RESUMEN

Doublecortin-like kinase 1 (DCLK1) is a proposed driver of gastric cancer (GC) that phosphorylates serine and threonine residues. Here, we showed that the kinase activity of DCLK1 orchestrated cancer cell-intrinsic and-extrinsic processes that led to pro-invasive and pro-metastatic reprogramming of GC cells. Inhibition of the kinase activity of DCLK1 reduced the growth of subcutaneous xenograft tumors formed from MKN1 human gastric carcinoma cells in mice and decreased the abundance of the stromal markers α-Sma, vimentin, and collagen. Similar effects were seen in mice with xenograft tumors formed from MKN1 cells expressing a kinase-inactive DCLK1 mutant (MKN1D511N). MKN1D511N cells also had reduced in vitro migratory potential and stemness compared with control cells. Mice orthotopically grafted with MKN1 cells overexpressing DCLK1 (MKN1DCLK1) showed increased invasiveness and had a greater incidence of lung metastases compared with those grafted with control MKN1 cells. Mechanistically, we showed that the chemokine CXCL12 acted downstream of DCLK1 in cultured MKN1 cells and in mice subcutaneously implanted with gastric tumors formed by MKN1DCLK1 cells. Moreover, inhibition of the kinase activity of DCLK1 or the expression of DCLK1D511N reversed the pro-tumorigenic and pro-metastatic phenotype. Together, this study establishes DCLK1 as a broadly acting and potentially targetable promoter of GC.

Asunto(s)

Progresión de la Enfermedad , Quinasas Similares a Doblecortina , Péptidos y Proteínas de Señalización Intracelular , Fenotipo , Proteínas Serina-Treonina Quinasas , Neoplasias Gástricas , Quinasas Similares a Doblecortina/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Neoplasias Gástricas/metabolismo , Animales , Humanos , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Línea Celular Tumoral , Movimiento Celular/genética , Carcinogénesis/genética , Carcinogénesis/metabolismo

RESUMEN

Nipple adenomas are rare, benign breast lesions that present similarly to breast malignancies, often manifesting with unilateral bloody discharge, a palpable mass, and/or nipple distortion. Imaging techniques have limited specificity in distinguishing nipple adenomas from malignancy; therefore, clinicians must rely on histologic and immunohistochemistry evaluation. Here, we highlight the case of a 69-year-old woman with bilateral nipple adenomas presenting as an enlarging nipple mass with chronic nipple discharge. Complete lesion resection with clear margins stands as the primary route of management and complete avoidance of re-occurrence. However, partial excision with nipple preservation has been reported to be successful in selected cases.

RESUMEN

With a renewed focus on health equity in the United States driven by national crises and legislation to improve digital healthcare innovation, there is a need for the designers of digital health tools to take deliberate steps to design for equity in their work. A concrete toolkit of methods to design for health equity is needed to support digital health practitioners in this aim. This narrative review summarizes several health equity frameworks to help digital health practitioners conceptualize the equity dimensions of importance for their work, and then provides design approaches that accommodate an equity focus. Specifically, the Double Diamond Model, the IDEAS framework and toolkit, and community collaboration techniques such as participatory design are explored as mechanisms for practitioners to solicit input from members of underserved groups and better design digital health tools that serve their needs. Each of these design methods requires a deliberate effort by practitioners to infuse health equity into the approach. A series of case studies that use different methods to build in equity considerations are offered to provide examples of how this can be accomplished and demonstrate the range of applications available depending on resources, budget, product maturity, and other factors. We conclude with a call for shared rigor around designing digital health tools that deliver equitable outcomes for members of underserved populations.

RESUMEN

The potential and threat of digital tools to achieve health equity has been highlighted for over a decade, but the success of achieving equitable access to health technologies remains challenging. Our paper addresses renewed concerns regarding equity in digital health access that were deepened during the COVID-19 pandemic. Our viewpoint is that (1) digital health tools have the potential to improve health equity if equitable access is achieved, and (2) improving access and equity in digital health can be strengthened by considering behavioral science-based strategies embedded in all phases of tool development. Using behavioral, equity, and access frameworks allowed for a unique and comprehensive exploration of current drivers of digital health inequities. This paper aims to present a compilation of strategies that can potentially have an actionable impact on digital health equity. Multilevel factors drive unequal access, so strategies require action from tool developers, individual delivery agents, organizations, and systems to effect change. Strategies were shaped with a behavioral medicine focus as the field has a unique role in improving digital health access; arguably, all digital tools require the user (individual, provider, and health system) to change behavior by engaging with the technology to generate impact. This paper presents a model that emphasizes using multilevel strategies across design, delivery, dissemination, and sustainment stages to advance digital health access and foster health equity.

