MYC targeting by OMO-103 in solid tumors: a phase 1 trial.

Among the 'most wanted' targets in cancer therapy is the oncogene MYC, which coordinates key transcriptional programs in tumor development and maintenance. It has, however, long been considered undruggable. OMO-103 is a MYC inhibitor consisting of a 91-amino acid miniprotein. Here we present results from a phase 1 study of OMO-103 in advanced solid tumors, established to examine safety and tolerability as primary outcomes and pharmacokinetics, recommended phase 2 dose and preliminary signs of activity as secondary ones. A classical 3 + 3 design was used for dose escalation of weekly intravenous, single-agent OMO-103 administration in 21-day cycles, encompassing six dose levels (DLs). A total of 22 patients were enrolled, with treatment maintained until disease progression. The most common adverse events were grade 1 infusion-related reactions, occurring in ten patients. One dose-limiting toxicity occurred at DL5. Pharmacokinetics showed nonlinearity, with tissue saturation signs at DL5 and a terminal half-life in serum of 40 h. Of the 19 patients evaluable for response, 12 reached the predefined 9-week time point for assessment of drug antitumor activity, eight of those showing stable disease by computed tomography. One patient defined as stable disease by response evaluation criteria in solid tumors showed a 49% reduction in total tumor volume at best response. Transcriptomic analysis supported target engagement in tumor biopsies. In addition, we identified soluble factors that are potential pharmacodynamic and predictive response markers. Based on all these data, the recommended phase 2 dose was determined as DL5 (6.48 mg kg-1).ClinicalTrials.gov identifier: NCT04808362 .

Pharmacokinetic Analysis of Omomyc Shows Lasting Structural Integrity and Long Terminal Half-Life in Tumor Tissue.

MYC is an oncoprotein causally involved in the majority of human cancers and a most wanted target for cancer treatment. Omomyc is the best-characterized MYC dominant negative to date. In the last years, it has been developed into a therapeutic miniprotein for solid tumor treatment and recently reached clinical stage. However, since the in vivo stability of therapeutic proteins, especially within the tumor vicinity, can be affected by proteolytic degradation, the perception of Omomyc as a valid therapeutic agent has been often questioned. In this study, we used a mass spectrometry approach to evaluate the stability of Omomyc in tumor biopsies from murine xenografts following its intravenous administration. Our data strongly support that the integrity of the functional domains of Omomyc (DNA binding and dimerization region) remains preserved in the tumor tissue for at least 72 hours following administration and that the protein shows superior pharmacokinetics in the tumor compartment compared with blood serum.

Síndrome de encefalopatía posterior reversible como comienzo de glomerulonefritis postinfecciosa / Posterior reversible encephalopathy syndrome as a debut of postinfectious glomerulonephritis

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Different Phenotypes of Schimke Immuno-Osseous Dysplasia (SIOD) in Two Sisters with the Same Mutation in the SMARCAL1 Gene.

BACKGROUND: Schimke immuno-osseous dysplasia (SIOD) is a very rare autosomal recessive genetic disease caused by mutations in the SMARCAL1 gene. It is characterized by spondyloepiphyseal dysplasia, T-cell immunodeficiency, hypercromic nevi, hypercholestero-lemia, and steroid-resistant nephrotic syndrome with progressive renal failure to end-stage kidney disease. CASE PRESENTATION: We report two cases of SIOD in sisters, diagnosed after the debut of nephrotic syndrome. Both had a personal history of short stature, acetabular hip dysplasia, and hypercholesterolemia. The first case, a 6-year-old girl, presented peripheral refractory edema, severe arterial hypertension, and progressive decrease of the glomerular filtration rate. Steroid-resistance of nephrotic syndrome was confirmed, treated with tacrolimus without response. Renal function worsened over the following 4 months, so haemodialysis was started. Her sister, a 5-year-old girl, had the steroid-resistant nephrotic syndrome and normal blood pressure and renal function under enalapril treatment. In view of the suspicion of SIOD, genetic studies were carried out, revealing the same mutation in homozygosis. CONCLUSION: SIOD has a variable expression with multi-systemic involvement with a short life expectancy. Early diagnosis is important, which can encourage the early start of treatment and anticipation of complications that may be life-threatening.

MYC Inhibition Halts Metastatic Breast Cancer Progression by Blocking Growth, Invasion, and Seeding.

