Method for production of cellulose and hemicellulose fibers from lignocellulose biomass obtained from sugarcane leaves and buds by applying a process comprising the stages of: a) Diminishing the particle size of the lignocellulose biomass to a range between 3 and 15 mm, b) Subjecting the product obtained to treatment with one or more solvents and/or a mixture of specific catalysts, c) Carry out sudden decompression to an atmospheric pressure, d) Collecting the pretreated material in a cyclone, e) Optionally separating the liquid and solid fractions through washing and filterung f) Optionally, treating the solid fraction in a reactor with a mixture of ethanol and chlorine dioxide, d) Wash the product obtained to achieve cellulose efficiency above 50% and of lignin of 5 to 7%, fiber lengtht in a range to 1,5 to 2,7 mm, breaking length (km) of 7,0 -8,9, Burst index (kPam2/g) of 4,5-7,2 and Tear index (mNm2/g) of 8,2-8, The obtained high-resistance cellulose and hemicellulose is especially suitable for the paper production and polymer-type plastics.

A tire having a tread includes an outer tread layer and an inner tread layer. The inner tread layer includes one of a first elastomeric compound and a second elastomeric compound. The outer tread layer includes the other of the first and second elastomeric compounds. The second elastomeric compound has a lower rolling resistance and greater resistance to treadwear than the first elastomeric compound. The inner tread layer increases in thickness across at least a widthwise portion of the outer tread layer with a maximum thickness of one of the inner tread layer and the outer tread layer occurring near at least one of a first shoulder and a second shoulder of the tread. As the tread wears, the inner tread layer defines a greater proportion of a running surface of the tread.

A tooth for a blade of a hair cutting apparatus includes a root secured to a base of the blade, a tip opposite the root, and a longitudinal axis of the tooth defined between the root and the tip. A lower, planar cutting surface is provided on the tooth, as is an upper surface opposite the lower surface, and sidewalls separating the upper surface from the lower surface. At least a portion of the upper surface and the sidewalls is elliptical in the direction of the longitudinal axis, beginning at the tip.

A high-strength seamless steel pipe for oil wells excellent in sulfide stress cracking resistance which comprises, on the percent by mass basis, C: 0.1 to 0.20%, Si: 0.05 to 1.0%, Mn: 0.05 to 1.0%, Cr: 0.05 to 1.5%, Mo: 0.05 to 1.0%, Al: 0.10% or less, Ti: 0.002 to 0.05% and B: 0.0003 to 0.005%, with a value of equation “C+(Mn/6)+(Cr/5)+(Mo/3)” of 0.43 or more, with the balance being Fe and impurities, and in the impurities P: 0.025% or less, S: 0.010% or less and N: 0.007% or less. The seamless steel pipe may contain a specified amount of one or more element(s) of V and Nb, and/or a specified amount of one or more element(s) of Ca, Mg and REM. The seamless steel pipe can be produced at a low cost by adapting an in-line tube making and heat treatment process having a high production efficiency since a reheating treatment for refinement of grains is not required.

Provided is bearing steel excellent in workability after spheroidizing-annealing and in hydrogen fatigue resistance property after quenching and tempering. The bearing steel has a chemical composition containing, by mass %: 0.85% to 1.10% C; 0.30% to 0.80% Si; 0.90% to 2.00% Mn; 0.025% or less P; 0.02% or less S; 0.05% or less Al; 1.8% to 2.5% Cr; 0.15% to 0.4% Mo; 0.0080% or less N; and 0.0020% or less O, which further contains more than 0.0015% to 0.0050% or less Sb, with the balance being Fe and incidental impurities, to thereby effectively suppress the generation of WEA even in environment where hydrogen penetrates into the steel, so as to improve the roiling contact fatigue life and also the workability such as cuttability and forgeability of the material.

The galvannealed steel sheet includes: a galvannealed layer formed on at least one surface of a steel sheet and contains includes an amount of 0.05 mass % to 0.5 mass % of Al, an amount of 6 mass % of 12 mass % of Fe, and the balance composed of Zn and inevitable impurities; and a mixed layer formed on a surface of the galvannealed layer and includes a composite oxide of Mn, Zn, and P and an aqueous P compound, wherein the composite oxide includes 0.1 mg/m2 to 100 mg/m2 of Mn, an amount of 1 mg/m2 to 100 mg/m2 of P, and Zn, and a P/Mn ratio is 0.3 to 50, and wherein the total size of an area of the mixed layer in which an attached amount of P is equal to or more than 20 mg/m2 is 20% to 80% of a surface area of the mixed layer.

