Although cisplatin has been a pivotal chemotherapy drug in treating patients with various types of cancer for decades, drug resistance has been a major clinical impediment. In general, cisplatin ...exerts cytotoxic effects in tumor cells mainly through the generation of DNA-platinum adducts and subsequent DNA damage response. Accordingly, considerable effort has been devoted to clarify the resistance mechanisms inside tumor cells, such as decreased drug accumulation, enhanced detoxification activity, promotion of DNA repair capacity, and inactivated cell death signaling. However, recent advances in high-throughput techniques, cell culture platforms, animal models, and analytic methods have also demonstrated that the tumor microenvironment plays a key role in the development of cisplatin resistance. Recent clinical successes in combination treatments with cisplatin and novel agents targeting components in the tumor microenvironment, such as angiogenesis and immune cells, have also supported the therapeutic value of these components in cisplatin resistance. In this review, we summarize resistance mechanisms with respect to a single tumor cell and crucial components in the tumor microenvironment, particularly focusing on favorable results from clinical studies. By compiling emerging evidence from preclinical and clinical studies, this review may provide insights into the development of a novel approach to overcome cisplatin resistance.
Huntington's disease (HD) is a neurodegenerative disorder that manifests with movement dysfunction. The expression of mutant Huntingtin (mHTT) disrupts the functions of brain cells. Galectin-3 (Gal3) ...is a lectin that has not been extensively explored in brain diseases. Herein, we showed that the plasma Gal3 levels of HD patients and mice correlated with disease severity. Moreover, brain Gal3 levels were higher in patients and mice with HD than those in controls. The up-regulation of Gal3 in HD mice occurred before motor impairment, and its level remained high in microglia throughout disease progression. The cell-autonomous up-regulated Gal3 formed puncta in damaged lysosomes and contributed to inflammation through NFκB- and NLRP3 inflammasome-dependent pathways. Knockdown of Gal3 suppressed inflammation, reduced mHTT aggregation, restored neuronal DARPP32 levels, ameliorated motor dysfunction, and increased survival in HD mice. Thus, suppression of Gal3 ameliorates microglia-mediated pathogenesis, which suggests that Gal3 is a novel druggable target for HD.
Objective To evaluate the use of prospective screening for the HLA-B*58:01 allele to identify Taiwanese individuals at risk of severe cutaneous adverse reactions (SCARs) induced by allopurinol ...treatment.Design National prospective cohort study.Setting 15 medical centres in different regions of Taiwan, from July 2009 to August 2014.Participants 2926 people who had an indication for allopurinol treatment but had not taken allopurinol previously. Participants were excluded if they had undergone a bone marrow transplant, were not of Han Chinese descent, and had a history of allopurinol induced hypersensitivity. DNA purified from 2910 participants’ peripheral blood was used to assess the presence of HLA-B*58:01. Main outcome measures Incidence of allopurinol induced SCARs with and without screening.Results Participants who tested positive for HLA-B*58:01 (19.6%, n=571) were advised to avoid allopurinol, and were referred to an alternate drug treatment or advised to continue with their prestudy treatment. Participants who tested negative (80.4%, n=2339) were given allopurinol. Participants were interviewed once a week for two months to monitor symptoms. The historical incidence of allopurinol induced SCARs, estimated by the National Health Insurance research database of Taiwan, was used for comparison. Mild, transient rash without blisters developed in 97 (3%) participants during follow-up. None of the participants was admitted to hospital owing to adverse drug reactions. SCARs did not develop in any of the participants receiving allopurinol who screened negative for HLA-B*58:01. By contrast, seven cases of SCARs were expected, based on the estimated historical incidence of allopurinol induced SCARs nationwide (0.30% per year, 95% confidence interval 0.28% to 0.31%; P=0.0026; two side one sample binomial test).Conclusions Prospective screening of the HLA-B*58:01 allele, coupled with an alternative drug treatment for carriers, significantly decreased the incidence of allopurinol induced SCARs in Taiwanese medical centres.
