bluuebunny/crossref_metadata_2025 huggingface dataset:
Macronutrients, vitamins and minerals intake and risk of esophageal squamous cell carcinoma: a case-control study in Iran
Authors: Jessri Mahsa , Rashidkhani Bahram , Hajizadeh Bahareh , Jessri Maryam , Gotay Carolyn
Published: December 2011

Background

Although Iran is a high-risk region for esophageal squamous cell carcinoma (ESCC), dietary factors that may contribute to this high incidence have not been thoroughly studied. The aim of this study was to evaluate the effect of macronutrients, vitamins and minerals on the risk of ESCC.

Methods

In this hospital-based case-control study, 47 cases with incident ESCC and 96 controls were interviewed and usual dietary intakes were collected using a validated food frequency questionnaire. Data were modeled through unconditional multiple logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI), controlling for age, sex, gastrointestinal reflux, body mass index, smoking history (status, intensity and duration), physical activity, and education.

Results

ESCC cases consumed significantly more hot foods and beverages and fried and barbecued meals, compared to the controls (p < 0.05). After adjusting for potential confounders, the risk of ESCC increased significantly in the highest tertiles of saturated fat [OR:2.88,95%CI:1.15-3.08], cholesterol [OR:1.53, 95%CI: 1.41-4.13], discretionary calorie [OR:1.51, 95%CI: 1.06-3.84], sodium [OR:1.49,95%CI:1.12-2.89] and total fat intakes [OR:1.48, 95%CI:1.09-3.04]. In contrast, being in the highest tertile of carbohydrate, dietary fiber and (n-3) fatty acid intake reduced the ESCC risk by 78%, 71% and 68%, respectively. The most cancer-protective effect was observed for the combination of high folate and vitamin E intakes (OR: 0.02, 95%CI: 0.00-0.87; p < 0.001). Controls consumed 623.5 times higher selenium, 5.48 times as much β-carotene and 1.98 times as much α-tocopherol as the amount ESCC cases consumed.

Conclusion

This study suggests that high intake of nutrients primarily found in plant-based foods is associated with a reduced esophageal cancer risk. Some nutrients such as folate, vitamin E and selenium might play major roles in the etiology of ESCC and their status may eventually be used as an epidemiological marker for esophageal cancer in Iran, and perhaps other high-risk regions.
Digital Subtraction Phonocardiography (DSP) applied to the detection and characterization of heart murmurs
Authors: Akbari Mohammad Ali , Hassani Kamran , Doyle John D , Navidbakhsh Mahdi , Sangargir Maryam , Bajelani Kourosh , Ahmadi Zahra Sadat
Published: December 2011

Background

During the cardiac cycle, the heart normally produces repeatable physiological sounds. However, under pathologic conditions, such as with heart valve stenosis or a ventricular septal defect, blood flow turbulence leads to the production of additional sounds, called murmurs. Murmurs are random in nature, while the underlying heart sounds are not (being deterministic).

Innovation

We show that a new analytical technique, which we call Digital Subtraction Phonocardiography (DSP), can be used to separate the random murmur component of the phonocardiogram from the underlying deterministic heart sounds.

Methods

We digitally recorded the phonocardiogram from the anterior chest wall in 60 infants and adults using a high-speed USB interface and the program Gold Wave http://www.goldwave.com. The recordings included individuals with cardiac structural disease as well as recordings from normal individuals and from individuals with innocent heart murmurs. Digital Subtraction Analysis of the signal was performed using a custom computer program called Murmurgram. In essence, this program subtracts the recorded sound from two adjacent cardiac cycles to produce a difference signal, herein called a "murmurgram". Other software used included Spectrogram (Version 16), GoldWave (Version 5.55) as well as custom MATLAB code.

Results

Our preliminary data is presented as a series of eight cases. These cases show how advanced signal processing techniques can be used to separate heart sounds from murmurs. Note that these results are preliminary in that normal ranges for obtained test results have not yet been established.

Conclusions

Cardiac murmurs can be separated from underlying deterministic heart sounds using DSP. DSP has the potential to become a reliable and economical new diagnostic approach to screening for structural heart disease. However, DSP must be further evaluated in a large series of patients with well-characterized pathology to determine its clinical potential.
Reduced inflammation and altered innate response in neonates during paramyxoviral infection
Authors: Bhattacharya Somashubhra , Beal Brandon T , Janowski Ann M , Shornick Laurie P
Published: December 2011

Background

Human infants are frequently hospitalized due to infection with the paramyxovirus respiratory syncytial virus (RSV). However, very little is known about the neonatal response to paramyxoviral infection. Here, a neonatal model of paramyxoviral infection is developed using the mouse pathogen Sendai virus (SeV).

Results

Adult mice infected with SeV developed a predominantly neutrophilic inflammatory cell influx and a concomitant reduction in lung function, as determined by oxygen saturation. In contrast, neonates with SeV had significantly reduced inflammation and normal lung function. Surprisingly, infected neonates had similar viral loads as adult mice. A reduced neutrophil influx in the neonates may be due in part to reduced expression of both CXCL2 and intracellular adhesion molecule-1 (ICAM-1). Expression of IFN-γ and TNF-α increased in a dose-dependent manner in adult lungs, but neonates did not increase expression of either of these cytokines, even at the highest doses. Importantly, the expression of the RIG-I-like receptors (RLRs) was delayed in the neonatal mice, which might have contributed to their reduced inflammation and differential cytokine expression.

