Regional delivery of mesothelin-targeted chimeric antigen receptor T-cell effectively and safely targets colorectal cancer liver metastases in mice.

Background: Liver metastasis is the major cause of colorectal cancer related death. Mesothelin (MSLN)-targeted chimeric antigen receptor (CAR) T-cell therapy has been illustrated effective and safe through regional delivery of breast cancer, ovarian cancer and malignant mesothelioma tumors. Herein, we investigated the safety, efficacy, and immune microenvironment of regional delivery of MSLN (CAR) T-cell in the treatment of colorectal carcinoma liver metastases (CRLM). Methods: Second-generation MSLN CAR T-cells were administered by portal vein (PV) or caudal vein (CV, systemic administration) delivery in an orthotopic MSLN+ CRLM nonobese diabetic (NOD)/severe combined immunodeficient (SCID)/γc-/- (NSG) mouse model. A total of 20 mice were randomly divided into control group, non-transduced T cell (NT)-CV group, NT-PV group, MSLN CAR T-cell CV (MSLN-CV) group, and MSLN CAR T-cell PV (MSLN-PV) group, with each group containing four mice to examine the safety and efficacy. The bioluminescence intensity (BLI) of tumor burden, tumor tissue macroscopic and microscopic observation were used to evaluate treatment efficacy. The safety was examined by body weight, survival time, and vital organ damage of mice. CAR T-cell infiltration and cytokine concentration were analyzed by flow cytometry, and immunostaining. The change of immune microenvironment between regional delivery and systemic delivery was investigated on an immune reconstructed CRLM patient-derived xenograft (PDX) model. Additionally, T cell subsets and immunosuppressive markers were examined. Results: PV administration of 1×107/100 µL MSLN CAR T-cells in 20 NSG mice was well tolerated, and no overt toxicity was observed. The tumor burden in the PV group was obviously alleviated. The BLI was (0.73±0.52)×109 in PV group and (1.97±0.11)×109 in CV group (P<0.05), CD8+ granzyme B (GB)+ T cell percentage (MSLN-CV 4.42%±0.47% vs. MSLN-PV 13.5%±4.67%, P<0.01) and cytokine concentration were obviously increased in the MSLN-PV group. In the immune reconstituted CRLM PDX model, intratumor (IT) delivery of MSLN CAR T-cells exhibited much more infiltration of CD4+ and CD8+ T cells accompanied with elevated expression levels of PD-1, LAG-3, and TIM-3. Conclusions: Regional delivery of MSLN-targeted CAR T-cell therapy has encouraging results in the orthotopic CRLM NSG mouse model and PDX model, and converts the tumor microenvironment from cold to hot. This study may provide a new therapeutic approach for CRLM. Further clinical study is needed.

Synergistic enhancement of electrocatalytic nitroarene hydrogenation over Mo2C@MoS2 heteronanorods with dual active-sites.

Electrocatalytic hydrogenation (ECH) enables the sustainable production of chemicals under ambient conditions, in which catalysts catering for the different chemisorption of reactants/intermediates are desired but still challenging. Here, Mo2C@MoS2 heteronanorods with dual active-sites are developed to accomplish efficient nitroarene ECH according to our theoretical prediction that the binding of atomic H and nitro substrates would be synergistically strengthened on Mo2C-MoS2 interfaces. They afford high faradaic efficiency (>85%), yield (>78%) and selectivity (>99%) for the reduction of 4-nitrostyrene (4-NS) to 4-vinylaniline (4-VA) in neutral electrolytes, outperforming not only the single-component counterparts of Mo2C nanorods and MoS2 nanosheets, but also recently reported noble-metals. Accordingly, in situ Raman spectroscopy combined with electrochemical tests clarifies the rapid ECH of 4-NS on Mo2C-MoS2 interfaces due to the facilitated elementary steps, quickly refreshing active sites for continuous electrocatalysis. Mo2C@MoS2 further confirms efficient and selective ECH toward functional anilines with other well-retained reducible groups in wide substrate scope, underscoring the promise of dual-site engineering for exploring catalysts.

Enhancing Low-Potential Electrosynthesis of 2,5-Furandicarboxylic Acid on Monolithic CuO by Constructing Oxygen Vacancies.

