Incidence and Overall Survival of Malignant Ameloblastoma

BackgroundMalignant ameloblastoma, comprising metastasizing ameloblastoma and ameloblastic carcinoma, represents 1.6–2.2% of all odontogenic tumors. Due to its rare nature, malignant ameloblastoma has only been reported in the literature in small case series or case reports. Using the Surveillance, Epidemiology and End-Results (SEER) database, we have performed a population-based study to determine the incidence rate and the absolute survival of malignant ameloblastoma.MethodUsing the International Classification of Diseases for Oncology (ICD-O) codes 9310/3 and 9270/3, data from the SEER database were used to calculate the incidence rate and absolute survival rate of population with malignant ameloblastoma.ResultsThe overall incidence rate of malignant ameloblastoma was 1.79 per 10 million person/year. The incidence rate was higher in males than females and also higher in black versus white population. The median overall survival was 17.6 years from the time of diagnosis and increasing age was associated with a statistically significant poorer survival.ConclusionsTo our best knowledge, we report the largest population-based series of malignant ameloblastoma. The incidence rate was 1.79 per 10 million person/year and the overall survival was 17.6 years.     

Perinatal and early life risk factors for childhood brain tumors: Is instrument-assisted delivery associated with higher risk?

BackgroundThe childhood peak of brain tumors suggests that early-life exposures might have a role in their etiology. Hence, we examined in the Greek National Registry for Childhood Hematological Malignancies and Solid tumors (NARECHEM-ST) whether perinatal and early-life risk factors influence the risk of childhood brain tumors.MethodsIn a nationwide case-control study, we included 203 cases (0–14 years) with a diagnosis of brain tumor in NARECHEM-ST (2010–2016) and 406 age-, sex-, and center-matched hospital controls. Information was collected via interviews with the guardians and we analyzed the variables of interest in multivariable conditional logistic regression models.ResultsInstrument-assisted delivery was associated with higher (OR: 7.82, 95%CI: 2.18–28.03), whereas caesarean delivery with lower (OR: 0.67, 95%CI: 0.45-0.99) risk of childhood brain tumors, as compared to spontaneous vaginal delivery. Maternal alcohol consumption during pregnancy (OR: 2.35, 95%CI: 1.45–3.81) and history of living in a farm (OR: 4.98, 2.40–10.32) increased the odds of childhood brain tumors. Conversely, higher birth order was associated with lower risk (OR for 2nd vs. 1st child: 0.60, 95%CI: 0.40-0.89 and OR for 3^rd vs. 1^st: 0.34, 95%CI: 0.18-0.63). Birth weight, gestational age, parental age, history of infertility, smoking during pregnancy, allergic diseases, and maternal diseases during pregnancy showed no significant associations.ConclusionsPerinatal and early-life risk factors, and specifically indicators of brain trauma, exposure to toxic agents and immune system maturation, might be involved in the pathogenesis of childhood brain tumors. Larger studies should aim to replicate our findings and examine associations with tumor subtypes.     

Synthesis,in vitro and in vivo characterization of <Superscript>64</Superscript>Cu(I) complexes derived from hydrophilic tris(hydroxymethyl)phosphane and 1,3,5-triaza-7-phosphaadamantane ligands

Four novel ⁶⁴Cu complexes ([⁶⁴Cu(thp)₄]⁺ (1), [⁶⁴Cu(TPA)₄]⁺ (2), [HC(CO₂)(pz^Me2)₂ ⁶⁴Cu(thp)₂] (3) and [HC(CO₂)(tz)₂ ⁶⁴Cu(thp)₂] (4), [where thp is tris(hydroxymethyl)phosphine, TPA is 1,3,5-triaza-7-phosphaadamantane, pz^Me2 is 3,5-dimethylpyrazole and tz is 1,2,4-triazole] were successfully synthesized and characterized. The complexes were produced in high radiochemical purity and yield (more than 98%) without the need for further purification. Their logP values and serum stabilities were measured and in vitro behavior was observed in cultured EMT-6 cells. The logP values (± standard deviation) obtained were −2.26 ± 0.04 (1), 0.01 ± 0.01 (2), −1.24 ± 0.03 (3) and −2.06 ± 0.03 (4). Complex 3 demonstrated the highest serum stability, with approximately 33% of the complex still intact after 1-h incubation. Complex 2 showed a rapid cell-association with EMT-6 cells, with more than 8.5% association at 2 h. This association was significantly higher (P < 0.001) than for the other three compounds after a 2-h incubation (1, 1.21%; 3, 0.63%; 4, 2.75%). Biodistribution and small-animal positron emission tomography/computed tomography was undertaken with 1 in mice bearing EMT-6 tumors. EMT-6 tumor uptake was high at 1 h (7.71 ± 2.17 %ID/g) and decreased slowly over 24 h (4 h, 4.90 ± 0.78 %ID/g; 24 h, 3.74 ± 0.73 %ID/g). The PET/CT images show that the EMT-6 tumors can be visualized at all time points. In this proof-of-concept study, we have successfully synthesized and characterized a novel series of versatile water-soluble Cu(I) complexes containing monophosphine ligands. We also report the use of 1 as a building block for new radiopharmaceuticals, perhaps the first time such a method has been used in the production of copper radiopharmaceuticals.     

