Microplastics and phthalate esters contamination in top oceanic predators: A study on multiple shark species in the Pacific Ocean.

Marine organisms, especially top predators such as sharks, are susceptible to environmental pollutants like microplastics (MPs) and phthalate esters (PAEs), leading to ecosystem risks. Research on contamination in these apex species is, however, still limited. This study investigated MPs and PAEs in multiple shark species (Isurus oxyrinchus, Alopias superciliosus, Alopias pelagicus, Carcharhinus brevipinna, and Sphyrna zygaena) off Taiwan's eastern coast. Gastric tissue analyses revealed ubiquitous microplastics (2-31 particles), which positively correlated with body lengths and weights for Isurus oxyrinchus. Blue, fiber-shaped (1-2 mm), and rayon-based MPs are likely associated with textile fiber pollution. The PAEs concentration mean was 7035 ± 6829 ng/g, ww, having DEHP and DiNP as primary compounds. This study highlights pervasive contamination in Pacific Ocean sharks, emphasizing anthropogenic impact on top oceanic predators and providing essential insights for food safety and MP accumulation.

Incorporating Tumor Genomic Profiling and Circulating Tumor Cell-derived Organoids into Clinical Practice for Gastrointestinal Cancers.

BACKGROUND/AIM: Precision medicine aims to revolutionize healthcare by tailoring treatment regimens. This study aimed to integrate comprehensive tumor genomic profiling (CTGP) by targeted-gene panel sequencing and drug screening by circulating tumor cell-derived organoids (CTOs) into clinical practice for the treatment of gastrointestinal (GI) cancers. PATIENTS AND METHODS: Nine patients with various GI cancers underwent CTGP and CTO drug sensitivity testing. CTGP results guided targeted therapy and immunotherapy, while CTO drug sensitivity predicted response to chemotherapy and targeted agents. The drug recommendations from two platforms were correlated with the treatment response to the suggested medications retrospectively. RESULTS: Five patients received therapies aligned with CTGP, including HER2-targeted treatment, immunotherapy, and BRAF/MEK dual inhibition, showing positive responses. CTO drug sensitivity predicted progression under regorafenib (low potential benefit) and good response to chemotherapy with high potential benefit. The combination of CTGP and CTO drug sensitivity may exhibit significant correlation with clinical outcomes during treatment with candidate drugs, demonstrating a sensitivity of 79% and an accuracy of 75%. This encompasses various treatment modalities, such as chemotherapy, targeted therapy, and immunotherapy. CONCLUSION: The present investigation elucidated the integration of CTGP and CTO drug sensitivity screening into clinical practice in a complementary manner, showcasing a significant correlation between treatment response and testing outcomes. Additional prospective evaluation of these two testing modalities in a large cohort is warranted to confirm whether the inclusion of CTO drug sensitivity screening confers enhanced survival benefits compared to utilizing CTGP alone.

Potential risks of accumulated microplastics in shells and soft tissues of cultured hard clams (Meretrix taiwanica) and associated metals.

Microplastics (MPs) pose risks to both aquatic ecosystems and human health. This study investigated MPs in the shells and soft tissues of hard clams (Meretrix taiwanica) cultured in the inland waters of Taiwan. This study further developed two novel risk indices for assessing the potential ecological and health consequences of MPs. Moreover, the metal concentrations in the clam's soft tissues and the associated consumption health risks were investigated. Clamshells contained significant amounts of MPs with an average abundance of 16.6 ± 6.9 MPs/ind., which was higher than in the soft tissues (2.7 ± 1.7 MPs/ind.). The distribution and sizes of MPs in shells and soft tissues were similar, primarily small-sized (<2 mm, >99 %), blue (>65 %), and fibrous (>99 %). Dominant MP polymer types included rayon (83.5 %), polyethylene terephthalate (11.8 %), and polyacrylonitrile (3.6 %). The proposed MP potential ecological risk index indicates a higher potential ecological MP risk in soft tissues (302-423) than in shells (270-278) of the clams. The MP potential hazard risk index showed that the risk of exposure to MP through shellfish consumption decreased with age. The total hazard index (THI) value suggested negligible health hazards from metal exposure through shellfish consumption. Moreover, there was no significant correlation between MPs and metal concentrations in soft tissues, suggesting that metals bound to MPs contribute minimally to the total accumulated metals in clam's soft tissues. This study confirms the presence of MPs in clam shells and provides a novel tool to assess the potential ecological and health risks associated with MPs in shellfish.