A method of producing an endodontic file that involves grinding in a plane substantially parallel to the longitudinal axis of a rotating dental instrument blank. By grinding the dental instrument blank in this manner, the torsional strength of the resulting endodontic file is not eroded during its production, thereby providing a file that is less susceptible to breakage during its use.

A combination massage table with one or more resistance bands (hereinafter, a combination table) is disclosed. In some embodiments, the combination table may comprise: a massage table; the one or more resistance bands; and a means for attaching the one or more resistance bands to the massage table; such that a client using the combination table receives at least one improved health benefit as compared against massage therapy without any resistance band use. Furthermore, methods for using the combination table are disclosed. Such methods may comprise: preparing the combination table for use; preparing the client so the client is laying on top of an upper surface of the combination table; and massaging the client while the client at least intermittently engages one or more resistance bands that are attached to the combination table; wherein in the at least intermittent engagement of the one or more resistance bands while the client is being massaged results in the at least one improved health benefit to the client.

A semiconductor structure is disclosed. The semiconductor structure includes a source trench in a drift region, the source trench having a source trench dielectric liner and a source trench conductive filler surrounded by the source trench dielectric liner, a source region in a body region over the drift region. The semiconductor structure also includes a patterned source trench dielectric cap forming an insulated portion and an exposed portion of the source trench conductive filler, and a source contact layer coupling the source region to the exposed portion of the source trench conductive filler, the insulated portion of the source trench conductive filler increasing resistance between the source contact layer and the source trench conductive filler under the patterned source trench dielectric cap. The source trench is a serpentine source trench having a plurality of parallel portions connected by a plurality of curved portions.

A polycrystalline diamond (PCD) with diamond grains includes a first zone of the diamond grains and a second zone of the diamond grains. The first zone forms a working surface and a first catalyzing material is disposed within voids of the diamond grains in the first zone. A second catalyzing material is bonded to the diamond grains disposed in the second zone. The first catalyzing material in the first zone is connected to the diamond grains disposed in the first zone less intimately than the second catalyzing material is bonded to the diamond grains in the second zone.

Various methods, apparatus, devices and systems are provided for electrically short antennas for efficient broadband transmission. In one example, among others, a system includes a segmentally time-variant antenna and a segment controller that can control conductivity of individual segments of the segmentally time-variant antenna. The conductivity of the individual segments is modulated to allow a pulse to propagate from the proximal end to the distal end of the segmentally time-variant antenna and impede a reflection of the pulse from propagating back to the proximal end of the segmentally time-variant antenna. In another embodiment, a method includes injecting a pulse at a first end of a segmentally time-variant antenna and modulating conductivity of individual segments to allow the pulse to propagate to a second end of the segmentally time-variant antenna and impede a reflection of the pulse from propagating back to the first end.

A method for protecting a surface of an article from sulfate corrosion resulting from exposure to a sulfate containing material at an elevated temperature includes coating the surface with a nickel based material to form an anti-corrosion coating. The nickel based material includes NiO, a spinel of formulation AB2O4, or a combination thereof, wherein A includes nickel, and B includes iron or a combination of manganese and a B site dopant.

The invention relates to a drilling-resistance measuring device (10) and to a method for material testing in a humid environment or underwater. The drilling-resistance measuring device (10) comprises a housing (1), in which a drive and a drill chuck (3) coupled to the drive are arranged, in which drill chuck a drilling needle (4) is or can be releasably held, wherein the housing (1) has a drilling-needle outlet opening (5') enclosed by a drilling-needle outlet guide (5), through which drilling-needle outlet opening the drilling needle (4) extends out of the housing (1). The drilling-resistance measuring device (10) comprises at least one water-tight bellows (6), which is arranged in the interior of the housing (1) around the drilling needle (4) between the drill chuck (3) and the drilling-needle outlet guide (5), wherein moisture or water can enter the bellows (6) through the drilling-needle outlet opening (5').

The present invention relates to the use of 1,1-diethoxyethane for increasing the knocking resistance of low-boiling gasoline with an initial boiling point (IBP) of 80° C. to 120° C. by at least 40 units (Research Octane Number).

