Intravenous immunoglobulin for acute exacerbation of fibrotic idiopathic interstitial pneumonias

Background and aim:Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is a fatal condition with no established treatment. Intravenous immunoglobulin (IVIG) is a unique therapy with both anti-inflammatory and anti-infective effects. Therefore, we hypothesized that IVIG may have a positive effect on AE of interstitial pneumonia. This study aimed to determine the effect of IVIG in patients with AE of fibrotic idiopathic interstitial pneumonias (IIPs), including IPF.Methods:We retrospectively analyzed consecutive patients who were diagnosed with AE of fibrotic IIPs and treated with pulse corticosteroid therapy (methylprednisolone 500–1000 mg/day for 3 days) between April 2018 and May 2021 at Kagawa Rosai Hospital and KKR Takamatsu Hospital.Results:This study included 52 patients with AE of fibrotic IIPs (IPF,41; fibrotic IIPs other than IPF,11). Thirteen patients received IVIG (5 g/day for 3–5 days) concurrently with pulse corticosteroid therapy. The remaining 39 patients were assigned to the control group. The survival rate on day 90 was significantly higher in the IVIG group than that in the control group (76.9% vs. 38.5%, p = 0.02). IVIG administration (odds ratio [OR], 0.11; 95% confidence interval [CI], 0.02–0.69; p = 0.02) and C- reactive protein (OR, 1.19; 95% CI, 1.06–1.33, p < 0.01) were independently associated with 90-day mortality.Conclusions:The results indicate that administration of IVIG may improve the survival of patients with AE of fibrotic IIPs. We are now conducting a prospective study to confirm the effect of IVIG on AE of IPF since May 2022 (jRCT1061220010).     

In Vitro and In Vivo Antidermatophyte Activities of NND-502, a Novel Optically Active Imidazole Antimycotic Agent

In vitro and in vivo antidermatophyte activities of NND-502, a new imidazole antimycotic agent, were compared with those of two existing antifungal agents, lanoconazole and terbinafine. NND-502 exhibited strong in vitro antifungal activity against Trichophyton spp.; its MIC was 1 to 4 times lower than that of lanoconazole or terbinafine. In an in vivo study with a guinea pig model of tinea pedis, 7-day topical treatment with a 0.5% solution of NND-502 (dissolved in polyethylene glycol 400) was more effective than that with a 0.5% solution of either lanoconazole or terbinafine for eradicating fungi from the infected feet. When the duration of treatment was shortened to 3 days, a topical 1% solution of NND-502 achieved a complete mycological cure, while topical 1% solutions of lanoconazole and terbinafine did not.     

The Impact of Purple-Flesh Potato (Solanum tuberosum L.) cv. “Shadow Queen” on Minor Health Complaints in Healthy Adults: A Randomized,Double-Blind,Placebo-Controlled Study

The purple-flesh potato (Solanum tuberosum L.) cultivar “Shadow Queen” (SQ) naturally contains anthocyanins. This randomized, double-blind, placebo-controlled study determines whether ingesting purple potatoes increases the number of mesenchymal stem cells (MSC) and improves stress response, a minor health complaint in healthy adults (registration number: UMIN000038876). A total of 15 healthy subjects (ages: 50–70 years) with minor health complaints were randomly assigned to one of two groups. For 8 weeks, the placebo group received placebo potatoes cv. “Haruka” and the test group received test potato cv. SQ containing 45 mg anthocyanin. The MSC count and several stress responses were analyzed at weeks 0 and 8 of the intake periods. The ingestion of a SQ potato did not affect the MSC count but markedly improved psychological stress response, irritability, and depression as minor health complaints compared with “Haruka”. No adverse effects were noted. Hence, an 8-week intake of SQ could improve stress responses.     

Fatty liver with metabolic disorder,such as metabolic dysfunction‐associated fatty liver disease,indicates high risk for developing diabetes mellitus

IntroductionNonalcoholic fatty liver disease (NAFLD) is diagnosed after excluding other liver diseases. The pathogenesis of NAFLD when complicated by other liver diseases has not been established completely. Metabolic dysfunction‐associated fatty liver disease (MAFLD) involves more metabolic factors than NAFLD, regardless of complications with other diseases. This study aimed to clarify the effects of fatty liver occurring with metabolic disorders, such as MAFLD without diabetes mellitus (DM), on the development of DM.Materials and MethodsWe retrospectively assessed 9,459 participants who underwent two or more annual health check‐ups. The participants were divided into the MAFLD group (fatty liver disease with overweight/obesity or non‐overweight/obesity complicated by metabolic disorders), simple fatty liver group (fatty liver disease other than MAFLD group), metabolic disorder group (metabolic disorder without fatty liver disease), and normal group (all other participants).ResultsThe DM onset rates in the normal, simple fatty liver, metabolic disorder, and MAFLD groups were 0.51, 1.85, 2.52, and 7.36%, respectively. In the multivariate analysis, the MAFLD group showed a significantly higher risk of DM onset compared with other three groups (P < 0.01). Additionally, the risk of DM onset was significantly increased in fatty liver disease with overweight/obesity or pre‐diabetes (P < 0.01).ConclusionsFatty liver with metabolic disorders, such as MAFLD, can be used to identify patients with fatty liver disease who are at high risk of developing DM. Additionally, patients with fatty liver disease complicated with overweight/obesity or prediabetes are at an increased risk of DM onset and should receive more attention.     

