Summary
Purpose
HLA‐B*15:02 screening is recommended before starting carbamazepine in Han Chinese and Southeast Asians because the allele is strongly predictive of Stevens‐Johnson syndrome ...(SJS)/toxic epidermal necrolysis (TEN) induced by the drug. We examined whether other HLA‐B alleles are also involved and whether the association extends to other antiepileptic drugs (AEDs).
Methods
Cases of SJS/TEN induced by any AEDs were recruited and matched (1:5) with AED‐tolerant controls. Carrier rates of HLA‐B alleles, determined by direct sequencing, were compared between cases and controls. Results were meta‐analyzed with previous studies to examine the associations between HLA‐B*15:02 and SJS/TEN induced by phenytoin and lamotrigine.
Key Findings
A total of 55 cases (27 carbamazepine, 15 phenytoin, 6 lamotrigine, 7 other AEDs) and 275 controls were recruited. In drug‐specific analysis, the carrier rate of HLA‐B*15:02 was significantly higher in carbamazepine‐SJS/TEN cases compared with carbamazepine‐tolerant controls (92.3% vs. 11.9%; p = 3.51 × 10−18; odds ratio (OR) 89.25; 95% confidence interval (CI) 19.25–413.83), and also in phenytoin‐SJS/TEN cases compared with phenytoin‐tolerant controls (46.7% vs. 20.0%; p = 0.045; OR 3.50; 95% CI 1.10–11.18). Meta‐analyses showed a strong association of HLA‐B*15:02 with phenytoin‐SJS/TEN (p < 3 × 10−4; OR 4.26; 95% CI 1.93–9.39) and, to a lesser extent, lamotrigine‐SJS/TEN (p = 0.03; OR 3.59; 95% CI 1.15–11.22). Compared with drug‐tolerant controls, the carrier rates of HLA‐B*40:01 and HLA‐B*58:01 were lower in cases of SJS/TEN induced by carbamazepine (p = 0.004) and other AEDs (p = 0.009), respectively.
Significance
SJS/TEN induced by carbamazepine and phenytoin is strongly and moderately associated with HLA‐B*15:02 in Han Chinese, respectively. Possible protective associations with HLA‐B*40:01 and HLA‐B*58:01 warrant further investigation.
A previous study conducted in Taiwan found a 100% association between HLA‐B*1502 allele and carbamazepine‐induced Stevens‐Johnson syndrome (SJS) in Han Chinese subjects, with an extremely high odds ...ratio compared with carbamazepine‐tolerant subjects (odds ratio = 2,504). We examined this association in 24 Hong Kong Han Chinese subjects who had cutaneous adverse reactions induced by different antiepileptic drugs (AEDs). They were matched with 48 AED‐tolerant controls. HLA‐B*1502 was associated with severe cutaneous reactions (SCR) induced by AEDs, which included carbamazepine, phenytoin, and lamotrigine (p = 0.001, odds ratio = 17.6), but was not associated with maculopapular exanthema (MPE) (p = 0.32). Further studies in larger samples of ethnically matched subjects should be conducted to confirm the findings. Identification of genetic polymorphisms predisposing to development of AED‐induced SCR offers the possibility of avoiding these high‐risk drugs in genetically susceptible individuals.
Hepatocellular carcinoma (HCC) is a highly malignant tumor with a poor prognosis. Treatment of HCC is complicated by the fact that the disease is often diagnosed at an advanced stage when it is no ...longer amenable to curative surgery, and current systemic chemotherapeutics are mostly inefficacious. Sirtuin 1 (SIRT1) is a class III histone deacetylase that is implicated in gene regulations and stress resistance. In this study, we found that SIRT1 is essential for the tumorigenesis of HCC. We showed that although SIRT1 was expressed at very low levels in normal livers, it was overexpressed in HCC cell lines and in a subset of HCC. Tissue microarray analysis of HCC and adjacent nontumoral liver tissues revealed a positive correlation between the expression levels of SIRT1 and advancement in tumor grades. Downregulation of SIRT1 consistently suppressed the proliferation of HCC cells via the induction of cellular senescence or apoptosis. SIRT1 silencing also caused telomere dysfunction-induced foci and nuclear abnormality that were clearly associated with reduced expressions of telomerase reverse transcriptase (TERT), and PTOP, which is a member of the shelter in complex. Ectopic expression of either TERT or PTOP in SIRT1-depleted cells significantly restored cell proliferation. There was also a positive correlation between the level of induction of SIRT1 and TERT corrected in human HCC. Finally, SIRT1-silencing sensitized HCC cells to doxorubicin treatment. Together, our findings reveal a novel function for SIRT1 in telomere maintenance of HCC, and they rationalize the clinical exploration of SIRT1 inhibitors for HCC therapy.