RAB31 drives extracellular vesicle fusion and cancer-associated fibroblast formation leading to oxaliplatin resistance in colorectal cancer.

Epithelial-mesenchymal transition (EMT) is associated with tumorigenesis and drug resistance. The Rab superfamily of small G-proteins plays a role in regulating cell cytoskeleton and vesicle transport. However, it is not yet clear how the Rab family contributes to cancer progression by participating in EMT. By analysing various in silico datasets, we identified a statistically significant increase in RAB31 expression in the oxaliplatin-resistant group compared to that in the parental or other chemotherapy drug groups. Our findings highlight RAB31's powerful effect on colorectal cancer cell lines when compared with other family members. In a study that analysed multiple online meta-databases, RAB31 RNA levels were continually detected in colorectal tissue arrays. Additionally, RAB31 protein levels were correlated with various clinical parameters in clinical databases and were associated with negative prognoses for patients. RAB31 expression levels in all three probes were calculated using a computer algorithm and were found to be positively correlated with EMT scores. The expression of the epithelial-type marker CDH1 was suppressed in RAB31 overexpression models, whereas the expression of the mesenchymal-type markers SNAI1 and SNAI2 increased. Notably, RAB31-induced EMT and drug resistance are dependent on extracellular vesicle (EV) secretion. Interactome analysis confirmed that RAB31/AGR2 axis-mediated exocytosis was responsible for maintaining colorectal cell resistance to oxaliplatin. Our study concluded that RAB31 alters the sensitivity of oxaliplatin, a supplementary chemotherapy approach, and is an independent prognostic factor that can be used in the treatment of colorectal cancer.

Durvalumab or placebo plus gemcitabine and cisplatin in participants with advanced biliary tract cancer (TOPAZ-1): updated overall survival from a randomised phase 3 study.

BACKGROUND: In the preplanned interim analysis of the TOPAZ-1 study, durvalumab plus gemcitabine-cisplatin significantly improved overall survival versus placebo plus gemcitabine-cisplatin in participants with advanced biliary tract cancer. We aimed to report updated overall survival and safety data from TOPAZ-1 with additional follow-up and data maturity beyond the interim analysis. METHODS: TOPAZ-1 was a phase 3, randomised, double-masked, placebo-controlled, global study done at 105 sites in 17 countries. Participants aged 18 years or older with unresectable, locally advanced, or metastatic biliary tract cancer were randomly assigned (1:1) to durvalumab plus gemcitabine-cisplatin or placebo plus gemcitabine-cisplatin using a computer-generated randomisation scheme, stratified by disease status and primary tumour location. Participants received durvalumab (1500 mg) or placebo on day 1 of each cycle every 3 weeks for up to eight cycles, plus gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) intravenously on days 1 and 8 of each cycle every 3 weeks for up to eight cycles, followed by durvalumab (1500 mg) or placebo monotherapy every 4 weeks until disease progression or other discontinuation criteria were met. Investigators and participants were masked to study treatment. The primary endpoint was overall survival. TOPAZ-1 met its primary endpoint at the preplanned interim analysis, and the study is active but no longer recruiting participants. Updated overall survival and safety data from TOPAZ-1, with additional follow-up (data cutoff Feb 25, 2022) and data maturity beyond the interim analysis, are reported here. Efficacy was assessed in the full analysis set (all randomly assigned participants). Safety was assessed in the safety analysis set (all participants who received at least one dose of study treatment). The TOPAZ-1 study is registered with ClinicalTrials.gov, NCT03875235. FINDINGS: From April 16, 2019, to Dec 11, 2020, 914 participants were enrolled, 685 of whom were randomly assigned (341 to the durvalumab plus gemcitabine-cisplatin group and 344 to the placebo plus gemcitabine-cisplatin group). 345 (50%) participants were male and 340 (50%) were female. Median follow-up at the updated data cutoff was 23·4 months (95% CI 20·6-25·2) in the durvalumab plus gemcitabine-cisplatin group and 22·4 months (21·4-23·8) in the placebo plus gemcitabine-cisplatin group. At the updated data cutoff, 248 (73%) participants in the durvalumab plus gemcitabine-cisplatin group and 279 (81%) participants in the placebo plus gemcitabine-cisplatin group had died (median overall survival 12·9 months [95% CI 11·6-14·1] vs 11·3 months [10·1-12·5]; hazard ratio 0·76 [95% CI 0·64-0·91]). Kaplan-Meier-estimated 24-month overall survival rates were 23·6% (95% CI 18·7-28·9) in the durvalumab plus gemcitabine-cisplatin group and 11·5% (7·6-16·2) in the placebo plus gemcitabine-cisplatin group. Maximum grade 3 or 4 adverse events occurred in 250 (74%) of 338 participants in the durvalumab plus gemcitabine-cisplatin group and 257 (75%) of 342 in the placebo plus gemcitabine-cisplatin group. The most common maximum grade 3 or 4 treatment-related adverse events were decreased neutrophil count (70 [21%] vs 86 [25%]), anaemia (64 [19%] vs 64 [19%]), and neutropenia (63 [19%] vs 68 [20%]). INTERPRETATION: Durvalumab plus gemcitabine-cisplatin showed robust and sustained overall survival benefit with no new safety signals. Findings continue to support the regimen as a standard of care for people with untreated, advanced biliary tract cancer. FUNDING: AstraZeneca.

