Hepatic amyloidosis in a patient with chronic liver failure: A case report.

BACKGROUND: Amyloidosis is a rare disorder that can be classified into various types, and the most common type is the systemic light chain type. The prognosis of this disease is extremely poor. In general, amyloidosis mainly affects the kidneys and heart and manifests as abnormal proliferation of clonal plasma cells. Cases in which the liver is the primary organ affected by amyloidosis, as in this report, are less common in clinical practice. CASE SUMMARY: A 62-year-old man was admitted with persistent liver dysfunction of unknown cause and poor treatment outcomes. His condition persisted, and he developed chronic liver failure, with severe cholestasis in the later stage that was gradually accompanied by renal injury. Ultimately, he was diagnosed with hepatic amyloidosis through liver biopsy and pathological examination. CONCLUSION: Hepatic amyloidosis rarely occurs in the clinic, and liver biopsy and pathological examination can assist in the accurate and effective diagnosis of this condition.

Investigation of multiple nosocomial infections using a semi-Markov multi-state model.

BACKGROUND: The prevalence of multiple nosocomial infections (MNIs) is on the rise, however, there remains a limited comprehension regarding the associated risk factors, cumulative risk, probability of occurrence, and impact on length of stay (LOS). METHOD: This multicenter study includes all hospitalized patients from 2020 to July 2023 in two sub-hospitals of a tertiary hospital in Guangming District, Shenzhen. The semi-Markov multi-state model (MSM) was utilized to analyze risk factors and cumulative risk of MNI, predict its occurrence probability, and calculate the extra LOS of nosocomial infection (NI). RESULTS: The risk factors for MNI include age, community infection at admission, surgery, and combined use of antibiotics. However, the cumulative risk of MNI is lower than that of single nosocomial infection (SNI). MNI is most likely to occur within 14 days after admission. Additionally, SNI prolongs LOS by an average of 7.48 days (95% Confidence Interval, CI: 6.06-8.68 days), while MNI prolongs LOS by an average of 15.94 days (95% CI: 14.03-18.17 days). Furthermore, the more sites of infection there are, the longer the extra LOS will be. CONCLUSION: The longer LOS and increased treatment difficulty of MNI result in a heavier disease burden for patients, necessitating targeted prevention and control measures.

Cryptosporidium parvum disrupts intestinal epithelial barrier in neonatal mice through downregulation of cell junction molecules.

BACKGROUND: Cryptosporidium spp. cause watery diarrhea in humans and animals, especially in infants and neonates. They parasitize the apical surface of the epithelial cells in the intestinal lumen. However, the pathogenesis of Cryptosporidium-induced diarrhea is not fully understood yet. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we infected C57BL/6j neonatal mice with C. parvum IIa and IId subtypes, and examined oocyst burden, pathological changes, and intestinal epithelial permeability during the infection. In addition, transcriptomic analyses were used to study the mechanism of diarrhea induced by the C. parvum IId subtype. The neonatal mice were sensitive to both C. parvum IIa and IId infection, but the IId subtype caused a wide oocyst shedding window and maintained the high oocyst burden in the mice compared with the IIa subtype. In addition, the mice infected with C. parvum IId resulted in severe intestinal damage at the peak of infection, leading to increased permeability of the epithelial barrier. The KEGG, GO and GSEA analyses revealed that the downregulation of adherens junction and cell junction molecules at 11 dpi. Meanwhile, E-cadherin, which is associated with adherens junction, was reduced at the protein level in mouse ileum at peak and late infection. CONCLUSIONS/SIGNIFICANCE: C. parvum IId infection causes more severe pathological damage than C. parvum IIa infection in neonatal mice. Furthermore, the impairment of the epithelial barrier during C. parvum IId infection results from the downregulation of intestinal junction proteins.

A combined amplicon approach to nematode polyparasitism occurring in captive wild animals in southern China.

