bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive analysis of spectral distribution of a large cohort of Chinese patients with non‐syndromic oculocutaneous albinism facilitates genetic diagnosis
Authors: Zhong Zilin , Gu Li , Zheng Xiujie , Ma Nengjun , Wu Zehua , Duan Juan , Zhang Jun , Chen Jianjun
Published: May 2019

Non‐syndromic oculocutaneous albinism (nsOCA) is a group of genetically heterogeneous autosomal recessive disorders with complete lack or decrease pigmentation in skin, hair, and eyes. TYR, OCA2, TYRP1, SLC45A2, SLC24A5, and LRMDA were reported to cause OCA1‐4 and OCA6‐7, respectively. By sequencing all the known nsOCA genes in 114 unrelated Chinese nsOCA patients combined with In silico analyses, splicing assay, and classification of variants according to the standards and guidelines of American College of Medical Genetics and Genomics, we detected seventy‐one different OCA‐causing variants separately in TYR, OCA2, SLC45A2, and SLC24A5, including thirty‐one novel variants (13 in TYR, 11 in OCA2, and 7 in SLC45A2). This study shows that OCA1 is the most common (75/114) and OCA2 ranks the second most common (16/114) in Chinese. 99 patients of our cohort were caused by variants of all the known nsOCA genes. Cutaneous phenotypes of OCA1, OCA2, and OCA4 patients were shown in this study. The second OCA6 case in China was identified here. These data expand the spectrum of OCA variants as well phenotype and facilitate clinical implement of Chinese OCA patients.
Investigating seed dormancy in cotton (Gossypium hirsutum L.): understanding the physiological changes in embryo during after‐ripening and germination
Authors: Wang L. R. , Yang X. N. , Gao Y. S. , Zhang X. Y. , Hu W. , Zhou Z. , Meng Y. L.
Published: May 2019

The dormancy of seeds of upland cotton can be broken during dry after‐ripening, but the mechanism of its dormancy release remains unclear.

Freshly harvested cotton seeds were subjected to after‐ripening for 180 days. Cotton seeds from different days of after‐ripening (DAR) were sampled for dynamic physiological determination and germination tests. The intact seeds and isolated embryos were germinated to assess effects of the seed coat on embryo germination. Content of H2O2 and phytohormones and activities of antioxidant enzymes and glucose‐6‐phosphate dehydrogenase were measured during after‐ripening and germination.

Germination of intact seeds increased from 7% upon harvest to 96% at 30 DAR, while embryo germination improved from an initial rate of 82% to 100% after 14 DAR. Based on T50 (time when 50% of seeds germinate) and germination index, the intact seed and isolated embryo needed 30 and 21 DAR, respectively, to acquire relatively stable germination. The content of H2O2 increased during after‐ripening and continued to increase within the first few hours of imbibition, along with a decrease in abscisic acid (ABA) content. A noticeable increase was observed in gibberellic acid content during germination when ABA content decreased to a lower level. Coat removal treatment accelerated embryo absorption of water, which further improved the accumulation of H2O2 and changed peroxidase content during germination.

For cotton seed, the alleviation of coat‐imposed dormancy required 30 days of after‐ripening, accompanied by rapid dormancy release (within 21 DAR) in naked embryos. H2O2 acted as a core link between the response to environmental changes and induction of other physiological changes for breaking seed dormancy.
Understanding the development of intermuscular bones in teleost: status and future directions for aquaculture
Authors: Nie Chun‐Hong , Hilsdorf Alexandre W. S. , Wan Shi‐Ming , Gao Ze‐Xia
Published: May 2019

As one of the most sustainable protein sources for humans, aquaculture is the fastest growing food production sector in agriculture. According to the recent FAO estimate, there are 21 principal aquaculture fish species around the worldwide. Among these cultured species, almost half of them belong to Cypriniformes, the species from which all have a certain number of intermuscular bones (IBs). IBs are small spicule‐like bones existing in the muscle fillet, which are existed only in lower teleost and of course have a negative effect on fish quality and aquatic product processing. Many studies have been focusing on IBs number, morphology, and more and more become focusing on its development molecular mechanism. In the review, we summarized the recent progress and discussed with following directions: (i) Controversial on the origin of IBs, ossified from tendons or ligaments? (ii) IBs counts and morphology revealed big variation among different species; (iii) Ossification patterns of IBs might be related with different swimming modes among the teleost fish, and its development belongs to intramembranous ossification without cartilaginous phase; (iv) Transcriptome/microRNA (miRNA)/proteomics and gene functional analysis had been used to investigate the molecular mechanism of IBs development and some genes showed certain regulatory roles during IBs’ development; (v) The reports showed that some breeding technologies could make a certain effect on IBs counts in fish species, but there are rare reports with success on deleting or significantly reducing IBs counts. Meanwhile, we also discuss the challenges and future directions of reducing or even deleting IBs in aquaculture.
Heritability estimates and genetic correlations of various production and reproductive traits of different grades of dairy cattle reared under subtropical condition
Authors: Ali Ilyas , Muhammad Suhail Syed , Shafiq Muhammad
Published: May 2019