Conclusions

Neonatal mice developed similar SeV titers and cleared the virus with similar efficiency despite developing a dramatically lower degree of pulmonary inflammation compared to adults. This suggests that inflammation in the lung may not be required to control viral replication. Future studies will be needed to determine any effect the reduced inflammation may have on the development of a protective memory response in neonates.
Rapid detection of wheat yellow mosaic virus by reverse transcription loop-mediated isothermal amplification
Authors: Zhang Zong-Ying , Liu Xiao-Jun , Li Da-Wei , Yu Jia-Lin , Han Cheng-Gui
Published: December 2011

For the detection of wheat yellow mosaic virus (WYMV), we established a reverse transcription loop-mediated isothermal amplification (RT-LAMP) method. Using Primer Explorer software, four sets of primers were designed and RT-LAMP assay reaction conditions were optimized. The RT-LAMP was performed at different times by four primer sets. Agarose gel analysis showed that WYMV could be detected after 30 min with the primer set III and after 45 min with the other three primer sets, both under the 80-min reaction time. RT-LAMP had the same results with the four primer sets, thus primer set III and 65°C for 80 min reaction were selected for virus detection. There was no significant different when avian myeloblastosis virus (AMV) and moloney murine leukemia virus (M-MLV) RT-LAMP with the four primer sets and M-MLV was chosen due to its relatively cheap price. The result on specificity showed that the assay could amplify WYMV specifically, and the sensitivity comparison showed that the RT-LAMP was 100 times more sensitive than conventional reverse-transcriptase-polymerase chain reaction (RT-PCR). Overall, RT-LAMP was found to be a simple, specific, sensitive, convenient and time-saving method for WYMV detection.
Complications and management of acute copper sulphate poisoning; a case discussion
Authors: Gamakaranage Champika SSK , Rodrigo Chaturaka , Weerasinghe Sajitha , Gnanathasan Ariaranee , Puvanaraj Visvalingam , Fernando Harshani
Published: December 2011

Copper sulphate ingestion (accidental or deliberate) is a rare form of poisoning usually limited to the Indian subcontinent. Though the rates are on the decline, it is essential that physicians are aware of its lethal complications and management strategies. The main complications of copper sulphate ingestion include intravascular haemolysis, methaemoglobinaemia, acute kidney injury and rhabdomyolysis. The lethal dose can be as small as 10 grams. We have explored the complications of acute copper sulphate poisoning with examples from two case presentations. We also recommend measures for prevention of such events.
Risk factors of distant brain failure for patients with newly diagnosed brain metastases treated with stereotactic radiotherapy alone
Authors: Chen Xiu-jun , Xiao Jian-ping , Li Xiang-pan , Jiang Xue-song , Zhang Ye , Xu Ying-jie , Dai Jian-rong , Li Ye-xiong
Published: December 2011

Objective

To explore the risk factors of distant brain failure (DBF) for patients with brain metastasis (BM) who were treated with stereotactic radiotherapy alone and to group the patients on the basis of their risk levels.

Methods and Materials

We retrospectively analyzed 132 newly diagnosed BM patients who were treated with stereotactic radiotherapy alone from May 2000 to April 2010. Kaplan-Meier and Cox proportional hazards regression analyses were performed for univariate and multivariate analyses.

Results

The 1-year incidence rate of DBF was 44.7%, and the median DBF time (MDBFT) was 18 months. In multivariate analysis, the risk factors of DBF were the number of BMs greater than 1 (p = 0.041), uncontrolled extracranial disease (p = 0.005), interval time (IT) of less than 60 months between the diagnosis of primary tumor and BM (p = 0.024), and total volume of BM was greater than 6 cc (p = 0.049). Each risk factor was assigned 1 score. The median survival times for the patients with scores of 0-1, 2-3, and 4 were 31, 12, and 10 months, respectively, and the corresponding MDBFTs were not reached, 13, and 3 months, respectively, (p < 0.001). The crude DBF incidence rates in patients with scores of 0-1, 2-3, and 4 were 14.8%, 50.0%, and 76.9%, respectively, (p < 0.001).

Conclusions

The patients with scores of 0-1 had a lower risk of DBF than the patients with higher scores did, and it may be reasonable to treat these patients with SRS alone and resort to whole-brain radiation therapy only for salvage. The patients with a score of 4 had the highest risk of developing DBF after stereotactic radiotherapy alone, these patients may be candidates for initial whole-brain radiation therapy or clinical trials. The patients with a score of 2-3 had a moderate risk of developing DBF, SRT alone combined with close clinical monitoring would be the optimal treatment regimen for such patients, and for those patients with difficulties in receiving close clinical mornitoring, SRT combined with WBRT will be more suitable.
An intracranial extramedullary hematopoiesis in a 34-year-old man with beta thalassemia: a case report
Authors: Tabesh Homayoun , Shekarchizadeh Ahmad , Mahzouni Parvin , Mokhtari Mojgan , Abrishamkar Saeid , Abbasi Fard Salman
Published: December 2011

Introduction

Extramedullary hematopoiesis occurs in approximately 15% of cases of thalassemia. Intracranial deposits of extramedullary hematopoiesis are an extremely rare compensatory process in intermediate and severe thalassemia.

Case presentation

We present an unusual case of an intracranial extramedullary hematopoiesis with a choroid plexus origin in a 34-year-old Caucasian man with beta thalassemia intermedia, who presented with the complaints of chronic headache and rapid progressive visual loss.

