ABSTRACT
Here we report a unique plant-insect interaction between the leafhopper Aloka depressa (tribe Phlogisini) and the host liana, Diploclisia glaucescens, from a Botanic Garden located at the southern edge of Western Ghats in India. Field observations and SEM micrographs were employed to derive evidences on this rare plant-insect interaction. 20-Hydroxyecdysone (20E), insect moulting hormone, was detected and quantified in the host plant D. glaucescens using HPTLC-densitometry. 20E was isolated and characterized from D. glaucescens using column chromatography, 1H-, 13C-NMR and HR-MS. 20E was also detected in A. depressa excrement using HPTLC-densitometry. The leafhopper A. depressa is functioning as a 'sharpshooter' drawing nutrients from the host liana, D. glaucescens, and flinging the waste fluid as droplets through their tail ends. SEM micrographs of A. depressa revealed its external morphological features, characteristic of a sharpshooter. We quantified 20E (0.44-1.44%, dry wt.) in various parts of D. glaucescens. 20E (1.47%, dry wt.) was also detected in the excrement of A. depressa. This plant (D. glaucescens)-insect (A. depressa) association crucially is not damaging the host liana. Considering the diseases caused by sharpshooting leafhoppers in the Americas, this association and the survival of the host plant (D. glaucescens) is illustrating a unique plant-insect interaction.
Subject(s)
Hemiptera , Menispermaceae , Animals , Gardens , Menispermaceae/chemistryABSTRACT
Microscale deformation processes, such as reorientation, buckling, and sliding of collagen fibrils, determine the mechanical behavior and function of collagenous tissue. While changes in the structure and composition of tendon have been extensively studied, the deformation mechanisms that modulate the interaction of extracellular matrix (ECM) constituents are not well understood, partly due to the lack of appropriate techniques to probe the behavior. In particular, the role of glycosaminoglycans (GAGs) in modulating collagen fibril interactions has remained controversial. Some studies suggest that GAGs act as crosslinkers between the collagen fibrils, while others have not found such evidence and postulate that GAGs have other functions. Here, we introduce a new framework, relying on orientation-dependent indentation behavior of tissue and computational modeling, to evaluate the shear-mediated function of GAGs in modulating the collagen fibril interactions at a length scale more relevant to fibrils compared to bulk tests. Specifically, we use chondroitinase ABC to enzymatically deplete the GAGs in tendon; measure the orientation-dependent indentation response in transverse and longitudinal orientations; and infer the microscale deformation mechanisms and function of GAGs from a microstructural computational model and a modified shear-lag model. We validate the modeling approach experimentally and show that GAGs facilitate collagen fibril sliding with minimal crosslinking function. We suggest that the molecular reconfiguration of GAGs is a potential mechanism for their microscale, strain-dependent viscoelastic behavior. This study reveals the mechanisms that control the orientation-dependent indentation response by affecting the shear deformation and provides new insights into the mechanical function of GAGs and collagen crosslinkers in collagenous tissue.
Subject(s)
Extracellular Matrix , Glycosaminoglycans , Glycosaminoglycans/chemistry , Tendons/physiology , Collagen/chemistry , Computer Simulation , Biomechanical PhenomenaABSTRACT
The spatial arrangement and interactions of the extracellular matrix (ECM) components control the mechanical behavior of tissue at multiple length scales. Changes in microscale deformation mechanisms affect tissue function and are often hallmarks of remodeling and disease. Despite their importance, the deformation mechanisms that modulate the mechanical behavior of collagenous tissue, particularly in indentation and compression modes of deformation, remain poorly understood. Here, we develop an integrated computational and experimental approach to investigate the deformation mechanisms of collagenous tissue at the microscale. While the complex deformation arising from indentation with a spherical probe is often considered a pitfall rather than an opportunity, we leverage this orientation-dependent deformation to examine the shear-regulated interactions of collagen fibrils and the role of crosslinks in modulating these interactions. We specifically examine tendon and cervix, two tissues rich in collagen with quite different microstructures and mechanical functions. We find that interacting, crosslinked collagen fibrils resist microscale longitudinal compressive forces, while widely used constitutive models fail to capture this behavior. The reorientation of collagen fibrils tunes the compressive stiffness of complex tissues like cervix. This study offers new insights into the mechanical behavior of collagen fibrils during indentation, and more generally, under longitudinal compressive forces, and illustrates the mechanisms that contribute to the experimentally observed orientation-dependent mechanical behavior. STATEMENT OF SIGNIFICANCE: Remodeling and disease can affect the deformation and interaction of tissue constituents, and thus mechanical function of tissue. Yet, the microscale deformation mechanisms are not well characterized in many tissues. Here, we develop a combined experimental-computational approach to infer the microscale deformation mechanisms of collagenous tissues with very different functions: tendon and cervix. Results show that collagen fibrils resist microscale forces along their length, though widely-used constitutive models do not account for this mechanism. This deformation process partially modulates the compressive stiffness of complex tissues such as cervix. Computational modeling shows that crosslink-mediated shear deformations are central to this unexpected behavior. This study offers new insights into the deformation mechanisms of collagenous tissue and the function of collagen crosslinkers.