Electrosynthesis of 2,5-furandicarboxylic acid (FDCA) from the biomass-derived 5-hydroxymethylfurfural (HMF) is one of the most potential means to produce a bioplastic monomer. Copper oxide (CuO) catalyst shows promising prospects due to its high surface activity, conductivity, and stability, but relatively poor capability of oxygen evolution; however, the weak adsorption of substrates and the lack of facile synthetic strategies largely restrict its practical application. Here, a novel facile in situ method, alternate cycle voltammetry (denoted as c) and potentiostatic electrolysis (denoted as p), was proposed to prepare a monolithic cpc-CuO/Cu-foam electrocatalyst. Along with the increment of CuO and its surficial oxygen vacancies (OV), the FDCA yield, productivity, and Faradaic efficiency can reach up to ∼98.5%, ∼0.2 mmol/cm2, and ∼94.5% under low potential of 1.404 VRHE. Such an efficient electrosynthesis system can be easily scaled up to afford pure FDCA powders. In a combinatory analysis via electron paramagnetic resonance spectroscopy, H2 temperature-programmed reduction, open circuit potential, infrared spectroscopy, zeta potential, electrochemical measurement, and theoretical calculation, we found that the CuO was the active phase and OV generated on CuO surface can dramatically enhance the adsorption of *HMF and *OH (* denotes an active site), accounting for its superior FDCA production. This work offers an excellent paradigm for enhancing biomass valorization on CuO catalysts by constructing surficial defects.

Inorganic arsenic-mediated upregulation of TUG1 promotes apoptosis in human bronchial epithelial cells by activating the p53 signaling pathway.

Exposure to arsenic, an environmental contaminant, is known to cause arsenicosis and cancer. Although considerable research has been conducted to understand the underlying mechanism responsible for arsenic-induced cancers, the precise molecular mechanisms remain unknown, especially at the epigenetic regulation level. Long non-coding RNAs (LncRNAs) that have been shown to mediate various biological processes, including proliferation, apoptosis, necrosis, and mutagenesis. There are few studies on LncRNAs and biological damage caused by environmental pollutants. The LncRNAs taurine upregulated gene 1 (TUG1) regulates cell growth both in vitro and in vivo, and contributes its oncogenic role. However, the precise roles and related mechanisms of arsenic-induced cell apoptosis are still not fully understood owing to controversial findings in the literature. In this study, quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed higher expression levels of TUG1 in people occupationally exposed to arsenic than in individuals living away from the source of arsenic exosure (N = 25). In addition, the results suggested that TUG1 was involved in arsenic-induced apoptosis. Furthermore, knockdown experiments showed that silencing of TUG1 markedly inhibited proliferation, whereas depletion of TUG1 led to increased apoptosis. The TUG1-small interfering RNA (siRNA) combination with arsenic (3 µM/L) slightly increased apoptosis compared with the TUG1-siRNA. Additionally, the knockdown experiments showed that the silencing of TUG1 by siRNA inhibited proliferation and promoted apoptosis by inducing p53, p-p53 (ser392), FAS, BCL2, MDM2, cleaved-caspase7 proteins in 16HBE cells. These results indicated that arsenic mediates the upregulation of TUG1 and induces cell apoptosis via activating the p53 signaling pathway.

The Morphological Evaluation of the Cervical Muscle in Patients With Basilar Invagination: A Magnetic Resonance Imaging-Based Study.

