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1.  Regulation of divalent metal transporter-1 by serine phosphorylation 
Biochemical Journal  2016;473(22):4243-4254.
Divalent metal transporter-1 (DMT1) mediates dietary iron uptake across the intestinal mucosa and facilitates peripheral delivery of iron released by transferrin in the endosome. Here, we report that classical cannabinoids (Δ9-tetrahydrocannabinol, Δ9-THC), nonclassical cannabinoids (CP 55,940), aminoalkylindoles (WIN 55,212-2) and endocannabinoids (anandamide) reduce 55Fe and 54Mn uptake by HEK293T(DMT1) cells stably expressing the transporter. siRNA knockdown of cannabinoid receptor type 2 (CB2) abrogated inhibition. CB2 is a G-protein (GTP-binding protein)-coupled receptor that negatively regulates signal transduction cascades involving serine/threonine kinases. Immunoprecipitation experiments showed that DMT1 is serine-phosphorylated under basal conditions, but that treatment with Δ9-THC reduced phosphorylation. Site-directed mutation of predicted DMT1 phosphosites further showed that substitution of serine with alanine at N-terminal position 43 (S43A) abolished basal phosphorylation. Concordantly, both the rate and extent of 55Fe uptake in cells expressing DMT1(S43A) was reduced compared with those expressing wild-type DMT1. Among kinase inhibitors that affected DMT1-mediated iron uptake, staurosporine also reduced DMT1 phosphorylation confirming a role for serine phosphorylation in iron transport regulation. These combined data indicate that phosphorylation at serine 43 of DMT1 promotes transport activity, whereas dephosphorylation is associated with loss of iron uptake. Since anti-inflammatory actions mediated through CB2 would be associated with reduced DMT1 phosphorylation, we postulate that this pathway provides a means to reduce oxidative stress by limiting iron uptake.
PMCID: PMC5103878  PMID: 27681840
cannabinoid receptor; Δ9-tetrahydrocannabinol; DMT1; iron transport; Slc11a2
2.  Relationship Between Development, Metabolism, and Mitochondrial Organization in 2-Cell Hamster Embryos in the Presence of Low Levels of Phosphate 
Biology of reproduction  2001;65(6):1648-1654.
The effect of low concentrations of inorganic phosphate (Pi) on development, metabolic activity, and mitochondrial organization in the same cohorts of cultured hamster embryos was evaluated. Two-cell embryos were collected from eCG-stimulated golden hamsters and cultured in HECM-10 with 0.0 (control), 1.25, 2.5, or 5.0 µM KH2PO4. Glucose utilization through the Embden-Meyerhof pathway (EMP) and tricarboxylic acid (TCA)-cycle activity were determined following 5 h of culture. Mitochondrial organization in living embryos was evaluated using multiphoton microscopy at 6 h of culture. Development was assessed at 27 h (on-time 8-cell stage) and 51 h (on-time blastocyst stage) of culture. Total cell numbers, as well as cell allocation to the trophectoderm and inner cell mass were determined for morula- and blastocyst-stage embryos. Culture with Pi did not alter TCA-cycle activity. However, culture with ≥2.5 µM Pi significantly increased (P < 0.01) EMP activity compared to control. Mitochondrial organization was significantly (P < 0.01) disrupted by Pi in a dose-dependent manner. Development to the 8-cell, morula/blastocyst, and blastocyst stages was significantly reduced (P < 0.05) in the presence of ≥2.5 µM Pi compared to both control and 1.25 µM Pi. This study clearly demonstrates that, for hamster embryos, inclusion of even exceptionally low concentrations of Pi in culture medium dramatically alters embryo physiology. Additionally, although 2-cell embryos can tolerate some structural disruption without concomitant, detrimental effects on development or metabolic activity, metabolic disturbance is associated with decreased developmental competence.
PMCID: PMC5087320  PMID: 11717124
developmental biology; early development; embryo
3.  Altering Intracellular pH Disrupts Development and Cellular Organization in Preimplantation Hamster Embryos 
Biology of reproduction  2001;64(6):1845-1854.
In early cleavage stage hamster embryos, the inability to regulate intracellular pH (pHi) properly is associated with reduced developmental competence in vitro. The disruption of mitochondrial organization is also correlated with reduced development in vitro. To determine the relationship between pHi and the disruption of cytoplasmic organization, we examined the effects of altering pHi on hamster embryo development, mitochondrial distribution, and cytoskeletal organization. The weak base trimethylamine was used to increase pHi and was found to reduce embryo development and disrupt the perinuclear organization of mitochondria. The weak acid 5,5-dimethyl-2,4-oxazolinedione was used to decrease pHi and was also found to reduce development and disrupt the perinuclear organization of mitochondria. With either treatment, the microfilament organization was perturbed, but the microtubule cytoskeleton was not. However, the temporal progression of the disruption of mitochondrial distribution was more rapid in alkalinized embryos than acidified embryos, as revealed by two-photon imaging of living embryos. Additionally, the disruption of the microfilament network by the two treatments was not identical. The cytoplasmic disruptions observed were not due to acute toxicity of the compounds because embryos recovered developmentally when the treatment compounds were removed. These observations link ionic homeostasis, structural integrity and developmental competence in preimplantation hamster embryos.
