N-MYC impairs innate immune signaling in high-grade serous ovarian carcinoma.

High-grade serous ovarian cancer (HGSC) is a challenging disease, especially for patients with immunologically "cold" tumors devoid of tumor-infiltrating lymphocytes (TILs). We found that HGSC exhibits among the highest levels of MYCN expression and transcriptional signature across human cancers, which is strongly linked to diminished features of antitumor immunity. N-MYC repressed basal and induced IFN type I signaling in HGSC cell lines, leading to decreased chemokine expression and T cell chemoattraction. N-MYC inhibited the induction of IFN type I by suppressing tumor cell-intrinsic STING signaling via reduced STING oligomerization, and by blunting RIG-I-like receptor signaling through inhibition of MAVS aggregation and localization in the mitochondria. Single-cell RNA sequencing of human clinical HGSC samples revealed a strong negative association between cancer cell-intrinsic MYCN transcriptional program and type I IFN signaling. Thus, N-MYC inhibits tumor cell-intrinsic innate immune signaling in HGSC, making it a compelling target for immunotherapy of cold tumors.

Emerging roles of TBK1 in cancer immunobiology.

TANK-binding kinase 1 (TBK1) is a versatile serine/threonine protein kinase with established roles in innate immunity, metabolism, autophagy, cell death, and inflammation. While best known for its role in regulating innate immunity, TBK1 has emerged as a cancer cell-intrinsic immune evasion gene by virtue of its role in modulating cellular responses to inflammatory signals emanating from the immune system. Beyond its effect on cancer cells, TBK1 appears to regulate lymphoid and myeloid cells in the tumor immune microenvironment. In this review, we detail recent advances in our understanding of the tumor-intrinsic and -extrinsic roles and regulation of TBK1 in tumor immunity.

Cytoplasmic switch of ARS2 isoforms promotes nonsense-mediated mRNA decay and arsenic sensitivity.

The life of RNA polymerase II (RNAPII) transcripts is shaped by the dynamic formation of mutually exclusive ribonucleoprotein complexes (RNPs) that direct transcript biogenesis and turnover. A key regulator of RNA metabolism in the nucleus is the scaffold protein ARS2 (arsenic resistance protein 2), bound to the cap binding complex (CBC). We report here that alternative splicing of ARS2's intron 5, generates cytoplasmic isoforms that lack 270 amino acids from the N-terminal of the protein and are functionally distinct from nuclear ARS2. Switching of ARS2 isoforms within the CBC in the cytoplasm has dramatic functional consequences, changing ARS2 from a NMD inhibitor to a NMD promoter that enhances the binding of UPF1 to NCBP1 and ERF1, favouring SURF complex formation, SMG7 recruitment and transcript degradation. ARS2 isoform exchange is also relevant during arsenic stress, where cytoplasmic ARS2 promotes a global response to arsenic in a CBC-independent manner. We propose that ARS2 isoform switching promotes the proper recruitment of RNP complexes during NMD and the cellular response to arsenic stress. The existence of non-redundant ARS2 isoforms is relevant for cell homeostasis, and stress response.

Significados atribuídos e sentimentos autorreferidos sobre adoecimento de pessoas que vivem com hanseníase / Attributed meanings and self-reported feelings about illness of people living with leprosy / Significados atribuidos y sentimientos autoinformados sobre la enfermedad de las personas que viven con lepra

Objetivo: compreender os significados atribuídos e sentimentos autorreferidos sobre o adoecimento por pesssoas que vivem com hanseníase. Método: pesquisa qualitativa, desenvolvida em um município da região norte da Bahia. Realizou-se entrevistas semiestruturadas e observação sistemática, que originou três categorias analíticas, por meio da análise temática categorial de Bardin. Resultados: os participantes revelaram sentimentos de medo, inferioridade e tristeza que coexistem com a discriminação e a falta de informação sobre o adoecimento. Estes sentimentos vivenciados cotidianamente os afastaram de familiares e pessoas próximas, reforçando sofrimentos e adoecimento psiquico. Conclusão: o enfrentamento diário do preconceito pode interferir no prognóstico da doença, na adesão ao tratamento e qualidade de vida, o que requer uma conduta profissional pautada em acolhimento, escuta qualificada e constante diálogo.

