Precise Sn-Doping Modulation for Optimizing CdWO4 Nanorod Photoluminescence.

The cadmium tungstate rods have been given much attention due to their potential for usage in numerous luminescent applications. We have prepared single crystalline Sn-doped Cd1-xSnxWO4 (where x = 0, 1, 3, and 5%) nanorods (NRDs) and characterized them using refined X-ray diffraction and TEM analysis, revealing a monoclinic phase and a crystallite size that decreased from 62 to 38 nm as Sn concentration increased. Precise Sn doping modulation in CdWO4 NRDs causes surface recombination of electrons and holes, which causes the PL intensity to decrease as the Sn content rises. The chromaticity diagram shows that an increase in the Sn content caused a change in the emission color from sky blue to light green, which was attributed to the increased defect density. The photoluminescence time decay curve of all samples fit well with double-order exponential decay, and the average decay lifetime was found to be 1.11, 0.93, and 1.16 ns for Cd1-xSnxWO4, x = 0, 1, and 5%, respectively. This work provides an understanding of the behavior of Sn-doped CdWO4 NRDs during electron transitions and the physical nature of emission that could be used in bio-imaging, light sources, displays, and other applications.

BPR1J373, a novel multitargeted kinase inhibitor, effectively suppresses the growth of gastrointestinal stromal tumor.

Gastrointestinal stromal tumor (GIST) is a type of KIT-driven cancer. KIT gene mutations are found in approximately 80% of GISTs, and most of these mutations occur in exon 9 and exon 11. Imatinib has been successfully used as a first-line treatment for advanced GIST, with a significant improvement in progression-free survival (PFS) and overall survival. However, disease progression might develop due to primary or secondary resistance to imatinib. Sunitinib and regorafenib have been approved as second- and third-line treatments for advanced GIST patients, with median PFS values of 6.8 and 4.8 months, respectively. However, these relatively modest improvements in PFS underscore the need for more effective KIT inhibitors. BPR1J373 is a multitargeted kinase inhibitor that has been shown to inhibit the proliferation of KIT-driven acute myeloid leukemia cells in vitro and in vivo. In this study, we found that BPR1J373 inhibited proliferation and induced apoptosis by targeting KIT in GIST cells with KIT gene mutations. BPR1J373 also induced cell cycle arrest and senescent change in KIT-mutant GIST48 cells, probably by targeting aurora kinase A. In the KIT-null COS-1 cell-based system, BPR1J373 effectively inhibited KIT with single or double mutations of KIT developed in GIST. The antiproliferative effect was also consistently evident in GIST430 tumor-grafted mice. The results suggest that BPR1J373 could be a potential anticancer drug for GIST and deserves further investigation for clinical applications.

Targeting Tumor Associated Phosphatidylserine with New Zinc Dipicolylamine-Based Drug Conjugates.

A series of zinc(II) dipicolylamine (ZnDPA)-based drug conjugates have been synthesized to probe the potential of phosphatidylserine (PS) as a new antigen for small molecule drug conjugate (SMDC) development. Using in vitro cytotoxicity and plasma stability studies, PS-binding assay, in vivo pharmacokinetic studies, and maximum tolerated dose profiles, we provided a roadmap and the key parameters required for the development of the ZnDPA based drug conjugate. In particular, conjugate 24 induced tumor regression in the COLO 205 xenograft model and exhibited a more potent antitumor effect with a 70% reduction of cytotoxic payload compared to that of the marketed irinotecan when dosed at the same regimen. In addition to the validation of PS as an effective pharmacodelivery target for SMDC, our work also provided the foundation that, if applicable, a variety of therapeutic agents could be conjugated in the same manner to treat other PS-associated diseases.

Direct evidence of mitochondrial G-quadruplex DNA by using fluorescent anti-cancer agents.

