Cancer-Stem-Cell Phenotype-Guided Discovery of a Microbiota-Inspired Synthetic Compound Targeting NPM1 for Leukemia.

The human microbiota plays an important role in human health and disease, through the secretion of metabolites that regulate key biological functions. We propose that microbiota metabolites represent an unexplored chemical space of small drug-like molecules in the search of new hits for drug discovery. Here, we describe the generation of a set of complex chemotypes inspired on selected microbiota metabolites, which have been synthesized using asymmetric organocatalytic reactions. Following a primary screening in CSC models, we identified the novel compound UCM-13369 (4b) whose cytotoxicity was mediated by NPM1. This protein is one of the most frequent mutations of AML, and NPM1-mutated AML is recognized by the WHO as a distinct hematopoietic malignancy. UCM-13369 inhibits NPM1 expression, downregulates the pathway associated with mutant NPM1 C+, and specifically recognizes the C-end DNA-binding domain of NPM1 C+, avoiding the nucleus-cytoplasm translocation involved in the AML tumorological process. The new NPM1 inhibitor triggers apoptosis in AML cell lines and primary cells from AML patients and reduces tumor infiltration in a mouse model of AML with NPM1 C+ mutation. The disclosed phenotype-guided discovery of UCM-13369, a novel small molecule inspired on microbiota metabolites, confirms that CSC death induced by NPM1 inhibition represents a promising therapeutic opportunity for NPM1-mutated AML, a high-mortality disease.

Assessing the Utility of Multiplexed Polymerase Chain Reaction in Detecting Microorganisms Causing Infections in Critically ill Patients.

Early sepsis diagnosis is crucial for implementing adequate antibiotic therapy and for patient survival. This study investigated whether using multiplexed PCR for detecting microorganisms in critical septic patients affects initial antibiotic treatment and compared it to microbiological culture. It also explored scenarios where PCR is more effective in clinical practice. One hundred nineteen specimens (83 blood and 36 respiratory specimens) belonging to 93 patients were analyzed. Multiplexed PCR determinations were performed using the FA-BCID Panel (bioMérieux) for blood samples and the FA-Pneumo for respiratory samples. The mean turnaround times were 1.7 h for the FA-BCID and 1.5h for the FA-Pneumo. Conversely, they were 96.1 h for blood cultures and 72.3 h for respiratory cultures. FA-BCID showed a mean sensitivity of 97% and specificity of 100%. FA-Pneumo showed a sensitivity of 100% and specificity of 90%. However, the positive predictive value was only 39%. Discrepancies were common in polymicrobial samples. Based on the PCR results, initial empirical treatment should have been changed in 71% of patients with bloodstream infections and 61% with respiratory infections. We conclude that multiplexed PCR improves the response time in identifying germs with a high degree of coincidence for blood cultures and moderate for respiratory cultures. These results highlight the importance of PCR in choosing an appropriate antibiotic therapy.

The Role of RNA-Binding Proteins in Hematological Malignancies.

Hematological malignancies comprise a plethora of different neoplasms, such as leukemia, lymphoma, and myeloma, plus a myriad of dysplasia, such as myelodysplastic syndromes or anemias. Despite all the advances in patient care and the development of new therapies, some of these malignancies remain incurable, mainly due to resistance and refractoriness to treatment. Therefore, there is an unmet clinical need to identify new biomarkers and potential therapeutic targets that play a role in treatment resistance and contribute to the poor outcomes of these tumors. RNA-binding proteins (RBPs) are a diverse class of proteins that interact with transcripts and noncoding RNAs and are involved in every step of the post-transcriptional processing of transcripts. Dysregulation of RBPs has been associated with the development of hematological malignancies, making them potential valuable biomarkers and potential therapeutic targets. Although a number of dysregulated RBPs have been identified in hematological malignancies, there is a critical need to understand the biology underlying their contribution to pathology, such as the spatiotemporal context and molecular mechanisms involved. In this review, we emphasize the importance of deciphering the regulatory mechanisms of RBPs to pinpoint novel therapeutic targets that could drive or contribute to hematological malignancy biology.

