Search

The high expression of the ATP-binding cassette (ABC) drug transporter ABCG2 in cancer cells contributes to the emergence of multidrug resistance (MDR) in individuals afflicted with either solid tumors or blood cancers. MDR poses a major impediment in the realm of clinical cancer chemotherapy. Recently, substantial endeavors have been dedicated to identifying bioactive compounds isolated from nature capable of counteracting ABCG2-mediated MDR in cancer cells. Imperatorin, a natural coumarin derivative renowned for its diverse pharmacological properties, has not previously been explored for its impact on cancer drug resistance. This study investigates the chemosensitizing potential of imperatorin in ABCG2-overexpressing cancer cells. Experimental results reveal that at sub-toxic concentrations, imperatorin significantly antagonizes the activity of ABCG2 and reverses ABCG2-mediated MDR in a concentration-dependent manner. Furthermore, biochemical data and in silico analysis of imperatorin docking to the inward-open conformation of human ABCG2 indicate that imperatorin directly interacts with multiple residues situated within the transmembrane substrate-binding pocket of ABCG2. Taken together, these results furnish substantiation that imperatorin holds promise for further evaluation as a potent inhibitor of ABCG2, warranting exploration in combination drug therapy to enhance the effectiveness of therapeutic agents for patients afflicted with tumors that exhibit high levels of ABCG2.

Abstract Background Health technology assessment (HTA) has become essential in many countries over the past few years, and the demand for HTA professionals has increased in academia, governments, and industries. This study aimed to examine which courses are most important and which training activities are most helpful for the development of HTA proficiency as perceived by HTA experts. Methods The survey questionnaire was developed by literature review and expert opinion. Convenience sampling was used to survey HTA experts from the industrial sector, academic/research units, and government/independent assessment organizations using an online survey tool, SurveyCake. We collected respondents’ demographic information and asked them to assess the importance of each course included in an HTA program on a 5-point Likert Scale (1 = least important; 5 = highly important). In addition, respondents were asked to assess the extent to which various activities are helpful for HTA proficiency development. Results A total of 158 domestic and overseas experts in HTA-related fields were invited to participate in the survey and 68 completed the questionnaire. Among the respondents, the majority were female (57.4%) and working in academia (44.1%). The mean ± standard deviation of respondents’ age and number of years spent in HTA-related fields were 43.2 ± 11.0 years and 11.3 ± 9.9 years, respectively. The course that was rated the most important was “Pharmacoeconomics/Cost-effectiveness analysis” with a score of 4.8 ± 0.4 points, followed by “Health economics” at 4.7 ± 0.7 points. Moreover, internships at HTA-related institutions were perceived to be the most helpful training activity for HTA proficiency development. Conclusions Our study findings provide a better understanding of the requirements for developing HTA proficiency and can serve as a reference for the modification of current HTA education and training programs.

This study investigated the antimicrobial resistance of isolates from patients with refractory Helicobacter pylori. The resistance rate was 34.1% for amoxicillin, 92.7% for clarithromycin, 65.9% for metronidazole, 85.4% for levofloxacin, and 29.3% for rifabutin. Dual resistance to both clarithromycin and levofloxacin was found in 73.2%. The antimicrobial resistance rate of refractory H. pylori was extremely high, which had become a major consideration in therapeutic challenge.

Background: Pneumocystis pneumonia (PCP) is a disease caused by the opportunistic infection of the fungus Pneumocystis jirovecii. Several PCR methods have been developed to aid in the diagnosis of PCP. In this study, we evaluated the performance of a real-time PCR in the diagnosis of PCP, in patients with various underlying diseases. Methods: Ninety-seven BAL samples and 94 sputum samples from 191 patients were used in the study. Patients were classified as PCP (121 patients) or non-PCP (70 patients) based on their clinical and radiological presentations. Results: Real time PCR amplified the P. jirovecii mitochondrial large-subunit rRNA gene with a detection limit of 68 copies of DNA per reaction. Non-PCP pathogens including 32 different fungi and bacteria were also evaluated. Overall, 71.9% of the samples from PCP patients and 14.5% of those from non-PCP patients were positive for the PCR test with a CT value of the real-time PCR below 45. The main underlying diseases of the patients were hematological or solid malignancies (47.1%) and HIV infection (8.9%). The CT values of the test were significantly lower in BAL samples from PCP patients than those from non-PCP patients (p = 0.024). No non-PCP patient had a CT value below 30, whereas samples from 24.8% of PCP patients with underlying diseases had a CT value below 30. Conclusion: Since false positive PCR results were obtained, perhaps due to colonization, we suggest that the diagnosis of PCP should be based on a combination of clinical symptoms, underlying diseases, and PCR results.

