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Manufacturing and testing of pharmaceutical products frequently occur in multiple facilities within a company's network. It is of interest to demonstrate equivalence among the alternative testing/manufacturing facilities to ensure product consistency and quality regardless of the facility where it was manufactured/tested. In the Frequentist framework, equivalence testing is well established when comparing two labs or manufacturing facilities; however, when considering more than two labs or production sites, the Frequentist approach may not always offer appropriate or interpretable estimates for demonstrating equivalence among all of them simultaneously. This paper demonstrates the utility of Bayesian methods to the equivalence assessment of multiple groups means, with a comparison against traditional Frequentist methods. We conclude that a Bayesian strategy is very useful for addressing the problem of multi-group equivalence. While it is not our intention to argue that Bayesian methods should always replace Frequentist ones, we show that among the advantages of a Bayesian analysis is that it provides a more nuanced understanding of the degree of similarity among sites than the hypothesis testing underpinning the Frequentist approach.

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PURPOSE: Data regarding the association between metabolically healthy obesity (MHO) and preclinical atherosclerosis in childhood are lacking. Carotid intima-media thickness (cIMT) is a noninvasive method used to assess cardiovascular risk. This study examined the relationships among cIMT, metabolic phenotypes, and cardiometabolic risk factors (CMRFs) in overweight and obese adolescents. METHODS: Anthropometric, biochemical, and cIMT data were collected. The study participants were categorized as MHO or metabolically unhealthy obesity (MUO) based on insulin resistance. CMRFs were assessed using blood pressure (BP); levels of triglycerides, high-density lipoprotein cholesterol (HDL-C), and fasting plasma glucose; or a diagnosis of diabetes mellitus. Differences in cIMT values were evaluated according to the metabolic phenotype and factors associated with cIMT. RESULTS: Among the 111 participants (80 boys, 72.1%), 23 (20.7%) were classified as MHO and 88 (79.3%) as MUO. The MHO group exhibited lower glycated hemoglobin and triglyceride levels and higher HDL-C levels compared to those exhibited by the MUO group (all P<0.01). The cIMT values did not differ significantly between the MHO and MUO groups. The high cIMT tertile group revealed higher systolic BP compared to that exhibited by the low cIMT tertile group (123.7±2.1 mmHg vs. 116.9±1.6 mmHg, P=0.028). Mean cIMT was positively correlated with age (ß=0.009) and body mass index (BMI) (ß=0.033) after adjusting for covariates (both P<0.05). CONCLUSION: In overweight and obese Korean adolescents, cIMT was associated with age and BMI but not with metabolic phenotype or CMRFs. Further research is warranted to determine the relationship between cIMT during adolescence and cardiovascular outcomes during adulthood.

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This study demonstrated that NiO and Ni(OH)2 as Ni(II) catalysts exhibited significant activity for organic oxidation in the presence of various oxyanions, such as hypochlorous acid (HOCl), peroxymonosulfate (PMS), and peroxydisulfate (PDS), which markedly contrasted with Co-based counterparts exclusively activating PMS to yield sulfate radicals. The oxidizing capacity of the Ni catalyst/oxyanion varied depending on the oxyanion type. Ni catalyst/PMS (or HOCl) degraded a broad spectrum of organics, whereas PDS enabled selective phenol oxidation. This stemmed from the differential reactivity of two high-valent Ni intermediates, Ni(III) and Ni(IV). A high similarity with Ni(III)OOH in a substrate-specific reactivity indicated the role of Ni(III) as the primary oxidant of Ni-activated PDS. With the minor progress of redox reactions with radical probes and multiple spectroscopic evidence on moderate Ni(III) accumulation, the significant elimination of non-phenolic contaminants by NiOOH/PMS (or HOCl) suggested the involvement of Ni(IV) in the substrate-insensitive treatment capability of Ni catalyst/PMS (or HOCl). Since the electron-transfer oxidation of organics by high-valent Ni species involved Ni(II) regeneration, the loss of the treatment efficiency of Ni/oxyanion was marginal over multiple catalytic cycles.

