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Abstract Polycystic kidney disease (PKD) is a genetic disorder characterized by bilateral cyst formation. We showed that PKD cells and kidneys display metabolic alterations, including the Warburg effect and glutaminolysis, sustained in vitro by the enzyme asparagine synthetase (ASNS). Here, we used antisense oligonucleotides (ASO) against Asns in orthologous and slowly progressive PKD murine models and show that treatment leads to a drastic reduction of total kidney volume (measured by MRI) and a prominent rescue of renal function in the mouse. Mechanistically, the upregulation of an ATF4–ASNS axis in PKD is driven by the amino acid response (AAR) branch of the integrated stress response (ISR). Metabolic profiling of PKD or control kidneys treated with Asns-ASO or Scr-ASO revealed major changes in the mutants, several of which are rescued by Asns silencing in vivo. Indeed, ASNS drives glutamine-dependent de novo pyrimidine synthesis and proliferation in cystic epithelia. Notably, while several metabolic pathways were completely corrected by Asns-ASO, glycolysis was only partially restored. Accordingly, combining the glycolytic inhibitor 2DG with Asns-ASO further improved efficacy. Our studies identify a new therapeutic target and novel metabolic vulnerabilities in PKD.

Abstract Fibrocystin/Polyductin (FPC), encoded by PKHD1, is associated with autosomal recessive polycystic kidney disease (ARPKD), yet its precise role in cystogenesis remains unclear. Here we show that FPC undergoes complex proteolytic processing in developing kidneys, generating three soluble C-terminal fragments (ICDs). Notably, ICD15, contains a novel mitochondrial targeting sequence at its N-terminus, facilitating its translocation into mitochondria. This enhances mitochondrial respiration in renal epithelial cells, partially restoring impaired mitochondrial function caused by FPC loss. FPC inactivation leads to abnormal ultrastructural morphology of mitochondria in kidney tubules without cyst formation. Moreover, FPC inactivation significantly exacerbates renal cystogenesis and triggers severe pancreatic cystogenesis in a Pkd1 mouse mutant Pkd1 V/V in which cleavage of Pkd1-encoded Polycystin-1 at the GPCR Proteolysis Site is blocked. Deleting ICD15 enhances renal cystogenesis without inducing pancreatic cysts in Pkd1 V/V mice. These findings reveal a direct link between FPC and a mitochondrial pathway through ICD15 cleavage, crucial for cystogenesis mechanisms.

Abstract MYC is a key oncogenic driver in multiple tumor types, but concomitantly endows cancer cells with a series of vulnerabilities that provide opportunities for targeted pharmacological intervention. For example, drugs that suppress mitochondrial respiration selectively kill MYC‐overexpressing cells. Here, we unravel the mechanistic basis for this synthetic lethal interaction and exploit it to improve the anticancer effects of the respiratory complex I inhibitor IACS‐010759. In a B‐lymphoid cell line, ectopic MYC activity and treatment with IACS‐010759 added up to induce oxidative stress, with consequent depletion of reduced glutathione and lethal disruption of redox homeostasis. This effect could be enhanced either with inhibitors of NADPH production through the pentose phosphate pathway, or with ascorbate (vitamin C), known to act as a pro‐oxidant at high doses. In these conditions, ascorbate synergized with IACS‐010759 to kill MYC‐overexpressing cells in vitro and reinforced its therapeutic action against human B‐cell lymphoma xenografts. Hence, complex I inhibition and high‐dose ascorbate might improve the outcome of patients affected by high‐grade lymphomas and potentially other MYC‐driven cancers.

Multiple molecular features, such as activation of specific oncogenes (e.g., MYC, BCL2) or a variety of gene expression signatures, have been associated with disease course in diffuse large B‐cell lymphoma (DLBCL), although their relationships and implications for targeted therapy remain to be fully unraveled. We report that MYC activity is closely correlated with—and most likely a driver of—gene signatures related to oxidative phosphorylation (OxPhos) in DLBCL, pointing to OxPhos enzymes, in particular mitochondrial electron transport chain (ETC) complexes, as possible therapeutic targets in high‐grade MYC‐associated lymphomas. In our experiments, indeed, MYC sensitized B cells to the ETC complex I inhibitor IACS‐010759. Mechanistically, IACS‐010759 triggered the integrated stress response (ISR) pathway, driven by the transcription factors ATF4 and CHOP, which engaged the intrinsic apoptosis pathway and lowered the apoptotic threshold in MYC‐overexpressing cells. In line with these findings, the BCL2‐inhibitory compound venetoclax synergized with IACS‐010759 against double‐hit lymphoma (DHL), a high‐grade malignancy with concurrent activation of MYC and BCL2. In BCL2‐negative lymphoma cells, instead, killing by IACS‐010759 was potentiated by the Mcl‐1 inhibitor S63845. Thus, combining an OxPhos inhibitor with select BH3‐mimetic drugs provides a novel therapeutic principle against aggressive, MYC‐associated DLBCL variants.

