Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma.

The mitochondrial genome (mtDNA) encodes essential machinery for oxidative phosphorylation and metabolic homeostasis. Tumor mtDNA is among the most somatically mutated regions of the cancer genome, but whether these mutations impact tumor biology is debated. We engineered truncating mutations of the mtDNA-encoded complex I gene, Mt-Nd5, into several murine models of melanoma. These mutations promoted a Warburg-like metabolic shift that reshaped tumor microenvironments in both mice and humans, consistently eliciting an anti-tumor immune response characterized by loss of resident neutrophils. Tumors bearing mtDNA mutations were sensitized to checkpoint blockade in a neutrophil-dependent manner, with induction of redox imbalance being sufficient to induce this effect in mtDNA wild-type tumors. Patient lesions bearing >50% mtDNA mutation heteroplasmy demonstrated a response rate to checkpoint blockade that was improved by ~2.5-fold over mtDNA wild-type cancer. These data nominate mtDNA mutations as functional regulators of cancer metabolism and tumor biology, with potential for therapeutic exploitation and treatment stratification.

Phenotypic profiling of solute carriers characterizes serine transport in cancer.

Serine is a vital amino acid in tumorigenesis. While cells can perform de novo serine synthesis, most transformed cells rely on serine uptake to meet their increased biosynthetic requirements. Solute carriers (SLCs), a family of transmembrane nutrient transport proteins, are the gatekeepers of amino acid acquisition and exchange in mammalian cells and are emerging as anticancer therapeutic targets; however, the SLCs that mediate serine transport in cancer cells remain unknown. Here we perform an arrayed RNAi screen of SLC-encoding genes while monitoring amino acid consumption and cell proliferation in colorectal cancer cells using metabolomics and high-throughput imaging. We identify SLC6A14 and SLC25A15 as major cytoplasmic and mitochondrial serine transporters, respectively. We also observe that SLC12A4 facilitates serine uptake. Dual targeting of SLC6A14 and either SLC25A15 or SLC12A4 diminishes serine uptake and growth of colorectal cancer cells in vitro and in vivo, particularly in cells with compromised de novo serine biosynthesis. Our results provide insight into the mechanisms that contribute to serine uptake and intracellular handling.

Positron emission tomography imaging of the sodium iodide symporter senses real-time energy stress in vivo.

BACKGROUND: Tissue environment is critical in determining tumour metabolic vulnerability. However, in vivo drug testing is slow and waiting for tumour growth delay may not be the most appropriate endpoint for metabolic treatments. An in vivo method for measuring energy stress would rapidly determine tumour targeting in a physiologically relevant environment. The sodium-iodide symporter (NIS) is an imaging reporter gene whose protein product co-transports sodium and iodide, and positron emission tomography (PET) radiolabelled anions into the cell. Here, we show that PET imaging of NIS-mediated radiotracer uptake can rapidly visualise tumour energy stress within minutes following in vivo treatment. METHODS: We modified HEK293T human embryonic kidney cells, and A549 and H358 lung cancer cells to express transgenic NIS. Next, we subjected these cells and implanted tumours to drugs known to induce metabolic stress to observe the impact on NIS activity and energy charge. We used [18F]tetrafluoroborate positron emission tomography (PET) imaging to non-invasively image NIS activity in vivo. RESULTS: NIS activity was ablated by treating HEK293T cells in vitro, with the Na+/K+ ATPase inhibitor digoxin, confirming that radiotracer uptake was dependent on the sodium-potassium concentration gradient. NIS-mediated radiotracer uptake was significantly reduced (- 58.2%) following disruptions to ATP re-synthesis by combined glycolysis and oxidative phosphorylation inhibition in HEK293T cells and by oxidative phosphorylation inhibition (- 16.6%) in A549 cells in vitro. PET signal was significantly decreased (- 56.5%) within 90 min from the onset of treatment with IACS-010759, an oxidative phosphorylation inhibitor, in subcutaneous transgenic A549 tumours in vivo, showing that NIS could rapidly and sensitively detect energy stress non-invasively, before more widespread changes to phosphorylated AMP-activated protein kinase, phosphorylated pyruvate dehydrogenase, and GLUT1 were detectable. CONCLUSIONS: NIS acts as a rapid metabolic sensor for drugs that lead to ATP depletion. PET imaging of NIS could facilitate in vivo testing of treatments targeting energetic pathways, determine drug potency, and expedite metabolic drug development.