Inheritance of economic traits and their genetic correlation was studied in different breeds and their various grades (crossbred’s cattle) under the subtropical condition. Data on principal parameters comprising 10 years, that is 2004–2014, were utilized for the present study. Different grades of dairy cows comprising Holstein Friesian (HF), Sahiwal x Friesian (SxHF), Jersey (J), Jersey x Achai (JxAC) and Achai (AC) were included in the study. Heritability estimates and genetic correlations of some important productive and reproductive traits were worked out. Heritability estimates of certain economic traits were found to be: birthweight, 0.32 ± 0.181; age at maturity, 0.11 ± 0.136; age at first calving, 0.19 ± 0.162; days open, 0.09 ± 0.121; calving interval, 0.14 ± 0.211; dry period, 0.11 ± 0.124; lactation length, 0.04 ± 0.212 and lactation yield, 0.46 ± 0.206. Genetic correlation showed that body weight was significantly and positively correlated with lactation length (0.30) and lactation yield (0.81), while negatively correlated with age at maturity, age at first calving, days open, calving interval and dry period (−0.09, −0.07, −0.16, −0.34 and −0.002, respectively). Calving interval was positively and significantly correlated with the dry period (0.56), lactation length (0.72) and lactation yield (0.37). Moderate to higher heritability estimates with adequate genetic variance was found for body weight and lactation yield. The moderate to higher heritability estimates of birthweight in the present study revealed that this important trait might be considered in selection criteria.
The challenge for the soil science community to contribute to the implementation of the UN Sustainable Development Goals
Authors: Bouma Johan , Montanarella Luca , Evanylo Gregory
Published: May 2019

Seventeen Sustainable Development Goals (SDGs) were adopted by 193 Governments at the General Assembly of the United Nations in 2015 for achievement by 2030. These SDGs present a roadmap to a sustainable future and a challenge to the science community. To guide activities and check progress, targets and indicators have been and are still being defined. The soil science community has published documents that describe the primary importance of soil for SDGs addressing hunger, water quality, climate mitigation and biodiversity preservation, and secondary relevance of soil for addressing several other SDGs. Soil scientists only marginally participated in the SDG discussions and are currently only peripherally engaged in discussions on targets or indicators. Agreement on several soil‐related indicators has still not been achieved. Involvement of soil scientists in SDG‐based studies is desirable for both developing solutions and increasing the visibility of the soil profession. Inputs into policy decisions should be improved as SDG committee members are appointed by Governments. Possible contributions of soil science in defining indicators for the SDGs are explored in this paper. We advocate the pragmatic use of soil–water–atmosphere–plant simulation models and available soil surveys and soil databases where “representative” soil profiles for mapping units (genetically defined genoforms) are functionally expressed in terms of several phenoforms reflecting effects of different types of soil use and management that strongly affect functionality.
Effects of depression on healing and inflammatory responses of acute wounds in rats
Authors: Jian Jin , Yi‐Heng Huang , Bang‐Hui Zhu , Jian‐Hua Chen , Xu‐Dong Zhang , Shi‐Chu Xiao , Peng‐Fei Luo , Xiao‐Yan Hu , Zhao‐Fan Xia
Published: May 2019

This study aimed to elucidate the effect of depression on the healing of acute wounds in rats. We hypothesized that depression would have negative effects on inflammation and wound healing and that antidepressant therapy would reverse these effects. This study included 100 rats randomly allocated into five groups: control group (CG), depression group (DG), pre‐depression group (PDG), antidepressant group (AG), and pre‐antidepressant group (PAG). Acute wounds were created on the rats' backs. The groups were subjected to no interventions (CG), aversive stimuli before (PDG) and after (DG) wound creation, and antidepressant treatment before (PAG) and after (AG) wound creation. On the day of wound creation and on days 3, 6, 9, and 12 after wound creation, observations of the wound area and degree of depression (evaluated using the sucrose preference test, open‐field test, and weight change) were recorded. On days 6 and 12 after wound creation, venous serum and wound tissues were collected. Tumor necrosis factor alpha (TNF‐α), interleukin (IL)‐1β, IL‐6, and IL‐10 levels were measured using the enzyme‐linked immunosorbent assay. Results showed an initial increase followed by a decrease in the degree of depression in all groups except DG (continuous decline). The wound‐healing rate was significantly lower in PDG and DG than in CG; it was higher in AG and PAG than in CG. DG and PDG had higher concentrations of inflammatory cytokines than CG, and AG and PAG had lower concentrations than CG. This indicates that the onset of depression delays the healing of acute wounds and aggravates the inflammatory response in rats. Antidepressant treatment counteracts both of these negative effects.
The exercise timing hypothesis: can exercise training compensate for the reduction in blood vessel function after menopause if timed right?
Authors: Gliemann L. , Hellsten Y.
Published: May 2019

As women enter menopause at mid‐life, oestrogen production ceases and its many beneficial effects on cardiovascular health are lost whereby the age‐related risk of cardiovascular disease is accelerated. Oestrogen acts via oestrogen receptors and can activate the oestrogen response element leading to upregulation of a number of proteins of importance for vascular health, including the vasodilator and anti‐atherogenic enzyme endothelial nitric oxide synthase and angiogenic factors. Hormone replacement therapy can to some extent counteract the loss of oestrogen although studies have shown that such treatment may only be effective if initiated soon after menopause, the so‐called timing hypothesis. An attractive alternative to hormone therapy is regular physical activity, as it is known that exercise induces many of the same cardiovascular health protective effects as oestrogen. Nevertheless, results from studies on the effect of physical activity on vascular function and cardiovascular health are inconsistent, with some studies showing a lack of effect of a physical activity programme and others showing a beneficial effect. The reason for this divergence is unclear but here we explore whether there may be a timing aspect also for exercise training, the exercise timing hypothesis, in which initiation of exercise interventions soon after menopause may be more effective than initiation many years after. The possibility that oestrogen‐related receptor‐α and oxidative stress may play a role in such a timing effect is discussed.