Este artigo tem como objetivo analisar as respostas dos Estados Unidos e da China em termos de políticas públicas de combate à pandemia da COVID-19, com ênfase no contexto atual de acirramento das tensões geopolíticas, na competição tecnológica e nos modelos de desenvolvimento de ambos os países. Considerando a importância da internet na contemporaneidade para áreas essenciais como economia, política, segurança e defesa, daremos destaque à corrida pela liderança no desenvolvimento das redes 5G. A questão principal que propomos é: qual foi o papel da pandemia na disputa geopolítica entre China e Estados Unidos, considerando sua dimensão tecnológica? A metodologia de pesquisa adotada é a análise qualitativa de documentos oficiais e bibliografia especializada sobre o tema. Nossa hipótese é que a pandemia pode ter conferido vantagem à China na corrida pela liderança no 5G, considerando o maior foco dado pelo governo chinês aos investimentos nessa tecnologia e sua importância no combate à pandemia no país asiático, em que a internet foi essencial para o controle do isolamento social como forma de conter a disseminação do vírus. Os Estados Unidos, por sua vez, concentraram seus esforços no setor de biotecnologia para combater a pandemia.

UNLABELLED: Directional beating of ependymal (E) cells cilia in the walls of the ventricles in the brain is essential for proper CSF flow. E cells display two forms of planar cell polarity (PCP): rotational polarity of individual cilium and translational polarity (asymmetric positioning of cilia in the apical area). The orientation of individual E cells varies according to their location in the ventricular wall (location-specific PCP). It has been hypothesized that hydrodynamic forces on the apical surface of radial glia cells (RGCs), the embryonic precursors of E cells, could guide location-specific PCP in the ventricular epithelium. However, the detection mechanisms for these hydrodynamic forces have not been identified. Here, we show that the mechanosensory proteins polycystic kidney disease 1 (Pkd1) and Pkd2 are present in primary cilia of RGCs. Ablation of Pkd1 or Pkd2 in Nestin-Cre;Pkd1(flox/flox) or Nestin-Cre;Pkd2(flox/flox) mice, affected PCP development in RGCs and E cells. Early shear forces on the ventricular epithelium may activate Pkd1 and Pkd2 in primary cilia of RGCs to properly polarize RGCs and E cells. Consistently, Pkd1, Pkd2, or primary cilia on RGCs were required for the proper asymmetric localization of the PCP protein Vangl2 in E cells apical area. Analyses of single- and double-heterozygous mutants for Pkd1 and/or Vangl2 suggest that these genes function in the same pathway to establish E cells PCP. We conclude that Pkd1 and Pkd2 mechanosensory proteins contribute to the development of brain PCP and prevention of hydrocephalus. SIGNIFICANCE STATEMENT: This study identifies key molecules in the development of planar cell polarity (PCP) in the brain and prevention of hydrocephalus. Multiciliated ependymal (E) cells within the brain ventricular epithelium generate CSF flow through ciliary beating. E cells display location-specific PCP in the orientation and asymmetric positioning of their cilia. Defects in this PCP can result in hydrocephalus. Hydrodynamic forces on radial glial cells (RGCs), the embryonic progenitors of E cells, have been suggested to guide PCP. We show that the mechanosensory proteins Pkd1 and Pkd2 localize to primary cilia in RGCs, and their ablation disrupts the development of PCP in E cells. Early shear forces on RGCs may activate Pkd1 and Pkd2 in RGCs primary cilia to properly orient E cells. This study identifies key molecules in the development of brain PCP and prevention of hydrocephalus.

Summary: Trained immunity (TI) is a de facto innate immune memory program induced in monocytes/macrophages by exposure to pathogens or vaccines, which evolved as protection against infections. TI is characterized by immunometabolic changes and histone post-translational modifications, which enhance production of pro-inflammatory cytokines. As aberrant activation of TI is implicated in inflammatory diseases, tight regulation is critical; however, the mechanisms responsible for this modulation remain elusive. Interleukin-37 (IL-37) is an anti-inflammatory cytokine that curbs inflammation and modulates metabolic pathways. In this study, we show that administration of recombinant IL-37 abrogates the protective effects of TI in vivo, as revealed by reduced host pro-inflammatory responses and survival to disseminated candidiasis. Mechanistically, IL-37 reverses the immunometabolic changes and histone post-translational modifications characteristic of TI in monocytes, thus suppressing cytokine production in response to infection. IL-37 thereby emerges as an inhibitor of TI and as a potential therapeutic target in immune-mediated pathologies.

