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Persistent infection with a protozoan parasite , Trypanosoma cruzi, causes Chagas disease. While it has been appreciated that adipose tissues are one of the sites of persistent infection, the mechanism of how the parasite survives in adipocytes remains to be established. Our study highlights FABP4, a key regulator of metabolic dysfunction and inflammation, as a therapeutic host target controlling T. cruzi infection in adipocytes. We uncover the importance of FABP4 for T. cruzi replication in mouse adipocytes through engagement with lipid droplet degradation and trafficking of liberated free fatty acids to the host cell’s mitochondria, which are utilized for fatty acid oxidation (FAO). T. cruzi infection-induced FAO fuels reactive oxygen species, and the subsequent iron mobilization accelerates parasite replication. These results shed light on the mechanisms of T. cruzi persistent infection in adipocytes, raising the possibility of host FABP4 as a drug target for T. cruzi infection.

Early diagnosis of pancreatic cancer (PC) can improve patients’ prognosis. We aimed to investigate the utility of endoscopic ultrasonography (EUS) for the early diagnosis of PC. This study included 64 patients with PC at an early stage treated at Onomichi General Hospital between January 2007 and January 2020. Diagnostic procedures included contrast computed tomography (CT), magnetic resonance cholangiopancreatography, EUS fine-needle aspiration, and endoscopic retrograde cholangiopancreatography (ERCP) for pancreatic juice cytology. The mean age was 71.3 years. In all, 32 patients were stage 0, and 32 were stage I. As for image findings, the main pancreatic duct (MPD) stenosis was detected in several cases, although CT and MRCP seldom detected tumors. EUS had a high detection rate for stage 0 tumor lesions. The median observation period was 3.9 years. In cases with stage 0, the 1 year and 5 year survival rates were 100% and 78.9%, respectively. In cases with stage I, the 1 year and 5 year survival rates were 96.4% and 66.7%, respectively. EUS has the highest sensitivity among all imaging modalities for detecting small pancreatic tumors. Cases with MPD dilation or stenosis, especially with tumors that cannot be identified on CT and MRI, should have EUS performed. In some cases, EUS was not able to detect any tumor lesions, and ERCP-based pancreatic juice cytology should be useful for pathological diagnosis.

Neutrophils are among the first cells to be recruited to the lungs during Chlamydia pneumoniae infection in mouse models; however, their regulatory functions are not yet fully understood. This study examined the mechanisms and significance of IL-10-producing neutrophils throughout C. pneumoniae pulmonary infection in C57BL/6 mice. Our findings revealed that infection with C. pneumoniae induces IL-10 secretion in bone marrow-derived neutrophils, depending on Toll-like receptor 2 (TLR2) activation. This process involves TLR2-dependent mitochondrial reactive oxygen species (ROS) production, which triggers the endoplasmic reticulum (ER) stress pathway, including IRE1α and subsequent Xbp1 splicing. Inhibition of this pathway or depletion of neutrophils (using the 1A8 monoclonal antibody) significantly reduces IL-10 levels in bronchoalveolar lavage fluid (BALF) in vivo. Conversely, the absence of IL-10-producing neutrophils, whether through depletion or TLR2 deficiency, leads to increased IL-12p70 and IFN-γ-positive NK cells, along with decreased regulatory T cells and M2-like macrophages. This results in a lower bacterial burden in the lungs but causes more severe pulmonary damage and decreased survival rates. These findings highlight that IL-10 produced by neutrophils via the TLR2-mitochondrial ROS–ER stress pathway is essential for modulating pulmonary immune responses and maintaining immune homeostasis during C. pneumoniae infection, thereby preventing excessive inflammation and tissue damage.

