Characterization of the bone marrow niche in patients with chronic myeloid leukemia identifies CXCL14 as a new therapeutic option.

Although tyrosine kinase inhibitors (TKIs) are effective in treating chronic myeloid leukemia (CML), they often fail to eradicate the leukemia-initiating stem cells (LSCs), causing disease persistence and relapse. Evidence indicates that LSC persistence may be because of bone marrow (BM) niche protection; however, little is known about the underlying mechanisms. Herein, we molecularly and functionally characterize BM niches in patients with CML at diagnosis and reveal the altered niche composition and function in these patients. Long-term culture initiating cell assay showed that the mesenchymal stem cells from patients with CML displayed an enhanced supporting capacity for normal and CML BM CD34+CD38- cells. Molecularly, RNA sequencing detected dysregulated cytokine and growth factor expression in the BM cellular niches of patients with CML. Among them, CXCL14 was lost in the BM cellular niches in contrast to its expression in healthy BM. Restoring CXCL14 significantly inhibited CML LSC maintenance and enhanced their response to imatinib in vitro, and CML engraftment in vivo in NSG-SGM3 mice. Importantly, CXCL14 treatment dramatically inhibited CML engraftment in patient-derived xenografted NSG-SGM3 mice, even to a greater degree than imatinib, and this inhibition persisted in patients with suboptimal TKI response. Mechanistically, CXCL14 upregulated inflammatory cytokine signaling but downregulated mTOR signaling and oxidative phosphorylation in CML LSCs. Together, we have discovered a suppressive role of CXCL14 in CML LSC growth. CXCL14 might offer a treatment option targeting CML LSCs.

Effects of Tofacitinib on Muscle Remodeling in Experimental Rheumatoid Sarcopenia.

Sarcopenia is a frequent comorbidity of rheumatoid arthritis (RA). Clinical trials have shown that JAK inhibitors (JAKi) produce an asymptomatic increase in serum creatine kinase (CK) in RA, suggesting an impact on muscle. We evaluated the effect of JAKi in muscle remodeling in an experimental RA model. Antigen-induced arthritis (experimental RA, e-RA) was performed in 14 rabbits. Seven rabbits received tofacitinib (TOFA, orally 10 mg/kg/day). Animals were euthanized one day after the last ovalbumin injection, and muscles were prepared for histology, RT-PCR, and WB. C-reactive protein (CRP) and Myostatin (MSTN) serum concentration were determined by ELISA. Creatine and creatine kinase (CK) were analyzed. An increase in body weight as well as tibialis anterior cross-sectional area and diameter was observed in e-RA+TOFA vs. e-RA. e-RA decreased type II fibers and increased the myonuclei number, with all reverted by TOFA. TOFA did not modify CRP levels, neither did MSTN. TOFA significantly reduced IL-6, atrogin-1, and MuRF-1 compared with e-RA. e-RA+TOFA showed higher CK and lower creatine levels compared with e-RA. No differences in PAX-7 were found, while TOFA prevented the increase in MyoD1 in e-RA. Our model reflects the features of rheumatoid sarcopenia in RA. JAKi increased muscle mass through attenuating IL-6/JAK/STAT activation, decreasing atrogenes, and restoring muscle differentiation markers. These data together with an increase in CK support the role of CK as a valuable marker of muscle gain following JAKi treatment.

Beta-3 adrenergic receptor overexpression reverses aortic stenosis-induced heart failure and restores balanced mitochondrial dynamics.

Aortic stenosis (AS) is associated with left ventricular (LV) hypertrophy and heart failure (HF). There is a lack of therapies able to prevent/revert AS-induced HF. Beta3 adrenergic receptor (ß3AR) signaling is beneficial in several forms of HF. Here, we studied the potential beneficial effect of ß3AR overexpression on AS-induced HF. Selective ß3AR stimulation had a positive inotropic effect. Transgenic mice constitutively overexpressing human ß3AR in the heart (c-hß3tg) were protected from the development of HF in response to induced AS, and against cardiomyocyte mitochondrial dysfunction (fragmented mitochondria with remodeled cristae and metabolic reprogramming featuring altered substrate use). Similar beneficial effects were observed in wild-type mice inoculated with adeno-associated virus (AAV9) inducing cardiac-specific overexpression of human ß3AR before AS induction. Moreover, AAV9-hß3AR injection into wild-type mice at late disease stages, when cardiac hypertrophy and metabolic reprogramming are already advanced, reversed the HF phenotype and restored balanced mitochondrial dynamics, demonstrating the potential of gene-therapy-mediated ß3AR overexpression in AS. Mice with cardiac specific ablation of Yme1l (cYKO), characterized by fragmented mitochondria, showed an increased mortality upon AS challenge. AAV9-hß3AR injection in these mice before AS induction reverted the fragmented mitochondria phenotype and rescued them from death. In conclusion, our results step out that ß3AR overexpression might have translational potential as a therapeutic strategy in AS-induced HF.