OBJECTIVE: To investigate the characteristics of functional muscle and muscle size in patients with basilar invagination (BI) and explore the effects of atlantoaxial dislocation. METHODS: Eighty BI patients (BI group) and 80 age- and sex-matched asymptomatic people (control group) were included. Axial T2 magnetic resonance imaging image was used to measure the cross-sectional area (CSA) and functional CSA (FCSA). The sternocleidomastoid (SCM), longus capitis and longus colli (LCap & LC), trapezius (Trap), splenius capitis (SpCap), splenius cervicis (SpC), semispinalis capitis (SSCap), semispinalis cervicis (SSC), multifidus (MS), levator scapulae (LS) and posterior deep layer muscles (PDLM) were evaluated. Correlations between age, atlantodental interval (ADI), Chamberlain distance and muscles were observed. RESULTS: BI group (39.4 ± 18.4 years; 33 males/47 females) exhibited significantly lower FCSA/CSA ratios than the control group in all extensor and flexor muscles, and presented smaller CSAs on the right and left Trap, SSC, LS, SCM, and left LCap & LC. FCSA/CSA ratios were significantly lower in BI patients with dislocation on the right Trap, SpCap, SpC, SSCap, MS, LS, LCap & LC, and PDLM, and the left SSCap, MS, and LCap & LC than in patients without deformity. Additionally, functional muscles of all parameters decreased with age in BI patients. Excluding children, the Trap, SpC, MS, and LS muscle sizes of BI patients tended to increase with age. ADI and Chamberlain distance tended to correlate negatively with FCSA/CSA ratio. CONCLUSION: The BI patients, especially those with atlantoaxial dislocation, had less functional muscles compared with the control group. Moreover, their functional muscles decreased with age more obviously.

DNA microarray chip assay in new use: early diagnostic value in cutaneous mycobacterial infection.

Introduction: The clinical practicability of DNA microarray chip in detecting the presence of mycobacterial species/isolates directly in the skin tissues has not been evaluated, nor the efficacy of DNA microarray chip as a novel diagnostic tool for the early diagnosis of cutaneous mycobacterial infections is known. Methods: The present study analyzed the incidence of cutaneous mycobacterial infections in Shanghai and explored the efficacy of a novel DNA microarray chip assay for the clinical diagnosis of the disease from skin tissue specimens compared to traditional detection methods. A total of 60 participants fulfilling the defined diagnostic criteria and confirmed positive for cutaneous mycobacterial infections from 2019 to 2021 were enrolled in the study. Subsequent to recording the participants' medical history and clinical characteristics, the skin tissue specimens were collected for analyses. The specimens underwent histopathological analyses, skin tissue culture, and DNA microarray chip assay. Results: Increased incidence of cutaneous mycobacterial infection was detected from 2019 to 2021. The most common infecting pathogen was M. marinum followed by M. abscessus. The sensitivity, specificity and accuracy of the skin tissue culture method were 70%, 100% and 76.62%, respectively, while that of the DNA microarray chip assay were 91.67%, 100% and 93.51%, respectively. The sensitivity and accuracy of the DNA microarray chip assay were significantly higher than those of the skin tissue culture method. The positive likelihood and diagnostic odds ratio were >10 and >1, respectively for both the methods. The negative likelihood ratio was significantly higher (30% vs 8.33%) and the Youden's index was significantly lower (70.00% vs 91.67%) in the skin culture method compared to that of the DNA microarray chip assay. There was a significant association of false negative results with a history of antibiotic use in the skin tissue culture method. Discussion: Given the increasing incidence of cutaneous mycobacterial infections, early diagnosis remains a prime clinical focus. The DNA microarray chip assay provides a simple, rapid, high-throughput, and reliable method for the diagnosis of cutaneous mycobacterial infections with potential for clinical application.

Identification and characterization of differentially expressed circRNA in 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced cleft palate.

Various circular RNAs (circRNAs) are novel class of non-coding RNAs, which are pervasively transcribed in the genome. CircRNAs play important roles in human, animals and plants. Up to now, there was no report regarding circRNAs of cleft palate by 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) induce. The present study screened identification and characterization of differential expressed-circRNAs in TCDD-induced cleft palate. 6903 circRNAs candidates came from cleft palates. Among them, 3525 circRNAs are up-regulation, and 3378 circRNAs are down-regulation by TCDD induce. The cluster and GO analysis found that circRNAs involved in biological process, cellular component, and molecular function. Through the analysis of KEGG Pathway, circRNAs made functions via classical signaling pathway in cleft palate, such as TGF-beta signaling pathway, BMP signal pathway, MAPK signaling pathway. In addition, we found down-regulated circRNA224, circRNA3302 and up-regulated circRNA5021 targeted tgfbr3, but up-regulated circRNA4451 targeted tgfbr2. circRNA4451 may make functions through TGF-beta signaling pathway. These results suggested that many different circRNAs may make important role in TCDD-induced cleft palate, which provided a theoretical basis for further research.

