Methadone Conversion Using a 3-Day Switch Strategy in Patients with Cancer on High-Dose Opioids: A Retrospective Study.

INTRODUCTION: Methadone has shown effectiveness in pain control in patients with cancer who are intolerant to other opioids in China. However, the optimal strategy for methadone conversion from previous high doses of opioids in refractory cancer pain remains debatable. This study aimed to describe the efficacy and safety of a 3-day switch (3DS) strategy for methadone conversion in patients with refractory cancer pain on high doses of opioids. METHODS: We retrospectively reviewed 30-day medical records of 70 patients with refractory cancer pain who used a 3DS strategy for methadone conversion from previous high doses of opioids from July 2018 to December 2022. The 3DS strategy indicated that the methadone dose was increased by one third every day for 3 days. Data on the rate of successful conversion, the time to stable analgesia after conversion, the conversion efficiency, the corrected QT (QTc) interval, the actual conversion ratios, adverse events (AEs), and quality of life were analyzed. RESULTS: Seventy patients received 3DS methadone conversion and 64 patients were eligible for analysis. Fifty patients (78%) achieved stable analgesia, and the median time to stable analgesia was 8.14 ± 2.70 (range 6-14) days. The average dose of methadone was 77.94 ± 42.74 mg. The most common AEs (≥ 10%) included constipation, dry mouth, nausea, and cold sweats. The incidence of constipation was reduced post-methadone conversion, and a statistically significant but asymptomatic prolongation of the QTc interval was observed. Additionally, the actual conversion ratios were lower than Ayonrinde's recommended ratios. CONCLUSIONS: The 3DS strategy for methadone conversion is applicable in Chinese patients with refractory cancer pain on high doses of opioids.

Rapid determination of toxic and essential metal binding proteins in biological samples by size exclusion chromatography-inductively coupled plasma tandem mass spectrometry.

Metalloproteins binding with trace elements play a crucial role in biological processes and on the contrary, those binding with exogenous heavy metals have adverse effects. However, the methods for rapid, high sensitivity and simultaneous analysis of these metalloproteins are still lacking. In this study, a fast method for simultaneously determination of both essential and toxic metal-containing proteins was developed by coupling size exclusion chromatography (SEC) with inductively coupled plasma tandem mass spectrometry (ICP-MS/MS). After optimization of the separation and detection conditions, seven metalloproteins with different molecular weight (from 16.0 to 443.0 kDa) were successfully separated within 10 min and the proteins containing iron (Fe), copper (Cu), zinc (Zn), iodine (I) and lead (Pb) elements could be simultaneously detected with the use of oxygen as the collision gas in ICP-MS/MS. Accordingly, the linear relationship between log molecular weight and retention time was established to estimate the molecular weight of unknown proteins. Thus, the trace metal and toxic metal containing proteins could be detected in a single run with high sensitivity (detection limits in the range of 0.0020-2.5 µg/mL) and good repeatability (relative standard deviations lower than 4.5 %). This method was then successfully used to analyze metal (e.g., Pb, Zn, Cu and Fe) binding proteins in the blood of Pb-intoxicated patients, and the results showed a negative correlation between the contents of zinc and lead binding proteins, which was identified to contain hemoglobin subunit. In summary, this work provided a rapid and sensitive tool for screening metal containing proteins in large number of biological samples.

Transformation of Mercuric Ions to Mercury Nanoparticles in Diatom Chaetoceros curvisetus.

Particulate HgS play crucial roles in the mercury (Hg) cycle. Approximately 20-90% of dissolved Hg can be transformed into particulate HgS by algae. However, detailed knowledge regarding these particles, including sizes and distribution, remains unknown. The present study explored the formation, distribution, and excretion of mercury nanoparticles (HgNPs) in diatom Chaetoceros curvisetus. The results demonstrated that HgNPs (HgS nanoparticles, 29.6-66.2 nm) formed intracellularly upon exposure to 5.0-100.0 µg L-1 Hg(II), accounting for 12-27% of the total Hg. HgNP concentrations significantly increased with increasing intracellular Hg(II) concentrations, while their sizes remained unaffected. HgNPs formed intracellularly and partly accumulated inside the cells (7-11%). Subsequently, the sizes of intracellular HgNPs gradually decreased to facilitate expulsion, 21-50% of which were excreted. These suggested the vital roles of HgNPs in comprehending marine Hg fate. Their unique physicochemical properties and bioavailability would influence Hg biotransformation in the ocean. Additionally, both intracellular and extracellular HgNPs contributed to Hg settling with cells, ultimately leading to Hg burial in sediments. Overall, these findings further deepened our understanding of Hg biotransformation and posed challenges in accurately estimating marine Hg flux and Hg burial.

