Parasitic copepods are frequently discovered in many marine animals, and they exhibit great species diversity with remarkable morphological adaptations to their parasitic lifestyle. Similar to their ...free-living relatives, parasitic copepods usually develop through complex life cycle, but they eventually transform into a modified adult form with reduced appendages. Although the life cycle and distinct larval stages have been described in a few species of parasitic copepods, particularly those infecting commercially valuable marine animals (such as fishes, oysters, and lobsters), very little is known about the developmental process of the species that transformed into extremely simplified adult body plan. This paucity also causes some difficulties when investigating the taxonomy and phylogeny of this kind of parasitic copepods. Here we describe the embryonic development and a series of sequential larval stages of a parasitic copepod, Ive ptychoderae, which is a vermiform endoparasite living inside the hemichordate acorn worms. We devised laboratory regimes that enable us raising large quantity of embryos and free living larvae, and obtaining post-infested I. ptychoderae samples from the host tissues. Using defined morphological features, the embryonic development of I. ptychoderae can be categorized into eight stages (1-, 2-, 4-, 8-, 16- cell stages, blastula, gastrula, and limb bud stages) and the post-embryonic development comprises six larval stages (2 naupliar and 4 copepodid stages). Based on the comparisons of morphological characters in the nauplius stage, our results provide evidence to support that the Ive-group is more closely related to the Cyclopoida, which represents one of the two major clades that contain many highly transformed parasitic copepods. Thus, our results help to resolve the problematic phylogenetic position of the Ive-group in previous study based on analysis using 18S rDNA sequences. Combining with more molecular data, future comparative analyses on the morphological features of copepodid stages will further refine our understanding of the phylogenetic relationships of parasitic copepods.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The automated blister epidermal micrograft (ABEM) is a newly introduced surgical transplantation for refractory vitiligo. Comparative analysis of other surgical methods is lacking. We conducted a ...retrospective study to compare the efficacy, safety, and experience of ABEM with conventional suction blister epidermal graft (SBEG). A total of 118 anatomically based vitiligo lesions from 75 patients were included. The primary outcome was the degree of repigmentation; the patient and operator experience were evaluated. SBEG had a significantly greater incidence of repigmentation (p < 0.001), as measured by the Physician Global Assessment, as well as improvements in the Vitiligo Area Scoring Index, particularly on the face/neck area (p < 0.001). ABEM, on the contrary, had reduced donor harvest time, a better patient operative experience, and more significant Dermatology Life Quality Index improvements. In a subgroup of 38 lesions from ten patients who received both SBEG and ABEM concomitantly, there was no difference in the degree of repigmentation in the same recipient area. Overall, the degree of repigmentation for SBEG is higher than ABEM, especially in the mobilized region, and the cost is less expensive. On the contrary, ABEM requires less procedure learning curve and can supply a greater transplanting zone with shorter donor site recovery. Understanding the benefits and drawbacks of two blister grafting procedures is essential for optimal surgical outcomes for vitiligo grafting.
Co-trimoxazole, a sulfonamide antibiotic, is used to treat a variety of infections worldwide, and it remains a common first-line medicine for prophylaxis against Pneumocystis jiroveci pneumonia. ...However, it can cause severe cutaneous adverse reaction (SCAR), including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms. The pathomechanism of co-trimoxazole–induced SCAR remains unclear.
We aimed to investigate the genetic predisposition of co-trimoxazole–induced SCAR.
We conducted a multicountry case-control association study that included 151 patients with of co-trimoxazole–induced SCAR and 4631 population controls from Taiwan, Thailand, and Malaysia, as well as 138 tolerant controls from Taiwan. Whole-genome sequencing was performed for the patients and population controls from Taiwan; it further validated the results from Thailand and Malaysia.