BACKGROUND: Gastrointestinal tract (GIT) nematodes prefer to live in the intestines of wild animals, causing damage and even death, and posing a zoonotic risk. The polyparasitism of GIT nematodes results in the complex dynamics of the nematode communities that occur naturally in wild animals. However, the nematode community in captive wild animals is poorly understood. METHODS: We combined  microscopic examination and amplicon sequencing for community diversity. RESULTS: We characterized GIT nematode assemblages to one order, one family, four genera, and ten species, in 512 fecal samples of 121 species from captive wild animals in southern China. The positive rate of GIT nematodes was 20.7% (106/512), including 42.3% (11/26) in reptiles, 26.5% (39/147) in herbivores, 25.0% (25/100) in non-human primates, 20.0% (5/25) in omnivores, 12.2% (9/74) in carnivores, and 12.1% (17/140) in avians. The dominant nematodes were Haemonchus contortus in herbivores and Trichuris species in primates. The nematode communities of arboreal primates differed from their terrestrial counterparts, reflecting both host phylogeny and ecological constraints. Soil-transmitted Strongyloides species were widespread throughout the herbivore, primate, avian, and carnivore communities, and tended to infect omnivorous primates and terrestrial herbivores. In addition, new Trichuris and Heterakis species were found in the nematode communities of captive porcupines and peafowls. CONCLUSION: This study highlights the variation in the composition of the GIT nematode community and strengthens the attention to the harms induced by zoonotic nematodes and co-infective nematodes with low species richness.

Effects of BRD4 inhibitor JQ1 on the expression profile of super-enhancer related lncRNAs and mRNAs in cervical cancer HeLa cells.

Objective: To investigate the effects of bromine domain protein 4 (BRD4) inhibitor JQ1 on the expression profile of super-enhancer-related lncRNAs (SE-lncRNAs) and mRNAs in cervical cancer (CC) HeLa-cells. Methods: The CCK8 method was implemented to detect the inhibitory effect of JQ1 on HeLa cells and explore the best inhibitory concentration. Whole transcriptome sequencing was performed to detect the changes of lncRNAs and mRNAs expression profiles in cells of the JQ1 treatment group and control group, respectively. The differentially expressed SE-lncRNAs were obtained by matching, while the co-expressed mRNAs were obtained by Pearson correlation analysis. Results: The inhibitory effect of JQ1 on HeLa cell proliferation increased significantly with increasing concentration and treatment time (P < 0.05). Under the experimental conditions of three concentrations of 0.01, 0.1 and 1 µmol/L of JQ1 on HeLa cells at 24, 48, 72 and 120 h, 1 µmol/L of JQ1 at 72 and 120 h had the same cell viability and the strongest cell proliferation inhibition. In order to understand the inhibitory mechanism of JQ1 on HeLa cells, this study analyzed the expression profile differences from the perspective of SE-lncRNAs and mRNAs. A total of 162 SE-lncRNAs were identified, of which 8 SE-lncRNAs were down-regulated and seven SE-lncRNAs were up-regulated. A total of 418 differentially expressed mRNAs related to SE-lncRNAs were identified, of which 395 mRNAs had positive correlation with 12 SE-lncRNAs and 408 mRNAs had negative correlation with 15 SE-lncRNAs. Conclusion: JQ1 can significantly inhibit the proliferation of HeLa cells and affect the expression profile of SE-lncRNAs and mRNAs.

Widespread distribution of human-infective Enterocytozoon bieneusi genotypes in small rodents in northeast China and phylogeny and zoonotic implications revisited.

Enterocytozoon bieneusi features high genetic diversity among host species and environmental sources and over 500 genotypes in 11 phylogenetic groups have been defined. Here we investigated 291 small rodents in Heilongjiang province, northeast China, for the presence of E. bieneusi by PCR of the ribosomal internal transcribed spacer (ITS). Nine of 60 (15.0 %) gray squirrels from a park in Harbin, 120 of 201 (59.7 %) guinea pigs from a pet shop in Harbin, and two of 30 (6.7 %) peridomestic rats from a pasture in Qiqihar were positive for the parasite. Six known genotypes (EbpB, SCC-1, SCC-2, D, S7 and HLJ-CP1) and two novel genotypes (NESQ1 and NEGP1) were identified by sequence analysis of the ITS, with EbpB, SCC-1, SCC-2 and NESQ1 found in squirrels, D, S7 and NEGP1 in guinea pigs, and EbpB and HLJ-CP1 in rats. Widespread distribution of human-infective Group 10 genotype S7 and Group 1 genotype D in guinea pigs raised our concerns about the importance of pet animals as zoonotic reservoirs of microsporidiosis. Co-occurrence of Group 1 genotypes D and HLJ-CP1 in cancer patients and rodents in Heilongjiang indicated a possibility of zoonotic transmission. The host range of Group 1 genotype EbpB previously considered pig-adapted was extended. A potential variant of genotype S7, namely NESQ1, went into the existing Group 10 in phylogenetic analysis. The other new genotype, NEGP1, was clustered in an undefined clade we proposed as Group 15. With the emerging epidemiologic evidence, the host specificity of existing E. bieneusi genotypes is now being challenged.