Reply to "A better interpretation of data regarding the opioid switching to methadone".

In our article ?Methadone switching for refractory cancer pain' (BMC palliative care, 2022) we explore the efficacy, safety and economics of methadone in treatment of patients with refractory cancer pain in China. Professor Mercadante provided a better interpretation of data regarding the opioid switching to methadone in the Matters Arising. In this article, we answered the questions in Mercadante et al.'s comments one by one.

Circular RNA cMras Suppresses the Progression of Lung Adenocarcinoma Through ABHD5/ATGL Axis Using NF-κB Signaling Pathway.

Background: Lung adenocarcinoma (LAC) is a common malignancy worldwide. Emerging findings indicated that circular RNAs possess complex capacities of gene modulation in tumorigenesis and metastasis. Nevertheless, the role of circular RNA in LAC is still largely unknown. Materials and Methods: The level of circular RNA cMras (circ_cMras), alpha-beta hydrolase domain 5 (ABHD5), and adipose triglyceride lipase (ATGL) was determined by quantitative real-time polymerase chain reaction assay. Protein levels of ABHD5, ATGL, p53, p65, and phospho-p65 (p-p65) were examined by Western blot. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) was used to detect cell proliferation in vitro. Cell apoptosis was estimated using flow cytometry. Transwell assay was used to measure cell migration and invasion in A549 and HCC827 cells. Finally, the role of circ_cMras was explored using xenograft tumor model. Results: Low levels of circ_cMras, ABHD5, and ATGL were observed in LAC tissues and cells. Upregulation of circ_cMras could hamper tumor aggression in vitro and in vivo, exhibiting as the inhibition of cell proliferation, migration, invasion, and promotion of cell apoptosis, as well as the inhibition on tumor growth in vivo. Moreover, ABHD5 deletion could overturn the effects of circ_cMras overexpression on cell behaviors in LAC cells. Furthermore, the inhibiting effects of ABHD5 on cell aggression were reversed by ATGL deficiency in vitro. Mechanically, circ_cMras/ABHD5/ATGL axis exerted its role through NF-κB signaling pathway in LAC cells. Conclusion: Circ_cMras exerted its function through ABHD5/ATGL axis using NF-κB signaling pathway in LAC, which might provide a novel insight for the diagnosis and prognosis of LAC.

Methadone switching for refractory cancer pain.

BACKGROUND: Methadone is commonly considered an alternative opioid treatment for refractory cancer pain. This study aims to investigate the efficacy, safety, and cost of methadone in the treatment of refractory cancer pain. METHODS: A retrospective study was conducted in patients who used methadone for refractory cancer pain from April 2016 to December 2020 at a cancer specialized hospital. Pain control, evaluated via pain score and breakthrough pain frequency, and adverse events of methadone were compared with analgesic regimens prior to methadone administration. The factors potentially affecting the switching outcome were analyzed via multivariate analysis. Moreover, the cost of pain control was estimated. RESULTS: Ninety patients received methadone for poor pain control (74.4%), intolerable adverse events (10.0%), or both (15.6%) after prior opioid treatments. Sixty-four patients (71.1%) were successfully switched to methadone with median pain score significantly decreased from 4.0 to 2.0 (p < 0.001) and median daily frequency of breakthrough pain from 3.0 to 0.0 (p < 0.001) at a maintained median conversion ratio of 6.3 [interquartile range (IQR): 4.0-10.0] to prior opioid treatment. Similar adverse event profiles of constipation, nausea, vomiting, and dizziness were observed between methadone and prior opioid regimens. The median daily cost of analgesic regimens was significantly reduced from $19.5 (IQR: 12.3-46.2) to $10.8 (IQR: 7.1-18.7) (p < 0.01) after switching to methadone. The 3-day switch method significantly improved the rate of successful switching compared with the stop and go method (odds ratio = 3.37, 95% CI: 1.30-8.76, p = 0.013). CONCLUSION: Methadone is an effective, safe, and cost-saving treatment for patients with refractory cancer pain.

