Paracoccidioidomycosis Mimicking Squamous Cell Carcinoma on the Dorsum of the Tongue and Review of Published Literature

Introduction

Paracoccidioidomycosis is a disease that is endemic to southern and southeastern Brazil, caused by the fungus Paracoccidioides brasiliensis. The most common clinical oral manifestation is the presence of multiple granulomatous ulcers with hemorrhagic dots, located mainly on the lips, palate, and buccal mucosa. However, the disease can manifest atypically as a single ulcer, mimicking oral squamous cell carcinoma (SCC) or tuberculosis.

Case report

A 65-year-old male patient presented with a complaint of a single ulcerated lesion on the dorsum of the tongue; the lesion had evolved over 6 months. The diagnostic hypotheses were SCC and oral manifestation of tuberculosis. An incisional biopsy was performed, and histopathological analysis of the specimen revealed pseudoepitheliomatous hyperplasia, a granulomatous structure of epithelioid histiocytes, multinucleated giant cells, and lymphocytes in the connective tissue. Grocott staining confirmed the presence of the fungus in the lesion, and a diagnosis was made of paracoccidioidomycosis. The patient was treated with 200 mg/day of itraconazole for 12 months and now shows no signs or symptoms of recurrence of the disease.

Conclusion

Correct diagnosis is essential for a successful therapeutic approach and resolution of the lesion.     

emperature and oil,and has a stable dis

ld,so we present the well logging series and gas drilling technique suited to Daqing area.Some proper logging evaluation approaches are used such as GR spectrometry log,CN log,induction log and NMR log,etc.well logging;technology;gas drilling;foam drilling;casing drilling;Daqing oilfield0测井技术Well Logging Technology20-22 104P631.8B019;B021;A011;A012;C;21;D3;A;B;B019_21;A011_D3;A012_C;B021_21;赵平;16-18 100高孔密复合射孔技术研究周志华;谭忠健;刘富奎;西安通源石油科技股份有限公司,中海石油(中国)有限公司天津分公司勘探部,中海石油(中国)有限公司天津分公司勘探部 陕西西安710065,天津300452,天津300452复合射孔;;高孔密;;p-t过程测试;;现场应用提出了一种新型装药结构并实现在高孔密条件下的复合射孔,所开发的产品进行了地面混凝土靶测试、地面动态压力-时间(p-t)过程测试和现场应用试验。试验结果表明,高孔密复合射孔器能够将高孔密的多孔道、多相位的射孔特点与高能气体压裂造缝机理有机地结合,形成了孔缝结合的深穿透、高孔密和多相位的沟通通道,有效地改善了近井带的渗流能力,实现了油井的高产和稳产。现场应用效果良好。On High Foramen Density Technology for the Fracture Perfo     

Merlin, a multi-suppressor from cell membrane to the nucleus

Recent evidence suggests that the neurofibromatosis type 2 (NF2) gene encoded protein merlin suppresses mitogenic signalling not only at the cell membrane but also in the nucleus. At the membrane, merlin inhibits signalling by integrins and tyrosine receptor kinases (RTKs) and the activation of downstream pathways, including the Ras/Raf/MEK/ERK, FAK/Src, PI3K/AKT, Rac/PAK/JNK, mTORC1, and Wnt/β-catenin pathways. In the nucleus, merlin suppresses the E3 ubiquitin ligase CRL4(DCAF1) to inhibit proliferation. Gene expression analysis suggested that CRL4(DCAF1) could also regulate the expression of integrins and RTKs. In this review, we explore the links between merlin function at the membrane and in the nucleus, and discuss the potential of targeting the master regulator CRL4 (DCAF1) to treat NF2 and other merlin-deficient tumours.     