Conclusion

An intracranial extramedullary hematopoiesis, although extremely rare, should be considered as a potential ancillary diagnosis in any thalassemic patient and therefore appropriate studies should be performed to investigate the probable intracranial ectopic marrow before any surgical intervention.
Male form of persistent Mullerian duct syndrome type I (hernia uteri inguinalis) presenting as an obstructed inguinal hernia: a case report
Authors: Gujar Nishikant N , Choudhari Ravikumar K , Choudhari Geeta R , Bagali Nasheen M , Mane Harish S , Awati Jilani S , Balachandran Vipin
Published: December 2011

Introduction

Persistent Mullerian duct syndrome is a rare form of male pseudo-hermaphroditism characterized by the presence of Mullerian duct structures in an otherwise phenotypically, as well as genotypically, normal man; only a few cases have been reported in the worldwide literature. We report the case of a 30-year-old man with unilateral cryptorchidism on the right side and a left-sided obstructed inguinal hernia containing a uterus and fallopian tube (that is, hernia uteri inguinalis; type I male form of persistent Mullerian duct syndrome) coincidentally detected during an operation for an obstructed left inguinal hernia.

Case presentation

A 30-year-old South Indian man was admitted to our facility with a left-sided obstructed inguinal hernia of one day's duration. He had a 12-year history of inguinal swelling and an absence of the right testis since birth. Our patient had well developed masculine features. Local physical examination revealed a left-sided obstructed inguinal hernia with an absence of the right testis in the scrotum. Exploration of the inguinal canal revealed an indirect inguinal hernia containing omentum, the left corner of the uterus and a left fallopian tube. Extension of the incision revealed a well formed uterus, cervix and upper part of the vagina attached to the prostate by a thick fibrosed band. Total excision of the uterus, bilateral fallopian tubes and right testis was performed. A biopsy was taken from the left testis. The operation was completed by left inguinal herniorraphy. Histopathological examination of the hernial contents was consistent with that of a uterus and fallopian tubes without ovaries. Both testes were atrophied, with complete arrest of spermatogenesis. Post-operative karyotype analyses were negative for 46,XY and Barr bodies on buccal smear. A semen examination revealed azoospermia with a low serum testosterone level.

Conclusions

In cases of unilateral or bilateral cryptorchidism associated with inguinal hernia, as in our patient's case, the possibility of persistent Mullerian duct syndrome should be kept in mind in order to prevent further complications such as infertility and malignant change. Hernia uteri inguinalis is the type I male form of persistent Mullerian duct syndrome, characterized by one descended testis and herniation of the ipsilateral corner of the uterus and fallopian tube into the inguinal canal.
A family presenting with multiple endocrine neoplasia type 2B: A case report
Authors: Majidi Mahnaz , Haghpanah Vahid , Hedayati Mahdi , Khashayar Patricia , Mohajeri-Tehrani Mohammad Reza , Larijani Bagher
Published: December 2011

Introduction

Multiple endocrine neoplasia 2B, a rare autosomal dominant syndrome, is characterized by early onset of medullary thyroid carcinoma, pheochromocytoma, marfanoid habitus and mucosal neuromas of the tongue, lips, inner cheeks and inner eyelids. Gangliomatosis of the gastrointestinal tract and its complications may also occur in patients with this disease.

Case presentation

We present the case of a 16-year-old Persian man diagnosed as having a non-invasive form of multiple endocrine neoplasia 2B (medullary thyroid cancer, mucosal neuroma of the tongue, lips and inner eyelids). Our patient, who had a positive family history of medullary thyroid cancer, was of normal height with no signs of marfanoid habitus.

Conclusions

Ophthalmological and oral manifestations of multiple endocrine neoplasia 2B, as in the case of our patient, are rare presentations of the disease; unfortunately in the case of our patient his condition had not been noted and acted upon until he presented to our department. The diagnosis in our patient's case was made only after his mother presented with the same condition. As a result, we emphasize that physicians should pay more attention to the oral and ocular signs of multiple endocrine neoplasia 2B in order to diagnose this fatal syndrome at an earlier phase.
Subacute dislocation of the elbow following Galeazzi fracture-dislocation of the radius: A case report
Authors: Rajeev Aysha , Senevirathna Shanaka , Harrison John
Published: December 2011

Introduction

The Galeazzi fracture-dislocation was originally described by Sir Astley Cooper in 1822 but was named after Italian surgeon Ricardo Galeazzi in 1934. It is an injury classified as a radial shaft fracture with associated dislocation of the distal radioulnar joint and disruption of the forearm axis joint. The associated distal radioulnar joint injury may be purely ligamentous in nature, tearing the triangular fibrocartilaginous complex, or involve bony tissue (that is, ulnar styloid avulsions) or both. We report this case because of the rare association of posterior dislocation of the elbow along with Galeazzi fracture-dislocation. To the best of our knowledge, this has not been previously reported in the English literature.

Case presentation

A 26-year-old Caucasian man presented to our department after a fall from a motorbike. He sustained a closed, isolated Galeazzi fracture-dislocation of the right forearm and no associated elbow injuries, and this necessitated open reduction and internal fixation of the radius. Post-operative radiographs films were satisfactory. However, clinical and radiological evidence of ipsilateral elbow dislocation was noted at a five-week follow-up, subsequently requiring open reduction of the joint and collateral ligament repair. Our patient was noted to have full elbow and forearm function at three months.