Abstract Background In this study, we tested the hypothesis that a combined adipose-derived mesenchymal stem cell (ADMSC) and ADMSC-derived exosome therapy protected rat kidney from acute ...ischemia–reperfusion (IR) injury (i.e., ligation both renal arteries for 1 h and reperfusion for 72 h prior to euthanization). Methods and Results Adult-male SD rats (n = 40) were equally categorized into group 1 (sham control), group 2(IR), group 3IR + exosome (100 μg), group 4 IR + ADMSC (1.2 × 106 cells), and group 5 (IR-exosome-ADMSC). All therapies were performed at 3 h after IR procedure from venous administration. By 72 h, the creatinine level and kidney injury score were lowest in group 1 and highest in group 2, significantly higher in group 3 than in groups 4 and 5, and significantly higher in group 4 than in group 5 (all P < 0.0001). The protein expression of inflammatory (TNF-α/NF-κB/IL-1β/MIF/PAI-1/Cox-2), oxidative-stress (NOX-1/NOX-2/oxidized protein), apoptotic (Bax/caspase-3/PARP), and fibrotic (Smad3/TGF-β) biomarkers showed an identical pattern, whereas the anti-apoptotic (Smad1/5, BMP-2) and angiogenesis (CD31/vWF/angiopoietin) biomarkers and mitochondrial cytochrome-C showed an opposite pattern of creatinine level among the five groups (all P < 0.001). The microscopic findings of glomerular-damage (WT-1), renal tubular-damage (KIM-1), DNA-damage (γ-H2AX), inflammation (MPO/MIF/CD68) exhibited an identical pattern, whereas the podocyte components (podocin/p-cadherin/synaptopodin) displayed a reversed pattern of creatinine level (all P < 0.0001). Conclusion Combined exosome-ADMSC therapy was superior to either one for protecting kidney from acute IR injury.
A high‐salt diet (HSD) elicits sustained sterile inflammation and worsens tissue injury. However, how this occurs after stroke, a leading cause of morbidity and mortality, remains unknown. Here, we ...report that HSD impairs long‐term brain recovery after intracerebral hemorrhage, a severe form of stroke, despite salt withdrawal prior to the injury. Mechanistically, HSD induces innate immune priming and training in hematopoietic stem and progenitor cells (HSPCs) by downregulation of NR4a family and mitochondrial oxidative phosphorylation. This training compromises alternative activation of monocyte‐derived macrophages (MDMs) without altering the initial inflammatory responses of the stroke brain. Healthy mice transplanted with bone marrow from HSD‐fed mice retain signatures of reduced MDM reparative functions, further confirming a persistent form of innate immune memory that originates in the bone marrow. Loss of NR4a1 in macrophages recapitulates HSD‐induced negative impacts on stroke outcomes while gain of NR4a1 enables stroke recovery in HSD animals. Together, we provide the first evidence that links HSD‐induced innate immune memory to the acquisition of persistent dysregulated inflammatory responses and unveils NR4a1 as a potential therapeutic target.
Synopsis
High‐salt intake induces trained immunity through metabolic reprogramming and downregulation of NR4a nuclear receptors. Trained monocyte‐derived macrophages reduce reparative activities in the stroke brain, and consequently, hematoma clearance, brain repair, and functional recovery are impaired.
Excessive dietary salt intake impedes long‐term stroke recovery even after high‐salt withdrawal prior to injury.
High‐salt intake triggers immunological priming and training of bone marrow progenitor cells.
The trained property is retained, which leads to diminished reparative macrophage polarization in the stroke brain.
Pharmacological activation of NR4a1 by celastrol treatment rescues the adverse effects induced by high‐salt diet.
High‐salt intake induces trained immunity through metabolic reprogramming and downregulation of NR4a nuclear receptors. Trained monocyte‐derived macrophages reduce reparative activities in the stroke brain, and consequently, hematoma clearance, brain repair, and functional recovery are impaired.
We investigated the cardioprotective effect of melatonin (Mel) and exendin‐4 (Ex4) treatment in a rat model of cardiorenal syndrome (CRS). Adult male SD rats (n=48) were randomly and equally divided ...into sham control (SC), dilated cardiomyopathy (DCM) (doxorubicin 7 mg/kg i.p. every five days/4 doses), CRS (defined as DCM+CKD) only, CRS‐Mel (20 mg/kg/d), CRS‐Ex4 (10 μg/kg/d), and CRS‐Mel‐Ex4 groups. In vitro results showed protein expressions of oxidative stress (NOX‐1/NOX‐2/oxidized protein), DNA/mitochondrial damage (γ‐H2AX/cytosolic cytochrome c), apoptosis (cleaved caspase‐3/PARP), and senescence (β‐galactosidase cells) biomarkers were upregulated, whereas mitochondrial ATP level was decreased in doxorubicin/p‐cresol‐treated H9c2 cells that were revised by Mel and Ex4 treatments (all P<.001). By day 60, LVEF was highest in the SC and lowest in the CRS, significantly lower in the DCM than in other treatment groups, lower in the CRS‐Mel and CRS‐Ex4 than in the CRS‐Mel‐Ex4, and lower in the CRS‐Mel than in the CRS‐Ex4, whereas LV chamber size and histopathology score showed a pattern opposite to that of LVEF among all groups (all P<.001). Plasma creatinine level was highest in the CRS and lowest in the SC and progressively decreased from the CRS‐Mel, CRS‐Ex4, CRS‐Mel‐Ex4 to DCM (P<.0001). Protein expressions of inflammation (TNF‐α/NF‐κB/MMP‐2/MMP‐9/IL‐1β), apoptosis/DNA damage (Bax/c‐caspase‐3/c‐PARP/γ‐H2AX), fibrosis (Smad3/TGF‐β), oxidative stress (NOX‐1/NOX‐2/NOX‐4/oxidized protein), cardiac hypertrophy/pressure overload (BNP/β‐MHC), and cardiac integrity (Cx43/α‐MHC) biomarkers in LV myocardium showed an opposite pattern compared to that of LVEF among all groups (all P<.001). Fibrotic area, DNA damage (γ‐H2AX+/53BP1+CD90+/XRCC1+CD90+), and inflammation (CD14+/CD68+) biomarkers in LV myocardium displayed a pattern opposite to that of LVEF among all groups (all P<.001). Combined melatonin and exendin‐4 treatment suppressed CRS‐induced deterioration of LVEF and LV remodeling.
