Breast cancer has been redefined into three clinically relevant subclasses: (i) estrogen/progesterone receptor positive (ER+/PR+), (ii) HER2/ERRB2 positive, and (iii) those lacking expression of all ...three markers (triple negative or basal-like). While targeted therapies for ER+/PR+ and HER2+ tumors have revolutionized patient treatment and increased lifespan, an urgent need exists for identifying novel targets for triple-negative breast cancers. Here, we used integrative genomic analysis to identify candidate oncogenes in triple-negative breast tumors and assess their function through loss of function screening. Using this approach, we identify lactate dehydrogenase B (LDHB), a component of glycolytic metabolism, as an essential gene in triple-negative breast cancer. Loss of LDHB abrogated cell proliferation in vitro and arrested tumor growth in fully formed tumors in vivo. We find that LDHB and other related glycolysis genes are specifically upregulated in basal-like/triple-negative breast cancers as compared with other subtypes, suggesting that these tumors are distinctly glycolytic. Consistent with this, triple-negative breast cancer cell lines were more dependent on glycolysis for growth than luminal cell lines. Finally, we find that patients with breast cancer and high LDHB expression in their tumors had a poor clinical outcome. While previous studies have focused on the ubiquitous role of LDHA in tumor metabolism and growth, our data reveal that LDHB is upregulated and required only in certain cancer genotypes. These findings suggest that targeting LDHB or other components of lactate metabolism would be of clinical benefit in triple-negative breast cancer.
Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively ...preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity.
This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1–3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy.
A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS 6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107).
Trilaciclib demonstrated an improvement in the patient’s tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib’s myelopreservation benefits.
NCT02499770.
Objective
To determine whether there is an association between T2/T2* mapping and supraspinatus tendon mechanical properties as assessed by shear-wave ultrasound elastography (SWE).
Materials and ...methods
This HIPAA-compliant prospective pilot study received approval from our hospital’s institutional review board. Eight patients (3 males/5 females; age range 44–72 years) and nine shoulders underwent conventional shoulder MRI, T2/T2* mapping on a 3-T scanner, and SWE. Two musculoskeletal radiologists reviewed the MRI examinations in consensus for evidence of supraspinatus tendon pathology, with tear size measured for full-thickness tears. T2/T2* values and ultrasound shear-wave velocities (SWV) were calculated in three corresponding equidistant regions of interest (ROIs) within the insertional 1–2 cm of the supraspinatus tendon (medial, middle, lateral). Pearson correlation coefficients between T2/T2* values and SWV, as well as among T2, T2*, SWV and tear size, were calculated.
Results
There was a significant negative correlation between T2* and SWV in the lateral ROI (
r
= −0.86,
p
= 0.013) and overall mean ROI (
r
= −0.90,
p
= 0.006). There was significant positive correlation between T2 and measures of tear size in the lateral and mean ROIs (
r
range 0.71–0.77,
p
range 0.016–0.034). There was significant negative correlation between SWV and tear size in the middle and mean ROIs (
r
range −0.79–-0.68,
p
range 0.011–0.046).
Conclusion
Our pilot study demonstrated a potential relationship between T2* values and shear wave velocity values in the supraspinatus tendon, a finding that could lead to an improved, more quantitative evaluation of the rotator cuff tendons.
ABSTRACT
Beta-keratin in poultry feathers is a structural protein that is resistant to degradation due to disulfide and hydrogen bonds. Feather meal can be a valuable feed compound if the ...digestibility can be increased. The objective of the present study was to analyze the effects of chemical, enzymatic, and pressure-thermic treatments for chicken feathers on solubility, in vitro protein digestibility (IVPD), and amino acid composition of solubilized and residual fractions. Two experiments were conducted. In experiment 1, models for solubility and IVPD were developed including the above factors applying a central composite face-centered design. Addition of sodium hydroxide (NaOH) and sodium sulfite (Na2SO3), and autoclaving time affected solubility and IVPD of the feather hydrolysates, but not addition of keratinolytic enzyme. In experiment 2, 7 combinations of the hydrolysis factors NaOH, Na2SO3, and autoclaving time with a predicted IVPD of 900 g/kg of DM, calculated for the sum of solubilized and residual feather fractions, were included to measure effects on IVPD and amino acid composition in each fraction. The IVPD values were higher for solubilized than residual fractions when treated with NaOH and autoclaving, but no differences were found when treated with Na2SO3 and autoclaving. Losses of cystine were substantial for all treatments, but lower for Na2SO3 than for NaOH. Furthermore, use of lower Na2SO3 concentration and longer autoclaving time reduced losses of cystine. Compared with NaOH treatments, Na2SO3 gave lower losses of threonine, arginine, serine, and tyrosine. With reference to the ideal protein profile for Atlantic salmon (Salmo salar L.), the treatments with 60 or 90 min autoclaving and 0.36 or 0.21% Na2SO3 had the highest chemical scores. The scores were generally higher for amino acids in residual than solubilized fractions, but with 90 min autoclaving and 0.21% Na2SO3 differences were small. In conclusion, hydrolysis of chicken feathers with low concentrations of Na2SO3 combined with autoclaving results in feather meal with high nutritional value for Atlantic salmon; separation of solubilized and residual fractions is not necessary.