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Aerobic exercise training and vascular function with ageing in healthy men and women
Authors: Seals Douglas R. , Nagy Erzsebet E. , Moreau Kerrie L.
Published: May 2019

Cardiovascular diseases (CVD) remain the leading cause of morbidity and mortality in both men and women in developed societies. Age is the greatest risk factor for CVD due largely to adverse changes to arteries that include stiffening of the large elastic arteries (aortic and carotid arteries) and endothelial dysfunction. Vascular ageing is driven by oxidative stress, which reduces nitric oxide (NO) bioavailability and stimulates changes in the extracellular matrix. In women, reductions in circulating oestrogens with menopause interact with ageing processes to induce vascular dysfunction. Regular aerobic exercise is the most evidence‐based strategy for reducing CVD risk with ageing in both men and women. Much of this cardiovascular‐protective effect of aerobic exercise is likely due to its vascular health‐enhancing influence. Large elastic artery stiffening with advancing age is attenuated in healthy adults engaged in aerobic exercise training, and aerobic exercise interventions improve arterial stiffness in previously sedentary middle‐aged and older men and postmenopausal women. Regular aerobic exercise also enhances endothelial function with ageing in men (by reducing oxidative stress and preserving NO bioavailability), but not consistently in oestrogen‐deficient postmenopausal women. In postmenopausal women, treatment with oestradiol appears to restore the ability of aerobic exercise to improve NO‐mediated endothelial function by reducing oxidative stress. Several research gaps exist in our understanding of potential sex differences in the vascular adaptations to regular aerobic exercise. More information is needed on the factors that are responsible for sex differences, including the role of circulating oestrogens in transducing the aerobic exercise training ‘stimulus’.

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On a Logistic Differential Model. Some Applications
Authors: Kyurkchiev Nikolay V.
Published: May 2019

In this article we will consider the possibility of approximating the input function s(t) (the nutrient supply for cell growth) of the form s(t)=1/(1+mt)exp(-mt)) where m>0 is parameter.We prove upper and lower estimates for the one--sided Hausdorff approximation of the shifted Heaviside function by means of the general solution of the differential equation y'(t)=ky(t)s(t) with y(t_0)=y_0.We will illustrate the evolution of the solution y(t) for approximating and modelling of three data sets: i) ''data on the development of the Drosophila melanogaster population'', published by Pearl in 1920, ii) dataStormIdentifications (Storm worm was one of the most biggest cyber threats of 2008, and ''cancer data''.Numerical examples using CAS Mathematica, illustrating our results are given.
Incorporating dextrose gel and feeding in the treatment of neonatal hypoglycaemia
Authors: Gregory Katherine , Turner Daria , Benjamin Charis Nicole , Monthe-Dreze Carmen , Johnson Lise , Hurwitz Shelley , Wolfsdorf Joseph , Sen Sarbattama
Published: May 2019

Objectives

To determine the impact of incorporating dextrose gel in the treatment of neonatal hypoglycaemia (NH) and the role of feeding type in NH outcomes.

Study design

We conducted a retrospective analysis of 2688 infants >35 weeks’ gestation who were screened for NH before and after implementation of a clinical guideline for NH evaluation and treatment. We analysed the proportion of infants who required intravenous dextrose for NH before and after guideline implementation, the change in blood glucose concentrations with gel by feeding type and the odds of successful NH treatment with gel and feeding by feeding type.

Results

Following implementation of the guideline, a lower proportion of infants required intravenous dextrose for NH treatment (8.6% (60 infants) before guideline vs. 5.6% (112 infants) after guideline (p=0.007)). The median rise in blood glucose concentration with gel administration in the entire cohort was 0.61 mmol/L (11 mg/dL) (IQR 0.28–1.06 mmol/L (5–19 mg/dL)). Blood glucose concentration of formula-fed infants rose more in response to feeding and gel than breastfed infants (p≤0.0001). Formula feeding was associated with a lower odds of recurrent hypoglycaemia, as defined by requiring a second gel, in a fully adjusted model. Specifically, in infants with a pregel blood glucose of 2.00–2.17 mmol/L (36–39 mg/dL), formula feeding with gel was associated with a lower odds of recurrent hypoglycaemia.

Conclusions

Dextrose gel is an effective tool in the treatment of NH. An infant’s pregel blood glucose concentration may be helpful in guiding decisions around type of feeding provided.
Novel non-sense mutation in RP2 (c.843_844insT/p.Arg282fs) is associated with a severe phenotype of retinitis pigmentosa without evidence of primary retinal pigment epithelium involvement
Authors: Horner Faye , Wawrzynski James , MacLaren Robert E
Published: May 2019

