bluuebunny/crossref_metadata_2025 huggingface dataset:
Contribution of Gag and Protease to HIV-1 Phenotypic Drug Resistance in Pediatric Patients Failing Protease Inhibitor-Based Therapy
Authors: Giandhari Jennifer , Basson Adriaan E. , Sutherland Katherine , Parry Chris M. , Cane Patricia A. , Coovadia Ashraf , Kuhn Louise , Hunt Gillian , Morris Lynn
Published: February 2016

Protease inhibitors (PIs) are used as a first-line regimen in HIV-1-infected children. Here we investigated the phenotypic consequences of amino acid changes in Gag and protease on lopinavir (LPV) and ritonavir (RTV) susceptibility among pediatric patients failing PI therapy. The Gag-protease from isolates from 20 HIV-1 subtype C-infected pediatric patients failing an LPV and/or RTV-based regimen was phenotyped using a nonreplicativein vitroassay. Changes in sensitivity to LPV and RTV relative to that of the matched baseline (pretherapy) sample were calculated. Gag and protease amino acid substitutions associated with PI failure were created in a reference clone by site-directed mutagenesis and assessed. Predicted phenotypes were determined using the Stanford drug resistance algorithm. Phenotypic resistance or reduced susceptibility to RTV and/or LPV was observed in isolates from 10 (50%) patients, all of whom had been treated with RTV. In most cases, this was associated with protease resistance mutations, but substitutions at Gag cleavage and noncleavage sites were also detected. Gag amino acid substitutions were also found in isolates from three patients with reduced drug susceptibilities who had wild-type protease. Site-directed mutagenesis confirmed that some amino acid changes in Gag contributed to PI resistance but only in the presence of major protease resistance-associated substitutions. The isolates from all patients who received LPV exclusively were phenotypically susceptible. Baseline isolates from the 20 patients showed a large (47-fold) range in the 50% effective concentration of LPV, which accounted for most of the discordance seen between the experimentally determined and the predicted phenotypes. Overall, the inclusion of thegaggene and the use of matched baseline samples provided a more comprehensive assessment of the effect of PI-induced amino acid changes on PI resistance. The lack of phenotypic resistance to LPV supports the continued use of this drug in pediatric patients.
Comparison of RELMα and RELMβ Single- and Double-Gene-Deficient Mice Reveals that RELMα Expression Dictates Inflammation and Worm Expulsion in Hookworm Infection
Authors: Chen Gang , Wang Spencer H. , Jang Jessica C. , Odegaard Justin I. , Nair Meera G.
Published: February 2016

Resistin-like molecules (RELMs) are highly expressed following helminth infection, where they impact both the host and helminth. While RELMα (
Retnla
) impairs helminth expulsion by inhibiting protective Th2 immunity, RELMβ (
Retnlb
) can promote its expulsion. We employed
Retnla
−/−
and
Retnlb
−/−
mice to delineate the function of both proteins following infection with
Nippostrongylus brasiliensis
, a hookworm that infects the lung and intestine. Whereas wild-type (WT) and
Retnlb
−/−
mice exhibited equivalent infection-induced inflammation,
Retnla
−/−
mice suffered a heightened inflammatory response, including increased mortality, weight loss, and lung inflammation. In the intestine,
Retnla
−/−
mice had low parasite egg burdens compared to those of WT mice, while
Retnlb
−/−
mice exhibited high egg burdens, suggesting that RELMα and RELMβ have functionally distinct effects on immunity and inflammation to
N. brasiliensis
. To test the importance of both proteins, we generated
Retnla
−/−
Retnlb
−/−
mice. Infected
Retnla
−/−
Retnlb
−/−
mice exhibited similar responses to
Retnla
−/−
mice, including increased mortality and lung inflammation. This inflammatory response in
Retnla
−/−
Retnlb
−/−
mice negatively impacted
N. brasiliensis
fitness, as demonstrated by significantly lower worm ATP levels and decreased intestinal worm burden and fecundity. Lung cytokine analysis revealed that
Retnla
−/−
and
Retnla
−/−
Retnlb
−/−
mice expressed significantly increased levels of interleukin-4 (IL-4). Finally, we generated
Retnla
−/−
mice on the
Rag
−/−
background and observed that the effects of RELMα were abrogated in the absence of adaptive immunity. Together, these data demonstrate that RELMα but not RELMβ significantly impacts the immune response to
N. brasiliensis
infection by downregulating the Th2 adaptive immune response in the lung, which protects the host but allows improved parasite fitness.
Patient with giant upper limb melanoma presenting to a UK plastic surgery unit: differentials and experience of management
Authors: Honeyman Calum Sinclair , Wilson Paul
Published: February 2016

A 57-year-old woman was referred to our regional sarcoma unit following a 2-year history of a progressively enlarging mass on her right forearm. At 14×7×12 cm, this mass turned out to be one of the largest upper limb cutaneous malignant melanomas ever described, and, to the best of our knowledge, the first documented in the UK. Remarkably, despite having a T4 malignant tumour with a Breslow thickness of 70 mm, this patient is still alive over 4 years later with no locoregional or distant metastatic spread. We present our experience in the management of this giant malignant melanoma of the upper limb and consider important differentials.
Does abortion increase women's risk for post-traumatic stress? Findings from a prospective longitudinal cohort study
Authors: Biggs M Antonia , Rowland Brenly , McCulloch Charles E , Foster Diana G
Published: February 2016

Objective

To prospectively assess women's risk for post-traumatic stress disorder (PTSD) and of experiencing post-traumatic stress symptoms (PTSS) over 4 years after seeking an abortion, and to assess whether symptoms are attributed to the pregnancy, abortion or birth, or other events in women's lives.

