-
1.
Clinical and ocular abnormalities in DEGCAGS syndrome-Developmental delay with gastrointestinal, cardiovascular, genitourinary, and skeletal abnormalities.
Ali, SM, AlMasri, DA, Prada, CE, Lin, D, Bosley, TM, Kozak, I
Molecular genetics & genomic medicine. 2024;(1):e2329
Abstract
PURPOSE To describe clinical and ocular abnormalities in a case of Developmental Delay with Gastrointestinal, Cardiovascular, Genitourinary, and Skeletal Abnormalities (DEGCAGS syndrome). METHODS A clinical report. CASE DESCRIPTION An infant born to a consanguineous Middle Eastern family who was delivered by cesarean section because of in utero growth restriction, premature labor, and breech presentation. Post-partum medical problems included hypotension, generalized hypotonia, bradycardia, apnea requiring resuscitation and positive pressure ventilation, facial dysmorphia, skeletal malformations, and disorders of the gastrointestinal, immune, urinary, respiratory, cardiac, and visual systems. The family reported that a previous child had severe hypotonia at birth and was given the diagnosis of hypoxic ischemic encephalopathy; that child remains on a ventilator in a chronic care facility. Our patient was found to be homozygous for a novel pathogenic missense variant in theZNF699 zinc finger gene on chromosome 19p13 causing a syndrome known as Developmental Delay with Gastrointestinal, Cardiovascular, Genitourinary, and Skeletal Abnormalities (DEGCAGS syndrome). We review this variable syndrome, including abnormalities of the visual system not described previously. CONCLUSIONS We describe the 15th child to be presumably identified with the DEGCAGS syndrome and the first individual with homozygous missense variants in the ZNF699 gene who had complete clinical examination and detailed retinal imaging.
-
2.
Targeting aryl hydrocarbon receptor to prevent cancer in barrier organs.
Congues, F, Wang, P, Lee, J, Lin, D, Shahid, A, Xie, J, Huang, Y
Biochemical pharmacology. 2024;:116156
Abstract
The skin, lung, and gut are important barrier organs that control how the body reacts to environmental stressors such as ultraviolet (UV) radiation, air pollutants, dietary components, and microorganisms. The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that plays an important role in maintaining homeostasis of barrier organs. AhR was initially discovered as a receptor for environmental chemical carcinogens such as polycyclic aromatic hydrocarbons (PAHs). Activation of AhR pathways by PAHs leads to increased DNA damage and mutations which ultimately lead to carcinogenesis. Ongoing evidence reveals an ever-expanding role of AhR. Recently, AhR has been linked to immune systems by the interaction with the development of natural killer (NK) cells, regulatory T (Treg) cells, and T helper 17 (Th17) cells, as well as the production of immunosuppressive cytokines. However, the role of AhR in carcinogenesis is not as straightforward as we initially thought. Although AhR activation has been shown to promote carcinogenesis in some studies, others suggest that it may act as a tumor suppressor. In this review, we aim to explore the role of AhR in the development of cancer that originates from barrier organs. We also examined the preclinical efficacy data of AhR agonists and antagonists on carcinogenesis to determine whether AhR modulation can be a viable option for cancer chemoprevention.
-
3.
Epidermal microorganisms contributed to the toxic mechanism of nZVI and TCEP in earthworms by robbing metal elements and nutrients.