Retinitis pigmentosa (RP) relates to a heterogeneous group of rod-cone dystrophies of varying genetic aetiology. There is currently great interest in gene replacement therapy. Phenotyping is of particular importance because some RP genes are expressed ubiquitously and it is critically important to understand which retinal layer is primarily affected.RP2is increasingly diagnosed in patients suffering from X-linked RP, which causes outer retinal degeneration. We present a case of a previously unreported null mutation inRP2associated with severe RP. Loss of the retinal pigment epithelium (RPE) was noted in the central macula but not around the disc or peripherally. There was therefore no evidence of independent degeneration of the RPE. Hence despite expression in all retinal cells, RP2 deficiency does not appear to be pathogenic to the RPE. This observation may be helpful in considering the promoter and route of delivery of adeno-associated viral gene therapy vectors encoding RP2.
Vernet syndrome: intracranial extension of a slow-growing mass
Authors: Monteiro Francisco , Oliveira Pedro , Peneda José , Condé Artur
Published: May 2019

Vernet syndrome, often referred to as jugular foramen syndrome, is a rare clinical entity characterised by a set of signs and symptoms caused by dysfunction of IX, X and XI cranial nerves. Although paraganglioma of the head and neck is the most frequent aetiology, it may also be caused by meningioma, VIII cranial nerve schwannoma, pontocerebellar cistern metastases, head and neck trauma, infections and very rarely by cholesteatoma which extends to the petrous apex. The authors describe a case of a patient with a jugulotympanic paraganglioma in which evolution ends up in Vernet syndrome. The patient preferred a ‘wait and scan’ strategy. With the lack of data available to develop an unequivocal algorithm for paraganglioma management, we always consider not only age but also comorbidities, prior treatment and progression of the lesion. Each case has to be addressed individually and treatment should be discussed in detail with every patient.
Massive upper gastrointestinal bleeding: a rare complication of cholecystoduodenal fistula
Authors: Vadioaloo Dinesh Kumar , Loo Guo Hou , Leow Voon Meng , Subramaniam Manisekar
Published: May 2019

A biliary fistula which may occur spontaneously or after surgery, is an abnormal communication from the biliary system to an organ, cavity or free surface. Spontaneous biliary-enteric fistula is a rare complication of gallbladder pathology, with over 90% of them secondary to cholelithiasis. Approximately 6% are due to perforating peptic ulcers. Symptoms of biliary-enteric fistula varies widely and usually non-specific, mimicking any chronic biliary disease. Cholecystoduodenal fistula causing severe upper gastrointestinal (UGI) bleed is very rare. Bleeding cholecystoduodenal fistula commonly requires surgical resection of the fistula and repair of the duodenal perforation. We describe the case of a previously healthy older patient who initially presented with symptoms suggestive of UGI bleeding. Bleeding could not be controlled endoscopically. When a laparotomy was performed, a cholecystoduodenal fistula was discovered and bleeding was noted to originate from the superficial branch of cystic artery.
Safety and tolerability of ranibizumab in uni/bilateral neovascular age-related macular degeneration: 12-month TWEYEs study
Authors: Bandello Francesco , Staurenghi Giovanni , Ricci Federico , Midena Edoardo , Viola Francesco , Lupieri Sinibaldi Tommaso , Colombo Laura , Peruzzi Elena , Bassanini Stefania
Published: May 2019

Background

To evaluate the safety and tolerability of ranibizumab 0.5 mg in patients with uni/bilateral neovascular age-related macular degeneration (nAMD) and best-corrected visual acuity (BCVA)<2/10 and/or second eye affected, regardless of BCVA.

Methods

In this 12-month, prospective, multicentre, open-label, single arm, pragmatic interventional study, patients (N=941) aged ≥ 50 years were to receive ranibizumab as per approved label, monthly until maximum stable visual acuity (VA) was achieved (initially, three or more injections may be required). Thereafter, patients were to be monitored monthly for VA and treatment was to be resumed if VA was reduced due to disease activity.

Results

Of the 936 patients treated with ranibizumab at least once during the study, 823/113 were unilaterally/bilaterally (not simultaneously) treated . The mean (SD) number of ranibizumab injections during the study was 5.4 (2.9)/10.6 (5.0) injections in uni/bilaterally treated patients. Three systemic drug-related adverse events (AEs) (all serious, all in unilaterally treated patients) and 18 systemic AE of special interest (AESIs) (11 serious, 16/2 in unilaterally/bilaterally treated patients) occurred during the study. The annual incidence rate (AIR) (events/1000 person-years) for systemic drug-related AEs, considering a 15-day/30-day risk period, 11.0/8.5 for unilaterally treated patients. Considering the same risk period, the AIR (events/1000 person-years) for systemic AESIs for unilaterally treated patients was 22.1/19.9. Considering a 30-day risk period, the AIR (events/1000 treated eye-years) of ocular drug-related AEs was 23 and AESIs was 11.5.

Conclusions

The low incidence of AEs and AESIs demonstrated the good safety and tolerability of ranibizumab in unilaterally/bilaterally treated patients with nAMD in this real-world setting.
Measuring e-cigarette addiction among adolescents
Authors: Vogel Erin A , Prochaska Judith J , Rubinstein Mark L
Published: May 2019

Background and objectives

With high rates of use and uncertain consequences, valid electronic cigarette (e-cigarette) use frequency and addiction measures for adolescents are needed. This cross-sectional study examined correlations for multiple measures of adolescent e-cigarette use with nicotine exposure quantified with salivary cotinine levels.