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Veterinary drugs play a crucial role in the treatment of various animal diseases. However, their residues, stemming from issues, such as withdrawal period lapses, overuse, or abuse, can jeopardize food safety and human health. This study addresses recent regulations in Korea concerning specific veterinary drugs (anacolin, ephedrine, menichlopholan, piperonyl butoxide, and etisazole HCl) and their ongoing discussions. This study aimed to validate two pre-developed methods for quantifying residues in livestock and fishery products using QuEChERS and liquid chromatography-tandem mass spectrometry. Both methods exhibited excellent linearity, recoveries (70.3-119%), and coefficient of variations (1.3-28%), along with low limits of detection and quantification (0.3-4 ng/g and 1-12 ng/g). This study is significant for its contribution to the detection of veterinary drugs in livestock and fishery products, given the limited research available on the methods for analyzing these substances.

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BACKGROUND: Calf circumference is currently recommended as a case-finding marker for sarcopenia, but its usefulness has not been determined in chronic pain conditions. Therefore, the present study aimed to evaluate the predictive performance of calf circumference in diagnosing sarcopenia in older patients with chronic low back pain. METHODS: Ambulatory adult patients aged ≥ 65 years with chronic low back pain were enrolled. A diagnosis of sarcopenia was established based on the criteria outlined by the Asian Working Group for Sarcopenia in 2019. Patient demographics, pain-related factors, clinical factors, and sarcopenia-related measurements were compared between non-sarcopenic and sarcopenic patients. Linear regression analysis was used to evaluate the correlation of calf circumference with muscle mass, strength, and physical performance. Also, a receiver operating characteristic curve analysis for calf circumference in predicting sarcopenia was conducted; and area under the curve (AUC) values, along with their corresponding 95% confidence intervals (CI), were calculated. RESULTS: Data from 592 patients were included in the analysis. Eighty-five patients were diagnosed with sarcopenia (14.3%), 71 of whom had severe sarcopenia (11.9%). A higher prevalence of sarcopenia was observed in female patients (9.0% vs. 16.7%, p = 0.016). After adjusting for age, BMI, and comorbidities, calf circumference correlated positively with muscle mass but not with muscle strength and physical performance. The AUC values for sarcopenia were 0.754 (95% CI = 0.636-0.871, p = 0.001) in males and 0.721 (95% CI = 0.657-0.786, p < 0.001) in females. The cut-offs for calf circumference in predicting sarcopenia were 34 cm (sensitivity 67.1%, specificity 70.6%) in males, and 31 cm (sensitivity 82.5%, specificity 51.5%) in females. CONCLUSIONS: Even though sex differences in its predictive value for sarcopenia should be considered, our findings suggest that calf circumference can be used as an indicator for predicting muscle mass and may serve as a potential marker for identifying sarcopenia in older patients with chronic low back pain.

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BACKGROUND: Recycling of integrin via endosomal vesicles is critical for the migration of cancer cells, which leads to the metastasis of pancreatic cancer and devastating cancer-related death. So, new diagnostic and therapeutic molecules which target the recycling of endosomal vesicles need to be developed. METHODS: Public databases including TCGA, ICGC, GSE21501, GSE28735, and GENT are analyzed to derive diagnostic and therapeutic targets. To reveal biological roles and underlying mechanisms of molecular targets, various molecular biological experiments were conducted. RESULTS: First, we identified UNC13D's overexpression in patients with pancreatic cancer (n = 824) and its prognostic significance and high hazard ratio (HR) in four independent pancreatic cancer cohorts (TCGA, n = 178, p = 0.014, HR = 3.629; ICGC, n = 91, p = 0.000, HR = 4.362; GSE21501, n = 102, p = 0.002, HR = 2.339; GSE28735, n = 45, p = 0.022, HR = 2.681). Additionally, its expression is associated with the clinicopathological progression of pancreatic cancer. Further biological studies have shown that UNC13D regulates the migration of pancreatic cancer cells by coupling the exocytosis of recycling endosomes with focal adhesion turnover via the regulation of FAK phosphorylation. Immunoprecipitation and immunocytochemistry showed the formation of the RAB11-UNC13D-FAK axis in endosomes during integrin recycling. We observed that UNC13D directly interacted with the FERM domain of FAK and regulated FAK phosphorylation in a calcium-dependent manner. Finally, we found co-expression of UNC13D and FAK showed the poorest survival (TCGA, p = 0.000; ICGC, p = 0.036; GSE28735, p = 0.006). CONCLUSIONS: We highlight that UNC13D, a novel prognostic factor, promotes pancreatic cancer progression by coupling integrin recycling with focal adhesion turnover via the RAB11-UNC13D-FAK axis for the migration of pancreatic cancer cells.

