Recommendations and guidance for herpes zoster vaccination for adults in Taiwan.

Herpes zoster (HZ) is a painful, vesicular, cutaneous eruption from reactivation of varicella zoster virus (VZV), which can lead to potentially debilitating complications. The lifetime risk of HZ is estimated to be 20%-30% in the general population, with an increased risk in the elderly and immunocompromised populations. The most effective strategy to prevent HZ and its complications is by vaccination. Two types of HZ vaccines, zoster vaccine live and recombinant zoster vaccine, have been approved for use. This guidance offers recommendations and suggestions for HZ vaccination in adults, aiming to reduce the disease burden of HZ and its complications. It is intended as a guide to first-line healthcare providers, but does not supersede clinical judgement when assessing risk and providing recommendations to individuals. The Working Group on Adult Immunization Practice was appointed by the Infectious Diseases Society of Taiwan (IDST) and recommendations were drafted after a full literature review, using the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system. The recommendations were reviewed and revised by expert review panels during a series of consensus meetings and endorsed by the IDST, Taiwan Association of Family Medicine, the Taiwanese Dermatological Association, the Taiwan Oncology Society, the Taiwan Society of Blood and Marrow Transplantation, the Transplantation Society of Taiwan, the Taiwan AIDS Society, and the Taiwan College of Rheumatology. This guidance describes the epidemiology of HZ and provides recommendations for HZ vaccination in adults with varying levels of risk, differing history of previous VZV infection and past varicella or zoster vaccinations.

Clinical outcomes and safety of remdesivir in hospitalized individuals with COVID-19, with or without severe renal impairment.

BACKGROUND: The use of remdesivir in patients with coronavirus disease 2019 (COVID-19) and severe renal impairment has been approved; however, limited clinical data exist. Accordingly, we aimed to compare outcomes and adverse events associated with remdesivir in hospitalized patients with COVID-19, with and without severe renal impairment. METHODS: Hospitalized patients with COVID-19 undergoing a 5-day remdesivir course at Taipei Veterans General Hospital from April 1 to July 31, 2022, were enrolled. Comparative analysis of outcomes and safety between patients with or without severe renal impairment (estimated glomerular filtration rate of < 30 mL/min per 1.73 m2) were conducted. Prognostic factors associated with 28-day mortality in patients with severe renal impairment were investigated using logistic regression analysis. RESULTS: A total of 671 hospitalized patients, including 132 patients with severe renal impairment, who received a 5-day course of remdesivir were analyzed. The 28-day mortality was higher in patients with severe renal impairment than in patients without severe renal impairment (15.2% vs. 7.8%). The proportion of patients with acute kidney injury (AKI) and deteriorated liver function after completing remdesivir therapy was similar between the patients with and without severe renal impairment, and the recovery rate of AKI was similar in both groups. The sequential organ failure assessment score was an independent factor associated with 28-day mortality in patients with severe renal impairment. CONCLUSIONS: Remdesivir was well-tolerated in hospitalized patients with COVID-19, regardless of renal function. Our findings support the recent recommendation to administer remdesivir in patients with severe renal impairment.

Ocular surface complications following biological therapy for cancer.

Novel and highly effective biological agents developed to treat cancer over the past two decades have also been linked to multiple adverse outcomes, including unanticipated consequences for the cornea. This review provides an overview of adverse corneal complications of biological agents currently in use for the treatment of cancer. Epidermal growth factor receptor inhibitors and immune checkpoint inhibitors are the two classes of biological agents most frequently associated with corneal adverse events. Dry eye, Stevens-Johnson syndrome, and corneal transplant rejection have all been reported following the use of immune checkpoint inhibitors. The management of these adverse events requires close collaboration between ophthalmologists, dermatologists, and oncologists. This review focuses in depth on the epidemiology, pathophysiology, and management of ocular surface complications of biological therapies against cancer.

HMGB1 mediates lipopolysaccharide-induced macrophage autophagy and pyroptosis.

