Search

Purpose: Breast cancer is the most common cancer in women. Triple-negative breast cancer (TNBC) is an aggressive disease with poor outcomes. TNBC lacks effective targeted treatments, and the development of drug resistance limits the effectiveness of chemotherapy. It is crucial to identify new drugs that can enhance the efficacy of traditional chemotherapy to reduce drug resistance and side effects. Methods: TNBC cell lines, MDA-MB-231 and Hs 578T, and a normal cell line, MCF-10 A, were included in this study. The cells were treated with gallium maltolate (GaM), and their transcriptome was analyzed. Ferroptosis and nucleolar stress markers were detected by qPCR, western blotting, fluorescence microscopy, and flow cytometry. The impairment of ribosome synthesis was evaluated by northern blotting and sucrose gradients. Results: GaM triggered cell death via apoptosis and ferroptosis. In addition, GaM impaired translation and activated nucleolar stress. Cisplatin (DDP) is a chemotherapeutic agent for advanced breast cancer. While single treatment with GaM or DDP at low concentrations did not impact cell growth, co-administration enhanced cell death in TNBC but not in normal breast cells. The enhancement of ferroptosis and nucleolar stress could be observed in TNBC cell lines after co-treatment. Conclusions: These results suggest that GaM synergizes with cisplatin via activation of nucleolar stress and ferroptosis in human breast carcinoma cells. GaM is marginally toxic to normal cells but impairs the growth of TNBC cell lines. Thus, GaM has the potential to be used as a therapeutic agent against TNBC. [ABSTRACT FROM AUTHOR]

Highlights: The state-of-the-art progress of flexible thermally conductive films with ultrahigh in-plane isotropic thermal conductivity (k) and potential application are summarized. The heat transfer mechanism, processing methods to enhance k, optimization strategies to reduce interface thermal resistance of flexible thermally conductive films are reviewed. The limitations and opportunities for the future development of flexible thermally conductive films are proposed.Effective thermal management is quite urgent for electronics owing to their ever-growing integration degree, operation frequency and power density, and the main strategy of thermal management is to remove excess energy from electronics to outside by thermal conductive materials. Compared to the conventional thermal management materials, flexible thermally conductive films with high in-plane thermal conductivity, as emerging candidates, have aroused greater interest in the last decade, which show great potential in thermal management applications of next-generation devices. However, a comprehensive review of flexible thermally conductive films is rarely reported. Thus, we review recent advances of both intrinsic polymer films and polymer-based composite films with ultrahigh in-plane thermal conductivity, with deep understandings of heat transfer mechanism, processing methods to enhance thermal conductivity, optimization strategies to reduce interface thermal resistance and their potential applications. Lastly, challenges and opportunities for the future development of flexible thermally conductive films are also discussed. [ABSTRACT FROM AUTHOR]

Copper is an essential micronutrient involved in many redox reactions in human cells. However, a high concentration of copper, intake from the environment or abnormal accumulation within cells because of genetic mutation, leads to cell toxicity. This is attributable to oxidative damage, altered gene expression, and functional impairment of the mitochondria. Copper stress also alters the morphology of the nucleolus, but the process has not been fully elucidated. In this study, cells were treated with copper sulfate at 3–9 ppm and examined if a high dose of copper would block ribosome biogenesis. With the incorrect distribution of nucleolar proteins nucleophosmin and fibrillarin to the nucleoplasm, ribosomal RNA (rRNA) processing was impaired; 34S rRNA from an abnormal A2 cut increased, and downstream pre-rRNAs decreased. The under-accumulation of 60S subunits was detected using sucrose gradients. From transcriptome analysis, ribosome synthesis–related genes were misregulated. Blockage in ribosome synthesis under copper-treatment induced nucleolar stress and triggered p53-independent apoptosis pathways. Thus, nucleolar stress is one cause of cell death under copper exposure. [ABSTRACT FROM AUTHOR]