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Histone H3K9 methylated heterochromatin silences repetitive non-coding sequences and lineage-specific genes during development, but how tissue-specific genes escape from heterochromatin in differentiated cells is unclear. Here, we examine age-dependent transcriptomic profiling of terminally differentiated mouse retina to identify epigenetic regulators involved in heterochromatin reorganization. The single-cell RNA sequencing analysis reveals a gradual downregulation of Kdm3b in cone photoreceptors during aging. Disruption of Kdm3b (Kdm3b +/- ) of 12-month-old mouse retina leads to the decreasing number of cones via apoptosis, and it changes the morphology of cone ribbon synapses. Integration of the transcriptome with epigenomic analysis in Kdm3b +/- retinas demonstrates gains of heterochromatin features in synapse assembly and vesicle transport genes that are downregulated via the accumulation of H3K9me1/2. Contrarily, losses of heterochromatin in apoptotic genes exacerbated retinal neurodegeneration. We propose that the KDM3B-centered epigenomic network is crucial for balancing of cone photoreceptor homeostasis via the modulation of gene set-specific heterochromatin features during aging.

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Metastatic castration-resistant prostate cancer (mCRPC) is an advanced disease in which patients ultimately fail standard of care androgen-deprivation therapies and exhibit poor survival rates. The prostate-specific membrane antigen (PSMA) has been validated as a mCRPC tumor antigen with over-expression in tumors and low expression in healthy tissues. Using our proprietary technology for incorporating synthetic amino acids (SAAs) into proteins at selected sites, we have developed ARX517, an antibody drug conjugate (ADC) which is composed of a humanized anti-PSMA antibody site-specifically conjugated to a tubulin inhibitor at a drug-to-antibody ratio of 2. After binding PSMA, ARX517 is internalized and catabolized, leading to cytotoxic payload delivery and apoptosis. To minimize premature payload release and maximize delivery to tumor cells, ARX517 employs a non-cleavable PEG linker and stable oxime conjugation enabled via SAA protein incorporation to ensure its overall stability. In vitro studies demonstrate that ARX517 selectively induces cytotoxicity of PSMA-expressing tumor cell lines. ARX517 exhibited a long terminal half-life and high serum exposure in mice, and dose-dependent anti-tumor activity in both enzalutamide-sensitive and -resistant CDX and PDX prostate cancer models. Repeat dose toxicokinetic studies in non-human primates demonstrated ARX517 was tolerated at exposures well above therapeutic exposures in mouse pharmacology studies, indicating a wide therapeutic index. In summary, ARX517 inhibited tumor growth in diverse mCRPC models, demonstrated a tolerable safety profile in monkeys, and had a wide therapeutic index based on preclinical exposure data. Based on the encouraging preclinical data, ARX517 is currently being evaluated in a Phase 1 clinical trial ([NCT04662580]).