PMCID: PMC5087321  PMID: 11369617
developmental biology; early development; embryo; gamete biology
4.  Transanal total mesorectal excision: Myths and reality 
Transanal total mesorectal excision (TaTME) is a new and promising approach for the treatment of rectal cancer. Whilst the experience is still limited, there are growing evidences that this approach might overcome the limits of standard low anterior resection. TaTME might help to decrease the conversion rate especially in difficult patients, and to improve the pathological results, while preserving the urogenital function. Evaluation of data from large registries and randomized studies should help to draw firmer conclusions. Beyond these technical considerations, the next challenge seems to be clearly the safe introduction of this approach, motivating the development of dedicated courses.
PMCID: PMC5056325  PMID: 27777876
Transanal total mesorectal excision; Bottom up; TAMIS; Laparoscopy; Robotic; Outcomes; Rectal cancer
5.  Oncogenic fingerprint of epidermal growth factor receptor pathway and emerging epidermal growth factor receptor blockade resistance in colorectal cancer 
Epidermal growth factor receptor (EGFR) has been an attractive target for treatment of epithelial cancers, including colorectal cancer (CRC). Evidence from clinical trials indicates that cetuximab and panitumumab (anti-EGFR monoclonal antibodies) have clinical activity in patients with metastatic CRC. The discovery of intrinsic EGFR blockade resistance in Kirsten RAS (KRAS)-mutant patients led to the restriction of anti-EGFR antibodies to KRAS wild-type patients by Food and Drug Administration and European Medicine Agency. Studies have since focused on the evaluation of biomarkers to identify appropriate patient populations that may benefit from EGFR blockade. Accumulating evidence suggests that patients with mutations in EGFR downstream signaling pathways including KRAS, BRAF, PIK3CA and PTEN could be intrinsically resistant to EGFR blockade. Recent whole genome studies also suggest that dynamic alterations in signaling pathways downstream of EGFR leads to distinct oncogenic signatures and subclones which might have some impact on emerging resistance in KRAS wild-type patients. While anti-EGFR monoclonal antibodies have a clear potential in the management of a subset of patients with metastatic CRC, further studies are warranted to uncover exact mechanisms related to acquired resistance to EGFR blockade.
PMCID: PMC5056326  PMID: 27777877
Epidermal growth factor receptor; Oncogenic signature; Kirsten RAS; BRAF; Cetuximab; Panitumumab; Epidermal growth factor receptor blockade resistance
6.  Role of Akt signaling in resistance to DNA-targeted therapy 
The Akt signal transduction pathway controls most hallmarks of cancer. Activation of the Akt cascade promotes a malignant phenotype and is also widely implicated in drug resistance. Therefore, the modulation of Akt activity is regarded as an attractive strategy to enhance the efficacy of cancer therapy and irradiation. This pathway consists of phosphatidylinositol 3 kinase (PI3K), mammalian target of rapamycin, and the transforming serine-threonine kinase Akt protein isoforms, also known as protein kinase B. DNA-targeted agents, such as platinum agents, taxanes, and antimetabolites, as well as radiation have had a significant impact on cancer treatment by affecting DNA replication, which is aberrantly activated in malignancies. However, the caveat is that they may also trigger the activation of repairing mechanisms, such as upstream and downstream cascade of Akt survival pathway. Thus, each target can theoretically be inhibited in view of improving the potency of conventional treatment. Akt inhibitors, e.g., MK-2206 and perifosine, or PI3K modulators, e.g., LY294002 and Wortmannin, have shown some promising results in favor of sensitizing the cancer cells to the therapy in vitro and in vivo, which have provided the rationale for incorporation of these novel agents into multimodality treatment of different malignancies. Nevertheless, despite the acceptable safety profile of some of these agents in the clinical studies, with regard to the efficacy, the results are still too preliminary. Hence, we need to wait for the upcoming data from the ongoing trials before utilizing them into the standard care of cancer patients.