MYC's role in promoting tumorigenesis is beyond doubt, but its function in the metastatic process is still controversial. Omomyc is a MYC dominant negative that has shown potent antitumor activity in multiple cancer cell lines and mouse models, regardless of their tissue of origin or driver mutations, by impacting on several of the hallmarks of cancer. However, its therapeutic efficacy against metastasis has not been elucidated yet. Here we demonstrate for the first time that MYC inhibition by transgenic Omomyc is efficacious against all breast cancer molecular subtypes, including triple-negative breast cancer, where it displays potent antimetastatic properties both in vitro and in vivo. Importantly, pharmacologic treatment with the recombinantly produced Omomyc miniprotein, recently entering a clinical trial in solid tumors, recapitulates several key features of expression of the Omomyc transgene, confirming its clinical applicability to metastatic breast cancer, including advanced triple-negative breast cancer, a disease in urgent need of better therapeutic options. Significance: While MYC role in metastasis has been long controversial, this manuscript demonstrates that MYC inhibition by either transgenic expression or pharmacologic use of the recombinantly produced Omomyc miniprotein exerts antitumor and antimetastatic activity in breast cancer models in vitro and in vivo, suggesting its clinical applicability.

Left Ventricular Hypertrophy in Patients with X-Linked Hypophosphataemia

X-linked hypophosphatemia (XLH) is a rare genetic disorder with X-linked dominant inheritance. Mutations in the PHEX gene increase fibroblast growth factor 23 (FGF23) concentrations, causing loss of phosphorus at the proximal tubule. Most pediatric patients debut in the first two years with short stature and bowed legs. Conventional treatment consists of oral supplements with phosphorus and calcitriol. Since 2018, burosumab has been approved as a novel therapeutic option for XLH, with promising results. The purpose of this study was to share our experience with two cases of XLH treated with burosumab. These patients presented with a broad phenotypical differences. One had the most severe radiological phenotype and developed left ventricular hypertrophy (LVH) and left ventricular dysfunction with preserved ejection fraction. Treatment with burosumab was well-tolerated and was followed by radiological stability and a striking improvement in both blood biochemistry and quality of life. The LVH was stable and left ventricular function normalized in the patient with cardiac involvement. In recent years many studies have been carried out to explain the role of FGF23 in cardiovascular damage, but the exact pathophysiological mechanisms are as yet unclear. The most intensively studied populations are patients with XLH or chronic kidney disease, as both are associated with high levels of FGF23. To date, cardiovascular involvement in XLH has been described in patients treated with conventional treatment, so it would be of interest to investigate if early use of burosumab at the time of diagnosis of XLH would prevent the occurrence of cardiovascular manifestations.

Integrated requirement of non-specific and sequence-specific DNA binding in Myc-driven transcription.

Eukaryotic transcription factors recognize specific DNA sequence motifs, but are also endowed with generic, non-specific DNA-binding activity. How these binding modes are integrated to determine select transcriptional outputs remains unresolved. We addressed this question by site-directed mutagenesis of the Myc transcription factor. Impairment of non-specific DNA backbone contacts caused pervasive loss of genome interactions and gene regulation, associated with increased intra-nuclear mobility of the Myc protein in murine cells. In contrast, a mutant lacking base-specific contacts retained DNA-binding and mobility profiles comparable to those of the wild-type protein, but failed to recognize its consensus binding motif (E-box) and could not activate Myc-target genes. Incidentally, this mutant gained weak affinity for an alternative motif, driving aberrant activation of different genes. Altogether, our data show that non-specific DNA binding is required to engage onto genomic regulatory regions; sequence recognition in turn contributes to transcriptional activation, acting at distinct levels: stabilization and positioning of Myc onto DNA, and-unexpectedly-promotion of its transcriptional activity. Hence, seemingly pervasive genome interaction profiles, as detected by ChIP-seq, actually encompass diverse DNA-binding modalities, driving defined, sequence-dependent transcriptional responses.

Imaginarios sexuales y des/atención médica: La ginecología como dispositivo de hetero-cis-normalización / Imaginários sexuais e des/atenção médica: a ginecologia como dispositivo de hetero-cis-normalização / Sexual Imaginaries and Medical In/Attention: Gynecology as Device for Hetero-Cis-Normalization

Resumen El presente artículo se propone, siguiendo el método genealógico foucaultiano, analizar la eficacia productiva y la violencia normativa que constituye a la ginecología en una tecnología de hetero-cis-normalización que produce una distribución diferencial de la precaridad, afectando principalmente a corporalidades y modos de vida lesbianos (cis y trans), transmasculinos, no-binarixs, bi y pansexuales. Para desarrollar estas tesis recuperaré, en primer lugar, los desarrollos butlerianos en torno a la heterosexualidad obligatoria, las normas sexo-generizadas y la vulnerabilidad, para pensar, desde allí, a la ginecología como una técnica de precarización. En segundo lugar, y recuperando las tesis de Rohden, Cabral y Preciado, desarrollaré el modo en que la ginecología opera como una "prótesis de género" que organiza y disciplina cuerpos a partir de un sistema binario. Para concluir, sostendré siguiendo a Foucault que esto implica una especie de extraña "paradoja" para la ginecología, en la medida en que la imposición de su matriz hetero-cis-normativa redunda en una inducida, y sistemática, desatención y descuido de la salud ginecológica de las personas LGTB.

