Nevoid melanoma and eruptive nevi from erlotinib.

Cutaneous side effects such as acneiform eruption, xerosis, and paronychia are frequently observed in patients undergoing treatment with epidermal growth factor receptor (EGFR) inhibitors for non-small cell lung cancer and other solid tumors. Interestingly, these side effects appear to positively correlate with length of remission, indicating that disruption of homeostatic EGFR signaling in the skin may serve as a marker of therapeutic EGFR inhibition in tumors. We report the case of a woman with metastatic lung cancer in remission being treated with the EGFR inhibitor, erlotinib, who experienced numerous commonly occurring adverse cutaneous reactions early in her treatment, and after two years of treatment developed eruptive nevi as well as a nevoid melanoma. Changes in pigmented lesions and the development of melanoma have been described during treatment with the BRAF inhibitor, vemurafenib, and are believed to relate to paradoxical activation of BRAF and the MAPK pathway. We speculate that a similar mechanism may occur during treatment with EGFR inhibitors. Therefore, thorough skin examinations are essential for patients undergoing long term treatment with erlotinib.

A Precocious Presentation of B-cell Acute Lymphoblastic Leukemia as Infiltrated Plaques on the Face.

Leukemia cutis, or infiltration of leukemic cells into the skin, occurs rarely in B-cell acute lymphocytic leukemia (ALL). Herein, we have described a rare, precocious presentation of B-cell ALL presenting as indurated facial plaques in a 69-year-old man. Biopsy of the facial plaques revealed precursor B-cell leukemia/lymphoma in the skin and prompted urgent hematologic-oncologic evaluation. Bone marrow biopsy yielded a final diagnosis of B-cell ALL. The patient underwent induction therapy, and at the last available follow-up, a matched unrelated donor transplant was planned.

Pleomorphic dermal sarcoma in a man with HIV: report with next-generation sequencing analysis and review of the atypical fibroxanthoma/pleomorphic dermal sarcoma spectrum.

Atypical fibroxanthoma (AFX) is a rare cutaneous fibrohistiocytic tumor that typically arises on chronically sun-damaged skin, such as the head and neck, as a nondescript ulcerated papule, nodule, or tumor. The clinical prognosis is usually favorable and metastasis is rare. Pleomorphic dermal sarcoma (PDS), or undifferentiated pleomorphic sarcoma, is a recently introduced diagnostic moniker for AFX-like tumors with more aggressive clinical and histologic features such as necrosis and vascular invasion. The exact relationship between AFX and PDS has been debated. Diagnosis of these tumors is generally based on immunohistochemical staining to exclude other mimics. A wholly specific marker for this tumor does not exist, leading to diagnostic ambiguity in certain cases. Herein, we present a case of pleomorphic dermal sarcoma in a 53-year-old man with human immunodeficiency virus that displayed patchy S100 staining concerning for melanoma upon hospital pathology review. Next-generation sequencing analysis confirmed a mutation pattern consistent with published molecular signatures of AFX/PDS. In discussing this case, we review the current understanding of AFX/PDS and discuss diagnostic pitfalls, as well as emphasize on how next-generation sequencing techniques might improve accuracy in the diagnosis of tumors in the spectrum of AFX/PDS.

Dupilumab for bullous pemphigoid with intractable pruritus.

Bullous pemphigoid (BP) is an autoimmune blistering disorder that predominantly affects the elderly. Treatment regimens typically include topical and systemic immunosuppressive medications. Although effective, systemic corticosteroids are sometimes poorly tolerated in the elderly patient, contributing to the overall morbidity and mortality of BP. Dupilumab is a monoclonal antibody targeting interleukin 4 receptor alpha (IL4R?), approved for the treatment of atopic dermatitis, as well as moderate to severe asthma and chronic rhinosinusitis with nasal polyposis. In recent reports, dupilumab has been successfully used off-label to treat a variety of pruritic disorders, including chronic spontaneous urticaria [1], anal and genital itch [2], allergic contact dermatitis [3], and prurigo nodularis [4, 5]. We report here a case of an elderly patient with refractory BP whose symptoms of pruritus and blistering became well-controlled with the addition of dupilumab to the treatment regimen.

Lichen planus pigmentosus.

Lichen planus pigmentosus (LPP) is a type oflichenoid dermatitis with superficial dermalmelanophages that presents as symmetrical,hyperpigmented macules and patches that aredistributed over the forehead, temples, cheeks, andneck. The condition most often occurs in darkerskinned individuals and is frequently resistant totreatment. Here we present a patient of Egyptiandecent with a lacy reticulated LPP eruption on theface.

Sarcoidosis with prominent necrosis on histopathology.

Sarcoidosis is a multiorgan inflammatory diseasewith variable clinical presentations and the commonhistopathologic finding of noncaseating granulomas.The etiology of the disease is not known, butevidence suggests both environmental and geneticcontributions to the pathogenesis. Depending onthe severity of cutaneous disease and extent ofextracutaneous involvement, therapies range fromtopical and intralesional glucocorticoids to systemicimmunomodulatory and immunosuppressiveagents. We present the case of a patient withcutaneous sarcoidosis with prominent necrosis onhistopathologic examination in the setting of severepulmonary sarcoidosis.

