ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma.

Cancer cellular heterogeneity and therapy resistance arise substantially from metabolic and transcriptional adaptations, but how these are interconnected is poorly understood. Here, we show that, in melanoma, the cancer stem cell marker aldehyde dehydrogenase 1A3 (ALDH1A3) forms an enzymatic partnership with acetyl-coenzyme A (CoA) synthetase 2 (ACSS2) in the nucleus to couple high glucose metabolic flux with acetyl-histone H3 modification of neural crest (NC) lineage and glucose metabolism genes. Importantly, we show that acetaldehyde is a metabolite source for acetyl-histone H3 modification in an ALDH1A3-dependent manner, providing a physiologic function for this highly volatile and toxic metabolite. In a zebrafish melanoma residual disease model, an ALDH1-high subpopulation emerges following BRAF inhibitor treatment, and targeting these with an ALDH1 suicide inhibitor, nifuroxazide, delays or prevents BRAF inhibitor drug-resistant relapse. Our work reveals that the ALDH1A3-ACSS2 couple directly coordinates nuclear acetaldehyde-acetyl-CoA metabolism with specific chromatin-based gene regulation and represents a potential therapeutic vulnerability in melanoma.

Stroma remodeling and reduced cell division define durable response to PD-1 blockade in melanoma.

Although immune checkpoint inhibitors (ICIs) have achieved unprecedented results in melanoma, the biological features of the durable responses initiated by these drugs remain unknown. Here we show the genetic and phenotypic changes induced by treatment with programmed cell death-1 (PD-1) blockade in a genetically engineered mouse model of melanoma driven by oncogenic BRAF. In this controlled system anti-PD-1 treatment yields responses in ~35% of the tumors, and prolongs survival in ~27% of the animals. We identify increased stroma remodeling and reduced expression of proliferation markers as features associated with prolonged response. These traits are corroborated in two independent early on-treatment anti-PD-1 melanoma patient cohorts. These insights into the biological responses of tumors to ICI provide a strategy for identification of durable response early during the course of treatment and could improve patient stratification for checkpoint inhibitory drugs.

Patients with Moderate to Severe Psoriasis Associate with Higher Risk of Depression and Anxiety Symptoms: Results of a Multivariate Study of 300 Spanish Individuals with Psoriasis.

Psoriasis is a chronic skin disease associated with considerable physical and psychological comorbidities. Stress and emotional disturbances have been implicated in both triggering the onset and exacerbation of psoriasis. In order to determine the level of perceived stress and mood alterations in patients with psoriasis and their association with disease severity, 300 individuals completed diverse validated questionnaires assessing stress and psychological mood. Evaluation of perception of disease was also measured. A significant association between psoriasis severity and mood, emotional disturbances and an impact on assessments of the quality of life were observed. Particularly, Montgomery-Asberg Depression Rating Scale, Hamilton Rating Scale and Hospital Anxiety and Depression Scale for Depression detected a significant risk for depression in relation to the disease severity. The association between depression features, anxiety and perceived stress with psoriasis severity is important and can influence the appropriate management of psoriasis.

Self-healing Cutaneous Mucinosis in Adulthood: The Adult Counterpart of the Juvenile Variant of the Disease?

Self-healing cutaneous mucinosis (SHCM) is an idiopathic localized cutaneous mucinosis mainly described in children and characterized clinically by an acute onset of papules and nodules that exhibit a spontaneous resolution in a period ranging from weeks to few months. Histologically, a diffuse mucin deposition in the dermis and/or hypodermis associated with a proliferation of spindle-shaped cells and some large epithelioid gangliocyte-like mononuclear cells is usually observed. An uncommon adult variant of SHCM has also been reported; however, the clinicopathological features described in these patients are extremely heterogeneous and differ significantly from the juvenile variant of the disease, often showing exclusively dermal involvement. We report a case of a 37-year-old female patient with multiple asymptomatic nodules located on the legs and arms that resolved spontaneously in a period of 2 years, showing the typical subcutaneous features of the juvenile variant of SHCM at the histological examination (ie, mucinous areas associated with dense bands of fibrosis containing arborizing thin-walled vessels, spindle-shaped fibroblasts, and some gangliocyte-like cells). To the best of our knowledge, this is the first report of SHCM showing the classic pattern of deep-seated subcutaneous involvement of the disease in an adult patient. We also review the cases of adult-onset SHCM reported in the literature.