Objective: understand the meanings attributed and self-reported feelings about falling ill by people living with leprosy. Method: qualitative research, developed in a municipality in the northern region of Bahia. Semi-structured interviews and systematic observation were carried out, which originated three analytical categories, through Bardin's categorical thematic analysis. Results: the participants revealed feelings of fear, inferiority and sadness that coexist with discrimination and the lack of information about illness. These feelings experienced daily removed them from family and close people, reinforcing suffering and psychic illness. Conclusion: the daily confrontation of prejudice can interfere in the prognosis of the disease, in adherence to treatment and quality of life, which requires professional conduct based on welcoming, qualified listening and constant dialogue.

Objetivo: comprender los significados atribuidos y los sentimientos autoinformados sobre enfermarse por las personas que viven con lepra. Método: investigación cualitativa, desarrollada en un municipio de la región norte de Bahía. Se realizaron entrevistas semiestructuradas y observación sistemática, que dieron origen a tres categorías analíticas, a través del análisis temático categórico de Bardin. Resultados: los participantes revelaron sentimientos de miedo, inferioridad y tristeza que conviven con la discriminación y la falta de información sobre la enfermedad. Estos sentimientos vividos a diario los alejaban de sus familiares y personas cercanas, reforzando el sufrimiento y la enfermedad psíquica. Conclusión: el enfrentamiento diario de los prejuicios puede interferir en el pronóstico de la enfermedad, en la adherencia al tratamiento y la calidad de vida, lo que requiere una conducta profesional basada en la acogida, la escucha calificada y el diálogo constante.

Outcomes of Micropulse Transscleral Cyclophotocoagulation in Eyes With Good Central Vision.

PRECIS: This study is the first to report micropulse transscleral cyclophotocoagulation (MP-TSCPC) use in only good vision patients. MP-TSCPC significantly reduced intraocular pressure (IOP) and glaucoma medication use without any significant reduction in visual acuity at every postoperative follow-up point. PURPOSE: To evaluate outcomes of MP-TSCPC in eyes with baseline best-corrected visual acuity (BCVA) of ≥20/60. METHODS: A retrospective review of patients who underwent MP-TSCPC at Mayo Clinic and Ross Eye Institute from July 2016 to August 2017 with BCVA of ≥20/60, and a minimum of 3 months follow-up. RESULTS: A total of 61 eyes of 46 patients (68.80±17.12 y) underwent MP-TSCPC with a mean follow-up of 10.2±3.1 months. Mean IOP and mean number of glaucoma medications used were significantly reduced from baseline at every follow-up time point (P<0.0001). At month 12, mean IOP was reduced 40.2% from baseline with 85.4% of the patients having an IOP reduction of ≥20%, and mean glaucoma medication use reduced by 0.82±0.53 with 79.6% of the patients having a reduction of ≥1 medication. There was no significant reduction in BCVA from baseline at any follow-up point (P>0.05), except for 10 eyes with a vision loss of ≥2 lines and 5 out of 10 eyes had cataract progression. The probability of complete success (IOP range, 6 to 21 mm Hg or ≥20% IOP reduction; BCVA loss ≤2 lines, no reoperation for glaucoma) was 74.14%, 83.61%, 84.21%, and 75.0% at months 1, 3, 6, 12, respectively. The probability of qualified success (above criteria for IOP, no reoperation and BCVA loss >2 lines) was 81.03%, 91.80%, 94.74%, and 93.75% at months 1, 3, 6, 12, respectively. CONCLUSIONS: MP-TSCPC should be considered earlier in the management of glaucoma and can possibly be offered as an alternative to incisional glaucoma surgeries.

Cancer stemness, intratumoral heterogeneity, and immune response across cancers.