Constitutive activation of the phosphoinositide-3-kinase (PI3K)/Akt signaling pathway is crucial for tumor growth and progression. As such, this pathway has been an enticing target for drug discovery. Although HS-173 is a potent PI3K inhibitor that halts cancer cell proliferation via G2/M cell cycle arrest, the resistance mechanisms to HS-173 have not been investigated. In this study, we investigated the susceptibility of HS-173 to efflux mediated by the multidrug efflux transporters ABCB1 and ABCG2, which are two of the most well-known ATP-binding cassette (ABC) transporters associated with the development of cancer multidrug resistance (MDR). We found that the overexpression of ABCB1 or ABCG2 significantly reduced the efficacy of HS-173 in human cancer cells. Our data show that the intracellular accumulation of HS-173 was substantially reduced by ABCB1 and ABCG2, affecting G2/M arrest and apoptosis induced by HS-173. More importantly, the efficacy of HS-173 in multidrug-resistant cancer cells could be recovered by inhibiting the drug-efflux function of ABCB1 and ABCG2. Taken together, our study has demonstrated that HS-173 is a substrate for both ABCB1 and ABCG2, resulting in decreased intracellular concentration of this drug, which may have implications for its clinical use.

The overexpression of P-glycoprotein (P-gp/ABCB1), an ATP-binding cassette (ABC) drug transporter, often contributes to the development of multidrug resistance (MDR) in cancer cells. P-gp mediates the ATP hydrolysis-dependent efflux of a wide range of chemotherapeutic agents out of cancer cells, thereby reducing the intracellular drug accumulation and decreasing the chemosensitivity of these multidrug-resistant cancer cells. Studies with tyrosine kinase inhibitors (TKIs) in P-gp-overexpressing cells have shown that certain TKIs could reverse MDR mediated by P-gp, while some TKIs are transported by P-gp. In the present work, we explored the prospect of repositioning branebrutinib (BMS-986195), a highly selective inhibitor of Bruton’s tyrosine kinase (BTK), to resensitize P-gp-overexpressing multidrug-resistant cancer cells to chemotherapeutic agents. Our results demonstrated that branebrutinib is capable of reversing P-gp-mediated MDR at sub-toxic concentrations, most likely by directly inhibiting the drug transport function of P-gp. Our findings were supported by the result of branebrutinib stimulating the ATPase activity of P-gp in a concentration-dependent manner and the in silico study of branebrutinib binding to the substrate-binding pocket of P-gp. In addition, we found that branebrutinib is equally cytotoxic to drug-sensitive parental cell lines and the respective P-gp-overexpressing multidrug-resistant variants, suggesting that it is unlikely that the overexpression of P-gp in cancer cells plays a significant role in reduced susceptibility or resistance to branebrutinib. In summary, we discovered an additional pharmacological action of branebrutinib against the activity of P-gp, which should be investigated further in future drug combination studies.

Taiwan's presidential-cum-parliamentary elections of January 2024 broke the traditional pattern of power turnover that happened every eight years (or two presidential terms). The political pendulum was stopped. The elections also brought about a Legislative Yuan devoid of a majority party. The direct cause of these two phenomena is to be found iii the rise of a significant third political force, Ko Wenje and his Taiwan People's Party (TPP). It was Ko's injection into the presidential race that divided the opposition and foiled the KNIT's aspiration to stage a political comeback. It is also because of the TPP's strong showing iii the party vote and the proportional seats it received that the party could play the role of a pivot, a veto player iii the new Legislative Yuan. Whether the Ko Wen-je phenomenon will last and the TPP thrive remains to be seen. A comparison with James Soong and his People First Party (PFP) is made. Reversion to the old system is deemed a likely outcome. The political implications of the elections are twofold: domestically the newly elected president will collide with the parliament over cabinet formation; externally mainland China is bound to put even greater pressure on Taiwan now that a pro-independence president has been elected. Voters extended the DPP government's mandate but put restrictions on its powers. This is the framework within which difficult decisions have to be made iii the following four years. [ABSTRACT FROM AUTHOR]