Methods

Adolescents (N=173, age 13–18) who reported past-month e-cigarette use were recruited from the San Francisco Bay Area. Participants self-reported: (1) days of e-cigarette use in a typical month, (2) number of e-cigarette sessions in a typical day (sessions per day; SPD) and the (3) E-Cigarette Addiction Severity Index (EASI). Participants also completed the 10-item Penn State Electronic Cigarette Dependence Index (ECDI), which we examined in full and as a 2-item Heaviness of Vaping Index (HVI; the sum of the ECDI items on use frequency and time to first vaping on wakening). Sessions per month (SPM) were calculated using days per month and SPD. Cotinine levels, SPD and SPM were log-transformed.

Results

Among frequency measures, SPM correlated most strongly with cotinine (r=0.59), followed closely by days per month (r=0.58) and SPD (r=0.57), p<0.001. Among dependence measures, the EASI correlated most strongly with cotinine (r=0.51), closely followed by the ECDI and HVI (r’s=0.50), all p’s<0.001.

Conclusions

Adolescents’ reports of frequency of e-cigarette use and degree of addiction correlated significantly with cotinine as a biomarker of nicotine exposure. We recommend the EASI and days per month as brief general measures. SPM and the ECDI are more extensive measures that may yield a more nuanced understanding of use.
Immune Suppression by PD-L2 against Spontaneous and Treatment-Related Antitumor Immunity
Authors: Tanegashima Tokiyoshi , Togashi Yosuke , Azuma Koichi , Kawahara Akihiko , Ideguchi Ko , Sugiyama Daisuke , Kinoshita Fumio , Akiba Jun , Kashiwagi Eiji , Takeuchi Ario , Irie Takuma , Tatsugami Katsunori , Hoshino Tomoaki , Eto Masatoshi , Nishikawa Hiroyoshi
Published: May 2019

Purpose:

To evaluate the detailed immunosuppressive role(s) of PD-L2 given that its detailed role(s) remains unclear in PD-1 signal blockade therapy in animal models and humans.

Experimental Design:

We generated mouse cell lines harboring various status of PD-L1/PD-L2 and evaluated the tumor growth and phenotypes of tumor-infiltrated lymphocytes using several PD-1 signal blockades in animal models. In humans, the correlation between immune-related gene expression and CD274 (encoding PD-L1) or PDCD1LG2 (encoding PD-L2) was investigated using The Cancer Genome Atlas (TCGA) datasets. In addition, PD-L1 or PD-L2 expression in tumor cells and CD8+ T-cell infiltration were assessed by IHC.

Results:

In animal models, we showed that PD-L2 expression alone or simultaneously expressed with PD-L1 in tumor cells significantly suppressed antitumor immune responses, such as tumor antigen–specific CD8+ T cells, and was involved in the resistance to treatment with anti-PD-L1 mAb alone. This resistance was overcome by anti-PD-1 mAb or combined treatment with anti-PD-L2 mAb. In clinical settings, antitumor immune responses were significantly correlated with PD-L2 expression in the tumor microenvironment in renal cell carcinoma (RCC) and lung squamous cell carcinoma (LUSC).

Conclusions:

We propose that PD-L2 as well as PD-L1 play important roles in evading antitumor immunity, suggesting that PD-1/PD-L2 blockade must be considered for optimal immunotherapy in PD-L2–expressing cancers, such as RCC and LUSC.
Abstract SY08-01: Cancer in immunosuppressed populations: Epidemiologic clues to causation
Authors: Engels Eric A.
Published: May 2019

Epidemiologic studies of immunosuppressed populations (HIV-infected people and solid organ transplant recipients) can identify candidate malignancies where infection, immunity, and inflammation are likely to be etiologically important. Such studies have revealed markedly elevated risk for cancers linked to oncogenic viral infections, e.g., Kaposi sarcoma (caused by human herpesvirus 8), some non-Hodgkin lymphoma subtypes and Hodgkin lymphoma (Epstein Barr virus), anogenital cancers (human papillomavirus), and liver cancer (hepatitis B and C viruses). For these cancers, the heightened risk arises from a high prevalence of viral infection and/or loss of immune control of the infection. In contrast, risk is not elevated in immunosuppressed populations for common malignancies not strongly linked to infection (e.g., colon, prostate, and breast cancers), arguing against a more general role for immune surveillance in protecting healthy people from cancer. For a few remaining cancers, an elevated risk is observed among both HIV-infected people and transplant recipients, but the increase is not as great as for malignancies known to be caused by viruses, or data are less clearcut. Examples include various skin cancers, lung cancer, and multiple myeloma. These increased risks suggest that specific infections (with either a known or unknown agent) or altered immunity are relevant for development of these malignancies. Another possibility is that repeated or chronic infections with diverse microbes, or chronic inflammation, play a role.

Citation Format: Eric A. Engels. Cancer in immunosuppressed populations: Epidemiologic clues to causation [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY08-01
Abstract SY15-02: Constructing and deconstructing cancer using mouse models and RNAi
Authors: Lowe Scott W.
Published: May 2019