Design

Prospective longitudinal cohort study which followed women from approximately 1 week after receiving or being denied an abortion (baseline), then every 6 months for 4 years (9 interview waves).

Setting

30 abortion facilities located throughout the USA.

Participants

Among 956 women presenting for abortion care, some of whom received an abortion and some of whom were denied due to advanced gestational age; 863 women are included in the longitudinal analyses.

Main outcome measures

PTSS and PTSD risk were measured using the Primary Care PTSD Screen (PC-PTSD). Index pregnancy-related PTSS was measured by coding the event(s) described by women as the cause of their symptoms.

Analyses

We used unadjusted and adjusted logistic mixed-effects regression analyses to assess whether PTSS, PTSD risk and pregnancy-related PTSS trajectories of women obtaining abortions differed from those who were denied one.

Results

At baseline, 39% of participants reported any PTSS and 16% reported three or more symptoms. Among women with symptoms 1-week post-abortion seeking (n=338), 30% said their symptoms were due to experiences of sexual, physical or emotional abuse or violence; 20% attributed their symptoms to non-violent relationship issues; and 19% said they were due to the index pregnancy. Baseline levels of PTSS, PTSD risk and pregnancy-related PTSS outcomes did not differ significantly between women who received and women who were denied an abortion. PTSS, PTSD risk and pregnancy-related PTSS declined over time for all study groups.

Conclusions

Women who received an abortion were at no higher risk of PTSD than women denied an abortion.
Systemic lupus erythematosus and primary fibromyalgia can be distinguished by testing for cell-bound complement activation products
Authors: Wallace Daniel J , Silverman Stuart L , Conklin John , Barken Derren , Dervieux Thierry
Published: February 2016

Objective

We sought to establish the performance of cell-bound complement activation products (CB-CAPs) as a diagnostic tool to distinguish primary fibromyalgia (FM) from systemic lupus erythematosus (SLE).

Methods

A total of 75 SLE and 75 primary FM adult subjects who fulfilled appropriate classification criteria were enrolled prospectively. CB-CAPs (erythrocyte-C4d (EC4d) and B-lymphocyte-C4d (BC4d)) were determined by flow cytometry. Antinuclear antibodies (ANAs) were determined using indirect immunofluorescence while other autoantibodies were determined by solid-phase assays. The CB-CAPs in a multi-analyte assay with algorithm (MAAA) relied on two consecutive tiers of analysis that was reported as an overall positive or negative assessment. Test performance was assessed using sensitivity, specificity, positive and negative likelihood ratio (LR).

Results

ANAs yielded 80% positives for SLE and 33% positives for FM. High CB-CAP expression (EC4d >14 units or BC4d >60 units) was 43% sensitive and 96% specific for SLE. The CB-CAPs in MAAA assessment was evaluable in 138 of the 150 subjects enrolled (92%) and yielded 60% sensitivity (CI 95% 48% to 72%) for SLE with no FM patient testing positive (100% specificity). A positive test result was associated with a strong positive LR for SLE (>24, CI 95%; 6 to 102), while a negative test result was associated with a moderate negative LR (0.40; CI 95% 0.30 to 0.54).

Conclusion

Our data indicate that CB-CAPs in MAAA can distinguish FM from SLE.
Insight into octoploid strawberry (Fragaria) subgenome composition revealed by GISH analysis of pentaploid hybrids
Authors: Liu Bo , Poulsen Elizabeth G. , Davis Thomas M.
Published: February 2016

As the product of interspecific hybridization between its two ancestral octoploid (2n = 8x = 56) species (Fragaria chiloensis and F. virginiana), the cultivated strawberry (F. ×ananassa) is among the most genomically complex of crop plants, harboring subgenomic components derived from as many as four different diploid ancestors. To physically visualize the octoploids’ subgenome composition(s), we launched molecular cytogenetic studies using genomic in situ hybridization (GISH), comparative GISH (cGISH), and rDNA-FISH techniques. First, GISH resolution in Fragaria was tested by using diploid and triploid hybrids with predetermined genome compositions. Then, observation of an octoploid genome was implemented by hybridizing chromosomes of pentaploid (2n = 5x = 35) hybrids from F. vesca × F. virginiana with genomic DNA probes derived from diploids (2n = 2x = 14) F. vesca and F. iinumae, which have been proposed by phylogenetic studies to be closely related to the octoploids yet highly divergent from each other. GISH and cGISH results indicated that octoploid-derived gametes (n = 4x = 28) carried seven chromosomes with hybridization affinities to F. vesca, while the remaining 21 chromosomes displayed varying affinities to F. iinumae, indicating differing degrees of subgenomic contribution to the octoploids by these two putatively ancestral diploids. Combined rDNA-FISH revealed severe 25S rDNA loss in both the F. vesca- and F. iinumae-like chromosome groups, while only the prior group retained its 5S loci.
Network Cost-Sharing without Anonymity
Authors: Roughgarden Tim , Schrijvers Okke
Published: February 2016

We consider network cost-sharing games with nonanonymous cost functions, where the cost of each edge is a submodular function of its users, and this cost is shared using the Shapley value. Nonanonymous cost functions model asymmetries between the players, which can arise from different bandwidth requirements, durations of use, services needed, and so on.

These games can possess multiple Nash equilibria of wildly varying quality. The goal of this article is to identify well-motivated equilibrium refinements that admit good worst-case approximation bounds. Our primary results are tight bounds on the cost of strong Nash equilibria and potential function minimizers in network cost-sharing games with nonanonymous cost functions, parameterized by the set
C
of allowable submodular cost functions.