The Chinese Government has proposed the 'Belt and Road Initiative' (BRI) in order to increase trade flows and economic prosperity among the Belt and Road (BR) member countries. The BRI may call for enlargement of economic cooperation as manifested by forming an economic or monetary union in the long term. It is therefore essential to choose a subset of member countries that fulfils the criteria for joining the potential economic or monetary union. The validity of purchasing power parity (PPP) implies well-integrated goods markets and is a pre-condition for further economic convergence. While the presence of transaction costs causes nonlinearities in the adjustment mechanism, our empirical study applies a three-regime threshold autoregressive (TAR) cointegration method for analysis. Our results support the existence of a PPP relationship with China for 12 sampled Asian member countries. Chinese policymakers can prioritize these BR countries for closer economic cooperation. Also, this TAR cointegration method can estimate the unobservable proportional transaction costs from the thresholds. The results reveal BR countries with large thresholds as targets to curtail transaction costs of trading in order to enhance the efficiency in international goods arbitrage and the degree of trade integration along the BR routes. [ABSTRACT FROM AUTHOR]

β-Linked polysaccharides including β-glucans are well known to be important functional ingredients, and are known to possess immunomodulatory and anti-tumor activities. This study aimed to investigate the anti-inflammatory properties and participating receptor of water soluble and insoluble bioactive polysaccharides from Grifola frondosa (GFP, non-digestible water soluble polysaccharides), Laminaria digitata (laminarin, a water soluble β-glucan) and Saccharomyces cerevisiae (zymosan, a water insoluble β-glucan) in lipopolysaccharide (LPS)-stimulated parental and Dectin-1 highly expressing RAW264.7 macrophages. Results showed that GFP and laminarin significantly inhibited nitric oxide and prostaglandin E2 production, but only the GFP with high molecular weight exhibited strong inhibition on pro-inflammatory cytokine (TNF-α and IL-6) secretion in a concentration-dependent manner. The activation of NF-κB was also significantly down-regulated by GFP treatment as compared with cells treated with LPS alone. Although GFP and laminarin were able to bind to β-glucan receptor Dectin-1, there was no relationship between the inhibitory potency and the content of β-glucans in GFP, and these inhibitory effects were not affected by the expression level of Dectin-1 in macrophage cells. In contrast, zymosan significantly intensified LPS-induced inflammatory responses through Dectin-1. In conclusion, these results suggest that the inhibitory effects of water soluble polysaccharides on LPS-induced pro-inflammatory mediator production in murine macrophages may not involve β-glucan receptor Dectin-1. [ABSTRACT FROM AUTHOR]

We hypothesized that Ventilator-Associated Event (VAE) within 28 days upon admission to medical intensive care units (ICUs) can be a predictor for poor outcomes in sepsis patients. We aimed to determine the risk factors and associated outcomes of VAE. A total of 453 consecutive mechanically ventilated (MV) sepsis patients were enrolled. Of them, 136 patients had immune profile study. Early VAE (< 7-day MV, n = 33) was associated with a higher mortality (90 days: 81.8% vs. 23.0% [non-VAE], P < 0.01), while late VAE (developed between 7 and 28 days, n = 85) was associated with longer MV day (43.8 days vs. 23.3 days [non-VAE], P < 0.05). The 90-day Kaplan–Meier survival curves showed three lines that separate the groups (non-VAE, early VAE, and late VAE). Cox regression models with time-varying coefficient covariates (adjusted for the number of days from intubation to VAE development) confirmed that VAE which occurred within 28 days upon admission to the medical ICUs can be associated with higher 90-day mortality. The risk factors for VAE development include impaired immune response (lower human leukocyte antigen D-related expression, higher interleukin-10 expression) and sepsis progression with elevated SOFA score (especially in coagulation sub-score). [ABSTRACT FROM AUTHOR]