PARIS (AP) — French Resistance member Cecile Rol-Tanguy, who risked her life during World War II by working to liberate Paris from Nazi occupation, has died. She was 101. Rol-Tanguy died on Friday at her home in Monteaux, in central France, as Europe commemorated the 75th anniversary of the surrender of Nazi Germany to Allied […]

PARIS (AP) — French Resistance member Cecile Rol-Tanguy, who risked her life during World War II by working to liberate Paris from Nazi occupation, has died. She was 101. Rol-Tanguy died on Friday at her home in Monteaux, in central France, as Europe commemorated the 75th anniversary of the surrender of Nazi Germany to Allied […]

The Jerramungup Shire says it is working with Bremer Bay residents to address concerns about proposed bushfire safety measures.

Historians often argue about the nature and extent of Aboriginal resistance to European settlement but one person who is clearly linked to that resistance is Pemulwuy.

Researchers from the University of Melbourne find fruit flies in temperate areas of Australia are building a resistance to common insecticides.

With skin sores, respiratory tract and ear infections and sore throats common in remote Indigenous communities, experts are urging immediate action to combat the rising rates of antibiotic resistance.

An in-depth understanding of immune escape mechanisms in cancer is likely to lead to innovative advances in immunotherapeutic strategies. However, much remains unknown regarding these mechanisms and how they impact immunotherapy resistance. Using several preclinical tumor models as well as clinical specimens, we identified a mechanism whereby CD8+ T cell activation in response to programmed cell death 1 (PD-1) blockade induced a programmed death ligand 1/NOD-, LRR-, and pyrin domain–containing protein 3 (PD-L1/NLRP3) inflammasome signaling cascade that ultimately led to the recruitment of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) into tumor tissues, thereby dampening the resulting antitumor immune response. The genetic and pharmacologic inhibition of NLRP3 suppressed PMN-MDSC tumor infiltration and significantly augmented the efficacy of anti–PD-1 antibody immunotherapy. This pathway therefore represents a tumor-intrinsic mechanism of adaptive resistance to anti–PD-1 checkpoint inhibitor immunotherapy and is a promising target for future translational research.

French Resistance member Cecile Rol-Tanguy, who risked her life during World War II by working to liberate Paris from Nazi occupation, has died. She was 101.

Certain habitats can help dampen the spread of ash dieback, which threatens ash trees.

Prostate cancer (PCa) cells heavily rely on an active androgen receptor (AR) pathway for their survival. Enzalutamide (MDV3100) is a second-generation antiandrogenic drug that was approved by the Food and Drug Administration in 2012 to treat patients with castration-resistant prostate cancer (CRPC). However, emergence of resistance against this drug is inevitable, and it has been a major challenge to develop interventions that help manage enzalutamide-resistant CRPC. Erythropoietin-producing human hepatocellular (Eph) receptors are targeted by ephrin protein ligands and have a broad range of functions. Increasing evidence indicates that this signaling pathway plays an important role in tumorigenesis. Overexpression of EPH receptor B4 (EPHB4) has been observed in multiple types of cancer, being closely associated with proliferation, invasion, and metastasis of tumors. Here, using RNA-Seq analyses of clinical and preclinical samples, along with several biochemical and molecular methods, we report that enzalutamide-resistant PCa requires an active EPHB4 pathway that supports drug resistance of this tumor type. Using a small kinase inhibitor and RNAi-based gene silencing to disrupt EPHB4 activity, we found that these disruptions re-sensitize enzalutamide-resistant PCa to the drug both in vitro and in vivo. Mechanistically, we found that EPHB4 stimulates the AR by inducing proto-oncogene c-Myc (c-Myc) expression. Taken together, these results provide critical insight into the mechanism of enzalutamide resistance in PCa, potentially offering a therapeutic avenue for enhancing the efficacy of enzalutamide to better manage this common malignancy.

Research Event

Event participants

Tim Jinks, Head of Drug-Resistant Infections Programme, Wellcome
Jim O’Neill, Chair, Review on Antimicrobial Resistance; Chair, Chatham House
Haileyesus Getahun, Director of Global Coordination and Partnership on Antimicrobial Resistance, World Health Organization 
Juan Lubroth, Chief Veterinary Officer, Food and Agriculture Organization (Videolink)
Jyoti Joshi, Head, South Asia, Center for Disease Dynamics, Economics & Policy
Estelle Mbadiwe, Coordinator-Nigeria, Global Antibiotic Resistance Partnership
Charles Clift, Senior Consulting Fellow, Chatham House; Report Author