Autophagy and pyroptosis of macrophages play important protective or detrimental roles in sepsis. However, the underlying mechanisms remain unclear. High mobility group box protein 1 (HMGB1) is associated with both pyroptosis and autophagy. lipopolysaccharide (LPS) is an important pathogenic factor involved in sepsis. Lentivirus-mediated HMGB1 shRNA was used to inhibit the expression of HMGB1. Macrophages were treated with acetylation inhibitor (AA) to suppress the translocation of HMGB1 from the nucleus to the cytosol. Autophagy and pyroptosis-related protein expressions were detected by Western blot. The levels of caspase-1 activity were detected and the rate of pyroptotic cells was detected by flow cytometry. LPS induced autophagy and pyroptosis of macrophages at different stages, and HMGB1 downregulation decreased LPS-induced autophagy and pyroptosis. Treatment with acetylation inhibitor (anacardic acid) significantly suppressed LPS-induced autophagy, an effect that was not reversed by exogenous HMGB1, suggesting that cytoplasmic HMGB1 mediates LPS-induced autophagy of macrophages. Anacardic acid or an anti-HMGB1 antibody inhibited LPS-induced pyroptosis of macrophages. HMGB1 alone induced pyroptosis of macrophages and this effect was inhibited by anti-HMGB1 antibody, suggesting that extracellular HMGB1 induces macrophage pyroptosis and mediates LPS-induced pyroptosis. In summary, HMGB1 plays different roles in mediating LPS-induced autophagy and triggering pyroptosis according to subcellular localization.

Tenofovir use is associated with a decreased risk of hepatocellular carcinoma among men with HIV irrespective of coinfection status.

Background & Aims: Tenofovir is recommended as part of the first-line antiretroviral therapy (ART) to treat people living with HIV (PLWH) with HBV coinfection. However, the effects of tenofovir-containing ART on hepatocellular carcinoma (HCC) risk among PLWH with/without chronic hepatitis virus infections remain unclear. Methods: This study included 23,838 PLWH. All of them were males aged ≥20 years and followed prospectively during 2000-2017. Four major nationwide registries - the Human Immunodeficiency Virus surveillance database, Taiwan Cancer Registry, Death Certification System, and National Health Insurance Database - were applied to define ART and comorbidities and ascertain newly diagnosed HCC. Tenofovir-containing ART was identified through prescription records. Cox proportional hazards models were used to determine the association of tenofovir use with HCC incidence. Results: HCC incidence was lower among ever users of tenofovir than among never users (24.2 and 85.7 per 100,000 person-years, respectively). Ever users had significantly reduced HCC risk (adjusted hazard ratio 0.20, 95% CI 0.13-0.31). The effect of tenofovir use on reduced risk for HCC consistently favored never users across many prespecified subgroups, including HBV or HCV coinfection (p <0.05). The findings were consistent in subgroups of PLWH diagnosed with HIV before tenofovir's approval and in those born before the nationwide roll-out of neonatal HBV vaccination. Conclusions: Our findings underscore the need for randomized controlled trials of tenofovir in combination with long-acting injectable ART regimens to assess its safety and efficacy in PLWH, particularly in those with HBV or HCV coinfection. Impact and implications: Tenofovir's effect on the risk of hepatocellular carcinoma (HCC) among people living with HIV with hepatitis B or C coinfection remains under investigated. This nationwide prospective cohort study, comprising 23,838 men living with HIV, showed that tenofovir-containing antiretroviral therapy was associated with reduced risk of HCC (adjusted relative risk: 0.20, 95% CI 0.13-0.31), which was consistently observed across many prespecified subgroups. The effect of tenofovir use on HCC risk should be further investigated in PLWH, particularly following the development of long-acting injectable ART regimens.

Resistance-proof antimicrobial drug discovery to combat global antimicrobial resistance threat.

Drug resistance is well-defined as a serious problem in our living world. To survive, microbes develop defense strategies against antimicrobial drugs. Drugs exhibit less or no effective results against microbes after the emergence of resistance because they are unable to cross the microbial membrane, in order to alter enzymatic systems, and/or upregulate efflux pumps, etc. Drug resistance issues can be addressed effectively if a "Resistance-Proof" or "Resistance-Resistant" antimicrobial agent is developed. This article discusses first the need for resistance-proof drugs, the imminent properties of resistance-proof drugs, current and future research progress in the discovery of resistance-proof antimicrobials, the inherent challenges, and opportunities. A molecule having imminent resistance-proof properties could target microbes efficiently, increase potency, and rule out the possibility of early resistance. This review triggers the scientific community to think about how an upsurge in drug resistance can be averted and emphasizes the discussion on the development of next-generation antimicrobials that will provide a novel effective solution to combat the global problem of drug resistance. Hence, resistance-proof drug development is not just a requirement but rather a compulsion in the drug discovery field so that resistance can be battled effectively. We discuss several properties of resistance-proof drugs which could initiate new ways of thinking about next-generation antimicrobials to resolve the drug resistance problem. This article sheds light on the issues of drug resistance and discusses solutions in terms of the resistance-proof properties of a molecule. In summary, the article is a foundation to break new ground in the development of resistance-proof therapeutics in the field of infection biology.

