[The Correlation Between Serum Hcy Level and Clinical Indicators in Systemic Lupus Erythematosus Patients].

OBJECTIVE: To explore the serum homocysteine (Hcy) level and its influence factors in systemic lupus erythematosus (SLE) patients. METHODS: 90 SLE patients were included in the study. According to the systemic lupus erythematosus disease activity index (SLEDAI) score, 41 patients were in active stage (> 9 scores), 49 patients were in inactive stage (≤9 scores), while 46 healthy individuals were selected as controls. Total cholesterol (TC), triacylglyceride (TG), serum creatinine (Ser), C-reactive protein (CRP), serum cystatin (cystin c, CysC) and Hcy level were measured. Analysis on the relationship between Hcy level and SLEDAI score, as well as serum indicators was conducted. RESULTS: The levels of Hcy, TG, TC, CRP and CysC in SLE patients were higher than healthy controls (P < 0.05), and the serum level in active SLE patients was higher than inactive SLE patients (P < 0.05). There was no significant difference in Ser level among the active SLE patients, inactive SLE patients and healthy controls (P>0.05). There was a positive correlation between Hcy level and SLEDAI score (r=0.698 3, P < 0.01), as well as CysC (r=0.597 5, P < 0.01). There was no significant correlation between Hcy level and CRP, TC, TG and Ser levels (P>0.05). CONCLUSIONS: The Hcy level in SLE patients was higher than healthy controls. The level of Hcy was positively correlated with the degree of disease activity. The Hcy level and SLEDAI score can be used as indicators to evaluate the activity of SLE.

Retracing from Outcomes to Causes: NRF2-Driven GSTA4 Transcriptional Regulation Controls Chronic Inflammation and Oxidative Stress in Atopic Dermatitis Recurrence.

Atopic dermatitis (AD), a chronic and recurrent inflammatory skin disorder, presents a high incidence and imposes a substantial economic burden. Preventing its recurrence remains a significant challenge in dermatological therapy due to poorly understood underlying mechanisms. In our study, we adopted a strategy of tracing the mechanisms of recurrence from clinical outcomes. We developed a mouse model of recurrent AD and applied clinically validated treatment regimens. Transcriptomic analyses revealed a pronounced enrichment in the glutathione metabolic pathway in the treated group. Through integrated bioinformatics and in vivo validation, we identified glutathione S-transferase alpha 4 (GSTA4) as a pivotal mediator in AD recurrence. Immunohistochemical analysis demonstrated decreased GSTA4 expression in lesions from AD patients. Functionally, in vitro overexpression of GSTA4 significantly curtailed AD-like inflammatory responses and reactive oxygen species (ROS) production. Moreover, we discovered that NRF2 transcriptional activity regulates GSTA4 expression and function. Our treatment notably augmented NRF2-mediated GSTA4 transcription, yielding pronounced anti-inflammatory and ROS-neutralizing effects. Conclusively, our findings implicate GSTA4 as a critical factor in the recurrence of AD, particularly in the context of oxidative stress and chronic inflammation. Targeting the NRF2-GSTA4 axis emerges as a promising anti-inflammatory and antioxidative strategy for preventing AD recurrence.

Efficacy and safety of Huzhang Granule, a compound Chinese herbal medicine, for acute gouty arthritis: A double-blind, randomized controlled trial.