Metabolic profiling stratifies colorectal cancer and reveals adenosylhomocysteinase as a therapeutic target.

The genomic landscape of colorectal cancer (CRC) is shaped by inactivating mutations in tumour suppressors such as APC, and oncogenic mutations such as mutant KRAS. Here we used genetically engineered mouse models, and multimodal mass spectrometry-based metabolomics to study the impact of common genetic drivers of CRC on the metabolic landscape of the intestine. We show that untargeted metabolic profiling can be applied to stratify intestinal tissues according to underlying genetic alterations, and use mass spectrometry imaging to identify tumour, stromal and normal adjacent tissues. By identifying ions that drive variation between normal and transformed tissues, we found dysregulation of the methionine cycle to be a hallmark of APC-deficient CRC. Loss of Apc in the mouse intestine was found to be sufficient to drive expression of one of its enzymes, adenosylhomocysteinase (AHCY), which was also found to be transcriptionally upregulated in human CRC. Targeting of AHCY function impaired growth of APC-deficient organoids in vitro, and prevented the characteristic hyperproliferative/crypt progenitor phenotype driven by acute deletion of Apc in vivo, even in the context of mutant Kras. Finally, pharmacological inhibition of AHCY reduced intestinal tumour burden in ApcMin/+ mice indicating its potential as a metabolic drug target in CRC.

NAD depletion mediates cytotoxicity in human neurons with autophagy deficiency.

Autophagy is a homeostatic process critical for cellular survival, and its malfunction is implicated in human diseases including neurodegeneration. Loss of autophagy contributes to cytotoxicity and tissue degeneration, but the mechanistic understanding of this phenomenon remains elusive. Here, we generated autophagy-deficient (ATG5-/-) human embryonic stem cells (hESCs), from which we established a human neuronal platform to investigate how loss of autophagy affects neuronal survival. ATG5-/- neurons exhibit basal cytotoxicity accompanied by metabolic defects. Depletion of nicotinamide adenine dinucleotide (NAD) due to hyperactivation of NAD-consuming enzymes is found to trigger cell death via mitochondrial depolarization in ATG5-/- neurons. Boosting intracellular NAD levels improves cell viability by restoring mitochondrial bioenergetics and proteostasis in ATG5-/- neurons. Our findings elucidate a mechanistic link between autophagy deficiency and neuronal cell death that can be targeted for therapeutic interventions in neurodegenerative and lysosomal storage diseases associated with autophagic defect.

Adenocarcinoma de vesícula biliar: un caso de presentación temprana / Gallbladder adenocarcinoma: an early-stage case

El cáncer de la vesícula biliar es una enfermedad rara, con una incidencia mundial de 2 casos por cada 100 000 individuos con un pronóstico desfavorable. Con el aumento de colecistectomías por causas benignas, se ha incrementado la detección incidental de neoplasias vesiculares en las piezas quirúrgicas, siendo este el método diagnóstico más frecuente, generando retrasos en el manejo y requiriendo reintervenciones extensas. Debido a lo anterior, se resalta la importancia de un diagnóstico temprano preoperatorio, con el objetivo de ofrecer un tratamiento quirúrgico potencialmente curativo. Se presenta el caso de un paciente masculino de 72 años con un cuadro intermitente de dolor abdominal y pérdida de peso de un año de evolución, el cual fue diagnosticado con cáncer vesicular en etapa temprana y sometido a una colecistectomía laparoscópica extendida con linfadenectomía y hepatectomía parcial con una evolución a 6 meses sin complicaciones y bajo un protocolo de vigilancia periódica.