G-quadruplex (G4) is a promising target for anti-cancer treatment. In this paper, we provide the first evidence supporting the presence of G4 in the mitochondrial DNA (mtDNA) of live cells. The molecular engineering of a fluorescent G4 ligand, 3,6-bis(1-methyl-4-vinylpyridinium) carbazole diiodide (BMVC), can change its major cellular localization from the nucleus to the mitochondria in cancer cells, while remaining primarily in the cytoplasm of normal cells. A number of BMVC derivatives with sufficient mitochondrial uptake can induce cancer cell death without damaging normal cells. Fluorescence studies of these anti-cancer agents in live cells and in isolated mitochondria from HeLa cells have demonstrated that their major target is mtDNA. In this study, we use fluorescence lifetime imaging microscopy to verify the existence of mtDNA G4s in live cells. Bioactivity studies indicate that interactions between these anti-cancer agents and mtDNA G4 can suppress mitochondrial gene expression. This work underlines the importance of fluorescence in the monitoring of drug-target interactions in cells and illustrates the emerging development of drugs in which mtDNA G4 is the primary target.

Long-Term Survival of Patients with Pulmonary Arterial Hypertension at a Single Center in Taiwan.

BACKGROUND: Clinical studies have suggested predictive parameters in mortality risk assessment for pulmonary arterial hypertension (PAH) patients. However, these studies predominantly include Caucasian population; information in Asian population is relatively deficient. In this study, we investigated the long-term survival of PAH patients and the predictors of mortality in our population. METHODS: We prospectively collected 70 patients with PAH at the Chang Gung Memorial Hospital between March 2002 and February 2015. Baseline data including functional class (FC), 6-minute walk distance (6MWD), hematological and biochemical data, echocardiography and cardiac catheterization were obtained before commencing PAH- targeted treatment. The follow-up period for analyses of survivors ended in October 2015. RESULTS: The mean age at diagnosis was 40.7 ± 15.2 years. Mean follow-up period was 4.6 ± 3.4 years, with 1-, 2-, 3-, and 5-year survival rates of 93%, 88%, 84%, and 77%, respectively. The baseline FC was worse in non-survivors than in survivors. More frequent presence of pericardial effusion, higher serum glucose levels, higher estimated systolic pulmonary artery pressure (SPAP) by echocardiography, and higher right atrial pressure (RAP) were found in non-survivors. Higher FC, lower 6MWD, and presence of pericardial effusion were associated with risk of mortality. Patients with worsening FC and increased serum uric acid had an increased risk of mortality during follow-up. CONCLUSIONS: The overall survival remained unsatisfactory in PAH patients. Baseline FC, 6MWD, pericardial effusion, RAP, and a worsening FC and an increased serum uric acid levels during follow-up were significant prognostic parameters.

Improvement of Right Ventricular Function in Pulmonary Arterial Hypertension with Disease-Specific Therapy - A Clinical Observational Study.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a serious and progressive disorder that can result in right ventricular (RV) dysfunction and mortality. Consequently, it is important to monitor RV function during management of PAH. The aim of this study was to investigate the change in RV function by echocardiography before and after disease-specific therapy. METHODS: We recruited 31 PAH patients with functional class (FC) III or IV. All the patients received a comprehensive assessment before disease-specific therapy was administered, including observation of clinical symptoms, 6-min walk distance (6MWD), serum brain natriuretic peptide (BNP) level, and transthoracic echocardiography. The assessment was repeated 12 weeks after therapy. RESULTS: Twenty-eight patients with a mean age of 40 years completed the study, of whom 82% were women. We found that the etiologies were mainly connective tissue disease-associated and idiopathic PAH. Of the patients in our study, 36% received endothelin receptor antagonist and 64% received phosphodiesterase-5 inhibitor. There was a significant improvement in FC after disease-specific therapy (p < 0.001). The 6MWD increased from 326 to 403 m (p < 0.001), and the serum BNP level decreased from 242 to 130 pg/mL (p = 0.008) after treatment. Echocardiography showed significant reduction in the right atrial and RV areas, pulmonary artery pressure, RV free wall thickness, and inferior vena cava diameter. The myocardial performance index and left ventricular eccentricity index were significantly reduced after therapy. CONCLUSIONS: For PAH patients in our study, disease-specific therapy for 12 weeks resulted in an improvement in FC, 6MWD, serum BNP levels, and RV function. KEY WORDS: Disease-specific therapy; Pulmonary arterial hypertension; Right ventricular function.

