molecular/cellular basis of DFU pathology that may lead to identification of novel treatment protocols. Tissue at the non-healing wound edge has been identified as one of major contributors to the DFU pathophysiology that provides important tool for translational and clinical investigations. To evaluate quality of tissue specimens and their potential use, we obtained 81 DFU specimens from 25 patients and performed histological analyses, immunohistochemistry and RNA quality assessments. We found that depth of the collected specimen is important determinant of research utility, and only specimens containing a full-thickness epidermis could be utilized for immunohistochemistry and RNA isolation. We showed that only two-thirds of collected specimens could be utilized in translational studies. This attrition rate is important for designs of future studies involving tissue specimen collection from DFU.

Presentation of reticulate acropigmentation of kitamura and dowling-degos disease overlap.

The authors report a case of overlapping reticulate acropigmentation of Kitamura and Dowling-Degos disease seen in a 57-year-old woman. This is a unique presentation of two rare entities that some believe to be the same disease with variable phenotypic expression. This is an interesting case of reticulated pigmentation that unfortunately has limited treatment options.

A prospective pilot study of ultrasound therapy effectiveness in refractory venous leg ulcers.

Venous insufficiency is the most common cause of leg ulcers in the United States. Venous leg ulcers cost the health care system billions of dollars annually, and healing rates are less than 70% with standard of care; therefore, new therapies are needed to increase healing times and minimize associated costs. Non contact ultrasound therapy has been used to treat a variety of chronic wounds including venous leg ulcers, and it is thought that ultrasound has an effect on decreasing the bacterial count in wounds, although the exact mechanism of action of ultrasound is yet to be determined. We conducted an open labelled pilot study of 10 refractory venous ulcers of large size to determine the effect of non contact ultrasound on wound closure, bacterial counts, expression of inflammatory cytokines and pain reduction. We lacked a sham control group but we compared the baseline and end of treatment assessments and noted the differences. We found a significant reduction in wound area (P = 0·0039) over the 4-week treatment period. We also found a decline in individual and total bacterial counts; however, these differences were not significant. For all patients, there was also a trend toward reduced inflammatory cytokine expression compared with baseline levels; however, this reduction did not reach statistical significance. Interestingly, there was a correlation between healing and change in cytokine expression, which showed statistically significance for tumour necrosis factor (TNF)-αP = 0·0395, IL-1a P = 0·0351, IL-6 P = 0·0508, IL-8 P = 0·0990. Pain as measured by the visual analogue scale (VAS) was reduced from 4 at the baseline to 2·7 by the end of the study. In conclusion, we found that patients treated with ultrasound therapy and compression therapy show clinical improvement over the course of 4 weeks and had a decrease in inflammatory cytokines, bacterial counts and pain.

State of the art in topical wound-healing products.

Chronic wounds represent a significant medical burden. Such wounds fail to normally progress through the stages of healing, often complicated by a proinflammatory milieu caused by increased proteinases, hypoxia, and bacterial burden. As a result, several modalities, such as dressings, antimicrobials, growth factors, and human skin substitutes, have been devised in an attempt to correct the chronic wound environment. This review addresses these modalities with a focus on evidence and randomized controlled trials.

Refractory erythromelalgia of the ears: response to mexiletine.

Erythromelalgia is a rare condition characterized by burning pain, erythema, swelling, and increased temperature usually in the extremities. We present an unusual presentation of erythromelalgia of the ears in a patient who has been refractory to multiple therapies and in whom relief of symptoms was achieved with the use of mexiletine. A review of clinical presentation, pathophysiology, and therapeutic options are presented.

New therapies for treatment of diabetic foot ulcers: a review of current clinical trials.

Diabetic foot ulcers are a common problem in clinical practice and one of the most common complications in diabetic patients, often leading to amputation and hospitalization. Although there are a number of options for coadjuvant therapy for diabetic foot ulcers, a considerable number of patients remain unhealed after 12 weeks of treatment and, in general, rates of healing remain low. For these reasons, as well as the rising costs of associated complications of nonhealing diabetic foot ulcers, there is an impetus for the research community to develop more sophisticated ways to manage this condition. We reviewed ongoing clinical trials (clinicaltrials.gov) testing new therapies for foot ulcers and searched the basic science literature for preclinical background of these products. We focused our review on new therapies that include topicals, skin substitutes, bioengineered skin, cellular therapy growth factors, devices, and herbal medications. All of these options are analyzed and presented in this review as promising new options for the treatment of diabetic foot ulcers.