These two worst-case bounds coincide for every set
C
, and equal the
summability
parameter introduced in Roughgarden and Sundararajan [2009] to characterize efficiency loss in a family of cost-sharing mechanisms. Thus, a single parameter simultaneously governs the worst-case inefficiency of network cost-sharing games (in two incomparable senses) and cost-sharing mechanisms. This parameter is always at most the
k
th Harmonic number

H

k

≈ ln
k
, where
k
is the number of players, and is constant for many function classes of interest.
Perceiving and acting upon weight illusions in the absence of somatosensory information
Authors: Buckingham Gavin , Michelakakis Elizabeth Evgenia , Cole Jonathan
Published: February 2016

When lifting novel objects, individuals' fingertip forces are influenced by a variety of cues such as volume and apparent material. This means that heavy-looking objects tend to be lifted with more force than lighter-looking objects, even when they weigh the same amount as one another. Expectations about object weight based on visual appearance also influence how heavy an object feels when it is lifted. For instance, in the “size-weight illusion,” small objects feel heavier than equally weighted large objects. Similarly, in the “material-weight illusion,” objects that seem to be made from light-looking materials feel heavier than objects of the same weight that appear to be made from heavy-looking materials. In this study, we investigated these perceptual and sensorimotor effects in IW, an individual with peripheral deafferentation (i.e., a loss of tactile and proprioception feedback). We examined his perceptions of heaviness and fingertip force application over repeated lifts of objects that varied in size or material properties. Despite being able to report real weight differences, IW did not appear to experience the size- or material-weight illusions. Furthermore, he showed no evidence of sensorimotor prediction based on size and material cues. The results are discussed in the context of forward models and their possible influence on weight perception and fingertip force control.
Clinical Effect and Mechanism of Yisui Shengxue Granules in Thalassemia Patients with Mild, Moderate, or Severe Anemia
Authors: Cheng Yan-Ling , Zhang Xin-Hua , Sun Yu-Wen , Wang Wen-Juan , Fang Su-Ping , Wu Zhi-Kui
Published: February 2016

Yisui Shengxue granules, which is a Chinese traditional medicine, can increase hemoglobin, red blood cells, and Ret of thalassemia patients with mild, moderate, and severe anemia and thus relieve clinical anemia symptoms. Studies on mechanism found that Yisui Shengxue granules can increase the proliferation ability of hematopoietic stem cells. Emodin promoted colony forming of hematopoietic stem cells. Yisui Shengxue granules can increase the activity of GSH‐PX in bone marrow blood and decreased the severity of inclusion bodies on the cytomembrane of RBCs. YSSXG attenuated anemia symptoms in patients with thalassemia mostly by increasing the proliferation of hematopoietic stem cells and decreasing the hemolysis of RBCs.
Incidental Papillary Thyroid Microcarcinoma in an Endemic Goiter Area
Authors: Gürleyik Emin , Gurleyik Gunay , Karapolat Banu , Onsal Ufuk
Published: February 2016

Clinical and pathological characteristics of incidental papillary thyroid microcancer cases, surgical, medical, and nuclear treatment methods, and patients’ outcome were studied during follow-up period of 102 months. We studied 37 patients with incidental papillary thyroid microcancer (I-PTM). The surgical procedure was total thyroidectomy in 29 and hemithyroidectomy in 8 patients. Size, multifocality, and bilateralism of PTM foci, thyroid capsule invasion, and presence of lymphovascular invasion were histopathological parameters. We analysed adjuvant medical and nuclear treatment and patients’ outcome during follow-up period of 102 (61–144) months. The prevalence rates of I-PTM were 9.4% in 395 thyroidectomy cases. Histopathological examination reported unifocal disease in 30 and multifocal disease in 7 (18%) patients. Multifocal disease was bilateral in 6 (20.1%) patients. The mean size of the PTM foci was 4.88 mm. The rate of thyroid capsule invasion was 5.4%. All patients received a suppressive dose of LT4 to achieve a low serum TSH level. Adjuvant surgical and nuclear treatment was not performed in our cases. We did not find any negative changes in blood chemistry and ultrasound imaging, and any unfavourable events as locoregional and systemic recurrence. In conclusion, diagnosis of I-PTM is common that multifocality and bilateralism appear as pathologic features. The prognosis is excellent after surgical treatment and TSH suppression. Routine adjuvant nuclear treatment is unnecessary in majority of patients.
Dosage Parameters in Pediatric Outcome Studies Reported in 9 Peer-Reviewed Occupational Therapy Journals from 2008 to 2014: A Content Analysis
Authors: Gee Bryan M. , Lloyd Kimberly , Devine Nancy , Tyrrell Erin , Evans Trisha , Hill Rebekah , Dineen Stacee , Magalogo Kristin
Published: February 2016

Occupational therapists determine the dosage when establishing the plan of care for their pediatric clients. A content analysis was conducted using 123 pediatric occupational therapy outcomes studies from 9 scholarly international occupational therapy journals. The parameters of dosage were calculated using descriptive statistics in order to obtain a representation of dosage available within the current collage of pediatric occupational therapy outcomes studies. The results revealed that most studies reported portions of dosage parameters within the published studies. The average findings for the subcomponents related to dosage were session length (minutes)M=58.7, duration of plan of care (weeks)M=12.1, session frequency (per week)M=3.4, and total hours of therapy (hours)M=18.1. This first attempt at describing and calculating dosage related to pediatric occupational therapy practice indicates that evidence is lacking within the published literature to adequately guide OT dosage decisions. Further research related to dosage in pediatric occupational therapy practice is needed.
A Liquid Metal Conical Helical Antenna for Circular Polarization-Reconfigurable Antenna
Authors: Zhou Yun , Fang Shaojun , Liu Hongmei , Fu Shiqiang
Published: February 2016