BACKGROUND: Acute gouty arthritis (AGA) is an inflammatory joint disease with a high prevalence. Typical medical interventions, including nonsteroidal anti-inflammatory drugs, colchicine and glucocorticoids, can have serious adverse reactions. Huzhang Granule (HZG), a compound Chinese herbal medicine, has been used to treat AGA for more than 30 years with satisfactory effects and no significant adverse reactions. However, the efficacy and safety of HZG in AGA patients remains unknown. OBJECTIVE: The present investigation was designed to examine the efficacy and safety profile of HZG in managing AGA patients. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: The current study was conducted as a noninferiority, randomized controlled clinical trial on 180 eligible enrolled participants. Participants were randomly assigned into the HZG and etoricoxib groups. Treatments were administered for 5 d, during which the HZG group received HZG and placebo etoricoxib, while the etoricoxib group received etoricoxib and placebo HZG in the same ratio (1:1). MAIN OUTCOME MEASURES: The primary outcome was pain experienced by the patient in the gout-afflicted joint from days 2 to 5 of the treatment window. The pain level was measured via a visual analogue scale, ranging from 0 mm to 100 mm. The secondary outcomes comprised joint tenderness and swelling, reduction of inflammatory biomarkers, and the patient's and investigator's global evaluations of therapeutic response. RESULTS: The mean reduction in pain was -51.22 mm (95% confidence interval [CI], [-53.42, -49.03] mm) for the HZG and -52.00 mm (95% CI, [-54.06, -49.94] mm) for the etoricoxib groups. The mean difference between the two groups was 0.78 mm (95% CI, [-2.25, 3.81] mm). All additional efficacy endpoints, covering decreased inflammation and pain relief, yielded compelling proof of noninferiority. Patients in the HZG group exhibited a comparatively lower rate of adverse events compared to those in the etoricoxib group (4.44% vs 13.33%; P ≤ 0.05). CONCLUSION: HZG and etoricoxib groups demonstrated similar levels of analgesic effectiveness. The safety and efficacy of HZG indicates that it can be used as a potential therapeutic option for treating AGA. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2000036970). Please cite this article as: Wang H, Chen ST, Ding XJ, Kuai L, Hua L, Li X, Wang YF, Zhang M, Li B, Wang RP, Zhou M. Efficacy and safety of Huzhang Granule, a compound Chinese herbal medicine, for acute gouty arthritis: A double-blind, randomized controlled trial. J Integr Med. 2024; 22(3): 270-278.

Current evidence on the role of lipid lowering drugs in the treatment of psoriasis.

Background: Abnormal lipid distribution is observed in patients with psoriasis, which increases their risk for atherosclerosis. Lipid-lowering drugs have a certain curative effect in the treatment of psoriasis, but there is no relevant evidence-based medical evaluation. Objective: The purpose of this systematic evaluation was to assess the efficacy, safety, and potential mechanisms of action of lipid-lowering drugs for the treatment of psoriasis. Methods: The PubMed, Embase, Cochrane Central Register of Controlled Trials, Clinical Trial, Chinese National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database, and Wanfang Database were searched for relevant articles from inception to 31 December 2021. The RevMan 5.3 and Cochrane risk-of-bias tool were used for data analysis and risk assessment, respectively. The psoriasis area and severity index (PASI) score is the primary outcome indicator in clinical studies. Based on preclinical studies, we elucidated and mapped the action mechanisms of lipid-lowering drugs in the treatment of psoriasis. Results: The study included eight randomized controlled studies, four single-arm studies, and four in vitro studies. The results showed that lipid-lowering drugs, particularly statins, administered both orally and topically, can significantly improve psoriatic skin lesions and reduce the PASI scores [standardized mean difference, (SMD): -0.94; 95% CI: [-1.58, -0.31]; p = 0.004]. Oral statins performed best at week eight (SMD: -0.92; 95% CI: [-1.39, -0.44]; p = 0.0001). The mechanism of lipid-lowering drugs in the treatment of psoriasis may be related to the inhibition of keratinocyte proliferation, inhibition of CCL20-CCR6 interaction, and reduction in the levels of inflammatory factors. Limitations: There are few studies on lipid-lowering drugs and psoriasis, and their small sample sizes may render the evidence unconvincing. Conclusion: The present findings suggest that lipid-lowering drugs are relieving symptoms in psoriasis. Lipid-lowering drugs, particularly statins, can be used to treat psoriasis with good efficacy and few side effects.