Gallbladder cancer is a rare disease, accounting a global incidence of 2 cases per 100 000 individuals with an unfavorable prognosis. The rise in cholecystectomies for benign causes has increased an incidental detection of vesicular neoplasms in the surgical specimens, being the main diagnostic method, therefore it generated delay in the management, requiring extensive re-interventions. It is important to improve early preoperative diagnosis, with the aim of offering a potentially curative surgical treatment. We present a case of a 72-year-old male with intermittent abdominal pain and weight loss of one year of evolution, who was diagnosed with early stage gallbladder cancer and underwent an extended laparoscopic cholecystectomy with lymphadenectomy and partial hepatectomy with a 6 months evolution without complications and under a periodic surveillance protocol.

Tumour mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade.

The mitochondrial genome encodes essential machinery for respiration and metabolic homeostasis but is paradoxically among the most common targets of somatic mutation in the cancer genome, with truncating mutations in respiratory complex I genes being most over-represented1. While mitochondrial DNA (mtDNA) mutations have been associated with both improved and worsened prognoses in several tumour lineages1-3, whether these mutations are drivers or exert any functional effect on tumour biology remains controversial. Here we discovered that complex I-encoding mtDNA mutations are sufficient to remodel the tumour immune landscape and therapeutic resistance to immune checkpoint blockade. Using mtDNA base editing technology4 we engineered recurrent truncating mutations in the mtDNA-encoded complex I gene, Mt-Nd5, into murine models of melanoma. Mechanistically, these mutations promoted utilisation of pyruvate as a terminal electron acceptor and increased glycolytic flux without major effects on oxygen consumption, driven by an over-reduced NAD pool and NADH shuttling between GAPDH and MDH1, mediating a Warburg-like metabolic shift. In turn, without modifying tumour growth, this altered cancer cell-intrinsic metabolism reshaped the tumour microenvironment in both mice and humans, promoting an anti-tumour immune response characterised by loss of resident neutrophils. This subsequently sensitised tumours bearing high mtDNA mutant heteroplasmy to immune checkpoint blockade, with phenocopy of key metabolic changes being sufficient to mediate this effect. Strikingly, patient lesions bearing >50% mtDNA mutation heteroplasmy also demonstrated a >2.5-fold improved response rate to checkpoint inhibitor blockade. Taken together these data nominate mtDNA mutations as functional regulators of cancer metabolism and tumour biology, with potential for therapeutic exploitation and treatment stratification.

Effects of sulfur and phosphorus concentration on the lipid accumulation and fatty acid profile in Chlorella vulgaris (Chlorophyta).

Nutrient deficiency induces a variety of cellular responses, including an increase in lipid accumulation in microalgae. Nitrogen starvation is the most studied deprivation. Here, we determine the effects of phosphorus and sulfur limitation on lipid accumulation in Chlorella vulgaris. A set of 9 experiments were performed, varying the initial concentration of these nutrients (set to 0, 50, and 100% of their original composition in Bold's basal medium). According to our results, the variation of P and S modified the specific growth rate, lag phase, and cell generation time. The ratio of 50%P and 0%S significantly increased the total lipid concentration. The fatty acid profile was dominated by C16:0, C18:0, and C18:1; a considerable increase in C20:5 was observed with 0%P and 50%S and 0%P and 100%S. Regarding neutral lipids, the response surface methodology (RSM) indicates that the maximum was observed when S was between 40 and 60% and P was between 95 and 100%. Therefore, the enhanced production of lipids caused by P and S limitation may contribute to the efficient oil production useful for algal biofuels.

Colon Cancer Cells Evade Drug Action by Enhancing Drug Metabolism.