A novel polarization-reconfigurable conical helical antenna based on the liquid metal is presented. The antenna is implemented by using truncated structure, variable pitch angle, a matching stub, and a mechanical autorotation device. The experimental results show that a good agreement between simulations and measurements is obtained. The gain of the antenna achieves higher than 8 dBi in the work band (1525–1660.5 MHz), and the 3 dB axial ratio (AR) bandwidth reaches 410 MHz. The polarization mode of the antenna can be switched between right-hand and left-hand circular polarization.
Low-Profile Repeater Antenna with Parasitic Elements for On-On-Off WBAN Applications
Authors: Kang Do-Gu , Tak Jinpil , Choi Jaehoon
Published: February 2016

A low-profile repeater antenna with parasitic elements for on-on-off WBAN applications is proposed. The proposed antenna consists of a planar inverted-F antenna (PIFA), two parasitic elements, and a ground plane with a slot. Due to the slot, the impedance matching of the resonance formed by the PIFA is improved, which makes the proposed antenna operate in the 5.8 GHz industrial, scientific, and medical (ISM) band. To cover the 5.2 GHz wireless local area network (WLAN) band, a dual resonance characteristic is realized by the slot and the two parasitic elements. The first coupling between the PIFA and the slot not only makes the slot operate as a resonator, but also forms secondary coupling between the slot and the two parasitic elements. The two parasitic elements operate as an additional resonator due to secondary coupling. The antenna has the enhanced near surface radiation in the 5.8 GHz ISM band due to addition of the slot and radiation toward off-body direction in the 5.2 GHz WLAN band. In order to evaluate antenna performance considering the human body effect, the antenna characteristics on a human equivalent phantom are analyzed.
Mucous Membrane Pemphigoid with Tracheal Involvement
Authors: Minaie Arash , Surani Salim R.
Published: February 2016

34-year-old African American female with history of pemphigoid presented with hemoptysis. Patient was found to have mucous membrane pemphigoid involving the oropharynx and extending to trachea, till just above main stem carina. Four other cases described mucosal pemphigoid involving the trachea. We hereby present a brief review of current consensus on management of mucous membrane pemphigoid with airway involvement.
Efficacy of Continuous S(+)-Ketamine Infusion for Postoperative Pain Control: A Randomized Placebo-Controlled Trial
Authors: Miziara Luiz Eduardo de Paula Gomes , Simoni Ricardo Francisco , Esteves Luís Otávio , Cangiani Luis Henrique , Grillo-Filho Gil Fernando Ribeiro , Paula Anderson Garcia Lima e
Published: February 2016

Aim.A double-blind, randomized, placebo-controlled trial was designed to evaluate the efficacy of continuous intraoperative infusion of S(+)-ketamine under intravenous anesthesia with target-controlled infusion of remifentanil and propofol for postoperative pain control.Methods.Forty-eight patients undergoing laparoscopic cholecystectomy were assigned to receive continuous S(+)-ketamine infusion at a rate of 0.3 mg·kg−1·h−1(n=24, intervention group) or an equivalent volume of saline at the same rate (n=24, placebo group). The same target-controlled intravenous anesthesia was induced in both groups. Pain was assessed using a 0 to 10 verbal numeric rating scale during the first 12 postoperative hours. Pain scores and morphine consumption were recorded in the postanesthesia care unit (PACU) and at 4 and 12 hours after surgery.Results.Pain scores were lower in the intervention group at all time points. Morphine consumption did not differ significantly between groups during PACU stay, but it was significantly lower in the intervention group at each time point after PACU discharge (P=0.0061). At 12 hours after surgery, cumulative morphine consumption was also lower in the intervention group (5.200±2.707) than in the placebo group (7.525±1.872).Conclusions.Continuous S(+)-ketamine infusion during laparoscopic cholecystectomy under target-controlled intravenous anesthesia provided better postoperative pain control than placebo, reducing morphine requirement.Trial Registration. This trial is registered with ClinicalTrials.govNCT02421913.
Role of the Frontal Cortex in Standing Postural Sway Tasks While Dual-Tasking: A Functional Near-Infrared Spectroscopy Study Examining Working Memory Capacity
Authors: Fujita Hiroyuki , Kasubuchi Kenji , Wakata Satoshi , Hiyamizu Makoto , Morioka Shu
Published: February 2016

Posture control during a dual-task involves changing the distribution of attention resources between the cognitive and motor tasks and involves the frontal cortex working memory (WM). The present study aimed to better understand the impact of frontal lobe activity and WM capacity in postural control during a dual-task. High and low WM-span groups were compared using their reading span test scores. High and low WM capacity were compared based on cognitive and balance performance and hemoglobin oxygenation (oxyHb) levels during standing during single (S-S), standing during dual (S-D), one leg standing during single (O-S), and one leg standing during dual (O-D) tasks. For sway pass length, significant difference in only the O-D task was observed between both groups. oxyHb levels were markedly increased in the right dorsolateral prefrontal cortex and supplementary motor area in the high-span group during a dual-task. Therefore, WM capacity influenced the allocation of attentional resources and motor performance.
Behavioural Change according to the Si/Al Ratio of Successive Na-Mordenites Observed through Their Dielectric Relaxation during Water Vapour Adsorption Process
Authors: Diaby Sekou
Published: February 2016

The experimental study of water vapour adsorption phenomenon on a zeolite, by dielectric relaxation measurement, makes it possible to determine the variations in the exchangeable cation hopping activation energy, on the surface of the solid, in relation to the number of adsorbed molecules. The present work shows that it is possible to explain the change observed in the energy, by means of simple assumptions based, on the one hand, on the models used in order to simulate the adsorption process and, on the other hand, on the distribution of the molecules adsorbed near the exchangeable cations. Thus, the phenomenological interpretation suggested here, about the change in the exchangeable cation hopping energy, obtained by dielectric relaxation measurement, makes us with a mind to conceive a simple method for explaining the results leading to new information on the organization of the first adsorbed molecules on the surface of the studied zeolite. Then, it can be verified that these conclusions confirm the assumptions already developed for interpreting the inferences from previous experiments carried out by means of other techniques.
Spectrum-Aware Geographic Routing in Cognitive Vehicular Ad Hoc Network Using a Kalman Filter
Authors: Ghafoor Huma , Koo Insoo
Published: February 2016