Incidence patterns and trends of malignant gonadal and extragonadal germ cell tumors in Germany, 1998–2008

BackgroundMalignant gonadal (GGCT) and extragonal germ cell tumors [GCT (EGCT)] are thought to originate from primordial germ cells. In contrast to well reported population-based data of GGCTs in males, analyses of GGCTs in females and EGCTs in both sexes remain limited.MethodsIn a pooling project of nine population-based cancer registries in Germany for the years 1998–2008, 16,883 malignant GCTs and their topographical sites were identified using ICD-O morphology and topography for persons aged 15 years and older. We estimated age-specific and age-standardized incidence rates.ResultsAmong males, the incidence of testicular GCTs increased over time. In contrast, there was no increase in the incidence of EGCTs. Among females, rates of ovarian GCTs were stable, while rates of EGCTs declined over time. The most frequent extragonadal sites were mediastinum among males and placenta among females.ConclusionsOur results underline different incidence trends and distinct age-specific incidence patterns of malignant GGCTs and EGCTs, as reported recently by several population-based registries. The differences suggest that GGCT and EGCT may have different etiologies.     

The high and heterogeneous burden of breast cancer in Hawaii: A unique multiethnic U.S. Population

BackgroundWhile breast cancer incidence and mortality rates differ across racial/ethnic populations in the U.S., little is known about Asian and Pacific Island subpopulations. Hawaii is one of the most racially/ethnically diverse states in the U.S. Overall, Hawaii ranks 5^th highest for breast cancer incidence in the nation (2010–2014) and rates have increased in recent years despite a stable national trend. In contrast, for breast cancer mortality, Hawaii has the 3^rd lowest rate in the nation, with rates demonstrating a steady decline for nearly 3 decades.MethodsWe examined incidence and mortality trends from 1984–2013 across the five major racial/ethnic populations of Hawaii (Native Hawaiian, White, Japanese, Chinese, and Filipino) using Hawaii’s Surveillance, Epidemiology, and End Results (SEER) registry data.ResultsWith the exception of Chinese, all groups experienced increasing incidence over the thirty year period. While Japanese experienced the most pronounced recent increase, with incidence now exceeding that of Whites, their mortality rates have remained low for decades. Native Hawaiians have consistently had the highest incidence and mortality rates in the state. The incidence rates of hormone receptor (HR)-positive breast cancer were higher among Japanese and Native Hawaiians as compared to Whites. Relative to Whites, Native Hawaiians also had a higher incidence rate of the HER2-positive subtype and, Japanese, of the triple-negative (HR-/HER2-) subtype of breast cancer.ConclusionsStudies such as this underscore the importance of considering the heterogeneity in breast cancer rates and subtypes across the different racial/ethnic populations.     

The relationship among primary anatomic subsite and risk and distribution of second malignant neoplasms in patients with stage I/II diffuse large B-cell lymphoma: An analysis of the surveillance,epidemiology, and end results database

BackgroundRecent studies have reported that diffuse large B-cell lymphoma (DLBCL) involving different primary extranodal sites have distinct clinicopathological characteristics and prognosis. However, the risk of secondary malignant neoplasms (SMNs) in DLBCL survivors with different primary extranodal sites are unknown.MethodsA total of 40,714 patients diagnosed with stage I/II DLBCL were included from the Surveillance, Epidemiology, and End Results (SEER) database from 1983 to 2015.The standardized incidence ratio (SIR) and absolute excess risk (AER) were used to assess the risk of SMNs.ResultsThe results show that the risk of SMN was significantly higher in extranodal DLBCL than in the US general population (SIR, 1.18; 95% CI, 1.11–1.26), and the risk of developing SMN remains significantly elevated with increased latency. Moreover, there were multiple site-specific risk patterns. There was a 22%, 44%, 66%, 123% and 151% increased risk of SMN 10 years after primary gastrointestinal tract, head/neck, skeletal, lung and liver/pancreas DLBCL diagnosis, respectively. There was a significant decrease risk of SMN with increasing age at diagnosis for primary gastrointestinal tract and skeletal DLBCL. In addition, DLBCL patients with primary sites in the gastrointestinal tract, thyroid and liver/pancreas had the highest incidences of secondary stomach cancer, second thyroid cancer, and second hepatobiliary cancer, respectively, which indicated that the initial site of DLBCL may predict the type of SMN.ConclusionsThe strategies for cancer surveillance after extranodal DLBCL diagnosis may need to be individualized according to the subsite of extranodal DLBCL.     