Rabbits as reservoirs: An updated perspective of the zoonotic risk from Cryptosporidium and Giardia.

Rabbits are highly abundant in many countries and can serve as reservoirs of diseases for a diversity of pathogens including the enteric protozoan parasites, Cryptosporidium and Giardia. Both parasites shed environmentally robust environmental stages (oo/cysts) and have been responsible for numerous waterborne outbreaks of diseases. Cryptosporidium hominis and C. parvum are responsible for most infections in humans, while Giardia duodenalis assemblages A and B, cause most human cases of giardiasis. Cryptosporidium cuniculus, the dominant species infecting rabbits, is the only spceies other than C. hominis and C. parvum to have caused a waterborne outbreak of gastritis, which occurred in the United Kingdom in 2008. This review examines the prevalence of Cryptosporidium and Giardia species in rabbits to better understand the public health risks of contamination of water sources with Cryptosporidium and Giardia oo/cysts from rabbits. Despite the abundance of C. cuniculus in rabbits, reports in humans are relatively rare, with the exception of the United Kingdom and New Zealand, and reports of C. cuniculus in humans from the United Kingdom have declined substantially since the 2008 outbreak. Subtyping of C. cuniculus has supported the potential for zoonotic transmission. Relatively few studies have been conducted on Giardia, but assemblage B dominates. However, improved typing methods are required to better understand the transmission dynamics of Giardia assemblages in rabbits. Similarly, it is not well understood if pet rabbits or contaminated water are the main source of C. cuniculus infections in humans. Well-planned studies using high-resolution typing tools are required to understand the transmission dynamics better and quantify the public health risk of Cryptosporidium and Giardia from rabbits.

Detection and Molecular Diversity of Cryptosporidium spp. and Giardia duodenalis in the Endangered Iberian Lynx (Lynx pardinus), Spain.

Cryptosporidium spp. and Giardia duodenalis are the main non-viral causes of diarrhoea in humans and domestic animals globally. Comparatively, much less information is currently available in free-ranging carnivore species in general and in the endangered Iberian lynx (Lynx pardinus) in particular. Cryptosporidium spp. and G. duodenalis were investigated with molecular (PCR and Sanger sequencing) methods in individual faecal DNA samples of free-ranging and captive Iberian lynxes from the main population nuclei in Spain. Overall, Cryptosporidium spp. and G. duodenalis were detected in 2.4% (6/251) and 27.9% (70/251) of the animals examined, respectively. Positive animals to at least one of them were detected in each of the analysed population nuclei. The analysis of partial ssu rRNA gene sequences revealed the presence of rodent-adapted C. alticolis (n = 1) and C. occultus (n = 1), leporid-adapted C. cuniculus (n = 2), and zoonotic C. parvum (n = 2) within Cryptosporidium, and zoonotic assemblages A (n = 5) and B (n = 3) within G. duodenalis. Subgenotyping analyses allowed for the identification of genotype VaA19 in C. cuniculus (gp60 locus) and sub-assemblages AI and BIII/BIV in G. duodenalis (gdh, bg, and tpi loci). This study represents the first molecular description of Cryptosporidium spp. and G. duodenalis in the Iberian lynx in Spain. The presence of rodent/leporid-adapted Cryptosporidium species in the surveyed animals suggests spurious infections associated to the Iberian lynx's diet. The Iberian lynx seems a suitable host for zoonotic genetic variants of Cryptosporidium (C. parvum) and G. duodenalis (assemblages A and B), although the potential risk of human transmission is regarded as limited due to light parasite burdens and suspected low excretion of infective (oo)cysts to the environment by infected animals. More research should be conducted to ascertain the true impact of these protozoan parasites in the health status of the endangered Iberian lynx.

Critters and contamination: Zoonotic protozoans in urban rodents and water quality.