We propose a position-based routing protocol for cognitive radio vehicular ad hoc networks (CR-VANETs) using aKalmanfilter algorithm. The protocol first selects an idle channel from among all the channels available to a vehicle while moving on a straight road and then finds the best relay node to deliver the packet to the destination. The selection of a relay node is done by dividing the vehicular transmission range into five regions, and then the source/relay node selects the one that is in the region having a higher preference than other regions. Communication between two vehicles occurs only when both the vehicles are on the same channel. Delay may increase while sensing the channel and selecting the relay node. To reduce the delay, we use aKalmanfilter to predict the future positions of all moving vehicles in the network. We consider vehicle-to-vehicle communication and compare our protocol for different probabilities of primary user being idle. Our proposed protocol shows improvement in both packet delivery ratio and end-to-end delay.
MCPIP1 Selectively Destabilizes Transcripts Associated with an Antiapoptotic Gene Expression Program in Breast Cancer Cells That Can Elicit Complete Tumor Regression
Authors: Lu Wenbao , Ning Huan , Gu Ling , Peng Hui , Wang Qinghong , Hou Rong , Fu Mingui , Hoft Daniel F. , Liu Jianguo
Published: February 2016

The ability of cancer cells to evade apoptosis is dictated by a shift in the balance between proapoptotic and antiapoptotic gene expression programs. Monocyte chemotactic protein-induced protein 1 (MCPIP1) is a zinc-finger RNA binding protein with important roles in mediating inflammatory responses. Overexpression of MCPIP1 in different cancer cell types has been implicated in eliciting an antitumor response, but a direct role of MCPIP1 in apoptosis has not been established. In this study, we demonstrate that MCPIP1 functions as a potent tumor suppressor that induces apoptosis of breast tumor cells by selectively enhancing mRNA decay of antiapoptotic gene transcripts, including Bcl2L1, Bcl2A1, RelB, Birc3, and Bcl3. Mechanistically, MCPIP1 physically interacted with a stem–loop structure in the 3′ untranslated region of these transcripts through its PIN domain, causing mRNA destabilization. Furthermore, we found that MCPIP1 expression was repressed in breast tumor cells, and overexpression of MCPIP1 induced apoptosis, whereas its depletion enhanced cancer cell proliferation. Moreover, MCPIP1 induction in vivo resulted in complete regression of established tumors and a significant reduction in metastatic disease. Notably, low MCPIP1 expression in tumor samples from breast cancer patients was strongly associated with poor survival over 13 years of follow-up. Collectively, our results highlight that MCPIP1 is a new tumor suppressor in breast cancer that induces cell death by tipping the balance in favor of proapoptotic gene expression. Cancer Res; 76(6); 1429–40. ©2016 AACR.
STK11/LKB1 Deficiency Promotes Neutrophil Recruitment and Proinflammatory Cytokine Production to Suppress T-cell Activity in the Lung Tumor Microenvironment
Authors: Koyama Shohei , Akbay Esra A. , Li Yvonne Y. , Aref Amir R. , Skoulidis Ferdinandos , Herter-Sprie Grit S. , Buczkowski Kevin A. , Liu Yan , Awad Mark M. , Denning Warren L. , Diao Lixia , Wang Jing , Parra-Cuentas Edwin R. , Wistuba Ignacio I. , Soucheray Margaret , Thai Tran , Asahina Hajime , Kitajima Shunsuke , Altabef Abigail , Cavanaugh Jillian D. , Rhee Kevin , Gao Peng , Zhang Haikuo , Fecci Peter E. , Shimamura Takeshi , Hellmann Matthew D. , Heymach John V. , Hodi F. Stephen , Freeman Gordon J. , Barbie David A. , Dranoff Glenn , Hammerman Peter S. , Wong Kwok-Kin
Published: February 2016

STK11/LKB1 is among the most commonly inactivated tumor suppressors in non–small cell lung cancer (NSCLC), especially in tumors harboring KRAS mutations. Many oncogenes promote immune escape, undermining the effectiveness of immunotherapies, but it is unclear whether the inactivation of tumor suppressor genes, such as STK11/LKB1, exerts similar effects. In this study, we investigated the consequences of STK11/LKB1 loss on the immune microenvironment in a mouse model of KRAS-driven NSCLC. Genetic ablation of STK11/LKB1 resulted in accumulation of neutrophils with T-cell–suppressive effects, along with a corresponding increase in the expression of T-cell exhaustion markers and tumor-promoting cytokines. The number of tumor-infiltrating lymphocytes was also reduced in LKB1-deficient mouse and human tumors. Furthermore, STK11/LKB1–inactivating mutations were associated with reduced expression of PD-1 ligand PD-L1 in mouse and patient tumors as well as in tumor-derived cell lines. Consistent with these results, PD-1–targeting antibodies were ineffective against Lkb1-deficient tumors. In contrast, treating Lkb1-deficient mice with an IL6-neutralizing antibody or a neutrophil-depleting antibody yielded therapeutic benefits associated with reduced neutrophil accumulation and proinflammatory cytokine expression. Our findings illustrate how tumor suppressor mutations can modulate the immune milieu of the tumor microenvironment, and they offer specific implications for addressing STK11/LKB1–mutated tumors with PD-1–targeting antibody therapies. Cancer Res; 76(5); 999–1008. ©2016 AACR.
Bidirectional Notch Signaling and Osteocyte-Derived Factors in the Bone Marrow Microenvironment Promote Tumor Cell Proliferation and Bone Destruction in Multiple Myeloma
Authors: Delgado-Calle Jesus , Anderson Judith , Cregor Meloney D. , Hiasa Masahiro , Chirgwin John M. , Carlesso Nadia , Yoneda Toshiyuki , Mohammad Khalid S. , Plotkin Lilian I. , Roodman G. David , Bellido Teresita
Published: February 2016