Effect of halometasone cream combined with Simiao pill on the therapeutic effect and expression of serum leukotriene B4 (LTB4) and thymic stromal lymphopoietin (TSLP) in patients with eczema, and the factors influencing its clinical efficacy.

BACKGROUND: Chronic eczema has the characteristics of a long treatment cycle and repeated attacks, which seriously affects the daily life and work of patients. Topical glucocorticoids are the first-line treatment for chronic eczema. This study aimed to retrospectively analyze the effects of halometasone cream combined with Simiao pill on the efficacy and expression of serum leukotriene B4 (LTB4) and thymic stromal lymphopoietin (TSLP) in patients with eczema, and identify the factors influencing its clinical efficacy. METHODS: We retrospectively collected the medical records of 195 patients with chronic eczema treated in the dermatology department from January 2020 to May 2021, and divided them into two groups according to medication: 98 cases were treated with halometasone cream (control group) and 97 cases were treated with halometasone ointment combined with Simiao pill (observation group). The severity of eczema, quality of life, clinical efficacy, LTB4 and TSLP levels, and safety were compared between the two groups. Multivariate logistic regression analysis was used to determine the independent factors affecting clinical efficacy. RESULTS: After treatment, the Eczema area and severity index (EASI) and Dermatology Life Quality Index (DLQI) scores in the observation group were markedly lower than those of the control group (P<0.05). The total clinical effective rate of the observation group was 88.8%, which was notably higher than that of the control group 70.1% (P=0.001). The concentrations of serum LTB4 and TSLP in the observation group were markedly lower than those in the control group (P<0.05). Logistic regression analysis showed that the treatment regimen, digestive system symptoms, heavy aching limbs, and damp-heat tongue and pulse were independent factors affecting the curative effect of the patients (P<0.05). CONCLUSIONS: Simiao pill combined with halometasone cream can effectively improve chronic eczema and enhance the clinical efficacy of treatment, which may be related to the reduction of serum LTB4 and TSLP levels. The treatment plan, digestive system symptoms, heavy aching limbs, and damp-heat tongue and pulse are the main factors that affecting the clinical curative effect. Thus, clinical intervention programs should be made according to the above factors to improve the quality of life of patients.

Analysis of the Effect of N555 Mutations on the Product Specificity of Dextransucrase Using Caffeic Acid Phenethyl Ester as an Acceptor Substrate.

Bioglycosylation is an efficient strategy to improve biological activities and physicochemical properties of natural compounds to develop structural modifications of drugs. In this study, an N555 residue was identified as a candidate for site-directed mutagenesis through sequence alignment with GTF180ΔN. Caffeic acid phenethyl ester (CAPE) was used as an acceptor substrate. Two generated mutants, N555Q and N555E, demonstrated significant specificity of distribution of products. Under identical conditions, the conversion rates of diglycoside products (CAPE-2G) generated by the N555E (80.8%) and N555Q (84.5%) mutants were 3.30- and 3.46-fold higher than those generated by the original enzyme (24.4%). The structural simulation results demonstrated that a new hydrogen bond was formed between the N555 residue and CAPE, and the N555 residue was closely related to substrate elongation. These results provide a reference for subsequent studies. Suitable mutants for transfer of diglycosides have important application potential in the food and pharmaceutical industries.

Modular pharmacology-based approach to identify hub genes and kernel pathways of taodan granules treated psoriasis.