The whole-genome sequencing study (43 case patients vs 507 controls) discovered that the single-nucleotide polymorphism rs41554616, which is located between the HLA-B and MICA loci, had the strongest association with co-trimoxazole–induced SCAR (P = 8.2 × 10−9; odds ratio OR = 7.7). There were weak associations of variants in co-trimoxazole–related metabolizing enzymes (CYP2D6, GSTP1, GCLC, N-acetyltransferase NAT2, and CYP2C8). A replication study using HLA genotyping revealed that HLA-B∗13:01 was strongly associated with co-trimoxazole–induced SCAR (the combined sample comprised 91 case patients vs 2545 controls P = 7.2 × 10−21; OR = 8.7). A strong HLA association was also observed in the case patients from Thailand (P = 3.2 × 10−5; OR = 3.6) and Malaysia (P = .002; OR = 12.8), respectively. A meta-analysis and phenotype stratification study further indicated a strong association between HLA-B∗13:01 and co-trimoxazole–induced drug reaction with eosinophilia and systemic symptoms (P = 4.2 × 10−23; OR = 40.1).
This study identified HLA-B∗13:01 as an important genetic factor associated with co-trimoxazole–induced SCAR in Asians.
Accumulating evidence suggests that human hepatocellular carcinoma (HCC) can be derived from cancer stem cells (CSCs), which contribute to tumor initiation, metastasis, chemoresistance, and ...recurrence. A great variety of HCC CSCs resulting in diverse clinical manifestations have been reported. However, how CSC diversity is regulated and generated remains unclear. Here we report that the miR‐200b–ZEB1 circuit is closely involved with the induction and maintenance of a diverse group of CSCs. We found that miR‐200b downregulation occurred in early HCC and associated with poor prognosis. The downregulation was attributable to genome deletion and promoter methylation of the miR‐200a/b/429 gene. Ectopic expression of miR‐200b or silencing of ZEB1 led to a decrease in CD13+ and CD24+ HCC CSCs and an increase in EpCAM+ HCC CSCs. Mechanistically, miR‐200b directly suppressed BMI1 and ZEB1 expressions. ZEB1 recognized promoters of CD13, CD24, and EpCAM genes resulting in CD13 and CD24 upregulation and EpCAM downregulation. Neither miR‐200b nor ZEB1 had obvious effects on CD133 or CD90 expression. Silencing CD13 or CD24 expression suppressed tumorigenicity of HCC cells. Ectopic expression of CD24 reversed the suppression of tumorigenicity by ectopic expression of miR‐200b. Clinically, miR‐200b downregulation was coupled with ZEB1 upregulation in approximately two‐thirds of HCC patients. ZEB1 expression was positively correlated with CD13 and CD24 expressions in HCCs, while miR‐200b expression was positively correlated with EpCAM. Our findings suggest that the miR‐200b–ZEB1 circuit is a master regulator of diverse stemness of HCC, which differentiates HCCs into those containing CD13+/CD24+ CSCs from those containing EpCAM+ CSCs.
To develop a pre‐emptive genetic test that comprises multiple predisposing alleles for the prevention of phenytoin‐related severe cutaneous adverse reactions (SCARs), three sets of patients with ...phenytoin‐SCAR and drug‐tolerant controls from Taiwan, Thailand, and Japan, were enrolled for this study. In addition to cytochrome P450 (CYP)2C9*3, we found that HLA‐B*13:01, HLA‐B*15:02, and HLA‐B*51:01 were significantly associated with phenytoin hypersensitivity with distinct phenotypic specificities. Strikingly, we showed an increase in predictive sensitivity of concurrently testing CYP2C9*3/HLA‐B*13:01/HLA‐B*15:02/HLA‐B*51:01 from 30.5–71.9% for selecting the individuals with the risk of developing phenytoin‐SCAR in Taiwanese cohorts, accompanied by a specificity of 77.7% (combined sensitivity, 64.7%; specificity, 71.9% for three Asian populations). Meta‐analysis of the four combined risk alleles showed significant associations with phenytoin‐SCAR in three Asian populations. In conclusion, combining the assessment of risk alleles of HLA and CYP2C9 potentiated the usefulness of predictive genetic tests to prevent phenytoin hypersensitivity in Asians.
Background:
Real-life data on patients with psoriasis treated with guselkumab are few and are needed to compare with trial-based data. We investigated the effect of clinical factors on real-world ...effectiveness of guselkumab.