Lung cancer incidence trends by histologic type in areas of California vs. other areas in the Surveillance,Epidemiology and End Results Program

Background: This study compared temporal trends in incidence rates for the major histological types of lung cancer in areas of California (CA), which started a comprehensive state tobacco control program in 1989, and other selected geographic areas for which data on long-term trends were available. Methods: Age-standardized incidence rates (ASIRs) within age 25–64 years, most likely to have been affected by tobacco control programs, were compared for lung-bronchus adenocarcinoma, squamous cell carcinoma, and small cell carcinoma in 1992–2005 for non-Hispanic whites in three areas of CA in the Surveillance, Epidemiology and End Results (SEER) Program vs. 10 non-CA SEER areas. For 1985–2005, data were available for all whites in the San Francisco-Oakland CA SEER area and eight non-CA SEER areas. Results: ASIRs were roughly similar in CA and non-CA areas in 1992, but declines from 1992 to 2005 were larger in CA than non-CA areas for each histological type. In San Francisco-Oakland CA, declines were not clearly evident from 1985 to 1988 (before the tobacco control program started) but from 1992 to 2005 declines were larger than in the non-CA areas. Conclusions: These findings provide further support for expansion of statewide tobacco control programs, in order to reduce incidence rates for all histologic types of lung cancer.     

Antigenic Heterogeneity in Cell Populations of Cloned Polyoma,Virus-induced Tumour Lines

WALLS and Negroni¹ isolated in tissue culture two cell clones from a polyoma virus-induced fibrosarcoma of H₃B/Bi mice. One (malignant cell line 7₁) produced transplantable tumours in adult syngeneic mice; the other (transformed non-malignant line 7₂) was not tumorigenic but induced resistance to the growth of the malignant cells. We have now confirmed these results and extended them to show that other malignant cells (tissue culture clones C₄ and C₅) from a polyoma virus-induced parotid tumour of syngeneic mice are also inhibited by pre-immunization with a non-malignant line (7₂). The number of cells required to induce tumours in 50% of the animals is ten times higher in the preimmunized mice than in the controls, for both fibrosarcoma and parotid malignant lines (Table 1).     

Epidemiology of pediatric primary malignant central nervous system tumors in Iran: A 10 year report of National Cancer Registry

BackgroundCNS tumors are the leading cause of cancer related deaths among children and adolescents. Nonetheless, the incidence of pediatric CNS tumors in developing countries is poorly understood. We aimed to provide epidemiologic features of primary malignant CNS tumors in Iranian children 0–19 years of age using National Cancer Registry (NCR) data bank.MethodsThe data recorded by NCR over a 10 year period (2000–2010) were reviewed.ResultsOf 1948 tumor cases, 93.3% were located in brain, 5.1% were found in the spinal cord & cauda equina, and 1.6% affected cranial nerves and other parts of the nervous system. The overall average annual age specific incidence rate was 1.43 per 100,000. Males were more likely to develop CNS tumors (1.65 per 100,000) compared to females (1.21 per 100,000, p < 0.01). Children under 5 years of age had the highest age specific incidence rate (1.86 per 100,000). Astrocytic tumors with the incidence rate of 0.61 per 100,000 were the most frequent specific histology followed by embryonal (0.38 per 100,000), and ependymal tumors (0.10 per 100,000). With regard to the histological distribution of tumors, some unique features including the high proportion of unspecified malignant neoplasms (7.6%) were noted.ConclusionThe overall incidence rate was markedly lower than western findings. Major differences were also observed in incidence rates of specific histologies. Although the discrepancies may be attributable to diversity in classification schemes and registration practices, a real ethnic and geographical variation in predisposition to development of pediatric CNS cancers is strongly suggested.     

Preoperative Diagnostic Strategy for Parotid Gland Tumors Using Diffusion-Weighted MRI and Technetium-99m Pertechnetate Scintigraphy: A Prospective Study

Objective

Fine needle aspiration cytology (FNAC) for diagnosis of a parotid gland tumor is widely used but its sensitivity is low and non-diagnostic rate is relatively high. In contrast, core needle biopsy (CNB) has a higher sensitivity and lower rate of sampling errors but has a higher risk of injury to adjacent organs such as facial nerve than FNAC. Screening of patients with parotid gland tumors to identify cases of pleomorphic adenoma (PA) and Warthin tumor (WT) may allow CNB to be confined to patients without PA and WT. We established an algorithm for preoperative diagnosis and management of parotid gland tumor using diffusion-weighted MRI and ^99mTc pertechnetate scintigraphy. This algorithm was developed with the goal of maximal reduction of the number of patients in whom CNB is required. The purpose of the study is to validate our algorithm prospectively.

Methods

A prospective study was conducted in 71 cases who were newly diagnosed with parotid gland tumor and 53 cases were enrolled in the study. In the algorithm, PA (high apparent diffusion coefficient (ADC) _mean≥1.5×10⁻³ mm²/s) and non-PA (low ADC_mean<1.5×10⁻³ mm²/s) cases are first distinguished based on the ADC_mean on diffusion-weighed MRI. Second, among suspected non-PA cases, WT and non-WT are distinguished using technetium-99m pertechnetate scintigraphy. CNB is then performed only in probable non-PA and non-WT cases.