ETHNOPHARMACOLOGICAL RELEVANCE: Taodan granules (TDG) have been observed to decrease interleukins, or psoriasis area and severity index (PASI) score for psoriasis vulgaris, without significant adverse events. However, the regulatory network remains elucidated. AIM OF THE STUDY: The objective is to identify critical genes and kernel pathways of TDG treated psoriasis. MATERIALS AND METHODS: Firstly, construct a network of components-targets of TDG using network pharmacology. Secondly, the ClusterONE algorithm was used to build a modular network and identify critical genes and corresponding pathways. Thirdly, the critical genes and kernel pathways were verified in imiquimod (IMQ) induced psoriasis-like mice model. RESULTS: The results validated that TDG downregulated the mRNA expression of MMP2 (degree = 5, P < 0.05), IL6 (degree = 9, P < 0.05), TNF (degree = 14, P < 0.05), CCL2 (degree = 8, P < 0.05), CXCL2 (degree = 8, P < 0.05), IL1B (degree = 9, P < 0.05), and JUN (degree = 9, P < 0.05), while upregulated IL10 (degree = 8) expression. Besides, TDG were observed to regulate IL17 signaling pathway and TNF signaling pathway (size = 18), via the skin tissue homogenate of psoriasis-like mice. CONCLUSION: In summary, this study identified the potential targets and pathways, providing additional evidence for the clinical application of TDG treated psoriasis.

The Identification of the Biomarkers of Sheng-Ji Hua-Yu Formula Treated Diabetic Wound Healing Using Modular Pharmacology.

Sheng-Ji Hua-Yu (SJHY) formula has been proved to reduce the severity of diabetic wound healing without significant adverse events in our previous clinical trials. However, based on multi-target characteristics, the regulatory network among herbs, ingredients, and hub genes remains to be elucidated. The current study aims to identify the biomarkers of the SJHY formula for the treatment of diabetic wound healing. First, a network of components and targets for the SJHY formula was constructed using network pharmacology. Second, the ClusterONE algorithm was used to build a modular network and identify hub genes along with kernel pathways. Third, we verified the kernel targets by molecular docking to select hub genes. In addition, the biomarkers of the SJHY formula were validated by animal experiments in a diabetic wound healing mice model. The results revealed that the SJHY formula downregulated the mRNA expression of Cxcr4, Oprd1, and Htr2a, while upregulated Adrb2, Drd, Drd4, and Hrh1. Besides, the SJHY formula upregulated the kernel pathways, neuroactive ligand-receptor interaction, and cAMP signaling pathway in the skin tissue homogenate of the diabetic wound healing mice model. In summary, this study identified the potential targets and kernel pathways, providing additional evidence for the clinical application of the SJHY formula for the treatment of diabetic wound healing.

Diagnosis and treatment of lymphocutaneous dermatosis caused by Nocardia brasiliensis: a case report.

Cutaneous nocardiosis is a skin disease mainly caused by Nocardia brasiliensis and Nocardia asteroides. Here, we report a rare case of lymphocutaneous dermatosis in an 87-year-old Chinese man infected with Nocardia brasiliensis. An 87-year-old Chinese man presented at our hospital after suffering erythema, nodules, abscesses, ulceration, and pain in the left upper limb for 10 days. The patient was initially misdiagnosed as lymphocutaneous sporotrichosis. The results of gram staining, acid-fast staining, mass spectrograph revealed Nocardia brasiliensis and 16S ribosomal RNA (16S rRNA) sequencing of samples showed that the patient had a Nocardia brasiliensis infection. Anti-infective therapy with sulfamethoxazole combined with amoxicillin clavulanate potassium was administered for 10 days, followed by sulfamethoxazole alone for 20 days. After 30 days of treatment, the abscess was treated with repeated pus extraction, debridement of erosion and ulcer, wet compress of povidone iodine solution and spectrum of multi-source instrument. The redness and swelling had subsided, and purulent secretion and ulceration had decreased. Lymphocutaneous nocardiosis can easily be misdiagnosed as sporotrichosis based on its clinical manifestations. However, mass spectrometry analysis showed Nocardia brasiliensis according to the fingerprint of the bacteria and 16S rRNA sequencing to identify bacterial DNA can assist with making a diagnosis. For patients with Nocardia brasiliensis, sulfamethoxazole combined with amoxicillin clavulanate potassium is an effective anti-infective treatment.