Eimeria aegoliusia n. sp. (Sporozoa: Eimeriidae) from the northern saw-whet owl Aegolius acadicus (Gmelin) (Strigiformes: Strigidae) in Mexico.

A new coccidian species (Chromista: Sporozoa: Eimeriidae) collected from the northern saw-whet owl Aegolius acadicus (Gmelin) is reported from Mexico. Eimeria aegoliusia n. sp. has subspherical oöcysts, with smooth, bi-layered wall. Micropyle and oöcyst residuum are both absent and a polar granule is present. To date, eight species of Eimeria Schneider, 1875 have been described from strigiform birds. Mean dimensions of sporulated oöcysts (23.7 × 22.4 µm) and sporocysts (12.8 × 8.3 µm) appear to be considerably smaller than those from other Eimeria spp. with owl definitive hosts: E. atheni Chauhan & Jain, 1979; E. megabubonis Upton, Campbell, Weigel & McKown, 1990; E. spenotytoi Carini, 1939; E. strigis Kutzer, 1963; and E. varia Upton, Campbell, Weigel & McKown. Dimensions of these sporulated oöcysts appear to be larger than those in E. bemricki Averbeck, Cooney, Guarnera, Redig & Stromberg, 1998. The presence of polar granules and their number allowed differentiation from E. bubonis Cawthorn & Stockdale, 1981 and E. nycteae Volf, Koudela & Modry, 1999. This is the first description of an eimeriid coccidian infecting A. acadicus.

Isospora toxostomai n. sp. (Apicomplexa: Eimeriidae) from the curved-billed thrasher Toxostoma curvirostre (Swainson) (Passeriformes: Mimidae) at the Central highlands of Mexico.

Isospora toxostomai n. sp. (Apicomplexa: Eimeriidae) is described based on material from the curved-billed thrasher Toxostoma curvirostre (Swainson) in the Central Highlands of Mexico. The new species possesses subspherical oöcysts, with a smooth, bi-layered wall. Sporulated oöcysts measure 22-25 × 21-24 (23.4 × 22.3) µm; length/width (L/W) ratio of 1.0-1.1 (1.1). Sporocysts are ellipsoidal, 15-17 × 10-11 (15.8 × 10.5); L/W ratio of 1.3-1.6 (1.5). Micropyle and oöcyst residuum are both absent, and a polar granule present (many fibrils). Mean dimensions of both sporulated oöcysts and sporocysts of I. toxostomai n. sp. appear to be considerably larger than those of Isospora mimusi Coelho, Berto, Neves, Oliveira Flausino & Lopes, 2011 from the tropical mockingbird Mimus gilvus (Vieilot) in Brazil. This is the second species of Isospora Schneider, 1881 infecting a host of the Mimidae in the Americas.

Isospora cardellinae n. sp. (Apicomplexa: Eimeriidae) from the red warbler Cardellina rubra (Swainson) (Passeriformes: Parulidae) in Mexico.

A new coccidian species (Protozoa: Apicomplexa: Eimeriidae) collected from the red warbler Cardellina rubra (Swainson) is reported from the Nevado de Toluca National Park, Mexico. Isospora cardellinae n. sp. has subspherical oöcysts, measuring on average 26.6 × 25.4 µm, with smooth, bi-layered wall, c.1.3 µm thick. Micropyle, oöcyst residuum, and polar granule are absent. Sporocysts are ovoidal, measuring on average 19.0 × 12.0 µm, with a knob-like Stieda body, a trapezoidal sub-Stieda body and sporocyst residuum composed of scattered spherules of different sizes. Sporozoites are vermiform with one refractile body and a nucleus. This is the fourth description of an isosporoid coccidian infecting a New World warbler.

Eimeria pileata n. sp. (Apicomplexa: Eimeriidae) from the rufous-capped brush finch Atlapetes pileatus Wagler (Passeriformes: Emberizidae) in Mexico.

