Tryptophan fuels MYC-dependent liver tumorigenesis through indole 3-pyruvate synthesis.

Cancer cells exhibit distinct metabolic activities and nutritional dependencies compared to normal cells. Thus, characterization of nutrient demands by individual tumor types may identify specific vulnerabilities that can be manipulated to target the destruction of cancer cells. We find that MYC-driven liver tumors rely on augmented tryptophan (Trp) uptake, yet Trp utilization to generate metabolites in the kynurenine (Kyn) pathway is reduced. Depriving MYC-driven tumors of Trp through a No-Trp diet not only prevents tumor growth but also restores the transcriptional profile of normal liver cells. Despite Trp starvation, protein synthesis remains unhindered in liver cancer cells. We define a crucial role for the Trp-derived metabolite indole 3-pyruvate (I3P) in liver tumor growth. I3P supplementation effectively restores the growth of liver cancer cells starved of Trp. These findings suggest that I3P is a potential therapeutic target in MYC-driven cancers. Developing methods to target this metabolite represents a potential avenue for liver cancer treatment.

Resource theory of quantum scrambling.

Quantum chaos has become a cornerstone of physics through its many applications. One trademark of quantum chaotic systems is the spread of local quantum information, which physicists call scrambling. In this work, we introduce a mathematical definition of scrambling and a resource theory to measure it. We also describe two applications of this theory. First, we use our resource theory to provide a bound on magic, a potential source of quantum computational advantage, which can be efficiently measured in experiment. Second, we also show that scrambling resources bound the success of Yoshida's black hole decoding protocol.

Tryptophan and its metabolites in normal physiology and cancer etiology.

Within the growing field of amino acid metabolism, tryptophan (Trp) catabolism is an area of increasing interest. Trp is essential for protein synthesis, and its metabolism gives rise to biologically active catabolites including serotonin and numerous metabolites in the kynurenine (Kyn) pathway. In normal tissues, the production of Trp metabolites is directly regulated by the tissue-specific expression of Trp-metabolizing enzymes. Alterations of these enzymes in cancers can shift the balance and lead to an increased production of specific byproducts that can function as oncometabolites. For example, increased expression of the enzyme indoleamine 2,3-dioxygenase, which converts Trp into Kyn, leads to an increase in Kyn levels in numerous cancers. Kyn functions as an oncometabolite in cancer cells by promoting the activity of the transcription factor aryl hydrocarbon receptor, which regulates progrowth genes. Moreover, Kyn also inhibits T-cell activity and thus allows cancer cells to evade clearance by the immune system. Therefore, targeting the Kyn pathway has become a therapeutic focus as a novel means to abrogate tumor growth and immune resistance. This review summarizes the biological role and regulation of Trp metabolism and its catabolites with an emphasis on tumor cell growth and immune evasion and outlines areas for future research focus.

The AHR target gene scinderin activates the WNT pathway by facilitating the nuclear translocation of ß-catenin.

The ligand-activated transcription factor aryl hydrocarbon receptor (AHR) regulates cellular detoxification, proliferation and immune evasion in a range of cell types and tissues, including cancer cells. In this study, we used RNA-sequencing to identify the signature of the AHR target genes regulated by the pollutant 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and the endogenous ligand kynurenine (Kyn), a tryptophan-derived metabolite. This approach identified a signature of six genes (CYP1A1, ALDH1A3, ABCG2, ADGRF1 and SCIN) as commonly activated by endogenous or exogenous ligands of AHR in multiple colon cancer cell lines. Among these, the actin-severing protein scinderin (SCIN) was necessary for cell proliferation; SCIN downregulation limited cell proliferation and its expression increased it. SCIN expression was elevated in a subset of colon cancer patient samples, which also contained elevated ß-catenin levels. Remarkably, SCIN expression promoted nuclear translocation of ß-catenin and activates the WNT pathway. Our study identifies a new mechanism for adhesion-mediated signaling in which SCIN, likely via its ability to alter the actin cytoskeleton, facilitates the nuclear translocation of ß-catenin. This article has an associated First Person interview with the first authors of the paper.