Subject(s)
Collagen , Extracellular Matrix , Tendons , Computer Simulation , Stress, Mechanical , Biomechanical PhenomenaABSTRACT
OBJECTIVES: To examine the relationship between Vitamin D status and pain intensity and disability in individuals with and without knee pain, and to examine the role of epigenetics in this relationship. DESIGN: Cross-sectional analysis of data from the UPLOAD-2 study (Understanding Pain and Limitations in OsteoArthritic Disease-2). PARTICIPANTS: 189 individuals aged 45-65 years and older. MEASUREMENTS: Serum Vitamin D levels, pain related interference and characteristic pain intensity measures, and the epigenetic clock GrimAge derived from blood analyses. RESULTS: Lower Vitamin D was associated with advanced epigenetic aging (AgeAccelGrim), greater pain and disability and that (AgeAccelGrim) mediated the relationship between Vitamin D status and self-reported pain (ab = -0.0799; CI [-0.1492, -0.0237]) and disability (ab = -0.0669; CI [-0.1365, -0.0149]) outcomes. CONCLUSION: These data support the notion that lifestyle factors such as nutrition status play a key role in aging process, as well as the development and maintenance of age-related diseases such as pain. Modifying nutrition status could help promote healthy aging and reduce pain.
Subject(s)
Independent Living , Vitamin D , Aging/genetics , Cross-Sectional Studies , Epigenesis, Genetic , Humans , Pain/genetics , VitaminsABSTRACT
The cervix acts as a dynamic barrier between the uterus and vagina, retaining the fetus during pregnancy and allowing birth at term. Critical to this function, the physical properties of the cervix change, or remodel, but abnormal remodeling can lead to preterm birth (PTB). Although cervical remodeling has been studied, the complex 3D cervical microstructure has not been well-characterized. In this complex, dynamic, and heterogeneous tissue microenvironment, the microstructural changes are likely also heterogeneous. Using quantitative, 3D, second-harmonic generation microscopy, we demonstrate that rat cervical remodeling during pregnancy is not uniform across the cervix; the collagen fibers orient progressively more perpendicular to the cervical canals in the inner cervical zone, but do not reorient in other regions. Furthermore, regions that are microstructurally distinct early in pregnancy become more similar as pregnancy progresses. We use a finite element simulation to show that heterogeneous regional changes influence cervical funneling, an important marker of increased risk for PTB; the internal cervical os shows â¼6.5x larger radial displacement when fibers in the inner cervical zone are parallel to the cervical canals compared to when fibers are perpendicular to the canals. Our results provide new insights into the microstructural and tissue-level cervical changes that have been correlated with PTB and motivate further clinical studies exploring the origins of cervical funneling. STATEMENT OF SIGNIFICANCE: Cervical funneling, or dilation of the internal cervical os, is highly associated with increased risk of preterm birth. This study explores the 3D microstructural changes of the rat cervix during pregnancy and illustrates how these changes influence cervical funneling, assuming similar evolution in rats and humans. Quantitative imaging showed that microstructural remodeling during pregnancy is nonuniform across cervical regions and that initially distinct regions become more similar. We report, for the first time, that remodeling of the inner cervical zone can influence the dilation of the internal cervical os and allow the cervix to stay closed despite increased intrauterine pressure. Our results suggest a possible relationship between the microstructural changes of this zone and cervical funneling, motivating further clinical investigations.