Colorectal cancer (CRC) is the second most deadly cancer worldwide. One key reason is the failure of therapies that target RAS proteins, which represent approximately 40% of CRC cases. Despite the recent discovery of multiple alternative signalling pathways that contribute to resistance, durable therapies remain an unmet need. Here, we use liquid chromatography/mass spectrometry (LC/MS) analyses on Drosophila CRC tumour models to identify multiple metabolites in the glucuronidation pathway-a toxin clearance pathway-as upregulated in trametinib-resistant RAS/APC/P53 ("RAP") tumours compared to trametinib-sensitive RASG12V tumours. Elevating glucuronidation was sufficient to direct trametinib resistance in RASG12V animals while, conversely, inhibiting different steps along the glucuronidation pathway strongly reversed RAP resistance to trametinib. For example, blocking an initial HDAC1-mediated deacetylation step with the FDA-approved drug vorinostat strongly suppressed trametinib resistance in Drosophila RAP tumours. We provide functional evidence that pairing oncogenic RAS with hyperactive WNT activity strongly elevates PI3K/AKT/GLUT signalling, which in turn directs elevated glucose and subsequent glucuronidation. Finally, we show that this mechanism of trametinib resistance is conserved in an KRAS/APC/TP53 mouse CRC tumour organoid model. Our observations demonstrate a key mechanism by which oncogenic RAS/WNT activity promotes increased drug clearance in CRC. The majority of targeted therapies are glucuronidated, and our results provide a specific path towards abrogating this resistance in clinical trials.

Unique long-term simultaneous complications of conventional Roux-en-Y gastric bypass after 27 years: A case report.

INTRODUCTION: We report a case of late concomitant complications caused by conventional Roux-en-Y gastric bypaas and its managements. PRESENTATION OF CASE: A 62-year-old male presented 27 years after conventional gastric bypass Y-de-Roux (BGYR) with, sudden, moderate intensity abdominal pain, nausea, biliary vomiting and hyporexia. Persistent abdominal pain was constant, so a thoracoabdominal tomography was requested by the surgeon. It confirmed the presence of intestinal intussusception associated with lithiasis and cholecystitis. The patient reported having lost 45 kg since the BGYR. He goes to the operating room for definitive management. DISCUSSION: The etiology of post-BGYR intussusception is largely unknown, and multiple hypotheses have been created, such as the iatrogenic stitch created by the suture line in the entero-enteric anastomosis and the most common pattern found is antegrade. The use of contrasted CT as the most reliable diagnostic method. CONCLUSION: The importance of taking into account the possible complications existing in bariatric patients and their frequency gives us the opportunity to suspect and detect them in time and in the most cases the management must be surgical.

Sensitisation of cancer cells to radiotherapy by serine and glycine starvation.

BACKGROUND: Cellular metabolism is an integral component of cellular adaptation to stress, playing a pivotal role in the resistance of cancer cells to various treatment modalities, including radiotherapy. In response to radiotherapy, cancer cells engage antioxidant and DNA repair mechanisms which mitigate and remove DNA damage, facilitating cancer cell survival. Given the reliance of these resistance mechanisms on amino acid metabolism, we hypothesised that controlling the exogenous availability of the non-essential amino acids serine and glycine would radiosensitise cancer cells. METHODS: We exposed colorectal, breast and pancreatic cancer cell lines/organoids to radiation in vitro and in vivo in the presence and absence of exogenous serine and glycine. We performed phenotypic assays for DNA damage, cell cycle, ROS levels and cell death, combined with a high-resolution untargeted LCMS metabolomics and RNA-Seq. RESULTS: Serine and glycine restriction sensitised a range of cancer cell lines, patient-derived organoids and syngeneic mouse tumour models to radiotherapy. Comprehensive metabolomic and transcriptomic analysis of central carbon metabolism revealed that amino acid restriction impacted not only antioxidant response and nucleotide synthesis but had a marked inhibitory effect on the TCA cycle. CONCLUSION: Dietary restriction of serine and glycine is a viable radio-sensitisation strategy in cancer.

Diagnosis and surgical intervention of acute appendicitis secondary to enterobius vermicularis: case report.

Acute appendicitis is the most common cause of acute abdominal pain in the pediatric population. The physiopathology is secondary to luminal obstruction of the appendix by several causes, among these, one of the rarest is due to parasitosis by Enterobius vermicularis in 0.005-3 %. We hereby present a case of a 10-year-old Latin male with abdominal pain with irradiation to right iliac fossa, nausea, vomiting and fever, following the national Mexican guides for ultrasound and blood tests were ordered, patient was treated with laparoscopic appendectomy with intraoperative finding of live helminths, which pathology examination revealed to be Enterovirus vermicularis. The patient has an uneventful postoperative course and was discharged after completing antiparasitic therapy. The lessons from this case are the importance of a good and quick diagnosis for acute abdomen in children, the possibility of a parasitic entity in the finding of eosinophilia with appendicitis and the good results with the correct surgical treatment.