Vesicular erythema migrans: an atypical and easily misdiagnosed form of Lyme disease.

Erythema migrans is the initial sign in the majority of patients infected with Borrelia, the genus of spirochetes that causes Lyme disease. Early identification and treatment decrease the risk of progression to later stages of disease. Although a "bull's eye" appearance owing to lesional clearing is considered classic for erythema migrans, this feature is surprisingly often lacking among patients in the United States. Furthermore, cutaneous Lyme disease can exhibit a wide range of morphologic variability in a minority of patients. Herein, we describe the case of a patient with Lyme disease in which the presence of atypical vesicular features, in conjunction with the initial absence of clearing, resulted in multiple misdiagnoses and delayed treatment. We also review the literature on the epidemiology and management of erythema migrans for cases in which the diagnosis may pose a challenge.

Possible photoactivated dermatitis with features of post-inflammatory pigmentary alteration (PIPA) and rosacea.

Cutaneous flushing and facial erythema are common dermatologic conditions that elicit a wide differential diagnosis that includes rosacea, seborrheic dermatitis, photodermatitis, connective-tissue diseases, carcinoid syndrome, and mastocytosis. Herein we present an usual case of a mask-like rosacea-PIPA overlap that occurred in a patient with prior history of rectal carcinoid tumor and a negative systemic evaluation.

Plate-like osteoma cutis.

Osteoma cutis is the aberrant development of bone within the skin. The bone formation may be de novo (primary) or result from an injury to the skin (secondary). Here we present a healthy 53-year-old man with no known abnormalities in calcium or phosphate metabolism with plate-like osteoma cutis of the scalp. Plate- or plaque-like osteoma cutis was initially described as a congenital condition but has now been reported several times in the literature as an idiopathic process that occurs in adults. Treatment options are limited and are only required if the lesion is bothersome to the patient.

Capillary malformation--arteriovenous malformation syndrome: review of the literature, proposed diagnostic criteria, and recommendations for management.

Capillary malformation-arteriovenous malformation syndrome is an autosomal dominant disorder caused by mutations in the RASA1 gene and characterized by multiple small, round to oval capillary malformations with or without arteriovenous malformations. Ateriovenous malformations occur in up to one-third of patients and may involve the brain and spine. Although making the diagnosis is straightforward in some patients, there are other patients for whom diagnostic criteria may be helpful in their evaluation. Here we review the literature regarding capillary malformation-arteriovenous malformation syndrome, propose diagnostic criteria, and discuss the care of patients with this condition.

Endoproteolytic cleavage of TUG protein regulates GLUT4 glucose transporter translocation.

To promote glucose uptake into fat and muscle cells, insulin causes the translocation of GLUT4 glucose transporters from intracellular vesicles to the cell surface. Previous data support a model in which TUG traps GLUT4-containing vesicles and tethers them intracellularly in unstimulated cells and in which insulin mobilizes this pool of vesicles by releasing this tether. Here we show that TUG undergoes site-specific endoproteolytic cleavage, which separates a GLUT4-binding, N-terminal region of TUG from a C-terminal region previously suggested to bind an intracellular anchor. Cleavage is accelerated by insulin stimulation in 3T3-L1 adipocytes and is highly dependent upon adipocyte differentiation. The N-terminal TUG cleavage product has properties of a novel 18-kDa ubiquitin-like modifier, which we call TUGUL. The C-terminal product is observed at the expected size of 42 kDa and also as a 54-kDa form that is released from membranes into the cytosol. In transfected cells, intact TUG links GLUT4 to PIST and also binds Golgin-160 through its C-terminal region. PIST is an effector of TC10α, a GTPase previously shown to transmit an insulin signal required for GLUT4 translocation, and we show using RNAi that TC10α is required for TUG proteolytic processing. Finally, we demonstrate that a cleavage-resistant form of TUG does not support highly insulin-responsive GLUT4 translocation or glucose uptake in 3T3-L1 adipocytes. Together with previous results, these data support a model whereby insulin stimulates TUG cleavage to liberate GLUT4 storage vesicles from the Golgi matrix, which promotes GLUT4 translocation to the cell surface and enhances glucose uptake.

The ubiquitin regulatory X (UBX) domain-containing protein TUG regulates the p97 ATPase and resides at the endoplasmic reticulum-golgi intermediate compartment.