Molecular imaging approaches for metabolic and physiologic imaging of tumors have become important for treatment planning and response monitoring. However, the relationship between the physiologic ...and metabolic aspects of tumors is not fully understood. Here, we developed new hyperpolarized MRI and electron paramagnetic resonance imaging procedures that allow more direct assessment of tumor glycolysis and oxygenation status quantitatively. We investigated the spatial relationship between hypoxia, glucose uptake, and glycolysis in three human pancreatic ductal adenocarcinoma tumor xenografts with differing physiologic and metabolic characteristics. At the bulk tumor level, there was a strong positive correlation between
F-FDG-PET and lactate production, while pO
was inversely related to lactate production and
F-2-fluoro-2-deoxy-D-glucose (
F-FDG) uptake. However, metabolism was not uniform throughout the tumors, and the whole tumor results masked different localizations that became apparent while imaging.
F-FDG uptake negatively correlated with pO
in the center of the tumor and positively correlated with pO
on the periphery. In contrast to pO
and
F-FDG uptake, lactate dehydrogenase activity was distributed relatively evenly throughout the tumor. The heterogeneity revealed by each measure suggests a multimodal molecular imaging approach can improve tumor characterization, potentially leading to better prognostics in cancer treatment. SIGNIFICANCE: Novel multimodal molecular imaging techniques reveal the potential of three interrelated imaging biomarkers to profile the tumor microenvironment and interrelationships of hypoxia, glucose uptake, and glycolysis.
The linear polarization behavior of La1−xSrxCoO3−δ electrodes has been measured as a function of x, T, and PO2 using a.c. impedance. These measurements indicate a reaction mechanism in which O2 is ...reduced chemically at the porous mixed conductor surface, followed by diffusion of oxygen through the mixed conductor to the electrolyte. Analysis of the electrode kinetics using a recent model for this mechanism yields values for the oxygen vacancy diffusion coefficient (Dv) and surface-exchange rate constant (r0) as a function of x, T, and PO2. These values agree well with published independent measurements of oxygen chemical diffusion and isotope surface exchange (D̃ and k). The distance (δ) that the reaction extends beyond the electrode/electrolyte interface depends on both Dv and r0, varying between 0.3 and 10 microns for a typical electrode surface area.
•Several floral traits are associated with pollinator-related microbe transmission.•Beneficial and pathogenic microbes may share some transmission constraints.•Plant and pollinator community context ...can mediate microbial transmission at flowers.•Future work should clarify the causal role of floral traits in microbe transmission.
Flowers provide resources for pollinators, and can also be transmission venues for beneficial or pathogenic pollinator-associated microbes. Floral traits could mediate transmission similarly for beneficial and pathogenic microbes, although some beneficial microbes can grow in flowers while pathogenic microbes may only survive until acquired by a new host. In spite of conceptual similarities, research on beneficial and pathogenic pollinator-associated microbes has progressed mostly independently. Recent advances demonstrate that floral traits are associated with transmission of beneficial and pathogenic microbes, with consequences for pollinator populations and communities. However, there is a near-absence of experimental manipulations of floral traits to determine causal effects on transmission, and a need to understand how floral, microbe and host traits interact to mediate transmission.
Capitalism in Question Adler, Paul S.
Journal of management inquiry,
04/2014, Letnik:
23, Številka:
2
Journal Article
Recenzirano
Paul Adler was Program Chair for the 2013 meeting of the Academy of Management in Orlando, Florida, in August. In this capacity, he organized the “All-Academy Theme” component of the meeting program, ...helped by a committee of Tom Kochan (MIT), Jerry Davis (U. Michigan), Carrie Leana (U. Pittsburgh), and Stella Nkomo (U. Pretoria). The theme was “Capitalism in Question.” The essay below is an edited version of Paul’s presentation of the theme at the Presidential breakfast session, August 11, 2013. He argues that recurrent economic and financial crises and the emergence of protest movements around the world should encourage us as management scholars to consider more carefully the broader “political–economic” context of business and management—how organizational behavior, structure, and strategy differ across societies characterized by different political–economic structures, whether variants of capitalism or alternatives to it.
PREMISE OF THE STUDY: Florivory could have direct negative effects on plant fitness due to consumption of floral organs, and indirect effects mediated through changes in traits important to ...pollination. These effects likely vary with plant sexual system, depending on sex-or morph-specific patterns of damage. We investigated the direct and indirect effects of simulated florivory on male and female components of reproduction in the native, distylous vine Gelsemium sempervirens. METHODS: We crossed floral damage and supplemental pollination treatments in a common garden array and tracked pollinator behavioral responses. We also estimated male function using fluorescent dye as an analog for pollen transfer, and measured both fruit and seed production. KEY RESULTS: The effects of floral damage varied by floral morph, the genus of floral visitor, and the component of reproduction measured. Damage reduced the number of pollinator visits to pin but not thrum plants, and increased the time some pollinators spent per flower in thrum but not pin plants. Flowers of damaged plants transferred more dye particles to recipient plants compared to undamaged plants, but only later in the season when the majority of dye transfer occurred. Damage had no effect on female reproduction. CONCLUSION: These results suggest that florivory can have positive indirect effects on estimated male plant reproduction through changes in different pollinators' behavior at flowers, but the effects of floral damage vary with male vs. female function. These results underscore the importance of other species' interactions at flowers in driving pollinator behavior and pollen transfer dynamics.
Adler explores major shifts in crime-control policies across the nation during the interwar period. At precisely the moment when crime rates were high in the 1920s, incarceration rates were low. As ...crime rates fell, incarceration rates increased, and the clients of the system shifted largely from white to black. his examination of this earlier period presages what comes later and offers historians much greater complexity for weighing in on the much-debated question of whether or how much crime rates drove mass incarceration of the past half century.
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