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Background: The Korean Journal of Family Medicine (KJFM), which is an official journal of the Korean Academy of Family Medicine, is an English-text medical journal published since 2009. Although nearly 15 years have passed since the journal was launched, to the best of our knowledge, no study has reviewed articles published in the KJFM. Accordingly, we analyzed articles published in the KJFM for the first time. Methods: Articles published in the KJFM between January 2018 and November 2023 were categorized according to article type. Information about author affiliations, study subjects, research methods, and modes of data collection was then scrutinized. Moreover, we compared the frequencies of subjects, research methods and modes of data collection before, during, and after the coronavirus disease 2019 pandemic. Results: Original article was the most common article type. Approximately 52% of the articles were published by authors affiliated with departments other than family medicine, and 40% were published by family medicine. Approximately 60% and 38% of the articles were published by Korean authors and authors of international affiliations, respectively. Throughout the pandemic periods, research subjects focusing on "diseases & symptoms" have diminished, while "principles of family medicine" have progressively increased. Additionally, the use of cross-sectional study methods has declined. In terms of data collection, the use of "big data," "medical records," and "questionnaires" has decreased, whereas the use of "study results" has increased. Conclusion: KJFM is journal with wide and international participation covering various research subjects and study methods. We believe that our study provides valuable data for the future direction and development of the KJFM.

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PURPOSE: Surgical site infections (SSIs) remain a concern after implant-based breast reconstruction, despite preventive measures. These infections can have serious consequences. This study evaluated the correlation between drain tip culture results and SSIs in this patient population. METHODS: We analyzed data from patients who underwent implant-based breast reconstruction between July 2021 and May 2023. Drain tip cultures were collected, and any SSIs occurring within one month of surgery were documented. We then compared clinical data with the culture results. RESULTS: A total of 263 drain tip cultures were included. Notably, none of the 61 patients who underwent tissue expander removal and implant insertion had positive cultures. However, among the 202 patients who received tissue expanders or direct-to-implant procedures, 11 (5.45%) had positive cultures, with a total of 12 SSIs identified. Importantly, five of the 11 culture-positive wounds developed SSIs. Multivariate analysis revealed a significant two-way association between infection and positive drain tip cultures. For Staphylococcus aureus specifically, drain tip cultures showed excellent predictive value: sensitivity (33.33%), specificity (100%), positive predictive value (100%), and negative predictive value (95.96%). CONCLUSION: Drain tip cultures from immediate implant-based breast reconstructions significantly correlated with SSIs. Close monitoring is crucial, especially when S. aureus is identified in the culture.

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Air pollution, a global health concern, has been associated with adverse effects on human health. In particular, particulate matter (PM), which is a major contributor to air pollution, impacts various organ systems including the skins. In fact, PM has been suggested as a culprit for accelerating skin aging and pigmentation. In this study, using single-cell RNA sequencing, IL-24 was found to be highly upregulated among the differentially expressed genes commonly altered in keratinocytes and fibroblasts of ex vivo skins exposed to PM. It was verified that PM exposure triggered the expression of IL-24 in keratinocytes, which subsequently led to a decrease in type I procollagen expression and an increase in MMP1 expression in fibroblasts. Furthermore, long-term treatment of IL-24 induced cellular senescence in fibroblasts. Through high-throughput screening, we identified chemical compounds that inhibit the IL-24-STAT3 signaling pathway, with lovastatin being the chosen candidate. Lovastatin not only effectively reduced the expression of IL24 induced by PM in keratinocytes but also exhibited a capacity to restore the decrease in type I procollagen and the increase in MMP1 caused by IL-24 in fibroblasts. This study provides insights into the significance of IL-24, illuminating mechanisms behind PM-induced skin aging, and proposes IL-24 as a promising target to mitigate PM-associated skin aging.

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A series of indazole analogs, derived from the B,C-ring-truncated scaffold of deguelin, were designed to function as C-terminal inhibitors of heat shock protein 90 (HSP90) and investigated as novel antitumor agents against HER2-positive breast cancer. Among the synthesized compounds, compound 12d exhibited substantial inhibitory effects in trastuzumab-sensitive (BT474) and trastuzumab-resistant (JIMT-1) breast cancer cells, with IC50 values of 6.86 and 4.42 µM, respectively. Notably, compound 12d exhibited no cytotoxicity in normal cells. Compound 12d markedly downregulated the expression of the major HSP90 client proteins in both cell types, attributing its cytotoxicity to the destabilization and inactivation of HSP90 client proteins. Molecular docking studies using the homology model of an HSP90 homodimer demonstrated that inhibitor 12d fit nicely into the C-terminal domain, boasting a higher electrostatic complementary score than ATP. In vivo pharmacokinetic study indicated the high oral bioavailability of compound 12 d at F = 66.9 %, while toxicological studies indicated its negligible impact on hERG channels and CYP isozymes. Genotoxicity tests further confirmed its safety profile. The findings collectively position compound 12d as a promising candidate for further development as an antitumor agent against HER2-positive breast cancer.