Treatment of patients with chronic lymphocytic leukemia (CLL) with inhibitors of Bruton's tyrosine kinase (BTK), such as ibrutinib, is limited by primary or secondary resistance to this drug. Examinations of CLL patients with late relapses while on ibrutinib, which inhibits BTK's catalytic activity, revealed several mutations in BTK, most frequently resulting in the C481S substitution, and disclosed many mutations in PLCG2, encoding phospholipase C-γ2 (PLCγ2). The PLCγ2 variants typically do not exhibit constitutive activity in cell-free systems, leading to the suggestion that in intact cells they are hypersensitive to Rac family small GTPases or to the upstream kinases spleen-associated tyrosine kinase (SYK) and Lck/Yes-related novel tyrosine kinase (LYN). The sensitivity of the PLCγ2 variants to BTK itself has remained unknown. Here, using genetically-modified DT40 B lymphocytes, along with various biochemical assays, including analysis of PLCγ2-mediated inositol phosphate formation, inositol phospholipid assessments, fluorescence recovery after photobleaching (FRAP) static laser microscopy, and determination of intracellular calcium ([Ca2+]i), we show that various CLL-specific PLCγ2 variants such as PLCγ2S707Y are hyper-responsive to activated BTK, even in the absence of BTK's catalytic activity and independently of enhanced PLCγ2 phospholipid substrate supply. At high levels of B-cell receptor (BCR) activation, which may occur in individual CLL patients, catalytically-inactive BTK restored the ability of the BCR to mediate increases in [Ca2+]i. Because catalytically-inactive BTK is insensitive to active-site BTK inhibitors, the mechanism involving the noncatalytic BTK uncovered here may contribute to preexisting reduced sensitivity or even primary resistance of CLL to these drugs.

Research Event

Event participants

Tim Jinks, Head of Drug-Resistant Infections Programme, Wellcome
Jim O’Neill, Chair, Review on Antimicrobial Resistance; Chair, Chatham House
Haileyesus Getahun, Director of Global Coordination and Partnership on Antimicrobial Resistance, World Health Organization 
Juan Lubroth, Chief Veterinary Officer, Food and Agriculture Organization (Videolink)
Jyoti Joshi, Head, South Asia, Center for Disease Dynamics, Economics & Policy
Estelle Mbadiwe, Coordinator-Nigeria, Global Antibiotic Resistance Partnership
Charles Clift, Senior Consulting Fellow, Chatham House; Report Author

8 October 2019

A startling lack of progress on critical recommendations to tackle antimicrobial resistance is highlighted in this new global progress report, as well as opportunities for further action and key obstacles that need to be overcome.

Use the Download button to choose either the Research Paper, or the Background and Analysis Paper.

Prostate cancer (PCa) cells heavily rely on an active androgen receptor (AR) pathway for their survival. Enzalutamide (MDV3100) is a second-generation antiandrogenic drug that was approved by the Food and Drug Administration in 2012 to treat patients with castration-resistant prostate cancer (CRPC). However, emergence of resistance against this drug is inevitable, and it has been a major challenge to develop interventions that help manage enzalutamide-resistant CRPC. Erythropoietin-producing human hepatocellular (Eph) receptors are targeted by ephrin protein ligands and have a broad range of functions. Increasing evidence indicates that this signaling pathway plays an important role in tumorigenesis. Overexpression of EPH receptor B4 (EPHB4) has been observed in multiple types of cancer, being closely associated with proliferation, invasion, and metastasis of tumors. Here, using RNA-Seq analyses of clinical and preclinical samples, along with several biochemical and molecular methods, we report that enzalutamide-resistant PCa requires an active EPHB4 pathway that supports drug resistance of this tumor type. Using a small kinase inhibitor and RNAi-based gene silencing to disrupt EPHB4 activity, we found that these disruptions re-sensitize enzalutamide-resistant PCa to the drug both in vitro and in vivo. Mechanistically, we found that EPHB4 stimulates the AR by inducing proto-oncogene c-Myc (c-Myc) expression. Taken together, these results provide critical insight into the mechanism of enzalutamide resistance in PCa, potentially offering a therapeutic avenue for enhancing the efficacy of enzalutamide to better manage this common malignancy.