PMCID: PMC5056327  PMID: 27777878
Phosphatidylinositol 3 kinase/Akt; Platinum; Taxane; Antimetabolite; Radiation
7.  Accelerated partial breast irradiation: Past, present, and future 
Accelerated partial breast irradiation (APBI) focuses higher doses of radiation during a shorter interval to the lumpectomy cavity, in the setting of breast conserving therapy for early stage breast cancer. The utilization of APBI has increased in the past decade because of the shorter treatment schedule and a growing body of outcome data showing positive cosmetic outcomes and high local control rates in selected patients undergoing breast conserving therapy. Technological advances in various APBI modalities, including intracavitary and interstitial brachytherapy, intraoperative radiation therapy, and external beam radiation therapy, have made APBI more accessible in the community. Results of early APBI trials served as the basis for the current consensus guidelines, and multiple prospective randomized clinical trials are currently ongoing. The pending long term results of these trials will help us identify optimal candidates that can benefit from ABPI. Here we provide an overview of the clinical and cosmetic outcomes of various APBI techniques and review the current guidelines for selecting suitable breast cancer patients. We also discuss the impact of APBI on the economics of cancer care and patient reported quality of life.
PMCID: PMC5056328  PMID: 27777879
Breast cancer; Intracavitary brachytherapy; Accelerated partial breast irradiation; Interstitial brachytherapy
8.  Granulocyte colony-stimulating factor-producing hepatocellular carcinoma with abrupt changes 
Granulocyte colony-stimulating factor (G-CSF)-producing tumor is one of the rare types of cancer clinically characterized by an elevated fever and white blood cell (WBC) increment. Although G-CSF producing tumors have been reported in several types of cancer including those of the lungs, cervix and bladder, G-CSF producing hepatocellular carcinoma is extremely rare. Here, we report the case of a rapidly growing and poorly differentiated hepatocellular carcinoma producing G-CSF. The patient showed symptoms of continuous high fever, stomach pain and cough, and high serum WBC counts, C-reactive protein (CRP) and G-CSF levels were found in laboratory tests. After a radical hepatectomy, the patient completely recovered from the above symptoms and inflammatory state. The serum levels of G-CSF were reduced to normal levels after radical surgery. An immunohistochemical analysis revealed the overexpression of G-CSF in the cytoplasm of certain hepatocellular carcinoma (HCC) cell. The patient’s serum WBC, CRP and G-CSF levels remained within normal levels in the six months after surgery without recurrence. This is the 9th case report of G-CSF producing hepatocellular carcinoma in English literature. We review the clinical characteristics of the G-CSF producing HCC and discuss a possible treatment strategy.
PMCID: PMC5056329  PMID: 27777880
Granulocyte colony stimulating factor; Granulocyte colony-stimulating factor producing tumor; Hepatocellular carcinoma; Immunohistochemistry; Sarcomatous changes
9.  Tumor infiltrating lymphocytes in triple negative breast cancer receiving neoadjuvant chemotherapy 
To determine influence of neoadjuvant-chemotherapy (NAC) over tumor-infiltrating-lymphocytes (TIL) in triple-negative-breast-cancer (TNBC).
TILs were evaluated in 98 TNBC cases who came to Instituto Nacional de Enfermedades Neoplasicas from 2005 to 2010. Immunohistochemistry staining for CD3, CD4, CD8 and FOXP3 was performed in tissue microarrays (TMA) sections. Evaluation of H/E in full-face and immunohistochemistry in TMA sections was performed in pre and post-NAC samples. STATA software was used and P value < 0.05 was considered statistically significant.
Higher TIL evaluated in full-face sections from pre-NAC tumors was associated to pathologic-complete-response (pCR) (P = 0.0251) and outcome (P = 0.0334). TIL evaluated in TMA sections showed low level of agreement with full-face sections (ICC = 0.017-0.20) and was not associated to pCR or outcome. TIL in post-NAC samples were not associated to response or outcome. Post-NAC lesions with pCR had similar TIL levels than those without pCR (P = 0.6331). NAC produced a TIL decrease in full-face sections (P < 0.0001). Percentage of TIL subpopulations was correlated with their absolute counts. Higher counts of CD3, CD4, CD8 and FOXP3 in pre-NAC samples had longer disease-free-survival (DFS). Higher counts of CD3 in pre-NAC samples had longer overall-survival. Higher ratio of CD8/CD4 counts in pre-NAC was associated with pCR. Higher ratio of CD4/FOXP3 counts in pre-NAC was associated with longer DFS. Higher counts of CD4 in post-NAC samples were associated with pCR.
TIL in pre-NAC full-face sections in TNBC are correlated to longer survival. TIL in full-face differ from TMA sections, absolute count and percentage analysis of TIL subpopulation closely related.
PMCID: PMC5056330  PMID: 27777881
Triple-negative breast cancer; Survival; Tumor-infiltrating lymphocytes; Neoadjuvant therapy
10.  Malignant transformation of hepatocellular adenoma with bone marrow metaplasia arising in glycogen storage disease type I: A case report 
Molecular and Clinical Oncology  2016;5(5):599-603.