Improvement in the Management of Oral Anticoagulation in Patients with Atrial Fibrillation in Primary Health Care.

(1) Background: Evaluation and improvement of the management of patients with atrial fibrillation in treatment with oral anticoagulants from primary health care. (2) Methods: prospective quasi-experimental study, conducted on 385 patients assisted with Atrial Fibrillation (AF) at the Las Fuentes Norte Health Center, before and after the implementation of actions to improve oral anticoagulants management from October 2015 to July 2017. (3) Results: The ACO-ZAR I study revealed that the population with AF presents a global prevalence of 1.7%, an indication of oral anticoagulants of 92.1%, undertreatment of 24%, suboptimal control of vitamin K antagonists of 43%, use of antiaggregant as primary prevention of 13.42%, and primary health care monitoring of 34%. The implementation of activities aimed at improving the management of oral anticoagulants in the ACO-ZAR II study achieves a reduction in undertreatment up to 16%, in the use of antiaggregant up to 9%, and in suboptimal control up to 30%, as well as an increase in control from primary health care up to 69.2% and of the penetrance of direct oral anticoagulants up to 28%. (4) Conclusions: In conclusion, the application of activities aimed at optimizing the management of oral anticoagulants in health center patients allowed the improvement of risk assessment and registration, undertreatment, use of antiaggregant, suboptimal control of vitamin K antagonists, control by primary health care center, and the penetrance of direct oral anticoagulants.

Perception of the primary health care response capacity by patients with and without mental health problems, and health professionals: qualitative study.

BACKGROUND: The objective of this study is to deepen our understanding of perceptions towards Primary Health Care Response Capacity by specifically using patients with and without mental disorders, as well as family doctors and a manager, in order to compare and endorse perspectives. For it, a qualitative study was performed. In-depth interviews were conducted with 28 patients with and without mental health disorders and focus groups were held with 21 professionals and a manager. An inductive thematic content analysis was performed in order to explore, develop and define the emergent categories of analysis. RESULTS: The fundamental domains for patients are dignity, communication, and rapid service. People with mental health problems also highlight the domain of confidentiality as relevant, while patients who do not have a mental health problem prioritize the domain of autonomy. Patients with mental health disorders report a greater number of negative experiences in relation to the domain of dignity. Patients do not consider their negative experiences to be a structural problem of the system. These findings are also endorsed by health care professionals. CONCLUSIONS: It is necessary to take these results into account as responsive systems can improve service uptake, ensure adherence to treatment, and ultimately enhance patient welfare.

Co-transmission of Related Malaria Parasite Lineages Shapes Within-Host Parasite Diversity.

In high-transmission regions, we expect parasite lineages within complex malaria infections to be unrelated due to parasite inoculations from different mosquitoes. This project was designed to test this prediction. We generated 485 single-cell genome sequences from fifteen P. falciparum malaria patients from Chikhwawa, Malawi-an area of intense transmission. Patients harbored up to seventeen unique parasite lineages. Surprisingly, parasite lineages within infections tend to be closely related, suggesting that superinfection by repeated mosquito bites is rarer than co-transmission of parasites from a single mosquito. Both closely and distantly related parasites comprise an infection, suggesting sequential transmission of complex infections between multiple hosts. We identified tetrads and reconstructed parental haplotypes, which revealed the inbred ancestry of infections and non-Mendelian inheritance. Our analysis suggests strong barriers to secondary infection and outbreeding amongst malaria parasites from a high transmission setting, providing unexpected insights into the biology and transmission of malaria.

Identification of coordinately regulated microRNA-gene networks that differ in baboons discordant for LDL-cholesterol.