Collective cell migration plays important roles in various physiological processes. To investigate this collective cellular movement, various wound-healing assays have been developed. In these assays, a "wound" is created mechanically, chemically, optically, or electrically out of a cellular monolayer. Most of these assays are subject to drawbacks of run-to-run variations in wound size/shape and damages to cells/substrate. Moreover, in all these assays, cells are cultured in open, static (non-circulating) environments. In this study, we reported a microfluidics-based wound-healing assay by using the trypsin flow-focusing technique. Fibroblasts were first cultured inside this chip to a cellular monolayer. Then three parallel fluidic flows (containing normal medium and trypsin solution) were introduced into the channels, and cells exposed to protease trypsin were enzymatically detached from the surface. Wounds of three different widths were generated, and subsequent wound-healing processes were observed. This assay is capable of creating three or more wounds of different widths for investigating the effects of various physical and chemical stimuli on wound-healing speeds. The effects of shear stresses, wound widths, and β-lapachone (a wound healing-promoting chemical) on wound-healing speeds were studied. It was found that the wound-healing speed (total area healed per unit time) increased with increasing shear stress and wound width, but under a shear stress of 0.174 mPa the linear healing speed (percent area healed per unit time) was independent of the wound width. Also, the addition of β-lapachone up to 0.5 μM did not accelerate wound healing. This microfluidics-based assay can definitely help in understanding the mechanisms of the wound-healing process and developing new wound-healing therapies. [ABSTRACT FROM AUTHOR]

The association between sepsis and segmented neutrophil-to-monocyte (SeMo) ratio is unclear. We postulated that an increase in dynamic SeMo ratio measurement can be applied in risk stratification. This retrospective study included 727 consecutive sepsis patients in medical intensive care units (ICUs), including a subpopulation of 153 patients. According to the leukocyte (white blood cell, WBC) count on day 3 (normal range, between 4,000/µL and 12,000/µL) and delta SeMo (value of SeMo ratio on day 3 minus value of SeMo ratio on day 1; normal delta SeMo, <7), patients were grouped into 3 (delta SeMo & WBC tool). The survival lines separated significantly with hazard ratios of 1.854 (1.342–2.560) for the delta SeMo or WBC abnormal group and 2.860 (1.849–4.439) for the delta SeMo and WBC abnormal group compared to the delta SeMo and WBC normal group. Delta SeMo & WBC tool and delta sequential organ failure assessment (SOFA) tool performed better than the other tools (delta SeMo, delta WBC, day 3 WBC, and day 1 WBC). Severity in delta SeMo & WBC tool and delta SeMo tool reflected the immune dysfunction score, cytokine expression, and human leukocyte antigen D-related monocyte expression on day 1 and day 3. There was correspondence between delta SOFA and delta WBC and between delta SeMo and delta cytokine expression. Incorporation of dynamic SeMo ratio with WBC count provides risk stratification for sepsis patients admitted in the ICU. [ABSTRACT FROM AUTHOR]

Changes in requirements may result in the increasing of product development project cost and lead time, therefore, it is important to understand how requirement changes propagate in the design of complex product systems and be able to select best options to guide design. Currently, a most approach for design change is lack of take the multi-disciplinary coupling relationships and the number of parameters into account integrally. A new design change model is presented to systematically analyze and search change propagation paths. Firstly, a PDS-Behavior-Structure-based design change model is established to describe requirement changes causing the design change propagation in behavior and structure domains. Secondly, a multi-disciplinary oriented behavior matrix is utilized to support change propagation analysis of complex product systems, and the interaction relationships of the matrix elements are used to obtain an initial set of change paths. Finally, a rough set-based propagation space reducing tool is developed to assist in narrowing change propagation paths by computing the importance of the design change parameters. The proposed new design change model and its associated tools have been demonstrated by the scheduling change propagation paths of high speed train's bogie to show its feasibility and effectiveness. This model is not only supportive to response quickly to diversified market requirements, but also helpful to satisfy customer requirements and reduce product development lead time. The proposed new design change model can be applied in a wide range of engineering systems design with improved efficiency. [ABSTRACT FROM AUTHOR]

With the increasing of complexity of complex mechatronic products, it is necessary to involve multidisciplinary design teams, thus, the traditional customer requirements modeling for a single discipline team becomes difficult to be applied in a multidisciplinary team and project since team members with various disciplinary backgrounds may have different interpretations of the customers' requirements. A new synthesized multidisciplinary customer requirements modeling method is provided for obtaining and describing the common understanding of customer requirements (CRs) and more importantly transferring them into a detailed and accurate product design specifications (PDS) to interact with different team members effectively. A case study of designing a high speed train verifies the rationality and feasibility of the proposed multidisciplinary requirement modeling method for complex mechatronic product development. This proposed research offersthe instruction to realize the customer-driven personalized customization of complex mechatronic product. [ABSTRACT FROM AUTHOR]