Conclusions

Although the Galeazzi fracture-dislocation has been classically described as involving only the distal radioulnar joint, traumatic forces can be transmitted to the elbow via the interosseous membrane of the forearm. This can lead to instability of the elbow joint. Therefore, we recommend that, in every case of forearm fracture, both elbow and wrist joints be assessed clinically as well as radiologically for subluxation or dislocation.
Ayurvedic herbal medicine and lead poisoning
Authors: Gunturu Krishna S , Nagarajan Priyadharsini , McPhedran Peter , Goodman Thomas R , Hodsdon Michael E , Strout Matthew P
Published: December 2011

Although the majority of published cases of lead poisoning come from occupational exposures, some traditional remedies may also contain toxic amounts of lead. Ayurveda is a system of traditional medicine that is native to India and is used in many parts of world as an alternative to standard treatment regimens. Here, we report the case of a 58-year-old woman who presented with abdominal pain, anemia, liver function abnormalities, and an elevated blood lead level. The patient was found to have been taking the Ayurvedic medicine Jambrulin prior to presentation. Chemical analysis of the medication showed high levels of lead. Following treatment with an oral chelating agent, the patient's symptoms resolved and laboratory abnormalities normalized. This case highlights the need for increased awareness that some Ayurvedic medicines may contain potentially harmful levels of heavy metals and people who use them are at risk of developing associated toxicities.
How to calculate the annual costs of NGO‐implemented programmes to support orphans and vulnerable children: a six‐step approach
Authors: Larson Bruce A , Wambua Nancy
Published: December 2011

Background

Information on the costs of implementing programmes designed to provide support of orphans and vulnerable children (OVC) in sub‐Saharan Africa and elsewhere is increasingly being requested by donors for programme evaluation purposes. To date, little information exists to document the costs and structure of costs of OVC programmes as actually implemented “on the ground” by local non‐governmental organizations (NGOs). This analysis provides a practical, six‐step approach that NGOs can incorporate into routine operations to evaluate their costs of implementing their OVC programmes annually. This approach is applied to the Community‐Based Care for Orphans and Vulnerable Children (CBCO) Program implemented by BIDII (a Kenyan NGO) in Eastern Province of Kenya.

Methods and results

The costing methodology involves the following six steps: accessing and organizing the NGO's annual financial report into logical sub‐categories; reorganizing the sub‐categories into input cost categories to create a financial cost profile; estimating the annual equivalent payment for programme equipment; documenting donations to the NGO for programme implementation; including a portion of NGO organizational costs not attributed to specific programmes; and including the results of Steps 3‐5 into an expanded cost profile. Detailed results are provided for the CBCO programme.

Conclusions

This paper shows through a concrete example how NGOs implementing OVC programmes (and other public health programmes) can organize themselves for data collection and documentation prospectively during the implementation of their OVC programmes so that costing analyses become routine practice to inform programme implementation rather than a painful and flawed retrospective activity. Such information is required if the costs and outcomes achieved by OVC programmes will ever be clearly documented and compared across OVC programmes and other types of programmes (prevention, treatment, etc.).
Direct Detection and Sequencing of Damaged DNA Bases
Authors: Clark Tyson A , Spittle Kristi E , Turner Stephen W , Korlach Jonas
Published: December 2011

Products of various forms of DNA damage have been implicated in a variety of important biological processes, such as aging, neurodegenerative diseases, and cancer. Therefore, there exists great interest to develop methods for interrogating damaged DNA in the context of sequencing. Here, we demonstrate that single-molecule, real-time (SMRT®) DNA sequencing can directly detect damaged DNA bases in the DNA template - as a by-product of the sequencing method - through an analysis of the DNA polymerase kinetics that are altered by the presence of a modified base. We demonstrate the sequencing of several DNA templates containing products of DNA damage, including 8-oxoguanine, 8-oxoadenine, O6-methylguanine, 1-methyladenine, O4-methylthymine, 5-hydroxycytosine, 5-hydroxyuracil, 5-hydroxymethyluracil, or thymine dimers, and show that these base modifications can be readily detected with single-modification resolution and DNA strand specificity. We characterize the distinct kinetic signatures generated by these DNA base modifications.
Development of a handoff continuity score to improve pediatric ICU physician schedule design for enhanced physician and patient continuity
Authors: Smalley Hannah K , Keskinocak Pinar , Vats Atul
Published: December 2011

Introduction

Few studies investigate the benefits of familiarity or continuity during physician-to-physician handoff of inpatients. Factors such as how recently physicians (MDs) have worked and successive days caring for patients increase continuity, and thus could lead to enhanced handoff efficiency. Evaluating the efficacy of MD scheduling to enhance continuity is currently subjective.

Methods

An MD group consisting of 9 attending physicians and 7 fellows redesigned its pediatric intensive care unit (PICU) coverage schedule with the goal of enhancing continuity of care. The attending PICU MDs were formally surveyed to rate the impact of the schedule change on continuity and efficiency (5 point Likert scale: 1 = worse, 3 = no change, 5 = better). A Handoff Continuity Score (HCS) was developed and used to analyze the 30-bed PICU MD schedule for continuity and handoff efficiency. MD service and call schedules were evaluated for 6-month periods before and after the schedule redesign. The HCS for each schedule was calculated by considering every shift change, or handoff, in the scheduling horizon, and assigning scores to oncoming physicians based on previous days worked. Specifically, for each handoff, each oncoming MD receives a score between 0 and 1, calculated as the summation of a series of 'familiarity factors', one for each recent day worked. The scores for all oncoming MDs are averaged to determine the score for that specific handoff, and the HCS is the average of all handoff scores. The HCS was incorporated into an integer programming (IP) model for scheduling MDs to maximize continuity. A z-test was used to assess the significance of improvement in the HCS.