SHMT2-mediated mitochondrial serine metabolism drives 5-FU resistance by fueling nucleotide biosynthesis.

5-Fluorouracil (5-FU) is a key component of chemotherapy for colorectal cancer (CRC). 5-FU efficacy is established by intracellular levels of folate cofactors and DNA damage repair strategies. However, drug resistance still represents a major challenge. Here, we report that alterations in serine metabolism affect 5-FU sensitivity in in vitro and in vivo CRC models. In particular, 5-FU-resistant CRC cells display a strong serine dependency achieved either by upregulating endogenous serine synthesis or increasing exogenous serine uptake. Importantly, regardless of the serine feeder strategy, serine hydroxymethyltransferase-2 (SHMT2)-driven compartmentalization of one-carbon metabolism inside the mitochondria represents a specific adaptation of resistant cells to support purine biosynthesis and potentiate DNA damage response. Interfering with serine availability or affecting its mitochondrial metabolism revert 5-FU resistance. These data disclose a relevant mechanism of mitochondrial serine use supporting 5-FU resistance in CRC and provide perspectives for therapeutic approaches.

Mitochondrial ROS signalling requires uninterrupted electron flow and is lost during ageing in flies.

Mitochondrial reactive oxygen species (mtROS) are cellular messengers essential for cellular homeostasis. In response to stress, reverse electron transport (RET) through respiratory complex I generates high levels of mtROS. Suppression of ROS production via RET (ROS-RET) reduces survival under stress, while activation of ROS-RET extends lifespan in basal conditions. Here, we demonstrate that ROS-RET signalling requires increased electron entry and uninterrupted electron flow through the electron transport chain (ETC). We find that in old fruit flies, ROS-RET is abolished when electron flux is decreased and that their mitochondria produce consistently high levels of mtROS. Finally, we demonstrate that in young flies, limiting electron exit, but not entry, from the ETC phenocopies mtROS generation observed in old individuals. Our results elucidate the mechanism by which ROS signalling is lost during ageing.

SARS-CoV-2 Drive/Walk-Thru screening centers in Colombia: The CoVIDA Project / Centros de tamizaje masivo para SARS COV-2 en Colombia: Proyecto CoVIDA

Abstract Objective: The CoVIDA project is a public-private collaboration led by Universidad de los Andes that contributed to the SARS-CoV-2 epidemiological surveillance in Bogotá and nearby municipalities. We aimed to describe the development and performance of the Drive/Walk-through free RT- PCR for SARS-CoV-2 testing strategy implemented by CoVIDA. Material and method: We performed a descriptive analysis of the characteristics and performance of the CoVIDA Drive/Walk-through testing centers. The model and the process indicators to assess the model's performance were based on international experiences and scientific literature. Two screening centers were imple mented in shopping centers in the north and south of Bogotá. We reported the number of tests taken, the number of positive tests, and the number of participants that used the model by the type of occupations. Results: In total, 36,689 nasopharyngeal RT-PCR tests for SARS-CoV-2 were performed with a 5.75% cumulative positivity. Process indicators showed an excellent performance and an important contribution in reducing barriers to access to testing. Conclusions: the CoVIDA Drive/Walk-through testing centers supported the epidemiological surveillance in asymptomatic or mild-symptomatic population in Bo gotá. Low and middle-income countries can use this model as a cost-effective and innovative solution strategy to intensify testing and help mitigate the pandemic.