Asunto(s)

COVID-19 , Equidad en Salud , Accesibilidad a los Servicios de Salud , Telemedicina , Humanos , COVID-19/epidemiología , Pandemias , SARS-CoV-2 , Tecnología Digital , Salud Digital

RESUMEN

Cell fate specification occurs along invariant species-specific trajectories that define the animal body plan. This process is controlled by gene regulatory networks that regulate the expression of the limited set of transcription factors encoded in animal genomes. Here we globally assess the spatial expression of ~90% of expressed transcription factors during sea urchin development from embryo to larva to determine the activity of gene regulatory networks and their regulatory states during cell fate specification. We show that >200 embryonically expressed transcription factors together define >70 cell fates that recapitulate the morphological and functional organization of this organism. Most cell fate-specific regulatory states consist of ~15-40 transcription factors with similarity particularly among functionally related cell types regardless of developmental origin. Temporally, regulatory states change continuously during development, indicating that progressive changes in regulatory circuit activity determine cell fate specification. We conclude that the combinatorial expression of transcription factors provides molecular definitions that suffice for the unique specification of cell states in time and space during embryogenesis.

Asunto(s)

Embrión no Mamífero , Desarrollo Embrionario , Regulación del Desarrollo de la Expresión Génica , Redes Reguladoras de Genes , Factores de Transcripción , Animales , Desarrollo Embrionario/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Embrión no Mamífero/metabolismo , Linaje de la Célula/genética , Erizos de Mar/embriología , Erizos de Mar/genética , Erizos de Mar/metabolismo , Diferenciación Celular/genética , Larva/metabolismo , Larva/genética , Larva/crecimiento & desarrollo

RESUMEN

More than 10 million people suffer from lung diseases caused by the pathogenic fungus Aspergillus fumigatus. Azole antifungals represent first-line therapeutics for most of these infections but resistance is rising, therefore the identification of antifungal targets whose inhibition synergises with the azoles could improve therapeutic outcomes. Here, we generate a library of 111 genetically barcoded null mutants of Aspergillus fumigatus in genes encoding protein kinases, and show that loss of function of kinase YakA results in hypersensitivity to the azoles and reduced pathogenicity. YakA is an orthologue of Candida albicans Yak1, a TOR signalling pathway kinase involved in modulation of stress responsive transcriptional regulators. We show that YakA has been repurposed in A. fumigatus to regulate blocking of the septal pore upon exposure to stress. Loss of YakA function reduces the ability of A. fumigatus to penetrate solid media and to grow in mouse lung tissue. We also show that 1-ethoxycarbonyl-beta-carboline (1-ECBC), a compound previously shown to inhibit C. albicans Yak1, prevents stress-mediated septal spore blocking and synergises with the azoles to inhibit A. fumigatus growth.

Asunto(s)

Antifúngicos , Aspergillus fumigatus , Quinasas DyrK , Proteínas Fúngicas , Proteínas Serina-Treonina Quinasas , Proteínas Tirosina Quinasas , Aspergillus fumigatus/genética , Aspergillus fumigatus/efectos de los fármacos , Aspergillus fumigatus/enzimología , Animales , Antifúngicos/farmacología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/antagonistas & inhibidores , Ratones , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Azoles/farmacología , Aspergilosis/microbiología , Aspergilosis/tratamiento farmacológico , Pulmón/microbiología , Esporas Fúngicas/efectos de los fármacos , Esporas Fúngicas/genética , Femenino