Abstract Background The tyrosine kinase Src is involved in the progression of many cancers. Moreover, inhibiting Src activity has been shown to obstruct several signaling pathways regulated by the EGFR. Thus, Src is a valuable target molecule in drug development. The purpose of this study was to identify compounds that directly or indirectly modulate Src to suppress lung cancer cell growth and motility and to investigate the molecular mechanisms underlying the effects of these compounds. Methods Human non-small cell lung cancer (NSCLC) cell lines (PC9, PC9/gef, A549, and H1975) with different EGFR statuses were tested by cytotoxicity and proliferation assays after AC-93253 iodide treatment. Src and Src-related protein expression in AC-93253 iodide-treated PC9, PC9/gef, and A549 cells were assessed by western blotting. The effects of AC-93253 iodide on cancer cell colony formation, invasion, and migration were assessed in PC9 and PC9/gef cells. The synergistic effects of gefitinib and AC-93253 iodide were evaluated by combination index (CI)-isobologram analysis in gefitinib-resistant cell lines. The efficacy of AC-93253 iodide in vivo was determined using nude mice treated with either the compound or the vehicle. Results Among the compounds, AC-93253 iodide exhibited the most potent dose-independent inhibitory effects on the activity of Src as well as on that of the Src-related proteins EGFR, STAT3, and FAK. Furthermore, AC-93253 iodide significantly suppressed cancer cell proliferation, colony formation, invasion, and migration in vitro and tumor growth in vivo. AC-93253 iodide sensitized tumor cells to gefitinib treatment regardless of whether the cells were gefitinib-sensitive (PC9) or resistant (H1975 and PC9/gef), indicating that it may exert synergistic effects when used in combination with established therapeutic agents. Our findings also suggested that the inhibitory effects of AC-93253 iodide on lung cancer progression may be attributable to its ability to modulate multiple proteins, including Src, PI3K, JNK, Paxillin, p130cas, MEK, ERK, and EGFR. Conclusions Our data suggest that AC-93253 iodide inhibits NSCLC cell growth and motility by regulating multiple Src-related pathways. Our findings may facilitate the development of therapeutic strategies and anti-tumor drugs that may be useful for treating lung cancer in the future.

Soybean is one of the major oil seed crops, which is usually intercropped with other crops to increase soybean production area and yield. However, soybean is highly sensitive to shading. It is unclear if soybean morphology responds to shading (i.e., shade tolerance or avoidance) and which features may be suitable as screening materials in relay strip intercropping. Therefore, in this study, various agronomic characteristics of different soybean genotypes were analyzed under relay intercropping conditions. The soybean materials used in this study exhibited genetic diversity, and the coefficient of variations of the agronomic parameters ranged from 13.84 to 72.08% during the shade period and from 6.44 to 52.49% during the maturity period. The ratios of shading to full irradiance in stem mass fraction (SMF) were almost greater than 1, whereas opposite results were found in the leaves. Compared with full irradiance, the average stem length (SL), leaf area ratio (LAR) and specific leaf area (SLA) for the two years (2013 and 2014) increased by 0.78, 0.47 and 0.65 under shady conditions, respectively. However, the stem diameter (SD), total biomass (TB), leaf area (LA), number of nodes (NN) on the main stem, and number of branches (BN) all decreased. During the shady period, the SL and SMF exhibited a significant negative correlation with yield, and the SD exhibited a significant positive correlation with yield. The correlation between the soybean yield and agronomic parameters during the mature period, except for SL, the first pod height (FPH), 100-seed weight (100-SW), and reproductive growth period (RGP), were significant (P

Three metal-organic coordination polymers {[Cu(L)(N3)]·(H2O)0.25}n (1), {[Zn(L)(N3)]·(H2O)0.5}n(2)and [Cd2(L)2(N3)2(H2O)]n(3)have been synthesized from hydrazone ligand N′-(1-(pyrazin-2-yl)ethylidene)isonicotinohydrazide (HL), NaN3 and corresponding metal nitrates. Complexes were characterized by elemental analysis, IR spectroscopy and single-crystal X-ray diffraction. All three complexes feature 2D coordination network in which L1– acts as NNON tetradentate ligand and azide acts as end-on bridging ligand. In complexes 1 and 2, only intra-sheet hydrogen bonding interactions are found, while the hydrogen bonding interactions between water molecules and host framework result in 3D network for 3. In addition, complexes 2 and 3 exhibited intense fluorescent emissions in the solid state at room temperature.

