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Dermatology is a competitive field for applicants pursuing a residency, and many applicants turn to dedicated research years to try and increase their competitiveness. Our study aimed to determine the financial costs of a research year and uncover how the costs of a research year vary for different demographic groups. We administered an anonymous survey through various dermatology listservs and social media platforms to prior, current, and future dermatology applicants who had completed a research fellowship during or after medical school. We found the median total fellowship cost ($26,443.20) was higher than the median fellowship income ($23,625.00). Furthermore, we found minority respondents had significantly lower total income, lower fellowship income, and higher net fellowship cost (p<0.05). Ninety participants completed surveys, and over half reported their research year as financially stressful. The majority did state that if given the opportunity, they would choose to do their research year again. Given the overall high costs of research years and the disparity in funding of these years, steps should be taken to address the disparities in fellowship funding or de-emphasize the importance of research fellowships in the dermatology residency selection process., (© 2023. W. Montague Cobb-NMA Health Institute.)

Background: Breast cancer's complex transcriptional landscape requires an improved understanding of cellular diversity to identify effective treatments. The study of genetic variations among breast cancer subtypes at single-cell resolution has potential to deepen our insights into cancer progression., Methods: In this study, we amalgamate single-cell RNA sequencing data from patient tumours and matched lymph metastasis, reduction mammoplasties, breast cancer patient-derived xenografts (PDXs), PDX-derived organoids (PDXOs), and cell lines resulting in a diverse dataset of 117 samples with 506 719 total cells. These samples encompass hormone receptor positive (HR+), human epidermal growth factor receptor 2 positive (HER2+), and triple-negative breast cancer (TNBC) subtypes, including isogenic model pairs. Herein, we delineated similarities and distinctions across models and patient samples and explore therapeutic drug efficacy based on subtype proportions., Results: PDX models more closely resemble patient samples in terms of tumour heterogeneity and cell cycle characteristics when compared with TNBC cell lines. Acquired drug resistance was associated with an increase in basal-like cell proportions within TNBC PDX tumours as defined with SCSubtype and TNBCtype cell typing predictors. All patient samples contained a mixture of subtypes; compared to primary tumours HR+ lymph node metastases had lower proportions of HER2-Enriched cells. PDXOs exhibited differences in metabolic-related transcripts compared to PDX tumours. Correlative analyses of cytotoxic drugs on PDX cells identified therapeutic efficacy was based on subtype proportion., Conclusions: We present a substantial multimodel dataset, a dynamic approach to cell-wise sample annotation, and a comprehensive interrogation of models within systems of human breast cancer. This analysis and reference will facilitate informed decision-making in preclinical research and therapeutic development through its elucidation of model limitations, subtype-specific insights and novel targetable pathways., Key Points: Patient-derived xenografts models more closely resemble patient samples in tumour heterogeneity and cell cycle characteristics when compared with cell lines. 3D organoid models exhibit differences in metabolic profiles compared to their in vivo counterparts. A valuable multimodel reference dataset that can be useful in elucidating model differences and novel targetable pathways., (© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Significance: NSCLC is the leading cause of cancer death due, in part, to a lack of active therapies in advanced disease. We demonstrate that combination therapy with a proteasome inhibitor, BH3-mimetic, and chemotherapy is an active precision therapy in NSCLC cells and tumors expressing Onc-p53 alleles., (©2024 The Authors; Published by the American Association for Cancer Research.)

Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF subunit SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-ncBAF-driven transcription, associated with DNA damage and cell death and resulting in tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, positioning the in-clinic TAK-981 to treat SS., Competing Interests: Additional Declarations: There is NO Competing Interest. DECLARATION OF INTERESTS A.C.F. is a consultant and equity holder in Treeline Biosciences and has previously served as a scientific advisor for AbbVie and has received research funding from IDP Pharma. K.V. receives support from AstraZeneca. R.L. is an inventor of a provisional patent on targeted killing of EBV-positive cancer cells by CRISPR/dCas9-mediated EBV reactivation. S.B. is Consultant for Caris Lifescience and has received honoraria from SpringWorks for an educational lecture. K.V. receives support from AstraZeneca with no relationship to the present study. The authors declare that these listed activities have no relationship to the present study.

Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein. and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF subunit SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-ncBAF-driven transcription, associated with DNA damage and cell death and resulting in tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, positioning the in-clinic TAK-981 to treat SS.