In multiple myeloma, an overabundance of monoclonal plasma cells in the bone marrow induces localized osteolytic lesions that rarely heal due to increased bone resorption and suppressed bone formation. Matrix-embedded osteocytes comprise more than 95% of bone cells and are major regulators of osteoclast and osteoblast activity, but their contribution to multiple myeloma growth and bone disease is unknown. Here, we report that osteocytes in a mouse model of human MM physically interact with multiple myeloma cells in vivo, undergo caspase-3–dependent apoptosis, and express higher RANKL (TNFSF11) and sclerostin levels than osteocytes in control mice. Mechanistic studies revealed that osteocyte apoptosis was initiated by multiple myeloma cell-mediated activation of Notch signaling and was further amplified by multiple myeloma cell-secreted TNF. The induction of apoptosis increased osteocytic Rankl expression, the osteocytic Rankl/Opg (TNFRSF11B) ratio, and the ability of osteocytes to attract osteoclast precursors to induce local bone resorption. Furthermore, osteocytes in contact with multiple myeloma cells expressed high levels of Sost/sclerostin, leading to a reduction in Wnt signaling and subsequent inhibition of osteoblast differentiation. Importantly, direct contact between osteocytes and multiple myeloma cells reciprocally activated Notch signaling and increased Notch receptor expression, particularly Notch3 and 4, stimulating multiple myeloma cell growth. These studies reveal a previously unknown role for bidirectional Notch signaling that enhances MM growth and bone disease, suggesting that targeting osteocyte-multiple myeloma cell interactions through specific Notch receptor blockade may represent a promising treatment strategy in multiple myeloma. Cancer Res; 76(5); 1089–100. ©2016 AACR.
Induction of miR-137 by Isorhapontigenin (ISO) Directly Targets Sp1 Protein Translation and Mediates Its Anticancer Activity BothIn VitroandIn Vivo
Authors: Zeng Xingruo , Xu Zhou , Gu Jiayan , Huang Haishan , Gao Guangxun , Zhang Xiaoru , Li Jingxia , Jin Honglei , Jiang Guosong , Sun Hong , Huang Chuanshu
Published: February 2016

Our recent studies found that isorhapontigenin (ISO) showed a significant inhibitory effect on human bladder cancer cell growth, accompanied with cell-cycle G0–G1 arrest as well as downregulation of Cyclin D1 expression at transcriptional level via inhibition of Sp1 transactivation in bladder cancer cells. In the current study, the potential ISO inhibition of bladder tumor formation has been explored in a xenograft nude mouse model, and the molecular mechanisms underlying ISO inhibition of Sp1 expression and anticancer activities have been elucidated both in vitro and in vivo. Moreover, the studies demonstrated that ISO treatment induced the expression of miR-137, which in turn suppressed Sp1 protein translation by directly targeting Sp1 mRNA 3′-untranslated region (UTR). Similar to ISO treatment, ectopic expression of miR-137 alone led to G0–G1 cell growth arrest and inhibition of anchorage-independent growth in human bladder cancer cells, which could be completely reversed by overexpression of GFP-Sp1. The inhibition of miR-137 expression attenuated ISO-induced inhibition of Sp1/Cyclin D1 expression, induction of G0–G1 cell growth arrest, and suppression of cell anchorage-independent growth. Taken together, our studies have demonstrated that miR-137 induction by ISO targets Sp1 mRNA 3′-UTR and inhibits Sp1 protein translation, which consequently results in reduction of Cyclin D1 expression, induction of G0–G1 growth arrest, and inhibition of anchorage-independent growth in vitro and in vivo. Our results have provided novel insights into understanding the anticancer activity of ISO in the therapy of human bladder cancer. Mol Cancer Ther; 15(3); 512–22. ©2016 AACR.
SPARC-Independent Delivery of Nab-Paclitaxel without Depleting Tumor Stroma in Patient-Derived Pancreatic Cancer Xenografts
Authors: Kim Harrison , Samuel Sharon , Lopez-Casas Pedro , Grizzle William , Hidalgo Manuel , Kovar Joy , Oelschlager Denise , Zinn Kurt , Warram Jason , Buchsbaum Donald
Published: February 2016

The study goal was to examine the relationship between nab-paclitaxel delivery and SPARC (secreted protein acidic and rich in cysteine) expression in pancreatic tumor xenografts and to determine the antistromal effect of nab-paclitaxel, which may affect tumor vascular perfusion. SPARC-positive and -negative mice bearing Panc02 tumor xenografts (n = 5–6/group) were injected with IRDye 800CW (IR800)-labeled nab-paclitaxel. After 24 hours, tumors were collected and stained with DL650-labeled anti-SPARC antibody, and the correlation between nab-paclitaxel and SPARC distributions was examined. Eight groups of mice bearing either Panc039 or Panc198 patient-derived xenografts (PDX; 4 groups/model, 5 animals/group) were untreated (served as control) or treated with gemcitabine (100 mg/kg body weight, i.p., twice per week), nab-paclitaxel (30 mg/kg body weight, i.v., for 5 consecutive days), and these agents in combination, respectively, for 3 weeks, and tumor volume and perfusion changes were assessed using T2-weighted MRI and dynamic contrast-enhanced (DCE) MRI, respectively. All tumors were collected and stained with Masson's Trichrome Stain, followed by a blinded comparative analysis of tumor stroma density. IR800-nab-paclitaxel was mainly distributed in tumor stromal tissue, but nab-paclitaxel and SPARC distributions were minimally correlated in either SPARC-positive or -negative animals. Nab-paclitaxel treatment neither decreased tumor stroma nor increased tumor vascular perfusion in either PDX model when compared with control groups. These data suggest that the specific tumor delivery of nab-paclitaxel is not directly related to SPARC expression, and nab-paclitaxel does not deplete tumor stroma in general. Mol Cancer Ther; 15(4); 680–8. ©2016 AACR.
Correlation between Maternal Characteristics during Early Pregnancy, Fetal Growth Rate and Newborn Weight in Healthy Pregnancies
Authors: Caradeux Javier , Serra Ramón , Palmeiro Yasna , Correa Paula J. , Valenzuela Ignacio , Olguin Jaime , Montenegro Lazaro , Nien Jyh Kae , Osorio Eduardo , Illanes Sebastián
Published: February 2016