RESUMEN

There are two known mechanisms by which natural killer (NK) cells recognize and kill diseased targets: (i) direct killing and (ii) antibody-dependent cell-mediated cytotoxicity (ADCC). We investigated an indirect NK cell activation strategy for the enhancement of human NK cell killing function. We did this by leveraging the fact that toll-like receptor 9 (TLR9) agonism within pools of human peripheral blood mononuclear cells (PBMCs) results in a robust interferon signaling cascade that leads to NK cell activation. After TLR9 agonist stimulation, NK cells were enriched and incorporated into assays to assess their ability to kill tumor cell line targets. Notably, differential impacts of TLR9 agonism were observed-direct killing was enhanced while ADCC was not increased. To ensure that the observed differential effects were not attributable to differences between human donors, we recapitulated the observation using our Natural Killer-Simultaneous ADCC and Direct Killing Assay (NK-SADKA) that controls for human-to-human differences. Next, we observed a treatment-induced decrease in NK cell surface CD16-known to be shed by NK cells post-activation. Given the essential role of CD16 in ADCC, such shedding could account for the observed differential impact of TLR9 agonism on NK cell-mediated killing capacity.

Asunto(s)

Citotoxicidad Celular Dependiente de Anticuerpos , Células Asesinas Naturales , Receptor Toll-Like 9 , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/metabolismo , Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Receptor Toll-Like 9/agonistas , Receptor Toll-Like 9/metabolismo , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/efectos de los fármacos , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Receptores de IgG/metabolismo , Receptores de IgG/inmunología , Línea Celular Tumoral , Citotoxicidad Inmunológica/efectos de los fármacos

RESUMEN

The aim of this study was to evaluate the circadian and seasonal variation of Ageratum conyzoides essential oil (EO) and its nematicidal effect on the free-living nematode Caenorhabditis elegans as a model for parasitic helminths. For the seasonal study, the plants were collected from January to December 2022, at 6 a.m., and to assess the circadian rhythm, the plants were collected in April (rainy season) and October (dry season), at 6, 9, 12 a.m. and 3 and 6 p.m. The fresh plants were then subjected to hydrodistillation, and their chemical composition was analyzed using gas chromatography coupled with mass spectrometry (GC-MS). The motility test with C. elegans was carried out. The primary constituent of the oils was precocene I (65.97 to 78.42 %, respectively), followed by E-caryophyllene (6.04 to 12.16 %), comprising an average of 79.87 % of the composition throughout the year. The average yields of EOs were slightly higher in the rainy season, at 0.68 %, compared to the dry season, at 0.62 %. High light hours in the rainy season (12 a.m., 0.96 %) and in the dry season (9 a.m., 0.88 %) seem to contribute to higher daily oil yields. It was observed that the variation between the main constituents of A. conyzoides occurs in inverse proportion when analyzing the main classes of compounds present in the oils: chromenes (CH) and sesquiterpene hydrocarbons (SH). And that the month of March had the highest content of E-caryophyllene (12.16 %) when compared to the other months of the year. On the other hand, January and December had the lowest levels of precocene I (65.97 and 66.85 %). The IC50 of the EO of A. conyzoides varied according to the month and time of collection. The EO obtained in January was the most effective against C. elegans, with an IC50 of 0.01 mg/mL. Thus, A. conyzoides EO could be an alternative for nematode control, exhibiting greater efficacy if extracted during specific seasonal periods.

Asunto(s)

Ageratum , Caenorhabditis elegans , Aceites Volátiles , Estaciones del Año , Animales , Aceites Volátiles/farmacología , Aceites Volátiles/química , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/fisiología , Ageratum/química , Antinematodos/farmacología , Antinematodos/química , Ritmo Circadiano/efectos de los fármacos , Cromatografía de Gases y Espectrometría de Masas