There is an urgent need for the identification as well as clinicopathological and functional characterization of potent prognostic biomarkers and therapeutic targets in acute myeloid leukemia (AML). ...Using immunohistochemistry and next-generation sequencing, we investigated the protein expression as well as clinicopathological and prognostic associations of serine protease inhibitor Kazal type 2 (SPINK2) in AML and examined its potential biological functions. High SPINK2 protein expression was an independent adverse biomarker for survival and an indicator of elevated therapy resistance and relapse risk. SPINK2 expression was associated with AML with an
mutation and an intermediate risk by cytogenetics and European LeukemiaNet (ELN) 2022 criteria. Furthermore, SPINK2 expression could refine the ELN2022prognostic stratification. Functionally, an RNA sequencing analysis uncovered a potential link of SPINK2 with ferroptosis and immune response. SPINK2 regulated the expression of certain P53 targets and ferroptosis-related genes, including
and
, and affected cystine uptake, intracellular iron levels and sensitivity to erastin, a specific ferroptosis inducer. Furthermore,
inhibition consistently increased the expression of
, an immune response enhancer and promoter of T-cell activity. Additionally, we identified a potential small-molecule inhibitor of SPINK2, which requires further characterization. In summary, high SPINK2 protein expression was a potent adverse prognostic marker in AML and might represent a druggable target.
The present study aimed to define a subtype of complex/monosomal karyotype (CK/MK) acute myeloid leukemia (AML) by its distinct clinical features, p53 signaling and responses to p53 targeting agents. ...Ninety‐eight young adults (range: 21‐60 years; median: 49 years) with CK/MK AML were studied. They received standard induction, consolidation and allogeneic hematopoietic stem cell transplantation from siblings or matched unrelated donors if available. Chromosomal abnormalities most commonly affected chromosome 5 (30%), 7 (22%) and 17 (21%). Next generation sequencing of a 54‐myeloid gene panel were available in 76 patients. Tumor protein 53 (TP53) mutations were most common (49%) and associated with the presence of −5/5q‐ (P < .001) and −17/17p‐ (P < .001), but not −7/7q‐ (P = .370). This “typical” CK/MK AML subtype was associated with significantly lower presenting white cell counts, higher number of karyotypic abnormalities, and inferior leukemia‐free and overall survivals, compared with CK/MK AML without the typical features. Blood or bone marrow samples from typical CK/MK AML patients showed defective p53 signaling upon induction by etoposide. In vitro drug sensitivity analysis showed that they were sensitive to APR‐246 that targeted mutant p53, but resistant to MDM2 antagonist MI‐77301. Novel therapeutic strategies targeting TP53 mutations in CK/MK AML should be developed and tested in clinical trials.
We investigated whether circulating osteopontin (OPN) could be used as a biomarker for cervical cancer. We employed a monoclonal antibody (mAb 659) specific for the unique and intact ...thrombin-sensitive site in OPN using an inhibition ELISA. We found significantly higher levels of OPN in 33 cervical cancer patients in both the plasma (mean +/- SD, 612 +/- 106 ng/mL) and serum (424 +/- 121 ng/mL) compared to healthy subjects 409 +/- 56 ng/mL, from 31 plasma samples (P < 0.0001), and 314 +/- 98 ng/mL, from 32 serum samples (P = 0.0002), respectively. Similar results were obtained when the plasma from a bigger group (147 individuals) of cervical cancer patients (560 +/- 211 ng/mL) were compared with the same plasma samples of the healthy individuals (P = 0.0014). More significantly, the OPN level was highest in stage III-IV disease (614 +/- 210 ng/mL, from 52 individuals; P = 0.0001) and least and non-discriminatory in stage I (473 +/- 110 ng/mL, from 40 individuals; P = 0.5318). No such discrimination was found when a mAb of a different specificity (mAb 446) was used in a similar inhibition ELISA to compare the two groups in the first study; a commercial capture ELISA also failed. The possibility that the target epitope recognized by the antibody probe in these assays was absent from the circulating OPN due to protein truncation was supported by gel fractionation of the OPN found in patients' plasma: 60-64 kDa fragments were found instead of the presumably full-length OPN (68 kDa) seen in healthy people. How these fragments are generated and what possible role they play in cancer biology remain interesting questions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Zinc finger transcription factors are involved broadly in development and tumorigenesis. Here, we report that the little studied zinc finger transcription factor ZNF382 functions as a tumor ...suppressor in multiple carcinomas. Although broadly expressed in normal tissues, ZNF382 expression was attenuated in multiple carcinoma cell lines due to promoter CpG methylation. ZNF382 was also frequently methylated in multiple primary tumors (nasopharyngeal, esophageal, colon, gastric, and breast). Ectopic expression of ZNF382 in silenced tumor cells significantly inhibited their clonogenicity and proliferation and induced apoptosis. We further found that ZNF382 inhibited NF-kappaB and AP-1 signaling and downregulated the expression of multiple oncogenes including MYC, MITF, HMGA2, and CDK6, as well as the NF-kappaB upstream factors STAT3, STAT5B, ID1, and IKBKE, most likely through heterochromatin silencing. ZNF382 could suppress tumorigenesis through heterochromatin-mediated silencing, as ZNF382 was colocalized and interacted with heterochromatin protein HP1 and further changed the chromatin modifications of ZNF382 target oncogenes. Our data show that ZNF382 is a functional tumor suppressor frequently methylated in multiple carcinomas.