Cost-effectiveness of ivosidenib versus chemotherapy for previously treated IDH1-mutant advanced intrahepatic cholangiocarcinoma in Taiwan.

BACKGROUND: International guidelines recommend ivosidenib followed by modified FOLFOX (mFOLFOX) for advanced intrahepatic cholangiocarcinoma (ICC) with isocitrate dehydrogenase 1 (IDH1) mutations. Taiwan National Health Insurance covers only fluorouracil/leucovorin (5-FU/LV) chemotherapy for this ICC group, and there has been no prior economic evaluation of ivosidenib. Therefore, we aimed to assess ivosidenib's cost-effectiveness in previously treated, advanced ICC-presenting IDH1 mutations compared with mFOLFOX or 5-FU/LV. METHODS: A 3-state partitioned survival model was employed to assess ivosidenib's cost-effectiveness over a 10-year horizon with a 3% discount rate, setting the willingness-to-pay threshold at 3 times the 2022 GDP per capita. Efficacy data for Ivosidenib, mFOLFOX, and 5-FU/LV were sourced from the ClarIDHy, ABC06, and NIFTY trials, respectively. Ivosidenib's cost was assumed to be NT$10,402/500 mg. Primary outcomes included incremental cost-effectiveness ratios (ICERs) and net monetary benefit. Deterministic sensitivity analyses (DSA) and probabilistic sensitivity analyses (PSA) were employed to evaluate uncertainty and explore price reduction scenarios. RESULTS: Ivosidenib exhibited ICERs of NT$6,268,528 and NT$5,670,555 compared with mFOLFOX and 5-FU/LV, respectively, both exceeding the established threshold. PSA revealed that ivosidenib was unlikely to be cost-effective, except when it was reduced to NT$4,161 and NT$5,201/500 mg when compared with mFOLFOX and 5-FU/LV, respectively. DSA underscored the significant influence of ivosidenib's cost and utility values on estimate uncertainty. CONCLUSIONS: At NT$10,402/500 mg, ivosidenib was not cost-effective for IDH1-mutant ICC patients compared with mFOLFOX or 5-FU/LV, indicating that a 50-60% price reduction is necessary for ivosidenib to be cost-effective in this patient group.

Controlling effects of terrestrial organic matter on metal contamination and toxicity risks in port sediments.