Results

The HCS before and after redesign was 0.57 and 0.68, respectively (19% increase, p < 0.01). Mean MD rating was 4.22 ± 0.56 for continuity, and 4.00 ± 0.65 for efficiency. With the goal of further improving the HCS and (partly) automating and streamlining the scheduling process, the IP was developed to populate physician service and night-call schedules while conforming to scheduling constraints; IP-generated schedules improved the HCS to 0.79 (39% increase).

Conclusions

The increased HCS was associated with the MD qualitative assessment of enhanced continuity and efficiency after implanting a schedule change. The IP identified the potential for additional scheduling improvements.
Loss of the bloom syndrome helicase increases DNA ligase 4-independent genome rearrangements and tumorigenesis in aging Drosophila
Authors: Garcia Ana Maria , Salomon Robert N , Witsell Alice , Liepkalns Justine , Calder R Brent , Lee Moonsook , Lundell Martha , Vijg Jan , McVey Mitch
Published: December 2011

Background

The BLM DNA helicase plays a vital role in maintaining genome stability. Mutations in BLM cause Bloom syndrome, a rare disorder associated with cancer predisposition and premature aging. Humans and mice with blm mutations have increased frequencies of spontaneous mutagenesis, but the molecular basis of this increase is not well understood. In addition, the effect of aging on spontaneous mutagenesis in blm mutants has not been characterized. To address this, we used a lacZ reporter system in wild-type and several mutant strains of Drosophila melanogaster to analyze mechanisms of mutagenesis throughout their lifespan.

Results

Our data show that Drosophila lacking BLM have an elevated frequency of spontaneous genome rearrangements that increases with age. Although in normal flies most genome rearrangements occur through DNA ligase 4-dependent classical end joining, most rearrangements that accumulate during aging in blm mutants do not require DNA ligase 4, suggesting the influence of an alternative end-joining mechanism. Adult blm mutants also display reduced lifespan and ligase 4-independent enhanced tumorigenesis in mitotically active tissues.

Conclusions

These results suggest that Drosophila BLM suppresses error-prone alternative end-joining repair of DNA double-strand breaks that can result in genome instability and tumor formation during aging. In addition, since loss of BLM significantly affects lifespan and tumorigenesis, the data provide a link between error-prone end joining, genome rearrangements, and tumor formation in a model metazoan.
Caenorhabditis elegans Heterochromatin protein 1 (HPL-2) links developmental plasticity, longevity and lipid metabolism
Authors: Meister Peter , Schott Sonia , Bedet Cécile , Xiao Yu , Rohner Sabine , Bodennec Selena , Hudry Bruno , Molin Laurent , Solari Florence , Gasser Susan M , Palladino Francesca
Published: December 2011

Background

Heterochromatin protein 1 (HP1) family proteins have a well-characterized role in heterochromatin packaging and gene regulation. Their function in organismal development, however, is less well understood. Here we used genome-wide expression profiling to assess novel functions of the Caenorhabditis elegans HP1 homolog HPL-2 at specific developmental stages.

Results

We show that HPL-2 regulates the expression of germline genes, extracellular matrix components and genes involved in lipid metabolism. Comparison of our expression data with HPL-2 ChIP-on-chip profiles reveals that a significant number of genes up- and down-regulated in the absence of HPL-2 are bound by HPL-2. Germline genes are specifically up-regulated in hpl-2 mutants, consistent with the function of HPL-2 as a repressor of ectopic germ cell fate. In addition, microarray results and phenotypic analysis suggest that HPL-2 regulates the dauer developmental decision, a striking example of phenotypic plasticity in which environmental conditions determine developmental fate. HPL-2 acts in dauer at least partly through modulation of daf-2/IIS and TGF-β signaling pathways, major determinants of the dauer program. hpl-2 mutants also show increased longevity and altered lipid metabolism, hallmarks of the long-lived, stress resistant dauers.

Conclusions

Our results suggest that the worm HP1 homologue HPL-2 may coordinately regulate dauer diapause, longevity and lipid metabolism, three processes dependent on developmental input and environmental conditions. Our findings are of general interest as a paradigm of how chromatin factors can both stabilize development by buffering environmental variation, and guide the organism through remodeling events that require plasticity of cell fate regulation.
Effects of Abiraterone Acetate on Androgen Signaling in Castrate-Resistant Prostate Cancer in Bone
Authors: Efstathiou Eleni , Titus Mark , Tsavachidou Dimitra , Tzelepi Vassiliki , Wen Sijin , Hoang Anh , Molina Arturo , Chieffo Nicole , Smith Lisa A. , Karlou Maria , Troncoso Patricia , Logothetis Christopher J.
Published: December 2011

Purpose

Persistent androgen signaling is implicated in castrate-resistant prostate cancer (CRPC) progression. This study aimed to evaluate androgen signaling in bone marrow–infiltrating cancer and testosterone in blood and bone marrow and to correlate with clinical observations.

Patients and Methods

This was an open-label, observational study of 57 patients with bone-metastatic CRPC who underwent transiliac bone marrow biopsy between October 2007 and March 2010. Patients received oral abiraterone acetate (1 g) once daily and prednisone (5 mg) twice daily. Androgen receptor (AR) and CYP17 expression were assessed by immunohistochemistry, testosterone concentration by mass spectrometry, AR copy number by polymerase chain reaction, and TMPRSS2-ERG status by fluorescent in situ hybridization in available tissues.