Methods:
This multicentre study retrospectively included 135 patients with psoriasis treated with guselkumab from June 2018 until November 2020. Effectiveness was assessed using the degree of improvement in the Psoriasis Area and Severity Index (PASI) scores at baseline and after 4, 12, 20, 28, and 36 weeks. Predictors of effectiveness were also evaluated.
Results:
At week 36, 67% of the patients achieved PASI 75. Multivariate logistic regression analysis revealed that heavier patients were less likely to achieve PASI 75 at week 4 than patients with lower body weights. Fewer patients exposed to only one biologic achieved PASI 75 at weeks 4, 20, 28, and 36 odds ratio (OR) = 0.08 (95% CI, 0.01–0.48), 0.21 (95% CI, 0.05–0.74), 0.04 (95% CI, 0.00–0.35), and 0.07 (95% CI, 0.00–0.68), respectively than biologic-naïve patients. Patients previously treated with more than one biologic were less likely to achieve PASI 75 at weeks 12, 20, 28, and 36 OR = 0.05 (95% CI, 0.01–0.22), 0.03 (95% CI, 0.01–0.16), 0.00 (95% CI, 0.00–0.03), and 0.00 (95% CI, 0.00–0.044), respectively than biologic-naïve patients. Patients with previous anti-interleukin (IL)-17 exposure, rather than tumour necrosis factor-α and IL-12/23 inhibitors, had lower PASI improvements to guselkumab than biologic-naïve patients at weeks 12, 20, and 28 OR = 0.19 (95% CI, 0.03–0.90), 0.10 (95% CI, 0.02–0.55), and 0.03 (95% CI, 0.00–0.29), respectively.
Conclusions:
The effectiveness of guselkumab was compromised in a real-world setting. Delayed onset of therapeutic response was noted in heavier patients. Biologic exposure, the number of previously used biologics, and previous exposure to IL-17 inhibitors were clinical predictors of a reduced response to guselkumab. Physicians may share this information with patients to make treatment decisions.
Axl is a cell surface receptor tyrosine kinase, and activation of the Axl attenuates inflammation induced by various stimuli. Growth arrest-specific 6 (Gas6) has high affinity for Axl receptor. The ...role of Gas6/Axl signaling in ischemia-reperfusion-induced acute lung injury (IR-ALI) has not been explored previously. We hypothesized that Gas6/Axl signaling regulates IR-induced alveolar inflammation via a pathway mediated by suppressor of cytokine signaling 3 (SOCS3).
IR-ALI was induced by producing 30 min of ischemia followed by 90 min of reperfusion in situ in an isolated and perfused rat lung model. The rats were randomly allotted to a control group and IR groups, which were treated with three different doses of Gas6. Mouse alveolar epithelium MLE-12 cells were cultured in control and hypoxia-reoxygenation (HR) conditions with or without Gas6 and Axl inhibitor R428 pretreatment.
We found that Gas6 attenuated IR-induced lung edema, the production of proinflammatory cytokines in perfusates, and the severity of ALI ex vivo. IR down-regulated SOCS3 expression and up-regulated NF-κB, and Gas6 restored this process. In the model of MLE-12 cells with HR, Gas6 suppressed the activation of TRAF6 and NF-κB by up-regulating SOCS3. Axl expression of alveolar epithelium was suppressed in IR-ALI but Gas6 restored phosphorylation of Axl. The anti-inflammatory effect of Gas6 was antagonized by R428, which highlighted that phosphorylation of Axl mediated the protective role of Gas6 in IR-ALI.