RATIONALE: Plasma low-density lipoprotein cholesterol (plasma LDL-C), vascular endothelial cells and peripheral blood mononuclear cells (PBMCs), particularly monocytes, play key roles in initiating atherosclerosis, the primary cause of cardiovascular disease (CVD). Although the mechanisms underlying development of atherosclerosis are not well understood, LDL-C is known to influence expression of endothelial microRNAs (miRNAs) and gene-targets of miRNAs to promote cell senescence. However, the impact of LDL-C on expression of PBMC miRNAs and miRNA targeted genes in response to an atherogenic diet is not known. In this study, we used unbiased methods to identify coordinately responsive PBMC miRNA- gene networks that differ between low and high LDL-C baboons when fed a high-cholesterol, high-fat (HCHF) diet. METHODS AND RESULTS: Using RNA Seq, we quantified PBMC mRNAs and miRNAs from half-sib baboons discordant for LDL-C plasma concentrations (low LDL-C, n = 3; high LDL-C, n = 3) before and after a 7-week HCHF diet challenge. For low LDL-C baboons, 626 genes exhibited significant change in expression (255 down-regulated, 371 up-regulated) in response to the HCHF diet, and for high LDL-C baboons 379 genes exhibited significant change in expression (162 down-regulated, 217 up-regulated) in response to the HCHF diet. We identified 494 miRNAs identical to human miRNAs and 47 novel miRNAs. Fifty miRNAs were differentially expressed in low LDL-C baboons (21 up- and 29 down-regulated) and 20 in high LDL-C baboons (11 up- and 9 down-regulated) in response to the HCHF diet. Among the differentially expressed miRNAs were miR-221/222 and miR-34a-3p, which were down-regulated, and miR-148a/b-5p, which was up-regulated. In addition, gene-targets of these miRNAs, VEGFA, MAML3, SPARC, and DMGDH, were inversely expressed and are central hub genes in networks and signaling pathways that differ between low and high LDL-C baboon HCHF diet response. CONCLUSIONS: We have identified coordinately regulated HCHF diet-responsive PBMC miRNA-gene networks that differ between baboons discordant for LDL-C concentrations. Our findings provide potential insights into molecular mechanisms underlying initiation of atherosclerosis where LDL-C concentrations influence expression of specific miRNAs, which in turn regulate expression of genes that play roles in initiation of lesions.

The baboon kidney transcriptome: analysis of transcript sequence, splice variants, and abundance.

The baboon is an invaluable model for the study of human health and disease, including many complex diseases of the kidney. Although scientists have made great progress in developing this animal as a model for numerous areas of biomedical research, genomic resources for the baboon, such as a quality annotated genome, are still lacking. To this end, we characterized the baboon kidney transcriptome using high-throughput cDNA sequencing (RNA-Seq) to identify genes, gene variants, single nucleotide polymorphisms (SNPs), insertion-deletion polymorphisms (InDels), cellular functions, and key pathways in the baboon kidney to provide a genomic resource for the baboon. Analysis of our sequencing data revealed 45,499 high-confidence SNPs and 29,813 InDels comparing baboon cDNA sequences with the human hg18 reference assembly and identified 35,900 cDNAs in the baboon kidney, including 35,150 transcripts representing 15,369 genic genes that are novel for the baboon. Gene ontology analysis of our sequencing dataset also identified numerous biological functions and canonical pathways that were significant in the baboon kidney, including a large number of metabolic pathways that support known functions of the kidney. The results presented in this study catalogues the transcribed mRNAs, noncoding RNAs, and hypothetical proteins in the baboon kidney and establishes a genomic resource for scientists using the baboon as an experimental model.

Micetoma por Nocardia sp: reporte del Cusco-Perú / Mycetoma by Nocardia sp: Report from Cusco-Peru

Se reporta el primer caso de micetoma bacteriano por Nocardia sp. en Cusco, Perú. Se trata de un paciente varón de 44 años quien presentó lesión a nivel de extremidad superior derecha. La infección fue controlada con ciprofloxacino en los tres primeros meses, seguido de trimetoprim/ sulfametoxazol por aproximadamente 15 meses. Se observó cicatrización completa de la lesión con formación de cicatrices queloides como secuela en la visita de control a los 20 meses...