Resumen Objetivo: El proyecto CoVIDA es una colaboración público-privada liderada por la Universidad de los Andes que contribuyó a la vigilancia epidemiológica del SARS-CoV-2 en Bogotá y municipios cercanos. Nuestro objetivo fue describir el desarrollo y rendimiento de la estrategia de tamizaje gratuito con RT-PCR mediante un modelo Drive/Walk through para SARS-CoV-2 implementado por CoVIDA. Materiales y métodos: Realizamos un análisis descriptivo de las características y desempeño de los centros de tamizaje Drive/Walk through de CoVIDA. El modelo y los indicadores de proceso para evaluar el desempeño del modelo se basaron en experiencias internacionales y la literatura científica. Se implementaron dos cen tros de tamizaje en centros comerciales del norte y sur de Bogotá. Se reportó la cantidad de pruebas tomadas, pruebas positivas y de participantes que utilizaron el modelo de acuerdo con el tipo de ocupaciones. Resultados : En total, se realizaron 36,689 pruebas RT-PCR nasofaríngeas para SARS-CoV-2 con una positividad acumulada del 5,75%. Los indicadores de proceso mostraron un excelente desempeño y una contribución importante en la reducción de las barreras de acceso a las pruebas. Conclusiones: los centros de tamizaje con modelo Drive/Walk through de CoVIDA apoyaron la vigilancia epidemiológica en población asintomática o con síntomas leves en Bogotá. Los países de ingresos bajos y medianos pueden utilizar este modelo como una estrategia innovadora y rentable para aumentar la realización de las pruebas y ayudar a mitigar la pandemia.

Caracterización del funcionamiento de los servicios de cirugía cardiovascular en Colombia durante la pandemia de COVID-19 / Performance of cardiovascular surgery services in Colombia during the COVID-19 pandemic

Resumen Introducción: La pandemia actual representa un reto para la atención hospitalaria, los servicios de cirugía cardiovascular han modificado su funcionamiento y están constantemente evaluando el riesgo cardiovascular frente al riesgo de la COVID-19. Objetivo: Caracterizar el funcionamiento de 23 centros cardiovasculares de Colombia, con el fin de generar información que permita optimizar los servicios y evitar muertes de causa cardiovascular prevenibles. Método: Estudio observacional transversal con fuente primaria de información. Muestra por conveniencia de 23 centros cardiovasculares de Colombia. Resultados: Se encontró que el 39.1% de los centros suspendieron la actividad en algún momento entre enero y mayo de 2020 y el 34.8% han tenido una disminución en la actividad del servicio del 76-100%; en los meses de abril y mayo se encontró una reducción de alrededor del 50% con referencia a los primeros 2 meses. De las 2258 intervenciones realizadas, solo el 0.17% fueron en pacientes con COVID-19. El estudio muestra que el 60.1% de los servicios han presentado problemas con la utilización de elementos de protección personal. El 17.4% de los centros realizan reacción en cadena de la polimerasa para el virus de forma sistemática en el prequirúrgico, y el 44% la realiza a pacientes con síntomas respiratorios. Conclusiones: Durante la pandemia se requiere una detección temprana de posibles infectados que vayan a cirugía, adaptar la programación y promocionar un adecuado uso de los equipos de protección personal. Urge aplicar estrategias dirigidas a pacientes que no pueden ser postergados para evitar segundas y terceras víctimas de la pandemia.

Abstract Introduction: The current pandemic represents a challenge at the hospital level, cardiovascular surgery services have modified their operation and are constantly evaluating cardiovascular risk vs. COVID-19 risk. Objective: To characterize the operation of 23 cardiovascular centers in Colombia, in order to obtain information that allows the optimization of services and to avoid preventable deaths from cardiovascular causes. Method: Cross sectional observational study with a primary source of information. A convenience sample of 23 cardiovascular centers in Colombia was used. Results: It was found that 39.1% of the centers suspended activity sometime between January to May 2020 and 34.8% had a decrease in service activity of 76-100%. In the months of April and May the reduction was around 50% compared to the first two months. Of the 2,258 interventions performed, only 0.17% were on positive COVID-19 patients. The study shows that 60.1% of the services have presented problems with the use of personal protection elements. 17.4% of the centers perform PCR to detect the virus in the preoperative routine, 44% perform it in respiratory symptomatic patients. Conclusions: During the pandemic, the need is to detect in early phases all the possible infected patients, that require surgical procedures, adapt the schedules and promote an adequate use of personal protective equipment. It is urgent to apply strategies aimed at patients in which surgical procedures cannot be postponed to avoid second and third victims of the pandemic.