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The biology of the cyclin-dependent kinase-like (CDKL) kinase family remains enigmatic. Contrary to their nomenclature, CDKLs do not rely on cyclins for activation and are not involved in cell cycle regulation. Instead, they share structural similarities with mitogen-activated protein kinases and glycogen synthase kinase-3, although their specific functions and associated signaling pathways are still unknown. Previous studies have shown that the activation of CDKL5 kinase contributes to the development of acute kidney injury (AKI) by suppressing the protective SOX9-dependent transcriptional program in tubular epithelial cells. In the current study, we measured the functional activity of all five CDKL kinases and discovered that, in addition to CDKL5, CDKL1 is also activated in tubular epithelial cells during AKI. To explore the role of CDKL1, we generated a germline knockout mouse that exhibited no abnormalities under normal conditions. Notably, when these mice were challenged with bilateral ischemia-reperfusion and rhabdomyolysis, they were found to be protected from AKI. Further mechanistic investigations revealed that CDKL1 phosphorylates and destabilizes SOX11, contributing to tubular dysfunction. In summary, this study has unveiled a previously unknown CDKL1-SOX11 axis that drives tubular dysfunction during AKI.NEW & NOTEWORTHY Identifying and targeting pathogenic protein kinases holds potential for drug discovery in treating acute kidney injury. Our study, using novel germline knockout mice, revealed that Cdkl1 kinase deficiency does not affect mouse viability but provides protection against acute kidney injury. This underscores the importance of Cdkl1 kinase in kidney injury and supports the development of targeted small-molecule inhibitors as potential therapeutics.

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The experimenters examined two different levels of acquisition criteria-Set and Operant Analysis-to assess acquisition and response maintenance of tact operants for four participants. Set Analysis involved replacing acquired operants at a set level, whereas Operant Analysis involved replacing acquired operants at an individual operant level. All participants required fewer instructional trials to acquire tacts under the Operant Analysis condition. Three participants maintained a similar number of operants in both conditions, whereas one participant maintained more operants under the Set Analysis condition.

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Flunixin is a veterinary nonsteroidal anti-inflammatory agent whose residues have been investigated in their original form within tissues such as muscle and liver. However, flunixin remains in milk as a metabolite, and 5-hydroxy flunixin has been used as the primary marker for its surveillance. This study aimed to develop a quantitative method for detecting flunixin and 5-hydroxy flunixin in milk and to strengthen the monitoring system by applying to other livestock and fishery products. Two different methods were compared, and the target compounds were extracted from milk using an organic solvent, purified with C18, concentrated, and reconstituted using a methanol-based solvent. Following filtering, the final sample was analyzed using liquid chromatography- tandem mass spectrometry. Method 1 is environmentally friendly due to the low use of reagents and is based on a multi-residue, multi-class analysis method approved by the Ministry of Food and Drug Safety. The accuracy and precision of both methods were 84.6%-115% and 0.7%-9.3%, respectively. Owing to the low matrix effect in milk and its convenience, Method 1 was evaluated for other matrices (beef, chicken, egg, flatfish, and shrimp) and its recovery and coefficient of variation are sufficient according to the Codex criteria (CAC/GL 71-2009). The limits of detection and quantification were 2-8 and 5-27 µg/kg for flunixin and 2-10 and 6-33 µg/kg for 5-hydroxy flunixin, respectively. This study can be used as a monitoring method for a positive list system that regulates veterinary drug residues for all livestock and fisheries products.

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[This retracts the article DOI: 10.1016/j.omtn.2019.02.007.].