Our previous studies have shown that serotonin (5‐hydroxytryptamine; 5‐HT) is a growth factor for hematopoietic stem/progenitor cells. In this study, we proposed a possible mechanism: 5‐HT may ...enhance megakaryopoiesis and proplatelet formation via Erk1/2 pathway and cytoskeleton reorganization. Here, 5‐HT2BR was first identified in megakaryocytic cells. 5‐HT also promoted the megakaryocytes (MKs) proliferation and reduced the cell apoptosis via the activation of 5‐HT2BR and Akt pathway. The effects were reduced by the 5‐HT2BR inhibitor ketanserin. The effect of 5‐HT on proplatelet formation in bone marrow MKs were further confirmed: the 5‐HT treated group had more proplatelet bearing MKs compared with the control group. To determine whether 5‐HT has effects on cytoskeleton reorganization of MKs, and whether these effects could be reduced by ketanserin or Erk1/2 inhibitor PD98059, MKs were stained with the F‐actin specific binder rhodamine–phalloidin. The polymerized actin level was lower in the control group than the 5‐HT group and was distributed throughout the cytoplasm with occasional aggregations. Our data demonstrated that Erk1/2 was activated in MKs treated with 5‐HT. This study suggests that 5‐HT has a potent effect on platelet formation and this effect is likely mediated via 5HT2BR with subsequent activation of p‐Erk1/2 and consequent F‐actin reorganization and proplatelet formation. We also demonstrated that melatonin, the metabolite of 5‐HT, exerts a protective effect on MK and platelet recovery in the irradiated mouse model. This study suggested that 5‐HT plays an important role in platelet formation via 5HT2BR, p‐Erk1/2, and F‐actin reorganization. Stem Cells 2014;32:2973–2982
Significant decreases in platelet counts and ITP relapses have been documented in ITP patients receiving COVID-19 mRNA vaccines; however, the effect of the inactivated COVID-19 vaccine on ITP ...patients remains unclear. The present study aimed to investigate the impact of inactivated COVID-19 vaccines on ITP patients, with a focus on platelet dropping events, bleeding events/scores, and the requirement of a new round of treatment. A total of 118 ITP patients, with 97 chronic ITP and 21 persistent ITP, who received inactivated COVID-19 immunization were investigated retrospectively. Following vaccination (within 1 month), ITP patients reported platelet dropping (31.36 %), new bleeding events (22.88 %), increases in bleeding scores (23.73 %), and new treatment requirements (22.03 %). Among them, persistent ITP patients with disease duration of 3-12 months had higher ratios of the above adverse events (71.43 %, 57.14 %, 61.90 % and 71.43 %, respectively) than chronic ITP patients with duration > 1 year (22.68 %, 15.46 %, 15.46 % and 11.34 %, respectively); patients' disease duration was negatively correlated with platelet dropping events and new treatment requirements. Furthermore, logistic regression analysis also supported the above findings, revealing that persistent ITP patients had 9.40-9.70, 7.24-10.08, and 27.17-28.51 times incidence of having platelet dropping events, new bleeding events, and new treatment requirements after vaccination, respectively, when compared to chronic ITP patients. In conclusion, the present study demonstrates that after receiving inactivated COVID-19 vaccines, ITP patients may experience platelet dropping, which may lead to new bleeding events and the requirement of a new round of treatment for ITP recurrence. As a result, platelet level monitoring is crucial for ITP patients during the vaccination, especially those with persistent ITP.
Minimal residual disease, or MRD, is an important prognostic indicator in childhood acute lymphoblastic leukemia. In ALL-IC-BFM 2002 study, we employed a standardized method of flow cytometry MRD ...monitoring for multiple centers internationally using uniformed gating, and determined the relevant MRD-based risk stratification strategies in our local patient cohort. We also evaluated a novel method of PCR MRD quantitation using peripheral blood plasma. For the bone marrow flow MRD study, patients could be stratified into 3 risk groups according to MRD level using a single time-point at day-15 (Model I) (I-A: <0.1%, I-B: 0.1-10%, I-C: >10%), or using two time-points at day-15 and day-33 (Model II) (II-A: day-15<10% and day-33<0.01%, II-B: day-15 ≥ 10% or day-33 ≥ 0.01% but not both, II-C: day-15 ≥ 10% and day-33 ≥ 0.01%), which showed significantly superior prediction of relapse (p = .00047 and <0.0001 respectively). Importantly, patients with good outcome (frequency: 56.0%, event-free survival: 90.1%) could be more accurately predicted by Model II. In peripheral blood plasma PCR MRD investigation, patients with day-15-MRD ≥ 10(-4) were at a significantly higher risk of relapse (p = 0.0117). By multivariate analysis, MRD results from both methods could independently predict patients' prognosis, with 20-35-fold increase in risk of relapse for flow MRD I-C and II-C respectively, and 5.8-fold for patients having plasma MRD of ≥ 10(-4). We confirmed that MRD detection by flow cytometry is useful for prognostic evaluation in our Chinese cohort of childhood ALL after treatment. Moreover, peripheral blood plasma DNA MRD can be an alternative where bone marrow specimen is unavailable and as a less invasive method, which allows close monitoring.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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