Uncovering the mechanism of Jueyin granules in the treatment of psoriasis using network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Our clinical practice demonstrated that Jueyin granules (JYG) benefit patients with mild to moderate psoriasis vulgaris without apparent adverse effects. JYG have been shown to inhibit epidermal proliferation in an imiquimod (IMQ)-induced psoriasis-like mouse model, as well as keratinocyte proliferation. Moreover, JYG causes no acute or chronic toxicity in animal models. However, its related molecular mechanism has still not been elucidated. AIM OF THE STUDY: To assess the mechanism of JYG against psoriasis. MATERIALS AND METHODS: This study combined network pharmacology analysis with experiments to investigate the mechanism of JYG against psoriasis. First, the molecular docking technology was used to construct the network of medicinal materials-core active plant ingredients-core targets and identify possible drug targets. Next, high-performance liquid chromatography (HPLC) was used for quality control of JYG. Finally, a mice model of psoriasis was used to further verify the effects of JYG. RESULTS: (1) Molecular docking analysis of network pharmacology revealed that the therapeutic effects of JYG on psoriasis might be achieved through Vitamin D Receptor (VDR) effects. (2) The concentrations of chlorogenic acid and paeoniflorin were determined using HPLC to establish quality control of JYG. (3) JYG ameliorated pathological characteristics that included in vivo reductions in erythema, scale, and infiltration scores of back and ear lesions in IMQ-induced psoriasis-like mice. Moreover, a reduced number of PCNA-positive and Ki67-positive cells were observed in the epidermis of JYG-treated lesions. JYG also reduced inflammation (interleukin (IL)-17, IL-23) in the peripheral blood of IMQ-induced psoriasis-like mice. As expected, JYG was found to upregulate VDR expression and downregulate p-STAT3 expression in the IMQ group, which may contribute to its mechanism against psoriasis. CONCLUSION: Overall, this study clarifies the mechanism of JYG against psoriasis and provides evidence to support its clinical use.

Association Between Psoriasis and Dementia: Current Evidence.

Background: Psoriasis and dementia are both inflammatory diseases. The association between psoriasis and dementia has rarely been investigated, and the existing results are conflicting. Thus, we conducted this study to evaluate whether an association exists between psoriasis and dementia. Methods: We searched for studies from six databases from inception to July 30, 2020, using subject and free words. RevMan 5.4 was used to calculate the risk ratio (RR) of dementia in the subjects with psoriasis. When heterogeneity was present, a random-effects model was used. Subgroup, sensitivity, and meta-regression analyses were performed using Stata 15.1. Results: Nine studies were identified and included in the study, of which seven that involved a total of 3,638,487 participants were included in the meta-analysis. We found that among the patients with psoriasis (RR: 1.14, 95% confidence interval [CI]: 1.06-1.24, p = 0.0009) and psoriatic arthritis (RR: 2.20, 95% CI: 1.29-3.78, p = 0.004), the proportions of those with non-vascular dementia (RR: 1.13, 95% CI: 1.11-1.15, p < 0.00001) and vascular dementia (RR: 1.41, 95% CI: 1.09-1.82, p = 0.009) were higher than that among the patients without psoriasis. Those with dementia were also more likely to develop psoriasis, and those with severe psoriasis were less likely to die from dementia (RR: 1.88, 95% CI: 0.72-4.90, p = 0.020). The meta-regression analysis did not show any significant sources of heterogeneity. Conclusions: The patients with psoriasis and psoriatic arthritis show high prevalence of different types of dementia. Based on the findings of this study, dementia may not be considered a high-risk factor of death from severe psoriasis. However, identification of this potential risk allows for early intervention, thereby reducing comorbidities and deaths.

MUC16 overexpression induced by gene mutations promotes lung cancer cell growth and invasion.