Utilizing isoquinoline as a carrier ligand, we have evaluated the reactivity of selected trans‑platinum planar amine (TPA) carboxylate compounds by varying the leaving carboxylate group (acetate, hydroxyacetate, and lactate) in an effort to optimize the cytotoxic and metabolic efficiency. To measure the pharmacological properties of these compounds, a combination of systematic biophysical and biological studies were carried out mainly involving substitution reaction with NAM (N-acetyl-methionine), effects on DNA structural perturbation, cytotoxicity, cellular accumulation, metabolic stability, and cell cycle effects. TPA compounds showed minimal losses in cytotoxic efficacy and outperformed cisplatin after pre-incubation with serum, while displaying a distinct micromolar cytotoxic activity with minimal DNA binding and unaltered cell cycle. Monitoring the TPA compounds with NAM suggests the following trend for the reactivity: hydroxyacetate > lactate > acetate. The same trend was seen for the cytotoxicity in tumor cells and DNA binding, while the rate of drug inactivation/protein binding in cells was not significantly different among these leaving groups. Thus, our results show superior cellular efficacy of TPA compounds and distinct micromolar cytotoxic activities different than cisplatin. Moreover, we found the TPA compounds had prolonged survival and decreased tumor burden compared to the control mice in a relevant human ovarian cancer mouse model with A2780 cells expressing luciferase. Therefore, we propose that further optimization of the basic TPA structure can give further enhanced in vivo activity and may eventually be translated into the development of clinically relevant non-traditional platinum drugs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could appear to influence the work reported in this paper. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nicholas Farrell reports partial financial support was provided by National Science Foundation. Nicholas Farrell reports a relationship with National Science Foundation that includes: funding grants. Partial financial support was provided by National Institutes of Health through the Massey Cancer Center. Nicholas Farrell has patent US 8,324,197 B2 on this technology. I have served on editorial board for J. Inorg. Biochem. Other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: There is paucity of data on how gender impacts melanoma prognosis in pediatric and adolescent patients., Objectives: This study explores gender differences in presentation and survival among pediatric and adolescent patients with melanoma., Methods: The National Cancer Database 2004-2018 was queried for cases of primary invasive cutaneous melanoma in pediatric and adolescent patients (birth to 21 years) for a retrospective cohort study., Results: Of the 4645 cases, 63.4% were female. Median Breslow depth was 1.05 mm for males (interquartile range 0.50-2.31) and 0.80 mm for females (interquartile range 0.40-1.67; P < .001). Trunk was the most common primary site for females (34.3%) and males (32.9%). More females than males were diagnosed with stage I disease (67.8% vs 53.6%). Males had higher rates of regional lymph node positivity (27.9% vs 18.1%; P < .001) and ulceration (17.1% vs 11.4%; P < .001). Five-year overall survival was 95.9% for females and 92.0% for males (P < .001). After adjusting for confounders, male gender independently increased mortality risk (reference: females; adjusted hazard ratio 1.57; 95% confidence interval 1.32-1.86)., Limitations: Retrospective study., Conclusion: Males exhibited more aggressive pathologic features including greater Breslow thickness and higher ulceration and lymph node positivity rates. Male gender independently increased mortality risk., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2023 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background and Aims: The oncogene Melanoma differentiation associated gene-9/syndecan binding protein (MDA-9/SDCBP) is overexpressed in many cancers, promoting aggressive, metastatic disease. However, the role of MDA-9 in regulating hepatocellular carcinoma (HCC) has not been well studied., Approach and Results: To unravel the function of MDA-9 in HCC, we generated and characterized a transgenic mouse with hepatocyte-specific overexpression of MDA-9 (Alb/MDA-9). Compared with wild-type (WT) littermates, Alb/MDA-9 mice demonstrated significantly higher incidence of N-nitrosodiethylamine/phenobarbital-induced HCC, with marked activation and infiltration of macrophages. RNA sequencing (RNA-seq) in naive WT and Alb/MDA-9 hepatocytes identified activation of signaling pathways associated with invasion, angiogenesis, and inflammation, especially NF-κB and integrin-linked kinase signaling pathways. In nonparenchymal cells purified from naive livers, single-cell RNA-seq showed activation of Kupffer cells and macrophages in Alb/MDA-9 mice versus WT mice. A robust increase in the expression of Secreted phosphoprotein 1 (Spp1/osteopontin) was observed upon overexpression of MDA-9. Inhibition of NF-κB pathway blocked MDA-9-induced Spp1 induction, and knock down of Spp1 resulted in inhibition of MDA-9-induced macrophage migration, as well as angiogenesis., Conclusions: Alb/MDA-9 is a mouse model with MDA-9 overexpression in any tissue type. Our findings unravel an HCC-promoting role of MDA-9 mediated by NF-κB and Spp1 and support the rationale of using MDA-9 inhibitors as a potential treatment for aggressive HCC., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Cutaneous diseases of the ear encompass a wide range of symptoms, complaints, and factors that negatively impact patients' well-being. These observations are frequently encountered by otolaryngologists and other physicians who treat individuals with ear-related issues. In this document, we aim to offer up-to-date information on diagnosing, predicting outcomes, and treating commonly occurring ear diseases., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Heparan sulfate proteoglycans (HSPGs) and their associated proteins aid in tumor progression through modulation of biological events such as cell invasion, angiogenesis, metastasis, and immunological responses. Metalloshielding of the anionic heparan sulfate (HS) chains by cationic polynuclear platinum complexes (PPCs) prevents the HS from interacting with HS-associated proteins and thus diminishes the critical functions of HSPG. Studies herein exploring the PPC-HS interactions demonstrated that a series of PPCs varying in charge, nuclearity, distance between Pt centers, and hydrogen-bonding ability influence HS affinity. We report that the polyamine-linked complexes have high HS affinity and display excellent in vivo activity against breast cancer metastases and those arising in the bone and liver compared to carboplatin. Overall, the PPC-HS niche offers an attractive approach for targeting HSPG-expressing tumor cells., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