The clinical relevance of unfolded protein response signaling in breast cancer

Protein homeostasis regulated by the Endoplasmic Reticulum (ER) is a recognized process involved in cancer progression. ER stress activates the Unfolded Protein Response (UPR) and has been implicated in a variety of cancers. Given the role of the UPR activation in carcinogenesis, we hypothesized that UPR activation could be associated with pathological progression, higher clinical stage, and worse survival in breast cancer. A total of 4,416 breast cancer patients from multiple independent cohorts were analyzed. We defined the UPR pathway score by the degree of enrichment by Gene Set Variant Analysis and median was used to divide high vs. low score groups in each cohort. High UPR breast cancer significantly enriched not only cell proliferation-related but also other pro-cancerous gene sets consistently in both METABIC and {"type":"entrez-geo","attrs":{"text":"GSE96058","term_id":"96058"}}GSE96058 cohort. Majority of UPR pathway score high cells in the bulk tumor were tumor cells compared to other cells, including stromal, T-, B-, and myeloid-cells (P<0.001). UPR score was significantly associated with advanced stage, high grade, and triple negative breast cancer (TNBC) (all P<0.001). High UPR breast cancer was associated with worse patient survival in both cohorts (all P<0.001). Among breast cancer subtype, ER-positive/HER2-negative breast cancer with high UPR was significantly associated with worse survival, but neither HER-positive nor TNBC. High UPR ER-positive/HER2-negative breast cancer was infiltrated with high level of Th1 and Th2 cells, M1 macrophage, and plasma cells. On the other hand, they were significantly infiltrated with high level of several types of stromal cells in tumor microenvironment (all P<0.001). Finally, high UPR metastatic breast cancer was also associated with worse patient survival (P=0.041). UPR signaling is associated with cancer aggressiveness, and worse survival, especially ER-positive/HER2-negative breast cancer subtype.     

A tumor metastasis‐associated molecule TWIST1 is a favorable target for cancer immunotherapy due to its immunogenicity

Although neoantigens are one of the most favorable targets in cancer immunotherapy, it is less versatile and costly to apply neoantigen‐derived cancer vaccines to patients due to individual variation. It is, therefore, important to find highly immunogenic antigens between tumor‐specific or associated antigens that are shared among patients. Considering the cancer immunoediting theory, immunogenic tumor cells cannot survive in the early phase of tumor progression including two processes: elimination and equilibrium. We hypothesized that highly immunogenic molecules are allowed to be expressed in tumor cells after an immune suppressive tumor microenvironment was established, if these molecules contribute to tumor survival. In the current study, we focused on TWIST1 as a candidate for highly immunogenic antigens because it is upregulated in tumor cells under hypoxia and promotes tumor metastasis, which is observed in the late phase of tumor progression. We demonstrated that TWIST1 had an immunogenic peptide sequence TWIST1_140–162, which effectively activated TWIST1‐specific CD4⁺ T‐cells. In a short‐term culture system, we detected more TWIST1‐specific responses in breast cancer patients compared with in healthy donors. Vaccination with the TWIST1 peptide also showed efficient expansion of TWIST1‐reactive HTLs in humanized mice. These findings indicate that TWIST1 is a highly immunogenic shared antigen and a favorable target for cancer immunotherapy.     

Correction to: The characteristics of gastrointestinal symptoms in patients with severe COVID-19: a systematic review and meta-analysis

Journal of Gastroenterology - A correction to this paper has been published: https://doi.org/10.1007/s00535-021-01786-z     

Factors Associated with Hepatitis B Surface Antigen Kinetics and Responses in Pegylated Interferon Alpha-2a Monotherapy for Patients with Chronic Hepatitis B

Objective Pegylated-interferon monotherapy is the standard treatment for patients with chronic hepatitis B; however, the factors associated with its therapeutic effects remain unclear. Methods Patients with chronic hepatitis B were treated with pegylated interferon α-2a for 48 weeks. We evaluated the kinetics of hepatitis B surface antigen (HBsAg) during treatment and follow-up periods and the factors associated with an HBsAg response (defined as a change in HBsAg of ≥-1 log IU/mL from baseline). Results The study population comprised 50 patients. The median baseline levels of hepatitis B virus DNA and HBsAg were 5.00 and 3.40 log IU/mL. The median values of HBsAg reduction from baseline were -0.44 (n=48), -0.41 (n=40), and -0.68 (n=11) log IU/mL at the end of treatment and at 48 and 144 weeks post-treatment, respectively. The rates of HBsAg response were 24.0% and 22.5% at the end of treatment and at 48 weeks post-treatment, respectively. A multivariate analysis identified HBsAg <3.00 log IU/mL as an independent baseline factor contributing to the HBsAg response at the end of treatment and 48 weeks post-treatment (p=1.07×10^-2 and 4.42×10^-2, respectively). There were significant differences in the reduction of the HBsAg levels at 12 weeks of treatment and in the incidence of serum ALT increase during treatment between patients with and without an HBsAg response. Conclusion These findings suggest that the baseline HBsAg level, HBsAg kinetics at 12 weeks of treatment, and ALT increase during treatment are important factors contributing to the HBsAg response in pegylated interferon α-2a monotherapy for patients with chronic hepatitis B.