ß-Elemene Improves Morphine Tolerance in Bone Cancer Pain via N-Methyl-D-Aspartate Receptor 2B Subunit-Mediated µ-Opioid Receptor.

Background: Improving morphine tolerance (MT) is an urgent problem in the clinical treatment of bone cancer pain. Considering that ß-Elemene is widely used in the treatment of cancer pain, we explored the effects and mechanism of ß-Elemene in preventing MT of bone cancer pain. Method: Bone cancer pain and chronic MT rat model was established by injecting MADB106 cells and morphine (10 mg/kg). SH-SY5Y cells were treated with morphine (10 µg/mL) for 48 h to establish a cell model. The mechanical withdrawal threshold and thermal withdrawal latency of rats were detected by mechanical allodynia and thermal hyperalgesia tests, respectively. The protein expressions of µ-opioid receptor (MOPR), cyclic adenosine monophosphate (cAMP), N-methyl-D-aspartate receptor subunit 2B (NR2B), phosphorylated-calmodulin-dependent protein kinase II (p-CaMKII), and CaMKII were detected by western blot. The viability of SH-SY5Y cells was determined by the cell counting kit-8 assay. cAMP content in SH-SY5Y cells was measured by a LANCE cAMP kit. Result: Animal experiments showed that MT strengthened over time, while increased ß-Elemene dosage alleviated MT. The viability of SH-SY5Y cells was down-regulated by high-dose ß-Elemene. In the rat and cell models, long-term morphine treatment decreased the expression of MOPR and increased the cAMP and NR2B expressions and p-CaMKII/CaMKII, while ß-Elemene and siNR2B counteracted the effects of morphine treatment. In addition, siNR2B reversed the effects of ß-Elemene on related protein expressions and cAMP content in the cell model. Conclusion: ß-Elemene improved MT in bone cancer pain through the regulation of NR2B-mediated MOPR.

Sensitive determination of metalloprotein in salt-rich matrices by size exclusion chromatography coupled with inductively coupled plasma-mass spectrometry.

Metalloproteins play crucial and distinct roles in a variety of biological processes that rely heavily on the metal ions and various proteins. However, there is still a lack of method for rapid analysis of metalloproteins in complex samples, especially in salt-rich matrices. In this study, a sensitive method for separation and determination of metalloproteins in salt-rich matrices was developed based on the size exclusion chromatography coupled with inductively coupled plasma-mass spectrometry (SEC-ICP-MS), combining with the high matrix introduction (HMI) mode, which is quite essential for biological system. The separation conditions of the SEC-ICP-MS system were optimized by using four iodine labeled proteins with different molecular weights, including bovine serum albumin (BSA, 66.0 kDa), ovalbumin (OVA, 44.0 kDa), carbonic anhydrase (CA, 29.0 kDa) and ribonuclease A (RA, 13.7 kDa). After optimization, four iodine labeled proteins and iodine ions were successfully separated within 30 min by using 10 mmol/L HEPES and 40 mmol/L Na2SO4 (pH=7.0) as mobile phase and a linear relationship between log molecular weight and retention time was established. The relative standard deviations (RSDs, n = 5) of the retention time and peak areas for the four iodine labeled proteins were in the range of 0.2-0.9% and 3.3-7.7%, respectively, suggesting good precision and repeatability. Then the proposed method was successfully applied to the rapid separation and detection of lead-binding proteins in real biological tissue samples.

Pinocembrin Inhibits the Proliferation, Migration, Invasiveness, and Epithelial-Mesenchymal Transition of Colorectal Cancer Cells by Regulating LACTB.