An Impact of COVID-19 on Cancer Care: An Update.

The world has been affected socioeconomically for the last two years due to the emergence of different variants of the COVID-19 virus. Vaccination is the major and most efficient way to prevent the widening of this pandemic. Those who are having comorbidities are more vulnerable to serious infections due to their immunocompromised state. Additionally, cancer patients could be at significant risk for COVID-19. In this pandemic era, the diagnosis and treatment of cancer were significantly affected. Clinical trials at the initial stage were performed on healthy or COVID-19 infected patients. This produces a greater level of hesitancy in cancer patients. This review article provide an update regarding the vaccination and treatment for COVID-19 in patients with cancer and future directions.

The influence of low-level viremia on CD4+ cell count in human immunodeficiency virus-infected patients.

BACKGROUND: Following initiation of combined antiretroviral therapy, the majority of human immunodeficiency virus-infected patients experience immune reconstitution indicated by virologic suppression and an increase in peripheral CD4+ T-cell counts. Some patients may suffer from low-level viremia, which was reported to be significantly associated with acquired immunodeficiency syndrome cases, virologic failure, and death. We aimed to further investigate the influence of low-level viremia on CD4+ T-cell count. METHODS: In our study, we included human immunodeficiency virus-seropositive patients on combined antiretroviral therapy, for at least 6 months, who received at least one assessment of human immunodeficiency virus plasma viral load and CD4+ cell count every 6 months, from January 2009 to January 2019. The copy-year viremia was determined by calculating the area under the curve of the plasma human immunodeficiency virus viral load. RESULTS: When comparing patients with a mean CD4+ cell count <200 cells/µL, there was no significant difference between patients with a mean viral load <1000 copies/mL and patients with a mean viral load ≥1000 copies/mL (p = 0.219). Among those with a mean viral load <1000 copies/mL, a higher proportion of patients had a mean CD4+ cell count ≥500 cells/µL (p < 0.001). The mean CD4+ cell count of patients with copy-years viremia (log10) <4 (577.7, interquartile range 429.2-736.7) was significantly higher than that of patients with copy-years viremia (log10) ≥4 (443.3, interquartile range 319.0-558.4) (p < 0.001). In multivariate logistic regression analysis, we observed that malignancy without history, lower copy-years viremia, and high nadir CD4+ cell count were independent predictors of mean CD4+ cell count ≥500 cells/µL. CONCLUSION: Human immunodeficiency virus-infected patients with a history of malignancy, high copy-year viremia, and lower nadir CD4+ cell counts should be monitored carefully in clinical settings.

PDCD5 inhibits progression of renal cell carcinoma by promoting T cell immunity: with the involvement of the HDAC3/microRNA-195-5p/SGK1.

BACKGROUND: Epigenetics exerts a vital role in the onset and development of renal cell carcinoma (RCC). Mounting evidence has shed light on the significance of human immune system in response to tumor infiltrating T cells. Hereby, we sought to unmask the immunomodulatory role of histone deacetylase 3 (HDAC3) and its potential upstream molecule, programmed cell death 5 (PDCD5) in RCC. METHODS: RCC and adjacent non-cancerous tissues were clinically resected from 58 patients, in which the expression profile of microRNA-195-5p (miR-195-5p), PDCD5, HDAC3, and serum glucocorticoid-inducible kinase 1 (SGK1) was determined by RT-qPCR and Western blot analysis. Their relations were investigated by a series of luciferase assays in combination with ChIP and co-IP. RCC cells (A498) were intervened using gain- and loss-of-function approaches, followed by cell proliferation evaluation. After co-culture with CD3+ T cells, flow cytometry and interferon-γ (IFN-γ) determination were performed. A xenograft tumor mouse model was developed for in vivo validation. RESULTS: PDCD5 was downregulated in RCC tissues and A498 cells. Upregulation of HDAC3, as well as of SGK1, resulted in suppression of A498 cell proliferation and promotion of T cell activation as evidenced by higher IFN-γ expression. Re-expression of PDCD5 downregulated HDAC3, causing a subsequent upregulation of miR-195-5p, while miR-195-5p could inversely modulate its target gene, SGK1. The regulatory mechanism appeared to be functional in vivo. CONCLUSION: Our results highlight the possible manipulation by PDCD5 on RCC cell proliferation and T cell activation, which provides new clues to better understand the immune balance in RCC progression.