Reasons for inpatient dermatological consultation requested by other specialities: a five-year data analysis of 1,052 patients from a Portuguese tertiary teaching hospital

Background: The involvement of a dermatologist in inpatient care can result in accurate diagnosis and prescription of appropriate treatment more promptly. Objectives: We aimed to analyse the main reasons for dermatological inpatient consultation in a tertiary centre. Materials & Methods: A retrospective analysis was performed based on clinical registries that included inpatients observed in emergency dermatology consultation between January 1st 2016 to December 31st 2020 at the Hospital de Santa Maria, a tertiary teaching hospital in Lisbon, Portugal. Results: In our dermatology emergency department, we performed 1,052 inpatient consultations during this five-year period. The most frequent diagnostic groups were infections and parasitic diseases (31.1%), inflammatory skin disorders (18.1%) and reactive erythemas (17.7%). Requests were most commonly (85.1%) made by medical specialities. Conclusion: Inpatient dermatological consultations grant access to expert management of drug-induced dermatoses, flares of chronic skin diseases, skin manifestations of systemic diseases and cutaneous infections. Prompt dermatological evaluation is essential for early diagnosis, thus enabling a better prognosis.

Machine learning and semi-targeted lipidomics identify distinct serum lipid signatures in hospitalized COVID-19-positive and COVID-19-negative patients.

BACKGROUND: Lipids are involved in the interaction between viral infection and the host metabolic and immunological responses. Several studies comparing the lipidome of COVID-19-positive hospitalized patients vs. healthy subjects have already been reported. It is largely unknown, however, whether these differences are specific to this disease. The present study compared the lipidomic signature of hospitalized COVID-19-positive patients with that of healthy subjects, as well as with COVID-19-negative patients hospitalized for other infectious/inflammatory diseases. METHODS: We analyzed the lipidomic signature of 126 COVID-19-positive patients, 45 COVID-19-negative patients hospitalized with other infectious/inflammatory diseases and 50 healthy volunteers. A semi-targeted lipidomics analysis was performed using liquid chromatography coupled to mass spectrometry. Two-hundred and eighty-three lipid species were identified and quantified. Results were interpreted by machine learning tools. RESULTS: We identified acylcarnitines, lysophosphatidylethanolamines, arachidonic acid and oxylipins as the most altered species in COVID-19-positive patients compared to healthy volunteers. However, we found similar alterations in COVID-19-negative patients who had other causes of inflammation. Conversely, lysophosphatidylcholine 22:6-sn2, phosphatidylcholine 36:1 and secondary bile acids were the parameters that had the greatest capacity to discriminate between COVID-19-positive and COVID-19-negative patients. CONCLUSION: This study shows that COVID-19 infection shares many lipid alterations with other infectious/inflammatory diseases, and which differentiate them from the healthy population. The most notable alterations were observed in oxylipins, while alterations in bile acids and glycerophospholipis best distinguished between COVID-19-positive and COVID-19-negative patients. Our results highlight the value of integrating lipidomics with machine learning algorithms to explore the pathophysiology of COVID-19 and, consequently, improve clinical decision making.

Emerging treatments for bullous pemphigoid.

Bullous pemphigoid (BP) is the most common autoimmune blistering disease. It is characterized by an immune response against the hemidesmosomal anchoring proteins BP180 and BP230. BP mainly affects elderly patients, with an increasing incidence over the past two decades. High potency topical and/or systemic corticosteroids as well as immunosuppressants are the current mainstay of treatment. However, long-term systemic immunosuppression may result in significant morbidity and mortality. Recent advances in the understanding of the pathogenesis of BP have enabled the investigation of newer therapies that specifically work against a variety of pro-inflammatory mediators associated with BP. These new treatments hold promise to be highly efficient and safer alternatives and are expected to be shortly available for the treatment of BP. This review discusses current evidence on the use of novel targeted therapeutic approaches in the treatment of BP.