Through a unique genomics and drug screening platform with ~800 solid tumor cell lines, we have found a subset of SCLC cell lines are hypersensitive to venetoclax, an FDA-approved inhibitor of BCL-2. SCLC-A (ASCL1 positive) and SCLC-P (POU2F3 positive), which make up almost 80% of SCLC, frequently express high levels of BCL-2. We found that a subset of SCLC-A and SCLC-P showed high BCL-2 expression but were venetoclax-resistant. In addition, most of these SCLC cell lines have TP53 missense mutations, which make a single amino acid change. These mutants not only lose wild-type (WT) p53 tumor suppressor functions, but also acquire novel cancer-promoting activities (oncogenic, gain-of-function). A recent study with oncogenic mutant (Onc)-p53 knock-in mouse models of SCLC suggests gain-of-function activity can attenuate chemotherapeutic efficacy. Based on these observations, we hypothesize that Onc-p53 confers venetoclax resistance and that simultaneous inhibition of BCL-2 and Onc-p53 induces synergistic anticancer activity in a subset of SCLC-A and SCLC-P. We show here that (1) down-regulation of Onc-p53 increases the expression of a BH3-only pro-apoptotic BIM and sensitizes to venetoclax in SCLC-P cells; (2) targeting Onc-p53 by the HSP90 inhibitor, ganetespib, increases BIM expression and sensitizes to venetoclax in SCLC-P and SCLC-A cells. Although there are currently many combination studies for venetoclax proposed, the concept of simultaneous targeting of BCL-2 and Onc-p53 by the combination of venetoclax and HSP90 inhibitors would be a promising approach for SCLC treatment.