Chlamydia trachomatis infection causes pelvic inflammatory disease and infertility, but how host immune factors control pathogen clearance or pathology is not fully understood. Using a mouse model of genital tract infection with Chlamydia muridarum, we examined the role of CD1d-restricted Natural killer T (NKT) cells. Invariant NKT cell-deficient mice (Jα18−/−) showed prolonged vaginal shedding of infectious elementary bodies (EBs), delayed clearance, and decreased early cytokine production compared to wild-type (WT) controls. Conversely, CD1d−/− mice, which lack both invariant and diverse NKT cells, did not show significant differences in vaginal shedding compared to WT mice. Surprisingly, both NKT-deficient mice (Jα18−/− and CD1d−/−) produced higher levels of inflammatory cytokines in the oviduct at day 35 post-infection (p.i.) and experienced more frequent upper genital tract pathology (hydrosalpinx) at day 80 p.i. However, no infectious EBs were recovered from the oviducts or uterine horns of NKT-deficient mice after day 35 p.i. Cortisone acetate reactivated infectious shedding in chronically infected NKT-deficient mice at day 100 p.i. These findings highlight distinct roles for NKT cell subsets: invariant NKT cells promote early clearance via rapid cytokine production, while the broader NKT population helps limit tissue damage. Targeting NKT pathways could help prevent chronic infection and infertility.

Endoscopic ultrasonography (EUS) is proven to be a more specific and sensitive method for detecting pancreatic lesions. However, usefulness of EUS after pancreatectomy has not been reported. This study aimed to evaluate the observational capability of EUS for the remnant pancreas (RP) after pancreatectomy. This single-center, retrospective study enrolled 395 patients who underwent pancreatectomy at Onomichi General Hospital between December 2002 and March 2016, 45 patients who underwent EUS for RP were included for analysis. We evaluated the usefulness of EUS for RP using logistic regression analysis. Complete observation of the RP was done in 42 patients (93%). In the initial surgical procedure, 21 patients underwent pancreaticoduodenectomy (PD), and 24 patients underwent distal pancreatectomy (DP). PD and DP were observed in 85% (18/21) and 100% (24/24) cases, respectively. A comparison of the detection capability of EUS and contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) showed that EUS was significantly superior to contrast-enhanced CT or MRI (p < 0.01). Eight of the 45 patients showed recurrence lesions in the RP. The median recurrence period was 33 months. Predictive factors for recurrence in the univariate and multivariate analyses were significantly different in space occupying lesion with EUS findings (p < 0.01) and elevated CA19-9(p < 0.01). EUS was able to observe the RP in almost all cases. In addition, the detection capability of EUS was significantly superior to those of CT or MRI. We recommend that all patients with RP should undergo EUS, and a longer follow-up must be performed.

It has been hypothesized that respiration defects caused by accumulation of pathogenic mitochondrial DNA (mtDNA) mutations and the resultant overproduction of reactive oxygen species (ROS) or lactates are responsible for aging and age-associated disorders, including diabetes and tumor development. However, there is no direct evidence to prove the involvement of mtDNA mutations in these processes, because it is difficult to exclude the possible involvement of nuclear DNA mutations. Our previous studies resolved this issue by using an mtDNA exchange technology and showed that a G13997A mtDNA mutation found in mouse tumor cells induces metastasis via ROS overproduction. Here, using transmitochondrial mice (mito-mice), which we had generated previously by introducing G13997A mtDNA from mouse tumor cells into mouse embryonic stem cells, we provide convincing evidence supporting part of the abovementioned hypothesis by showing that G13997A mtDNA regulates diabetes development, lymphoma formation, and metastasis—but not aging—in this model.