Anticancer effect of Indanone-based thiazolyl hydrazone derivative on p53 mutant colorectal cancer cell lines: An in vitro and in vivo study.

Colorectal cancer is a major health problem, and it is the third most diagnosed cancer in the United States. The current treatment for colorectal cancer includes irinotecan, a topoisomerase I inhibitor, and other targeted drugs, such as bevacizumab and regorafenib. The low response rates and incidence of high toxicity caused by these drugs instigated an evaluation of the anticancer efficacy of a series of 13 thiazolyl hydrazone derivatives of 1-indanone, and four compounds among them show favorable anticancer activity against some of the tested colorectal cancer cell lines with IC50 values ranging from 0.41 ± 0.19 to 6.85 ± 1.44 µM. It is noteworthy that one of the indanone-based thiazolyl hydrazone (ITH) derivatives, N-Indan-1-ylidene-N'-(4-Biphenyl-4-yl-thiazol-2-yl)-hydrazine (ITH-6), has a better cytotoxicity profile against p53 mutant colorectal cancer cells HT-29, COLO 205, and KM 12 than a p53 wild-type colorectal cancer cell line, such as HCT 116. Mechanistic studies show that ITH-6 arrests these three cancer cell lines in the G2/M phase and induces apoptosis. It also causes a rise in the reactive oxygen species level with a remarkable decrease in the glutathione (GSH) level. Moreover, ITH-6 inhibits the expression of NF-κB p65 and Bcl-2, which proves its cytotoxic action. In addition, ITH-6 significantly decreased tumor size, growth rate, and tumor volume in mice bearing HT-29 and KM 12 tumor xenografts. Moreover, CRISPR/Cas9 was applied to establish an NF-κB p65 gene knockout HT-29 cell line model to validate the target of ITH-6. Overall, the results suggest that ITH-6 could be a potential anticancer drug candidate for p53 mutant colorectal cancers.

The Synergistic Effect of Ruthenium Complex Δ-Ru1 and Doxorubicin in a Mouse Breast Cancer Model.

BACKGROUND: Doxorubicin is a significant drug for the treatment of breast cancer, but its cardiotoxicity is an obvious obstacle. Previously, we confirmed that ruthenium complex (Δ-Ru1) and doxorubicin (Δ-Ru1/Dox) combination had a synergistic effect in MCF-7 cells, but its biological effect in vivo is unknown. PURPOSES: To find a way to overcome the toxicity of doxorubicin and build MCF-7 xenograft tumor mouse model to test whether this potential combination has better efficacy and less toxicity. METHODS: The tumor model of nude mice was established to verify the synergistic antitumor effect of the drug combination in vivo. H&E staining was used to detect the toxicity of major organs in mice. Sirius red staining and transmission electron microscopy were used to detect cardiotoxicity. Prussian blue was used to measure iron accumulation in heart tissue. TUNEL staining was used to detect the antitumor effect in vivo. Immunohistochemical staining was used to detect the expression of iron death-related pathway proteins. High-throughput sequencing techniques were used to determine the molecular mechanism of ferroptosis. RESULTS: Histopathological analysis of tumor tissues indicated that the Δ-Ru1/Dox combination significantly promoted tumor cell apoptosis. Doxorubicin damaged cardiac tissue by inducing fibrosis and iron accumulation, but it was reversed by the Δ-Ru1/Dox combination treatment. Further exploration found that doxorubicin could regulate iron accumulation in the ferroptosis pathway and the expression of lipid peroxidation-related proteins, including upregulation of Tf, DMT1, and HO-1, and downregulation of Nrf2, SLC7A11, and GPX4. CONCLUSION: Δ-Ru1/Dox combination synergistically inhibits tumor growth, and it can significantly reduce and alleviate the toxic side effects of doxorubicin, especially cardiac injury.