We report the first case of bacterial mycetoma caused by nocardia sp., in Cusco, Peru. A 44 years-old male patient presented with a lesion in the upper right limb. Infection was controlled after a 3 month course of ciprofloxacin, followed by trimethoprim/sulfamethoxazole for approximately 15 months. Complete healing of the lesion with keloid scarring as sequel was observed after 20 months...

A genome resource to address mechanisms of developmental programming: determination of the fetal sheep heart transcriptome.

The pregnant sheep has provided seminal insights into reproduction related to animal and human development (ovarian function, fertility, implantation, fetal growth, parturition and lactation). Fetal sheep physiology has been extensively studied since 1950, contributing significantly to the basis for our understanding of many aspects of fetal development and behaviour that remain in use in clinical practice today. Understanding mechanisms requires the combination of systems approaches uniquely available in fetal sheep with the power of genomic studies. Absence of the full range of sheep genomic resources has limited the full realization of the power of this model, impeding progress in emerging areas of pregnancy biology such as developmental programming. We have examined the expressed fetal sheep heart transcriptome using high-throughput sequencing technologies. In so doing we identified 36,737 novel transcripts and describe genes, gene variants and pathways relevant to fundamental developmental mechanisms. Genes with the highest expression levels and with novel exons in the fetal heart transcriptome are known to play central roles in muscle development. We show that high-throughput sequencing methods can generate extensive transcriptome information in the absence of an assembled and annotated genome for that species. The gene sequence data obtained provide a unique genomic resource for sheep specific genetic technology development and, combined with the polymorphism data, augment annotation and assembly of the sheep genome. In addition, identification and pathway analysis of novel fetal sheep heart transcriptome splice variants is a first step towards revealing mechanisms of genetic variation and gene environment interactions during fetal heart development.

[Chromomycosis: report of a disabling case]. / Cromomicosis: reporte de un caso incapacitante.

Chromomycosis is a deep subcutaneous mycosis caused by different dymorphic fungi species that normally live in vegetal debris. We report the case of a 51 year-old patient that six years previous to the evaluation worked making roof tiles in Madre de Dios, Peru; where he presented an initial papular lesion in a leg, which continued expanding until the 4 limbs were affected with disabling verrucous lesions. Fumagoid cells were found in the skin biopsy. The patient was hospitalized and received topical cleaning, antibiotics and terbinafine. He was discharged two months later with clinical improvement.

Cromomicosis: reporte de un caso incapacitante / Chromomycosis: report of a disabling case

La cromomicosis es una micosis profunda subcutánea producida por hongos dimórficos que de forma habitual habitan en restos vegetales. Se presenta el caso de un paciente de 51 años que seis años antes del ingreso se dedicaba a la fabricación de tejas en Madre de Dios, Perú; donde sufrió una lesión inicial papular en una pierna la cual se extendió hasta comprometer los cuatro miembros, con lesiones verrucosas que lo llevaron a la discapacidad. Se observaron cuerpos fumagoides en la biopsia de piel. El paciente fue hospitalizado y recibió curaciones tópicas, antibioticoterapia y terbinafina. Fue dado de alta al cabo de dos meses con mejoría clínica.

Chromomycosis is a deep subcutaneous mycosis caused by different dymorphic fungi species that normally live in vegetal debris. We report the case of a 51 year-old patient that six years previous to the evaluation worked making roof tiles in Madre de Dios, Peru; where he presented an initial papular lesion in a leg, which continued expanding until the 4 limbs were affected with disabling verrucous lesions. Fumagoid cells were found in the skin biopsy. The patient was hospitalized and received topical cleaning, antibiotics and terbinafine. He was discharged two months later with clinical improvement.