Malignant transformation of hepatocellular adenoma (HA) is relatively rare and has been reported to be associated with dysregulation of the β-catenin pathway. The presence of bone marrow metaplasia in HA is an uncommon histological characteristic. The current report presents the case of a 46-year-old woman with glycogen storage disease type I (von Gierke's disease) who underwent resection of hepatocellular carcinoma (HCC) arising in a HA with associated bone marrow metaplasia producing three series of hematopoietic cells. The serum level of proteins induced by des-gamma-carboxy prothrombin (DCP) gradually increased as the tumors grew; following hepatic resection, DCP levels returned to normal. Nuclear accumulation of β-catenin was shown in HCC by immunohistochemistry; however, no mutation was detected in exon 3 of β-catenin. To the best of our knowledge, this is the first report of HA with absolute bone marrow metaplasia producing three series of hematopoietic cells. This occurrence suggests that elevated DCP may be an indicator of malignant transformation of HA.
PMCID: PMC5103882  PMID: 27900094
hepatocellular carcinoma; hepatocellular adenoma; bone marrow metaplasia; des-gamma-carboxy prothrombin; β-catenin
11.  Intravenous leiomyomatosis with right atrium extension in two patients: A case report 
Molecular and Clinical Oncology  2016;5(5):604-606.
Intravenous leiomyomatosis (IVL) is a rare benign tumor of the uterus mesoderm, which can spread via the vein, from the micro-vein to the inferior vena cava, and even to the right atrium. IVL was first described this disease in 1896 and the first presented case of IVL with right atrium extension in the autopsy was described in 1907. On rare occasions, the tumors may extend into the regional and systemic veins, thus reaching the heart. This may subsequently cause intracardiac leiomyomatosis (ICL), which may lead to congestive heart failure and on occasion, sudden fatalities. Due to its rarity and diffuse symptoms, the misdiagnosis of ICL is common and as a result, the condition may be under-reported. The present study reported two cases of IVL resected at the General Hospital of Shenyang Military Command. A hysteromyomectomy for uterine fibroids was performed on each patient (Case 1, 41 years ago; Case 2, 3 years ago). One patient presented with chest pain following a period of activity and the other presented with heart neoplasm during a routine health examination.
PMCID: PMC5103883  PMID: 27900095
intravenous leiomyomatosis; right atrium extension; computed tomography
12.  Post-transplant lymphoproliferative disorder presenting with skin ulceration in a renal transplant recipient who achieved sustained remission with rituximab therapy: A case report 
Molecular and Clinical Oncology  2016;5(5):610-612.
Post-transplant lymphoproliferative disorder (PTLD) is associated with a variety of clinical presentations, but rarely involves the skin. We herein report a case of PTLD presenting with skin ulceration in a renal transplant recipient. A biopsy of the ulcer confirmed the diagnosis of diffuse large B-cell lymphoma. The patient was initially treated with immunosuppression reduction, but the skin ulcer persisted. He was then treated with two courses of chemotherapy, but his condition was complicated with cryptococcal infection. Antifungal agents were administered to control the fungal infection. The patient later developed lymphoma recurrence and was successfully treated with single-agent rituximab. The patient remains well 6 years after treatment, with no evidence of disease relapse. Therefore, PTLD may manifest as skin lesions and physicians must be aware of this rare presentation.
PMCID: PMC5103884  PMID: 27900097
post-transplant lymphoproliferative disorder; skin lesion; rituximab
13.  Huge retroperitoneal liposarcoma with renal involvement requires nephrectomy: A case report and literature review 
Molecular and Clinical Oncology  2016;5(5):607-609.
A 60-year-old female visited Guihang Guiyang Hospital (Guiyang, China). She presented with abdominal pain in the right side for the previous 2-months, with a touchable mass identified for the previous 1-month. Computed tomography with magnetic resonance imaging revealed a huge mass in the right abdomen. The diagnosis of well-differentiated retroperitoneal liposarcoma with renal involvement was made. During surgery, the tumor was removed, including the fatty renal capsule; however, the kidney was preserved. It is currently debatable whether resection of adjacent organs is required to obtain the negative margins. Conventional viewpoints advise that multi-organ resection is required in order to obtain the negative-margin. However, even if an R0 resection is achieved, the local recurrence rate remains markedly high. Additionally, the complications of organ resection have more impact on patients. Radiotherapy and chemotherapy are an important adjuvant method for these patients. In conclusion, retroperitoneal liposarcoma is a rare disease with a high rate of recurrence. Complete resection is the predominant treatment; however, combined resection of adjacent organs must be considered.
PMCID: PMC5103881  PMID: 27900096
retroperitoneal liposarcoma; nephrectomy; case report; renal involvement
14.  The legacy of the F344 rat as a cancer bioassay model (a retrospective summary of three common F344 rat neoplasms) 
Critical Reviews in Toxicology  2016;46(8):641-675.