Results

Median overall survival was 555 days (95% CI, 440 to 965+ days). Maximal prostate-specific antigen decline ≥ 50% occurred in 28 (50%) of 56 patients. Homogeneous, intense nuclear expression of AR, combined with ≥ 10% CYP17 tumor expression, was correlated with longer time to treatment discontinuation (> 4 months) in 25 patients with tumor-infiltrated bone marrow samples. Pretreatment CYP17 tumor expression ≥ 10% was correlated with increased bone marrow aspirate testosterone. Blood and bone marrow aspirate testosterone concentrations declined to less than picograms-per-milliliter levels and remained suppressed at progression.

Conclusion

The observed pretreatment androgen-signaling signature is consistent with persistent androgen signaling in CRPC bone metastases. This is the first evidence that abiraterone acetate achieves sustained suppression of testosterone in both blood and bone marrow aspirate to less than picograms-per-milliliter levels. Potential admixture of blood with bone marrow aspirate limits our ability to determine the origin of measured testosterone.
Risk Factors for Obesity in Adult Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study
Authors: Green Daniel M. , Cox Cheryl L. , Zhu Liang , Krull Kevin R. , Srivastava Deo Kumar , Stovall Marilyn , Nolan Vikki G. , Ness Kirsten K. , Donaldson Sarah S. , Oeffinger Kevin C. , Meacham Lillian R. , Sklar Charles A. , Armstrong Gregory T. , Robison Leslie L.
Published: December 2011

Purpose

Many Childhood Cancer Survivor Study (CCSS) participants are at increased risk for obesity. The etiology of their obesity is likely multifactorial but not well understood.

Patients and Methods

We evaluated the potential contribution of demographic, lifestyle, treatment, and intrapersonal factors and self-reported pharmaceutical use to obesity (body mass index ≥ 30 kg/m2) among 9,284 adult (> 18 years of age) CCSS participants. Independent predictors were identified using multivariable regression models. Interrelationships were determined using structural equation modeling (SEM).

Results

Independent risk factors for obesity included cancer diagnosed at 5 to 9 years of age (relative risk [RR], 1.12; 95% CI, 1.01 to 1.24; P = .03), abnormal Short Form–36 physical function (RR, 1.19; 95% CI, 1.06 to 1.33; P < .001), hypothalamic/pituitary radiation doses of 20 to 30 Gy (RR, 1.17; 95% CI, 1.05 to 1.30; P = .01), and paroxetine use (RR, 1.29; 95% CI, 1.08 to 1.54; P = .01). Meeting US Centers for Disease Control and Prevention guidelines for vigorous physical activity (RR, 0.90; 95% CI, 0.82 to 0.97; P = .01) and a medium amount of anxiety (RR, 0.86; 95% CI, 0.75 to 0.99; P = .04) reduced the risk of obesity. Results of SEM (N = 8,244; comparative fit index = 0.999; Tucker Lewis index = 0.999; root mean square error of approximation = 0.014; weighted root mean square residual = 0.749) described the hierarchical impact of the direct predictors, moderators, and mediators of obesity.

Conclusion

Treatment, lifestyle, and intrapersonal factors, as well as the use of specific antidepressants, may contribute to obesity among survivors. A multifaceted intervention, including alternative drug and other therapies for depression and anxiety, may be required to reduce risk.
Substantial Susceptibility of Chronic Lymphocytic Leukemia to BCL2 Inhibition: Results of a Phase I Study of Navitoclax in Patients With Relapsed or Refractory Disease
Authors: Roberts Andrew W. , Seymour John F. , Brown Jennifer R. , Wierda William G. , Kipps Thomas J. , Khaw Seong Lin , Carney Dennis A. , He Simon Z. , Huang David C.S. , Xiong Hao , Cui Yue , Busman Todd A. , McKeegan Evelyn M. , Krivoshik Andrew P. , Enschede Sari H. , Humerickhouse Rod
Published: December 2011

Purpose

BCL2 overexpression is a hallmark of chronic lymphocytic leukemia (CLL). The novel BH3 mimetic navitoclax (ABT-263) specifically inhibits BCL2 and related proteins BCL-xl and BCL-w, potently inducing apoptosis of CLL cells in vitro. A phase I trial in patients with CLL was conducted to evaluate the safety, pharmacokinetics, and biologic activity of oral navitoclax.

Patients and Methods

Twenty-nine patients with relapsed or refractory CLL received daily navitoclax for 14 days (10, 110, 200, or 250 mg/d; n = 15) or 21 days (125, 200, 250, or 300 mg/d; n = 14) of each 21-day cycle. Dose escalation decisions were informed by continual reassessment methodology.

Results

Lymphocytosis was reduced by more than 50% in 19 of 21 patients with baseline lymphocytosis. Among 26 patients treated with navitoclax ≥ 110 mg/d, nine (35%) achieved a partial response and seven maintained stable disease for more than 6 months. Median treatment duration was 7 months (range, 1 to ≥ 29 months). Median progression-free survival was 25 months. Activity was observed in patients with fludarabine-refractory disease, bulky adenopathy, and del(17p) CLL. Thrombocytopenia due to BCL-xl inhibition was the major dose-limiting toxicity and was dose-related. Low MCL1 expression and high BIM:MCL1 or BIM:BCL2 ratios in leukemic cells correlated with response. We determined that the navitoclax dose of 250 mg/d in a continuous dosing schedule was optimal for phase II studies.