Cancer arises through an evolutionary process whereby normal cells acquire mutations that erode growth controls, leading to the inappropriate expansion of aberrantly proliferating cells. Such mutations can involve activation of oncogenes or inactivation of tumor-suppressor genes, each contributing one or more new capabilities to the developing cancer cell. However, cancer is not an inevitable consequence of oncogenic mutations; instead, cells acquiring such mutations can be eliminated or kept in check by innate tumor-suppressor programs that can be activated in these damaged cells. Our laboratory studies tumor-suppressor networks controlling apoptosis and senescence and how their disruption influences malignant behavior. We previously showed that apoptosis and cellular senescence are potent barriers to oncogene-driven tumorigenesis and that each contributes to the antitumor action of many chemotherapeutic drugs. Thus, not only do mutations that disrupt apoptosis and senescence promote tumor progression but, depending on the particular lesion, they can also reduce the efficacy of cancer therapy. To facilitate our research, we have recently developed new mouse cancer models based on the genetic manipulation of stem and progenitor cells ex vivo followed by transplantation of the altered cells into the appropriate organ of syngeneic recipient mice. This approach allows us to rapidly study the impact of many genes and gene combinations on tumorigenesis in a “mosaic” setting where tumor-initiating cells are embedded in normal tissues. Furthermore, we have developed powerful methods for using RNAi to suppress gene function in vivo in either a stable and reversible manner. Current efforts in the laboratory strive to integrate mosaic mouse models, RNA interference, and cancer genomics to identify new components of tumor suppressor gene networks and characterize their impact on tumorigenesis and treatment response. In addition, we are developing new RNAi interference methods to explore the role of tumor suppressor genes in tumor maintenance, and the cell death mechanisms involved in tumor regression.

Citation Format: Scott W. Lowe. Constructing and deconstructing cancer using mouse models and RNAi [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY15-02
Abstract SY18-01: Targeting the p53-MDM2 interaction for cancer therapy
Authors: Vassilev Lyubomir T.
Published: May 2019

The p53 tumor suppressor is tightly controlled by MDM2 which binds p53 and negatively modulates its transcriptional activity and stability. Many tumors overproduce MDM2 to impair p53 function. Restoration of p53 activity by inhibiting the p53-MDM2 interaction may offer a novel approach to cancer therapy. Recently developed potent and selective small-molecule MDM2 antagonists, the nutlins, interact specifically with the p53-binding pocket of MDM2 and release p53 from negative control. Treatment of cancer cells expressing wild-type p53 with nutlins stabilized p53 and activated the p53 pathway.

Although half of human tumors retain wild-type p53, the function of the tumor suppressor could be compromised by defective signaling in the pathway. Using nutlin-3a to probe downstream p53 signaling we find that the cell cycle arrest function of p53 is preserved in all tested cancer cell lines expressing wild-type p53 but many have compromised ability to undergo p53-dependent apoptosis. The p53 transcription target and potent CDK inhibitor, p21, has been shown to inhibit the apoptotic response to genotoxic p53 activation. Although it is strongly upregulated by MDM2 antagonists in all tested cancer cell lines, p21 does not affect the apoptotic outcome of nutlin treatment, suggesting that it does not play anti-apoptotic role during non-genotoxic p53 activation. MDM2 controls p53 stability and activity through a feedback mechanism by which both proteins mutually regulate their cellular levels. Nutlins disrupt this regulatory circuit leading to upregulation of both p53 and MDM2. They selectively block the p53-MDM2 interaction but do not affect MDM2 E3 ligase activity that is elevated in the presence of the drug. MDMX, a known p53 inhibitor and MDM2 ubiqutination target decreased with the increase of MDM2, suggesting that MDM2 contributes to antitumor activity of nutlins at least in part by facilitating MDMX degradation. Elevated MDM2 contributes to the apoptotic outcome of nutlin treatment also by interfering with the maturation of subsets of microRNAs. Nutlin-3a doses that shrink xenograft tumors activated p53 signaling in mouse tissues but caused only mild changes in bone marrow, thymus and spleen. These results suggest that p53 activation by MDM2 antagonists may provide an acceptable safety window for cancer therapy. A member of the nutlin family of MDM2 antagonists is currently undergoing Ph I clinical testing in patients with solid and hematological malignancies.

Citation Format: Lyubomir T. Vassilev. Targeting the p53-MDM2 interaction for cancer therapy [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY18-01
Abstract SY20-03: Novel radiotracers for clinical molecular imaging in oncology
Authors: Larson Steven M.
Published: May 2019

In cancer, molecular imaging (MI) can be thought of as imaging the key molecules and molecular based events that are fundamental to promoting and maintaining the malignant state. Although MI is multimodality, the focus of this discussion will be on the use of positron emitting radiotracers for Positron Emission Tomography (PET), an imaging methodogy that can bridge the divide between discovery in the laboratory and application in clinical medicine. Modern PET incorporates CT into the same gantry and as PET/CT has rapidly penetrated clinical oncology, providing improved tumor staging and the detection of recurrence.. F[18]-2-flouro-2-deoxy-D-glucose (FDG) and PET is being used to imaging more tha 1 million cancer patients per year in the US along. The biologic basis for the successful use of FDG-PET/CT is as follows. Many cancers exhibit a characteristic biochemical phenotype, which is altered in comparison to tissues from which the neoplasm originated. In particular, tumor tissues often exhibit the “Warburg Effect” which is an accelerated aerobic glyolysis. The reasons behind the Warburg effect are thought to relate to a need for carbon backbones for tumor growth, as well as to control.altered REDOX state within the cell. Other metabolic markers useful in functional imaging of cancer include radiolabeled nucleosides like [F-18]-Fluorothymidine (FLT) for proliferation, and radiolabeled amino acids, like [C-11] methionine for imaging amino acid transport. Molecular imaging in oncology is increasingly being applied for evaluation of treatment response,to radiation and chemotherapy, using FDG, FLT, and F-18 misonidazole (FMISO) a nitroimidazole which is taken up in hypoxic tissues. Molecular imaging is also applied clinically for drug discovery, and a large number of targeted agents have been radiolabeled and are being studied in man. At MSKCC our group has used PET imaging to study targeting at both a basic and clinical level with a variety of drugs and monoclonal antibodies, includine antibodyA33, which recognizes the epithelial marker A33, and antibody cG250 which recognizes carbonic anydrase IX, a marker of clear cell lung cancer and hypoxia. Finally, endocrine responsive maligancies form a fascinating group for which specific receptor directed agents, and natural substrates, may open a window on the biology of human disease including lesion by lesion heterogeneity. In this regard, [F-18]FDHT, an agent targeting androgen receptor, in prostate cancer and [I-124] NaI, for sodium iodide symporter in thyroid cancer, are giving new information about the behavior of human tumors studied in situ.