2014 Guidelines of Taiwan Society of Cardiology (TSOC) for the Management of Pulmonary Arterial Hypertension.

UNLABELLED: Pulmonary hypertension (PH) is a hemodynamic and pathophysiologic condition, defined as a mean pulmonary arterial pressure exceeding 25 mmHg at rest. According to the recent classifications, it is grouped into pulmonary arterial hypertension (PAH), heart-related, lung-related, thromboembolic, and miscellaneous PH. In the past two decades, tremendous advances have occurred in the field of PH. These include (1) development of clinical diagnostic algorithm and a monitoring strategy dedicated to PAH, (2) defining strong rationales for screening at-risk populations, (3) advent of pulmonary specific drugs which makes PAH manageable, (4) recognition of needs of having proper strategy of combining existing pulmonary specific drugs, and/or potential novel drugs, (5) pursuit of clinical trials with optimal surrogate endpoints and study durations, (6) recognition of critical roles of PH/right ventricular function, as well as interdependence of ventricles in different conditions, especially those with various phenotypes of heart failure, and (7) for rare diseases, putting equal importance on carefully designed observation studies, various registries, etc., besides double blind randomized studies. In addition, ongoing basic and clinical research has led to further understanding of relevant physiology, pathophysiology, epidemiology and genetics of PH/PAH. This guidelines from the working group of Pulmonary Hypertension of the Taiwan Society of Cardiology is to provide updated guidelines based on the most recent international guidelines as well as Taiwan's domestic research on PH. The guidelines are mainly for the management of PAH (Group 1) ; however the majority of content can be helpful for managing other types of PH. KEY WORDS: Pulmonary arterial hypertension; Taiwan guidelines.

Exploring the multifaceted impact of lanthanides on physiological pathways in human breast cancer cells.

Lanthanum (La) and cerium (Ce), rare earth elements with physical properties similar to calcium (Ca), are generally considered non-toxic when used appropriately. However, their ions possess anti-tumor capabilities. This investigation explores the potential applications and mechanisms of LaCl3 or CeCl3 treatment in triple-negative breast cancer (TNBC) cell lines. TNBC, characterized by the absence of estrogen receptor (ERα), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression, is prone to early metastasis and resistant to hormone therapy. Our results demonstrate that La/Ce treatment reduces cell growth, and when combined with cisplatin, it synergistically inhibits cell growth and the PI3K/AKT pathway. La and Ce induce oxidative stress by disrupting mitochondrial function, leading to protein oxidation. Additionally, they interfere with protein homeostasis and induce nucleolar stress. Furthermore, disturbance in F-actin web formation impairs cell migration. This study delves into the mechanism by which calcium-like elements La and Ce inhibit breast cancer cell growth, shedding light on their interference in mitochondrial function, protein homeostasis, and cytoskeleton assembly.

Resistance studies of a dithiazol analogue, DBPR110, as a potential hepatitis C virus NS5A inhibitor in replicon systems.

Hepatitis C virus (HCV), a member of the Flaviviridae family, affects approximately 3% of the world's population and is becoming the leading cause of liver disease in the world. Therefore, the development of novel or more effective treatment strategies to treat chronic HCV infection is urgently needed. In our previous study, we identified a potential HCV NS5A inhibitor, BP008. After further systemic optimization, we discovered a more potent HCV inhibitor, DBPR110. DBPR110 reduced the reporter expression of the HCV1b replicon with a 50% effective concentration (EC(50)) and a selective index value of 3.9 ± 0.9 pM and >12,800,000, respectively. DBPR110 reduced HCV2a replicon activity with an EC(50) and a selective index value of 228.8 ± 98.4 pM and >173,130, respectively. Sequencing analyses of several individual clones derived from the DBPR110-resistant RNAs purified from cells harboring genotype 1b and 2a HCV replicons revealed that amino acid substitutions mainly within the N-terminal region (domain I) of NS5A were associated with decreased inhibitor susceptibility. P58L/T and Y93H/N in genotype 1b and T24A, P58L, and Y93H in the genotype 2a replicon were the key substitutions for resistance selection. In the 1b replicon, V153M, M202L, and M265V play a compensatory role in replication and drug resistance. Moreover, DBPR110 displayed synergistic effects with alpha interferon (IFN-α), an NS3 protease inhibitor, and an NS5B polymerase inhibitor. In summary, our results present an effective small-molecule inhibitor, DBPR110, that potentially targets HCV NS5A. DBPR110 could be part of a more effective therapeutic strategy for HCV in the future.