Subject(s)
Cervix Uteri , Premature Birth , Animals , Cervix Uteri/diagnostic imaging , Computer Simulation , Female , Pregnancy , Premature Birth/etiology , Rats , UterusABSTRACT
Severe coronavirus disease 2019 (COVID-19) pneumonia survivors often exhibit long-term pulmonary sequelae, but the underlying mechanisms or associated local and systemic immune correlates are not known. Here, we have performed high-dimensional characterization of the pathophysiological and immune traits of aged COVID-19 convalescents, and correlated the local and systemic immune profiles with pulmonary function and lung imaging. We found that chronic lung impairment was accompanied by persistent respiratory immune alterations. We showed that functional severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)specific memory T and B cells were enriched at the site of infection compared with those of blood. Detailed evaluation of the lung immune compartment revealed that dysregulated respiratory CD8+ T cell responses were associated with the impaired lung function after acute COVID-19. Single-cell transcriptomic analysis identified the potential pathogenic subsets of respiratory CD8+ T cells contributing to persistent tissue conditions after COVID-19. Our results have revealed pathophysiological and immune traits that may support the development of lung sequelae after SARS-CoV-2 pneumonia in older individuals, with implications for the treatment of chronic COVID-19 symptoms.
Subject(s)
B-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/microbiology , Immunologic Memory , Lung/immunology , SARS-CoV-2/immunology , B-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/pathology , COVID-19/pathology , Female , Humans , Lung/pathology , Lung/virology , Male , Middle AgedABSTRACT
The structural and mechanical properties of tissue and the interplay between them play a critical role in tissue function. We introduce the optomechanogram, a combined quantitative and qualitative visualization of spatially co-registered measurements of the microstructural and micromechanical properties of any tissue. Our approach relies on the co-registration of two independent platforms, second-harmonic generation (SHG) microscopy for quantitative assessment of 3D collagen-fiber microstructural organization, and nanoindentation (NI) for local micromechanical properties. We experimentally validate our method by applying to uterine cervix tissue, which exhibits structural and mechanical complexity. We find statistically significant agreement between the micromechanical and microstructural data, and confirm that the distinct tissue regions are distinguishable using either the SHG or NI measurements. Our method could potentially be used for research in pregnancy maintenance, mechanobiological studies of tissues and their constitutive modeling and more generally for the optomechanical metrology of materials.
Subject(s)
Mechanical Phenomena , Microscopy , Biomechanical Phenomena , Cervix Uteri/cytology , Collagen/metabolism , Female , Humans , Imaging, Three-DimensionalABSTRACT
Herbivores are a diverse group of fauna that shape the distribution and composition of plant communities. In some cases, herbivory may prevent the re-establishment of submerged aquatic vegetation (SAV), such as Vallisneria americana, into systems. The goal of this study was to investigate the role and nature of herbivory on V. americana transplants with camera and transect surveys of grazing intensity and with field and laboratory grazing experiments using a suspected herbivore, the blue crab, Callinectes sapidus. Camera surveys recorded C. sapidus clipping and consuming shoots of V. americana for the first time. Grazing intensity surveys in low-salinity regions of the lower Chesapeake Bay indicated that the majority of V. americana transplants (50-75%) were clipped off at their base within one week of planting. Field and laboratory experiments demonstrated that C. sapidus clips and consumes V. americana as well as other rapidly colonizing, non-native SAV. Analysis of the gut contents of C. sapidus caught in SAV beds in the Chesapeake Bay revealed that SAV comprised 16% of their stomach contents, suggesting low levels of C. sapidus herbivory occurred over a wide area. Callinectes sapidus is yet another animal documented to consume SAV for some portion of their diet. These results also suggest that herbivores or omnivores, including C. sapidus, can serve as bottlenecks to recovery of SAV, like V. americana, in some areas. Herbivores may not serve as bottlenecks in other environments or to other SAV with more rapid plant growth or higher recruitment levels that may overcome grazing pressure.