A new coccidian species (Protista: Apicomplexa: Eimeriidae) collected from the rufous-capped brush finch Atlapetes pileatus Wagler in the Nevado de Toluca Natural Protected Area, Mexico. Oöcysts of Eimeria pileata n. sp. are ellipsoidal, measuring on average 16.5 × 14.1 µm, with a smooth, bi-layered wall. Micropyle and oöcyst residuum are absent, but a polar granule is present. Sporocysts are ellipsoidal, measuring on average 9.0 × 5.4 µm. Stieda and sub-Stieda bodies are both present. A sporocyst residuum is present as a compact mass of granules. This is the third description of an eimeriid coccidian infecting passerines.

Isospora celata n. sp. (Apicomplexa: Eimeriidae) from the orange-crowned warbler Oreothlypis celata (Say) (Passeriformes: Parulidae) in Mexico.

A new coccidian species (Protista: Apicomplexa: Eimeriidae) is described from the orange-crowned warbler Oreothlypis celata (Say) collected in the Nevado de Toluca National Park, Mexico at 3,000 metres above sea level. Isospora celata n. sp. has subspheroidal oöcysts, measuring 28.4 × 26.4 µm, with smooth, bi-layered wall c.1.2 µm thick. Micropyle and polar granule are absent, but oöcyst residuum is present as a compact mass. Sporocysts are ovoidal, 18.2 × 12.8 µm. Stieda body knob-like and sub-Stieda body irregular and barely discernible. Sporocyst residuum is composed of granules of different sizes. Sporozoites are vermiform with one refractile body and a nucleus. This is the third description of an isosporoid coccidian infecting a New World warbler.

MSC therapy ameliorates experimental gouty arthritis hinting an early COX-2 induction.

Objective: The specific effect of Adipose-Derived Mesenchymal Stem Cells (Ad-MSC) on acute joint inflammation, where the response mostly depends on innate immunity activation, remains elusive. The pathogenesis of gouty arthritis, characterized by the deposition of monosodium urate (MSU) crystals in the joints, associated to acute flares, has been associated to NLRP3 inflammasome activation and subsequent amplification of the inflammatory response. Our aim was to study the effect of human Ad-MSC administration in the clinical inflammatory response of rabbits after MSU injection, and the molecular mechanisms involved. Methods: Ad-MSC were administered by intraarterial route shortly after intraarticular MSU crystal injections. Joint and systemic inflammation was sequentially studied, and the mechanisms involved in NLRP3 inflammasome activation, and the synthesis of inflammatory mediators were assessed in the synovial membranes 72h after insult. Ad-MSC and THP-1-derived macrophages stimulated with MSU were co-cultured in transwell system. Results: A single systemic dose of Ad-MSC accelerated the resolution of local and systemic inflammatory response. In the synovial membrane, Ad-MSC promoted alternatively M2 macrophage presence, inhibiting NLRP3 inflammasome and inducing the production of anti-inflammatory cytokines, such as IL-10 or TGF-ß, and decreasing nuclear factor-κB activity. Ad-MSC induced a net anti-inflammatory balance in MSU-stimulated THP-1 cells, with a higher increase in IL-10 and IDO expression than that observed for IL-1ß and TNF. Conclusion: Our in vivo and in vitro results showed that a single systemic dose of Ad-MSC decrease the intensity and duration of the inflammatory response by an early local COX-2 upregulation and PGE2 release. Ad-MSCs suppressed NF-kB activity, NLRP3 inflammasome, and promoted the presence of M2 alternative macrophages in the synovium. Therefore, this therapeutic approach could be considered as a pharmacological alternative in patients with comorbidities that preclude conventional treatment.

Corrigendum: MSC therapy ameliorates experimental gouty arthritis hinting an early COX-2 induction.

[This corrects the article DOI: 10.3389/fimmu.2023.1193179.].

Purinergic System Signaling in Metainflammation-Associated Osteoarthritis.

Inflammation triggered by metabolic imbalance, also called metainflammation, is low-grade inflammation caused by the components involved in metabolic syndrome (MetS), including central obesity and impaired glucose tolerance. This phenomenon is mainly due to excess nutrients and energy, and it contributes to the pathogenesis of osteoarthritis (OA). OA is characterized by the progressive degeneration of articular cartilage, which suffers erosion and progressively becomes thinner. Purinergic signaling is involved in several physiological and pathological processes, such as cell proliferation in development and tissue regeneration, neurotransmission and inflammation. Adenosine and ATP receptors, and other members of the signaling pathway, such as AMP-activated protein kinase (AMPK), are involved in obesity, type 2 diabetes (T2D) and OA progression. In this review, we focus on purinergic regulation in osteoarthritic cartilage and how different components of MetS, such as obesity and T2D, modulate the purinergic system in OA. In that regard, we describe the critical role in this disease of receptors, such as adenosine A2A receptor (A2AR) and ATP P2X7 receptor. Finally, we also assess how nucleotides regulate the inflammasome in OA.