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This study comprehensively investigates the phase evolution of silver-carbon composite (Ag/C) layers in anode-less batteries with both liquid and solid electrolytes. The results of in situ X-ray diffraction and cross-sectional electron microscopy analyses reveal that the alloying reaction of Ag and Li is more homogeneous in solid-electrolyte-based cells compared to liquid-electrolyte-based cells. This homogeneity is attributed to diffusional Coble creep across the heterogeneous interfaces of Ag/C layers and solid electrolytes.

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BACKGROUND: Dual-phase fluorine-18 labeled N-3-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl) nortropane (18F-FP-CIT) positron emission tomography (PET) scans could be used to support disorders like Parkinson's disease (PD). Dopamine transporter (DAT) binding and cerebral perfusion are associated with ageing and gender. We investigated the effects of age and gender on non-degenerative parkinsonism, using automated quantification in striatum: specific binding ratios (SBRs) for DAT binding in delayed phase PET (dCIT) and standardized-uptake-value ratios (SUVRs) for cerebral perfusion in early phase PET (eCIT). We also examined the correlations between SBR and SUVR. METHODS: This retrospective study analyzed subjects with dual-phase 18F-FP-CIT PET scans. The eCIT images were acquired immediately post-injection, and dCIT images were taken 120 min later. With Brightonix software, automated quantification of SBRs for dCIT and SUVRs for eCIT were acquired from visually normal scans. The effects of aging and gender were assessed by regressing SBRs and SUVRs on age for both genders. The correlations between SUVRs and SBRs were evaluated. RESULTS: We studied 79 subjects (34 males and 45 females). An age-related reduction in SBRs was observed in the dorsal striatum, ventral striatum, caudate nucleus, and putamen for both genders. SUVRs were found to negatively correlate with age in the dorsal striatum, ventral striatum, caudate nucleus, and putamen for males and in the dorsal striatum and caudate nucleus for females. Positive correlations between SBRs and SUVRs in the dorsal striatum, ventral striatum, caudate nucleus, and putamen for male and in the dorsal striatum, caudate nucleus, and putamen for females. CONCLUSIONS: Using quantified values from dual-phase 18F-FP-CIT PET with a single injection, we demonstrate a negative impact of age on SBRs (DAT binding) in the striatum for both genders and SUVRs (cerebral perfusion) in the dorsal striatum and caudate nucleus for both genders and in the ventral striatum and putamen for males. Additionally, we found positive associations between SBR and SUVR values in the dorsal striatum, caudate nucleus, and putamen for both genders and in the ventral striatum for males.

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BACKGRUOUND: Poorly differentiated thyroid carcinoma (PDTC) accounts for a small portion of thyroid carcinomas but contributes to a significant proportion of thyroid carcinoma-associated deaths. The clinicopathological prognostic factors and clinical outcomes of PDTC remain unclear. We aimed to evaluate the clinical outcomes of patients with PDTC after curative treatment. METHODS: A comprehensive search was performed up to September 2023. We included studies investigating treatment outcomes in patients with PDTC who underwent initial surgery. The 5-year disease-free survival (DFS) and overall survival (OS) were extracted. In this meta-analysis, the enrolled PDTC histological criteria included 3rd, 4th, and 5th World Health Organization (WHO) and Memorial Sloan Kettering Cancer Center (MSKCC) classification. A random-effects model was used for the pooled proportion analysis. Meta-regression analysis was conducted to evaluate the prognostic factors. RESULTS: Twenty retrospective studies published between 2007 and 2023, including 1,294 patients, met all inclusion criteria. Studies that diagnosed PDTC based on various histological criteria including 3rd WHO (n=5), 4th WHO (n=12), 5th WHO (n=2), and MSKCC (n=1) were included. Overall, 5-year DFS and 5-year OS were 49.4% (95% confidence interval [CI], 42.3 to 56.4) and 73.8% (95% CI, 66.5 to 79.9), with moderate heterogeneity of 58% and 55%, respectively. In meta-regression analysis, extrathyroidal extension (ETE) was a prognostic factor for OS. CONCLUSION: The meta-analysis of DFS and OS in patients with PDTC show the moderate heterogeneity with a variety of histological criteria. ETE appears to have a significant impact on OS, regardless of histological criteria.

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