Artesunate induces necrotic cell death in schwannoma cells

Established as a potent anti-malaria medicine, artemisinin-based drugs have been suggested to have anti-tumour activity in some cancers. Although the mechanism is poorly understood, it has been suggested that artemisinin induces apoptotic cell death. Here, we show that the artemisinin analogue artesunate (ART) effectively induces cell death in RT4 schwannoma cells and human primary schwannoma cells. Interestingly, our data indicate for first time that the cell death induced by ART is largely dependent on necroptosis. ART appears to inhibit autophagy, which may also contribute to the cell death. Our data in human schwannoma cells show that ART can be combined with the autophagy inhibitor chloroquine (CQ) to potentiate the cell death. Thus, this study suggests that artemisinin-based drugs may be used in certain tumours where cells are necroptosis competent, and the drugs may act in synergy with apoptosis inducers or autophagy inhibitors to enhance their anti-tumour activity.Artemisinin, a sesquiterpene lactone isolated from the Chinese herb Artemisia annua L., has profound activity against malaria.¹ Artemisinin contains an endoperoxide moiety that reacts with iron to produce toxic reactive oxygen species (ROS). When malaria parasite (Plasmodia) consumes iron-rich haemoglobin within its acidic food vacuole in erythrocytes, the exposure of artemisinin to haem-derived iron results in lethal ROS production that exerts fatal toxicity to the parasite.² Therefore, artemisinin, its water-soluble derivative artesunate (ART) and other analogues are potent in killing malarial parasites.^1,3Cancer cells contain substantial free iron, resulting from their higher-rate iron uptake via transferrin receptors compared with normal cells. Therefore, artemisinin-based drugs such as ART possess selective toxicity to cancer cells.^{4, 5, 6} Importantly, the pharmacokinetics and tolerance of ART as an anti-malarial drug have been well documented, with clinical studies showing excellent safety. Collectively, these properties make artemisinin-based compounds attractive drug candidates for cancer chemotherapy. Artemisinin and ART have been shown to induce cell death in multiple cancer cells, including colon, breast, ovarian, prostate,⁷ pancreatic⁸ and leukaemia⁹ cancer cells. Preliminary in vivo experiments also indicate the therapeutic potential for these drugs as anti-cancer treatments. In animal models, artemisinin or ART has shown promising results in Kaposi Sarcoma,¹⁰ pancreatic cancer¹¹ and hepatoma,¹² while compassionate use of ART in uveal melanoma patients fortifies standard chemotherapy potential for the patients.¹³ Currently, ART is on clinical trial for breast cancer treatment (ClinicalTrials.gov ID: {"type":"clinical-trial","attrs":{"text":"NCT00764036","term_id":"NCT00764036"}}NCT00764036).Programmed cell death (PCD) is one of the critical terminal paths for the cells of metazoans. Among PCD, apoptosis has been well studied and it is known that caspase activation is essential in this process.¹⁴ In addition to apoptosis, necroptosis is another form of PCD. The RIP1-RIP3 complex highlights the signals that regulate necroptosis.^{15, 16, 17} Artemisinin derivatives, mostly ART, have been suggested to lead to apoptosis via ROS production in cancer cells. Efforts have been focused on ROS-mediated mitochondrial apoptosis,^9,18,19 and DNA damage²⁰ in cancer cells. Recent data suggest that artemisinin and its derivatives may induce cell death or inhibit proliferation through diverse mechanisms in different cell types. Artemisinin or its analogues were shown to inhibit cell proliferation in multiple cancer cells by regulating cell-cycle arrest^{21, 22, 23} or inducing apoptosis.^24,25 Nevertheless, the detailed molecular mechanisms underlying artemisinin or ART-induced cell death are poorly understood, thus need to be further addressed.Neurofibromatosis 2 (NF2) is caused by the loss of NF2 gene encoding Merlin protein. NF2 gene mutations cause the low grade tumour syndrome, composed of schwannomas, meningiomas and ependymomas.²⁶ All spontaneous schwannomas, the majority of meningiomas and a third of ependymomas are caused by NF2 gene mutations. Notably, approximately 10% of intracranial tumours are schwannomas.²⁷ Interestingly, NF2 gene mutations are also found in a variety of cancers, including breast cancer and mesothelioma.^{28, 29, 30} The low grade tumours caused by NF2 gene mutations do not respond well to current cancer drugs and therapy is restricted to surgery and radiosurgery.²⁶ Therefore, there is a need for drug treatment of the diseases. Here, we show that ART sufficiently induced schwannoma cell death in both RT4 cell line and human primary cells. Importantly, we show, for the first time, that ART-induced cell death is largely dependent on necroptosis. Our data suggest that ART has great potential in schwannoma chemotherapy, especially when used in synergy with an apoptosis-inducing drug and/or an autophagy-inhibitory drug.     