Nail Surgery: General Principles, Fundamental Techniques, and Practical Applications.

Despite being an integral part of dermatologic surgery, nail surgery is infrequently performed in daily practice. Indeed, it is frequently considered difficult, time-consuming, and the results take a long time to be observed. Nonetheless, nail pathology is a frequent cause of dermatology consultation, so dermatologists should be familiar with its diagnosis and therapeutic approach, which often involves surgical procedures. This article provides a review of nail surgery, focusing on the anatomy of this region, anesthesia of the ungual apparatus, common surgical techniques, reconstruction of defects in these locations, and a general approach to the most frequently encountered conditions in clinical practice.

Molecular and clinical characterization of transient antithrombin deficiency: A new concept in congenital thrombophilia.

Antithrombin deficiency, the most severe thrombophilia, might be underestimated, since it is only investigated in cases with consistent functional deficiency or family history. We have analyzed 444 consecutive, unrelated cases, from 1998 to 2021, with functional results supporting antithrombin deficiency in at least one sample. Plasma antithrombin was evaluated by functional and biochemical methods in at least two samples. SERPINC1 gene was analyzed by sequencing and MPLA. Hypoglycosylation was studied by electrophoresis and high-performance liquid chromatography (HPLC). In 260 of 305 cases (85.2%) with constitutive deficiency (activity < 80% in all samples), a SERPINC1 (N = 250), or N-glycosylation defect (N = 10) was observed, while 45 remained undetermined. The other 139 cases had normal antithrombin activity (≥ 80%) in at least one sample, what we called transient deficiency. Sixty-one of these cases (43.9%) had molecular defects: 48 had SERPINC1 variants, with two recurrent mutations (p.Ala416Ser[Cambridge II], N = 15; p.Val30Glu[Dublin], N = 12), and 13 hypoglycosylation. Thrombotic complications occurred in transient deficiency, but were less frequent, latter-onset, and had a higher proportion of arterial events than in constitutive deficiency. Two mechanisms explained transient deficiency: The limitation of functional methods to detect some variants and the influence of external factors on the pathogenic consequences of these mutations. Our study reveals a molecular defect in a significant proportion of cases with transient antithrombin deficiency, and changes the paradigm of thrombophilia, as the pathogenic effect of some mutations might depend on external factors and be present only at certain timepoints. Antithrombin deficiency is underestimated, and molecular screening might be appropriate in cases with fluctuating laboratory findings.

Psicanálise no tratamento multidisciplinar e cirúrgico da obesidade mórbida: estudo de caso / Psychoanalysis in the multidisciplinary and surgical treatment of morbid obesity: a case study / La psychanlyse dans le traitement multidisciplinaire et chirurgie de l'obésité morbide: une étude de cas / Psicoanálisis en el tratamiento multidisciplinario y quirúrgico de la obesidad mórbida: estudio de caso

O objetivo do estudo é avaliar o processo psicoterapêutico de abordagem psicanalítica kleiniana como contribuição na melhoria da saúde de pacientes submetidos a cirurgia bariátrica. O método é de estudo de caso baseado na análise de vinheta clínica, acompanhado de levantamento bibliográfico. Analisaram-se trechos de conversas do processo psicoterapêutico de uma mulher obesa de 53 anos que procurou uma instituição dedicada ao tratamento cirúrgico da obesidade grave com enfoque multiprofissional. Após diagnóstico de obesidade mórbida, foi efetuada uma avaliação psicológica inicial. Como extensão, seguiu-se o processo psicoterapêutico de abordagem psicanalítica com frequência de uma vez por semana, passando depois a duas vezes. Dois meses após o primeiro encontro, a paciente submeteu-se à cirurgia bariátrica. A psicoterapia já tem a duração de três anos. Como resultado, a paciente tornou-se mais capaz de entrar em contato com o sentimento de desamparo associado ao fator destrutividade, que aparece em cenas narrativas de vingança, inveja e ciúme. Concluiu-se que o processo psicanalítico se mostrou efetivo: a paciente adquiriu mais condições de preservar suas redes afetivas constituintes, e tornou-se menos vulnerável à ansiedade e impulsividade, favorecendo a permanência da redução da obesidade e evitando a formação de outras situações de padecimento, como o alcoolismo. Essas observações confirmam algumas referências já apontadas na literatura.