Evaluation of the efficacy and safety of ionic liquids containing ketoconazole in patients with tinea pedis: A randomized controlled clinical trial.

Ionic liquids (ILs) loading ketoconazole (KCZ) have shown better efficacy on rats with tinea pedis than the marketed Daktarin® but clinical studies are still lacking. In this study, we described the clinical translation of ILs containing KCZ (KCZ-ILs) from the lab into the clinic and evaluated the efficacy and safety of KCZ-ILs in patients with tinea pedis. Thirty-six enrolled participants were randomized to receive either KCZ-ILs (KCZ, 4.72 mg/g) or Daktarin® (control group; KCZ, 20 mg/g) topically twice daily, making the lesion be covered with a thin layer of medication. The randomized controlled trial lasted for 8 weeks including 4 weeks of intervention and 4 weeks of follow-up. Primary efficacy outcome was the proportion of treatment success responders, defined as patients achieving negative mycological result and ≥60% relative reduction in total clinical symptom score (TSS) from baseline at week 4. Secondary outcomes mainly for evaluating the relapse of disease included the proportion of treatment success individuals at week 8 and fungal recurrence rate at weeks 2, 3, 4, and 8. After 4 weeks of medication, 47.06% of the KCZ-ILs subjects were treatment successes compared with only 25.00% of those using Daktarin®. Throughout the trial period, KCZ-ILs induced a significantly lower recurrence rate (52.94%) than that of control patients (68.75%). Furthermore, KCZ-ILs were found to be safe and well-tolerated. In conclusion, ILs loading only 1/4 KCZ dose of Daktarin® showed a better efficacy and safety profile in the management of tinea pedis, creating a new opportunity for the treatment of skin diseases caused by fungal infection and is worthy of clinical application.

Synergistic activity of the combination of falcarindiol and itraconazole in vitro against dermatophytes.

Previous studies have shown that natural polyacetylene alcohols, such as falcarindiol (FADOH), have good antifungal effects on plant fungi. While its effect on fungi that infect humans remains to be explored. In our study, checkerboard microdilution, drop-plate assay, and time-growth method were employed to analyze the interactions between FADOH and itraconazole (ITC) in vitro against dermatophytes, including 12 Trichophyton rubrum (T. rubrum), 12 Trichophyton mentagrophytes (T. mentagrophytes), and 6 Microsporum canis (M. canis). The results showed that the combination of FADOH and ITC exhibited synergistic and additive activity against 86.7% of all tested dermatophytes. FADOH had an excellent synergistic effect on ITC against T. rubrum and T. mentagrophytes; the synergistic rates were 66.7% and 58.3%, respectively. On the contrary, FADOH combined with ITC showed poor synergistic inhibitory activity (16.7%) against M. canis. Moreover, the additive rates of these two drugs against T. rubrum, T. mentagrophytes, and M. canis were 25%, 41.7%, and 33.3%, respectively. No antagonistic interactions were observed. The drop-plate assay and time-growth curves confirmed that the combination of FADOH and ITC had a potent synergistic antifungal effect. The in vitro synergistic effect of FADOH and ITC against dermatophytes is reported here for the first time. Our findings suggest the potential use of FADOH as an effective antifungal drug in the combined therapy of dermatophytoses caused especially by T. rubrum and T. mentagrophytes.

Analysis of the synergistic antifungal activity of everolimus and antifungal drugs against dematiaceous fungi.

Introduction: Chromoblastomycosis (CBM) is a form of chronic mycosis that affects the skin and mucous membranes and is caused by species of dematiaceous fungi including Exophiala spp., Phialophora spp., and Fonsecaea spp. The persistence of this disease and limitations associated with single-drug treatment have complicated efforts to adequately manage this condition. Methods: In this study, a microdilution assay was used to explore the synergistic antifungal activity of everolimus (EVL) in combination with itraconazole (ITC), voriconazole (VRC), posaconazole (POS), and amphotericin B (AMB) against a range of clinical dematiaceous fungal isolates. Results: These analyses revealed that the EVL+POS and EVL+ITC exhibited superior in vitro synergistic efficacy, respectively inhibiting the growth of 64% (14/22) and 59% (13/22) of tested strains. In contrast, the growth of just 9% (2/22) of tested strains was inhibited by a combination of EVL+AMB, and no synergistic efficacy was observed for the combination of EVL+VRC. Discussion: Overall, these findings indicate that EVL holds promise as a novel drug that can be synergistically combined with extant antifungal drugs to improve their efficacy, thereby aiding in the treatment of CBM.