Las caras del poroma / Poroma's faces

Introducción: El poroma es un tumor benigno de la glándula sudorípara, que se presenta usualmente en plantas y palmas. Se confunde con numerosos cuadros cutáneos y es casi siempre diagnosticado erróneamente. Objetivo: Describir las características clínicas y patológicas de los poromas vistos en el HNSE EsSalud del Cusco entre febrero del 2006 y diciembre del 2008. Tratamos de dar una guía para el enfoque de este tumor. Material y métodos: Estudio descriptivo de ocho casos de poromas que fueron confirmados por histopatología. Adicionalmente en tres casos realizamos estudios con inmunohistoquímica con CEA y EMA. Seis casos fueron tratados con electrocirugía de radiofrecuencia y dos con exéresis convencional. Resultados: Reportamos ocho casos de poromas, cuatro de sexo femenino, con un tiempo de enfermedad entre tres meses y 20 años,dos casos con tiempo de evolución de tres meses se presentaron en mujeres de 25 y 30 años. Siete casos fueron asintomáticos. Cinco casos se ubicaron en miembros inferiores, dos en cuello y uno en cara. La apariencia de las lesiones fue polipoide en un caso, uno con aspecto de placa verrucoide, dos angioides, dos tipo placas anfractuosas, uno fue nodular lobulado oscuro y otro papuloso oscuro. El patrón histopatológico fue epidérmico en dos casos, yuxtaepidérmico en tres y tres correspondieron al tipo dérmico. Tres casos marcaron positivamente con ECA y EMA. La respuesta al tratamiento quirúrgico fue óptima. No se objetivaron recidivas. Conclusiones: Los poromas tienen diversidad clínica, de modo que se pueden confundir con otros cuadros. Es de esperar que ocurran también en adultos jóvenes y en localizaciones insospechadas. Generalmente no dan molestias. El estudio histopatológico es de rigor, mostrando patrones variados, finalmente la inmunohistoquímica afianza el diagnóstico.

Background: Poroma is a benign sweat gland tumor, usually seen in the palm and sole. It may be confused with numerous skin diseases, and it is almost always misdiagnosed. Objective: To describe the clinical and histopathologic features of 8 patients with poroma, seen at the EsSalud National Hospital of Cusco, Peru, between February 2006 and December 2008. We try to give guidance for the management of poromas. Methods: Descriptive study of 8 cases of poroma, confirmed with histopathologic examination. Additionally we made inmunohistochemical evaluation with CEA and EMA in 3 cases. Six patients were treated with radiofrequency surgery and 2 with standard local excision. Results: We report 8 patients with poromas, there were 4 females, with a time of disease between three months and 20 years, the two cases where it was three months occurred in women between 25 and 30. Seven cases were asymptomatic. The lesions in 5 cases were located in the lower limbs, 2 cases in the neck and one in the face. The appearance of the lesions was polypoid in one case, one was a verrucous plaque, 2 had angioid appearance, 2 had simplex plaques, one was a dark multilobulated nodule and one was a dark papule. The histological pattern was epidermic in 2 cases, yuxtaepidermic in 3 and 3 belonged to the dermal type. Three of them marked positive with ECA and EMA. The treatment, mainly with radiosurgery, was satisfactory in all cases. No local recurrences were observed. Conclusions: Poromas have a wide range of clinical presentations, the reason why it can be confused with other conditions. It is also expected to occur in young adults and in unusual locations. They are almost always asymptomatic. Histopatologic evaluation is very important showing varied patterns ant it is immunohistochemistry what ultimately enhances the diagnostic.

Activation of stat3 in primary tumors from high-risk breast cancer patients is associated with elevated levels of activated SRC and survivin expression.