Subject(s)
Brachyura , Herbivory , Animals , Estuaries , Plant Development , PlantsABSTRACT
The aim of this study was to ascertain farmers' knowledge of the risk of spread of infection from animals to humans, and their transmission prevention practices. This was a survey of farmers who submitted material to Ireland's Regional Veterinary Laboratories in 2015. There was an 84% response rate (1044 farmers). Ninety per cent of farmers were not aware that infection can be acquired from apparently healthy animals. Over half were not aware that disease could be contracted from sick poultry or pets. Conversely, the knowledge of the risk to pregnant women of infection from birthing animals was high (88%). Four-fifths of farmers sourced drinking water from a private well, and of these, 62% tested their water less frequently than once a year. Of dairy farmers, 39% drank unpasteurised milk once a week or more frequently. Veterinarians were the most commonly cited information source for diseases on farms. The survey findings indicate that the level of farmers' knowledge and awareness of the spread of infection from animals to humans is a concern. Further education of the farming community is needed to increase awareness of both the potential biohazards present on farms and the practical measures that can be taken to mitigate the risk of zoonoses.
Subject(s)
Farmers/psychology , Health Knowledge, Attitudes, Practice , Zoonoses/prevention & control , Zoonoses/transmission , Adolescent , Adult , Aged , Aged, 80 and over , Animals , Female , Humans , Ireland , Male , Middle Aged , Risk Assessment , Young Adult , Zoonoses/psychologyABSTRACT
We report on the detection of the time-dependent B-field amplitude and topology in a laser-driven solenoid. The B-field inferred from both proton deflectometry and Faraday rotation ramps up linearly in time reaching 210 ± 35 T at the end of a 0.75-ns laser drive with 1 TW at 351 nm. A lumped-element circuit model agrees well with the linear rise and suggests that the blow-off plasma screens the field between the plates leading to an increased plate capacitance that converts the laser-generated hot-electron current into a voltage source that drives current through the solenoid. ALE3D modeling shows that target disassembly and current diffusion may limit the B-field increase for longer laser drive. Scaling of these experimental results to a National Ignition Facility (NIF) hohlraum target size (â¼0.2cm^{3}) indicates that it is possible to achieve several tens of Tesla.
Subject(s)
C2 Domains/genetics , Drug Resistance, Neoplasm/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Mutation , Phospholipase C gamma/genetics , Protein Kinase Inhibitors/therapeutic use , Protein-Tyrosine Kinases/genetics , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Adenine/analogs & derivatives , Agammaglobulinaemia Tyrosine Kinase , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , PiperidinesABSTRACT
INTRODUCTION: The U.S. Military Health System cares for over 9 million patients and encompasses 63 hospitals and 413 clinics worldwide. Military medicine balances the simultaneous tasks of caring for those patients wounded in military engagements, treating large numbers of families of service men and women, and training the next generation of health care providers and ancillary staff. Similar to civilian health care delivery in the United States, military medicine has also seen increased scrutiny in the areas of cost and quality. In 2014, the U.S. military medical health care system was criticized for higher than average surgical complication rates and concerns regarding patient safety, quality of care, lack of transparency, and compartmentalized leadership. The San Antonio Military Medical Center was specifically cited as having "a perennial problem with surgical infection control the infection rate of surgical wounds was 77% higher than expected given the mix of cases, according to a Pentagon-ordered comparison with civilian hospitals." To determine the scope of complication rates, data from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) were analyzed. The goal of this article is to describe the NSQIP surgical outcome data for the U.S. Military's largest medical center from 2009 to 2014 and compare national averages in the areas of mortality, morbidity, cardiac occurrences, pneumonia, unplanned intubation, ventilator use greater than 48 hours, infections, readmissions, and return to operating room. MATERIALS AND METHODS: Retrospective data analysis of NSQIP data from 2009 to 2014 at the San Antonio Military Medical Center, a level I trauma center for military members and eligible dependents along with civilian trauma patients. Observed event rates were compared with expected event rates for each year with the 2-tail Fisher's exact test to determine if rates were significantly different from each other. Cochran-Armitage Trend Test was performed to compare trends in time for the observed event rates. This study was exempt from institutional review board Approval. RESULTS: Complication rates remained stable or decreased over the 5 years studied. Significant improvement in morbidity and surgical site infections were observed during the observation period. All other variables except urinary tract infections were within expected range or decreased during this time. Urinary tract infection rates, although decreasing, remain above the expected value. CONCLUSIONS AND RELEVANCE: NSQIP data at the Department of Defense's largest hospital reveals complication rates similar to civilian hospitals. The majority of areas studied revealed improving or stable complication rates. The ACS NSQIP is a nationally validated, risk-adjusted, outcomes program that is widely used by many leading hospital institutions. Similar to most quality data reporting articles, a weakness of our study may have been collection of all complications. Yet, we are confident that the majority of complications were captured as we have dedicated personnel monitoring the adverse events measured by ACS NSQIP. Future areas of study should focus on continued analysis of surgical quality improvement within the entire military system.