Melanoma in Black patients carries a poor prognosis. Due to its rarity, melanoma in this population has not been well characterized. This study evaluates survival predictors in Black patients with melanoma. This was a retrospective cohort study of Black patients with cutaneous melanoma from the National Cancer Database 2004-2018. Of the 2464 cases, melanoma was more common among females than males (57.1% vs. 42.9%, p < .001). Median Breslow depth was 1.8 mm (interquartile range 0.4-4.4). Lower extremities were the most common location (52.8%), followed by upper extremities (13.1%) along with otherwise specified/overlapping/other (13.1%), then by trunk (11.8%), and lastly head and neck (9.2%). Stage at diagnosis was I (30.7%), II (27.5%), III (24.1%), and IV (17.7%). Ulceration was observed in 41.4% of lesions. Acral lentiginous melanoma (ALM) was the most common specific histologic subtype (20.3%), followed by superficial spreading melanoma (9.4%). After adjusting for confounders, higher stages and primary site on the head and neck were the strongest independent predictors of worse overall survival. Melanoma in Black patients is most likely to appear on the lower extremities. A large portion (41.8%) presented with stage III or IV disease. ALM was the most common specific histologic subtype., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Triple negative breast cancer (TNBC) accounts for over 30% of all breast cancer (BC)-related deaths, despite accounting for only 10% to 15% of total BC cases. Targeted therapy development has largely stalled in TNBC, underlined by a lack of traditionally druggable addictions like receptor tyrosine kinases (RTKs). Here, through full genome CRISPR/Cas9 screening of TNBC models, we have uncovered the sensitivity of TNBCs to the depletion of the ubiquitin-like modifier activating enzyme 1 (UBA1). Targeting UBA1 with the first-in-class UBA1 inhibitor TAK-243 induced unresolvable endoplasmic reticulum (ER)-stress and activating transcription factor 4 (ATF4)-mediated upregulation of proapoptotic NOXA, leading to cell death. c-MYC expression correlates with TAK-243 sensitivity and cooperates with TAK-243 to induce a stress response and cell death. Importantly, there was an order of magnitude greater sensitivity of TNBC lines to TAK-243 compared to normal tissue-derived cells. In five patient derived xenograft models (PDXs) of TNBC, TAK-243 therapy led to tumor inhibition or frank tumor regression. Moreover, in an intracardiac metastatic model of TNBC, TAK-243 markedly reduced metastatic burden, indicating UBA1 is a potential new target in TNBC expressing high levels of c-MYC., (© The Author(s) 2022. Published by Oxford University Press on behalf of National Academy of Sciences.)

Preclinical and clinical studies have evidenced that effective targeted therapy treatment against receptor tyrosine kinases (RTKs) in different solid tumor paradigms is predicated on simultaneous inhibition of both the PI3K and MEK intracellular signaling pathways. Indeed, re-activation of either pathway results in resistance to these therapies. Recently, oncogenic phosphatase SHP2 inhibitors have been developed with some now reaching clinical trials. To expand on possible indications for SHP099, we screened over 800 cancer cell lines covering over 25 subsets of cancer. We found HNSCC was the most sensitive adult subtype of cancer to SHP099. We found that, in addition to the MEK pathway, SHP2 inhibition blocks the PI3K pathway in sensitive HNSCC, resulting in downregulation of mTORC signaling and anti-tumor effects across several HNSCC mouse models, including an HPV+ patient-derived xenograft (PDX). Importantly, we found low levels of the RTK ligand epiregulin identified HNSCCs that were sensitive to SHP2 inhibitor, and, adding exogenous epiregulin mitigated SHP099 efficacy. Mechanistically, epiregulin maintained SHP2-GAB1 complexes in the presence of SHP2 inhibition, preventing downregulation of the MEK and PI3K pathways. We demonstrate HNSCCs were highly dependent on GAB1 for their survival and knockdown of GAB1 is sufficient to block the ability of epiregulin to rescue MEK and PI3K signaling. These data connect the sensitivity of HNSCC to SHP2 inhibitors and to a broad reliance on GAB1-SHP2, revealing an important and druggable signaling axis. Overall, SHP2 inhibitors are being heavily developed and may have activity in HNSCCs, and in particular those with low levels of epiregulin., Competing Interests: Conflict of Interest Disclosure: The work in the laboratory of C.H.B. is funded in part by Amgen and Novartis. A.C.F. has served as a scientific advisor for AbbVie and currently serves as a scientific advisor for Treeline Biosciences.

Despite recent advances in radiotherapeutic strategies, acquired resistance remains a major obstacle, leading to tumor recurrence for many patients. Once thought to be a strictly cancer cell intrinsic property, it is becoming increasingly clear that treatment-resistance is driven in part by complex interactions between cancer cells and non-transformed cells of the tumor microenvironment. Herein, we report that radiotherapy induces the production of extracellular vesicles by breast cancer cells capable of stimulating tumor-supporting fibroblast activity, facilitating tumor survival and promoting cancer stem-like cell expansion. This pro-tumor activity was associated with fibroblast production of the paracrine signaling factor IL-6 and was dependent on the expression of the heparan sulfate proteoglycan CD44v3 on the vesicle surface. Enzymatic removal or pharmaceutical inhibition of its heparan sulfate side chains disrupted this tumor-fibroblast crosstalk. Additionally, we show that the radiation-induced production of CD44v3 + vesicles is effectively silenced by blocking the ESCRT pathway using a soluble pharmacological inhibitor of MDA-9/Syntenin/SDCBP PDZ1 domain activity, PDZ1i. This population of vesicles was also detected in the sera of human patients undergoing radiotherapy, therefore representing a potential biomarker for radiation therapy and providing an opportunity for clinical intervention to improve treatment outcomes., Competing Interests: PBF is a scientific co-founder and has equity in InterLeukin Combinatorial Therapies, Inc. (ILCT). VCU also has equity in ILCT. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest, (Copyright © 2022 Clark, Hampton, Koblinski, Quinn, Mahmoodi, Metcalf, Guo, Peterson, Fisher, Farrell, Wang and Mikkelsen.)