Treatment of patients with chronic lymphocytic leukemia (CLL) with inhibitors of Bruton's tyrosine kinase (BTK), such as ibrutinib, is limited by primary or secondary resistance to this drug. Examinations of CLL patients with late relapses while on ibrutinib, which inhibits BTK's catalytic activity, revealed several mutations in BTK, most frequently resulting in the C481S substitution, and disclosed many mutations in PLCG2, encoding phospholipase C-γ2 (PLCγ2). The PLCγ2 variants typically do not exhibit constitutive activity in cell-free systems, leading to the suggestion that in intact cells they are hypersensitive to Rac family small GTPases or to the upstream kinases spleen-associated tyrosine kinase (SYK) and Lck/Yes-related novel tyrosine kinase (LYN). The sensitivity of the PLCγ2 variants to BTK itself has remained unknown. Here, using genetically-modified DT40 B lymphocytes, along with various biochemical assays, including analysis of PLCγ2-mediated inositol phosphate formation, inositol phospholipid assessments, fluorescence recovery after photobleaching (FRAP) static laser microscopy, and determination of intracellular calcium ([Ca2+]i), we show that various CLL-specific PLCγ2 variants such as PLCγ2S707Y are hyper-responsive to activated BTK, even in the absence of BTK's catalytic activity and independently of enhanced PLCγ2 phospholipid substrate supply. At high levels of B-cell receptor (BCR) activation, which may occur in individual CLL patients, catalytically-inactive BTK restored the ability of the BCR to mediate increases in [Ca2+]i. Because catalytically-inactive BTK is insensitive to active-site BTK inhibitors, the mechanism involving the noncatalytic BTK uncovered here may contribute to preexisting reduced sensitivity or even primary resistance of CLL to these drugs.

VOLUME 292 (2017) PAGES 3531–3540This article has been withdrawn by Shuofeng Hu, Xiaomin Ying, Xiangming Zhang, and Ya Wang. Baocheng Hu, Xiang Wang, Ping Wang, Jian Wang, and Hongyan Wang could not be reached. In Fig. 1C, the DAPI and merged images for the no IR control were switched. The DNA-PKcs and actin immunoblots on the left appear to have been spliced. In Fig. 4C, the DNA-PKcs immunoblot appears to have been spliced. In Fig. 4D, lanes 1 and 5; lanes 2, 6, and 8; and lanes 3 and 7 of the DNA-PKcs immunoblot are the same. In the p-DNA-PKcs immunoblot, lanes 1 and 8, lanes 2 and 6, and lanes 3 and 7 are the same. In the CRY2 immunoblot, lanes 5 and 7 are the same. In the CDC25A immunoblot, lanes 3 and 8 are the same. In the GSK3B immunoblot, lanes 1 and 5 and lanes 3 and 7 are the same. Also in the GSK3B immunoblot, the upper GSK3B bands in lanes 6 and 8 are the same. Lanes 4 and 8 of the cyclin D1 immunoblot are the same. In Fig. 5A, the CDC25A immunoblot appears to have been spliced. Also in Fig. 5A, lanes 2–4 and lanes 6–8 of the CDC25A immunoblot are the same. Lanes 4–6 and 7–9 of the actin immunoblot are the same. In Fig. 5C, lane 1 of the CDC25A immunoblot was reused in lane 5, and lanes 3 and 4 were reused in lanes 7 and 8. In the...

(University of Johannesburg) Fly ash generated by coal-fired power stations is a global environmental headache, creating groundwater and air pollution from vast landfills and ash dams. The waste product can be repurposed into geopolymer concrete, such as precast heat-cured structural elements for buildings. However, a critical durability problem has been low resistance to extreme alkali attack. UJ researchers found that high temperature heat-treatment at 200 degrees Celsius can halve this harmful mechanism in fly ash geopolymer concretes.