The contents of metals, total carbon, total nitrogen (TN), total organic carbon (TOC), and stable isotope composition (δ13Corg and δ15N) of sediment organic matter (SOM) were investigated to explore the sources and spatial distribution of metals and SOM in the surface sediments (Kaohsiung Port, Taiwan). Results showed that TOC and metals in estuarine sediments are high, gradually decreasing toward the port entrances. The δ13Corg, δ15N, and TOC/TN ratios indicate that SOM comes mainly from terrestrial sources. This study proposes a befitting model between metal pollution and toxicity risk index and SOM sources in port sediments by combining stable isotope composition, correlation matrix, and multiple linear regression analysis. The model indicates that the degree of metal pollution and toxicity risk in sediments are mainly affected by TOCterr content and SOM source. The results help to understand the influence of organic matter sources in port sediments on metal concentration distribution.

A Facile NMR Method for Pre-MRI Evaluation of Trigger-Responsive T1 Contrast Enhancement.

There is a growing interest in developing paramagnetic nanoparticles as responsive magnetic resonance imaging (MRI) contrast agents, which feature switchable T1 image contrast of water protons upon biochemical cues for better discerning diseases. However, performing an MRI is pragmatically limited by its cost and availability. Hence, a facile, routine method for measuring the T1 contrast is highly desired in early-stage development. This work presents a single-point inversion recovery (IR) nuclear magnetic resonance (NMR) method that can rapidly evaluate T1 contrast change by employing a single, optimized IR pulse sequence that minimizes water signal for "off-state" nanoparticles and allows for sensitively measuring the signal change with "switch-on" T1 contrast. Using peptide-induced liposomal gadopentetic acid (Gd3+ -DTPA) release and redox-sensitive manganese oxide (MnO2 ) nanoparticles as a demonstration of generality, this method successfully evaluates the T1 shortening of water protons caused by liposomal Gd3+ -DTPA release and Mn2+ formation from MnO2 reduction. Furthermore, the NMR measurement is highly correlated to T1 -weighted MRI scans, suggesting its feasibility to predict the MRI results at the same field strength. This NMR method can be a low-cost, time-saving alternative for pre-MRI evaluation for a diversity of responsive T1 contrast systems.

Phthalate esters and nonylphenol concentrations correspond with microplastic distribution in anthropogenically polluted river sediments.

This paper presents the phthalate esters (PAEs), nonylphenol (NPs), and microplastics (MPs) in river sediments. Results showed that sediments near residential areas were mainly composed of fine particles, potentially influencing the adsorption of PAEs and NPs in the area. The concentrations of Σ10 PAEs in the sediments ranged between 2448 and 63,457 µg/kg dw, dominated by DEHP and DnOP. Microplastics were detected in all samples, with higher abundances found in sediments near residential areas dominated by polypropylene. Toxicological risk assessment indicated potential risks to sensitive aquatic organisms exposed to the sediments. Correlations between MPs, PAEs, and NPs suggest that MPs may serve as possible sources of PAEs in the sediments. Principal component analysis explained 95.4 % of the pollutant variability in the sediments. Overall, this study emphasizes the significance of monitoring and understanding the presence and interactions of PAEs and MPs in river sediments to assess their potential impacts on aquatic ecosystems.

Comparison of therapeutic outcomes in esophageal squamous cell carcinoma following neoadjuvant chemoradiotherapy: A prospective observational cohort study.

BACKGROUND: Patients with locally advanced esophageal squamous cell carcinoma (ESCC) following neoadjuvant chemoradiotherapy (nCRT) may not always receive resection despite the possible achievement of a pathologic complete response (pCR) being associated with superior survival benefit. We aimed to compare outcomes among ESCC patients with or without pCR and those refusing surgery. METHODS: In total, 111 medically operable, non-cervical ESCC patients after the same protocol of nCRT (platinum/5-fluorouracil plus radiation 50Gy) were prospectively enrolled between 2011 and 2021. Eighty-three of them underwent esophagectomy comprising pCR (n = 32) and non-pCR (n = 51), while 28 operable patients declined surgery (refusal-of-surgery group). Predictors and survival data were analyzed. RESULTS: In terms of esophagectomy, 38.5% (32/83) patients achieved pCR. The pCR group exhibited better pretreatment performance status than the non-pCR group (adjusted odds ratio: 0.11, 95% confidence interval: 0.03-0.58; p = 0.01). Among pCR, non-pCR, and refusal-of-surgery groups, the 5-year overall survival (OS) rates were 56%, 29% and 50% (p = 0.08) and progression-free survival (PFS) rates were 52%, 28% and 36% (p = 0.07) respectively. The pCR group had significantly better OS and PFS than the non-PCR group (adjusted hazard ratio: 2.33 and 1.93, p = 0.02 and 0.049 respectively) but not the refusal-of-surgery group. CONCLUSION: Better pretreatment performance status is associated with higher chance of pCR. Consistent with previous studies, we found attainment of pCR confers the best OS and PFS. Suboptimal OS in the refusal-of-surgery group reflects some of them would have residual disease in addition to complete remission. Further studies are needed to identify prognostic factors of pCR to select candidates who could validly decline esophagectomy.