Background A new circulating biomarker superior to carbohydrate antigen 19–9 (CA19-9) is needed for diagnosing pancreatobiliary cancer (PBca). The aim of this study was to identify serum microRNA (miRNA) signatures comprising reproducible and disease-related miRNAs. Methods This multicenter study involved patients with treatment-naïve PBca and healthy participants. The optimized serum processing conditions were evaluated using t -distributed stochastic neighbor embedding ( t -SNE) visualization. Serum miRNA candidates for disease association were selected using weighted gene coexpression network analysis (WGCNA). A miRNA signature combining multiple serum miRNAs was tested in exploratory, validation, and independent validation sets. The synthesis and secretion of diagnostic miRNAs were evaluated using human pancreatic cancer cells. Results In total, 284 (150 healthy and 134 PBca) of 827 serum samples were processed within 2 h of blood collection before freezing, distributed in the same area as that in the t -SNE map, and assigned to an exploratory set. The 193 optimized samples were assigned to either the validation (50 healthy, 47 PBca) or independent validation (50 healthy, 46 PBca) set. Index-1, a combination of five serum miRNAs (hsa-miR-1343-5p, hsa-miR-4632-5p, hsa-miR-4665-5p, hsa-miR-665, and hsa-miR-6803-5p) with disease association in WGCNA, showed a sensitivity and specificity of > 80% and an AUC outperforming that of CA19-9 in the exploratory, validation, and independent validation sets. The AUC of Index-1 was superior to that of CA19-9 (0.856 vs. 0.649, p  = 0.038) for detecting T1 tumors. miR-665, a component of Index-1, was expressed in human pancreatic cancer cells, and its transfection inhibited cell growth. Conclusions The serum miRNA signature Index-1 is useful for detecting PBca and could facilitate the early diagnosis of PBca. These findings can help improve clinical PBca detection by providing an optimized biomarker that overcomes the limitations of the current standard.

We generated transmitochondrial mice (mito-mice) that carry a mutation in the tRNA ᴸʸˢ gene encoded by mtDNA for use in studies of its pathogenesis and transmission profiles. Because patients with mitochondrial diseases frequently carry mutations in the mitochondrial tRNA ᴸʸˢ and tRNA ᴸᵉᵘ⁽ᵁᵁᴿ⁾ genes, we focused our efforts on identifying somatic mutations of these genes in mouse lung carcinoma P29 cells. Of the 43 clones of PCR products including the tRNA ᴸʸˢ or tRNA ᴸᵉᵘ⁽ᵁᵁᴿ⁾ genes in mtDNA of P29 cells, one had a potentially pathogenic mutation (G7731A) in the tRNA ᴸʸˢ gene. P29 subclones with predominant amounts of G7731A mtDNA expressed respiration defects, thus suggesting the pathogenicity of this mutation. We then transferred G7731A mtDNA into mouse ES cells and obtained F ₀ chimeric mice. Mating these F ₀ mice with C57BL/6J (B6) male mice resulted in the generation of F ₁ mice with G7731A mtDNA, named “mito-mice-tRNA ᴸʸˢ⁷⁷³¹.” Maternal inheritance and random segregation of G7731A mtDNA occurred in subsequent generations. Mito-mice-tRNA ᴸʸˢ⁷⁷³¹ with high proportions of G7731A mtDNA exclusively expressed respiration defects and disease-related phenotypes and therefore are potential models for mitochondrial diseases due to mutations in the mitochondrial tRNA ᴸʸˢ gene. Moreover, the proportion of mutated mtDNA varied markedly among the pups born to each dam, suggesting that selecting oocytes with high proportions of normal mtDNA from affected mothers with tRNA ᴸʸˢ-based mitochondrial diseases may be effective as a primary prevention for obtaining unaffected children.

Delayed perforation after gastric endoscopic mucosal resection (EMR) is a rare but serious complication that can lead to intra‐abdominal abscess (IAA) formation. Efficacy of endoscopic ultrasound (EUS)‐guided drainage for IAA remains to be elucidated. A man in his 50s was admitted for EMR of hyperplastic polyps located in the gastric body. The procedure was performed uneventfully; however, on postoperative day (POD) 4, the patient developed a sudden fever accompanied by an elevation in inflammatory markers. Abdominal computed tomography (CT) revealed a localized area of increased fat attenuation, leading to a diagnosis of delayed perforation. The patient's condition temporarily improved with conservative therapy; however, fever and elevated inflammatory markers recurred on POD 17. CT demonstrated IAA requiring drainage. On POD 22, EUS‐guided transgastric drainage was performed using a nasobiliary drainage tube and double‐pigtail stent. After drainage, fever and inflammatory markers promptly alleviated; follow‐up CT demonstrated shrinkage of the abscess cavity. The clinical course was uneventful. EUS‐guided transgastric drainage could be a safe and effective therapeutic option for IAA secondary to delayed perforation after gastric EMR, particularly when conservative therapy fails and percutaneous drainage is not feasible.