Shifty salamanders: transient trophic polymorphism and cannibalism within natural populations of larval ambystomatid salamanders

Introduction

Many species of ambystomatid salamanders are dependent upon highly variable temporary wetlands for larval development. High larval densities may prompt the expression of a distinct head morphology that may facilitate cannibalism. However, few studies have characterized structural cannibalism within natural populations of larval salamanders. In this study we used two species of larval salamanders, long-toed (Ambystoma macrodactylum) and ringed salamanders (A. annulatum). Head morphometrics and stable isotopic values of carbon (δ¹³C) and nitrogen (δ¹⁵N) were used to identify the presence or absence of structural cannibalism. Weather conditions were also analyzed as a potential factor associated with the expression of cannibalistic morphology.

Results

Populations of salamander larvae did not consistently exhibit cannibalistic morphologies throughout collection periods. Larval long-toed salamanders exhibited trophic polymorphisms when relatively lower precipitation amounts were observed. Larval ringed salamanders were observed to be cannibalistic but did not exhibit polymorphisms in this study.

Conclusions

Structural cannibalism may be transient in both species; however in long-toed salamanders this morphology is necessary for cannibalism. Ringed salamanders can be cannibalistic without morphological adaptations; however the cannibal morph may prolong the viable time period for cannibalism. Additionally, weather conditions may alter pond hydroperiod, subsequently influencing head morphology and cannibalism.

     

X4 tropic multi-drug resistant quasi-species detected at the time of primary HIV-1 infection remain exclusive or at least dominant far from PHI

Our objective was to analyze the evolution of resistance mutations (RM) and viral tropism of multi-drug-resistant (MDR) strains detected at primary HIV-1 infection (PHI). MDR HIV strain was defined as the presence of genotypic resistance to at least 1 antiretroviral of the 3 classes. Tropism determinations (CCR5 or CXCR4) were performed on baseline plasma HIV-RNA and/or PBMC-HIV-DNA samples, then during follow-up using population-based sequencing of V3 loop and phenotypic tests. Clonal analysis was performed at baseline for env, RT and protease genes, and for HIV-DNA env gene during follow-up. Five patients were eligible. At baseline, RT, protease and env clones from HIV-RNA and HIV-DNA were highly homogenous for each patient; genotypic tropism was R5 in 3 (A,B,C) and X4 in 2 patients (D,E). MDR strains persisted in HIV-DNA throughout follow-up in all patients. For patient A, tropism remained R5 with concordance between phenotypic and genotypic tests. Clonal analysis on Month (M) 78 HIV-DNA evidenced exclusively R5 (21/21) variants. In patient B, clonal analysis at M36 showed exclusively R5 variants (19/19) using both genotypic and phenotypic tests. In patient C, baseline tropism was R5 by genotypic test and R5/X4 by phenotypic test. An expansion of these X4 clones was evidenced by clonal analysis on M72 HIV-DNA (12/14 X4 and 2/14 R5 variants). In patient D, baseline tropism was X4 with concordance between both techniques and HIV-RNA and HIV-DNA remained X4-tropic up to M72, confirmed by the clonal analysis. Patient E harboured highly homogenous X4-using population at baseline; tropism was unchanged at M1 and M18. In all patients, the initial MDR population was highly homogenous initially, supporting the early expansion of a monoclonal population and its long-term persistence. X4-tropic variants present at baseline were still exclusive (patients D and E) or dominant (at least one time point, patient C) far from PHI.     