RESUMO Objetivo: Avaliar características do melanoma em idosos. Método: Pesquisa retrospectiva mediante revisão de prontuários de idosos diagnosticados com melanoma cutâneo primário, no período de 2013 a 2017, atendidos no Hospital Erasto Gaertner, em Curitiba-Paraná. Resultados: Amostra com 139 pacientes, mulheres (52,5%), média de 70,3 anos de idade, com lesão em membro superior ou membro inferior (32,3%) e cabeça (24,4%), sinais de ulceração (33,8%) e classificação em tipo histológico nodular (29,5%), extensivo superficial (27,3%) e acral (11,5%). Média do índice de Breslow de 3,7 mm. Metástases ocorreram em 33% dos pacientes, para linfonodos (36%) e sistema nervoso central (20%). Pesquisa do linfonodo sentinela foi realizada em 41,7% e tratamento cirúrgico isolado em 70% dos casos. Houve recidiva em 34,5% pacientes e 17,9% evoluíram com óbito. Esses achados apontam características prognósticas sombrias relacionadas ao diagnóstico e tratamento tardio da neoplasia. Conclusões: Melanoma em membros e cabeça, índice de Breslow intermediário, metastático para linfonodos e sistema nervoso central, recidiva e tem desfecho fatal. Há necessidade de direcionar estratégias para melhor abordagem da doença em idosos, como prevenção, detecção precoce e oferta de tratamento uniforme e adequado.

Abstract Protein synthesis is traditionally associated with specific cytoplasmic compartments. We now show that OFD1, a centrosomal/basal body protein, interacts with components of the Preinitiation complex of translation (PIC) and of the eukaryotic Initiation Factor (eIF)4F complex and modulates the translation of specific mRNA targets in the kidney. We demonstrate that OFD1 cooperates with the mRNA binding protein Bicc1 to functionally control the protein synthesis machinery at the centrosome where also the PIC and eIF4F components were shown to localize in mammalian cells. Interestingly, Ofd1 and Bicc1 are both involved in renal cystogenesis and selected targets were shown to accumulate in two models of inherited renal cystic disease. Our results suggest a possible role for the centrosome as a specialized station to modulate translation for specific functions of the nearby ciliary structures and may provide functional clues for the understanding of renal cystic disease.

Modeling renal cancer in the mouse has been challenging. We recently showed that upregulation of mechanistic target of rapamycin complex 1 (mTORC1) in a restricted segment of the renal tubule leads to downregulation of the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase, to accumulation of the oncometabolite fumarate, and gradual transformation from benign cysts into cystadenomas and papillary carcinomas.

NRF2 is a transcription factor that coordinates the antioxidant response in many different tissues, ensuring cytoprotection from endogenous and exogenous stress stimuli. In the kidney, its function is essential in appropriate cellular response to oxidative stress, however its aberrant activation supports progression, metastasis, and resistance to therapies in renal cell carcinoma, similarly to what happens in other nonrenal cancers. While at the moment direct inhibitors of NRF2 are not available, understanding the molecular mechanisms that regulate its hyperactivation in specific tumor types is crucial as it may open new therapeutic perspectives. Here, we focus our attention on renal cell carcinoma, describing how NRF2 hyperactivation can contribute to tumor progression and chemoresistance. Furthermore, we highlight the mechanism whereby the many pathways that are generally altered in these tumors converge to dysregulation of the KEAP1-NRF2 axis.

Polycystic kidney disease (PKD) is a ciliopathy resulting from defective localization of membrane proteins such as PC-1 to the primary cilium, resulting in renal cysts, and is associated with another cystic genetic disease called tuberous sclerosis complex (TSC). Here the authors use kidney-specific Tsc1 and Pkd1 mice to show that mTORC1 signalling inhibits PC-1 biogenesis as a potential mechanism of TSC/PKD contiguous gene syndrome.

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Cystic kidney diseases (CKD) is a class of disorders characterized by ciliary dysfunction and, therefore, belonging to the ciliopathies. The prototype CKD is autosomal dominant polycystic kidney disease (ADPKD), whose mutated genes encode for two membrane-bound proteins, polycystin-1 (PC-1) and polycystin-2 (PC-2), of unknown function. Recent studies on CKD-associated genes identified new mechanisms of morphogenesis that are central for establishment and maintenance of proper renal tubular diameter. During embryonic development in the mouse and lower vertebrates a convergent-extension (CE)-like mechanism based on planar cell polarity (PCP) and cellular intercalation is involved in “sculpting” the tubules into a narrow and elongated shape. Once the appropriate diameter is established, further elongation occurs through oriented cell division (OCD). The polycystins (PCs) regulate some of these essential processes. In this review we summarize recent work on the role of PCs in regulating cell migration, the cytoskeleton, and front-rear polarity. These important properties are essential for proper morphogenesis of the renal tubules and the lymphatic vessels. We highlight here several open questions and controversies. Finally, we try to outline some of the next steps required to study these processes and their relevance in physiological and pathological conditions.