Rodents represent the single largest group within mammals and host a diverse array of zoonotic pathogens. Urbanisation impacts wild mammals, including rodents, leading to habitat loss but also providing new resources. Urban-adapted (synanthropic) rodents, such as the brown rat (R. norvegicus), black rat (R. rattus), and house mouse (Mus musculus), have long successfully adapted to living close to humans and are known carriers of zoonotic pathogens. Two important enteric, zoonotic protozoan parasites, carried by rodents, include Cryptosporidium and Giardia. Their environmental stages (oocysts/cysts), released in faeces, can contaminate surface and wastewaters, are resistant to common drinking water disinfectants and can cause water-borne related gastritis outbreaks. At least 48 species of Cryptosporidium have been described, with C. hominis and C. parvum responsible for the majority of human infections, while Giardia duodenalis assemblages A and B are the main human-infectious assemblages. Molecular characterisation is crucial to assess the public health risk linked to rodent-related water contamination due to morphological overlap between species. This review explores the global molecular diversity of these parasites in rodents, with a focus on evaluating the zoonotic risk from contamination of water and wasterwater with Cryptosporidium and Giardia oocysts/cysts from synanthropic rodents. Analysis indicates that while zoonotic Cryptosporidium and Giardia are prevalent in farmed and pet rodents, host-specific Cryptosporidium and Giardia species dominate in urban adapted rodents, and therefore the risks posed by these rodents in the transmission of zoonotic Cryptosporidium and Giardia are relatively low. Many knowledge gaps remain however, and therefore understanding the intricate dynamics of these parasites in rodent populations is essential for managing their impact on human health and water quality. This knowledge can inform strategies to reduce disease transmission and ensure safe drinking water in urban and peri­urban areas.

Ultrasound diagnosis and treatment of branchial cleft cyst and preoperative management.

OBJECTIVE: The ultrasonic diagnosis of cervical and facial cystic masses, as well as cases of missed diagnosis and misdiagnosis, was examined, to improve the diagnosis of branchial cleft anomalies. METHODS: A retrospective analysis was conducted on 17 patients with branchial cleft cyst anomalies, including 11 males and 6 females, aged 12-53 years, with an average age of 33 ± 2 years, were unilateral single. All patients who underwent an ultrasound examination and image storage for retrospective analysis, and both longitudinal and transverse sections were scanned to observe the shape, size, boundary, peripheral relationship, and blood flow signal of the masses. All cases were examined with an enhanced CT scan, and pathological reports were generated. RESULTS: Among the 17 cases of branchial cleft anomalies, 15 cases were branchial cleft cysts, while one case involved fistula formation and one case involved sinus tract formation. Based on the type of branchial cleft, the first, second, and third cysts were classified in 4, 12, and 1 case, respectively. The sensitivity rate and specificity of ultrasonic diagnosis were 14/17 (82.4%) and 4/6 (66.7%), respectively. Ultrasonic characteristic analysis for the masses can be found in simple cystic masses or hypoechoic masses, most of them are of a regular shape and have a distinct boundary, and almost no blood flow signal. All patients who were misdiagnosed exhibited blood flow signals, including 1 patient with an abundant blood flow signal, 1 patient suspected of having ectopic thyroid with an abnormal function due to the rat-tail sign, 2 patients misdiagnosed as local inflammatory focus, and 1 patient misdiagnosed with tuberculous lymphadenitis. CONCLUSION: Ultrasound has a detection rate of up to 100% for cervical and facial masses, providing a fundamental determination of lesion characteristics and specific guidance for preoperative diagnosis. If the blood flow signals can be identified and carefully considered their peripheral relationship, the diagnostic rate can be improved.

The risk of wild birds contaminating source water with zoonotic Cryptosporidium and Giardia is probably overestimated.

Cryptosporidium and Giardia are important waterborne protozoan parasites that are resistant to disinfectants commonly used for drinking water. Wild birds, especially wild migratory birds, are often implicated in the contamination of source and wastewater with zoonotic diseases, due to their abundance near water and in urban areas and their ability to spread enteric pathogens over long distances. This review summarises the diversity of Cryptosporidium and Giardia in birds, with a focus on zoonotic species, particularly in wild and migratory birds, which is critical for understanding zoonotic risks. The analysis revealed that both avian-adapted and zoonotic Cryptosporidium species have been identified in birds but that avian-adapted Cryptosporidium species dominate in wild migratory birds. Few studies have examined Giardia species and assemblages in birds, but the non-zoonotic Giardia psittaci and Giardia ardeae are the most commonly reported species. The identification of zoonotic Cryptosporidium and Giardia in birds, particularly C. parvum and G. duodenalis assemblages A and B in wild migratory birds, is likely due to mechanical carriage or spillback from birds co-grazing pastures contaminated with C. parvum from livestock. Therefore, the role of wild migratory birds in the transmission of zoonotic Cryptosporidium and Giardia to source water is likely overestimated. To address knowledge gaps, it is important to conduct more extensive studies on the prevalence of Cryptosporidium and Giardia in a broader range of migratory wild birds. There is also a need to investigate the extent to which zoonotic infections with C. hominis/C. parvum and G. duodenalis assemblages A and B are mechanical and/or transient, and to assess the load and viability of zoonotic oo/cysts shed in avian faeces. Understanding the contribution of birds to zoonoses is essential for effective disease surveillance, prevention, and control.