Background: The objective of this study was to evaluate the association between maternal characteristics in early pregnancy and fetal growth (FG) and birth weight (BW). Methods: A prospective cohort study was performed in unselected pregnant women who attended an ultrasound evaluation at 11-14 weeks of pregnancy. Medical history, biochemical blood tests, biophysical variables and fetal weight at 20-25 and 30-36 weeks as well as the BW were assessed. Bivariate and multivariate linear models were constructed. Results: In all, 543 patients with normal pregnancy and labor were selected. The multiple regression analysis showed a statistically significant association between maternal body mass index (BMI) in early pregnancy and the uterine artery pulsatility index (UtAPI) in the first trimester with BW (p < 0.0008) and with the ratio of fetal growth between the second and third trimesters (p < 0.0001). No correlation was found between these variables and first trimester levels of hemoglobin or glycemia. Conclusion: Maternal first trimester BMI and UtAPI correlate with the rate of intrauterine FG and with the BW. This evidence highlights the influence of maternal first trimester variables on fetuses with normal growth and the potential role of these variables in fetal programming.
Docosahexaenoic Acid-Rich Fish Oil Supplementation Improves Body Composition without Influence of the PPARγ Pro12Ala Polymorphism in Patients with Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial
Authors: Mansoori Anahita , Sotoudeh Gity , Djalali Mahmoud , Eshraghian Mohammad-Reza , Keramatipour Mohammad , Nasli-Esfahani Ensieh , Shidfar Farzad , Alvandi Ehsan , Toupchian Omid , Koohdani Fariba
Published: February 2016

Background: The aims of this research were to investigate (1) the impact of docosahexaenoic acid (DHA)-rich fish oil supplementation on body composition, plasma adiponectin level, and peroxisome proliferator-activated receptor γ (PPARγ) gene expression, and (2) whether the effect of DHA-rich fish oil supplementation on the aforementioned variables is modulated by PPARγ Pro12Ala polymorphism. Methods: We genotyped PPARγ Pro12Ala polymorphism in subjects with type 2 diabetes mellitus (T2DM). Ala carriers and non-Ala carriers were randomly assigned to DHA-rich fish oil or placebo intake for 8 weeks. Results: Glycemic control was not affected by the intervention. The supplementation with DHA-rich fish oil decreased waist circumference (p < 0.001), body fat mass (p = 0.01), body fat percent (p = 0.04), and visceral fat rating (p = 0.02) as well as trunk fat mass (p = 0.04). Weight, body mass index, fat-free mass, adiponectin level, and PPARγ gene expression changes showed no significant difference. No gene-diet interaction was found on body composition, adiponectin level, and PPARγ gene expression. Conclusions: DHA-rich fish oil supplementation favorably modulated body composition in patients with T2DM and could be useful to reduce visceral obesity. However, the PPARγ Pro12Ala polymorphism did not influence the changes in the desired variables.
Elie Metchnikoff, the Man and the Myth
Authors: Gordon Siamon
Published: February 2016

The year 2016 marks the centenary of the death of Elie Metchnikoff, the father of innate immunity and discoverer of the significance of phagocytosis in development, homeostasis and disease. Through a series of intravital experiments on invertebrates and vertebrates, he described the role of specialised phagocytic cells, macrophages and microphages, subsequently renamed neutrophils and polymorphonuclear leucocytes, in the host response to injury, inflammation, infection and tissue repair. As a vigorous proponent of cellular immunity, he championed its importance versus humoral immunity in the so-called antibody wars. By 1908, when the Nobel Prize was awarded to Elie Metchnikoff and Paul Ehrlich, this debate was not yet resolved. Even earlier, Metchnikoff had turned his research interests to the process of ageing and the possible link to intestinal auto-intoxication, giving rise to the current interest in the microbiome of the gut and the use of probiotics to promote health and longevity. During the past century, Metchnikoff's reputation has waxed and waned, as lymphocyte heterogeneity, specificity and memory began to dominate the field of adaptive immunity, yet his benign visage continues to provide an iconic presence for specialists in innate immunology, whose studies have made a striking comeback in the past decade. In this review, I shall consider the nature of his studies and the person as well as the legendary description of his Eureka experience in Messina in 1882, a story loved by students and investigators alike, that marked, in his own words, his transformation from zoologist to pathologist.
Molecular and Cytogenetic Characterization of a Powdery Mildew-Resistant Wheat-Aegilops mutica Partial Amphiploid and Addition Line
Authors: Liu Cheng , Li Guang-Rong , Gong Wen-Ping , Li Gen-Ying , Han Ran , Li Hao-Sheng , Song Jian-Min , Liu Ai-Feng , Cao Xin-You , Chu Xiu-Sheng , Yang Zu-Jun , Huang Cheng-Yan , Zhao Zhen-Dong , Liu Jian-Jun
Published: February 2016