We assessed the psychotherapeutic process based on a Kleinian psychoanalytic approach as a contribution to improve the health of patients undergoing bariatric surgery. To that end, we performed a case study based on the analysis of a clinical vignette accompanied by a literature review. We analyzed excerpts of conversations of the psychotherapeutic process of a very obese 53-year-old woman who sought an institution dedicated to the surgical treatment of severe obesity relying on a multidisciplinary approach. After a diagnosis of morbid obesity, an initial psychological evaluation was performed. As an extension, a psychotherapeutic process based on a psychoanalytical approach took place once a week and then later twice a week. Two months after the first meeting, the patient underwent bariatric surgery. To date, the psychotherapeutic process has lasted for three years. As a result, the patient managed to get in touch with her feeling of helplessness associated with a destructiveness factor, which appears in narrative scenes of revenge, envy and jealousy. We conclude that the psychoanalytic process proved to be effective: the patient was able to preserve her constituent affective networks and became less vulnerable to anxiety and impulsivity, favoring reduction of obesity and avoiding situations of suffering such as alcoholism. Our observations confirm some references already mentioned in the literature.

Le but de cette étude est d'évaluer le processus psychothérapeutique à l'aide d'une approche psychanalytique kleinienne pour contribuer à l'amélioration de la santé des patients subissant une chirurgie bariatrique. Pour atteindre ce but, une étude de cas a été développée à partir de la littérature et de l'analyse de vignettes cliniques et on a analysé des extraits de conversations du processus psychothérapeutique d'une femme de 53 ans qui recherchait une institution de traitement chirurgical de l'obésité sévère qui a pour base une approche multidisciplinaire. Après un diagnostic d'obésité morbide, un premier bilan psychologique a été réalisé. En prolongement, le processus psychothérapeutique basé sur une approche psychanalytique a été suivi, une fois par semaine au début et plus tard deux fois par semaine. Deux mois après la première rencontre, la patiente a subi une chirurgie bariatrique. La psychothérapie dure depuis trois ans et a permis à la patiente de faire face à son sentiment de détresse associé au facteur destructif qui surgit dans des scènes narratives de vengeance, d'envie et de jalousie. On conclut que le processus psychanalytique s'est avéré efficace: la patiente a réussi à préserver ses réseaux constitutifs affectifs et est moins vulnérable à l'anxiété et à l'impulsivité, favorisant la permanence de la réduction de l'obésité et évitant la formation d'autres situations de souffrance, comme l'alcoolisme. Ces observations confirment certaines références que l'on trouve dans la littérature.

El objetivo del estudio es evaluar el proceso psicoterapéutico a través de un enfoque psicoanalítico kleiniano como contribución a la mejora de la salud de los pacientes sometidos a cirugía bariátrica. Se trata de un estudio de caso basado en el análisis de una viñeta clínica acompañada por una encuesta bibliográfica. Se analizaron extractos de conversaciones del proceso psicoterapéutico de una mujer obesa de 53 años que acudió a una institución dedicada al tratamiento quirúrgico de la obesidad severa con un abordaje multidisciplinario. Después de un diagnóstico de obesidad mórbida, se realizó una evaluación psicológica inicial. Como extensión, se siguió el proceso psicoterapéutico con enfoque psicoanalítico, inicialmente, una vez por semana y después, dos veces por semana. Dos meses después del primer encuentro, la paciente fue sometida a cirugía bariátrica. La psicoterapia ha durado tres años. Como resultado, la paciente se volvió más capaz de conectarse al sentimiento de desamparo asociado al factor destructividad, que aparece en escenas narrativas de venganza, envidia y celos. Se concluyó que el proceso psicoanalítico resultó ser efectivo: la paciente adquirió más condiciones para preservar sus redes afectivas constituyentes y se volvió menos vulnerable a la ansiedad y a la impulsividad, favoreciendo la permanencia de la reducción de la obesidad y evitando la formación de otras situaciones de sufrimiento, como el alcoholismo. Estas observaciones confirman algunas referencias ya mencionadas en la literatura.