Background: Patients with NHL who are treated with rituximab may develop resistant disease, often associated with changes in expression of CD20. The next generation β-particle emitting radioimmunoconjugate ¹⁷⁷Lu-lilotomab-satetraxetan (Betalutin®) was shown to up-regulate CD20 expression in different rituximab-sensitive NHL cell lines and to act synergistically with rituximab in a rituximab-sensitive NHL animal model. We hypothesized that ¹⁷⁷Lu-lilotomab-satetraxetan may be used to reverse rituximab-resistance in NHL. Methods: The rituximab-resistant Raji2R and the parental Raji cell lines were used. CD20 expression was measured by flow cytometry. ADCC was measured by a bioluminescence reporter assay. The efficacies of combined treatments with ¹⁷⁷Lu-lilotomab-satetraxetan (150MBq/kg or 350MBq/kg) and rituximab (4x10mg/kg) were compared with those of single agents or saline in a Raji2R-xenograft model. Cox-regression and the Bliss independence model were used to assess synergism. Results: Rituximab-binding in Raji2R cells was 36±5% of that in the rituximab-sensitive Raji cells. ¹⁷⁷Lu-lilotomab-satetraxetan treatment of Raji2R cells increased the binding to 53±3% of the parental cell line. Rituximab ADCC-induction in Raji2R cells was 20±2% of that induced in Raji cells, while treatment with ¹⁷⁷Lu-lilotomab-satetraxetan increased the ADCC-induction to 30±3% of the Raji cells, representing a 50% increase (p<0.05). The combination of rituximab with 350MBq/kg ¹⁷⁷Lu-lilotomab-satetraxetan synergistically suppressed Raji2R tumor growth in athymic Foxn1^nu mice. Conclusion: ¹⁷⁷Lu-lilotomab-satetraxetan has the potential to reverse rituximab-resistance; it increases binding and ADCC-activity in-vitro and can synergistically improve anti-tumor efficacy in-vivo.

Multidrug resistance-associated protein 1 (ABCC1) is abundantly expressed at the lung epithelial barrier, where it may influence the pulmonary disposition of inhaled drugs and contribute to variability in therapeutic response. Aim of this study was to assess the impact of ABCC1 on the pulmonary disposition of 6-bromo-7-¹¹C-methylpurine (¹¹C-BMP), a prodrug radiotracer which is intracellularly conjugated with glutathione to form the ABCC1 substrate S-(6-(7-¹¹C-methylpurinyl))glutathione (¹¹C-MPG). Methods: Groups of Abcc1(-/-) rats, wild-type rats pretreated with the ABCC1 inhibitor MK571 and wild-type control rats underwent dynamic PET scans after administration of ¹¹C-BMP intravenously (i.v.) or by intratracheal aerosolization (i.t.). In vitro transport experiments were performed with unlabeled BMP in the human distal lung epithelial cell line NCI-H441. Results: Pulmonary kinetics of radioactivity were significantly different between wild-type and Abcc1(-/-) rats, but differences were more pronounced after i.t. than after i.v. administration. After i.v. administration lung exposure (AUClung) was 77% higher and the elimination slope of radioactivity washout from the lungs (kE,lung) was 70% lower, whereas after i.t. administration AUClung was 352% higher and kE,lung was 86% lower in Abcc1(-/-) rats. Pretreatment with MK571 decreased kE,lung by 20% after i.t. radiotracer administration. Intracellular accumulation of MPG in NCI-H441 cells was significantly higher and extracellular efflux was lower in presence than in absence of MK571. Conclusion: PET with pulmonary administered ¹¹C-BMP can measure ABCC1 activity at the lung epithelial barrier and may be applicable in humans to assess the effects of disease, genetic polymorphisms or concomitant drug intake on pulmonary ABCC1 activity.

The molecular mechanisms underlying exceptional radioresistance in pancreatic cancer remain elusive. In the present study, we established a stable radioresistant pancreatic cancer cell line MIA PaCa-2-R by exposing the parental MIA PaCa-2 cells to fractionated ionizing radiation (IR). Systematic proteomics and bioinformatics analysis of protein expression in MIA PaCa-2 and MIA PaCa-2-R cells revealed that several growth factor-/cytokine-mediated pathways, including the OSM/STAT3, PI3K/AKT, and MAPK/ERK pathways, were activated in the radioresistant cells, leading to inhibition of apoptosis and increased epithelial-mesenchymal plasticity. In addition, the radioresistant cells exhibited enhanced capabilities of DNA repair and antioxidant defense compared with the parental cells. We focused functional analysis on one of the most up-regulated proteins in the radioresistant cells, ecto-5'-nucleotidase (CD73), which is a cell surface protein that is overexpressed in different types of cancer. Ectopic overexpression of CD73 in the parental cells resulted in radioresistance and conferred resistance to IR-induced apoptosis. Knockdown of CD73 re-sensitized the radioresistant cells to IR and IR-induced apoptosis. The effect of CD73 on radioresistance and apoptosis is independent of the enzymatic activity of CD73. Further studies demonstrate that CD73 up-regulation promotes Ser-136 phosphorylation of the proapoptotic protein BAD and is required for maintaining the radioresistant cells in a mesenchymal state. Our findings suggest that expression alterations in the IR-selected pancreatic cancer cells result in hyperactivation of the growth factor/cytokine signaling that promotes epithelial-mesenchymal plasticity and enhancement of DNA repair. Our results also suggest that CD73, potentially a novel downstream factor of the enhanced growth factor/cytokine signaling, confers acquired radioresistance by inactivating proapoptotic protein BAD via phosphorylation of BAD at Ser-136 and by maintaining the radioresistant pancreatic cancer cells in a mesenchymal state.