Subject(s)
Patient Safety/statistics & numerical data , Postoperative Complications/epidemiology , Program Evaluation/methods , Hospital Mortality/trends , Hospitals, Military/standards , Hospitals, Military/statistics & numerical data , Humans , Quality Improvement , Quality Indicators, Health Care/statistics & numerical data , Retrospective Studies , Surgical Wound Infection/epidemiology , United States/epidemiologyABSTRACT
Methicillin-resistant Staphylococcus aureus (MRSA) infections cause significant morbidity and mortality in neonatal intensive care units (NICUs). We characterized the clinical and molecular epidemiology of MRSA strains colonizing NICU patients. Nasal MRSA isolates (n = 250, from 96 NICU patients) recovered through active surveillance from 2009 to 2014 were characterized with staphylococcal cassette chromosome mec (SCCmec) typing and detection of mupA (marker of high-level mupirocin resistance) and qacA/B (marker associated with chlorhexidine resistance). Factors associated with community-associated (CA-) or healthcare-associated (HA-) MRSA were evaluated. The overall prevalence of MRSA nasal colonization was 3.9%. Of 96 neonates in our retrospective cohort, 60 (63%) were colonized with CA-MRSA strains and 35 (36%) were colonized with HA-MRSA strains. Patients colonized with HA-MRSA were more likely to develop MRSA infections than patients colonized with CA-MRSA (13/35, 37% versus 8/60, 13%; p 0.007), although the interval from colonization to infection was shorter in CA-MRSA-colonized infants (median 0 days, range -1 to 4 versus HA-MRSA-colonized infants, 7 days, -1 to 43; p 0.005). Maternal peripartum antibiotics were associated with CA-MRSA colonization (adjusted odds ratio (aOR) 8.7; 95% CI 1.7-45.0); intubation and surgical procedures were associated with HA-MRSA colonization (aOR 7.8; 95% CI 1.3-47.6 and aOR 6.0; 95% CI 1.4-24.4, respectively). Mupirocin- and chlorhexidine-resistant MRSA was isolated from four and eight patients, respectively; carriage of a mupirocin-resistant strain precluded decolonization. CA-MRSA strains are prominent in the NICU and associated with distinct risk factors. Given community reservoirs for MRSA acquisition and transmission, novel infection prevention strategies are needed.
Subject(s)
Carrier State/epidemiology , Infection Control/methods , Intensive Care Units, Neonatal , Methicillin-Resistant Staphylococcus aureus/isolation & purification , Nasal Mucosa/microbiology , Patient Safety , Staphylococcal Infections/epidemiology , Anti-Infective Agents/administration & dosage , Anti-Infective Agents/pharmacology , Carrier State/microbiology , Carrier State/prevention & control , Chlorhexidine/administration & dosage , Chlorhexidine/pharmacology , Disease Transmission, Infectious/prevention & control , Drug Resistance, Bacterial , Female , Genotype , Humans , Infant, Newborn , Male , Methicillin-Resistant Staphylococcus aureus/classification , Methicillin-Resistant Staphylococcus aureus/genetics , Molecular Typing , Mupirocin/administration & dosage , Mupirocin/pharmacology , Prevalence , Retrospective Studies , Staphylococcal Infections/microbiology , Staphylococcal Infections/prevention & controlABSTRACT
AIM: To investigate the use of clinical head magnetic resonance imaging (MRI) in determining body composition and to evaluate how well it correlates with established measures based on abdominal computed tomography (CT). MATERIALS AND METHODS: Ninety-nine consecutive patients were identified who had undergone both brain MRI and abdominal CT within a 2-week span. Volumes of fat and muscle in the extracranial head were measured utilising several techniques by both abdominal CT and head MRI. RESULTS: MRI-based total fat volumes in the head correlated with CT-based measurements of fat in the abdomen using both single-section (r=0.64, p<0.01) and multisection (r=0.60, p<0.01) techniques. No significant correlation was found between muscle volumes in the abdomen and head. CONCLUSION: Based on the present results, head MRI-based measures may provide a useful surrogate for CT measurements of abdominal fat, particularly in patients with neurological cancers, as head MRI (and not abdominal CT) is routinely and repeatedly obtained for the purpose of clinical care for these patients.