Polycyclic aromatic hydrocarbons in 55-120 µm phytoplankton.

A baseline study was undertaken on polycyclic aromatic hydrocarbons (PAHs) in phytoplankton. Plankton samples from six stations (duplicates) in Kaohsiung Harbor (KH), Taiwan along with a phytoplankton control sample afar from the harbor, were collected. We applied size-fractionation to isolate phytoplankton (55-120 µm), followed by sedimentation and centrifugation to remove abiogenic particulates. The phytoplankton was freeze-dried, extracted with acetone: n-hexane (1:1, v/v), and analyzed using GC-MS. ΣPAHs in phytoplankton ranged between 5204 and 28,903 ng/g dry weight (mean: 12,150 ng/g). The ΣPAHs in KH were >7 times than the control site (C1: 3972 ng/g). Cluster analysis showed spatial gradients (northern < southern KH). Accumulated PAHs in phytoplankton were from petrogenic (fishing ports and ships) and pyrogenic (river outflows), dominated by lower-ring PAHs, likely due to their higher bioavailability in the dissolved phase. We present a practical phytoplankton isolation technique for more accurate phytoplankton PAH concentrations with insights into their distribution and sources.

Analysis of the Treatment Strategy of Heart Failure with Preserved Ejection Fraction Based on ZHANG Boli's Theory of “Damp-turbidity and Phlegm-rheum Type of Diseases” / 中医杂志

Professor ZHANG Boli believed that the core pathogenesis of heart failure with preserved ejection fraction （HFpEF） is weak pulse at yang and wiry pulse at yin. By referring to the theory of “damp-turbidity and phlegm-rheum type of diseases”， he proposed that yin pathogens of damp-turbidity and phlegm-rheum may damage yang qi in each stage of HFpEF， thus aggravating the trend of weak pulse at yang and wiry pulse at yin， which played an important role in the deterioration of HFpEF. Therefore， Professor ZHANG Boli advocated that importance should be attached to the elimination of yin pathogen and the protection of yang qi during the various stages of HFpEF in order to delay the aggravation of weak pulse at yang and wiry pulse at yin； he put forward the idea of staged treatment that “yin pathogen should be dispelled and yang qi should be demonstrated”； and he formulated the treatment strategy of treating the disease as early as possible， eliminating pathogens and protecting yang， interrupting the disease trend， using warm-like medicinals， and activating blood circulation， to enrich the theoretical system of traditional Chinese medicine in the treatment of HFpEF.

Harnessing Acoustic Dispersions in YX-LN/SiO2/Si SH-SAW Resonators for Electromechanical Coupling Optimization and Rayleigh Mode Suppression.

In this study, we investigate the dispersive behavior of the electromechanical coupling coefficient ( [Formula: see text]) for shear-horizontal (SH) and Rayleigh surface acoustic wave (SAW) modes in a YX-LiNbO3 (LN)/SiO2/Si substrate across various wavelengths. Due to the difference in velocity dispersion between the SH and Rayleigh modes, mode coupling can be observed when these two modes operate at closely proximate frequencies, leading to a notable variation in their [Formula: see text]. With a careful design, SH and Rayleigh modes can be tuned to achieve a mode-decoupling state for enhancing [Formula: see text] of the SH-SAW and suppressing the presence of the Rayleigh mode in YX-LN/SiO2/Si. Consequently, a series of proof-of-concept SH-SAW resonators with wavelengths ( λ ) ranging from 1.6 to [Formula: see text] are fabricated. The optimized resonator with a λ of [Formula: see text] exhibits a resonant frequency of 1.064 GHz, an effective [Formula: see text] of 47.7%, a maximum Bode- Q of around 900, and an 18-dB rejection of spurious modes spanning from 0.5 to 3 GHz, without the presence of the Rayleigh mode.