Hou, J, Yang, M, Wu, X, Chen, Q, Lu, Y, Zhang, J, Lin, D
Eco-Environment & Health. 2024;(1):80-88
Abstract
Disrupting effects of pollutants on symbiotic microbiota have been regarded as an important mechanism of host toxicity, with most current research focusing on the intestinal microbiota. In fact, the epidermal microbiota, which participates in the nutrient exchange between hosts and environments, could play a crucial role in host toxicity via community changes. To compare the contributions of intestinal and epidermal symbiotic microorganisms to host toxicity, this study designed single and combined scenarios of soil contamination [nano zero-valent iron (nZVI) and tris (2-chloroethyl) phosphate (TCEP)], and revealed the coupling mechanisms between intestinal/epidermal symbiotic bacterial communities and earthworm toxicological endpoints. Microbiome analysis showed that 15% of intestinal microbes were highly correlated with host endpoints, compared to 45% of epidermal microbes showing a similar correlation. Functional comparisons revealed that key species on the epidermis were mainly heterotrophic microbes with genetic abilities to utilize metal elements and carbohydrate nutrients. Further verifications demonstrated that when facing the co-contamination of nZVI and TCEP, certain symbiotic microorganisms became dominant and consumed zinc, copper, and manganese along with saccharides and amino acids, which may be responsible for the nutritional deficiencies in the host earthworms. The findings can enrich the understanding of the coupling relationship between symbiotic microorganisms and host toxicity, highlighting the importance of epidermal microorganisms in host resistance to environmental pollution.
-
4.
Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population.
Shi, J, Shiraishi, K, Choi, J, Matsuo, K, Chen, TY, Dai, J, Hung, RJ, Chen, K, Shu, XO, Kim, YT, et al
Nature communications. 2023;(1):3043
Abstract
Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.
-
5.
WISER Survivor Trial: Combined Effect of Exercise and Weight Loss Interventions on Adiponectin and Leptin Levels in Breast Cancer Survivors with Overweight or Obesity.
Lin, D, Sturgeon, KM, Gordon, BR, Brown, JC, Sears, DD, Sarwer, DB, Schmitz, KH
Nutrients. 2023;(15)
Abstract
Adipocyte dysregulation is one mechanism linking overweight and breast cancer recurrence. Exercise and weight loss are associated with a decreased risk of breast cancer recurrence in breast cancer survivors with overweight or obesity, which may be mediated through reduced leptin levels, increased adiponectin levels, and an elevated adiponectin to leptin (A:L) ratio. The four-arm randomized controlled WISER Survivor trial examined the 12-month intervention effects of exercise, weight loss, and the combination of exercise and weight loss on adipokine levels among breast cancer survivors (n = 339) with overweight or obesity. Compared with Control, the Combination of Exercise and Weight Loss decreased leptin levels (-35.9%; 95% CI: -46.8%, -25.0%) and increased A:L ratio (11.6%; 95% CI: 5.6%, 17.6%) but did not change adiponectin levels (4.1%; 95% CI: -3.1%, 11.2%). Compared with Control, Weight Loss Alone decreased leptin levels (-35.6%; 95% CI: -46.6%, -24.5%) and increased A:L ratio (10.6%; 95% CI: 4.7%, 16.5%) but did not change adiponectin levels (0.9%; 95% CI: -6.0%, 7.9%). Compared with Control, Exercise Alone did not change leptin levels, adiponectin levels, or A:L ratio. In analyses that consolidated intervention groups, compared with Control, weight loss of ≥5% decreased leptin levels (p trend < 0.01) and increased A:L ratio (p trend < 0.01) but did not alter adiponectin levels (p trend = 0.53). Weight loss, with or without exercise, was associated with decreased leptin levels in breast cancer survivors with overweight or obesity. Improvements in the adipokine secretion profile (A:L ratio) were primarily driven by a weight loss-induced change in leptin levels.
-
6.
Role of breastfeeding on maternal and childhood cancers: An umbrella review of meta-analyses.