Cryptosporidium and Giardia in cats and dogs: What is the real zoonotic risk?

Due to the close bond between humans and companion animals, a thorough understanding of the diversity of Cryptosporidium species and Giardia assemblages in cats and dogs is essential to determine the potential zoonotic risks. Analysis of molecular studies shows that C. felis and C. canis are the main species infecting cats and dogs, respectively. These species are largely host-specific, as despite intense association with humans, prevalence of C. felis and C. canis in humans is low and predominantly in immunocompromised individuals and low-income countries. There have been reports of C. parvum in cats and dogs and two reports of C. hominis in dogs. In most studies conducted to date, however, the prevalence of zoonotic species was low and may be associated with coprophagy and or/spillback, but this remains to be determined. Results of subtyping studies suggest that for C. felis and C. canis, some zoonotic transmission may occur but host-adapted subtypes also exist. Giardia duodenalis assemblages C and D are commonly reported in dogs, with assemblages F and A most common in cats. Assemblages C, D and F are largely host-specific as there are only a handful of reports of them in humans. Reports of assemblage A and B in cats and dogs may be due to coprophagy or spillback from owners. Despite the extent of pet ownership and the close contact between humans and companion animals worldwide, the overall risk of zoonotic transmission from cats and dogs to humans is uncertain but thought to be low due to C. canis, C. felis and G. duodenalis assemblages C, D and F being predominantly host-specific, the relatively low prevalence of C. parvum (and C. hominis) in cats and dogs (which may be due to mechanical carriage), and low oo/cyst shedding. Carefully designed epidemiological studies of cats and dogs and their owners using subtyping tools are essential to better quantify the extent of spillover and spillback of Cryptosporidium and Giardia between pets and their owners.

Prevalence and public health relevance of enteric parasites in domestic dogs and cats in the region of Madrid (Spain) with an emphasis on Giardia duodenalis and Cryptosporidium sp.

BACKGROUND: Pet dogs and cats exert an unquestionable beneficial effect in the well-being of their owners, but can also act as a source of zoonotic infections if improperly cared. OBJECTIVES: We investigated the occurrence, risk factors, genetic variability and zoonotic potential of intestinal parasites in dogs and cats attended in a clinical veterinary setting in Spain. METHODS: Canine (n = 252) and feline (n = 35) faecal samples were collected during 2017-2019 and analysed by coproparasitological methods. A rapid lateral immunochromatographic test (ICT) was used for detecting Giardia duodenalis and Cryptosporidium sp. Samples positive at microscopy examination and/or ICT were reassessed by molecular methods. RESULTS: Overall, 48.8% (123/252) of dogs and 48.6% (17/35) of cats were infected by enteric parasites. In dogs, G. duodenalis was the most prevalent species (40.9%), followed by Cystoisospora sp. (7.1%), and Toxocara canis (5.2%). In cats, Joyeuxiella sp. and Toxocara cati were the dominant species (20.0% each), followed by G. duodenalis (14.3%), D. caninum (5.7%) and Cystoisospora felis and Toxascaris leonina (2.9% each). Pups and kittens were more likely to harbour intestinal parasites and develop clinical signs. Sequence analyses of dog isolates revealed the presence of assemblages A (n = 1), C (n = 4), D (n = 4) and C+D (n = 1) within G. duodenalis; C. parvum (n = 1) and C. canis (n = 4) within Cryptosporidium and PtEb IX (n = 1) in Enterocytozoon bieneusi. A novel C. canis subtype family, named XXi, is reported. CONCLUSIONS: Our results highlight that (i) well-cared dogs carry zoonotic enteric protozoan parasites of public health relevance, (ii) proper hygiene practices and routine veterinary treatment are essential to prevent zoonotic infections, (iii) vulnerable populations should avoid contact with pups/kittens with diarrhoea and (iv) infected dogs might be major contributors to the environmental contamination with soil-transmitted helminths (STHs) eggs.