Conclusion

BCL2 is a valid therapeutic target in CLL, and its inhibition by navitoclax warrants further evaluation as monotherapy and in combination in this disease.
Impact of Long-Term Serum Platinum Concentrations on Neuro- and Ototoxicity in Cisplatin-Treated Survivors of Testicular Cancer
Authors: Sprauten Mette , Darrah Thomas H. , Peterson Derick R. , Campbell M. Ellen , Hannigan Robyn E. , Cvancarova Milada , Beard Clair , Haugnes Hege S. , Fosså Sophie D. , Oldenburg Jan , Travis Lois B.
Published: December 2011

Purpose

Cisplatin-induced neurotoxicity and ototoxicity (NTX) are important adverse effects after chemotherapy for testicular cancer (TC). Although serum platinum is measurable years after therapy, its impact on NTX has not been evaluated.

Patients and Methods

In all, 169 cisplatin-treated survivors of TC provided blood samples at Survey I and reported NTX during Survey I (1998-2002) and Survey II (2007-2008). Serum platinum was quantified by inductively coupled plasma mass spectrometry. Patient-reported outcomes were evaluated with the Scale for Chemotherapy-Induced Neurotoxicity (SCIN), regarding the extent of symptom bother as 0, “not at all”; 1, “a little”; 2, “quite a bit”; or 3, “very much.” Summing the six symptom scores yielded a total SCIN score of 0 to 18. Categorizing total SCIN scores into quartiles yielded similar-sized groups with increasing symptoms. Multivariate ordinal logistic regression analyses evaluated associations between NTX and long-term serum platinum levels, adjusting for cisplatin dose, dosing schedule, and age.

Results

At Survey I, a significant four- to five-fold association with total SCIN score emerged for the highest serum platinum quartile (odds ratio [OR], 4.69; 95% CI, 1.82 to 12.08). Paresthesias and Raynaud's syndrome (hands and feet) showed significant two- to four-fold increased risks with the highest platinum quartile. At Survey II, total SCIN score remained significantly associated with the highest platinum quartile (OR, 4.28; 95% CI, 1.36 to 13.48). Paresthesias (hands and feet) and tinnitus showed significant three- to four-fold increased risks for the highest platinum quartile. Cumulative cisplatin dose was not associated with total SCIN score or individual SCIN symptoms in multivariate analyses.

Conclusion

Here we document a significant relationship between increasing levels of residual serum platinum and NTX severity after adjusting for initial cisplatin dose.
Safety and Efficacy of Combination Immunotherapy With Interferon Alfa-2b and Tremelimumab in Patients With Stage IV Melanoma
Authors: Tarhini Ahmad A. , Cherian John , Moschos Stergios J. , Tawbi Hussein A. , Shuai Yongli , Gooding William E. , Sander Cindy , Kirkwood John M.
Published: December 2011

Purpose

We tested the hypothesis that the combination of tremelimumab and interferon alfa-2b acting via different and possibly synergistic mechanisms would overcome tumor immune tolerance and lead to significant and durable clinical responses.

Patients and Methods

We conducted a phase II study in which patients were administered tremelimumab 15 mg/kg/course (three cycles [one cycle = 4 weeks]) intravenously every 12 weeks. High-dose interferon alfa-2b (HDI) was administered concurrently, including intravenous induction at 20 MU/m2/d for 5 d/wk for 4 weeks followed by maintenance at 10 MU/m2/d subcutaneously three times a week for 8 weeks per course. From course 2 onward, HDI maintenance was administered subcutaneously.

Results

Thirty-seven patients with American Joint Committee on Cancer stage IV (9M1a, 6M1b, and 22M1c) were enrolled. Two patients had previously treated brain metastases. Grades 3 and 4 toxicities included neutropenia (six patients; 17%), diarrhea/colitis (four patients; 11%), liver enzyme increase (four patients; 11%), rash (four patients; 11%), fatigue (15 patients; 40%), and anxiety/depression (five patients; 14%). Response data were available for 35 patients. The best objective response rate (RR; Response Evaluation Criteria in Solid Tumors) by intention to treat was 24% (90% CI, 13% to 36%; four complete responses [CRs] and five partial responses [PRs] that lasted 6, 6, > 12, > 14, > 18, 20, > 28, 30, and > 37 months, respectively). Fourteen patients (38%) had stable disease (SD) that lasted 1.5 to 21 months. The median progression-free survival was 6.4 months (95% CI, 3.3 to 12.1 months). The median overall survival (OS) was 21 months (95% CI, 9.5 to not reached). There was a weak association between therapy-induced autoimmunity and clinical benefits (CR/PR/SD; P = .0059), baseline C-reactive protein (CRP) less than or equal to 2.7× the upper limit of normal and clinical benefits (P = .0494) and improved probability of survival (P = .0032), and baseline lymphocyte count of at least 1,000/μL and response (CR/PR; P = .0183) and clinical benefits (CR/PR/SD; P = .0255). Biomarker associations were not significant after adjustment for multiple comparisons.

Conclusion

HDI can be administered combined with tremelimumab with acceptable toxicity and promising durable antitumor efficacy that warrant further testing in a randomized trial.
Phase III Trial Comparing Capecitabine Plus Cisplatin Versus Capecitabine Plus Cisplatin With Concurrent Capecitabine Radiotherapy in Completely Resected Gastric Cancer With D2 Lymph Node Dissection: The ARTIST Trial
Authors: Lee Jeeyun , Lim Do Hoon , Kim Sung , Park Se Hoon , Park Joon Oh , Park Young Suk , Lim Ho Yeong , Choi Min Gew , Sohn Tae Sung , Noh Jae Hyung , Bae Jae Moon , Ahn Yong Chan , Sohn Insuk , Jung Sin Ho , Park Cheol Keun , Kim Kyoung-Mee , Kang Won Ki
Published: December 2011

Purpose

The ARTIST (Adjuvant Chemoradiation Therapy in Stomach Cancer) trial was the first study to our knowledge to investigate the role of postoperative chemoradiotherapy therapy in patients with curatively resected gastric cancer with D2 lymph node dissection. This trial was designed to compare postoperative treatment with capecitabine plus cisplatin (XP) versus XP plus radiotherapy with capecitabine (XP/XRT/XP).