Results

Although CNB was only required in 40% (21/53) of all cases, we made a preoperative histopathological diagnosis with an accuracy of 87% (46/53) and we correctly diagnosed whether a tumor was benign or malignant with an accuracy of 96% (51/53). Preoperative surgical planning had to be changed during surgery in only one case (2%)

Conclusions

Our algorithm is valuable in terms of clinical practice with highly potential for preoperative diagnosis and with less risk of CNB procedure.     

Trends of incidence and survival of patients with chronic myelomonocytic leukemia between 1999 and 2014: A comparison between Swiss and American population-based cancer registries

BackgroundChronic myelomonocytic leukemia (CMML) is a rare hematopoietic malignancy. Treatment with hypomethylating agents (HMA) was introduced between 2004 and 2006 but its impact on population-based survival remains controversial. The aim of this study was to investigate epidemiological characteristics and survival before and after introduction of HMA treatment.MethodsWe performed a population-based analysis of CMML cases reported to the Cantonal Cancer Registries in Switzerland (SWISS) and the Surveillance, Epidemiology, and End Results (SEER) Program from the United States for 1999–2006 (before HMA) and 2007–2014 (after HMA). Time trends were compared for these two time periods.Results423 and 4144 new CMML cases were reported to the SWISS and SEER registries, respectively. We observed an increasing proportion of older patients ≥75 years in the SWISS (50.3%–62.3%) compared to a decreasing one in the SEER population (59.1%–55.1%). Age standardized incidence-rates were similar and remained stable in both countries (0.32–0.38 per 100’000 py). Relative survival (RS) improved significantly in the SEER (3 years 27%–37%; 5 years 19%–23%; p < 0.001 for both) but remained stable in the SWISS population (3 years 48% to 40%; 5 years 34% to 26%; n.s. for both).ConclusionsWith the exception of opposing age-trends, epidemiologic characteristics are similar in both countries and comparable to other population-based registries. RS remains poor and different time trends of population-based survival cannot be faithfully explained by HMA but most likely by changes in diagnostic accuracy within prognostically distinct age-groups.     

Nucleostemin和HDAC1在卵巢肿瘤中的表达及意义

目的:研究核干细胞因子(Nucleostemin, NS)和组蛋白去乙酰化酶1(HDAC1)在卵巢肿瘤及正常卵巢组织中的表达,并分析其表达与临床指标的关系及两者间的表达相关性。方法:选择2010年至2017年我院卵巢石蜡标本60例,其中卵巢肿瘤50例,正常卵巢组织10例。应用免疫组化法检测NS与HDAC1的表达,并分析它们与年龄、肿瘤分期等临床指标的相关性。结果:在30例卵巢恶性肿瘤、10例卵巢交界性肿瘤、10例卵巢良性肿瘤组织中,NS表达的阳性率分别为93.3%、40%、20%,HDAC1的阳性率分别为90%、60%、20%。在正常卵巢组织中未见NS及HDAC1表达。在卵巢恶性肿瘤组中,NS和HDAC1的阳性表达率显著高于其他三组(P0.05),两者表达呈正相关(r=0.56, P0.05),且均与分化程度呈负相关(r=-0.76, P0.001; r=-0.53, P0.01),而与患者年龄、术前血清CA125水平、临床分期和病理类型无关。结论:NS和HDAC1倾向于卵巢恶性肿瘤中表达,且与卵巢恶性肿瘤的分化程度负相关。     

Use of phosphodiesterase-5 inhibitors and the incidence of melanoma

IntroductionRecent evidence of a causal link between Phosphodiesterase-5-inhibitor (PDE-5i) use and melanoma has caused concern in PDE-5i use and was even addressed in the 2018 American Urological Association guideline on erectile dysfunction (ED). Given that several studies have affirmed this low probability but statistically significant association, one might expect a shift in melanoma diagnoses since PDE-5is were introduced in 1998. We sought to determine if the introduction of PDE-5i drugs for ED treatment increased incidence of melanoma.MethodsThe Surveillance, Epidemiology, and End Results (SEER) database was used to compare the incidence of melanoma diagnosis in American men between 1973 and 2015, providing over a decade of data before and after PDE-5i introduction in 1998. Interrupted time-series and logistic regression were used to assess this relationship.ResultsOver 43 years, the SEER database has reported 292,166 cases of Melanoma, with males accounting for 53.7% of cases (Standard deviation [SD] 3%, Range 47.5–58.3%). After the introduction of PDE-5i, there was no proportional increase in melanoma diagnoses, in fact demonstrating a 2% lower incidence from prediction models (p < 0.05).ConclusionOur analysis of the SEER database demonstrates that the trend in incidence of melanoma has fallen in the era of PDE-5i use for ED. These findings may be of value in counseling patients anxious about the potential association between PDE-5i use and skin cancer; however, continued research analyzing individual-level risk are needed.     