Role of 6-phosphogluconate dehydrogenase enzyme 1 in growth and virulence of Toxoplasma gondii and development of attenuated live vaccine.

Toxoplasma gondii is a ubiquitous pathogen that infects all warm-blooded animals, including humans, causing substantial socioeconomic and healthcare burdens. However, there is no ideal vaccine for toxoplasmosis. As metabolism is important in the growth and virulence of Toxoplasma, some key pathways are promising antiparasitic targets. Here, we identified 6-phosphogluconate dehydrogenase 1 (Tg6PGDH1) in the oxidative pentose phosphate pathway as a cytoplasmic protein that is dispensable for tachyzoite growth of T. gondii in vitro but critical for virulence and cyst formation in vivo. The depletion of Tg6PGDH1 causes decreased gene transcription involved in signal transduction, transcriptional regulation and virulence. Furthermore, we analysed the protective effect of the ME49Δ6pgdh1 mutant as an attenuated vaccine and found that ME49Δ6pgdh1 immunization stimulated strong protective immunity against lethal challenges and blocked cyst formation caused by reinfection. Furthermore, we showed that ME49Δ6pgdh1 immunization stimulated increased levels of interferon-gamma, tumour necrosis factor-alpha and Toxoplasma-specific IgG antibodies. These data highlight the role of Tg6PGDH1 in the growth and virulence of T. gondii and its potential as a target for the development of a live-attenuated vaccine.

Detection of unusual Cryptosporidium parvum subtype in patients with gastrointestinal cancer in Egypt.

While the importance of cryptosporidiosis in immunocompromised persons is well known, the prevalence of Cryptosporidium spp. in cancer patients is not clear. The current study was designed to assess the occurrence and genetic characteristics of Cryptosporidium spp. in patients with gastrointestinal (GI) cancer in Egypt. Stool samples were collected from 100 patients with GI malignancies and 20 healthy individuals without any GI manifestations (control group). They were screened by microscopy and the immunochromatographic RIDA®QUICK Cryptosporidium kit. Subtyping of Cryptosporidium spp. was conducted by sequence analysis of the glycoprotein 60 (gp60) locus. Sociodemographic, environmental data and information on GI symptoms, cancer types, and clinical treatment were obtained via a questionnaire. By microscopy and RIDA®QUICK, only 7% (7/100) of GI cancer patients were positive for Cryptosporidium, compared with 40% (40/100) by gp60 nPCR. No positives were obtained from the control group. Male sex (P = 0.02) and younger age (P = 0.004) were major Cryptosporidium risk factors for infection. The occurrence of Cryptosporidium was also significantly more frequent (P = 0.003) in watery stool samples. Sequence analysis of the gp60 amplicons (~ 400 bp) identified a novel C. parvum subtype with nine TCA repeats and eleven ACATCA repeats. A formal subtype designation could not be made due to the short sequence length. More studies should be conducted to verify the common occurrence of this unusual C. parvum subtype and establish its genetic identity.

Association between dietary antioxidant levels and chronic obstructive pulmonary disease: a mediation analysis of inflammatory factors.

Introduction: The development of chronic obstructive pulmonary disease (COPD) is strongly associated with oxidative stress, but it is unclear whether increasing dietary antioxidant intake reduces the risk of COPD. Therefore, this study assessed the association between antioxidant intake and COPD in US adults aged ≥ 40 years and further examined the correlation using the Composite Dietary Antioxidant Index (CDAI). Methods: The study included 8,257 US adults aged ≥ 40 years using data from the National Health and Nutrition Examination Survey (NHANES) for three cycles from 2007-2012. Multivariate logistic regression models were used to calculate the correlation between antioxidant intake and CDAI with COPD. Restricted cubic spline was further used to explore the exposure-response relationship. Mediation analysis was used to explore the role of inflammatory factors in the association between CDAI and COPD. Results: This study included 8257 participants (4111 women [weighted, 50.7%]; mean [SD] age, 58.8 [11.2] years). In a multivariable-adjusted model of single antioxidant intake, a linear downward association between carotenoid intake and the incidence of COPD (P for trend = 0.052; Pnon- linear = 0.961). In a multivariable adjusted model for CDAI, this association is similarly present (P for trend = 0.018; Pnon-linear = 0.360). Multiple linear regression modeling showed that leukocytes (P = 0.002), alkaline phosphatase (P< 0.001), and c-reactive protein (P< 0.001) were negatively associated with CDAI levels. Meanwhile, mediation analysis revealed that alkaline phosphatase and c-reactive protein partially influenced the association between CDAI and COPD prevalence, with mediation ratios of 6.4% (P< 0.01) and 4.68% (P = 0.04), respectively. Conclusion: The risk of COPD decreased with increased carotenoid intake and CDAI. In addition, CDAI has been found to be strongly associated with inflammatory factors and can reduce the incidence of COPD by mediating inflammatory factors.