Triple-negative breast cancer (TNBC) is characterized by its aggressive biology, early metastatic spread, and poor survival outcomes. TNBC lacks expression of the targetable receptors found in other breast cancer subtypes, mandating use of cytotoxic chemotherapy. However, resistance to chemotherapy is a significant problem, encountered in about two-thirds of TNBC patients, and new strategies are needed to mitigate resistance. In this issue of the Journal of Biological Chemistry, Geck et al. report that TNBC cells are highly sensitive to inhibition of the de novo polyamine synthesis pathway and that inhibition of this pathway sensitizes cells to TNBC-relevant chemotherapy, uncovering new opportunities for addressing chemoresistance.

Treatment of patients with chronic lymphocytic leukemia (CLL) with inhibitors of Bruton's tyrosine kinase (BTK), such as ibrutinib, is limited by primary or secondary resistance to this drug. Examinations of CLL patients with late relapses while on ibrutinib, which inhibits BTK's catalytic activity, revealed several mutations in BTK, most frequently resulting in the C481S substitution, and disclosed many mutations in PLCG2, encoding phospholipase C-γ2 (PLCγ2). The PLCγ2 variants typically do not exhibit constitutive activity in cell-free systems, leading to the suggestion that in intact cells they are hypersensitive to Rac family small GTPases or to the upstream kinases spleen-associated tyrosine kinase (SYK) and Lck/Yes-related novel tyrosine kinase (LYN). The sensitivity of the PLCγ2 variants to BTK itself has remained unknown. Here, using genetically-modified DT40 B lymphocytes, along with various biochemical assays, including analysis of PLCγ2-mediated inositol phosphate formation, inositol phospholipid assessments, fluorescence recovery after photobleaching (FRAP) static laser microscopy, and determination of intracellular calcium ([Ca2+]i), we show that various CLL-specific PLCγ2 variants such as PLCγ2S707Y are hyper-responsive to activated BTK, even in the absence of BTK's catalytic activity and independently of enhanced PLCγ2 phospholipid substrate supply. At high levels of B-cell receptor (BCR) activation, which may occur in individual CLL patients, catalytically-inactive BTK restored the ability of the BCR to mediate increases in [Ca2+]i. Because catalytically-inactive BTK is insensitive to active-site BTK inhibitors, the mechanism involving the noncatalytic BTK uncovered here may contribute to preexisting reduced sensitivity or even primary resistance of CLL to these drugs.

Glucagon secretion is regulated by circulating glucose, but it has turned out that amino acids also play an important role, and that hepatic amino acid metabolism and glucagon are linked in a mutual feed-back cycle, the liver-alpha cell axis. On this background, we hypothesized that hepatic steatosis might impair glucagon’s action on hepatic amino acid metabolism and lead to hyperaminoacidemia and hyperglucagonemia.

We subjected 15 healthy lean and 15 obese steatotic male participants to a pancreatic clamp with somatostatin and evaluated hepatic glucose and amino acid metabolism during basal and high physiological levels of glucagon. The degree of steatosis was evaluated from liver biopsies.

Total RNA sequencing of liver biopsies revealed perturbations in the expression of genes predominantly involved in amino acid metabolism in the obese steatotic individuals. This group was also characterized by fasting hyperglucagonemia, hyperaminoacidemia and an absent lowering of amino acid levels in response to high levels of glucagon. Endogenous glucose production was similar between lean and obese individuals.

Our results suggest that hepatic steatosis causes resistance to the effect of glucagon on amino acid metabolism resulting in increased amino acid concentrations as well as increased glucagon secretion providing a likely explanation of fatty liver-associated hyperglucagonemia.