Resumo A partir do método genealógico foucaultiano, o presente artigo tem o intuito de analisar a eficácia produtiva e a violência normativa que configura a ginecologia como tecnologia de hetero-cis-normalização, produzindo uma distribuição diferencial da precariedade que afeta, principalmente as corporeidades e modos de vida lésbicos (cis e trans), transmasculinos, não-binarixs, bi e pansexuais. Para tal trarei à tona, em primeiro lugar, as análises butlerianas em torno da heterossexualidade compulsória, as normas sexo-generificadas e a vulnerabilidade para pensar a ginecologia como técnica de precarização. Em segundo lugar, e recuperando os supostos de Rhoden, Cabral e Preciado, desenvolverei os modos em que a ginecologia opera como uma "prótese de gênero" que organiza e disciplina corpos a partir de um sistema binário. Para concluir, e seguindo a Foucault, sustentarei a ideia que isso supõe uma espécie de estranho "paradoxo" para a ginecologia; uma desatenção induzida e sistemática e um desleixo da saúde ginecológica das pessoas LGTB.

Abstract This paper seeks to examine the productive effectiveness and normative violence of Gynecology, following Foucault's genealogical method, in terms of a technology of heterocis-normalization that induces a differential distribution of precarity, affecting mainly lesbian (cis or trans), transmasculine, bi, non-binary and pansexual bodies and forms of life. In order to develop this analysis, I will first consider Butler´s developments on compulsive heterosexuality, sex and gender norms and vulnerability as a way of thinking Gynecology as a technic of precarity. Secondly, and following Rohden´s, Cabral´s and Preciado´s thoughts, I will argue that Gynecology operates as a "gender prosthesis" that organizes and discipline bodies through a binary system. Finally, and following Foucault, I will conclude that this implies a paradoxical situation for Gynecology, since its heteronormative matrix produces and induces a systematical inattention and carelessness of LGTB people.

Intrinsic cell-penetrating activity propels Omomyc from proof of concept to viable anti-MYC therapy.

Inhibiting MYC has long been considered unfeasible, although its key role in human cancers makes it a desirable target for therapeutic intervention. One reason for its perceived undruggability was the fear of catastrophic side effects in normal tissues. However, we previously designed a dominant-negative form of MYC called Omomyc and used its conditional transgenic expression to inhibit MYC function both in vitro and in vivo. MYC inhibition by Omomyc exerted a potent therapeutic impact in various mouse models of cancer, causing only mild, well-tolerated, and reversible side effects. Nevertheless, Omomyc has been so far considered only a proof of principle. In contrast with that preconceived notion, here, we show that the purified Omomyc mini-protein itself spontaneously penetrates into cancer cells and effectively interferes with MYC transcriptional activity therein. Efficacy of the Omomyc mini-protein in various experimental models of non-small cell lung cancer harboring different oncogenic mutation profiles establishes its therapeutic potential after both direct tissue delivery and systemic administration, providing evidence that the Omomyc mini-protein is an effective MYC inhibitor worthy of clinical development.

Síndrome hemolítico-urémico causado por Aeromona caviae en un paciente pediátrico / Hemolytic uremic syndrome caused by Aeromona caviae in a pediatric patient

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Daño renal precoz en pacientes nacidos con agenesia renal unilateral / Early kidney damage in patients born with unilateral renal agenesis

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The Alzheimer disease protective mutation A2T modulates kinetic and thermodynamic properties of amyloid-ß (Aß) aggregation.

Missense mutations in alanine 673 of the amyloid precursor protein (APP), which corresponds to the second alanine of the amyloid ß (Aß) sequence, have dramatic impact on the risk for Alzheimer disease; A2V is causative, and A2T is protective. Assuming a crucial role of amyloid-Aß in neurodegeneration, we hypothesized that both A2V and A2T mutations cause distinct changes in Aß properties that may at least partially explain these completely different phenotypes. Using human APP-overexpressing primary neurons, we observed significantly decreased Aß production in the A2T mutant along with an enhanced Aß generation in the A2V mutant confirming earlier data from non-neuronal cell lines. More importantly, thioflavin T fluorescence assays revealed that the mutations, while having little effect on Aß42 peptide aggregation, dramatically change the properties of the Aß40 pool with A2V accelerating and A2T delaying aggregation of the Aß peptides. In line with the kinetic data, Aß A2T demonstrated an increase in the solubility at equilibrium, an effect that was also observed in all mixtures of the A2T mutant with the wild type Aß40. We propose that in addition to the reduced ß-secretase cleavage of APP, the impaired propensity to aggregate may be part of the protective effect conferred by A2T substitution. The interpretation of the protective effect of this mutation is thus much more complicated than proposed previously.