α-Synuclein is a central component of the pathogenesis of Parkinson's disease (PD). Phosphorylation at serine-129 represents an important post-translational modification and constitutes the major form of the protein in Lewy bodies. Several kinases have been implicated in the phosphorylation of α-synuclein. The targeting of kinase pathways as a potential to influence the pathogenesis of PD is an important focus of attention, given that mutations of specific kinases (LRRK2 and PINK1) are causes of familial PD. Pramipexole (PPX) is a dopamine agonist developed for the symptomatic relief of PD. Several in vitro and in vivo laboratory studies have demonstrated that PPX exerts neuroprotective properties in model systems of relevance to PD. The present study demonstrates that PPX inhibits the phosphorylation of α-synuclein and that this is independent of dopamine receptor activation. PPX blocks the increase in phosphorylated α-synuclein induced by inhibition of the ubiquitin proteasomal system. The phosphorylation of α-synuclein occurs in part at least through casein kinase 2, and PPX in turn reduces the phosphorylation of this enzyme, thereby inhibiting its activity. Thus, PPX decreases the phosphorylation of α-synuclein, and this mechanism may contribute to its protective properties in PD models. [ABSTRACT FROM AUTHOR]

The optical light curve of the BL Lac object OQ 530 is constructed based on published data. Diagrams showing the correlations of fluxes in different wavelength ranges are constructed and used to analyze the color variations. The relative spectral energy distribution of the variable source in the optical can be represented by a power law that is stable on long time scales. The average spectral index is −1.15±0.02, indicating that the radiation of the variable source probably has a synchrotron nature. [ABSTRACT FROM AUTHOR]

The Trömner sign is commonly used as a clinical neurological examination for upper motor neuron lesions above the fifth or sixth cervical segments of the spinal cord. This study aims to assess and quantify the Trömner signs utilizing electrophysiological test, and correlate to the severity of cord compression in cervical spondylotic myelopathy (CSM). We enlisted 46 CSM patients, and 30 healthy persons as controls. Manual Trömner and Hoffmann signs were tested in all subjects. By using a self-designed instrument, we performed electrophysiological assessments for the Trömner signs in patients and controls. Parameters of conduction latencies and amplitude of muscle action potentials were measured and compared with the cord compression ratios in CSM patients. The results showed a greater diagnostic sensitivity for the quantified Trömner signs in comparison to those of manual Trömner signs and Hoffmann signs. We found a positive correlation between the amplitude of muscle action potentials obtained in the Trömner signs and the cord compression ratios in the patients with CSM. In conclusion, the Trömner signs can be measured by electrophysiological assessments. We demonstrate a new quantification method for an established neurological sign. Not only is Trömner sign a highly sensitive test in clinical neurological examination, the electrophysiological assessment of this sign can also serve as an objective marker for evaluation of the severity of cervical cord compression. [ABSTRACT FROM AUTHOR]

The Trömner sign is commonly used as a clinical neurological examination for upper motor neuron lesions above the fifth or sixth cervical segments of the spinal cord. This study aims to assess and quantify the Trömner signs utilizing electrophysiological test, and correlate to the severity of cord compression in cervical spondylotic myelopathy (CSM). We enlisted 46 CSM patients, and 30 healthy persons as controls. Manual Trömner and Hoffmann signs were tested in all subjects. By using a self-designed instrument, we performed electrophysiological assessments for the Trömner signs in patients and controls. Parameters of conduction latencies and amplitude of muscle action potentials were measured and compared with the cord compression ratios in CSM patients. The results showed a greater diagnostic sensitivity for the quantified Trömner signs in comparison to those of manual Trömner signs and Hoffmann signs. We found a positive correlation between the amplitude of muscle action potentials obtained in the Trömner signs and the cord compression ratios in the patients with CSM. In conclusion, the Trömner signs can be measured by electrophysiological assessments. We demonstrate a new quantification method for an established neurological sign. Not only is Trömner sign a highly sensitive test in clinical neurological examination, the electrophysiological assessment of this sign can also serve as an objective marker for evaluation of the severity of cervical cord compression. [ABSTRACT FROM AUTHOR]