Control of lytic development in the Streptomyces temperate phage φC31

The repressor gene. c, is required for maintenance of lysogeny in the Streptomyces phage φC31. The c gene expresses three in-frame N-terminally different protein isoforms at least one of which is thought to bind to a 17bp highly conserved inverted repeat (CIR) sequence found at 18 (or more) loci throughout the φC31 genome. Here we present evidence that one of these loci, CIR6, and its interaction with the products of the repressor gene are critical in the control of the lytic pathway in φC31. To the right of CIR6, according to the standard map of φC31, an ‘immediate-early’ promoter. ap1, was discovered after insertion of a fragment containing CIR6 upstream of a promoterless kanamycin-resistance gene. aphll, to form pCIA2. pCIA2 conferred kanamycin resistance upon Streptomyces coelicolor A3(2) but not upon a φC31 lysogen of S. coelicolor. Operator-constitutive (O^c) mutants of pCIA2 were isolated and the mutations lay in CIR6, i.e. CIR6:G14T and CIR6:C2A. Primer extension analysis of RNA prepared from an induced, temperature-sensitive lysogen of S. coelicolor localized a mRNA 5′ endpoint 21 bp to the right of CIR6. The importance of the ap1/CIR6 region in the regulation of lytic growth was demonstrated by the analysis of a virulent mutant, φC31 vir1, capable of forming plaques on an S. coelicolorφC31 lysogen, φC31 vir1 contained a DNA inversion with the breakpoints lying within the integrase gene (which lies approximately 7kbp to the right of CIR6) and in the essential early region between CIR6 and the -10 sequence for ap1. The separation of ap1 from its operator was thought to be the basis for the virulent phenotype in φC31 vir1. Band-shift assays and DNase I footprinting experiments using purified 42kDa repressor isoform confirmed that CIRs 5 and 6 were indeed the targets for binding of this protein. The 42 kDa repressor bound to CIR6 with higher affinity than to CIR5 in spite of their identical core sequences. Repressor bound at CIR6 facilitated binding at CIR5. The high-affinity binding to CIR6 was abolished with the O^c mutant, CIR6:G14T. Hydroxyl radical footprinting and dimethyl sulphate methylation protection of the 42 kDa repressor–CIR6 interaction suggested that the protein bound in the major groove and to one face of the DNA.     

Synthesis of Base Substituted 2-Hydroxy-3-(purin-9-yl)-propanoic Acids and 4-(Purin-9-yl)-3-butenoic Acids

Abstract

Alkylation of 6-chloropurine and 2-amino-6-chloropurine with bromoacetaldehyde diethyl acetal afforded 6-chloro-9-(2,2-diethoxyethyl)purine (3a) and its 2-amino congener (3b). Treatment of compounds 3 with primary and secondary amines gave the N⁶-substituted adenines (5a–5c) and 2,6-diaminopurines (5d–5f). Hydrolysis of 3 resulted in hypoxanthine (6a) and guanine (6b) derivatives, while their reaction with thiourea led to 6-sulfanylpurine (7a) and 2-amino-6-sulfanylpurine (7b) compounds. Treatment with diluted acid followed by potassium cyanide treatment and acid hydrolysis afforded 6-substituted 3-(purin-9-yl)- and 3-(2-aminopurin-9-yl)-2-hydroxypropanoic acids (8–10). Reaction of compounds 3 with malonic acid in aqueous solution gave exclusively the product of isomerisation, 6-substituted 4-(purin-9-yl)-3-butenoic acids (15).     

Comparison of quadrant-specific breast cancer incidence trends in the United States and England between 1975 and 2013

BackgroundUK breast cancer incidence rates suggest that upper outer quadrant (UOQ) cancers have risen disproportionately compared with other areas over time. We aimed to provide a comparison of the trend in quadrant-specific breast cancer incidence between the United States (US) and England, and determine whether a disproportionate UOQ increase is present.MethodsSurveillance Epidemiology and End Results (SEER) cancer registry data were obtained on 630,007 female breast cancers from 1975 to 2013. English cancer registry data were obtained on 1,121,134 female breast cancers from 1979 to 2013. Temporal incidence changes were analysed using negative binomial regression. Interaction terms determined whether incidence changes were similar between sites.ResultsEnglish breast cancer incidence in the UOQ rose significantly from 13% to 28% from 1979 to 2013 whereas no significant increase was observed among SEER data. The significant interaction between quadrant and year of diagnosis (p < 0.001) in both SEER and English data indicates that breast cancer incidence in each quadrant changed at a different rate. Incidence in the UOQ rose disproportionately compared to the nipple (SEER IRR = 0.81, p < 0.001; England IRR = 0.78, p < 0.001) and axillary tail (SEER IRR = 0.87, p = 0.018; England IRR = 0.69, p < 0.001) in both SEER and England. In addition, incidence rose disproportionately in the UOQ compared to non-site-specific tumours in England (Overlapping lesions IRR = 0.81, p = 0.002; NOS IRR = 0.78, p < 0.001). The proportion of non-site-specific tumours was substantially higher in England than SEER throughout the study period (62% in England; 39% in SEER).ConclusionsBreast cancer incidence in the UOQ increased disproportionately compared to non-site-specific tumours in England but not in SEER, likely due to the decrease in non-site-specific tumours observed in England over time. There may be real differences in incidence between the two countries, possibly due to differences in aetiology, but is much more likely to be an artefact of changing data collection methods and improvements in site coding in either country.     