Gas6 up-regulates phosphorylation of Axl on alveolar epithelium in IR-ALI. The Gas6/Axl signaling activates the SOCS3-mediated pathway and attenuates IR-related inflammation and injury.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Studies in various animals have shown that asymmetrically localized maternal transcripts play important roles in axial patterning and cell fate specification in early embryos. However, comprehensive ...analyses of the maternal transcriptomes with spatial information are scarce and limited to a handful of model organisms. In cephalochordates (amphioxus), an early branching chordate group, maternal transcripts of germline determinants form a compact granule that is inherited by a single blastomere during cleavage stages. Further blastomere separation experiments suggest that other transcripts associated with the granule are likely responsible for organizing the posterior structure in amphioxus; however, the identities of these determinants remain unknown. In this study, we used high-throughput RNA sequencing of separated blastomeres to examine asymmetrically localized transcripts in two-cell and eight-cell stage embryos of the amphioxus Branchiostoma floridae. We identified 111 and 391 differentially enriched transcripts at the 2-cell stage and the 8-cell stage, respectively, and used in situ hybridization to validate the spatial distribution patterns for a subset of these transcripts. The identified transcripts could be categorized into two major groups: (1) vegetal tier/germ granule-enriched and (2) animal tier/anterior-enriched transcripts. Using zebrafish as a surrogate model system, we showed that overexpression of one animal tier/anterior-localized amphioxus transcript, zfp665, causes a dorsalization/anteriorization phenotype in zebrafish embryos by downregulating the expression of the ventral gene, eve1, suggesting a potential function of zfp665 in early axial patterning. Our results provide a global transcriptomic blueprint for early-stage amphioxus embryos. This dataset represents a rich platform to guide future characterization of molecular players in early amphioxus development and to elucidate conservation and divergence of developmental programs during chordate evolution.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background & Aims
Thrombocytosis is associated with metastasis in many human cancers. Most hepatocellular carcinomas (HCC) develop in cirrhotic livers, which are characterized by thrombocytopenia. We ...aimed to elucidate the pretreatment platelet count in prediction of extrahepatic metastasis of HCC during the follow‐up.
Methods
Three cohorts containing 1660, 480 and 965 HCC patients enrolled from three hospitals were used for discovery and validation respectively. Pretreatment clinical factors associated with extrahepatic metastasis during follow‐up up to 5 years were identified using multivariate Cox regression model.
Results
In early‐stage HCC (BCLC stage 0‐A), pretreatment platelet count (hazard ratio HR, 1.04 per 10,000/μl; 95% CI, 1.01–1.07; P = 0.010) and serum alpha‐foetoprotein (AFP) >100 ng/ml (HR, 1.70; 95% CI, 1.04–2.78; P = 0.033) were the only two independent factors associated with extrahepatic metastasis. Receiver operating characteristic evidenced that pretreatment platelet count predicted metastasis better than AFP did. Survival tree analysis identified platelet counts <118,000/μl (HR, 0.49; 95% CI, 0.38–0.63; P < 0.001) or >212,000/μl (HR, 2.12; 95% CI, 1.67–2.70; P < 0.001) to categorize patients into low and high risk of metastasis subgroups, which were verified using both validation cohorts.
Conclusions
Pretreatment platelet count is a reliable marker to predict extrahepatic metastasis of early‐stage HCC following curative treatment. Cirrhotic thrombocytopenia contributes to relatively low metastasis incidence of HCC than many other cancers. High platelet count identifies a subgroup of HCC patients at high risk of metastasis, who might benefit from adjuvant therapies following initial curative treatment.
Endogenous K. pneumoniae endophthalmitis (EKE) has a higher incidence among East Asians, and the most common infectious source of EKE is pyogenic liver abscess (PLA). We investigate the risk factors ...for poor visual outcomes in patients with PLA-related EKE. The retrospective medical records of 104 patients (120 eyes) diagnosed with PLA-related EKE between 1996 and 2015. In univariate logistic regression analysis, the risk factors for poor visual outcomes were initial visual acuity (VA) worse than counting fingers (CF) (p < 0.001), eye pain (p = 0.013), hypopyon (p = 0.003), ocular hypertension (p = 0.003), positive intraocular fluids cultures (p < 0.001), subretinal abscess (p = 0.025), unilateral involvement (p = 0.017), delayed ophthalmologic visit (p = 0.022), initially presented with ocular symptoms ahead of systemic symptoms (p < 0.001), and corneal edema (p < 0.001). Intravitreal dexamethasone reduced the requirement of enucleation or evisceration (p = 0.01). The multivariate logistic regression revealed that poor initial VA worse than CF (p = 0.004) and initially presented with ocular symptoms ahead of systemic symptoms (p = 0.007) were the significant independent factors for poor visual outcomes. Early diagnosis and prompt treatment may salvage useful vision in some eyes.
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