Background: Recent efforts suggest an etiologic role of hepatitis B virus (HBV) infection in intrahepatic cholangiocarcinoma (ICC) and the involvement of hepatic progenitor cell in ICC development, without definitive conclusions. This case-control study was undertaken to investigate risk factors for ICC, and clinicopathological features of HBV-associated ICC were analyzed. Methods: The report comprised 98 patients with pathologically confirmed ICC and 196 healthy control subjects. Logistic regression was used to determine odds ratios and 95% confidence intervals. The sex and age distributions of HBV-related and unrelated ICC patients were compared respectively with those of 882 HBV-associated hepatocellular carcinoma patients from a random selection, and the clinicopathological data of 62 ICC patients with or without HBV infection undergoing surgical resection were compared. Results: There was an association between ICC and each of HBV infection, liver cirrhosis, hepatolithiasis, and liver fluke infestation with the odds ratios (95% confidence intervals) of 2.75 (1.27-5.95), 8.42 (2.50-28.37), 22.81 (7.16-72.68), and 3.55 (1.60-7.89), respectively, with a marked synergism of cirrhosis and HBV infection (20.67; 5.40-79.06). Compared with HBV-unrelated ICC patients, HBV-related ICC patients were more common in male and younger subjects, had a higher incidence of abnormal serum alfa-fetoprotein level, cirrhosis, and neutrophilic infiltration, and had a lower proportion of elevated carbohydrate antigen 19-9 (CA19-9) values. Conclusions: The independent association of HBV infection with ICC, synergy between cirrhosis and HBV infection, and some clinicopathological similarities between HBV-related ICC and hepatocellular carcinoma suggests that both may share similar or common tumorigenic process and may possibly originate from malignant transformation of hepatic progenitor cell. [ABSTRACT FROM AUTHOR]

Aim:To determine the effects and potential mechanisms of ibrolipim on ATP-binding membrane cassette transporter A-1 (ABCA1) and ATP-binding membrane cassette transporter G-1 (ABCG1) expression from human macrophage foam cells, which may play a critical role in atherogenesis.Methods:Human THP-1 cells pre-incubated with ox-LDL served as foam cell models. Specific mRNA was quantified using real-time RT-PCR and protein expression using Western blotting. Cellular cholesterol handling was studied using cholesterol efflux experiments and high performance liquid chromatography assays.Results:Ibrolipim 5 and 50 μmol/L significantly increased cholesterol efflux from THP-1 macrophage-derived foam cells to apoA-I or HDL. Moreover, it upregulated the expression of ABCA1 and ABCG1. In addition, LXRα was also upregulated by the ibrolipim treatment. In addition, LXRα small interfering RNA completely abolished the promotion effect that was induced by ibrolipim.Conclusion:Ibrolipim increased ABCA1 and ABCG1 expression and promoted cholesterol efflux, which was mediated by the LXRα signaling pathway. [ABSTRACT FROM AUTHOR]

The synthesis, characterization and photophysics of a solution-processable metallopolyyne of platinum ( P1) functionalized with the dioctyloxyphenyl-substituted thienopyrazine–thiophene hybrid spacer and its model molecular complex ( M1) are described. Such metallopolymer P1 possesses a very low bandgap of 1.50 eV which extends towards the near-infrared (NIR) range of the solar spectrum, and represents one of the lowest optical bandgaps reported for metallopolyynes. With the capability of spanning a wider solar-radiation range, P1 can be used to fabricate efficient solar cells with power conversion efficiencies (PCEs) of up to 0.46% under air mass (AM1.5) simulated solar illumination. The electronic effect of the central heterocyclic ring sandwiched between the two thiophene units on the optical properties of these metallopolyynes has been investigated. The present study provides a good approach towards achieving conjugated polymeric materials with a broad solar absorption and demonstrates the potential of low-bandgap metallopolyynes for simultaneous visible and NIR light power generation. [ABSTRACT FROM AUTHOR]