The Fischer 344 (F344) rat was used by the National Toxicology Program (NTP) for over 5 decades for toxicity and carcinogenicity studies. However, in 2006, the NTP decided to switch to a different rat stock due largely to high background control incidences of Leydig cell tumors (LCTs) and mononuclear cell leukemia (MNCL), also known as large granular lymphocytic (LGL) leukemia. In the current review, we aim (1) to provide a summary of NTP bioassays with treatment-associated effects involving MNCL and LCTs in addition to male F344-specific tunica vaginalis mesothelioma (TVM); (2) to describe important pathobiological differences between these F344 rat tumor responses and similar target tissue-tumor response in humans; and (3) to present the NTP reasons for switching away from the F344 rat. We show that due to the highly variable background incidence of F344 MNCL, more reliance on historical control data than is usual for most tumor responses is warranted to evaluate potential effect of any chemical treatment in this rat strain. The high spontaneous incidence of LCTs in the testes of male F344 rats has made this tumor endpoint of little practical use in identifying potential testicular carcinogenic responses. TVM responses in F344 rats have a biological plausible relationship to LCTs unlike TVM in humans. Given their high spontaneous background incidence and species-specific biology, we contend that MNCL and LCT, along with TVM responses, in F344 rat carcinogenicity studies are inappropriate tumor types for human health risk assessment and lack relevance in predicting human carcinogenicity.
PMCID: PMC5020328  PMID: 27278595
Cancer bioassay; carcinogenesis bioassay; Leydig cell tumor; LGL leukemia; mononuclear cell leukemia; National Toxicology Program; staging leukemia; tunica vaginalis mesothelioma
15.  Substance Use among a Sample of Healthcare Workers in Kenya: A Cross-Sectional Study 
Journal of Psychoactive Drugs  2016;48(4):310-319.
This study describes reported substance use among Kenyan healthcare workers (HCWs), as it has implications for HCWs’ health, productivity, and their ability and likelihood to intervene on substance use. The Alcohol Smoking and Substance Involvement Screening Test (ASSIST) was administered to a convenience sample of HCWs (n = 206) in 15 health facilities. Reported lifetime use was 35.8% for alcohol, 23.5% for tobacco, 9.3% for cannabis, 9.3% for sedatives, 8.8% for cocaine, 6.4% for amphetamine-like stimulants, 5.4% for hallucinogens, 3.4% for inhalants, and 3.9% for opioids. Tobacco and alcohol were also the two most commonly used substances in the previous three months. Male gender and other substance use were key predictors of both lifetime and previous three months’ use rates. HCWs’ substance use rates appear generally higher than those seen in the general population in Kenya, though lower than those reported among many HCWs globally. This pattern of use has implications for both HCWs and their clients.
PMCID: PMC5020342  PMID: 27485987
Alcohol; cannabis; health worker; prevalence; substance use; tobacco
16.  Primary gastrointestinal stromal tumour of the ileum pre-operatively diagnosed as an abdominal abscess 
Molecular and Clinical Oncology  2016;5(5):596-598.
The present case report described the acute presentation, diagnosis and management of a primary gastrointestinal stromal tumour (GIST) of the ileum. A male patient (age, 51 years) was admitted to Maggiore Hospital (Parma, Italy) due to presenting with fever, dysuria and lower abdominal pain. Ultrasonography and computed tomography showed a 7,5×5,5-cm pelvic mass containing air and purulent fluid indicative of an intraperitoneal abscess. The patient was subjected to diagnostic laparoscopy, which revealed a huge, soft cystic mass arising from the small bowel. The procedure was then converted to an open exploration through a midline incision. Ileal resection including a Meckel's diverticulum was performed. Macroscopic examination revealed that the cystic mass was filled with a large amount of pus, probably due to communication between the tumour mass and the small bowel lumen. In fact, the surgical specimen showed enteric leakage from the ileal mucosal ulcer into the tumour mass. Histopathology and immunohistochemistry of the abscess wall identified a spindle-cell mesenchymal-type, c-KIT-positive neoplasm. The post-operative course was uneventful and adjuvant imatinib mesylate was administered for 1 year. Follow-up by computed tomography demonstrated no tumour recurrence at 72 months after surgery.
PMCID: PMC5103879  PMID: 27900093
abdominal abscess; gastrointestinal stromal tumour; acute abdomen
17.  Primary orbital precursor T-cell lymphoblastic lymphoma: Report of a unique case 
Molecular and Clinical Oncology  2016;5(5):593-595.