Ribociclib Inhibits P-gp-Mediated Multidrug Resistance in Human Epidermoid Carcinoma Cells.

The efficacy of cancer chemotherapy can be attenuated or abrogated by multidrug resistance (MDR) in cancer cells. In this study, we determined the effect of the CDK4/6 inhibitor, ribociclib (or LEE011), on P-glycoprotein (P-gp)-mediated MDR in the human epidermoid carcinoma MDR cell line, KB-C2, which is widely used for studying P-gp-mediated MDR in cancers. The incubation of KB-C2 cells with ribociclib (3-9 µM) increased the efficacy of colchicine, a substrate for P-gp. The cell expression of P-gp was down-regulated at both translation and transcription levels. Furthermore, ribociclib produced a 3.5-fold increase in the basal activity of P-gp ATPase, and the concentration required to increase basal activity by 50% (EC50) was 0.04 µM. Docking studies indicated that ribociclib interacted with the drug-substrate binding site of P-gp. The short-term and long-term intracellular accumulation of doxorubicin greatly increased in the KB-C2 cells co-cultured with ribociclib, indicating ribociclib inhibited the drug efflux activity of P-gp. The results of our study indicate that LEE011 may be a potential agent for combined therapy of the cancers with P-gp mediated MDR.

The epidemiology and etiologies of respiratory tract infection in Northern Taiwan during the early phase of coronavirus disease 2019 (COVID-19) outbreak.

BACKGROUND: Coronavirus disease 2019 (COVID-19) manifests symptoms as common etiologies of respiratory tract infections (RTIs). During the pandemic of COVID-19, identifying the etiologies correctly from patients with RTI symptoms was crucial in not only disease control but preventing healthcare system from collapsing. By applying sensitive PCR-based molecular assays, we detected the etiologic agents and delineated the epidemiologic picture of RTIs in the early phase of COVID-19 pandemic. METHODS: From December 2019 to February 2020, we screened patients presented with RTIs using multiplex PCR-based diagnostic assays. Data from pediatric and adult patients were compared with different months and units in the hospital. RESULTS: Of all 1631 patients including 1445 adult and 186 pediatric patients screened, 8 viruses and 4 bacteria were identified. Positive rates were 25% in December, 37% in January, and 20% in February, with pediatric patients having higher positive rates than adults (Ps < 0.001). In pediatric patients, RhV/EnV was the most commonly detected, followed by parainfluenza viruses. Most Mycoplasma pneumoniae infection occurred in pediatric patients. RhV/EnV was the most commonly detected agent in pediatric patients admitted to intensive care units (ICUs), while influenza accounted for the majority of adult cases with critical illness. Noticeably, seasonal coronavirus ranked second in both adult and pediatric patients with ICU admission. CONCLUSION: While we focused on the pandemic of COVID-19, common etiologies still accounted for the majority of RTIs and lead to severe diseases, including other seasonal coronaviruses.

ZFP36 protects lungs from intestinal I/R-induced injury and fibrosis through the CREBBP/p53/p21/Bax pathway.

Acute lung injury induced by ischemia-reperfusion (I/R)-associated pulmonary inflammation is associated with high rates of morbidity. Despite advances in the clinical management of lung disease, molecular therapeutic options for I/R-associated lung injury are limited. Zinc finger protein 36 (ZFP36) is an AU-rich element-binding protein that is known to suppress the inflammatory response. A ZFP36 binding site occurs in the 3' UTR of the cAMP-response element-binding protein (CREB) binding protein (CREBBP) gene, which is known to interact with apoptotic proteins to promote apoptosis. In this study, we investigate the involvement of ZFP36 and CREBBP on I/R-induced lung injury in vivo and in vitro. Intestinal ischemia/reperfusion (I/R) activates inflammatory responses, resulting in injury to different organs including the lung. Lung tissues from ZFP36-knockdown mice and mouse lung epithelial (MLE)-2 cells were subjected to either Intestinal I/R or hypoxia/reperfusion, respectively, and then analyzed by Western blotting, immunohistochemistry, and real-time PCR. Silico analyses, pull down and RIP assays were used to analyze the relationship between ZFP36 and CREBBP. ZFP36 deficiency upregulated CREBBP, enhanced I/R-induced lung injury, apoptosis, and inflammation, and increased I/R-induced lung fibrosis. In silico analyses indicated that ZFP36 was a strong negative regulator of CREBBP mRNA stability. Results of pull down and RIP assays confirmed that ZFP36 direct interacted with CREBBP mRNA. Our results indicated that ZFP36 can mediate the level of inflammation-associated lung damage following I/R via interactions with the CREBBP/p53/p21/Bax pathway. The downregulation of ZFP36 increased the level of fibrosis.