Promoted electrocatalytic hydrogenation of furfural in a bi-phasic system.

The promoted electrocatalytic hydrogenation of biomass-derived furfural to 2-methylfuran is for the first time identified in a water/oil bi-phasic system, in which the oil phase can quickly separate hydrophobic products from the electrode/electrolyte interfaces, resulting in a beneficial equilibrium toward hydrodeoxygenation.

The transcript NR 134251.1 of lncRNA APTR with an opposite function to all transcripts inhibits proliferation and induces apoptosis by regulating proliferation and apoptosis-related genes.

Arsenic (As) exposure has been a global public health concern for hundreds of millions worldwide. LncRNA APTR (Alu-mediated p21 transcriptional regulator) plays an essential role in tumor growth and development. However, its function in arsenic-induced toxicological responses is still unknown. In this study, we found that the expressions of all transcripts and the transcript NR 134251.1 of APTR were increased in a dose-dependent manner in 16HBE cells treated with sodium arsenite (NaAsO2). Silencing the transcript NR 134251.1 of APTR inhibited cell proliferation and induced apoptosis. However, silencing all transcripts of APTR had the opposite function to the transcript NR 134251.1. Then we examined the protein level of the proliferation and apoptosis-related genes after silencing the transcript NR 134251.1 of APTR. The results showed that silencing the transcript NR 134251.1 of APTR up-regulated the expression of transcription factor E2F1 and regulated its downstream genes involved in proliferation and apoptosis, including p53, phospho-p53-S392, phospho-p53-T55, p21, Cyclin D1, PUMA, Fas, Bim, BIK, Caspase-3, Caspase-7, and Cyt-c. In conclusion, arsenic induced APTR expression and the transcript NR 134251.1 of APTR have an opposite function to all transcripts, providing a theoretical basis for the prevention and treatment of arsenic exposure.

Magnetic resonance imaging-based deep learning model to predict multiple firings in double-stapled colorectal anastomosis.

BACKGROUND: Multiple linear stapler firings during double stapling technique (DST) after laparoscopic low anterior resection (LAR) are associated with an increased risk of anastomotic leakage (AL). However, it is difficult to predict preoperatively the need for multiple linear stapler cartridges during DST anastomosis. AIM: To develop a deep learning model to predict multiple firings during DST anastomosis based on pelvic magnetic resonance imaging (MRI). METHODS: We collected 9476 MR images from 328 mid-low rectal cancer patients undergoing LAR with DST anastomosis, which were randomly divided into a training set (n = 260) and testing set (n = 68). Binary logistic regression was adopted to create a clinical model using six factors. The sequence of fast spin-echo T2-weighted MRI of the entire pelvis was segmented and analyzed. Pure-image and clinical-image integrated deep learning models were constructed using the mask region-based convolutional neural network segmentation tool and three-dimensional convolutional networks. Sensitivity, specificity, accuracy, positive predictive value (PPV), and area under the receiver operating characteristic curve (AUC) was calculated for each model. RESULTS: The prevalence of ≥ 3 linear stapler cartridges was 17.7% (58/328). The prevalence of AL was statistically significantly higher in patients with ≥ 3 cartridges compared to those with ≤ 2 cartridges (25.0% vs 11.8%, P = 0.018). Preoperative carcinoembryonic antigen level > 5 ng/mL (OR = 2.11, 95%CI 1.08-4.12, P = 0.028) and tumor size ≥ 5 cm (OR = 3.57, 95%CI 1.61-7.89, P = 0.002) were recognized as independent risk factors for use of ≥ 3 linear stapler cartridges. Diagnostic performance was better with the integrated model (accuracy = 94.1%, PPV = 87.5%, and AUC = 0.88) compared with the clinical model (accuracy = 86.7%, PPV = 38.9%, and AUC = 0.72) and the image model (accuracy = 91.2%, PPV = 83.3%, and AUC = 0.81). CONCLUSION: MRI-based deep learning model can predict the use of ≥ 3 linear stapler cartridges during DST anastomosis in laparoscopic LAR surgery. This model might help determine the best anastomosis strategy by avoiding DST when there is a high probability of the need for ≥ 3 linear stapler cartridges.