Background: Colorectal cancer (CRC) is a common malignancy of digestive tract. Pinocembrin (PINO) has been discovered to have a proapoptotic effect on CRC. This study aimed to elucidate how other biological behaviors of CRC cells were affected under PINO treatment. Materials and Methods: The effect of PINO on HT29 and HCT116 cells were detected through treatment of different concentrations of PINO. The role of LACTB in PINO treatment was investigated by transfection of siRNA-LACTB. Cell counting kit-8 assay, wound healing assay, and Transwell assay were conducted to evaluate the proliferation, migration, and invasiveness of CRC cells, respectively. Western blot or quantitative reverse transcription-polymerase chain reaction was carried out to measure the expressions of LACTB, matrix metalloproteinase (MMP)-2, E-cadherin, and N-cadherin. Results: Gradient PINO inhibited the viability, migration, invasiveness, and expressions of MMP-2 and N-cadherin in CRC cells, while promoted E-cadherin and LACTB expressions. Silencing LACTB promoted the viability, migration, invasiveness, and expressions of MMP-2 and N-cadherin in CRC cells and inhibited E-cadherin expression. PINO counteracted the effect of silenced LACTB, and yet silencing LACTB partially abolished the effect of PINO on CRC cells. Conclusion: PINO inhibited the proliferation, migration, invasiveness, and epithelial-to-mesenchymal transition of CRC cells by regulating LACTB.

Case Report: Postoperative Recurrence of Adrenal Epithelioid Angiosarcoma Achieved Complete Response by Combination Chemotherapy With Liposomal Doxorubicin and Paclitaxel.

BACKGROUND: Primary adrenal epithelioid angiosarcoma is an extremely rare cancer with a poor prognosis. Because of the rarity of this disease, treatment options have not been well-studied. CASE PRESENTATION: A 51-year-old man was admitted to Zhejiang Cancer Hospital, diagnosed with a recurrence of adrenal epithelioid angiosarcoma. He had undergone a surgical resection seven months earlier. Combination chemotherapy with liposomal doxorubicin and paclitaxel was administered. After two cycles of chemotherapy, his pain was relieved. Computed tomography (CT) suggested that the soft tissue tumour lesions in the surgical area had disappeared, mediastinal and mediastinal-hilar lymph nodes were significantly reduced or had disappeared, and the patient had achieved a partial response (PR). CT after six cycles of chemotherapy indicated that the patient had achieved a complete response (CR). CONCLUSION: Combination chemotherapy with liposomal doxorubicin and paclitaxel may be a preferred therapy for recurrent or advanced adrenal epithelioid angiosarcoma.

Durvalumab monotherapy as a third-line treatment for extensive-stage small-cell lung cancer: a case report.

The global incidence and mortality rates of lung cancer are the highest of any cancer. Smallcell lung cancer (SCLC) is an undifferentiated carcinoma which accounts for 15-20% of all lung cancers. Compared with the other major lung cancer type, non-small cell lung cancer, SCLC exhibits worse biological behavior, has a higher degree of malignancy, and develops more rapidly. The majority of SCLC present with extensive-stage disease, and the prognosis for these patients remains poor. Recently, immunotherapy has been demonstrated clinical activity in extensive-stage SCLC (ES-SCLC); however, the efficacy and safety of immunotherapy in ES-SCLC needs further confirmation. Durvalumab, a selective, high-affinity human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80, showed durable clinical activity and a manageable safety profile in patients with pretreated ES-SCLC as a first-line treatment. Here, we report the case of an ES-SCLC patient who achieved complete remission (CR) of local lesions after receiving durvalumab monotherapy as a third-line treatment, experiencing no obvious immune-related side effects, such as rash, diarrhea, fatigue, myelosuppression, or thyroid dysfunction. No immune-related pulmonary or hepatorenal toxicities occurred. The case suggests that immunotherapy can be selected for third-line or multi-line treatment of ES-SCLC, and anti-PD-L1 antibody may be the better choice for patients who have poor performance status (PS) scores.

Determination and characterization of metal nanoparticles in clams and oysters.