Citation Format: Steven M. Larson. Novel radiotracers for clinical molecular imaging in oncology [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY20-03
Abstract SY30-03: First impressions of the multiple myeloma genome
Authors: Golub Todd R.
Published: May 2019

Multiple myeloma is a malignancy of mature B-lymphoid cells whose pathogenesis remains obscure. To address this, we undertook a large-scale effort to characterize the genomes of multiple myleoma tumor samples and their matched normal DNAs. Funded by the Multiple Myeloma Research Foundation, this sequencing effort is one of the largest cancer genome sequencing projects completed to date, representing 29 patients (22 whole genomes and 17 whole exomes) sequenced to an average of 30X coverage. Improvements in mutation-calling algorithms yielded a mutation rate of ~ 10-6, with a mutation validation rate of 97%, indicating that the false-positive rate of mutations in this dataset is extremely low. Highlights of novel and biologically important findings from this dataset will be presented, and include: 1) mutations in the transcription factor IRF4; 2) mutations in histone methyltransferases; 3) mutations in genes involved in protein translation; 4) mutations in genes involved in blood coagulation; and 5) an activating mutation in BRAF, for which small-molecule inhibitors are in clinical development. These results suggest that sequencing of the multiple myeloma genome will provide new insights into the pathogenesis of multiple myeloma, and moreover suggest that while mutations in particular genes may be rare, they may result in the aberrant activity of common pathways. This in turn suggests that the sequencing of large numbers of cancer genomes may be required to develop a full understanding of the biological consequences of somatic mutations.

Citation Format: Todd R. Golub. First impressions of the multiple myeloma genome [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY30-03
Abstract SY31-04: Metabolic regulation of tumor cells survival
Authors: Mak Tak W.
Published: May 2019

Today's targeted therapeutics exert their anti-cancer effects mainly by blocking molecular signals that promote tumor cell proliferation, obstruct cell death, hamper cellular differentiation, or facilitate angiogenesis. However, the molecular pathways that underlie these cellular processes are multifaceted and often redundant, allowing tumor cells to escape these drugs. Another approach may be to target tumor cell metabolism. In the 1920s, Warburg noted that cancers exhibit increased rates of glycolysis even in the presence of oxygen, a phenomenon known as aerobic glycolysis or the ‘Warburg effect’. The switch from oxidative phosphorylation to glycolysis that underlies the Warburg effeect represents an alteration to tumor cell metabolism that permits cancer cells to adapt and thrive in conditions that kill normal cells Such adaptations may include upregulated or altered molecular pathways to increase energy production, expansion of the cell's biosynthetic capacity, and/or adoption of an enhanced redox state to cope with elevated levels of deleterious reactive oxygen species. Understanding the energy sources and metabolic pathways utilized by cancer cells to survive should allow the exploitation of this knowledge to design more effective anti-cancer drugs.

Citation Format: Tak W. Mak. Metabolic regulation of tumor cells survival [abstract]. In: Proceedings of the AACR 101st Annual Meeting 2010; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr SY31-04
Abstract 1599: Oral epithelium as a surrogate tissue for assessing smoking-induced molecular alterations in lungs
Authors: Bhutani Manisha , Pathak Ashutosh K , Fan You Hong , Liu Diane D , Lee J. Jack , Tang Hongli , Kurie Jonathan M , Morice Rodolfo C , Kim Edward S , Hong Waun K , Mao Li
Published: May 2019

Background: Because lungs and oral cavity are both exposed to tobacco-carcinogens, we hypothesized that the oral epithelium undergoes molecular alterations similar to those in other airway areas and therefore may be used as a surrogate tissue to assess tobacco-induced molecular alterations in lungs.

Methods: Promoter methylation of p16 and FHIT genes was analyzed in 127 chronic smokers enrolled in a prospective randomized placebo-controlled chemoprevention trial with 1,774 samples from oral and bronchial brushes (baseline and 3-months after intervention) using methylation-specific PCR (MSP). Methylation patterns in oral tissues were correlated with bronchial methylation indices (methylated sites/total sites per subject).

Results: At baseline, promoter methylation was observed in 23%, 17%, and 35% of the bronchial tissues for p16, FHIT, and any of the two genes, respectively, which is comparable to 19%, 15%, and 31% observed in the oral tissues. Among the 125 individuals with available baseline data from both oral and bronchial tissues, strong correlations were observed between tissues from the two organ sites (P < 0.0001 for both p16 and FHIT genes). Among the 39 individuals with oral tissue methylation in any of the two genes, the mean bronchial methylation index was 0.53 (±0.29) compared to only 0.27 (±0.26) for the 86 cases without oral tissue methylation (P < 0.0001). Similar correlations were also observed in samples obtained at 3 months after chemopreventive intervention.