Air pollution is one of the leading causes of lung cancer. Air pollution-related lung cancer is a deteriorating public health problem, particularly in developing countries. The MUC16 gene is one of the most frequently mutated genes in air pollution-related lung cancer. In the present study, MUC16 mRNA expression was increased in ∼50% of air pollution-related lung cancer samples obtained from patients residing in air-polluted regions (Xuanwei and Fuyuan, Yunnan, China), and MUC16 mRNA levels were correlated with the degree of air pollution. Furthermore, sequencing of the captured MUC16 gene identified 561 mutation sites within the MUC16 gene in the air pollution-related lung cancer tissues. Interestingly, some mutations at specific sites and one region were associated with MUC16 mRNA up-regulation. Therefore, we further investigated the impacts of gene mutation on MUC16 expressions and cell behaviors in cultured cells by inducing certain mutations within the MUC16 gene using CRISPER/Cas9 genome editing technology. Certain mutations within the MUC16 gene induced MUC16 overexpression at both the mRNA and the protein level in the cultured cells. Additionally, MUC16 overexpression induced by gene mutations had functional effects on the behavior of lung cancer cells, including increasing their resistance to cisplatin, promoting their growth, and enhancing their migration and invasion capabilities. Based on the data, we suggest that MUC16 mutations potentially associated with air pollution may participate in the development and progression of air pollution-related lung cancer. In addition to ovarian cancer, MUC16 may be a candidate biomarker for lung cancer.

Characterization of germline mutations in familial lung cancer from the Chinese population.

Compared with numerous studies of somatic mutations using sporadic lung cancer, the research into germline mutations using familial lung cancer (FLC) is limited. In the present study, we used FLC samples obtained from the Chinese population in highly air-polluted regions to screen for novel germline mutations in lung cancer. Through a whole genome sequencing (WGS) analysis of the nine subjects (four lung cancer patients and five normal family members of FLC), we obtained a whole genome dataset of DNA alterations in FLC samples. A total of 1218 genes were identified with mutations of multiple types. Subsequently, the top 12 highly mutated genes were selected for validation by polymerase chain reaction and DNA sequencing in an expanded sample set including FLC, sporadic lung cancer, and healthy population. Mutations of the five genes (ARHGEF5, ANKRD20A2, ZNF595, ZNF812, MYO18B) may be potential germline mutations of lung cancer. We also analyzed specific mutations within the 12 genes and found that some specific mutations within the MUC12, FOXD4L3 and FOXD4L5 genes showed higher frequencies in the samples of FLC and/or lung cancer tissue, compared with the healthy population. Moreover, some genes with copy number variation may be potentially associated with a predisposition to lung cancer. Furthermore, non-coding DNA alterations of the WGS data in FLC were systematically analyzed and arranged. Interestingly, we found that germline mutations also occurred in many genes of non-coding RNA. This study uncovered the mutation spectrum in FLC and provided important clues for the evaluation of the genetic susceptibility to lung cancer.

Production and characterization of monoclonal antibody against recombinant human erythropoietin.

OBJECTIVE: To produce specific monoclonal antibody (mAb) against recombinant human erythropoietin (rHuEPO) for development of highly efficient methods for erythropoietin detection in biological fluids. METHODS: rHuEPO was covalently coupled with bovine serum albumin (BSA) and the conjugate was used to immunize mice to produce specific mAb against rHuEPO based on hybridoma technology. The obtained F3-mAb was characterized by enzyme-linked immunosorbent assay (ELISA), SDS-PAGE and Western blot. RESULTS: The isotype of F3-mAb was found to be IgM with an affinity constant of 2.1 x 10(8) L/mol. The competitive ELISA using the obtained IgM showed a broader linear range and lower detection limit compared with previous work. CONCLUSIONS: The modification of rHuEPO was proved to be successful in generating required specific mAb with high avidity to rHuEPO.

TERT promoter mutated WHO grades II and III gliomas are located preferentially in the frontal lobe and avoid the midline.