Primary T-cell lymphoblastic lymphoma (T-LBL) in the eye region is very rare. The present study described a unique case of T-LBL involving the extraocular muscles. A 22-year-old male patient presented with a 3-week history of headache, reduced visual acuity and edema of the left eye. Clinical examination revealed left-sided exophthalmus, periorbital edema, chemosis, and reduced motility of the left eye. A magnetic resonance imaging scan revealed thickening of the left orbital muscles and a positron emission tomography-computed tomography scan also demonstrated activity in a subclavicular lymph node. Histopathological analysis of both lesions revealed infiltration by medium-sized neoplastic lymphoid cells with a high nuclear-cytoplasmic ratio and a high mitotic index. Immunostaining revealed positivity for CD2, CD3, CD99, Tia-1, and GranzymB, and variable positivity for CD4. There was no involvement of the bone marrow. Based on the clinical and histopathological findings, a diagnosis of T-LBL was made. There was no evidence of NOTCH1 mutation or rearrangements of the ETV6 and MLL genes and high-resolution array-based comparative genomic hybridization (arrayCGH) analysis revealed a normal genomic profile. The patient received chemotherapy according to the high-risk NOPHO protocol, followed by myeloablative allogenic bone marrow transplantation. At 35 months after diagnosis, the patient remained in complete first remission, but without light perception on his left eye. To the best of our knowledge, this is the first report of a case of T-LBL involving the extraocular muscles. Although primary T-LBL in the eye region is very rare, our findings demonstrate that lymphoma should be considered in the differential diagnosis of patients with similar symptoms.
PMCID: PMC5103880  PMID: 27900092
T-cell lymphoblastic lymphoma; orbital manifestation; array-based comparative genomic hybridization analysis
18.  Testing the Feasibility of a Passive and Active Case Ascertainment System for Multiple Rare Conditions Simultaneously: The Experience in Three US States 
Owing to their low prevalence, single rare conditions are difficult to monitor through current state passive and active case ascertainment systems. However, such monitoring is important because, as a group, rare conditions have great impact on the health of affected individuals and the well-being of their caregivers. A viable approach could be to conduct passive and active case ascertainment of several rare conditions simultaneously. This is a report about the feasibility of such an approach.
To test the feasibility of a case ascertainment system with passive and active components aimed at monitoring 3 rare conditions simultaneously in 3 states of the United States (Colorado, Kansas, and South Carolina). The 3 conditions are spina bifida, muscular dystrophy, and fragile X syndrome.
Teams from each state evaluated the possibility of using current or modified versions of their local passive and active case ascertainment systems and datasets to monitor the 3 conditions. Together, these teams established the case definitions and selected the variables and the abstraction tools for the active case ascertainment approach. After testing the ability of their local passive and active case ascertainment system to capture all 3 conditions, the next steps were to report the number of cases detected actively and passively for each condition, to list the local barriers against the combined passive and active case ascertainment system, and to describe the experiences in trying to overcome these barriers.
During the test period, the team from South Carolina was able to collect data on all 3 conditions simultaneously for all ages. The Colorado team was also able to collect data on all 3 conditions but, because of age restrictions in its passive and active case ascertainment system, it was able to report few cases of fragile X syndrome. The team from Kansas was able to collect data only on spina bifida. For all states, the implementation of an active component of the ascertainment system was problematic. The passive component appears viable with minor modifications.
Despite evident barriers, the joint passive and active case ascertainment of rare disorders using modified existing surveillance systems and datasets seems feasible, especially for systems that rely on passive case ascertainment.
PMCID: PMC5020310  PMID: 27574026
spina bifida; muscular dystrophy; fragile X syndrome; surveillance
19.  Japanese Consumer Perceptions of Genetically Modified Food: Findings From an International Comparative Study 
Reports of food-related incidents, such as cows infected with bovine spongiform encephalopathy (2001) and the Fukushima nuclear accident (2011), engendered significant fear among Japanese consumers and led to multiple farmer suicides, even when no actual health damage occurred. The growing availability of genetically modified (GM) food is occurring against this backdrop of concern about food safety. Consumers need information to assess risk and make informed purchasing decisions. However, we lack a clear picture of Japanese consumer perceptions of GM food.
This study aims to understand Japanese consumer perceptions of GM food for risk communication. Consumer perceptions of GM food were compared among 4 nations.
A Web-based survey was conducted in Japan, the United States, the United Kingdom, and France. Participants were asked about demographics, fear of health hazards, resistance to GM and breeding-improved products, perception of GM technology and products, and willingness to pay. Multiple linear regression analyses were conducted, as were t tests on dichotomous variables, and 1-way analysis of variance and post hoc tests.
Of 1812 individuals who agreed to participate, 1705 (94%) responded: 457 from Japan and 416 each from France, the United States, and the United Kingdom. The male/female and age group ratios were all about even. Some resistance to GM food was seen in all countries in this study. France showed the strongest resistance (P<.001), followed by Japan, which had stronger resistance than the United States and the United Kingdom (P<.001). Overall, females, people in their 60s and older, and those without higher education showed the greatest resistance to GM food. Japan showed stronger fear of food hazards than other nations (P<.001, odds ratio=2.408, CI: 1.614-3.594); Japanese and French respondents showed the strongest fear of hazards from GM food (P<.001). Regarding perceptions of GM technology and products, consumers in nations other than Japan would accept GM food if it were appropriately explained, they were provided with scientific data supporting its safety, and they understood that all food carries some risk. However, Japanese consumers tended to accept GM technology but rejected its application to food (P<.001). Of those willing to purchase GM food, consumers in Japan required a discount of 30% compared with about 20% in other nations.