Subject(s)
Body Composition , Brain/anatomy & histology , Head/anatomy & histology , Magnetic Resonance Imaging , Abdominal Fat/diagnostic imaging , Adipose Tissue , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Radiography, Abdominal , Reproducibility of Results , Tomography, X-Ray Computed , Young AdultABSTRACT
Bamboos are one of the fastest growing plants on Earth, and are widely considered to have high ability to capture and sequester atmospheric carbon, and consequently to mitigate climate change. We tested this hypothesis by measuring carbon dioxide (CO2 ) emissions from bamboo culms and comparing them with their biomass sequestration potential. We analysed diurnal effluxes from Bambusa vulgaris culm surface and gas mixtures inside hollow sections of various bamboos using gas chromatography. Corresponding variations in gas pressure inside the bamboo section and culm surface temperature were measured. SEM micrographs of rhizome and bud portions of bamboo culms were also recorded. We found very high CO2 effluxes from culm surface, nodes and buds of bamboos. Positive gas pressure and very high concentrations of CO2 were observed inside hollow sections of bamboos. The CO2 effluxes observed from bamboos were very high compared to their carbon sequestration potential. Our measurements suggest that bamboos are net emitters of CO2 during their lifespan.
Subject(s)
Bambusa/metabolism , Carbon Dioxide/metabolism , Carbon/metabolism , Climate Change , Rhizome/metabolism , TemperatureABSTRACT
UNLABELLED: The purpose of this study was to investigate motorcycle crash thumb injury patterns. We hypothesized that ulnar collateral ligament injuries at the thumb metacarpophalangeal joint would be most common and there would be a side predilection due to the clutch and brake positions. Motorcyclist admissions following injury between 2002 and 2013 were reviewed, and phalangeal and metacarpal injuries treated acutely identified. Demographics, injury, and treatment characteristics were recorded. Association between laterality and injury type was assessed. Of 128 patients, 59 underwent acute treatment for thumb injuries. Eleven patients sustained thumb ulnar collateral ligament injuries; 27 sustained thumb carpometacarpal injuries. Most carpometacarpal injuries were fracture-dislocations (19/27). Thumb carpometacarpal injuries had no overall side predilection; ulnar collateral ligament injuries occurred more on the right. Carpometacarpal fractures and dislocations are the most frequent motorcycle crash thumb injury, probably due to the mechanics of gripping handlebars and the high-energy force directed into the palm and against the metacarpal base. LEVEL OF EVIDENCE: Level IV.
Subject(s)
Accidents, Traffic , Finger Phalanges/injuries , Fractures, Bone/epidemiology , Joint Dislocations/epidemiology , Motorcycles , Thumb/injuries , Adult , Carpometacarpal Joints/injuries , Collateral Ligaments/injuries , Fractures, Bone/diagnosis , Fractures, Bone/therapy , Humans , Joint Dislocations/diagnosis , Joint Dislocations/therapy , Middle Aged , Retrospective StudiesABSTRACT
Dinaciclib (SCH727965) is a selective CDKi chosen for clinical development based upon a favorable therapeutic index in cancer xenograft models. We performed a phase I dose escalation study of dinaciclib in relapsed and refractory chronic lymphocytic leukemia (CLL) patients with intact organ function and WBC<200 × 10(9) /l. Five separate dose levels (5 mg/m(2), 7 mg/m(2), 10 mg/m(2), 14 mg/m(2) and 17 mg/m(2)) were explored dosing on a weekly schedule × 3 with 1 week off (4-week cycles) using a standard 3+3 design with expansion cohorts to optimize safety. Fifty-two patients were enrolled with relapsed and refractory CLL. Escalation through cohorts occurred with two dose-limiting toxicity (DLTs) at the 17 mg/m(2) dose (tumor lysis syndrome (TLS) and pneumonia). The phase II expansion occurred at 14 mg/m(2) with 16 patients receiving this dose with one DLT (TLS). Additional stepped up dosing to the maximum tolerated dose was examined in 19 patients at this dose. Adverse events included cytopenias, transient laboratory abnormalities and TLS. Responses occurred in 28 (54%) of patients independent of del(17)(p13.1) with a median progression-free survival of 481 days. Dinaciclib is clinically active in relapsed CLL including those patients with high risk del(17)(p13.1) disease and warrants future study.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Cyclin-Dependent Kinases/antagonists & inhibitors , Drug Resistance, Neoplasm/drug effects , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Neoplasm Recurrence, Local/drug therapy , Pyridinium Compounds/therapeutic use , Salvage Therapy , Adult , Aged , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Cohort Studies , Cyclic N-Oxides , Female , Follow-Up Studies , Humans , Indolizines , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Prognosis , Pyridinium Compounds/pharmacokinetics , Tissue DistributionABSTRACT