Validation of Musculoskeletal Ultrasound in the Assessment of Experimental Gout Synovitis.

The objective of this study was to validate musculoskeletal ultrasound (US) in a rabbit model of acute gout. Acute gout was induced by intra-articular injection of monosodium urate (MSU) crystals in 10 rabbits; the 3 controls received vehicle. Rabbit knees were assessed by B-mode and power Doppler (PD) US 24 and 72 h after injections. After 72 h, all rabbits were euthanized. US discriminated between the MSU-injected and control groups with respect to the different inflammatory findings at both at 24 and 72 h and for MSU crystal-related findings after 24 h of injection. US synovial thickening, intra-synovial power Doppler signal and global joint distension significantly correlated with the synovial global histopathological score (r = 0.47, p = 0.0188), tissue vascularization measured by CD31 immunohistochemical-positive staining (r = 0.46, p = 0.0172) and tissue levels of interleukin-1ß (r = 0.53, p = 0.0078), respectively. US is a valid method for assessment of synovial inflammation in experimental gouty arthritis in rabbits.

Eimeria atlapetesi nom. nov., a replacement name for Eimeria pileata Soriano-Vargas et al., 2015 (Apicomplexa: Eimeriidae), preoccupied by Eimeria pileata Straneva and Kelley, 1979 (Apicomplexa: Eimeriidae), with observations on histopathology and phylogenetic analysis.

Eimeria pileata Soriano-Vargas, Medina, Salgado-Miranda, García-Conejo, Galindo-Sánchez, Janczur, Berto and Lopes, 2015 is a junior homonym of Eimeria pileata Straneva and Kelley, 1979 and needs to be replaced. This coccidium was described from a rufous-capped brush finch Atlapetes pileatus Wagler in the Nevado de Toluca Natural Protected Area, Mexico. Thus, to maintain the original intent of the specific epithet derived from the scientific name of the type-host, the name Eimeria atlapetesi nom. nov. is proposed as a replacement name. Additionally, the current work reports another rufous-capped brush finch A. pileatus parasitized by E. atlapetesi in co-infection with an Isospora sp., providing observations of histopathology and phylogenetic analysis of 18S ribosomal RNA (rRNA) gene from E. atlapetesi. Endogenous forms of E. atlapetesi and Isospora sp. were observed in intestinal sections. Few oocysts of Isospora sp. were observed; therefore they were not morphologically or molecularly identified. In return, E. atlapetesi was identified and it was phylogenetically close to Eimeria dispersa Tyzzer, 1929 from the domestic turkey Meleagris gallopavo Linnaeus.

Significancia pronóstica del tamaño tumoral en la sobrevida de pacientes con carcinoma gástrico avanzado / Pronostic significance of tumoral size in the survival of advanced gastric carcinoma

Objetivo: Determinar la significancia pronóstica del tamaño del tumor en la sobrevida de pacientes con carcinoma gástrico avanzado. Material y método: Este estudio retrospectivo evaluó 95 pacientes con adenocarcinoma gástrico avanzado con un diámetro menor de 7 centímetros (grupo I) y 85 casos con lesiones con diámetro mayor o igual a 7 centímetros (Grupo II), sometidos a gastrectomía radical con linfadenectomía DO-D1 (n igual 148) y linfadenectomía extendida D2-D3-D4 (N igual 32) en el Hospital Belén, Trujillo, Perú, entre 1966 y 1998. Resultados: la edad promedio del grupo I y II fue de 58.05 más menos 12.9 y 58.53 más menos 15.26 años, respectivamente. Los pacientes del grupo II tuvieron un menor nivel de hemoglobina sérica (p igual 0.007) y mayor frecuencia de lesiones tipo Borrmann III y IV (p igual 0.003), en comparación con el grupo I. Entre ambos grupos, usando el tst de log - rank, no se encontró diferencia estadísticamente significativa con relación a la sobrevida quinquenal (p mayor 0.05). Realizando el análisis multivariado de regresión de Cox, tampoco se encontró significancia estadística entre el tamaño tumoral y la sobrevida, pero fueron factores independientes estadísticamente relacionados con la sobrevida: profundidad de la invasión (p igual 0.017) y el estado ganglionar regional (p igual 0.014). Conclusiones: Clínicamente el tamaño del tumor no es un factor a tomar como parámetro en la predicción de la sobrevida actuarial en pacientes con cáncer gástrico avanzado.

