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Abstract The cyclin D1-Cyclin-Dependent Kinases 4 and 6 (CDK4/6) complex is crucial for the development of melanoma. We previously demonstrated that targeting CDK4/6 using small molecule inhibitors (CDK4/6i) suppresses BrafV600E melanoma growth in vitro and in vivo through induction of cellular senescence. However, clinical trials investigating CDK4/6i in melanoma have not yielded successful outcomes, underscoring the necessity to enhance the therapeutic efficacy of CDK4/6i. Accumulated research has shown that while senescence initially suppresses cell proliferation, a prolonged state of senescence eventually leads to tumor relapse by altering the tumor microenvironment, suggesting that removal of those senescent cells (in a process referred to as senolysis) is of clinical necessity to facilitate clinical response. We demonstrate that glutaminase 1 (GLS1) expression is specifically upregulated in CDK4/6i-induced senescent BrafV600E melanoma cells. Upregulated GLS1 expression renders BrafV600E melanoma senescent cells vulnerable to GLS1 inhibitor (GLS1i). Furthermore, we demonstrate that this senolytic approach targeting upregulated GLS1 expression is applicable even though those cells developed resistance to the BrafV600E inhibitor vemurafenib, a frequently encountered substantial clinical challenge to treating patients. Thus, this novel senolytic approach may revolutionize current CDK4/6i mediated melanoma treatment if melanoma cells undergo senescence prior to developing resistance to CDK4/6i. Given that we demonstrate that a low dose of vemurafenib induced senescence, which renders BrafV600E melanoma cells susceptible to GLS1i and recent accumulated research shows many cancer cells undergo senescence in response to chemotherapy, radiation, and immunotherapy, this senolytic therapy approach may prove applicable to a wide range of cancer types once senescence and GLS1 expression are induced.

Primary cutaneous CD30+ T-cell lymphoproliferative disorders are the second most common cutaneous lymphomas. According to the World Health Organization, CD30+ T-cell lymphoproliferative disorders include primary cutaneous anaplastic large cell lymphoma (C-ALCL) and lymphomatoid papulosis (LyP) as well as borderline lesions. C-ALCL and LyP are thought to represent two ends of a spectrum of diseases that have different clinical presentations, clinical courses, and prognoses in their classic forms but share the same histology of medium to large CD30+ atypical lymphoid cell infiltrates. Because the behavior of these entities is different clinically and prognostically, we aim to search for oncogenic genomic variants using whole-exome sequencing that drive the development of LyP and C-ALCL. Clinical information, pathology, immunohistochemistry, and T-cell rearrangements on six cases of LyP and five cases of C-ALCL were reviewed to confirm the rendered diagnosis before whole-exome sequencing of all specimens. Both LyP and C-ALCL had recurrent alterations in epigenetic modifying genes affecting histone methylation and acetylation (SETD2, KMT2A, KMT2D, and CREBBP). However, they also harbor unique differences with mutations in signal transducer and activator of transcription gene STAT3 of the Jak/signal transducer and activator of transcription pathway and EOMES, a transcription factor involved in lymphocyte development, only noted in C-ALCL specimens. Genomic characterization of LyP and C-ALCL in this series confirms the role of multiple pathways involved in the biology and development of these lymphomatous processes. The identification of similar aberrations within the epigenetic modifying genes emphasizes common potential development mechanisms of lymphomagenesis within lymphoproliferative disorders being shared between LyP and C-ALCL; however, the presence of differences may account for the differences in clinical course.

Substation expansion planning (SEP) is a major part of every power system expansion problem. The large number of design variables, and combination of discrete and continuous variables makes the SEP a very challenging problem. The choice of the substation to be expanded, and the location and the size of the new substation to be installed, are the factors that should be determined very effectively, since these factors have a great impact on the operational cost of the system. This paper proposes a new method for SEP based on the notion of mathematical clustering. One main feature of the proposed method is that it can determine the locations of new substations on very large networks with a high efficiency. In order to verify the efficiency of the proposed approach, it is applied to a benchmark problem and the results are compared with those achieved from the genetic algorithm. [ABSTRACT FROM AUTHOR]

Objective To examine the diagnostic value of the sentinel lymph node biopsy in pediatric through young adult head and neck melanocytic tumors of unknown malignant potential. Study Design Retrospective case series. Setting Single academic institution. Subjects and Methods Demographics, histology, and outcomes were examined in 14 patients aged 4 to 24 years with head and neck melanocytic tumors of unknown malignant potential. Information on age at diagnosis, primary lesion characteristics, and sentinel lymph node biopsy were compared. Results Of 14 patients meeting criteria for head and neck melanocytic tumors of unknown malignant potential, 8 patients underwent sentinel lymph node biopsy (57%). Of those, 4 biopsies (50%) had positive sentinel nodes. All patients undergoing sentinel lymph node biopsy had primary lesions greater than 1 mm depth or mitotic rate of at least 1 mitosis per mm 2 . No patients had recurrence of their primary lesion at time of follow-up. Conclusion Our data show a high rate of node-positive sentinel lymph node biopsy for pediatric and young adult head and neck patients with melanocytic tumors of unknown malignant potential, supporting the value of sentinel lymph node biopsy in this population.