RESUMEN

The highly conserved angiosperm immune receptor HOPZ-ACTIVATED RESISTANCE 1 (ZAR1) is a bacterial pathogen recognition hub that mediates resistance by guarding host kinases for modification by pathogen effectors. The pseudokinase HOPZ-ETI DEFICIENT 1 (ZED1) is the only known ZAR1-guarded protein that interacts directly with a pathogen effector, HopZ1a, from the bacterial pathogen Pseudomonas syringae, making it a promising system for rational design of effector recognition for plant immunity. Here, we conducted an in-depth molecular analysis of ZED1. We generated a library of 164 random ZED1 mutants and identified 50 mutants that could not recognize the effector HopZ1a when transiently expressed in Nicotiana benthamiana. Based on our random mutants, we generated a library of 27 point mutants and found evidence of minor functional divergence between Arabidopsis (Arabidopsis thaliana) and N. benthamiana ZAR1 orthologs. We leveraged our point mutant library to identify regions in ZED1 critical for ZAR1 and HopZ1a interactions and identified two likely ZED1-HopZ1a binding conformations. We explored ZED1 nucleotide and cation binding activity and showed that ZED1 is a catalytically dead pseudokinase, functioning solely as an allosteric regulator upon effector recognition. We used our library of ZED1 point mutants to identify the ZED1 activation loop regions as the most likely cause of interspecies ZAR1-ZED1 incompatibility. Finally, we identified a mutation that abolished ZAR1-ZED1 interspecies incompatibility while retaining the ability to mediate HopZ1a recognition, which enabled recognition of HopZ1a through tomato (Solanum lycopersicum) ZAR1. This provides an example of expanded effector recognition through a ZAR1 ortholog from a non-model species.

Asunto(s)

Arabidopsis , Inmunidad de la Planta , Pseudomonas syringae , Solanum lycopersicum , Solanum lycopersicum/genética , Solanum lycopersicum/microbiología , Solanum lycopersicum/inmunología , Solanum lycopersicum/enzimología , Solanum lycopersicum/metabolismo , Pseudomonas syringae/patogenicidad , Arabidopsis/genética , Arabidopsis/inmunología , Arabidopsis/metabolismo , Inmunidad de la Planta/genética , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Nicotiana/genética , Nicotiana/microbiología , Nicotiana/inmunología , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/química , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/inmunología , Enfermedades de las Plantas/genética , Mutación/genética , Fosfotransferasas , Péptidos y Proteínas de Señalización Intracelular

RESUMEN

BACKGROUND: Cancer cachexia is a life-threatening, inflammation-driven wasting syndrome that remains untreatable. Adiponectin, the most abundant adipokine, plays an important role in several metabolic processes as well as in inflammation modulation. Our aim was to test whether administration of AdipoRon (AR), a synthetic agonist of the adiponectin receptors, prevents the development of cancer cachexia and its related muscle atrophy. METHODS: The effect of AR on cancer cachexia was investigated in two distinct murine models of colorectal cancer. First, 7-week-old CD2F1 male mice were subcutaneously injected with colon-26 carcinoma cells (C26) or vehicle (CT). Six days after injection, mice were treated for 5 days with AdipoRon (50 mg/kg/day; C26 + AR) or the corresponding vehicle (CT and C26). Additionally, a genetic model, the ApcMin/+ mouse, that develops spontaneously numerous intestinal polyps, was used. Eight-week-old male ApcMin/+ mice were treated with AdipoRon (50 mg/kg/day; Apc + AR) or the corresponding vehicle (Apc) over a period of 12 weeks, with C57BL/6J wild-type mice used as controls. In both models, several parameters were assessed in vivo: body weight, grip strength and serum parameters, as well as ex vivo: molecular changes in muscle, fat and liver. RESULTS: The protective effect of AR on cachexia development was observed in both cachectic C26 and ApcMin/+ mice. In these mice, AR administration led to a significant alleviation of body weight loss and muscle wasting, together with rescued muscle strength (P < 0.05 for all). In both models, AR had a strong anti-inflammatory effect, reflected by lower systemic interleukin-6 levels (-55% vs. C26, P < 0.001 and -80% vs. Apc mice, P < 0.05), reduced muscular inflammation as indicated by lower levels of Socs3, phospho-STAT3 and Serpina3n, an acute phase reactant (P < 0.05 for all). In addition, AR blunted circulating levels of corticosterone (-46% vs. C26 mice, P < 0.001 and -60% vs. Apc mice, P < 0.05), the predominant murine glucocorticoid known to induce muscle atrophy. Accordingly, key glucocorticoid-responsive factors implicated in atrophy programmes were-or tended to be-significantly blunted in skeletal muscle by AR. Finally, AR protected against lipid metabolism alterations observed in ApcMin/+ mice, as it mitigated the increase in circulating triglyceride levels (-38%, P < 0.05) by attenuating hepatic triglyceride synthesis and fatty acid uptake by the liver. CONCLUSIONS: Altogether, these results show that AdipoRon rescued the cachectic phenotype by alleviating body weight loss and muscle atrophy, along with restraining inflammation and hypercorticism in preclinical murine models. Therefore, AdipoRon could represent an innovative therapeutic strategy to counteract cancer cachexia.