Pathogenetic and Prognostic Implications of Increased Mitochondrial Content in Multiple Myeloma.

Many studies over the last 20 years have investigated the role of mitochondrial DNA (mtDNA) alterations in carcinogenesis. However, the status of the mtDNACN in MM and its implication in the pathogenesis of the disease remains unclear. We examined changes in plasma cell mtDNACN across different stages of MM by applying RT-PCR and high-throughput sequencing analysis. We observed a significant increase in the average mtDNACN in myeloma cells compared with healthy plasma cells (157 vs. 40 copies; p = 0.02). We also found an increase in mtDNACN in SMM and newly diagnosed MM (NDMM) paired samples and in consecutive relapses in the same patient. Survival analysis revealed the negative impact of a high mtDNACN in progression-free survival in NDMM (p = 0.005). Additionally, we confirmed the higher expression of mitochondrial biogenesis regulator genes in myeloma cells than in healthy plasma cells and we detected single nucleotide variants in several genes involved in mtDNA replication. Finally, we found that there was molecular similarity between "rapidly-progressing SMM" and MM regarding mtDNACN. Our data provide evidence that malignant transformation of myeloma cells involves the activation of mitochondrial biogenesis, resulting in increased mtDNA levels, and highlights vulnerabilities and potential therapeutic targets in the treatment of MM. Accordingly, mtDNACN tracking might guide clinical decision-making and management of complex entities such as high-risk SMM.

The Eµ-hnRNP K Murine Model of Lymphoma: Novel Insights into the Role of hnRNP K in B-Cell Malignancies.

B-cell lymphomas are one of the most biologically and molecularly heterogeneous group of malignancies. The inherent complexity of this cancer subtype necessitates the development of appropriate animal model systems to characterize the disease with the ultimate objective of identifying effective therapies. In this article, we discuss a new driver of B-cell lymphomas - hnRNP K (heterogenous nuclear ribonucleoprotein K)-an RNA-binding protein. We introduce the Eµ-Hnrnpk mouse model, a murine model characterized by hnRNP K overexpression in B cells, which develops B-cell lymphomas with high penetrance. Molecular analysis of the disease developed in this model reveals an upregulation of the c-Myc oncogene via post-transcriptional and translational mechanisms underscoring the impact of non-genomic MYC activation in B-cell lymphomas. Finally, the transplantability of the disease developed in Eµ-Hnrnpk mice makes it a valuable pre-clinical platform for the assessment of novel therapeutics.

Myc-Related Mitochondrial Activity as a Novel Target for Multiple Myeloma.

Mitochondria are involved in the development and acquisition of a malignant phenotype in hematological cancers. Recently, their role in the pathogenesis of multiple myeloma (MM) has been suggested to be therapeutically explored. MYC is a master regulator of b-cell malignancies such as multiple myeloma, and its activation is known to deregulate mitochondrial function. We investigated the impact of mitochondrial activity on the distinct entities of the disease and tested the efficacy of the mitochondrial inhibitor, tigecycline, to overcome MM proliferation. COXII expression, COX activity, mitochondrial mass, and mitochondrial membrane potential demonstrated a progressive increase of mitochondrial features as the disease progresses. In vitro and in vivo therapeutic targeting using the mitochondrial inhibitor tigecycline showed promising efficacy and cytotoxicity in monotherapy and combination with the MM frontline treatment bortezomib. Overall, our findings demonstrate how mitochondrial activity emerges in MM transformation and disease progression and the efficacy of therapies targeting these novel vulnerabilities.