Aegilops mutica Boiss., a diploid species (2n = 2x = 14, TT), has been rarely studied before. In this research, a hexaploid wheat (cv. Chinese Spring)-Ae. mutica partial amphiploid and a wheat-Ae. mutica addition line were characterized by chromosome karyotyping, FISH using oligonucleotides Oligo-pTa535-1, Oligo-pSc119.2-1, and (GAA)8 as probes, and EST-based molecular markers. The results showed that the partial amphiploid strain consisted of 20 pairs of wheat chromosomes and 7 pairs of Ae. mutica chromosomes, with both wheat 7B chromosomes missing. EST-based molecular marker data suggested that the wheat-Ae. mutica addition line carries the 7T chromosome. Resistance tests indicated that both the partial amphiploid and the 7T addition line were highly resistant to powdery mildew, whereas the wheat control line Chinese Spring was highly susceptible, indicating the presence of a potentially new powdery mildew resistance gene on the Ae. mutica 7T chromosome. The karyotype, FISH patterns, and molecular markers can now be used to identify Ae. mutica chromatin in a wheat background, and the 7T addition could be used as a new powdery mildew resistance source for wheat breeding.
Growth, trade, well-being and environmental: the effects of technological spillovers
Authors: Sousa Lucas Vitor de Carvalho , Fernandes Elaine Aparecida , Silva Evaldo Henrique da , Cirino Jader Fernandes
Published: February 2016

O presente trabalho procurou analisar como o crescimento econômico, o comércio internacional, as emissões de CO2 e o bem-estar variam na presença e na ausência de externalidades tecnológicos incorporadas (spillovers embodied) em duas regiões: Brasil e Países do Anexo I do Protocolo de Quioto. Os resultados mostraram que as externalidades tecnológicas afetaram positivamente o desempenho econômico brasileiro, entretanto, não houve qualquer efeito sobre os níveis de bem-estar social e de emissões de CO2. Esse fato sugere que apenas o progresso técnico não é capaz de conter a pressão antrópica sobre a atmosfera.
Ética médica e bioética
Authors: Oliveira Reinaldo Ayer de
Published: February 2016

A expressão ética médica pode ser definida como aquilo que os médicos tomaram por hábito denominar “o cumprimento ao determinado pelo código de ética: deveres e direitos dos médicos”. A bioética afirma-se como uma área do conhecimento humano que relaciona os valores éticos com fatos biológicos sobretudo aqueles fatos que envolvem a vida e a saúde do seres humanos dentro de um meio ambiente adequado.
Principais aspectos legais e constitucionais da clonagem reprodutiva humana
Authors: Glina Nathan
Published: February 2016

O objetivo do estudo é delinear os principais aspectos da clonagem humana reprodutiva, sob a ótica da Constituição Federal Brasileira de 1988. Para atingir esse objetivo, foram realizadas a pesquisa e análise relativa aos aspectos constitucionais e da legislação atual que podem ser aplicados à clonagem humana reprodutiva.
As alterações legislativas do código de trânsito brasileiro
Authors: Araújo Julyver Modesto de
Published: February 2016

O atual Código de Trânsito Brasileiro (CTB) vigora desde 23/09/1997. Desde então, sete leis que alteram o referido código foram aprovadas. O uso de películas nos vidros dos autos, a obrigatoriedade do kit de primeiros socorros e a penalização relacionada à não observância de limites de circulação são alguns dos temas presentes nas leis propostas. O autor observa que o número de propostas de alteração do CTB é grande – só em janeiro de 2007 foram arquivadas 306 – e que, geralmente, essas propostas não representam reais contribuições ao aperfeiçoamento do Código; ao contrário disso, elas têm acrescentado maior confusão. O autor sugere ainda que as boas idéias devam ser aproveitadas como emendas às propostas já em tramitação.
Saúde Reprodutiva, fecundidade e aborto provocado: análise de seis inquéritos populacionais realizados em São Paulo, Brasil
Authors: Silva Rebeca De Souza e , Fusco Carmen Linda Brasiliense
Published: February 2016

O Aborto Inseguro é, ainda, um grave problema de Saúde Pública e sua solução, um desafio a exigir medidas urgentes que passam, fatalmente, pelo processo de descriminalização do aborto. Conhecer o perfil das mulheres que recorrem ao aborto provocado, especialmente ao clandestino, inseguro, é de suma importância tanto para a área de Saúde Pública, em particular para a Saúde Reprodutiva, quanto para a área de Demografia. A partir da análise de 6 (seis) inquéritos populacionais, conduzidos em populações diferentes quanto à renda e quanto às características sociodemográficas, em São Paulo, nos últimos anos, as autoras procuram aproximar-se desse perfil.
Ayahuasca: entre o legal e o cultural
Authors: Garrido Rodrigo Grazinoli , Sabino Bruno Duarte
Published: February 2016

A Ayahuasca, chá produzido pela decocção do caule do cipó Jagube (Banisteriopsis caapi) e das folhas da Chacrona (Psychotria viridis), é um alucinógeno ritualístico que alcançou a atualidade através de várias doutrinas religiosas. No Brasil, entre as tradições religiosas que fazem uso da bebida estão o Santo Daime, a Barquinha e a União do Vegetal. A bebida contém a substância N,N-dimetiltriptamina, psicotrópico de uso proscrito pela Portaria SVS/MS 344/1998 e considerado droga pela Lei 11.343/2006. Apesar disto, o uso religioso do chá foi reconhecido
pelo CONAD em 2004 (Resolução 4/2004) e ratificado pela Resolução 1/2010. A partir daí, posicionamentos repletos de preconceitos e desprovidos de fundamentação científica têm sido gerados. A fim de contribuir com a discussão, o presente trabalho sistematiza o conhecimento antropológico, farmacológico e legal sobre o chá.