Asunto(s)

Caquexia , Inflamación , Receptores de Adiponectina , Animales , Caquexia/etiología , Caquexia/tratamiento farmacológico , Caquexia/metabolismo , Ratones , Receptores de Adiponectina/agonistas , Receptores de Adiponectina/metabolismo , Masculino , Inflamación/tratamiento farmacológico , Modelos Animales de Enfermedad , Línea Celular Tumoral , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Piperidinas

RESUMEN

EphB6 is an understudied ephrin receptor tyrosine pseudokinase that is downregulated in multiple types of metastatic cancers. Unlike its kinase-active counterparts which autophosphorylate and transmit signals upon intercellular interaction, little is known about how EphB6 functions in the absence of intrinsic kinase activity. Here, we unveil a molecular mechanism of cell-cell interaction driven by EphB6. We identify ephrinB1 as a cognate ligand of EphB6 and show that in trans interaction of EphB6 with ephrinB1 on neighboring cells leads to the formation of large co-clusters at the plasma membrane. These co-clusters exhibit a decreased propensity towards endocytosis, suggesting a unique characteristic for this type of cell-cell interaction. Using lattice light-sheet microscopy, 3D structured illumination microscopy and cryo-electron tomography techniques, we show that co-clustering of EphB6 and ephrinB1 promotes the formation of double-membrane tubular structures between cells. Importantly, we also demonstrate that these intercellular structures stabilize cell-cell adhesion, leading to a reduction in the invasive behavior of cancer cells. Our findings rationalize a role for EphB6 pseudokinase as a tumor suppressor when interacting with its ligands in trans.

Asunto(s)

Fosforilación , Invasividad Neoplásica

RESUMEN

Motivated by the implementation of a SARS-Cov-2 sewer surveillance system in Chile during the COVID-19 pandemic, we propose a set of mathematical and algorithmic tools that aim to identify the location of an outbreak under uncertainty in the network structure. Given an upper bound on the number of samples we can take on any given day, our framework allows us to detect an unknown infected node by adaptively sampling different network nodes on different days. Crucially, despite the uncertainty of the network, the method allows univocal detection of the infected node, albeit at an extra cost in time. This framework relies on a specific and well-chosen strategy that defines new nodes to test sequentially, with a heuristic that balances the granularity of the information obtained from the samples. We extensively tested our model in real and synthetic networks, showing that the uncertainty of the underlying graph only incurs a limited increase in the number of iterations, indicating that the methodology is applicable in practice.

Asunto(s)

COVID-19 , Pandemias , Humanos , Incertidumbre , COVID-19/epidemiología , Brotes de Enfermedades , SARS-CoV-2

RESUMEN

BACKGROUND: The broad concept of health as "the ability to adapt and self-manage in the face of social, physical and emotional challenges" has been operationalized by "Positive Health," a framework increasingly used in the Netherlands. We explored to what degree the impact of the COVID-19 pandemic and preventive measures on Positive Health differed between community-dwelling older adults without, with mild and with complex health problems, as well as differences flowing from their use of preventive measures. METHODS: During the second wave in the Netherlands (November 2020-February 2021), a convenience sample of adults aged ≥65 years completed an online questionnaire. Positive Health impact was measured based on self-reported change of current health status, across six dimensions, compared to before the pandemic (decreased/unchanged/increased). The complexity of health problems (past month) was assessed using the validated ISCOPE tool, comparing subgroups without, with mild or with complex health problems. High use of preventive measures was defined as ≥9 of 13 measures and compared to low use (<9 measures). RESULTS: Of the 2397 participants (median age 71 years, 60% female, and 4% previous COVID-19 infection), 31% experienced no health problems, 55% mild health problems, and 15% complex health problems. Overall, participants reported a median decrease in one Positive Health dimension (IQR 1-3), most commonly in social participation (68%). With an increasing complexity of health problems, subjective Positive Health declined more often across all six dimensions, ranging from 3.3% to 57% in those without, from 22% to 72% in those with mild, and from 47% to 75% in those with complex health problems (p-values for trend <0.001; independent of age and sex). High users of preventive measures more often experienced declined social participation (72% vs. 62%, p < 0.001) and a declined quality of life (36% vs. 30%, p = 0.007) than low users, especially those with complex health problems. CONCLUSION: As the complexity of health problems increased, the adverse impact of the COVID-19 pandemic and related preventive measures was experienced more frequently across all dimensions of Positive Health. Acknowledging this heterogeneity is pivotal to the effective targeting of prevention and healthcare to those most in need.