Factores pronósticos de sobrevida quinquenal de pacientes con carcinoma gástrico avanzado resecable con serosa expuesta / Five-year survival prognosis factors in patients with resectable advanced serosa exposed gastric carcinoma

Objetivos: Identificar los principales factores pronósticos de sobrevida quinquenal en pacientes con carcinoma gástrico avanzado resecable con serosa expuestas sometidos a gastrectomía radical con linfadenectomía limitada y extendida. Material y Métodos: Este estudio retrospectivo evaluó 137 pacientes con adenocarcinoma gástrico avanzado resecable con serosa expuesta atendidos en el Hospital Belén, Trujillo, Perú, entre 1991 y 2000. Resultados: La edad media de la serie total fue de 58.1± 14.8 años (límites, 20 a 84 años). La presente serie estuvo constituida por 137 pacientes,de los cuales 77 (56.2 por ciento) fueron varones y 60 (43.8 por ciento) mujeres (proporción M:F,1.3:1. En el análisis univariado usando el test de log-rank, las siguientes variables estuvieron asociadas significativamente con la sobrevida quinquenal: ausencia de masa palpable (p = 0.0308), hemoglobina sérica mayor o igual a 10 g/dl (p = 0.059, neoplasias ubicadas en el tercio distal del estómago (p = 0.0001), estado ganglionar regional NO-N1 (p = 0.03), estadio clínico II (p = 0.0327), disección ganglionar D2-D3 ( p = 0.0366) y cirugía con intención curativa (p = 0.000). La tasa de sobrevida actuarial de toda la serie a los 5 años fue de 16.3 por ciento. En el grupo sometido a linfadenectomía D0-D1 (n= 105) la sobrevida a los 5 años fue de 12.6 por ciento; en cambio en el grupo sometido a D2-D3 (n = 32) fue de 30.2 por ciento (p = 0.0366). En los pacientes que tuvieron cirugía con intención curativa (n = 56) la sobrevida quinquenal fue de 33.4 por ciento respectivamente y los que tuvieron resección paliativa (n = 81) fue 3.1 por ciento (p<0.0001). Conclusiones: La detección precoz, la disponibilidad de resección curativa y el uso de linfadenectomía extendida son factores que influyen en la sobrevida; parámetros que deberían ser considerados para estratificación de pacientes y su posterior tratamiento adyuvante postoperatorio.

Carcinoma avanzado del tercio proximal - medio estómago: Cuadro clínico-patológico y factores pronósticos de sobrevida / Advanced gastric carcinoma in the proximal third and half of the stomach: clinical and pathological characteristics and survival prognosis factors

Objetivos: Identificar el cuadro clínico-patológico y factores pronósticos de sobrevida quinquenal de pacientes con carcinoma gástrico avanzado del tercio proximal-medio (U-M) sometidos a gastrectomía con linfadenectomía limitada y extendida. Material y Métodos: El presente estudio retrospectivo analizó información de una serie de 39 pacientes con diagnóstico histológico de adenocarcionoma gástrico avanzado del tercio superior y medio del estómago (U-M) y que fueron sometidos a gastrectomía con linfadenectomía limitada (DO-D1) y extendida (D2-D3) y en el Hospital Belén de Trujillo entre el 1º de enero de 1966 al 31 de diciembre del 2000. Resultados: La edad promedio del grupo U-M fue de 55.56 + 16.24 años. Hubo 27 varones (69.2 por ciento) y 12 mujeres (30.8 por ciento) (proporción H.M=2.3:1). Los síntomas más frecuentes fueron dolor abdominal (94.9 por ciento) y pérdida de peso (59.0 por ciento). El signo más común fue la palidez (61.5 por ciento). Los factores pronósticos independientes estadísticamente relacionados con la sobrevida fueron: profundidad de la invasión T2 (p=0.017), presencia de metástasis a distancia (P=0.013), el estadío clínico I-II (p=0.005), lesiones Bormann I-II (p=0.005) y la cirugía con intención curativa (p=0.003). La sobrevida actuarial en la serie total a los 5 años fue de 13.6 por ciento. Conclusiones: La detección temprana y la disponibilidad de una gastrectomía con preservación de la cola del páncreas tendrían que ser considerados en pacientes con carcinoma gástrico avanzado del tercio proximal y medio y así mejorar su sobrevida.