Factors Associated With SARS-CoV-2 Infection in Bogotá, Colombia: Results From a Large Epidemiological Surveillance Study.

BACKGROUND: Epidemiologic surveillance of COVID-19 is essential to collect and analyse data to improve public health decision making during the pandemic. There are few initiatives led by public-private alliances in Colombia and Latin America. The CoVIDA project contributed with RT-PCR tests for SARS-CoV-2 in mild or asymptomatic populations in Bogotá. The present study aimed to determine the factors associated with SARS-CoV-2 infection in working adults. METHODS: COVID-19 intensified sentinel epidemiological surveillance study, from April 18, 2020, to March 29, 2021. The study included people aged 18 years or older without a history of COVID-19. Two main occupational groups were included: healthcare and essential services workers with high mobility in the city. Social, demographic, and health-related factors were collected via phone survey. Afterwards, the molecular test was conducted to detect SARS-CoV-2 infection. FINDINGS: From the 58,638 participants included in the study, 3,310 (5·6%) had a positive result. A positive result was associated with the age group (18-29 years) compared with participants aged 60 or older, participants living with more than three cohabitants, living with a confirmed case, having no affiliation to the health system compared to those with social health security, reporting a very low socioeconomic status compared to those with higher socioeconomic status, and having essential occupations compared to healthcare workers. INTERPRETATION: The CoVIDA study showed the importance of intensified epidemiological surveillance to identify groups with increased risk of infection. These groups should be prioritised in the screening, contact tracing, and vaccination strategies to mitigate the pandemic. FUNDING: The CoVIDA study was funded through donors managed by the philanthropy department of Universidad de los Andes.

Immune-regulated IDO1-dependent tryptophan metabolism is source of one-carbon units for pancreatic cancer and stellate cells.

Cancer cells adapt their metabolism to support elevated energetic and anabolic demands of proliferation. Folate-dependent one-carbon metabolism is a critical metabolic process underpinning cellular proliferation supplying carbons for the synthesis of nucleotides incorporated into DNA and RNA. Recent research has focused on the nutrients that supply one-carbons to the folate cycle, particularly serine. Tryptophan is a theoretical source of one-carbon units through metabolism by IDO1, an enzyme intensively investigated in the context of tumor immune evasion. Using in vitro and in vivo pancreatic cancer models, we show that IDO1 expression is highly context dependent, influenced by attachment-independent growth and the canonical activator IFNγ. In IDO1-expressing cancer cells, tryptophan is a bona fide one-carbon donor for purine nucleotide synthesis in vitro and in vivo. Furthermore, we show that cancer cells release tryptophan-derived formate, which can be used by pancreatic stellate cells to support purine nucleotide synthesis.

Perfil clínico, epidemiológico y descripción de los resultados de la Tomografía ósea computarizada con emisión simple de fotones (SPECT) en pacientes con dolor de cuello y espalda. Estudio de cohorte transversal / Clinical and epidemiological profile and description of the results of bone single photon emission computed tomography (SPECT) in patients with neck and back pain: Cross-sectional study