Treatment- and immune-related adverse events of immune checkpoint inhibitors in esophageal or gastroesophageal junction cancer: A network meta-analysis of randomized controlled trials.

Objective: To systematically evaluate the safety and adverse event profiles of immune checkpoint inhibitors (ICIs) in patients with esophageal cancer (EPC) or gastroesophageal junction cancer (GEJC). Methods: PubMed, Web of Science, Cochrane Library, and major conference proceedings were systematically searched for all phase II or phase III randomized controlled trials (RCTs) in EPC or GEJC using ICIs. Safety outcomes including treatment-related adverse events (trAEs), immune-related adverse events (irAEs), and serious trAEs were evaluated by network meta-analysis or dichotomous meta-analysis based on the random-effects model. Results: Eleven RCTs involving EPC (five RCTs) and GEJC (six RCTs) were included in the final meta-analysis. NMA showed that placebo was associated with the best safety ranking for grade 3-5 trAEs (SUCRA = 96.0%), followed by avelumab (78.6%), nivolumab (73.9%), ipilimumab (57.0%), and pembrolizumab (56.6%). Conventional pairwise meta-analysis (CPM) showed that ICIs have similar grade 3-5 trAE risk compared with chemotherapy (RR = 0.764, 95% CI: 0.574 to 1.016, I 2 = 95.7%, Z = 1.85, P = 0.065). NMA showed that the general safety of grade 3-5 irAEs ranked from high to low is as follows: ChT (85.1%), placebo (76.5%), ipilimumab (56.0%), nivolumab (48.5%), avelumab (48.4%), camrelizumab (41.8%), pembrolizumab (36.4%), and nivolumab + ipilimumab (21.6%). CPM showed that the rates of grade 3-5 irAEs in the ICI group and the chemotherapy group were 7.35% (154/2,095, 95% CI: [6.23%, 8.47%]) versus 2.25% (42/1,869, 95% CI: [1.58%, 2.92%]), with statistical significance (RR = 3.151, 95% CI = 2.175 to 4.563, Z = 6.07, P = 0.000). The most common irAEs in the ICI group were skin reaction (15.76%, 95% CI: [13.67%, 17.84%]), followed by hypothyroidism (9.73%, 95% CI: [8.07%, 11.39%]), infusion-related reactions (5.93%, 95% CI: [4.29%, 7.58%]), hepatitis (5.25%, 95% CI: [4.28%, 6.22%]), and pneumonitis (4.45%, 95% CI: [3.5%, 5.4%]). Conclusion: Different ICIs had different toxicity manifestations and should not be considered as an entity. Compared with chemotherapy, ICIs were more prone to irAEs, but the overall rates remained low and acceptable. For clinicians, it is important to recognize and monitor the adverse events caused by ICIs for patients with EPC or GEJC.

Paradigm Shift in Phytochemicals Research: Evolution from Antioxidant Capacity to Anti-Inflammatory Effect and to Roles in Gut Health and Metabolic Syndrome.

Food bioactive components, particularly phytochemicals with antioxidant capacity, have been extensively studied over the past two decades. However, as new analytical and molecular biological tools advance, antioxidants related research has undergone significant paradigm shifts. This review is a high-level overview of the evolution of phytochemical antioxidants research. Early research used chemical models to assess the antioxidant capacity of different phytochemicals, which provided important information about the health potential, but the results were overused and misinterpreted despite the lack of biological relevance (Antioxidants v1.0). This led to findings in the anti-inflammatory properties and modulatory effects of cell signaling of phytochemicals (Antioxidants v2.0). Recent advances in the role of diet in modulating gut microbiota have suggested a new phase of food bioactives research along the phytochemicals-gut microbiota-intestinal metabolites-low-grade inflammation-metabolic syndrome axis (Antioxidants v3.0). Polyphenols and carotenoids were discussed in-depth, and future research directions were also provided.