Conclusions: Oral epithelium may be used as a surrogate tissue to assess tobacco-induced molecular damages in lungs, which has potential implications in lung cancer prevention trials.
Abstract 2100: Inhibition of androgen-independent growth of LNCaP xenograft tumors in immunodeficient mice by a combination of atorvastatin (Lipitor) and celecoxib (Celebrex)
Authors: Zheng Xi , Cui Xiao-Xing , Huang Mou-Tuan , Liu Yue , Paulino Raphael , Rabson Arnold , Reddy Bandaru , Conney Allan H.
Published: May 2019

Epidemiological studies indicate that statins and non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of prostate cancer. In the present study, we assessed the effects of Lipitor and Celebrex alone or in combination on androgen-independent growth of human prostate cancer LNCaP cells cultured in vitro or grown as xenograft tumors in immunodeficient mice. In the in vitro studies, LNCaP cells were cultured in medium supplemented with charcoal-stripped fetal bovine serum to mimic androgen-deprivation treatment. We found that treatment of LNCaP cells cultured in androgen-depleted medium with Lipitor or Celebrex alone resulted in growth inhibition and apoptosis. A combination of Lipitor and Celebrex had more potent effects on growth inhibition and apoptosis than either agent alone. In animal studies, severe combined immunodeficient (SCID) mice were injected subcutaneously with LNCaP cells in Matrigel. After 4-6 weeks, mice with LNCaP tumors (about 0.6 cm wide and 0.6 cm long) were surgically castrated and received daily i.p injections with vehicle, Lipitor (10 μg/g body weight/day), Celebrex (10 μg/g/day) or a combination of Lipitor (5 μg/g/day) and Celebrex (5 μg/g/day) for 42 days. In the vehicle control group, LNCaP tumors regressed initially in response to castration and then re-grew in 2 weeks after castration to develop androgen-independent tumors. Treatment of the mice with Lipitor or Celebrex alone suppressed the re-growth of LNCaP tumors after castration. A combination of low doses of Lipitor and Celebrex had a more potent effect for inhibiting the androgen-independent growth of LNCaP tumors than a higher dose of either agent alone. The results from our study indicate that a combination of Lipitor and Celebrex may be an effective strategy for the prevention of prostate cancer progression from androgen-dependence to an androgen-independent stage.
Abstract 2102: Nanochemoprevention: Introducing a novel concept in cancer chemoprevention with a proof of principle for superior activity of green tea polyphenol epigallocatechin-3-gallate encapsulated in PLGA/PVA nanoparticles
Authors: Siddiqui Imtiaz A , Adhami Vaqar M , Bin Hafeez Bilal , Asim Mohammad , Khwaja Sabih I , Bharali Dhruba , Mousa Shaker A , Mukhtar Hasan
Published: May 2019

Despite extensive efforts that have been put to prevent cancer through chemoprevention, lack of delivery of desired levels of bioactive agents thus limiting their bioavailability, remains a challenging issue for effective clinical outcome. Thus, there is a strong unmet need in the biomedical technology community to find novel tools for making chemoprevention a success. Because most biological processes including those that are cancer-related occur at nanoscale, nanoparticulate technology has emerged as a potential tool to diagnose and treat cancer. We considered that nanoparticulate technology can prove to be very useful in cancer chemoprevention by allowing for effective and targeted delivery of chemopreventive agents. This delivery system could overcome many biological, biophysical and biomedical barriers that the body stages. Here, for the first time we introduce a concept of ‘nanochemoprevention’. To demonstrate the proof of principle we selected green tea polyphenol epigallocatechin-3-gallate (EGCG) with which we have considerable experience. We encapsulated EGCG in Poly (DL-lactide-co-glycolide acid) (PLGA)/Polyvinyl alcohol (PVA) nanoparticles, hereafter referred to as nano-EGCG, and evaluated it for cytotoxic response against human prostate cancer (PCa) PC3, DU145, 22Rν1 and LNCaP cells. MTT assay showed that treatment of cells with PLGA/PVC nanoparticles alone had negligible effect on cell growth. Interestingly, nano-EGCG, compared to EGCG in PBS, produced remarkably superior effects. For PC3 cells, the IC50 value at 24 hours of nano-EGCG was 3.75 μM compared to 40 μM of EGCG in PBS; 3.75 μM of EGCG in PBS had no effect. These differential effects were persistent at 48 and 72 hours. Similar effects of nano-EGCG were observed in 22Rν1, LNCaP and DU145, other human PCa cells. EGCG in PBS treatment to cells is known to result in induction of apoptosis and inhibition of colony formation which is considered essential for its chemopreventive effects. Next series of experiments were conducted to determine the effect of nano-EGCG on apoptosis and colony formation potential of PC3 cells. Treatment of the cells for 48 hours with nano-EGCG led to significant induction of PARP cleavage in a dose dependent manner and modulation of bax and bcl2 ratio that favored apoptosis. Further, nano-EGCG treatment also led to a dramatic increase in the levels of annexin V, an early marker of apoptosis. We then performed a 2-dimensional colony formation assay to evaluate the effect of nano-EGCG on the cellular growth pattern of PC3 cells and observed a marked decrease in colony number. Validation of these cell culture data to animal model systems could pave way for developing new avenues for cancer chemoprevention.