Fan, D, Xia, Q, Lin, D, Ma, Y, Rao, J, Liu, L, Tang, H, Xu, T, Li, P, Chen, G, et al
Journal of global health. 2023;:04067
Abstract
BACKGROUND Multiple studies and meta-analyses have claimed that breastfeeding is inversely correlated with maternal and childhood cancers. These results could either be causal or confounded by shared risk factors. By conducting an umbrella review, we aimed to consolidate the relationship between breastfeeding and maternal and childhood cancers. METHODS We searched PubMed, Embase, Web of Science, Elsevier ScienceDirect, and Cochrane Library databases from inception to December 2022. Two reviewers independently extracted the data and assessed the quality of the studies using standardised forms. We considered two types of breastfeeding comparisons ("ever" vs "never" breastfeeding; and "longest" vs "shortest" duration). We estimated the pooled risk and 95% confidence interval (CI) for each meta-analysis. RESULTS We included seventeen meta-analyses with 55 comparisons. There was an inverse correlation between breastfeeding and childhood leukaemia (pooled risk = 0.90, 95% CI = 0.81-0.99), neuroblastoma (pooled risk = 0.81, 95% CI = 0.71-0.93), maternal ovarian cancer (pooled risk = 0.76, CI = 0.71-0.81), breast cancer (pooled risk = 0.85, 95% CI = 0.82-0.88), and oesophageal cancer (pooled risk = 0.67, 95% CI = 0.54-0.81) for "ever" vs "never" breastfeeding; and with childhood leukaemia (pooled risk = 0.94, 95% CI = 0.89-0.98), and maternal ovarian cancer (pooled risk = 0.84, 95% CI = 0.78-0.90) and breast cancer (pooled risk = 0.92, 95% CI = 0.89-0.96) for "longest" vs "shortest" breastfeeding duration. CONCLUSIONS We found evidence that breastfeeding may reduce the risk of maternal breast cancer, ovarian cancers, and childhood leukaemia, suggesting positive implications for influencing women's decision in breastfeeding. REGISTRATION PROSPERO (CRD42021255608).
-
7.
Research Advances in Mechanical Properties and Applications of Dual Network Hydrogels.
Ning, X, Huang, J, A, Y, Yuan, N, Chen, C, Lin, D
International journal of molecular sciences. 2022;(24)
Abstract
Hydrogels with a three-dimensional network structure are particularly outstanding in water absorption and water retention because water exists stably in the interior, making the gel appear elastic and solid. Although traditional hydrogels have good water absorption and high water content, they have poor mechanical properties and are not strong enough to be applied in some scenarios today. The proposal of double-network hydrogels has dramatically improved the toughness and mechanical strength of hydrogels that can adapt to different environments. Based on ensuring the properties of hydrogels, they themselves will not be damaged by excessive pressure and tension. This review introduces preparation methods for double-network hydrogels and ways to improve the mechanical properties of three typical gels. In addition to improving the mechanical properties, the biocompatibility and swelling properties of hydrogels enable them to be applied in the fields of biomedicine, intelligent sensors, and ion adsorption.
-
8.
Mechanism of action and therapeutic effects of oxidative stress and stem cell-based materials in skin aging: Current evidence and future perspectives.
Qian, H, Shan, Y, Gong, R, Lin, D, Zhang, M, Wang, C, Wang, L
Frontiers in bioengineering and biotechnology. 2022;:1082403
Abstract
Aging is associated with multiple degenerative diseases, including atherosclerosis, osteoporosis, and Alzheimer's disease. As the most intuitive manifestation of aging, skin aging has received the most significant attention. Skin aging results from various intrinsic and extrinsic factors. Aged skin is characterized by wrinkles, laxity, elastosis, telangiectasia, and aberrant pigmentation. The underlying mechanism is complex and may involve cellular senescence, DNA damage, oxidative stress (OS), inflammation, and genetic mutations, among other factors. Among them, OS plays an important role in skin aging, and multiple antioxidants (e.g., vitamin C, glutathione, and melatonin) are considered to promote skin rejuvenation. In addition, stem cells that exhibit self-replication, multi-directional differentiation, and a strong paracrine function can exert anti-aging effects by inhibiting OS. With the further development of stem cell technology, treatments related to OS mitigation and involving stem cell use may have a promising future in anti-skin aging therapy.