All consumers in our study showed resistance to GM food. Although no health hazards are known, respondents in Japan and France strongly recognized GM food as a health risk. Price discounts of 30% and GM technology may be communication cues to start discussions about GM food among Japanese consumers. Although education-only risk communication generally is not effective, such an approach may work in Japan to help consumers better understand GM technology and, eventually, GM food. The gap between accepting GM technology and rejecting its application to food should be explored further.
PMCID: PMC5020312  PMID: 27573588
genetically modified food; Japan; perception; health; risk
20.  The Top Chinese Mobile Health Apps: A Systematic Investigation 
China’s mHealth market is on track to become a global leader by industry size. The Chinese mobile app market and health care system have peculiarities that distinguish them from other app markets. To date, Chinese mHealth apps have not been systematically investigated.
The objective of this study was to provide an overview of Chinese mHealth apps as of December 2015.
We identified and investigated the most downloaded apps from the iOS and Android platforms. For each app, we analyzed and recorded its main service offered, mHealth initiative, disease and specialty focus, app cost, target user, Web app availability, and emphasis on information security. Standard descriptive statistics were used.
A total of 234 apps met the inclusion criteria and were investigated. The apps targeting nonhealth care professionals focused on providing telemedicine and appointment-making services. The apps targeting health care professionals focused on education and peer reviewed articles. The most common disease-specific apps focused primarily on diabetes, hypertension, and hepatitis management. Most apps were free and available on both iOS and Android platforms.
The primary mHealth initiatives targeted by the apps reflect Chinese patients’ demand for access to medical care. Disease-specific apps are also representative of disease prevalence in China. Government press releases suggest that new policies on the horizon may shift the industry.
PMCID: PMC5020314  PMID: 27573724
mobile health applications; mHealth; medical informatics; China
21.  Characterizing Twitter Discussions About HPV Vaccines Using Topic Modeling and Community Detection 
In public health surveillance, measuring how information enters and spreads through online communities may help us understand geographical variation in decision making associated with poor health outcomes.
Our aim was to evaluate the use of community structure and topic modeling methods as a process for characterizing the clustering of opinions about human papillomavirus (HPV) vaccines on Twitter.
The study examined Twitter posts (tweets) collected between October 2013 and October 2015 about HPV vaccines. We tested Latent Dirichlet Allocation and Dirichlet Multinomial Mixture (DMM) models for inferring topics associated with tweets, and community agglomeration (Louvain) and the encoding of random walks (Infomap) methods to detect community structure of the users from their social connections. We examined the alignment between community structure and topics using several common clustering alignment measures and introduced a statistical measure of alignment based on the concentration of specific topics within a small number of communities. Visualizations of the topics and the alignment between topics and communities are presented to support the interpretation of the results in context of public health communication and identification of communities at risk of rejecting the safety and efficacy of HPV vaccines.
We analyzed 285,417 Twitter posts (tweets) about HPV vaccines from 101,519 users connected by 4,387,524 social connections. Examining the alignment between the community structure and the topics of tweets, the results indicated that the Louvain community detection algorithm together with DMM produced consistently higher alignment values and that alignments were generally higher when the number of topics was lower. After applying the Louvain method and DMM with 30 topics and grouping semantically similar topics in a hierarchy, we characterized 163,148 (57.16%) tweets as evidence and advocacy, and 6244 (2.19%) tweets describing personal experiences. Among the 4548 users who posted experiential tweets, 3449 users (75.84%) were found in communities where the majority of tweets were about evidence and advocacy.
The use of community detection in concert with topic modeling appears to be a useful way to characterize Twitter communities for the purpose of opinion surveillance in public health applications. Our approach may help identify online communities at risk of being influenced by negative opinions about public health interventions such as HPV vaccines.
PMCID: PMC5020315  PMID: 27573910
topic modelling; graph algorithms analysis; social media; public health surveillance
22.  Aulonastus similis n. sp., a new quill mite species (Syringophilidae) parasitising passeriform birds (Tyrannidae and Cardinalidae) in Mexico 
Systematic Parasitology  2016;93:715-719.
A new quill mite species, Aulonastus similis n. sp. (Acariformes: Syringophilidae), parasitising Myiozetetes similis (Spix) (Tyrannidae) and Habia fuscicauda (Cabanis) (Cardinalidae) in Mexico is described and DNA barcode sequences of the mitochondrial cytochrome c oxidase subunit I (cox1) and D1–D3 region of the nuclear 28S rRNA gene are provided. Morphologically, females of A. similis are close to A. euphagus Skoracki, Hendricks & Spicer, 2010 but differ from this species in the length ratios of the idiosomal setae: ve:si (2–2.3:1 vs 1:1) and f2:f1 (4.7–6.3:1 vs 3.3:1).