Abstract  In this paper, the antenna-radome system in millimeter wave band is analyzed by the aperture integration-surface integration (AI-SI) method. When the electromagnetic wave passes through the radome, the transmission coefficient is determined by the transmission line analogy. However, the conventional transmission coefficient always ignores the phase factor of the lateral transmission in the dielectric. In the present work, the modified transmission coefficient is proposed and verified by both the theoretical derivation and the experimental measurement. The measured results of the antenna-radome systems at W-band show that the modified transmission coefficient is more accurate than the conventional one in the antenna-radome analysis. [ABSTRACT FROM AUTHOR]

BACKGROUND AND OBJECTIVE: In Hong Kong, about 10% of adults 25–74 years of age have diabetes mellitus. The management of dyslipidemia with lipid-lowering agents (LLAs), including HMG-CoA reductase inhibitors (statins) for the primary prevention of cardiovascular complications, has been found to be beneficial. This study examined statin utilization patterns for the primary prevention of cardiovascular events in patients with diabetes mellitus in two public hospitals in Kong Kong; clinical outcomes in patients who received statins for primary prevention were compared with those in patients not treated with any LLAs. METHODS: This was a retrospective study in patients who were diagnosed with diabetes mellitus. Only patients with no prior history of coronary artery disease were included in the study. Utilization patterns of LLAs and the incidences of cardiovascular complications were recorded from 1 January 2002 to 31 December 2003. RESULTS: A total of 222 patient records were reviewed. Only 75/222 (33.8%) of patients with diabetes mellitus received one or more LLAs for the primary prevention of cardiovascular events. Among these patients, only 21% of patients attained target lipid goals. Nearly half of the patients who were not treated with LLAs (n = 147) had dyslipidemia problems. The overall incidence of cardiovascular complications in patients treated and not treated with LLAs was 12.2%. Absence of routine screening for cardiovascular risk and sub-optimal utilization and inadequate dosage titration of LLAs were identified as contributory factors towards cardiovascular events in this patient group. CONCLUSION: The current study failed to prove the benefits of LLAs in reducing the risk of first cardiovascular events in diabetic patients. This may have been due to the use of low doses of LLAs and a lack of laboratory monitoring of cholesterol levels. Development and implementation of guidelines may help promote the use of LLAs in primary prevention of cardiovascular complications. [ABSTRACT FROM AUTHOR]

Bulk heterojunction solar cells have been extensively studied owing to their great potential for cost-effective photovoltaic devices. Although recent advances resulted in the fabrication of poly(3-hexylthiophene) (P3HT)/fullerene derivative based solar cells with efficiencies in the range 4.4–5.0%, theoretical calculations predict that the development of novel donor materials with a lower bandgap is required to exceed the power-conversion efficiency of 10%. However, all of the lower bandgap polymers developed so far have failed to reach the efficiency of P3HT-based cells. To address this issue, we synthesized a soluble, intensely coloured platinum metallopolyyne with a low bandgap of 1.85 eV. The solar cells, containing metallopolyyne/fullerene derivative blends as the photoactive material, showed a power-conversion efficiency with an average of 4.1%, without annealing or the use of spacer layers needed to achieve comparable efficiency with P3HT. This clearly demonstrates the potential of metallated conjugated polymers for efficient photovoltaic devices. [ABSTRACT FROM AUTHOR]

This paper undertakes an empirical investigation into the existence of inflationary bubbles during the inter-war European hyperinflation for Germany, Hungary, Poland and Russia. Our Monte Carlo simulations show that the residual-based threshold cointegration methodology of Caner and Hansen (2001) is better able to detect periodically collapsing bubbles. Moreover, this methodology possesses greater power against nonlinear stationary alternatives in a finite sample than several commonly used cointegration tests that do not allow for multiple regime shifts. The empirical results of the threshold cointegration tests provide evidence of stationary, regime-switching processes in money demand dynamics, but suggest that there are no inflationary bubbles in any of the countries. [ABSTRACT FROM AUTHOR]