The promoter region of telomerase reverse transcriptase (TERTp) and isocitrate dehydrogenase (IDH) have been regarded as biomarkers with distinct clinical and phenotypic features. Investigated the possible correlations between tumor location and genetic alterations would enhance our understanding of gliomagenesis and heterogeneity of glioma. We examined mutations of TERTp and IDH by direct sequencing and fluorescence in-situ hybridization in a cohort of 225 grades II and III diffuse gliomas. Correlation analysis between molecular markers and tumor locations was performed by Chi-square tests/Fisher's exact test and multivariate logistic regression analysis. We found gliomas in frontal lobe showed higher frequency of TERTp mutation (P=0.0337) and simultaneously mutations of IDH and TERTp (IDH (mut)-TERTp(mut)) (P=0.0281) than frequency of biomarkers mutation of tumors in no-Frontal lobes, while lower frequency of TERTp mutation (P<0.0001) and simultaneously wild type of IDH and TERTp (IDH (wt)-TERTp(wt)) (P<0.0001) in midline than no-midline lobes. Logistic regression analysis indicated that locations of tumors associated with TERTp mutation (OR=0.540, 95% CI 0.324-0.900, P=0.018) and status of combinations of IDH and TERTp (IDH (mut)-TERTp (mut) vs. IDH (wt)-TERTp (wt) OR=0.162, 95% CI 0.075-0.350, P<0.001). In conclusion, grades II and III gliomas harboring TERTp mutation were located preferentially in the frontal lobe and rarely in midline. Association of IDH-TERTp status and tumor location suggests their potential values in molecular classification of grades II and III gliomas.

TERT promoter mutations contribute to IDH mutations in predicting differential responses to adjuvant therapies in WHO grade II and III diffuse gliomas.

IDH mutations frequently occur in WHO grade II and III diffuse gliomas and have favorable prognosis compared to wild-type tumors. However, whether IDH mutations in WHO grade II and II diffuse gliomas predict enhanced sensitivity to adjuvant radiation (RT) or chemotherapy (CHT) is still being debated. Recent studies have identified recurrent mutations in the promoter region of telomerase reverse transcriptase (TERT) in gliomas. We previously demonstrated that TERT promoter mutations may be promising biomarkers in glioma survival prognostication when combined with IDH mutations. This study analyzed IDH and TERT promoter mutations in 295 WHO grade II and III diffuse gliomas treated with or without adjuvant therapies to explore their impact on the sensitivity of tumors to genotoxic therapies. IDH mutations were found in 216 (73.2%) patients and TERT promoter mutations were found in 112 (38%) patients. In multivariate analysis, IDH mutations (p < 0.001) were independent prognostic factors for PFS and OS in patients receiving genotoxic therapies while TERT promoter mutations were not. In univariate analysis, IDH and TERT promoter mutations were not significant prognostic factors in patients who did not receive genotoxic therapies. Adjuvant RT and CHT were factors independently impacting PFS (RT p = 0.001, CHT p = 0.026) in IDH mutated WHO grade II and III diffuse gliomas but not in IDH wild-type group. Univariate and multivariate analyses demonstrated TERT promoter mutations further stratified IDH wild-type WHO grade II and III diffuse gliomas into two subgroups with different responses to genotoxic therapies. Adjuvant RT and CHT were significant parameters influencing PFS in the IDH wt/TERT mut subgroup (RT p = 0.015, CHT p = 0.015) but not in the IDH wt/TERT wt subgroup. Our data demonstrated that IDH mutated WHO grade II and III diffuse gliomas had better PFS and OS than their IDH wild-type counterparts when genotoxic therapies were administered after surgery. Importantly, we also found that TERT promoter mutations further stratify IDH wild-type WHO grade II and III diffuse gliomas into two subgroups with different responses to adjuvant therapies. Taken together, TERT promoter mutations may predict enhanced sensitivity to genotoxic therapies in IDH wild-type WHO grade II and III diffuse gliomas and may justify intensified treatment in this subgroup.