YTHDF2 interference suppresses the EMT of cervical cancer cells and enhances cisplatin chemosensitivity by regulating AXIN1.

M6A reader YTH structural domain family 2 (YTHDF2) has been recognized to play an oncogenic role in numerous tumors, but its role in cervical cancer has not been extensively discussed yet. This paper was designed to explore the role of YTHDF2 in cervical cancer and identify its underlying mechanism. The expression of YTHDF2 was first determined in cervical cancer cells by quantitative reverse-transcription polymerase chain reaction and western blot. Then, the migration, invasion, and epithelial-mesenchymal transition (EMT) process were observed in YTHDF2-knockdown Hela cells using wound healing, transwell and immunofluorescence assays. The cisplatin chemosensitivity of Hela cells was also investigated by assessing cell activity with cell counting kit-8 and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling). After MeRIP-Seq assay and actinomycin D treatment to confirm the binding relationship between YTHDF2 and AXIN1, the migration, invasion, EMT process, and cisplatin chemosensitivity were assessed again in Hela cells silenced by YTHDF2 and AXIN1 or treated with Wnt agonist. YTHDF2 was increased in cervical cancer cells, and depletion of YTHDF2 led to reduced migration, invasion and EMT process but enhanced chemosensitivity of cisplatin in Hela cells. Furthermore, YTHDF2 could bind to and stabilize the expression of AXIN1. When the YTHDF2-knockdown Hela cells were further transfected with AXIN1 knockdown or treated with Wnt agonist, the effects of YTHDF2 knockdown on the migration, invasion and EMT process were partially abolished, together with reduced cisplatin chemosensitivity. To sum up, we reported that YTHDF2 interference could suppress the EMT of cervical cancer cells and enhance cisplatin chemosensitivity by regulating AXIN1.

Genus-level evolutionary relationships of FAR proteins reflect the diversity of lifestyles of free-living and parasitic nematodes.

BACKGROUND: Nematodes are a widespread and diverse group comprising free-living and parasitic species, some of which have major detrimental effects on crops, animals, and human health. Genomic comparisons of nematodes may help reveal the genetic bases for the evolution of parasitic lifestyles. Fatty acid and retinol-binding proteins (FARs) are thought to be unique to nematodes and play essential roles in their development, reproduction, infection, and possibly parasitism through promoting the uptake, transport, and distribution of lipid and retinol. However, the evolution of FAR family proteins across the phylum Nematoda remains elusive. RESULTS: We report here the evolutionary relationship of the FAR gene family across nematodes. No FAR was found in Trichocephalida species and Romanomermis culicivorax from Clade I, and FAR could be found in species from Clades III, IV, and V. FAR proteins are conserved in Clade III species and separated into three clusters. Tandem duplications and high divergence events lead to variable richness and low homology of FARs in Steinernema of Clade IVa, Strongyloides of Clade IVb, and intestinal parasitic nematodes from Clades Vc and Ve. Moreover, different richness and sequence variations of FARs in pine wood, root-knot, stem, and cyst nematodes might be determined by reproduction mode or parasitism. However, murine lungworm Angiostrongylus and bovine lungworm Dictyocaulus viviparus from Clade Vd have only 3-4 orthologs of FAR. RNA-seq data showed that far genes, especially far-1 and far-2, were highly expressed in most nematodes. Angiostrongylus cantonensis FAR-1 and FAR-3 have low sequence homology and distinct ligand-binding properties, leading to differences in the cavity volume of proteins. These data indicate that FAR proteins diverged early and experienced low selective pressure to form genus-level diversity. The far genes are present in endophyte or root-colonized bacteria of Streptomyces, Kitasatospora sp., Bacillus subtilis, and Lysobacter, suggesting that bacterial far genes might be derived from plant-parasitic nematodes by horizontal gene transfer. CONCLUSIONS: Data from these comparative analyses have provided insights into genus-level diversity of FAR proteins in the phylum Nematoda. FAR diversification provides a glimpse into the complicated evolution history across free-living and parasitic nematodes.