Asunto(s)

COVID-19 , Humanos , Femenino , Anciano , Masculino , COVID-19/epidemiología , Pandemias , Calidad de Vida , Autoevaluación Diagnóstica , Emociones

RESUMEN

BACKGROUND: Black patients are at a higher risk of experiencing less safe and lower quality care during pregnancy and childbirth, compared to their White counterparts. Behaviors that healthcare professionals engage in that can facilitate or hinder high-quality care for this population are underexplored. We sought to explore Black patients' experiences with healthcare professionals during and after pregnancy, as a needs assessment to inform the development of training for healthcare professionals. METHODS: We conducted semi-structured interviews of Black patients who were in their third trimester of pregnancy or within 18 months of giving birth. Questions focused on experiences with healthcare professionals during pregnancy-related healthcare, including quality of care and discrimination. Thematic analysis was conducted using a combined deductive-inductive approach. Findings were considered in the context of the Institute of Medicine's Six Domains of Quality (equitable, patient-centered, timely, safe, effective, efficient). RESULTS: We interviewed 8 participants who received care from various clinics and institutions. Over half (62%) described experiencing discrimination or microaggressions during their pregnancy-related healthcare. Participants most commonly reflected upon experiences within the patient-centered care domain, regarding whether care was in alignment with their preferences, positive and negative interpersonal interactions, and varied experiences with patient education/shared decision-making. CONCLUSIONS: Black patients commonly report experiencing discrimination from healthcare professionals during pregnancy-related healthcare. Reducing microaggressions and improving patient-centered care is a key focus for healthcare professionals who serve this group. Training needs include addressing implicit bias, educating on common microaggressions, improving communication, and promoting an inclusive workplace.

Asunto(s)

Población Negra , Instituciones de Salud , Femenino , Humanos , Embarazo , Evaluación de Necesidades , Relaciones Interpersonales , Calidad de la Atención de Salud

RESUMEN

Widespread use of azole antifungals in agriculture has been linked to resistance in the pathogenic fungus Aspergillus fumigatus. We show that exposure of A. fumigatus to the agrochemical fungicide, ipflufenoquin, in vitro can select for strains that are resistant to olorofim, a first-in-class clinical antifungal with the same mechanism of action. Resistance is caused by non-synonymous mutations within the target of ipflufenoquin/olorofim activity, dihydroorotate dehydrogenase (DHODH), and these variants have no overt growth defects.

Asunto(s)

Aspergillus fumigatus , Fungicidas Industriales , Aspergillus fumigatus/genética , Fungicidas Industriales/farmacología , Agroquímicos , Pirroles/farmacología , Antifúngicos/farmacología