Targeted HAI-2 deletion causes excessive proteolysis with prolonged active prostasin and depletion of HAI-1 monomer in intestinal but not epidermal epithelial cells.

Mutations of SPINT2, the gene encoding the integral membrane, Kunitz-type serine inhibitor HAI-2, primarily affect the intestine, while sparing many other HAI-2-expressing tissues, causing sodium loss in patients with syndromic congenital sodium diarrhea. The membrane-bound serine protease prostasin was previously identified as a HAI-2 target protease in intestinal tissues but not in the skin. In both tissues, the highly related inhibitor HAI-1 is, however, the default inhibitor for prostasin and the type 2 transmembrane serine protease matriptase. This cell-type selective functional linkage may contribute to the organ-selective damage associated with SPINT 2 mutations. To this end, the impact of HAI-2 deletion on matriptase and prostasin proteolysis was, here, compared using Caco-2 human colorectal adenocarcinoma cells and HaCaT human keratinocytes. Greatly enhanced prostasin proteolytic activity with a prolonged half-life and significant depletion of HAI-1 monomer were observed with HAI-2 loss in Caco-2 cells but not HaCaT cells. The constitutive, high level prostasin zymogen activation observed in Caco-2 cells, but not in HaCaT cells, also contributes to the excessive prostasin proteolytic activity caused by HAI-2 loss. HAI-2 deletion also caused increased matriptase zymogen activation, likely as an indirect result of increased prostasin proteolysis. This increase in activated matriptase, however, only had a negligible role in depletion of HAI-1 monomer. Our study suggests that the constitutive, high level of prostasin zymogen activation and the cell-type selective functional relationship between HAI-2 and prostasin renders Caco-2 cells more susceptible than HaCaT cells to the loss of HAI-2, causing a severe imbalance favoring prostasin proteolysis.

ZFP36L2 regulates myocardial ischemia/reperfusion injury and attenuates mitochondrial fusion and fission by LncRNA PVT1.

Among several leading cardiovascular disorders, ischemia-reperfusion (I/R) injury causes severe manifestations including acute heart failure and systemic dysfunction. Recently, there has been increasing evidence suggesting that alterations in mitochondrial morphology and dysfunction also play an important role in the prognosis of cardiac disorders. Long non-coding RNAs (lncRNAs) form major regulatory networks altering gene transcription and translation. While the role of lncRNAs has been extensively studied in cancer and tumor biology, their implications on mitochondrial morphology and functions remain to be elucidated. In this study, the functional roles of Zinc finger protein 36-like 2 (ZFP36L2) and lncRNA PVT1 were determined in cardiomyocytes under hypoxia/reoxygenation (H/R) injury in vitro and myocardial I/R injury in vivo. Western blot and qRT-PCR analysis were used to assess the levels of ZFP36L2, mitochondrial fission and fusion markers in the myocardial tissues and cardiomyocytes. Cardiac function was determined by immunohistochemistry, H&E staining, and echocardiogram. Ultrastructural analysis of mitochondrial fission was performed using transmission electron microscopy. The mechanistic model consisting of PVT1 with ZFP36L2 and microRNA miR-21-5p with E3 ubiquitin ligase MARCH5 was assessed by subcellular fraction, RNA pull down, FISH, and luciferase reporter assays. These results identified a novel regulatory axis involving PVT1, miR-21-5p, and MARCH5 that alters mitochondrial morphology and function during myocardial I/R injury. Using an in vivo I/R injury mouse model and in vitro cardiomyocytes H/R model, we demonstrated that ZFP36L2 directly associates with PVT1 and alters mitochondrial fission and fusion. PVT1 also interactes with miR-21-5p and suppresses its expression and activity. Furthermore, we identified MARCH5 as a modifier of miR-21-5p, and its effect on mitochondrial fission and fusion are directly proportional to PVT1 expression during H/R injury. Our findings show that manipulation of PVT1-miR-21-5p-MARCH5-mediated mitochondrial fission and fusion via ZFP36L2 may be a novel therapeutic approach to regulate myocardial I/R injury.