Efficacy and prognostic value of delta radiomics on dual-energy computed tomography for gastric cancer with neoadjuvant chemotherapy: a preliminary study.

BACKGROUND: A non-invasive tool for tumor regression grade (TRG) evaluation is urgently needed for gastric cancer (GC) treated with neoadjuvant chemotherapy (NAC). PURPOSE: To develop and validate a radiomics signature (RS) to evaluate TRG for locally advanced GC after NAC and assess its prognostic value. MATERIAL AND METHODS: A total of 103 patients with GC treated with NAC were retrospectively recruited from April 2018 to December 2019 and were randomly allocated into a training cohort (n = 69) and a validation cohort (n = 34). Delineation was performed on both mixed and iodine-uptake images based on dual-energy computed tomography (DECT). A total of 4094 radiomics features were extracted from the pre-NAC, post-NAC, and delta feature sets. Spearman correlation and the least absolute shrinkage and selection operator were used for dimensionality reduction. Multivariable logistic regression was used for TRG evaluation and generated the optimal RS. Kaplan-Meier survival analysis with the log-rank test was implemented in an independent cohort of 40 patients to validate the prognostic value of the optimal RS. RESULTS: Three, five, and six radiomics features were finally selected for the pre-NAC, post-NAC, and delta feature sets. The delta model demonstrated the best performance in assessing TRG in both the training and the validation cohorts (AUCs=0.91 and 0.76, respectively; P>0.1). The optimal RS from the delta model showed a significant capability to predict survival in the independent cohort (P<0.05). CONCLUSION: Delta radiomics based on DECT images serves as a potential biomarker for TRG evaluation and shows prognostic value for patients with GC treated with NAC.

Involvement of a AS3MT/c-Fos/p53 signaling axis in arsenic-induced tumor in human lung cells.

Arsenite methyltransferase (AS3MT) is an enzyme that catalyzes the dimethylation of arsenite (+3 oxidation state). At present, the studies on arsenic carcinogenicity mainly focus on studying the polymorphisms of AS3MT and measuring their catalytic activities. We recently showed that AS3MT was overexpressed in lung cancer patients who had not been exposed to arsenic. However, little is known about the molecular mechanisms of AS3MT in arsenite-induced tumorigenesis. In this study, we showed that AS3MT protein expression was higher in the arsenic-exposed population compared to the unexposed population. AS3MT was also overexpressed in human lung adenocarcinoma (A549) and human bronchial epithelial (16HBE) cells exposed to arsenic (A549: 20-60 µmol/L; 16HBE: 2-6 µmol/L) for 48 h. Furthermore, we investigated the effects of AS3MT on cell proliferation and apoptosis using siRNA. The downregulation of AS3MT inhibited the proliferation and promoted the apoptosis of cells. Mechanistically, AS3MT was found to specifically bind to c-Fos, thereby inhibiting the binding of c-Fos to c-Jun. Additionally, the siRNA-mediated knockdown of AS3MT enhanced the phosphorylation of Ser392 in p53 by upregulating p38 MAPK expression. This led to the activation of p53 signaling and the upregulated expression of downstream targets, such as p21, Fas, PUMA, and Bax. Together, these studies revealed that the inorganic arsenic-mediated upregulation of AS3MT expression directly affected the proliferation and apoptosis of cells, leading to arsenic-induced toxicity or carcinogenicity.

Gastroenterology Practice Patterns Contribute to Missed Diagnoses of Eosinophilic Gastritis and Duodenitis.