The Virological and Immunological Characteristics of the HIV-1-Infected Population in Brazil: From Initial Diagnosis to Impact of Antiretroviral Use

BackgroundImmunological and virological status of HIV-infected individuals entering the Brazilian public system over time was analyzed. We evaluated the impact of ART on virological, immunological and antiretroviral resistance over time.MethodsCD4+ T cell counts, viral loads and genotypes from patients over 13 years old from 2001–2011 were analyzed according to demographic data. We compared groups using parametric t-tests and linear regression analysis in the R statistical software language.ResultsMean baseline CD4+ T cell counts varied from 348 (2003) to 389 (2009) and was higher among women (p = 1.1 x 10⁻⁸), lower in older patients (p< 1 x 10⁻⁸) and lower in less developed regions (p = 1.864 x 10⁻⁵). Percentage of treated patients with undetectable viral loads increased linearly from 46% (2001) to 77% (2011), was lower among women (p = 2.851 x 10⁻⁶), younger ages (p = 1 x 10⁻³), and in less developed regions (p = 1.782 x 10⁻⁴). NRTI acquired resistance was 86% in 2001–3 and decreased over time. NNRTI resistance increased from 2001-3(50%) to 2006–9 (60%), PI resistance decreased from 2001–3 (60%) to 2009 (40%), and 3-class resistance was stable over time around 25%. Subtype prevalence comprised B (75.3%), B/F recombinants (12.2%), C (5.7%), F (5.3%) and B/C recombinants (1.5%), with regional variations. Three-class resistance was 26.5% among Bs, 22.4% among Fs and 17.2% among Cs.ConclusionsHIV diagnosis occurs late, especially among elderly Brazilians. Younger individuals need special attention due to poor virological response to treatment. Antiretroviral Resistance profile is subtype related.     

Heterogeneity in head and neck cancer incidence among black populations from Africa,the Caribbean and the USA: Analysis of cancer registry data by the AC3

BackgroundAfrica and the Caribbean are projected to have greater increases in Head and neck cancer (HNC) burden in comparison to North America and Europe. The knowledge needed to reinforce prevention in these populations is limited. We compared for the first time, incidence rates of HNC in black populations from African, the Caribbean and USA.MethodsAnnual age-standardized incidence rates (IR) and 95% confidence intervals (95%CI) per 100,000 were calculated for 2013–2015 using population-based cancer registry data for 14,911 HNC cases from the Caribbean (Barbados, Guadeloupe, Trinidad & Tobago, N = 443), Africa (Kenya, Nigeria, N = 772) and the United States (SEER, Florida, N = 13,696). We compared rates by sub-sites and sex among countries using data from registries with high quality and completeness.ResultsIn 2013–2015, compared to other countries, HNC incidence was highest among SEER states (IR: 18.2, 95%CI = 17.6–18.8) among men, and highest in Kenya (IR: 7.5, 95%CI = 6.3–8.7) among women. Nasopharyngeal cancer IR was higher in Kenya for men (IR: 3.1, 95%CI = 2.5–3.7) and women (IR: 1.5, 95%CI = 1.0–1.9). Female oral cavity cancer was also notably higher in Kenya (IR = 3.9, 95%CI = 3.0–4.9). Blacks from SEER states had higher incidence of laryngeal cancer (IR: 5.5, 95%CI = 5.2–5.8) compared to other countries and even Florida blacks (IR: 4.4, 95%CI = 3.9–5.0).ConclusionWe found heterogeneity in IRs for HNC among these diverse black populations; notably, Kenya which had distinctively higher incidence of nasopharyngeal and female oral cavity cancer. Targeted etiological investigations are warranted considering the low consumption of tobacco and alcohol among Kenyan women. Overall, our findings suggest that behavioral and environmental factors are more important determinants of HNC than race.     

Synthesis of AZT analogues: 7-(3-azido-2hydroxypropyl)-, 7-(3-amino-2-hydroxypropyl)-, 7-(3-triazolyl-2-hydroxypropyl)theophyllines

Nucleophilic displacement of the tosyloxy group in 7-(2-hydroxy-3-p-toluenesulfonyloxypropyl)theophylline (1) with azide anion afforded 7-(3-azido-2-hydroxypropyl)theophylline (2). Reduction of the 3-azido group in 2 with Ph₃P/Py/NH₄OH afforded the 3-amino derivative 4, alternatively obtained by regioselective amination of 7-(2,3-epoxypropyl)theophylline (3). Selective acetylation of 4 gave the N-acetyl derivative 5. 1,3-Dipolar cycloaddition of the azide group in 2 with N¹-propargyl thymine (6) afforded the regioisomeric triazole 7.     