p97/VCP is a hexameric ATPase that is coupled to diverse cellular processes, such as membrane fusion and proteolysis. How p97 activity is regulated is not fully understood. Here we studied the potential role of TUG, a widely expressed protein containing a UBX domain, to control mammalian p97. In HEK293 cells, the vast majority of TUG was bound to p97. Surprisingly, the TUG UBX domain was neither necessary nor sufficient for this interaction. Rather, an extended sequence, comprising three regions of TUG, bound to the p97 N-terminal domain. The TUG C terminus resembled the Arabidopsis protein PUX1. Similar to the previously described action of PUX1 on AtCDC48, TUG caused the conversion of p97 hexamers into monomers. Hexamer disassembly was stoichiometric rather than catalytic and was not greatly affected by the p97 ATP-binding state or by TUG N-terminal regions in vitro. In HeLa cells, TUG localized to the endoplasmic reticulum-to-Golgi intermediate compartment and endoplasmic reticulum exit sites. Although siRNA-mediated TUG depletion had no marked effect on total ubiquitylated proteins or p97 localization, TUG overexpression caused an accumulation of ubiquitylated substrates and targeted both TUG and p97 to the nucleus. A physiologic role of TUG was revealed by siRNA-mediated depletion, which showed that TUG is required for efficient reassembly of the Golgi complex after brefeldin A removal. Together, these data support a model in which TUG controls p97 oligomeric status at a particular location in the early secretory pathway and in which this process regulates membrane trafficking in various cell types.

Dual-mode of insulin action controls GLUT4 vesicle exocytosis.

Insulin stimulates translocation of GLUT4 storage vesicles (GSVs) to the surface of adipocytes, but precisely where insulin acts is controversial. Here we quantify the size, dynamics, and frequency of single vesicle exocytosis in 3T3-L1 adipocytes. We use a new GSV reporter, VAMP2-pHluorin, and bypass insulin signaling by disrupting the GLUT4-retention protein TUG. Remarkably, in unstimulated TUG-depleted cells, the exocytic rate is similar to that in insulin-stimulated control cells. In TUG-depleted cells, insulin triggers a transient, twofold burst of exocytosis. Surprisingly, insulin promotes fusion pore expansion, blocked by acute perturbation of phospholipase D, which reflects both properties intrinsic to the mobilized vesicles and a novel regulatory site at the fusion pore itself. Prolonged stimulation causes cargo to switch from approximately 60 nm GSVs to larger exocytic vesicles characteristic of endosomes. Our results support a model whereby insulin promotes exocytic flux primarily by releasing an intracellular brake, but also by accelerating plasma membrane fusion and switching vesicle traffic between two distinct circuits.

A large-scale screen for mutagen-sensitive loci in Drosophila.

In a screen for new DNA repair mutants, we tested 6275 Drosophila strains bearing homozygous mutagenized autosomes (obtained from C. Zuker) for hypersensitivity to methyl methanesulfonate (MMS) and nitrogen mustard (HN2). Testing of 2585 second-chromosome lines resulted in the recovery of 18 mutants, 8 of which were alleles of known genes. The remaining 10 second-chromosome mutants were solely sensitive to MMS and define 8 new mutagen-sensitive genes (mus212-mus219). Testing of 3690 third chromosomes led to the identification of 60 third-chromosome mutants, 44 of which were alleles of known genes. The remaining 16 mutants define 14 new mutagen-sensitive genes (mus314-mus327). We have initiated efforts to identify these genes at the molecular level and report here the first two identified. The HN2-sensitive mus322 mutant defines the Drosophila ortholog of the yeast snm1 gene, and the MMS- and HN2-sensitive mus301 mutant defines the Drosophila ortholog of the human HEL308 gene. We have also identified a second-chromosome mutant, mus215(ZIII-2059), that uniformly reduces the frequency of meiotic recombination to <3% of that observed in wild type and thus defines a function required for both DNA repair and meiotic recombination. At least one allele of each new gene identified in this study is available at the Bloomington Stock Center.

A deficiency screen of the major autosomes identifies a gene (matrimony) that is haplo-insufficient for achiasmate segregation in Drosophila oocytes.

In Drosophila oocytes, euchromatic homolog-homolog associations are released at the end of pachytene, while heterochromatic pairings persist until metaphase I. A screen of 123 autosomal deficiencies for dominant effects on achiasmate chromosome segregation has identified a single gene that is haplo-insufficient for homologous achiasmate segregation and whose product may be required for the maintenance of such heterochromatic pairings. Of the deficiencies tested, only one exhibited a strong dominant effect on achiasmate segregation, inducing both X and fourth chromosome nondisjunction in FM7/X females. Five overlapping deficiencies showed a similar dominant effect on achiasmate chromosome disjunction and mapped the haplo-insufficient meiotic gene to a small interval within 66C7-12. A P-element insertion mutation in this interval exhibits a similar dominant effect on achiasmate segregation, inducing both high levels of X and fourth chromosome nondisjunction in FM7/X females and high levels of fourth chromosome nondisjunction in X/X females. The insertion site for this P element lies immediately upstream of CG18543, and germline expression of a UAS-CG18543 cDNA construct driven by nanos-GAL4 fully rescues the dominant meiotic defect. We conclude that CG18543 is the haplo-insufficient gene and have renamed this gene matrimony (mtrm). Cytological studies of prometaphase and metaphase I in mtrm hemizygotes demonstrate that achiasmate chromosomes are not properly positioned with respect to their homolog on the meiotic spindle. One possible, albeit speculative, interpretation of these data is that the presence of only a single copy of mtrm disrupts the function of whatever "glue" holds heterochromatically paired homologs together from the end of pachytene until metaphase I.