Background and Aims: Eosinophilic gastritis and eosinophilic duodenitis (EoG/EoD) are often misdiagnosed as functional gastrointestinal (GI) disorders. Consequently, patients with GI symptoms of EoG/EoD may not undergo the necessary steps for diagnosis. We studied gastroenterologists' evaluations of patients with chronic, unexplained, moderate-to-severe GI symptoms that were unresponsive to over-the-counter medications. Methods: We performed a cross-sectional online survey of 202 board-certified gastroenterologists at office-based practices, community hospitals, or academic institutions. Respondents had been in active clinical practice for 3-35 years post-residency training, spent most of their time on direct patient care, managed ≥1 patient with irritable bowel syndrome and/or functional dyspepsia, and performed ≥1 endoscopy per month. Responses were analyzed to identify barriers to EoG/EoD diagnosis and management. Results: Respondents managed a mean of 1880 patients per year; the most common diagnoses were functional dyspepsia (36%) and gastroesophageal reflux disease (19%). Mean proportions of patients who underwent upper endoscopy ranged from 42% to 84%. Biopsies were collected from >90% of patients with visible endoscopic mucosal abnormalities vs 42%-72% of patients with normal-appearing mucosae. Approximately 20% of respondents collected only 1-2 biopsies from each site of the GI tract. Only 30% routinely requested pathologists to count eosinophils, and nearly 40% had no histologic threshold for EoG/EoD diagnosis. Conclusion: Gastroenterologists vary in their evaluation of patients with chronic, unexplained moderate-to-severe GI symptoms. Limited gastric and duodenal biopsy collection, particularly from normal-appearing mucosae, and failure to request tissue eosinophil counts might contribute to underdiagnosis of EoG/EoD. Availability and awareness of EoG/EoD diagnostic guidelines should improve detection in clinical practice.

Synergistic Effect of the Combination of Deferoxamine and Fluconazole In Vitro and In Vivo against Fluconazole-Resistant Candida Spp.

The opportunistic fungal infections are an increasing threat to humans due to the increasing number of patients with immunodeficiency, in which the most popular fungal pathogen is Candida albicans. Fluconazole (FLC) is the common drug for treating C. albicans infections, but increasing drug resistance has limited its clinical use. Currently, combination therapy is being investigated as a treatment to overcome the resistance of C. albicans. This report investigated the synergistic properties of deferoxamine (DFO) and FLC combination therapy in vitro and in vivo against drug-resistant C. albicans. The results showed that the combination of DFO and FLC had a great synergistic antifungal effect against C. albicans, an FLC-resistant strain, with a fractional inhibition concentration index (FICI) of 0.25 by the broth microdilution checkerboard assay. Furthermore, the combination of DFO and FLC significantly inhibited the activity of C. glabrata cells (approximately 30% of C. glabrata cells are azole-resistant). The time-growth curves confirmed that the combination of DFO and FLC have a potent synergistic antifungal effect. Hyphal formation assays confirmed that DFO inhibited the hyphal induction of C. albicans. In addition, the combination of DFO and FLC significantly inhibited the expression of the adhesion gene (ALS1). In vivo experiments showed that the combination of DFO and FLC significantly reduced pustules, CFU counts and inflammatory cell infiltration in skin tissue. These results suggest that the combination of DFO and FLC inhibits yeast-hyphae transformation, reduces C. albicans infectivity and resistance in vitro and in vivo, and affects Cek1 MAPK signaling. This may offer a new option for the treatment of cutaneous candidiasis.

Case report: Severe deep ulcer on the left abdomen mimicking mycosis fungoides caused by Trichophyton tonsurans in a patient with novel CARD9 mutation.

Dermatophytosis is the most common type of superficial fungal infection caused by dermatophytes. Occasionally, the fungus invades deep into the dermis or other tissues, causing deep dermatophytosis. Deep dermatophytosis is often associated with Caspase Recruitment Domain-containing protein 9 (CARD9) deficiency in patients. Here, we report the first case of deep dermatophytosis with a rare mycosis fungoides manifestation caused by T. tonsurans in a patient with a novel mutation in exon 4 of CARD9. The condition presented with heterozygous K196E mutation, which leads to deficiency of innate and adaptive immune responses in the patient, and caused intractable severe lesions. The patient received treatment with multiple antifungal drugs and was ultimately alleviated by posaconazole. These findings extend the pathogen spectrum of deep dermatophytosis linked with CARD9 deficiency and enriched their phenotypic spectrum.