Homologues of Arabidopsis Microtubule-Associated AIR9 in Trypanosomatid Parasites: Hints on Evolution and Function

AIR9 is an essential microtubule-associated protein from Arabidopsis. Sequence similarity searches indicate homologues of AIR9 in land plants and in excavate protists, including trypanosomatid parasites and Trichomonas. The AIR9-like protein from Trypanosoma brucei was recently detected in the proteome of the trypanosome flagellum, raising the possibility that trypanosomatid AIR9-like proteins also associate with microtubules. Because microtubule functions are essential to the viability of trypanosomatid parasites AIR9-like proteins may be exploited as drug targets without homology in humans. We further discuss the unexpected phylogeny of AIR9-like proteins from plants and protozoans.Key Words: plant, cortical microtubules, preprophase band, A9 domain, flagellum, ExcavataUsing a proteomic approach we recently determined that the protein encoded by the single-copy AIR9 (Auxin-Induced in Root Cultures 9) gene from Arabidopsis is a novel microtubule-associated protein (MAP). GFP-AIR9 associates with cortical microtubules of the plant interphase array and with the preprophase band (PPB). The plant-specific PPB is a transient microtubule array that marks the cortical division site and determines the plane of cytokinesis. The PPB disassembles at the onset of mitosis but leaves behind an unknown mark that during cytokinesis serves to attract the new cross-wall (the out-growing cell plate). GFP-AIR9 is not present at the PPB site during mitosis, but returns to this location when the cell plate inserts. Forming a torus, GFP-AIR9 then moves inward along the new cross-wall. By doing this, microtubule-associated AIR9 transiently behaves like a peripheral membrane protein. If cell plates are experimentally induced to insert at ectopic positions no AIR9 torus is formed. We conclude that AIR9 is capable of associating with a component of the enigmatic PPB memory.¹The 187 kDa Arabidopsis AIR9 protein consists of (seen from N- to C-terminus) a serine-rich microtubule-binding domain, a leucine-rich repeat (LRR) domain, a large region of eleven repeated A9 domains and a C-terminal region that is conserved among plant homologues (Fig. 1A). Our analyses revealed that A9 domains are likely to adopt g-immunoglobulin-like (IgG-like) folds. Using BLAST we detected AIR9 homologues in various land plants and in the genomes of the three sequenced trypanosomatid parasites.² The trypanosomatid proteins contain the LRR domain and the region of repeated A9 domains found in the Arabidopsis prototype and were therefore termed AIR9-like proteins. PSI-BLAST searches³ indicate distantly related sequences with A9 domains in several prokaryotes (mainly proteobacteria) but these proteins are lacking the LRR domain.Open in a separate windowFigure 1Domain structure of Arabidopsis AIR9 and protozoan AIR9-like proteins and phylogenetic position of AIR9-like proteins in the tree of life. (A) All AIR9-like proteins contain an LRR domain and a region of repeated A9 domains. Arabidopsis AIR9 additionally shows an N-terminal serine-rich basic region that confers microtubule binding (MT) and a C-terminal conserved region of unknown function (cc). The multicopy genome of Trichomonas harbours several genes potentially coding for AIR9-like proteins (shown in this order: gene1 {"type":"entrez-protein","attrs":{"text":"EAY10472","term_id":"121905546","term_text":"EAY10472"}}EAY10472, gene2 {"type":"entrez-protein","attrs":{"text":"EAY06037","term_id":"121901014","term_text":"EAY06037"}}EAY06037, gene3 {"type":"entrez-protein","attrs":{"text":"EAX99086","term_id":"121893848","term_text":"EAX99086"}}EAX99086, gene4 {"type":"entrez-protein","attrs":{"text":"EAY04681","term_id":"121899624","term_text":"EAY04681"}}EAY04681, gene5 {"type":"entrez-protein","attrs":{"text":"EAX86457","term_id":"121880222","term_text":"EAX86457"}}EAX86457). (B) Phylogenetic tree showing key eukaryotic taxa. All organisms found to encode AIR9-like proteins are highlighted in green. Numbers in parenthesis indicate tested genomes devoid of AIR9-like proteins. This phylogenetic tree has been redrawn and is based on results published elsewhere.^7,16,17New genomic sequence data revealed the presence of AIR9-like proteins in the human parasite Trichomonas vaginalis⁴ (Fig. 1A). We intensified our searches for AIR9-like proteins in eukaryotes using EST datasets (http://tbestdb.bcm.umontreal.ca) and genome project BLAST servers (http://genome.jgi-psf.org) revealing a curious distribution of AIR9-like proteins in the eukaryotic tree of life (Fig. 1B). AIR9-like proteins are present in land plants (including the moss Physcomitrella) and in several protists of the excavate class (Trypanosomas, Leishmania, Trichomonas, Naegleria, Seculamonas, Reclinomonas). However, AIR9 is apparently missing in all other bikont organisms: it is missing in green algae (three sequenced genomes), in red algae (two sequenced genomes) and in all Chromalveolata sequenced to date (six genomes). As stated earlier,¹ AIR9 is missing in all unikont organisms (metazoan, fungi, Amoebozoa) (Fig. 1B). This distribution of AIR9-like proteins is curious because land plants cannot be considered to be a sister group of Excavata.^5,6 This may indicate a lateral gene transfer of AIR9-like genes between both groups. However, a different scenario may be based on independent losses of AIR9-like proteins in certain groups, i.e., in green and red algae, and possibly in Chromalveolata. It will be important to establish how widespread AIR9-like proteins are among organisms of the heterogenous Excavata. Unravelling the phylogenetic relationship between the groups Plantae, Chromalveolata and Excavata may explain this curious distribution of AIR9-like proteins in the tree of life.