Regulatory programs that control the function of stem cells are active in cancer and confer properties that promote progression and therapy resistance. However, the impact of a stem cell-like tumor phenotype ("stemness") on the immunological properties of cancer has not been systematically explored. Using gene-expression-based metrics, we evaluated the association of stemness with immune cell infiltration and genomic, transcriptomic, and clinical parameters across 21 solid cancers. We found pervasive negative associations between cancer stemness and anticancer immunity. This occurred despite high stemness cancers exhibiting increased mutation load, cancer-testis antigen expression, and intratumoral heterogeneity. Stemness was also strongly associated with cell-intrinsic suppression of endogenous retroviruses and type I IFN signaling, and increased expression of multiple therapeutically accessible immunosuppressive pathways. Thus, stemness is not only a fundamental process in cancer progression but may provide a mechanistic link between antigenicity, intratumoral heterogeneity, and immune suppression across cancers.

Interfaces of Malignant and Immunologic Clonal Dynamics in Ovarian Cancer.

High-grade serous ovarian cancer (HGSC) exhibits extensive malignant clonal diversity with widespread but non-random patterns of disease dissemination. We investigated whether local immune microenvironment factors shape tumor progression properties at the interface of tumor-infiltrating lymphocytes (TILs) and cancer cells. Through multi-region study of 212 samples from 38 patients with whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T and B cell receptor sequencing, we identified three immunologic subtypes across samples and extensive within-patient diversity. Epithelial CD8+ TILs negatively associated with malignant diversity, reflecting immunological pruning of tumor clones inferred by neoantigen depletion, HLA I loss of heterozygosity, and spatial tracking between T cell and tumor clones. In addition, combinatorial prognostic effects of mutational processes and immune properties were observed, illuminating how specific genomic aberration types associate with immune response and impact survival. We conclude that within-patient spatial immune microenvironment variation shapes intraperitoneal malignant spread, provoking new evolutionary perspectives on HGSC clonal dispersion.

Oncogenic Transformation Can Orchestrate Immune Evasion and Inflammation in Human Mesenchymal Stem Cells Independently of Extrinsic Immune-Selective Pressure.

Immune escape is a hallmark of cancer, but whether it relies upon extrinsic immune-selective pressure or is inherently orchestrated by oncogenic pathways is unresolved. To address this question, we took advantage of an in vitro model of sequentially transformed human mesenchymal stem cells (hMSC). Neoplastic transformation in this model increased the natural immune-evasive properties of hMSC, both by reducing their immunogenicity and by increasing their capacity to inhibit mitogen-driven T-cell proliferation. We also found that IFNγ signaling was globally affected in transformed hMSC. As a consequence, the natural inhibitory effect of hMSC on T-cell proliferation switched from an inducible mechanism depending on IFNγ signaling and mediated by indoleamine 2,3-dioxygenase to a constitutive mechanism that relied upon IL1ß involving both secreted and membrane-expressed molecules. After transformation, increased IL1ß expression both sustained the immunosuppressive properties of hMSC and increased their tumorigenicity. Thus, in this model system, IL1ß acted as intrinsic inflammatory mediator that exerted an autocrine influence on tumor growth by coordinately linking immune escape and tumorigenicity. Collectively, our findings show how oncogenes directly orchestrate inflammation and immune escape to drive the multistep process of cancer progression, independently of any need for immunoediting in the tumor microenvironment.

Oncogenic transformation tunes the cross-talk between mesenchymal stem cells and T lymphocytes.

Stem cells from mesenchymal origin (MSC) exert a plethora of immunomodulatory effects. We created a neoplastic model based on in vitro step-wise transformation to assess whether oncogenic pathways have the capacity to mould the cross-talk of MSC and lymphocytes. Neoplastic MSC exhibit an increased inhibitory effect on T cell proliferation, either directly or mediated by myeloid derived suppressor cells. Additionally, transformation of MSC enhances T cell apoptosis without reducing either the percentage of CD25 expressing cells or the level of this protein expression. Malignant transformation drives MSC to lose dependency on nitric oxide for immunosuppression whilst increasing the constitutive production of PGE2. Our results indicate that oncogenesis tunes the interplay between MSC and immune cells, favoring cancer immune evasion.