Susceptibility to hypertension based on MTHFR rs1801133 single nucleotide polymorphism and MTHFR promoter methylation.

Background: The aetio-pathologenesis of hypertension is multifactorial, encompassing genetic, epigenetic, and environmental factors. The combined effect of genetic and epigenetic changes on hypertension is not known. We evaluated the independent and interactive association of MTHFR rs1801133 single nucleotide polymorphism (SNP) and MTHFR promoter methylation with hypertension among Taiwanese adults. Methods: We retrieved data including, MTHFR promoter methylation, MTHFR rs1801133 genotypes (CC, CT, and TT), basic demography, personal lifestyle habits, and disease history of 1,238 individuals from the Taiwan Biobank (TWB). Results: The distributions of hypertension and MTHFR promoter methylation quartiles (ß < 0.1338, 0.1338 ≤ ß < 0.1385, 0.1385 ≤ ß < 0.1423, and ß ≥ 0.1423 corresponding to

Taiwan renal data report system: Framework, function, and development.

The world healthcare system is actively seeking possible solutions for the rapid growth of kidney disease threats. The Taiwan Renal Data System (TWRDS) was central in assisting kidney health and care policymaking to reduce end-stage kidney disease incidence and mortality. This article summarizes the TWRDS framework, recent applications, and developments to provide new insights for some international researchers to promote planetary kidney health. The TWRDS originated in 1987 for the accreditation and quality monitoring of dialysis units and was connected with enriched health claim databases after the implementation of universal national health insurance in Taiwan in 1995. As a healthcare information centre, TWRDS has published annual reports forming indispensable instructions for renal care improvement since 2014. The TWRDS possesses three main functions: (1) kidney disease surveillance; (2) offering rich materials for research purposes; (3) achieving precision prevention and care through complex algorithms. In the new era, TWRDS can help build a more resilient society against communicable disease threats by integrating remote sensor techniques for developing future remote healthcare structures, as well as identifying kidney health inequity populations and promoting healthcare resources distributed equity. The global healthcare system is facing escalating burdens of non-communicable disease care due to the rapidly growing elderly population. Therefore, a considerable-scale data system is an essential decision-supportive tool in promoting an evidence-based, resilient, sustainable, equity care environment. Undoubtedly, TWRDS experience is a practical example of leveraging healthcare providers' decisions, care outcomes, and renovation.

Reactive Cutaneous Capillary Endothelial Proliferation Caused by Camrelizumab: Sixteen Case Reports.

To investigate the regularity and characteristics of adverse drug reaction (ADR) of reactive cutaneous capillary endothelial proliferation caused by Camrelizumab, so as to provide reference for clinical rational use of drugs. Searching for case reports of Camrelizumab-induced reactive cutaneous capillary endothelial proliferation (RCCEP) in databases such as China Biology Medicine disc, VIP Database, CNKI, Wanfang Medical, PubMed, Wiley online library, Embase with "Carritzumab/Ericab," "SHR-1210," "Reactive cutaneous capillary endothelial proliferation," "Reactive capillary hemangiomas," and "Capillary proliferation" as search terms. The retrieval time is from the establishment of the database to February 2022. After eliminating clinical trials and incomplete literature, information of patients included in the literature was analyzed, which included gender, age, reason for medication, usage and dosage, time of ADR, concomitant medication, clinical manifestations, intervention measures, outcomes of patients, etc. A total of 11 articles involving 16 patients were included, including 11 males and five females, with an average age of 60.5 years. Reasons for medication included nine cases of non-small cell lung cancer (NSCLC), four cases of liver cancer, one case of small cell lung cancer (SCLC), one case of synovial sarcoma, and one case of Hodgkin lymphoma. Thirteen patients recorded in detail that the dosage of Camrelizumab was 200 mg, and the frequency of medication was q2w~q4w. Eight patients were treated with Camrelizumab alone, and eight patients were treated with combined medication. RCCEP occurred in nine patients after the first medication, and in seven patients after two-four cycles of medication, the average medication cycle was two cycles, and the average occurrence time was 12.5 days after the last medication. The main clinical manifestations were that several different sizes of growths such as red nevus-like, pearl-like, and mulberry-like growths appear on the head, face, neck, torso, limbs, and other parts of the body, all of which were grade 1-2. The RCCEP of all patients was controlled after treatment. During the treatment, 11 patients were stable and five patients were local remission. RCCEP is caused by Camrelizumabis a special skin immune response, which will not cause life-threatening to patients. However, clinicians and pharmacists should be familiar with the characteristics and regularities of the adverse reaction, to do a good job in medication monitoring and management, as for ensuring the safety of patients with medication.