Cognitive ability screening instrument (CASI) is a cross-cultural mental screening test to evaluate the severity of dementia of Alzheimer's disease. In this research, a characteristic-point-based fuzzy inference system (CPFIS) is proposed to predict the CASI scores from the single-photon emission computed tomography (SPECT) volumes. Experiment results showed that CPFIS could provide a rough estimation of CASI scores that the P value for the hypothesis that the average of absolute errors of CPFIS is less than the average of absolute differences from the mean values was 0.0447. For comparison, a weighted support vector regression (SVR) machines was also tried. The performance of CPFIS was slightly better than SVR in this study (P=0.068). [ABSTRACT FROM AUTHOR]

Two patients with Hoffa fracture of the knee, both suffering from poliomyelitis are reported. Both had unicondylar coronal plane fracture of the medial femoral condyle. The patients were treated with open reduction and screw fixation. Due to poor screw purchase, reoperation was necessary in one patient. The results were satisfactory in both patients. [ABSTRACT FROM AUTHOR]

Thallium is considered as an emergent contaminant owing to its potential use in the superconductor alloys. The monovalent thallium, Tl(I), is highly toxic to the animals as it can affect numerous metabolic processes. Here we observed that Tl(I) decreased protein synthesis and phosphorylated eukaryotic initiation factor 2α. Although Tl(I) has been shown to interact with the sulfhydryl groups of proteins and cause the accumulation of reactive oxygen species, it did not activate endoplasmic reticulum stress. Notably, the level of 60S ribosomal subunit showed significant under-accumulation after the Tl(I) treatment. Given that Tl(I) shares similarities with potassium in terms of the ionic charge and atomic radius, we proposed that Tl(I) occupies certain K+-binding sites and inactivates the ribosomal function. However, we observed neither activation of ribophagy nor acceleration of the proteasomal degradation of 60S subunits. On the contrary, the ribosome synthesis pathway was severely blocked, i.e., the impairment of rRNA processing, deformed nucleoli, and accumulation of 60S subunits in the nucleus were observed. Although p53 remained inactivated, the decreased c-Myc and increased p21 levels indicated the activation of nucleolar stress. Therefore, we proposed that Tl(I) interfered the ribosome synthesis, thus resulting in cell growth inhibition and lethality. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article published in July 2007 which discusses the platinum metallopolyyne donor polymer.

Globally, colorectal cancer (CRC) is the third most frequently occurring cancer. Progression on to an advanced metastatic malignancy (metCRC) is often indicative of poor prognosis, as the 5-year survival rates of patients decline rapidly. Despite the availability of many systemic therapies for the management of metCRC, the long-term efficacies of these regimens are often hindered by the emergence of treatment resistance due to intratumoral and intertumoral heterogeneity. Furthermore, not all systemic therapies have associated biomarkers that can accurately predict patient responses. Hence, a functional personalised oncology (FPO) approach can enable the identification of patient-specific combinatorial vulnerabilities and synergistic combinations as effective treatment strategies. To this end, we established a panel of CRC patient-derived organoids (PDOs) as clinically relevant biological systems, of which three pairs of matched metCRC PDOs were derived from the primary sites (ptCRC) and metastatic lesions (mCRC). Histological and genomic characterisation of these PDOs demonstrated the preservation of histopathological and genetic features found in the parental tumours. Subsequent application of the phenotypic-analytical drug combination interrogation platform, Quadratic Phenotypic Optimisation Platform, in these pairs of PDOs identified patient-specific drug sensitivity profiles to epigenetic-based combination therapies. Most notably, matched PDOs from one patient exhibited differential sensitivity patterns to the rationally designed drug combinations despite being genetically similar. These findings collectively highlight the limitations of current genomic-driven precision medicine in guiding treatment strategies for metCRC patients. Instead, it suggests that epigenomic profiling and application of FPO could complement the identification of novel combinatorial vulnerabilities to target synchronous ptCRC and mCRC., (© 2024. The Author(s).)