Merkel cell polyomavirus (MCV) causes the majority of human Merkel cell carcinomas (MCC) and encodes a small T (sT) antigen that transforms immortalized rodent fibroblasts in vitro. To develop a mouse model for MCV sT-induced carcinogenesis, we generated transgenic mice with a flox-stop-flox MCV sT sequence homologously recombined at the ROSA locus (ROSAsT), allowing Cre-mediated, conditional MCV sT expression. Standard tamoxifen (TMX) administration to adult UbcCreERT2; ROSAsT mice, in which Cre is ubiquitously expressed, resulted in MCV sT expression in multiple organs that was uniformly lethal within 5 days. Conversely, most adult UbcCreERT2; ROSAsT mice survived low-dose tamoxifen administration but developed ear lobe dermal hyperkeratosis and hypergranulosis. Simultaneous MCV sT expression and conditional homozygous p53 deletion generated multi-focal, poorly-differentiated, highly anaplastic tumors in the spleens and livers of mice after 60 days of TMX treatment. Mouse embryonic fibroblasts from these mice induced to express MCV sT exhibited anchorage-independent cell growth. To examine Merkel cell pathology, MCV sT expression was also induced during mid-embryogenesis in Merkel cells of Atoh1CreERT2/+; ROSAsT mice, which lead to significantly increased Merkel cell numbers in touch domes at late embryonic ages that normalized postnatally. Tamoxifen administration to adult Atoh1CreERT2/+; ROSAsT and Atoh1CreERT2/+; ROSAsT; p53flox/flox mice had no effects on Merkel cell numbers and did not induce tumor formation. Taken together, these results show that MCV sT stimulates progenitor Merkel cell proliferation in embryonic mice and is a bona fide viral oncoprotein that induces full cancer cell transformation in the p53-null setting.

Egzotycznym rozdziałem w historii małego księstwa Kurlandii i Semigalii jest jego ambitna polityka kolonialna pod rządami księcia Jakuba. Książę, który podejmował dalekie podróże, zmodernizował sposób rządzenia na podległych sobie terenach na wzór niderlandzki i w połowie XVII wieku rozpoczął forsowanie własnych przedsięwzięć kolonialnych. Pierwszą kolonię, Gambię w Afryce Zachodniej, utracono już w 1661 roku, podczas gdy druga kolonia, Tobago na Karaibach, przypadła po roku 1682 Anglikom. Mimo że cały wiek naznaczyły konflikty wyznaniowe, książę Jakub prowadził politykę tolerancji religijnej, której celem był gospodarczy zysk. I tak, próbował wykorzystać papieża i katolicki świat do własnej polityki kolonialnej, chociaż sam został ochrzczony w obrządku luterańskim. Ponieważ kolonie ze względu na swój klimat nie były zbyt atrakcyjne dla osiedleńców, książę zabiegał dodatkowo, choć bezskutecznie, o dysydentów religijnych prześladowanych w większej części Europy.

Primary cicatricial alopecia (PCA) is a group of inflammatory hair disorders that cause scarring and permanent hair loss. Previous studies have implicated PPARγ, a transcription factor that integrates lipogenic and inflammatory signals, in the pathogenesis of PCA. However, it is unknown what triggers the inflammatory response in these disorders, whether the inflammation is a primary or secondary event in disease pathogenesis, and whether the inflammatory reaction reflects an autoimmune process. In this paper, we show that the cholesterol biosynthetic pathway is impaired in the skin and hair follicles of PCA patients. Treatment of hair follicle cells with BM15766, a cholesterol biosynthesis inhibitor, or 7-dehydrocholesterol (7-DHC), a sterol precursor, stimulates the expression of pro-inflammatory chemokine genes. Painting of mouse skin with 7-DHC or BM15766 inhibits hair growth, causes follicular plugging and induces the infiltration of inflammatory cells into the interfollicular dermis. Our results demonstrate that cholesterologenic changes within hair follicle cells trigger an innate immune response that is associated with the induction of toll-like receptor (TLR) and interferon (IFN) gene expression, and the recruitment of macrophages that surround the hair follicles and initiate their destruction. These findings reveal a previously unsuspected role for cholesterol precursors in PCA pathogenesis and identify a novel link between sterols and inflammation that may prove transformative in the diagnosis and treatment of these disorders.