PMCID: PMC4983287  PMID: 27522369
23.  NOX2 Inhibition Impairs Early Muscle Gene Expression Induced by a Single Exercise Bout 
Reactive oxygen species (ROS) participate as signaling molecules in response to exercise in skeletal muscle. However, the source of ROS and the molecular mechanisms involved in these phenomena are still not completely understood. The aim of this work was to study the role of skeletal muscle NADPH oxidase isoform 2 (NOX2) in the molecular response to physical exercise in skeletal muscle. BALB/c mice, pre-treated with a NOX2 inhibitor, apocynin, (3 mg/kg) or vehicle for 3 days, were swim-exercised for 60 min. Phospho–p47phox levels were significantly upregulated by exercise in flexor digitorum brevis (FDB). Moreover, exercise significantly increased NOX2 complex assembly (p47phox–gp91phox interaction) demonstrated by both proximity ligation assay and co-immunoprecipitation. Exercise-induced NOX2 activation was completely inhibited by apocynin treatment. As expected, exercise increased the mRNA levels of manganese superoxide dismutase (MnSOD), glutathione peroxidase (GPx), citrate synthase (CS), mitochondrial transcription factor A (tfam) and interleukin-6 (IL-I6) in FDB muscles. Moreover, the apocynin treatment was associated to a reduced activation of p38 MAP kinase, ERK 1/2, and NF-κB signaling pathways after a single bout of exercise. Additionally, the increase in plasma IL-6 elicited by exercise was decreased in apocynin-treated mice compared with the exercised vehicle-group (p < 0.001). These results were corroborated using gp91-dstat in an in vitro exercise model. In conclusion, NOX2 inhibition by both apocynin and gp91dstat, alters the intracellular signaling to exercise and electrical stimuli in skeletal muscle, suggesting that NOX2 plays a critical role in molecular response to an acute exercise.
PMCID: PMC4944119  PMID: 27471471
redox signaling; antioxidant defense; reactive oxygen species; IL-6; NADPH oxidase; muscle adaptation
24.  Evolving the l-lysine high-producing strain of Escherichia coli using a newly developed high-throughput screening method 
This study provided a new method which applied a selected l-lysine-inducible promoter for evolving lysine industrial strains of E. coli. According to the intracellular levels of the enhanced green fluorescent protein (EGFP) whose expression was controlled by the promoter, 186 strains were preliminarily selected using fluorescence-activated cell sorting from a 10-million-mutant library generated from a l-lysine high-producing E. coli strain. By subsequent multiple parameter evaluation of the 186 selected strains according to the concentration and the yield of lysine, the productivity per unit of cell in 96-deep-well blocks, two mutants MU-1 and MU-2 were obtained. They produced 136.51 ± 1.55 and 133.2 9 ± 1.42 g/L of lysine, respectively, in 5-L jars. Compared with the lysine concentration and the yield of the original strain, those of strain MU-1 improved by 21.00 and 9.05 %, respectively, and those of strain MU-2 improved by 18.14 and 10.41 %, respectively. The mutant selection and evaluation system newly established in our study should be useful for continuous improvement of the current E. coli strains in the lysine industry.
PMCID: PMC4983297  PMID: 27369765
Lysine production; Escherichia coli; Lysine biosensor; High-throughput screening; Strain evolution
25.  Disease activity, quality of life and indirect costs of psoriatic arthritis in Poland 
Rheumatology International  2016;36:1223-1230.
The aim of the study was to assess the indirect costs, health-related quality of life and clinical characteristics of patients with psoriatic arthritis (PsA), measured using a PsA disease activity index in Poland. Additionally, we aimed to investigate the association between the activity, utility of PsA-affected patients and productivity loss in a Polish setting. A questionnaire survey was conducted to assess disease activity, as well as productivity loss, and a paper version of the EuroQoly-5D-3L questionnaire was used to assess productivity loss and the quality of life. Indirect costs were assessed with the human capital approach employing the gross domestic product (GDP) per capita, gross value added (GVA) and gross income (GI) per worker in 2014 in Poland and were expressed in Polish zlotys (PLN) as well as in euros. The correlation was presented using the Spearman correlation coefficient. Our analysis was performed on the basis of 50 full questionnaires collected. We observed a mean utility value of 0.6567. The mean number of days off work was 2.88 days per month, and mean on-the-job productivity loss was 24.1 %. Average monthly indirect costs per patient were €206.7 (864.01 PLN) calculated using the GDP; €484.56 (2025.46 PLN) calculated using the GVA; and €209.70 (876.56 PLN) calculated using the GI. PsA reduces the patients’ quality of life as well as their productivity loss associated with both absenteeism and presenteeism. Total indirect costs were negatively correlated with utility. The greater the disease activity, the lower the utility and the greater the indirect costs.
PMCID: PMC4983289  PMID: 27339273
Quality of life; Indirect costs; Productivity loss; Psoriatic arthritis

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