Poly(methyl methacrylate) (PMMA) is the most frequently used bone void filler in orthopedic surgery. However, the interface between the PMMA-based cement and adjacent bone tissue is typically weak as PMMA bone cement is inherently bioinert and not ideal for bone ingrowth. The present study aims to improve the affinity between the polymer and ceramic interphases. By surface modifying nano-sized hydroxyapatite (nHAP) with ethylene glycol and poly(ɛ-caprolactone) (PCL) sequentially via a two-step ring opening reaction, affinity was improved between the polymer and ceramic interphases of PCL-grafted ethylene glycol-HAP (gHAP) in PMMA. Due to better affinity, the compressive strength of gHAP/PMMA was significantly enhanced compared with nHAP/PMMA. Furthermore, PMMA with 20 wt.% gHAP promoted pre-osteoblast cell proliferation in vitro and showed the best osteogenic activity between the composites tested in vivo. Taken together, gHAP/PMMA not only improves the interfacial adhesion between the nanoparticles and cement, but also increases the biological activity and affinity between the osteoblast cells and PMMA composite cement. These results show that gHAP and its use in polymer/bioceramic composite has great potential to improve the functionality of PMMA cement.

Ataxia is one of the most devastating symptoms of many neurodegenerative disorders. As of today, there is not any effective treatment to retard its progression. Mesenchymal stem cells (MSCs) have shown promise in treating neurodegenerative diseases. We hereby report the results of a phase I/IIa clinical study conducted in Taiwan to primarily evaluate the safety, tolerability, and, secondarily, the possible efficacy of intravenous administration of allogeneic adipose tissue-derived MSCs from healthy donors. Six patients with spinocerebellar ataxia type 3 and one with multiple system atrophy-cerebellar type were included in this open-label study with intravenous administration of 10 6 cells/kg body weight. The subjects were closely monitored for 1 year for safety (vital signs, complete blood counts, serum biochemical profiles, and urinalysis) and possible efficacy (scale for assessment and rating of ataxia and sensory organization testing scores, metabolite ratios on the brain magnetic resonance spectroscopy, and brain glucose metabolism of 18-fluorodeoxyglucose using positron emission tomography). No adverse events related to the injection of MSCs during the 1-year follow-up were observed. The intravenous administration of allogeneic MSCs seemed well tolerated. Upon study completion, all patients wished to continue treatment with the allogeneic MSCs. We conclude that allogeneic MSCs given by intravenous injection seems to be safe and tolerable in patients with spinocerebellar ataxia type 3, thus supporting advancement of the clinical development of allogeneic MSCs for the treatment of spinocerebellar ataxias (SCAs) in a randomized, double-blind, placebo-controlled phase II trials.

China's perspective of the Indo-Pacific as a set of strategies initially developed by Japan but mainly driven by the United States (US), appears to be shifting. Beijing originally viewed such approaches as directly countering its influence in the mega-region of the same name. Yet, more recently China has made pronouncements that seem to suggest its relative support of particular state and regional organisation's Indo-Pacific strategies. This article explores this changing perspective and the dilemmas facing China as a rising global power in a liberal international order through the lens of strategic narratives. On the one hand China understands that it needs to engage the global system and cannot isolate from it, and at the same time, Beijing seeks to challenge the US-led liberal international order to achieve its ambitions. This dual approach is explained through China's use of alternative diplomacy and is further explored through two examples. The first is China's engagement in the Western Indo-Pacific and specifically Africa (an emphasis of this journal volume), where it remains a strategic partner in the political and tangible economic sense. Secondly, at the conceptual level, the Indo-Pacific is not yet an institutionalised concept and its contours and future are left open to interpretation. Since allegiances and interests are shifting, China has the opportunity to contribute to the very ideas and norms that inform what the 'Indo-Pacific' means in ways that can further its own strategic interests. [ABSTRACT FROM AUTHOR]

This article explores the evolution of the 'Indo-Pacific' as a concept and geopolitical social construct. Since 2007, the concept has been framed predominatly to fit the geostrategic concerns of global North powers. Contrary to this slant taken by an array of recent Indo-Pacific strategies, the concept itself is historically rooted in ideas of anticolonial politics, social justice, developmentalism, and cooperation. Regional Security Complex (RSC) theory is applied as a useful conceptual framework and shows how security problems and concerns are intimately tied to others and are thereby relational. Indeed, such a theory will need to increasingly account for ocean regions and move away from a terra-centric focus. Finally, the article explores the role of political geography. While the security complex in this mega-region is defined by particular states, the physical boundaries remain open to interpretation based on a state's view of itself and its geography, as well as how it makes sense and projects its changing interests. It is for these reasons that the western Indo-Pacific and African littoral states remain unevenly accounted for. [ABSTRACT FROM AUTHOR]

The article discusses The concept of 'Indo-Pacific' has rapidly evolved over the past decade and a half, with a shift from the previous emphasis on 'Asia Pacific'. Countries and regional organizations have released Indo-Pacific strategies or policies, indicating their recognition of the growing importance of the Indo-Pacific in the global political and economic arenas, as well as their efforts to address the rise of China and its global influence.