Patients and Methods

The XP arm received six cycles of XP (capecitabine 2,000 mg/m2 per day on days 1 to 14 and cisplatin 60 mg/m2 on day 1, repeated every 3 weeks) chemotherapy. The XP/XRT/XP arm received two cycles of XP followed by 45-Gy XRT (capecitabine 1,650 mg/m2 per day for 5 weeks) and two cycles of XP.

Results

Of 458 patients, 228 were randomly assigned to the XP arm and 230 to the XP/XRT/XP arm. Treatment was completed as planned by 75.4% of patients (172 of 228) in the XP arm and 81.7% (188 of 230) in the XP/XRT/XP arm. Overall, the addition of XRT to XP chemotherapy did not significantly prolong disease-free survival (DFS; P = .0862). However, in the subgroup of patients with pathologic lymph node metastasis at the time of surgery (n = 396), patients randomly assigned to the XP/XRT/XP arm experienced superior DFS when compared with those who received XP alone (P = .0365), and the statistical significance was retained at multivariate analysis (estimated hazard ratio, 0.6865; 95% CI, 0.4735 to 0.9952; P = .0471).

Conclusion

The addition of XRT to XP chemotherapy did not significantly reduce recurrence after curative resection and D2 lymph node dissection in gastric cancer. A subsequent trial (ARTIST-II) in patients with lymph node–positive gastric cancer is planned.
Ectopic retinoic acid signaling affects outflow tract cushion development through suppression of the myocardial Tbx2-Tgfβ2 pathway
Authors: Sakabe Masahide , Kokubo Hiroki , Nakajima Yuji , Saga Yumiko
Published: December 2011

The progress of molecular genetics has enabled us to identify the genes responsible for congenital heart malformations. However, recent studies suggest that congenital heart diseases are induced not only by mutations in certain genes, but also by abnormal maternal factors. A high concentration of maternal retinoic acid (RA), the active derivative of vitamin A, is well known as a teratogenic agent that can cause developmental defects. Our previous studies have shown that the maternal administration of RA to mice within a narrow developmental window induces outflow tract (OFT) septum defects, a condition that closely resembles human transposition of the great arteries (TGA), although the responsible factors and pathogenic mechanisms of the TGA induced by RA remain unknown. We herein demonstrate that the expression of Tbx2 in the OFT myocardium is responsive to RA, and its downregulation is associated with abnormal OFT development. We found that RA could directly downregulate the Tbx2 expression through a functional retinoic acid response element (RARE) in the Tbx2 promoter region, which is also required for the initiation of Tbx2 transcription during OFT development. Tgfb2 expression was also downregulated in the RA-treated OFT region and was upregulated by Tbx2 in a culture system. Moreover, defective epithelial-mesenchymal transition caused by the excess RA was rescued by the addition of Tgfβ2 in an organ culture system. These data suggest that RA signaling participates in the Tbx2 transcriptional mechanism during OFT development and that the Tbx2-Tgfβ2 cascade is one of the key pathways involved in inducing the TGA phenotype.
Palatogenesis: morphogenetic and molecular mechanisms of secondary palate development
Authors: Bush Jeffrey O. , Jiang Rulang
Published: December 2011

Mammalian palatogenesis is a highly regulated morphogenetic process during which the embryonic primary and secondary palatal shelves develop as outgrowths from the medial nasal and maxillary prominences, respectively, remodel and fuse to form the intact roof of the oral cavity. The complexity of control of palatogenesis is reflected by the common occurrence of cleft palate in humans. Although the embryology of the palate has long been studied, the past decade has brought substantial new knowledge of the genetic control of secondary palate development. Here, we review major advances in the understanding of the morphogenetic and molecular mechanisms controlling palatal shelf growth, elevation, adhesion and fusion, and palatal bone formation.
A complex choreography of cell movements shapes the vertebrate eye
Authors: Kwan Kristen M. , Otsuna Hideo , Kidokoro Hinako , Carney Keith R. , Saijoh Yukio , Chien Chi-Bin
Published: December 2011

Optic cup morphogenesis (OCM) generates the basic structure of the vertebrate eye. Although it is commonly depicted as a series of epithelial sheet folding events, this does not represent an empirically supported model. Here, we combine four-dimensional imaging with custom cell tracking software and photoactivatable fluorophore labeling to determine the cellular dynamics underlying OCM in zebrafish. Although cell division contributes to growth, we find it dispensable for eye formation. OCM depends instead on a complex set of cell movements coordinated between the prospective neural retina, retinal pigmented epithelium (RPE) and lens. Optic vesicle evagination persists for longer than expected; cells move in a pinwheel pattern during optic vesicle elongation and retinal precursors involute around the rim of the invaginating optic cup. We identify unanticipated movements, particularly of central and peripheral retina, RPE and lens. From cell tracking data, we generate retina, RPE and lens subdomain fate maps, which reveal novel adjacencies that might determine corresponding developmental signaling events. Finally, we find that similar movements also occur during chick eye morphogenesis, suggesting that the underlying choreography is conserved among vertebrates.