Clinical characteristics and outcomes of 56 patients with pneumonia caused by carbapenem-resistant Klebsiella pneumoniae.

OBJECTIVES: Pneumonia caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) is associated with high mortality. However, clinical studies on CRKP infections often exclusively involve bacteraemia, with only a few studies having focused on pneumonia. This retrospective study was conducted to investigate the clinical and microbiological characteristics of pneumonia caused by CRKP. METHODS: Adult patients diagnosed with CRKP monomicrobial pneumonia treated with at least one active antimicrobial agent within 5 days of the pneumonia diagnosis were identified in a medical centre in Taiwan between January 2017 and April 2019. Clinical characteristics and outcomes of these patients were determined. Resistance mechanisms and capsular types of the CRKP isolates were determined by PCR. RESULTS: A total of 56 patients with CRKP monomicrobial pneumonia were identified. The 7-day and 14-day mortality rates were 7.1% and 23.2%, respectively. Malignancy [adjusted odds ratio (aOR) = 8.87, 95% confidence interval (CI) 1.66-47.26; P = 0.011] and Acute Physiology and Chronic Health Evaluation (APACHE) II score (aOR = 1.12, 95% CI 1-1.25; P = 0.048) were independently associated with 14-day mortality. Most CRKP clinical isolates were carbapenemase-producers (39/44; 88.6%), of which K. pneumoniae carbapenemase type 2 (KPC-2)-producing isolates were most prevalent (30/39; 76.9%). The most prevalent capsular type in these isolates was K47 (30/44; 68.2%). CONCLUSION: CRKP pneumonia is associated with high 14-day mortality. Malignancy and APACHE II score were independently associated with 14-day mortality.

Cancer Associated Fibroblasts Promote Renal Cancer Progression Through a TDO/Kyn/AhR Dependent Signaling Pathway.

Cancer associated fibroblasts (CAFs) play crucial roles in cancer development, however, the specific mechanisms of CAFs associated renal cancer progression remain poorly understood. Our study observed enriched CAFs in high degree malignant tumor tissues from renal cancer patients. These CAFs isolated from tumor tissues are prone to facilitate drugs resistance and promote tumor progression in vitro and in vivo. Mechanistically, CAFs up-regulated tryptophan 2, 3-dioxygenase (TDO) expression, resulting in enhanced secretion of kynurenine (Kyn). Kyn produced from CAFs could up-regulated the expression of aromatic hydrocarbon receptor (AhR), eventually resulting in the AKT and STAT3 signaling pathways activation. Inhibition of AKT signal prevented cancer cells proliferation, while inhibition of the STAT3 signal reverted drugs resistance and cancer migration induced by kynurenine. Application of AhR inhibitor DMF could efficiently suppress distant metastasis of renal cancer cells, and improve anticancer effects of sorafenib (Sor)/sunitinib (Sun), which described a promising therapeutic strategy for clinical renal cancer.

Overcoming multidrug resistance by knockout of ABCB1 gene using CRISPR/Cas9 system in SW620/Ad300 colorectal cancer cells.

Multidrug resistance (MDR) has been extensively reported in colorectal cancer patients, which remains a major cause of chemotherapy failure. One of the critical mechanisms of MDR in colorectal cancer is the reduced intracellular drug level led by the upregulated expression of the ATP-binding cassette (ABC) transporters, particularly, ABCB1/P-gp. In this study, the CRISPR/Cas9 system was utilized to target ABCB1 in MDR colorectal cancer SW620/Ad300 cell line with ABCB1 overexpression. The results showed that stable knockout of ABCB1 gene by the CRISPR/Cas9 system was achieved in the MDR cancer cells. Reversal of MDR against ABCB1 chemotherapeutic drugs increased intracellular accumulation of [3H]-paclitaxel accumulation, and decreased drug efflux activity was observed in MDR SW620/Ad300 cells after ABCB1 gene knockout. Further tests using the 3D multicellular tumor spheroid model suggested that deficiency in ABCB1 restrained tumor spheroid growth and restore sensitivity to paclitaxel in MDR tumor spheroids. Overall, the CRISPR/Cas9 system targeting the ABCB1 gene can be an effective approach to overcome ABCB1-mediated MDR in colorectal cancer SW620/Ad300 cells.