Surgically treated incidentally discovered low-grade gliomas are mostly IDH mutated and 1p19q co-deleted with favorable prognosis.

OBJECTIVE: LGGs (low-grade gliomas) are sometimes encountered by chance during radiological examinations. These incidentally discovered LGGs (IDLGGs) were relatively under-studied in the literature. The purpose of current study is to review a cohort of patients with IDLGGs surgically treated in our institution for their clinical and histological aspects and determine their IDH1 and 1p19q status. METHODS: All patients with hemispheric LGGs receiving operation in our institution between 2001 and 2004 were reviewed. Clinical, radiological and treatment data of the patients were collected and IDLGGs were retrieved and compared with symptomatic LGGs. Histological review was carried out and formalin-fixed paraffin embedded (FFPE) tissues of IDLGGs were examined for IDH1/IDH2 mutation and 1p/19q codeletion. RESULTS: Twenty three IDLGGs (10.4%) were identified while 196 patients had symptomatic LGGs. The reasons for patients with IDLGGs having radiological examination included trauma (47.8%), dizziness (26.1%), unrelated headache (21.7%), and health checkup (4.4%). Clinically, patients with IDLGGs had higher preoperative KPS (P < 0.001), smaller tumor volume (P = 0.014), lower frequency of eloquent areas involvement (P < 0.001) and higher rate of complete resection (P = 0.037) comparing to those with symptomatic LGGs. Histologically, there is a preponderance of oligodendroglial differentiation with 6 oligodendrogliomas and 11 oligoastrocytomas but there were also 6 astrocytomas. IDH1 mutation and 1p/19q co-deletion were detected in 95.7% (22/23) and 69.6% (16/23) of IDLGGs, respectively. The latter encompassed all but one of the cases of oligodendroglial tumors. Patients with IDLGGs had longer overall survival than those with symptomatic LGGs (P = 0.027). CONCLUSIONS: We conclude that the majority of IDLGGs are IDH1 mutated and are predominantly oligodendroglial tumors. With a median follow-up of 9.3 years to our series, we conclude that patients with IDLGGs had better prognosis than those with symptomatic LGGs. The favorable prognosis of IDLGGs may be accounted by the higher practicability of extensive resection, non-eloquent tumor location and smaller tumor volume. Frequent IDH1 mutation and 1p/19q co-deletion in IDLGGs may also contribute to the favorable prognosis of this subgroup of patients.

Frequent loss of heterozygosity on chromosome 12q in non-small-cell lung carcinomas.

Chromosomal aberrations in non-small-cell lung carcinomas (NSCLCs) are common events. In our study, the lung cancer cell lines (NCI-H446 and SPC-A-1) displayed numerous numerical and structural alterations in their chromosomes by G-banded karyotypic analysis, and abnormalities of chromosome 12 by fluorescence in situ hybridization. Sequentially, we used 14 microsatellite markers within 12q to analyze loss of heterozygosity (LOH) in lung cancer cell lines and NSCLCs. Possible LOH on 12q were statistically inferred to occur in five lung cell lines. Importantly, 17 out of 25 NSCLCs (68%) showed LOH at chromosome 12q. Frequencies of LOH for individual markers ranged from 18% to 44%. Several deletions which were marked with D12S1301, D12S2196, D12S398, D12S90, D12S1056, D12S1713, D12S375, D12S1040, D12S326, and D12S106 were newly detected. Allelic loss on 12q15-q21 detected with D12S1040 occurred at the later stages of NSCLC progression (p < 0.05, Fisher's exact test). LOH on 12q marked with D12S2196, D12S398, D12S326, and D12S106 were frequently found in NSCLCs from the patients without smoking history (p < 0.05, Fisher's exact test). These findings indicated that allelic loss on 12q is commonly involved in NSCLCs, and new tumor suppressor genes may occur within 12q.