Bilateral urinary calculi with discordant stone composition.

OBJECTIVES: To describe a cohort of bilateral stone formers with significantly different compositions between renal units. METHODS: Patients treated for bilateral nephrolithiasis over a 4-year period (2007-2010) were identified. Stones were categorized by dominant (≥50%) mineralogical component. Patients with significant compositional differences between renal units (discordant stone formers) were compared to patients with a similar stone type in each kidney. RESULTS: Fifteen of the 59 bilateral stone formers (25.4%) were discordant stone formers with significant differences in stone composition between renal units. Forty-four of the 59 patients (74.6%) had the same stone composition on each side. Thirty percent of discordant stones had calcium phosphate as the dominant stone component. Discordant stone formers were younger, had better renal function, and tended to have a larger stone burden (p < 0.05). CONCLUSIONS: A significant minority of bilateral stone formers form a different type of stone in each kidney. Local or micro-environmental etiologies may explain this phenomenon and may also account for failure of preventive therapy in some patients.

Metallic ureteral stents: a cost-effective method of managing benign upper tract obstruction.

INTRODUCTION: The management of patients with upper urinary tract obstruction who are not candidates for definitive reconstruction often presents a challenge. We report our initial experience with the Resonance (Cook Urological, Spencer, IN) metallic ureteral stent for the management of benign ureteral obstruction and present a comparative cost analysis of metallic to standard polymer stent use. METHODS: Data were retrospectively gathered on all patients undergoing metallic ureteral stent placement for benign causes from July 2007 to February 2009. Baseline demographics, previous method of drainage, pre- and postoperative creatinine levels, procedural complications, stent-related side effects, and metallic stent dwell time were recorded. The cost of stent maintenance for polymer and metallic stents for a 12-month interval was calculated for each patient. RESULTS: Fifteen stents were placed in 13 patients to manage obstruction due to a variety of benign etiologies. Metallic stents provided adequate drainage in 12/13 patients, but were discontinued prematurely in 3 patients (2 for voiding symptoms, 1 for hematuria). Eight patients had their metallic stents changed after a mean time of 11.6 months, with no encrustation. The yearly cost associated with polymer and metallic stent use was $23,999 and $11,183, respectively. This amounted to a $10,394 annual cost reduction (43%) for each patient. CONCLUSIONS: Metallic ureteral stents provide effective upper tract drainage for the majority of patients with benign upper tract obstruction, with significant cost benefit, largely because of the shorter exchange interval.

The FECal Double-J: a simplified approach in the management of encrusted and retained ureteral stents.

INTRODUCTION: The management of the forgotten, encrusted, calcified (FECal) Double-J ureteral stents can represent one of the most difficult and challenging surgical conditions for the practicing urologist. We present a novel and simple grading system for the FECal stent and, taking into account our own experience and literature review, propose an algorithm in the management of the encrusted stent based on this new system. MATERIALS AND METHODS: A retrospective analysis of our stone database was performed from March 2000 to April 2007 revealing a total of nine patients presented with a FECal Double-J stent managed at our institution and included in our series for further analysis. Based on this population, our experience, and current surgical techniques, we designed a simplified grading system to universally define the retained indwelling FECal ureteral stents. RESULTS: A total of nine patients with encrusted and retained ureteral stents were identified, graded, classified, and treated at our institution. Our population consisted of five women and four men with an average age of 54.4 years and average stent indwelling time of 11.44 months. We present our novel management algorithm based on our simplified FECal stent grading system. CONCLUSION: The management of the FECal ureteral stent represents a formidable challenge due to the need for a multimodal approach with advanced endourological techniques. Our proposed grading system and management algorithm provide a simplified and directed alternative for the surgical management dilemma of the encrusted retained ureteral stent.