Synthesis of acylguanidine zanamivir derivatives as neuraminidase inhibitors and the evaluation of their bio-activities.

A series of acylguanidine-modified zanamivir analogs were synthesized and their inhibitory activities against the NAs of avian influenza viruses (H1N1 and H3N2) were evaluated. In particular, zanamivir derivative , with a hydrophobic naphthalene substituent, exhibits the best inhibitory activity against group-1 NA with an IC50 of 20 nM.

Discovery of 3-phenyl-1H-5-pyrazolylamine derivatives containing a urea pharmacophore as potent and efficacious inhibitors of FMS-like tyrosine kinase-3 (FLT3).

Preclinical investigations and early clinical trials suggest that FLT3 inhibitors are a viable therapy for acute myeloid leukemia. However, early clinical data have been underwhelming due to incomplete inhibition of FLT3. We have developed 3-phenyl-1H-5-pyrazolylamine as an efficient template for kinase inhibitors. Structure-activity relationships led to the discovery of sulfonamide, carbamate and urea series of FLT3 inhibitors. Previous studies showed that the sulfonamide 4 and carbamate 5 series were potent and selective FLT3 inhibitors with good in vivo efficacy. Herein, we describe the urea series, which we found to be potent inhibitors of FLT3 and VEGFR2. Some inhibited growth of FLT3-mutated MOLM-13 cells more strongly than the FLT3 inhibitors sorafenib (2) and ABT-869 (3). In preliminary in vivo toxicity studies of the four most active compounds, 10f was found to be the least toxic. A further in vivo efficacy study demonstrated that 10f achieved complete tumor regression in a higher proportion of MOLM-13 xenograft mice than 4 and 5 (70% vs 10% and 40%). These results show that compound 10f possesses improved pharmacologic and selectivity profiles and could be more effective than previously disclosed FLT3 inhibitors in the treatment of acute myeloid leukemia.

Development of Furanopyrimidine-Based Orally Active Third-Generation EGFR Inhibitors for the Treatment of Non-Small Cell Lung Cancer.

The development of orally bioavailable, furanopyrimidine-based double-mutant (L858R/T790M) EGFR inhibitors is described. First, selectivity for mutant EGFR was accomplished by replacing the (S)-2-phenylglycinol moiety of 12 with either an ethanol or an alkyl substituent. Then, the cellular potency and physicochemical properties were optimized through insights from molecular modeling studies by implanting various solubilizing groups in phenyl rings A and B. Optimized lead 52 shows 8-fold selective inhibition of H1975 (EGFRL858R/T790M overexpressing) cancer cells over A431 (EGFRWT overexpressing) cancer cells; western blot analysis further confirmed EGFR mutant-selective target modulation inside the cancer cells by 52. Notably, 52 displayed in vivo antitumor effects in two different mouse xenograft models (BaF3 transfected with mutant EGFR and H1975 tumors) with TGI = 74.9 and 97.5% after oral administration (F = 27%), respectively. With an extraordinary kinome selectivity (S(10) score of 0.017), 52 undergoes detailed preclinical development.

Resistance analysis and characterization of a thiazole analogue, BP008, as a potent hepatitis C virus NS5A inhibitor.

Hepatitis C virus (HCV) is a global health problem, affecting approximately 3% of the world's population. The standard treatment for HCV infection is often poorly tolerated and ineffective. Therefore, the development of novel or more effective treatment strategies to treat chronic HCV infection is urgently needed. In this report, BP008, a potent small-molecule inhibitor of HCV replication, was developed from a class of compounds with thiazol core structures by means of utilizing a cell-based HCV replicon system. The compound reduced the reporter expression of the HCV1b replicon with a 50% effective concentration (EC(50)) and selective index value of 4.1 ± 0.7 nM and >12,195, respectively. Sequencing analyses of several individual clones derived from BP008-resistant RNAs purified from cells harboring HCV1b replicon revealed that amino acid substitutions mainly within the N-terminal region (domain I) of NS5A were associated with decreased inhibitor susceptibility. Q24L, P58S, and Y93H are the key substitutions for resistance selection; F149L and V153M play the compensatory role in the replication and drug resistance processes. Moreover, BP008 displayed synergistic effects with alpha interferon (IFN-α), NS3 protease inhibitor, and NS5B polymerase inhibitor, as well as good oral bioavailability in SD rats and favorable exposure in rat liver. In summary, our results pointed to an effective small-molecule inhibitor, BP008, that potentially targets HCV NS5A. BP008 can be considered a part of a more effective therapeutic strategy for HCV in the future.