RESUMEN

BACKGROUND: Fungal infections are common in HIV-infected individuals and significantly contribute to mortality. However, a substantial number of cases are undiagnosed before death. OBJECTIVE: To determine the frequency of fungal pathogens in autopsy studies of people who died with HIV in Africa. METHODS: We conducted a scoping review of autopsy studies conducted in Africa. DATA SOURCES: PubMed, Scopus, Web of Science, Embase, Google Scholar, and African Journal Online. STUDY ELIGIBILITY CRITERIA: The review encompasses studies published from inception to September 2023, and no language restrictions were imposed during the search process. We included studies that reported histopathological or microbiological evidence for the diagnosis of fungal infections and other pathogens. DATA SYNTHESIS: Data were summarized using descriptive statistics and no meta-analysis was performed. RESULTS: We examined 30 articles reporting studies conducted between 1991 and 2019, encompassing a total of 13 066 HIV-infected decedents across ten African countries. In five studies, the autopsy type was not specified. Among those studies with specified autopsy types, 20 involved complete diagnostic autopsies, whereas 5 were categorized as partial or minimally invasive autopsies. There were 2333 pathogens identified, with 946 (40.5%) being mycobacteria, 856 (36.7%) fungal, 231 (3.8%) viral, 208 (8.9%) parasitic, and 92 (3.9%) bacterial. Of the 856 fungal pathogens identified, 654 (28.0%) were Cryptococcus species, 167 (7.2%) Pneumocystis jirovecii, 16 (0.69%) Histoplasma species, 15 (0.64%) Aspergillus species, and 4 (0.17%) Candida species. Other major non-fungal pathogens identified were cytomegalovirus 172 (7.37%) and Toxoplasma gondii 173 (7.42%). CONCLUSIONS: Invasive fungal infections occur in over one-third of people who succumb to HIV in Africa. In addition to cryptococcosis and Pneumocystis jirovecii pneumonia, integrating other priority fungal pathogen detection and management strategies into the broader framework of HIV care in Africa is recommended. This involves increasing awareness regarding the impact of fungal infections in advanced HIV disease and strengthening diagnostic and treatment capacity.

Asunto(s)

Autopsia , Infecciones por VIH , Micosis , Humanos , África/epidemiología , Infecciones por VIH/complicaciones , Micosis/epidemiología , Micosis/microbiología , Micosis/mortalidad , Hongos/aislamiento & purificación , Hongos/clasificación , Infecciones Oportunistas Relacionadas con el SIDA/microbiología , Infecciones Oportunistas Relacionadas con el SIDA/mortalidad , Infecciones Oportunistas Relacionadas con el SIDA/epidemiología

RESUMEN

Alcohol-associated liver disease (ALD)-related morbidity and mortality are rising in the United States. Although effective medications and behavioral interventions are available for the treatment of patients with alcohol use disorder (AUD), patients with ALD are profoundly undertreated for AUD. This article reviews the management of AUD in patients with ALD, with a focus on appropriate screening and diagnosis, management of alcohol withdrawal syndrome, pharmacotherapy for AUD, alcohol biomarkers, and behavioral interventions. Expanding access to AUD treatment is imperative for improving health outcomes in patients with ALD.

Asunto(s)

Alcoholismo , Hepatopatías Alcohólicas , Síndrome de Abstinencia a Sustancias , Humanos , Estados Unidos , Alcoholismo/complicaciones , Alcoholismo/diagnóstico , Alcoholismo/terapia , Síndrome de Abstinencia a Sustancias/complicaciones , Hepatopatías Alcohólicas/complicaciones , Hepatopatías Alcohólicas/diagnóstico , Hepatopatías Alcohólicas/terapia , Consumo de Bebidas Alcohólicas , Etanol

RESUMEN

Assays to quantify natural killer (NK) cell killing efficacy have traditionally focused on assessing either direct killing or antibody dependent cell-mediated cytotoxicity (ADCC) independently. Due to the probability that immunotherapeutic interventions affect NK cell-mediated direct killing and NK cell-mediated ADCC differently, we developed an assay with the capacity to measure NK cell-mediated direct killing and ADCC simultaneously with cells from the same human donor. Specifically, this design allows for a single NK cell population to be split into several experimental conditions (e.g., direct killing, ADCC), thus controlling for potential confounders associated with human-to-human variation when assessing immunotherapy impacts. Our Natural Killer cell Simultaneous ADCC and Direct Killing Assay (NK-SADKA) allows researchers to reproducibly quantify both direct killing and ADCC by human NK cells. Furthermore, this optimized experimental design allows for concurrent analysis of the NK cells via flow cytometric immunophenotyping of NK cell populations which will facilitate the identification of relationships between NK cell phenotype and the subsequent killing potential. This assay will be valuable for assessing the broader impact(s) of immunotherapy strategies on both modes of NK cell killing.