^7–9AIR9-like proteins are found in several important human parasites. Trypanosomatid parasites are the causal agent of African trypanosomiasis (sleeping sickness), Chagas disease and leishmaniasis. Other trypanosomatid species are pathogens of crops and live stock. Vaccines for humans are missing and effective drugs without side-effects are needed.² Proteins restricted to plants and protists, as in the case of AIR9, could be exploited as drug targets against trypanosomatids -with no or little side-effects to humans.^10,11 More plant-like traits were recently reported for Trypanosoma and Leishmania and assumed to stem from lateral gene-transfer events with an endosymbiosis-derived plastid organelle.^12,13 It was speculated that trypanosomatid organisms once possessed an algal endosymbiont, but that this organelle was lost during evolution^12,14 (for a different view, however, see Ref. ¹⁰). The phylogenetic comparison of AIR9-like proteins based on the LRR domain reveals two sub-classes of AIR9-like proteins resembling the groups land plants and excavate protists, respectively (Fig. 2A). The AIR9-like protein from the moss Physcomitrella patens tightly clusters with the sub-class from land plants. This is consistent with the last common ancestor of both AIR9 sub-classes being much older than the origin of land plants, excluding the possibility of a “very late” transfer of an AIR9-like gene between land plants and protists. Our findings on the phylogenetic distribution of AIR9 do not support nor reject the possibility of a green endosymbiont in early trypanosomatid organisms. They do, however, support the idea that new drug targets in trypanosomatid parasites could be discovered by analyzing drug targets from plants.Open in a separate windowFigure 2Phylogenetic relationship of AIR9-like proteins and amino acid scans of plant and protozoan AIR9-like proteins. (A) Phylogenetic comparison based on the LRR domain reveals two subclasses of AIR9-like proteins corresponding to land plants and protozoans, respectively. (B) Amino-acid scans using a 104 amino-acid window. Note the serine-rich regions in AIR9 homologues from land plants all of which present N-terminal peaks above 20 serines in 104 amino acids. otherwise, the sequence similarity between these serine-rich regions is not statistically significant according to BLAST sequence similarity analyses [3]. Arginine plus lysine content in all plant homologues peak above 20 in 104 amino acids in N-terminal (and C-terminal) regions. The N-terminal basic region corresponds to the microtubule-binding domain found in Arabidopsis AIR9. N-terminal basic serine-rich extensions are not found in the AIR9-like proteins from trypanosomatid parasites. Some of the predicted AIR9-like proteins from Trichomonas peak with basic residues in the N-terminus. Green = plant proteins, pink = trypanosomatid proteins, white = Trichomonas proteins. Squences were obtained from protein databases, inferred from EST sequences, or derived from genomic sequences using homologous proteins as template. All sequences are available upon request.Do the AIR9-like proteins from trypanosomatids and other excavates function in a similar way to AIR9 from plants, and are they MAPs? In a remarkable study Broadhead et al¹⁵ isolated the flagellum from blood-stream Trypanosoma brucei and identified its proteome by HPLC-assisted mass-spectrometry. RNA-interference with selected proteins of the flagellar proteome established that flagellar motility is essential for viability of the blood-stream Trypanosoma.¹⁵ The flagellum of trypanosomatids consists of the 9+2 axoneme and an associated structure, the paraflagellar rod. Interestingly, the trypanosomatid AIR9-like protein (Tb11.01.8770) is among the 331 proteins of the flagellum proteome (see supplemental data by Broadhead et al Ref. ¹⁵). This raises the possibility that the AIR9-like protein from Trypanosoma binds microtubules. In Arabidopsis AIR9, the N-terminal basic serine-rich extension functions in microtubule binding.¹ The basic residues of this extension may confer binding to the acidic surface of tubulins. However, in linear alignments the microtubule binding site of Arabidopsis AIR9 appears to be only weakly conserved among land plants and no similarity to the AIR9-like proteins from protozoans is found (data not shown). We therefore scanned AIR9-like proteins from plants, trypanosomatid parasites and Trichomonas for serine-rich and basic regions. Using a 104 amino-acid window we found that all investigated plant proteins show a serine-rich and basic N-terminal extension. The AIR9-like proteins from trypanosomatid parasites do not show N-terminal serine-rich regions and the content of basic residues in these regions is far less pronounced when compared to the plant homologues. Trichomonas encodes at least five AIR9-like proteins, probably as a result of genome amplification events observed in this parasite.⁴ Interestingly, some of the putative Trichomonas AIR9-like proteins contain N-terminal basic regions (Fig. 2B). However, this is not mirrored by an elevated serine content. Taken together, these results show that all AIR9-like proteins from land plants exhibit N-terminal basic serine-rich extensions and therefore are likely to be MAPs. Further research is needed to show whether AIR9-like proteins from trypanosomatid parasites, Trichomonas and other protozoans have microtubule binding sites.