Introducción La tomografía ósea computarizada (TAC) con emisión simple de fotones (SPECT: single photon emission computed tomography) es una herramienta diagnóstica importante en los pacientes con dolor de cuello y espalda. Es una prueba funcional que se adelanta a los cambios estructurales en algunas patologías de columna. El objetivo del estudio es definir el perfil epidemiológico de pacientes con dolor axial crónico y/o subagudo en la columna vertebral. Materiales y Métodos Serie de casos cuyo objetivo general es presentar las características clínicas y sociodemográficas, así como los resultados de TAC con SPECT de los pacientes que consultaron al Hospital en un periodo de tiempo con diagnóstico de dolor de cuello o espalda y se les solicitó dicho examen. Resultados 77 pacientes cumplieron los criterios de inclusión, La mediana para la edad fue de 48 años, 57.1% eran hombres y 42.9% mujeres. 57 pacientes tenían localización única del dolor (74%) y 20 pacientes tenían localización múltiple (26%), los segmentos afectados fueron 57 lumbar (74%), cervical 15 (19.5%) y sacro 1 (1.3%). La impresión diagnóstica preexamen más común fue enfermedad facetaría en 25 casos para un 32.5%. En cuanto a los resultados del SPECT el radiofármaco captó en 48 ocasiones (62.3%) y los sitios en que captó el radiofármaco se distribuyeron así: facetas 13 (16.9%), cuerpo vertebral 28 (36.4%), Pars Interarticularis 3 (3.8%), disco intervertebral 1 (1.3%), 3 (3.8%) captaron en sitios diferentes al raquis, El índice de concordancia diagnóstica luego del SPECT se dio en 33 casos (42.85%). Discusión La mayoría de las gammagrafías con captación fueron en los cuerpos vertebrales, en el contexto de nuestro hospital como centro de trauma y que muchos de los pacientes tenían dolor secundario a accidentes de tránsito o accidentes laborales, se correlacionan con microfracturas o contusiones óseas. La gammagrafía con SPECT sigue siendo una prueba funcional que nos puede ayudar en el diagnóstico, pronóstico y enfoque terapéutico de los pacientes con dolor raquídeo axial en sus diferentes estadios.

Background SPECT bone scan with is an important diagnostic tool in patients with neck and back pain. It is a functional test that anticipates structural changes in some spinal pathologies. Aim of study is to define the epidemiological profile of patients with chronic and/or subacute axial spine pain. Methods A retrospective descriptive study whose general objective is to present the clinical and sociodemographic characteristics, as well as the results of the SPECT scans of the patients who visited the Hospital in a period of time with a diagnosis of neck or back pain and were requested such an examination. Results Seventy-seven patients met the inclusion criteria. The median age was 48 years, 57.1% were men and 42.9% were women. Fifty-seven patients had a single location of pain (74%) and 20 patients had multiple location (26%), the affected segments were 57 lumbar (74%), cervical 15 (19.5%) and sacrum 1 (1.3%). The most common pre-examination diagnostic impression was facet disease in 25 cases for 32.5%. Regarding the SPECT results, the radiopharmaceutical captured on 48 occasions (62.3%) and the sites where it captured the radiopharmaceutical were distributed as follows: facets 13 (16.9%), vertebral body 28 (36.4%), pars interarticularis 3 (3.8%).), intervertebral disc 1 (1.3%), 3 (3.8%) captured in sites other than the spine. The diagnostic concordance index after SPECT occurred in 33 cases (42.85%). Discussion Most of the uptake scans were in the vertebral bodies, beneath the context of our hospital, as a trauma center, and that many of the patients had pain secondary to traffic accidents or work behavior accidents, they are correlated with micro-fractures or bone contusions. SPECT scintigraphy continues to be a functional test that can help us in the diagnosis, prognosis and therapeutic approach of patients with axial spinal pain in its different stages.

Polyamine pathway activity promotes cysteine essentiality in cancer cells.

Cancer cells have high demands for non-essential amino acids (NEAAs), which are precursors for anabolic and antioxidant pathways that support cell survival and proliferation. It is well-established that cancer cells consume the NEAA cysteine, and that cysteine deprivation can induce cell death; however, the specific factors governing acute sensitivity to cysteine starvation are poorly characterized. Here, we show that that neither expression of enzymes for cysteine synthesis nor availability of the primary precursor methionine correlated with acute sensitivity to cysteine starvation. We observed a strong correlation between efflux of the methionine-derived metabolite methylthioadenosine (MTA) and sensitivity to cysteine starvation. MTA efflux results from genetic deletion of methylthioadenosine phosphorylase (MTAP), which is frequently deleted in cancers. We show that MTAP loss upregulates polyamine metabolism which, concurrently with cysteine withdrawal, promotes elevated reactive oxygen species and prevents cell survival. Our results reveal an unexplored metabolic weakness at the intersection of polyamine and cysteine metabolism.