With the extensive application of nanotechnology, metal nanoparticles (MNPs) have been widely used, thus are universally detected in the environment. This has caused increasingly concerns due to their toxicity and the potential health risks they pose to humans. In this work, the concentrations and particle size distributions of MNPs and concentrations of associated metal ionic species in shellfish seafood (clams and oysters) were investigated using single particle inductively coupled plasma mass spectrometry (sp-ICP-MS) and inductively coupled plasma mass spectrometry (ICP-MS). The MNPs in the clam and oyster tissues were extracted via an alkaline digestion method with a recovery rate of 95.9% (for gold nanoparticles (AuNPs)). Then total concentrations of 41 metal elements were measured in the two types of seafood, of which 20 were selected for sp-ICP-MS analysis. The results showed that 5 types of MNPs were detectable in clams (Y, La, Ce, Pr, Gd) and 5 types of MNPs were detectable in oysters (Y, La, Ce, Pr, Nd). Size distributions of MNPs in clams and oysters were in the range of 35-55 nm and 30-65 nm, respectively. Nanoparticle concentrations in clams and oysters ranged from 0.6 to 37.7 ng/g and 4.2-19.7 ng/g, and accounted for 3.4%-50% and 5.5%-46% of the total metal content, respectively. Based on this analysis, the health risks of metals in the two kinds of seafood were evaluated by comparing the Provisional Tolerable Weekly Intake (PTWI) with limits recommended by the World Health Organization (WHO)/Food and Agriculture Organization (FAO). These results provide important information about the presence of metal nanoparticles in seafood and, to the best of our knowledge, this is the first time that the nanoparticles of rare earth elements have been detected and reported in bivalve mollusc tissues.

Diosgenin inhibits tumor angiogenesis through regulating GRP78-mediated HIF-1α and VEGF/VEGFR signaling pathways.

The present paper describes the molecular mechanism of diosgenin on tumor microenvironment angiogenesis and the regulation of GRP78 in angiogenesis signaling pathway. CCK8 method was used to evaluate the effect of different concentrations of diosgenin on HUVEC activity in hypoxic microenvironment. Apoptosis was detected by Annexin V/PI staining. Tube Formation experiment was conducted to evaluate angiogenesis. Western Blot assay was applied to detect the expressions and phosphorylation levels of the angiogenesis-related pathways HIF-1α, GRP78, VEGF/VEGFR, PI3K/AKT, ERK, and FAK in rheumatoid HUVEC. Silencing GRP78 by siRNA interference technology was employed to investigate the mechanism of GRP78 involved in the regulation of angiogenesis. The results indicated that diosgenin can significantly inhibit the cell viability of hypoxic HUVEC and the significance is dependent on drug concentration. As the concentration increases, HUVEC activity decreases. Cell apoptosis is induced in a dose-dependent manner and angiogenesis can be significantly inhibited. The hypoxic microenvironment can significantly increase the expressions of HIF-lα, GRP78, VEGF/VEGFR, PI3K/AKT, ERK, FAK proteins in angiogenesis-related pathways, and can also enhance the phosphorylation of AKT, ERK1/2 and FAK proteins, which can be decreased by drug intervention. After silencing GRP78, the angiogenesis-related pathway proteins HIF-lα and VEGF/VEGFR are significantly reduced, thus inhibiting the activation of AKT, ERK1/2, and FAK. The anti-tumor angiogenesis mechanism of diosgenin inhibiting the expression of HIF-lα, GRP78, VEGF/VEGFR, PI3K/AKT, ERK1/2 and FAK signaling pathways may be through multiple pathways and targets, and GRP78 is involved in the regulation of angiogenesis signaling pathway.

Meat and nutritional quality comparison of purebred and crossbred pigs.

Crossbreeding is an effective method of improving the efficiency and profit of production in commercial pig operations. To understand the effect of crossbreeding on meat and nutrient quality, a combination including three purebred (Duroc, D; Landrace, L; Yorkshire, Y) and two crossbred pig lines (Landrace × Yorkshire, LY; Duroc × (Landrace × Yorkshire), DLY) frequently used internationally were studied. The results showed that meat from the LY and DLY crosses had lower values for lightness L24h∗, shear force and epinephrine and higher values for drip loss, C18:1, insulin, glucagon and monounsaturated fatty acids than D, L and Y pigs. Moreover, LY had higher values for post mortem pH and lower values for a* and b* than the purebreds. In contrast, DLY had lower values for pH and higher values for a* and b* than the purebreds. Meat quality-related gene analysis showed that the CAST, IGF2 and MC4R gene expression levels in the LY and DLY pigs were significantly higher than those in the D, L and Y pigs. These results indicate that crossbreeding can alter the meat quality, nutritive value, energy metabolism and gene expression of pigs. Future research should focus on microRNA expression and DNA methylation that regulate gene expression and thus affect the meat quality.