Ultraviolet radiation-induced DNA damage is prognostic for outcome in melanoma.

The melanoma genome is dominated by ultraviolet radiation (UVR)-induced mutations. Their relevance in disease progression is unknown. Here we classify melanomas by mutation signatures and identify ten recurrently mutated UVR signature genes that predict patient survival. We validate these findings in primary human melanomas; in mice we show that this signature is imprinted by short-wavelength UVR and that four exposures to UVR are sufficient to accelerate melanomagenesis.

Publisher Correction: Ultraviolet radiation-induced DNA damage is prognostic for outcome in melanoma.

In the version of this article originally published, Extended Data Fig. 3 was incorrect. A duplicate of Extended Data Fig. 4 was uploaded in place of Extended Data Fig. 3. Extended Data Fig. 3 has now been uploaded. The error has been fixed in the PDF and HTML versions of this article.

Multiple progressive annular telangiectasias: A clinicopathological variant of cutaneous collagenous vasculopathy?

Telangiectasias are the clinical manifestation of diverse processes affecting blood vessels. Herein we report the case of a 60-year-old man presenting long-standing asymptomatic annular telangiectatic lesions with whitish centers. The histopathologic examination revealed thickened blood dermal vessel walls in the superficial dermis showing reduplication of the basement membrane resembling cutaneous collagenous vasculopathy (CCV). We suggest that this atypical clinicopathological presentation may represent either a localized annular variant of CCV or a previously unreported clinical form of multiple cutaneous telangiectasias.

Balanoposthitis and Penile Edema: Atypical Manifestations of Primary Syphilis.

The typical finding in primary syphilis stage is a unique, painless chancre with indurated borders. We report a case of primary syphilis presenting as erosive and crusted balanoposthitis with an underlying chancre, penile edema, and bilateral inguinal lymphadenopathy in a heterosexual man.

Dynamics of sonoluminescing bubbles within a liquid hammer device.

We studied the dynamics of a single sonoluminescing bubble (SBSL) in a liquid hammer device. In particular, we investigated the phosphoric acid-xenon system, in which pulses up to four orders of magnitude brighter than SBSL in water systems (about 10;{12} photons per pulse) have been previously reported [Chakravarty, Phys. Rev. E 69, 066317 (2004)]. We used stroboscopic photography and a Mie scattering technique in order to measure the radius evolution of the bubbles. Under adequate conditions we may position a bubble at the bottom of the tube (cavity) and a second bubble trapped at the middle of the tube (upper bubble). During its collapse, the cavity produces the compression of the liquid column. This compression drives impulsively the dynamics of the upper bubble. Our measurements reveal that the observed light emissions produced by the upper bubble are generated at its second collapse. We employed a simple numerical model to investigate the conditions that occur during the upper bubble collapse. We found good agreement between numerical and experimental values for the light intensity (fluence) and light pulse widths. Results from the model show that the light emission is increased mainly due to an increase in noble gas ambient radius and not because the maximum temperature increases. Even for the brightest pulses obtained ( 2x10;{13} photons, about 20W of peak power) the maximum temperatures computed for the upper bubble are always lower than 20000K .

Single-bubble sonoluminescence in sulfuric acid and water: bubble dynamics, stability, and continuous spectra.

We present theoretical calculations of an argon bubble in a liquid solution of 85%wt sulfuric acid and 15%wt water in single-bubble sonoluminescence. We used a model without free parameters to be adjusted. We predict from first principles the region in parameter space for stable bubble evolution, the temporal evolution of the bubble radius, the maximum temperature, pressures, and the light spectra due to thermal emissions. We also used a partial differential equation based model (hydrocode) to compute the temperature and pressure evolutions at the center of the bubble during maximum compression. We found the behavior of this liquid mixture to be very different from water in several aspects. Most of the models in sonoluminescence were compared with water experimental results.