Context: Colorectal cancer (CRC) is the second leading cause of cancer related deaths in the US. There is paucity of data regarding CRC and the spinal cord injury (SCI) community. Persons with SCI have suboptimal rates of colonoscopies and face extensive barriers to care. The aim of our study was to compare CRC mortality in persons with SCI to CRC mortality in the general population. Design: A prospective follow-up study. Setting: Analysis of the National SCI database. Participants: 54,965 persons with SCI. Interventions: Not applicable. Outcome Measures: Current survival status and causes of death were determined. The expected number of CRC deaths was calculated for the general US population, using ICD-10 codes. Standardized mortality ratios (SMR) were calculated as the ratio of observed to expected CRC deaths stratified by current age, sex, race, time post-injury and neurologic group. Results: The CRC mortality was 146 persons out of 54,965 persons with SCI. The overall SMR was determined to be 1.11 (95% CI [0.94, 1.31]). Among subgroups, one finding was significant and this was for patients with injury level C1-4 with an American Spinal Injury Association Impairment Scale Grade of A, B or C with an SMR of 1.68 ([95% CI [1.03-2.61]). Conclusion: Although persons with SCI receive suboptimal rates of preventative care screenings and report extensive barriers to care, overall, they are not at an increased risk of CRC mortality. The current recommendations for CRC screening should be continued for these individuals while reducing barriers to care.

Acral lentiginous melanoma is commonly misdiagnosed, and when detected late it portends a poor prognosis. Acral lentiginous melanoma can be mistaken for verruca, pyogenic granuloma, poroma, an ulcer, or other benign skin conditions. Patients with acral skin growths often present initially to a podiatric physician or their primary care physician. It is at this point when the growth is triaged as benign or potentially malignant. Dermoscopy aids in this decision making. Historically, dermoscopy training has been geared toward dermatologists, but there is increasing recognition of the need for dermoscopy training in primary care and podiatric medicine. Dermoscopy is particularly helpful in pink (amelanotic) growths, which can lack the traditional clinical findings of melanoma. A literature review of acral melanoma and dermoscopy was performed in PubMed. We also describe a case of amelanotic acral melanoma in a 58-year-old with a rapidly enlarging painful mass on her heel. The lesion was initially thought to be a pyogenic granuloma and was treated with debridement (curettage). She was ultimately seen in the dermatology clinic, and the findings under dermoscopy were worrisome for amelanotic melanoma. Biopsy confirmed the diagnosis. The cancer metastasized, and the patient died less than 2 years later.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer lacking targetable biomarkers. TNBC is known to be most aggressive and when metastatic is often drug-resistant and uncurable. Biomarkers predicting response to therapy improve treatment decisions and allow personalized approaches for patients with TNBC. This study explores sulfated glycosaminoglycan (sGAG) levels as a predictor of TNBC response to platinum therapy. sGAG levels were quantified in three distinct TNBC tumor models, including cell line-derived, patient-derived xenograft (PDX) tumors, and isogenic models deficient in sGAG biosynthesis. The in vivo antitumor efficacy of Triplatin, a sGAG-directed platinum agent, was compared in these models with the clinical platinum agent, carboplatin. We determined that >40% of TNBC PDX tissue microarray samples have high levels of sGAGs. The in vivo accumulation of Triplatin in tumors as well as antitumor efficacy of Triplatin positively correlated with sGAG levels on tumor cells, whereas carboplatin followed the opposite trend. In carboplatin-resistant tumor models expressing high levels of sGAGs, Triplatin decreased primary tumor growth, reduced lung metastases, and inhibited metastatic growth in lungs, liver, and ovaries. sGAG levels served as a predictor of Triplatin sensitivity in TNBC. Triplatin may be particularly beneficial in treating patients with chemotherapy-resistant tumors who have evidence of residual disease after standard neoadjuvant chemotherapy. More effective neoadjuvant and adjuvant treatment will likely improve clinical outcome of TNBC., (©2021 American Association for Cancer Research.)