Durability and Effectiveness of Maraviroc-Containing Regimens in HIV-1-Infected Individuals with Virological Failure in Routine Clinical Practice

Introduction

Limited data are available on the durability and effectiveness of maraviroc in routine clinical practice. We assessed the durability of maraviroc-containing regimens during a 30-month period, as well as their immunovirological and clinical efficacy, according to viral tropism in treatment-experienced individuals with viral load (VL) >50 copies/ml in the French Hospital Database on HIV.

Methods

Virological success was defined as VL<50 copies/ml, immunological success as a confirmed increase of at least 100 CD4 cells/mm³ measured twice at least one month apart, and clinical failure as hospitalization for a non-AIDS event, an AIDS event, or death. Multivariable Cox regression models adjusted for potential confounders were used to assess the influence of viral tropism on durability, the immunovirological responses, and clinical outcome.

Results

356 individuals started maraviroc with VL>50 copies/ml of whom 223 harbored R5 viruses, 44 non-R5 viruses and 89 viruses of unknown tropism. Individuals with non-R5 viruses were more likely than individuals with R5 viruses to discontinue maraviroc (75% vs 34%, p<0.0001). At 30 months, the estimated rates of virological and immunological success were respectively 89% and 51% in individuals with R5 viruses and 48% and 23% in individuals with non-R5 viruses. In multivariable analysis, non-R5 viruses were associated with a lower likelihood of both virological success (hazard ratio (HR): 0.42; 95% confidence interval (CI), 0.25–0.70) and immunological success (HR: 0.37; 95% CI, 0.18–0.77). No difference in clinical outcome was found between individuals with R5 and non-R5 viruses. The effectiveness of maraviroc-containing regimens in individuals with unknown viral tropism was not significantly different from that in individuals with R5 viruses. A limitation of the study is the absence of genotypic susceptibility score.

Conclusion

In this observational study, maraviroc-containing regimens yielded high rates of viral suppression and immunological responses in individuals with R5 viruses in whom prior regimens had failed.     

Blunted Response to Combination Antiretroviral Therapy in HIV Elite Controllers: An International HIV Controller Collaboration

Objective

HIV “elite controllers” (ECs) spontaneously control viral load, but some eventually require combination antiretroviral treatment (cART), due to a loss of viral control or a decline in CD4 T-cell counts. Here we studied the CD4 T-cell count dynamics after cART initiation among 34 ECs followed in U.S. and European cohorts, by comparison with chronically viremic patients (VIRs).

Methods

ECs were defined as patients with at least ≥5 viral load (VL) measurements below 400 copies/mL during at least a 5-year period despite never receiving ART and were selected from the French ANRS CO18 cohort, the U.S. SCOPE cohort, the International HIV Controllers study and the European CASCADE collaboration. VIRs were selected from the ANRS COPANA cohort of recently-diagnosed (<1 year) ART-naïve HIV-1-infected adults. CD4 T-cell count dynamics after cART initiation in both groups were modelled with piecewise mixed linear models.

Results

After cART initiation, CD4 T-cell counts showed a biphasic rise in VIRs with: an initial rapid increase during the first 3 months (+0.63/month), followed by +0.19/month. This first rapid phase was not observed in ECs, in whom the CD4Tc count increased steadily, at a rate similar to that of the second phase observed in VIRs. After cART initiation at a CD4 T-cell count of 300/mm³, the estimated mean CD4 T-cell gain during the first 12 months was 139/mm³ in VIRs and 80/mm³ in ECs (p = 0.048).

Conclusions

cART increases CD4 T-cell counts in elite controllers, albeit less markedly than in other patients.