Microplastics in coastal farmed oyster (Crassostrea angulata) shells: Abundance, characteristics, and diversity.

One of the most concerning emerging pollutants is microplastics (MPs), which can infiltrate soft tissues of organisms by ingestion, adhesion, and fusing and may even become embedded in biominerals. However, very little evidence is available about MPs in biominerals found in the wild. This study detected the abundance and characteristics of MPs in the shells of farmed oysters (Crassostrea angulata) off the coast of Taiwan and discussed the distribution, accumulation, and diversity in the oyster shells. The results showed that MPs were ubiquitous in oyster shells, with an average abundance of 0.70 ± 0.40 MPs/g. MPs abundance was significantly (p < 0.01) higher in small oyster shells (shell length < 6.5 cm, weight 5-10 g) and inorganic (CaCO3) fraction (HCl digestion) than in large oyster shells (>6.5 cm, 10-25 g) and an organic fraction (H2O2 digestion), respectively. However, there was no significant difference in MPs abundance between the top and bottom shells (p > 0.05). MPs with a size <2 mm accounted for 78.5 %, fibrous MPs for 93.7 %, and rayon for 89.5 %. The MPs diversity integrated index (MPDII) in oyster shells was low (0.27), and the small and fibrous MPs seemed more easily embedded in biominerals. The findings confirm the presence of MPs in oyster shells in coastal environments. In addition, oyster shells may contain higher amounts of MPs than soft tissues 4-5 times, which needs to be confirmed. Further revealing the distribution and accumulation of MPs in water/terrestrial biominerals will help to understand the fate of MPs in the environment.

Mucin 4 Confers Gemcitabine Resistance and an Unfavorable Prognosis in Patients with Cholangiocarcinoma via AKT Activation.

Cholangiocarcinoma (CCA) exhibits aggressive biological behavior and a poor prognosis. Gemcitabine (GEM)-based chemotherapy is the first-line chemotherapy for advanced CCA but has a response rate of only 20-30%. Therefore, investigating treatments to overcome GEM resistance in advanced CCA is crucial. Among mucin (MUC) family members, MUC4 showed the greatest increase in the resistant versus parental sublines. MUC4 was upregulated in whole-cell lysates and conditioned media from gemcitabine-resistant (GR) CCA sublines. MUC4 mediated GEM resistance by activating AKT signaling in GR CCA cells. The MUC4-AKT axis induced BAX S184 phosphorylation to inhibit apoptosis and downregulated GEM transporter human equilibrative nucleoside transporter 1 (hENT1) expression. The combination of AKT inhibitors and GEM or afatinib overcame GEM resistance in CCA. In vivo, capivasertib (an AKT inhibitor) increased GEM sensitivity in GR cells. MUC4 promoted EGFR and HER2 activation to mediate GEM resistance. Finally, MUC4 expression in patient plasma correlated with MUC4 expression. Paraffin-embedded specimens from non-responders expressed significantly more MUC4 than did those from responders, and this upregulation was associated with poor progression-free survival and overall survival. In GR CCA, high MUC4 expression promotes sustained EGFR/HER2 signaling and AKT activation. The combination of AKT inhibitors with GEM or afatinib might overcome GEM resistance.