Obesity is one of the most important public health issues worldwide. Moreover, an extreme phenotype, morbid obesity (MO) has insidiously become a global problem. Therefore, we aimed to document the ...prevalence trend and to unveil the epidemiological characteristics of MO in Taiwan.
Nationally representative samples aged 19 years and above from three consecutive waves of Nutrition and Health survey in Taiwan: 1993-1996, 2005-2008, and 2013-2014 (n = 3,071; 1,673; and 1,440; respectively) were analyzed for prevalence trend. And 39 MO (BMI ≥35 kg/m2) cases from the two recent surveys compared with 156 age, gender, and survey-matched normal weight controls (BMI: 18.5-24 kg/m2) for epidemiological characteristics study. The reduced rank regression analysis was used to find dietary pattern associated with MO.
The prevalence of overweight and obesity together (BMI ≥24 kg/m2) was stabilized in the recent two surveys, but that of MO (0.4%, 0.6%, to 1.4%) and obesity (BMI ≥27 kg/m2) (11.8%, 17.9%, to 22.0%) increased sharply. MO cases tended to have lower levels of education, personal income, and physical activity. Furthermore, their dietary pattern featured with a higher consumption frequency of red meat, processed animal products, and sweets/sweetened beverage, but lower frequencies of fresh fruits, nuts, breakfast cereal, and dairy products.
This study documents a polarization phenomenon with smaller proportion of overweight people at the center and higher proportions of normal weight and obesity subjects at two extremes. MO was associated with low socioeconomic status and poor dietary pattern. The obesogenic dietary pattern became more prevalent in later time.
Patients with early-stage lung cancer who have a high baseline lymphocyte-to-monocyte ratio (LMR) have a favorable prognosis. However, the prognostic significance of LMR in patients with ...advanced-stage EGFR-mutant non-small cell lung cancer (NSCLC) receiving first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has not been established. We conducted a retrospective analysis to investigate the influence of LMR on clinical outcomes including progression-free survival (PFS) and overall survival (OS) in EGFR-mutant patients with NSCLC.
Of 1310 lung cancer patients diagnosed between January 2011 and October 2013, 253 patients receiving first-line EGFR-TKIs for EGFR-mutant NSCLC were included. The cut-off values for baseline and the 1-month-to-baseline ratio of LMR (MBR), determined by using receiver operating characteristic curves, were 3.29 and 0.63, respectively. Patients were divided into 3 prognostic groups: high LMR and MBR, high LMR or MBR, and low LMR and MBR.
The mean patient age was 65.2 years, and 41% were men. The median PFS and OS were 10.3 and 22.0 months, respectively. The PFS in patients with high LMR and MBR, high LMR or MBR, and low LMR and MBR were 15.4, 7.1, and 2.0 months, respectively (p < 0.001), whereas the OS were 32.6, 13.7, and 5.1 months, respectively (p < 0.001).
A combination of baseline and trend of LMR can be used to identify patients with a high mortality risk in EGFR-mutant NSCLC patients receiving first-line EGFR-TKIs.
Trapped atoms near nanophotonics form an exciting platform for bottom-up synthesis of strongly interacting quantum matter. The ability to induce tunable long-range atom-atom interactions with photons ...presents an opportunity to explore many-body physics and quantum optics. Here we implement a configurable optical tweezer array over a planar photonic circuit tailored for cold atom integration and control for trapping and high-fidelity imaging of one or more atoms in an array directly on a photonic structure. Using an optical conveyor belt formed by a moving optical lattice within a tweezer potential, we show that single atoms can be transported from a reservoir into close proximity of a photonic interface, potentially allowing for the synthesis of a defect-free atom-nanophotonic hybrid lattice. Our experimental platform can be integrated with generic planar photonic waveguides and resonators, promising a pathway towards on-chip many-body quantum optics and applications in quantum technology.
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