PURPOSE: Constitutive activation of signal transducer and activator of transcription 3 (Stat3) protein has been observed in a wide variety of tumors, including breast cancer, and contributes to oncogenesis at least in part by prevention of apoptosis. In a study of 45 patients with high-risk breast cancer enrolled in a phase II neoadjuvant chemotherapy trial with docetaxel and doxorubicin, we evaluated the levels of Stat3 activation and potentially associated molecular biomarkers in invasive breast carcinoma compared with matched nonneoplastic tissues. EXPERIMENTAL DESIGN: Using immunohistochemistry and image analysis, we quantified the levels of phospho-Stat3 (pY-Stat3), phospho-Src (pY-Src), epidermal growth factor receptor, HER2/neu, Ki-67, estrogen receptor, Bcl-2, Bcl-xL, Survivin, and apoptosis in formalin-fixed, paraffin-embedded sections from invasive carcinomas and their paired nonneoplastic parenchyma. The levels of molecular biomarkers in nonneoplastic and tumor tissues were analyzed as continuous variables for statistically significant correlations. RESULTS: Levels of activated pY-Stat3 and pY-Src measured by immunohistochemistry were significantly higher in invasive carcinoma than in nonneoplastic tissue (P < 0.001). In tumors, elevated levels of pY-Stat3 correlated with those of pY-Src and Survivin. Levels of pY-Stat3 were higher in partial pathologic responders than in complete pathologic responders. In partial pathologic responders, pY-Stat3 levels correlated with Survivin expression. CONCLUSIONS: Our findings suggest important roles for elevated activities of Stat3 and Src, as well as Survivin expression, in malignant progression of breast cancer. Furthermore, elevated Stat3 activity correlates inversely with complete pathologic response. These findings suggest that specific Stat3 or Src inhibitors could offer clinical benefits to patients with breast cancer.

An initial genetic linkage map of the rhesus macaque (Macaca mulatta) genome using human microsatellite loci.

Rhesus macaques (Macaca mulatta) are the most widely used nonhuman primate species in biomedical research. To create new opportunities for genetic and genomic studies using rhesus monkeys, we constructed a genetic linkage map of the rhesus genome. This map consists of 241 microsatellite loci, all previously mapped in the human genome. These polymorphisms were genotyped in five pedigrees of rhesus monkeys totaling 865 animals. The resulting linkage map covers 2048 cM including all 20 rhesus autosomes, with average spacing between markers of 9.3 cM. Average heterozygosity among those markers is 0.73. This linkage map provides new comparative information concerning locus order and interlocus distances in humans and rhesus monkeys. The map will facilitate whole-genome linkage screens to locate quantitative trait loci (QTLs) that influence individual variation in phenotypic traits related to basic primate anatomy, physiology, and behavior, as well as QTLs relevant to risk factors for human disease.

A panel of 20 highly variable microsatellite polymorphisms in rhesus macaques (Macaca mulatta) selected for pedigree or population genetic analysis.

This paper reports 20 new microsatellite loci that are highly polymorphic in rhesus macaques (Macaca mulatta). We screened known human microsatellite loci to identify markers that are polymorphic in rhesus macaques, and then selected specific loci that show substantial levels of heterozygosity and robust, reliable amplification. The 20 loci reported here were chosen to include one highly informative microsatellite from each rhesus monkey autosomal chromosome. Fourteen of the 20 polymorphisms are tetranucleotide repeats, and all can be analyzed using standard PCR and electrophoresis procedures. These new rhesus markers have an average of 15.5 alleles per locus and average heterozygosity of 0.83. This panel of DNA polymorphisms will be useful for a variety of different genetic analyses, including pedigree testing, paternity analysis, and population genetic studies. Many of these loci are also likely to be informative in other closely related Old World monkey species.

Cutaneous psammomatous melanotic schwannoma: non-recurrence with surgical excision.

BACKGROUND: Melanotic schwannoma is a pigmented nerve tumor that may be located in the skin and express local aggressivity. This tumor may occur singly. It may also be part of the Carney complex which consists of various, but specific, tumors. OBJECTIVE: We report two cases of subcutaneous melanotic schwannoma localized on the trunk in two men aged 37 and 45 years. METHODS: Conventional histology and immunohistochemistry were performed. RESULTS: One melanotic schwannoma was associated with a cutaneous atypical myxoma and multiple melanocytic lesions, all being part of the Carney complex. The other case had no associated signs. In both cases, the melanotic schwannoma was completely excised and did not recur. CONCLUSION: Melanotic schwannoma is rare and curable by surgery. It must not be confused with malignant melanoma and other pigmented neoplasms. The Carney complex should be carefully ruled out.