Immunoprofile of adenosquamous carcinoma in gastric cancer.

BACKGROUND: Gastric adenosquamous carcinoma (GASC) is a rare subtype of gastric cancer. Research on GASC treatment is limited, and its outcome is usually poor. We investigated the clinical features, immunoprofile of GASC, and determined the optimal treatment modality for these patients. METHODS: Patients with GASC from Taipei Veterans General Hospital were retrospectively reviewed. Clinical features and treatment outcomes were evaluated. Adequate samples were examined for surrogate biomarkers for immunotherapy by IHC staining. RESULTS: Total 14 (0.35%) GASC patients were found among 4034 gastric cancer patients. The median tumor size was 6.8 cm in 10 patients with stage III GASC, and all these patients underwent radical gastrectomy followed by adjuvant therapy. The median progression-free survival (PFS) and overall survival (OS) were 6.0 and 11.5 months, respectively. Two patients with stage IV GASC received frontline immunotherapy. Their median PFS and OS were 9.0 and 12.5 months. In immunoprofiling, 25.0% (n = 3), 75.0% (n = 9), and 33.3% (n = 4) of the samples had deficient mismatch repair (dMMR) protein, combined positive score (CPS) of ≥1, and CPS of ≥10, respectively. The univariate analysis revealed that programmed death-ligand 1 ≥5% (HR: 0.12; 95% CI: 0.01-0.97; p = 0.047) was significant associated with superior OS. One stage IV patient with CPS ≥10 and dMMR proteins received nivolumab monotherapy as frontline treatment that resulted 14-month PFS. CONCLUSION: Patients with GASC are more likely to yield positive results for CPS and dMMR. Biomarkers should be examined, and immunotherapy can be considered as frontline systemic treatment.

Camrelizumab Plus Apatinib in Patients With Recurrent or Metastatic Nasopharyngeal Carcinoma: An Open-Label, Single-Arm, Phase II Study.

PURPOSE: Immune checkpoint inhibitors combined with antiangiogenic therapy reportedly have potential synergistic antitumor activity. We investigated the activity and safety of this regimen for recurrent/metastatic nasopharyngeal carcinoma (NPC). METHODS: This single-arm, Simon two-stage study enrolled patients with recurrent/metastatic NPC who were refractory to at least first-line systemic therapy and treatment-naive to immune checkpoint inhibitors. The patients received camrelizumab 200 mg once every 3 weeks and apatinib 250 mg once per day. The primary end point was the objective response rate. Key secondary end points included disease control rate, progression-free survival, duration of response, overall survival, and safety. RESULTS: Between October 14, 2020, and December 23, 2021, 58 patients were enrolled, and all were included in the efficacy and safety analysis set. The objective response rate was 65.5% (95% CI, 51.9 to 77.5), and the disease control rate was 86.2% (95% CI, 74.6 to 93.9). The median duration of response was not reached, and the median progression-free survival was 10.4 months (95% CI, 7.2 to 13.6), with a median follow-up duration of 12.4 months (range, 2.1-19.9 months). Treatment-related adverse events (TRAEs) of grade 3 or higher were reported in 34 (58.6%) patients, with the most common being hypertension (19.0%), nasopharyngeal necrosis (15.5%), headache (12.1%), AST elevation (10.3%), and creatine phosphokinase elevation (10.3%). Sixteen (27.6%) patients discontinued apatinib treatment before progression because of unbearable TRAEs, and the most common complication was nasopharyngeal necrosis (9/16; 56.3%). Recurrent nasopharyngeal lesions (odds ratio, 5.94 [95% CI, 1.45 to 24.24]) and reirradiation (odds ratio, 5.33 [95% CI, 1.15 to 24.79]) were significantly positively correlated with nasopharyngeal necrosis. CONCLUSION: Camrelizumab plus apatinib had promising antitumor activity in patients with refractory recurrent/metastatic NPC who failed first-line therapy. Moderate to severe TRAEs were experienced by 58.6%, including nasopharyngeal necrosis associated with local recurrence and a history of reirradiation.