CSE1L, a novel microvesicle membrane protein, mediates Ras-triggered microvesicle generation and metastasis of tumor cells.

Tumor-derived microvesicles are rich in metastasis-related proteases and play a role in the interactions between tumor cells and tumor microenvironment in tumor metastasis. Because shed microvesicles may remain in the extracellular environment around tumor cells, the microvesicle membrane protein may be the potential target for cancer therapy. Here we report that chromosome segregation 1-like (CSE1L) protein is a microvesicle membrane protein and is a potential target for cancer therapy. v-H-Ras expression induced extracellular signal-regulated kinase (ERK)-dependent CSE1L phosphorylation and microvesicle biogenesis in various cancer cells. CSE1L overexpression also triggered microvesicle generation, and CSE1L knockdown diminished v-H-Ras-induced microvesicle generation, matrix metalloproteinase (MMP)-2 and MMP-9 secretion and metastasis of B16F10 melanoma cells. CSE1L was preferentially accumulated in microvesicles and was located in the microvesicle membrane. Furthermore, anti-CSE1L antibody-conjugated quantum dots could target tumors in animal models. Our findings highlight a novel role of Ras-ERK signaling in tumor progression and suggest that CSE1L may be involved in the "early" and "late" metastasis of tumor cells in tumorigenesis. Furthermore, the novel microvesicle membrane protein, CSE1L, may have clinical utility in cancer diagnosis and targeted cancer therapy.

Synthesis and biological evaluation of 2-amino-1-thiazolyl imidazoles as orally active anticancer agents.

Designed from a high throughput screened hit compound, novel 2-amino-1-thiazolyl imidazoles were synthesized and demonstrated cytotoxicity against human cancer cells. 1-(4-Phenylthiazol-2-yl)-4-(thiophen-2-yl)-1H-imidazol-2-amine (compound 2), a 2-amino-1-thiazolyl imidazole, inhibited tubulin polymerization, interacted with the colchicine-binding sites of tubulins, and caused cell cycle arrest at the G(2)/M phase in human gastric cancer cells. Disruption of the microtubule structure in cancer cells by compound 2 was also observed. Compound 2 concentration-dependently inhibited the proliferation of cancer cells in histocultured human gastric and colorectal tumors. Given orally, compound 2 prolonged the lifespans of leukemia mice intraperitoneally inoculated with the murine P388 leukemic cells. We report 2-amino-1-thiazolyl imidazoles as a novel class of orally active microtubule-destabilizing anticancer agents.

3-Phenyl-1H-5-pyrazolylamine-based derivatives as potent and efficacious inhibitors of FMS-like tyrosine kinase-3 (FLT3).

A new class of FLT3 inhibitors has been identified based on the 3-phenyl-1H-5-pyrazolylamine scaffold. The structure-activity relationships led to the discovery of two carbamate series, and some potent compounds within these two series exhibited better growth inhibition of FLT3-mutated MOLM-13 cells than FLT3 inhibitors sorafenib (2) and ABT-869 (3). In particular, compound 8d exhibited the ability to regress tumors in mouse xenograft model using MOLM-13 cells.

Acyl-Coenzyme A Synthetase Long-Chain Family Member 4 Is Involved in Viral Replication Organelle Formation and Facilitates Virus Replication via Ferroptosis.