-
9.
Bevacizumab-induced hypertension and proteinuria: a genome-wide study of more than 1000 patients.
Quintanilha, JCF, Wang, J, Sibley, AB, Jiang, C, Etheridge, AS, Shen, F, Jiang, G, Mulkey, F, Patel, JN, Hertz, DL, et al
British journal of cancer. 2022;(2):265-274
-
-
Free full text
-
Abstract
BACKGROUND Hypertension and proteinuria are common bevacizumab-induced toxicities. No validated biomarkers are available for identifying patients at risk of these toxicities. METHODS A genome-wide association study (GWAS) meta-analysis was performed in 1039 bevacizumab-treated patients of European ancestry in four clinical trials (CALGB 40502, 40503, 80303, 90401). Grade ≥2 hypertension and proteinuria were recorded (CTCAE v.3.0). Single-nucleotide polymorphism (SNP)-toxicity associations were determined using a cause-specific Cox model adjusting for age and sex. RESULTS The most significant SNP associated with hypertension with concordant effect in three out of the four studies (p-value <0.05 for each study) was rs6770663 (A > G) in KCNAB1, with the G allele increasing the risk of hypertension (p-value = 4.16 × 10-6). The effect of the G allele was replicated in ECOG-ACRIN E5103 in 582 patients (p-value = 0.005). The meta-analysis of all five studies for rs6770663 led to p-value = 7.73 × 10-8, close to genome-wide significance. The most significant SNP associated with proteinuria was rs339947 (C > A, between DNAH5 and TRIO), with the A allele increasing the risk of proteinuria (p-value = 1.58 × 10-7). CONCLUSIONS The results from the largest study of bevacizumab toxicity provide new markers of drug safety for further evaluations. SNP in KCNAB1 validated in an independent dataset provides evidence toward its clinical applicability to predict bevacizumab-induced hypertension. ClinicalTrials.gov Identifier: NCT00785291 (CALGB 40502); NCT00601900 (CALGB 40503); NCT00088894 (CALGB 80303) and NCT00110214 (CALGB 90401).
-
10.
Population pharmacokinetics of posaconazole in Chinese pediatric patients with acute leukaemia: Effect of food on bioavailability and dose optimization.
Lin, D, Yu, L, Shang, D, Huang, L, Wu, L, Liao, X, Zhang, Y, Zi, J, Zhang, J, Zeng, Y, et al
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. 2022;:106289
-
-
Free full text
-
Abstract
This study aimed to investigate the effect of food on the pharmacokinetics of posaconazole suspension in pediatric patients with acute leukaemia and to recommend optimal dosing strategies. This single-site, prospective, open-label, observational study was conducted in 42 patients and included 186 plasma concentrations of posaconazole. Sparse data were analyzed using population pharmacokinetic modeling. Monte Carlo simulations were conducted to predict the morning trough concentrations at steady-state with the proposed dose of 2-7 mg/kg three times daily (tid) or four times daily (qid) for bodyweights of 10-36 kg. The target concentrations were 700 ng/mL for prophylaxis and 1000 ng/mL for treatment. Dosage regimens with percentage of target attainment (PTA) ≥70% were recommended. A one-compartment model with allometric scaling adequately described the pharmacokinetic profile. The apparent clearance was 9.05 L/h (95% confidence interval [CI] 7.14-11.09) and the apparent volume of distribution was 283 L (95% CI 168-491) for a typical individual of 17.5 kg. The relative bioavailability with high-fat diet was as high as 1.95-fold compared with regular food. Following the intake of regular meals, 4 mg/kg qid was adequate with a PTA ≥ 71.8% for prophylaxis. A dosage of 6 mg/kg qid under a regular diet reached a PTA ≥ 73.4% for treatment. The recommended dosage of posaconazole for prophylaxis and treatment could be predicted by the pharmacokinetic model based on bodyweight and diet type in pediatric patients.