Evidence is emerging that some proteins secreted by gall-forming parasites of plants act as effectors responsible for systemic changes in the host plant, such as galling and nutrient tissue formation. A large number of secreted salivary gland proteins (SSGPs) that are the putative effectors responsible for the physiological changes elicited in susceptible seedling wheat by Hessian fly, Mayetiola destructor (Say), larvae have been documented. However, how the genes encoding these candidate effectors might respond under field conditions is unknown. The goal of this study was to use microarray analysis to investigate variation in SSGP transcript abundance amongst field collections from different geographical regions (southeastern USA, central USA, and the Middle East). Results revealed significant variation in SSGP transcript abundance amongst the field collections studied. The field collections separated into three distinct groups that corresponded to the wheat classes grown in the different geographical regions as well as to recently described Hessian fly populations. These data support previous reports correlating Hessian fly population structure with micropopulation differences owing to agro-ecosystem parameters such as cultivation of regionally adapted wheat varieties, deployment of resistance genes and variation in climatic conditions.
Subject(s)
Diptera/genetics , Insect Proteins/genetics , Salivary Proteins and Peptides/genetics , Animals , Diptera/metabolism , Expressed Sequence Tags , Gene Expression , Host-Parasite Interactions , Israel , Larva/genetics , Larva/metabolism , Molecular Sequence Data , Phylogeny , Salivary Glands/metabolism , Triticum/parasitology , United StatesSubject(s)
Antineoplastic Agents/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , MicroRNAs/metabolism , Protein-Tyrosine Kinases/metabolism , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Adenine/analogs & derivatives , Agammaglobulinaemia Tyrosine Kinase , Alemtuzumab , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Disease Progression , Disease-Free Survival , Gene Expression Regulation, Leukemic , Humans , Immunotherapy/methods , Kaplan-Meier Estimate , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Multivariate Analysis , Piperidines , Rituximab , Treatment Outcome , Vidarabine/administration & dosage , Vidarabine/analogs & derivativesABSTRACT
UNLABELLED: HOM6 is a major gene in the aspartate pathway which leads to biosynthesis of threonine and methionine. The phenotypes of the gene deletion mutant (hom6∆) in a variety of cultural conditions have previously provided meaningful insights into the biological roles of HOM6 and its upstream intermediate metabolites. Here, we conducted a survey on a spectrum of metal ions for their effect on the aspartate pathway and broader sulphur metabolism. We show that manganese (Mn(2+) ) promoted the growth of hom6∆ under both anaerobic and aerobic conditions. Unexpectedly, 4 mmol l(-1) hydrogen peroxide (H2 O2 ), a dose normally causing temporary cell growth arrest, enhanced the growth of hom6∆ under the anaerobic condition only, while it had no effect on the wild type strain BY4743. We propose that Mn(2+) and H2 O2 promote the growth of hom6∆ by reducing the accumulation of the toxic intermediate metabolite-aspartate ß-semialdehyde, via directing the aspartate pathway to the central sugar metabolism-tricarboxylic acid cycle. SIGNIFICANCE AND IMPACT OF THE STUDY: This study focuses on the yeast strain which lacks homoserine dehydrogenase encoded by HOM6 gene in aspartate metabolism. The HOM6-deletion mutant (hom6Δ) was analysed in the context of varying environmental parameters such as metal ions and oxidants, under anaerobic and aerobic conditions. We demonstrated that both manganese and hydrogen peroxide can promote the growth of hom6Δ, with the latter exerting such effect only under anaerobic condition. The findings are relevant to the research areas of ageing and anti-fungal drug development. It highlights the importance of interactions between gene expression and environmental factors as well as culture conditions.