Enterovirus infections can cause severe complications, such as poliomyelitis, encephalitis, myocarditis, meningitis, neurological pulmonary edema, and even death. Here, we used genome-wide CRISPR screens to gain new insight into the mechanism by which enteroviruses co-opt host pathways to potentiate replication and propagation. We found that acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) is involved in viral replication organelle formation. ACSL4 is a key component of ferroptosis, an iron-dependent, nonapoptotic programmed cell death. Our results indicated that enteroviruses and coronaviruses can induce ferroptosis via ACSL4. Most importantly, ferroptosis inhibitors, including two FDA-approved drugs, rosiglitazone (ROSI; ACSL4 inhibitor) and pioglitazone (PIO; ACSL4 inhibitor), decreased the viral load of human enteroviruses and coronaviruses, suggesting that ACSL4 is a target for counteracting viral infection. IMPORTANCE We provide the first evidence for the role of ACSL4 in enterovirus replication organelle formation. Moreover, both enteroviruses and coronaviruses induce ferroptosis via ACSL4. These findings establish a novel regulatory mechanism for viral replication. The inhibition of ACSL4 by ferroptosis inhibitors can reduce viral yields of enteroviruses and coronaviruses, including SARS-CoV-2, implying that ACSL4-mediated ferroptosis is a promising therapeutic target for viral diseases.

Targeting the Phosphatidylserine-Immune Checkpoint with a Small-Molecule Maytansinoid Conjugate.

Ligand-targeting drug delivery systems have made significant strides for disease treatments with numerous clinical approvals in this era of precision medicine. Herein, we report a class of small molecule-based immune checkpoint-targeting maytansinoid conjugates. From the ligand targeting ability, pharmacokinetics profiling, in vivo anti-pancreatic cancer, triple-negative breast cancer, and sorafenib-resistant liver cancer efficacies with quantitative mRNA analysis of treated-tumor tissues, we demonstrated that conjugate 40a not only induced lasting regression of tumor growth, but it also rejuvenated the once immunosuppressive tumor microenvironment to an "inflamed hot tumor" with significant elevation of gene expressions that were not accessible in the vehicle-treated tumor. In turn, the immune checkpoint-targeting small molecule drug conjugate from this work represents a new pharmacodelivery strategy that can be expanded with combination therapy with existing immune-oncology treatment options.

Synthesis and Evaluation of Small Molecule Drug Conjugates Harnessing Thioester-Linked Maytansinoids.

Ligand-targeting drug conjugates are a class of clinically validated biopharmaceutical drugs constructed by conjugating cytotoxic drugs with specific disease antigen targeting ligands through appropriate linkers. The integrated linker-drug motif embedded within such a system can prevent the premature release during systemic circulation, thereby allowing the targeting ligand to engage with the disease antigen and selective accumulation. We have designed and synthesized new thioester-linked maytansinoid conjugates. By performing in vitro cytotoxicity, targeting ligand binding assay, and in vivo pharmacokinetic studies, we investigated the utility of this new linker-drug moiety in the small molecule drug conjugate (SMDC) system. In particular, we conjugated the thioester-linked maytansinoids to the phosphatidylserine-targeting small molecule zinc dipicolylamine and showed that Zn8_DM1 induced tumor regression in the HCC1806 triple-negative breast cancer xenograft model. Moreover, in a spontaneous sorafenib-resistant liver cancer model, Zn8_DM1 exhibited potent antitumor growth efficacy. From quantitative mRNA analysis of Zn8_DM1 treated-tumor tissues, we observed the elevation of gene expressions associated with a "hot inflamed tumor" state. With the identification and validation of a plethora of cancer-associated antigens in the "omics" era, this work provided the insight that antibody- or small molecule-based targeting ligands can be conjugated similarly to generate new ligand-targeting drug conjugates.

Isatin-ß-thiosemicarbazones as potent herpes simplex virus inhibitors.

A series of isatin-ß-thiosemicarbazones have been designed and evaluated for antiviral activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in a plaque reduction assay. Their cytotoxicity was examined using human rhabdomyosarcoma cells (RD cells). Several derivatives of isatin-ß-thiosemicarbazone exhibited significant and selective antiviral activity with low cytotoxicity. It was found that the thiourea group at thiosemicarbazone and the NH functionality at isatin were essential for their antiherpetic activity. The synthesis and structure-activity relationship studies are presented.