Prostate cancer (PCa) cells heavily rely on an active androgen receptor (AR) pathway for their survival. Enzalutamide (MDV3100) is a second-generation antiandrogenic drug that was approved by the Food and Drug Administration in 2012 to treat patients with castration-resistant prostate cancer (CRPC). However, emergence of resistance against this drug is inevitable, and it has been a major challenge to develop interventions that help manage enzalutamide-resistant CRPC. Erythropoietin-producing human hepatocellular (Eph) receptors are targeted by ephrin protein ligands and have a broad range of functions. Increasing evidence indicates that this signaling pathway plays an important role in tumorigenesis. Overexpression of EPH receptor B4 (EPHB4) has been observed in multiple types of cancer, being closely associated with proliferation, invasion, and metastasis of tumors. Here, using RNA-Seq analyses of clinical and preclinical samples, along with several biochemical and molecular methods, we report that enzalutamide-resistant PCa requires an active EPHB4 pathway that supports drug resistance of this tumor type. Using a small kinase inhibitor and RNAi-based gene silencing to disrupt EPHB4 activity, we found that these disruptions re-sensitize enzalutamide-resistant PCa to the drug both in vitro and in vivo. Mechanistically, we found that EPHB4 stimulates the AR by inducing proto-oncogene c-Myc (c-Myc) expression. Taken together, these results provide critical insight into the mechanism of enzalutamide resistance in PCa, potentially offering a therapeutic avenue for enhancing the efficacy of enzalutamide to better manage this common malignancy.

Multidrug resistance (MDR) in cancer arises from cross-resistance to structurally- and functionally-divergent chemotherapeutic drugs. In particular, MDR is characterized by increased expression and activity of ATP-binding cassette (ABC) superfamily transporters. Sphingolipids are substrates of ABC proteins in cell signaling, membrane biosynthesis, and inflammation, for example, and their products can favor cancer progression. Glucosylceramide (GlcCer) is a ubiquitous glycosphingolipid (GSL) generated by glucosylceramide synthase, a key regulatory enzyme encoded by the UDP-glucose ceramide glucosyltransferase (UGCG) gene. Stressed cells increase de novo biosynthesis of ceramides, which return to sub-toxic levels after UGCG mediates incorporation into GlcCer. Given that cancer cells seem to mobilize UGCG and have increased GSL content for ceramide clearance, which ultimately contributes to chemotherapy failure, here we investigated how inhibition of GSL biosynthesis affects the MDR phenotype of chronic myeloid leukemias. We found that MDR is associated with higher UGCG expression and with a complex GSL profile. UGCG inhibition with the ceramide analog d-threo-1-(3,4,-ethylenedioxy)phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (EtDO-P4) greatly reduced GSL and monosialotetrahexosylganglioside levels, and co-treatment with standard chemotherapeutics sensitized cells to mitochondrial membrane potential loss and apoptosis. ABC subfamily B member 1 (ABCB1) expression was reduced, and ABCC-mediated efflux activity was modulated by competition with nonglycosylated ceramides. Consistently, inhibition of ABCC-mediated transport reduced the efflux of exogenous C6-ceramide. Overall, UGCG inhibition impaired the malignant glycophenotype of MDR leukemias, which typically overcomes drug resistance through distinct mechanisms. This work sheds light on the involvement of GSL in chemotherapy failure, and its findings suggest that targeted GSL modulation could help manage MDR leukemias.

Triple-negative breast cancer (TNBC) is characterized by its aggressive biology, early metastatic spread, and poor survival outcomes. TNBC lacks expression of the targetable receptors found in other breast cancer subtypes, mandating use of cytotoxic chemotherapy. However, resistance to chemotherapy is a significant problem, encountered in about two-thirds of TNBC patients, and new strategies are needed to mitigate resistance. In this issue of the Journal of Biological Chemistry, Geck et al. report that TNBC cells are highly sensitive to inhibition of the de novo polyamine synthesis pathway and that inhibition of this pathway sensitizes cells to TNBC-relevant chemotherapy, uncovering new opportunities for addressing chemoresistance.

Mandeep Bajaj
Dec 1, 2012; 61:3078-3080
Commentary

Roy Taylor
Apr 1, 2012; 61:778-779
Commentary

Patrice D. Cani
Jul 1, 2007; 56:1761-1772
Obesity Studies

Marlou L. Dirks
Oct 1, 2016; 65:2862-2875
Metabolism

Adipose tissue macrophages (ATMs) are involved in the development of insulin resistance in obesity. We have recently shown that myeloid cell–specific reduction of HMG-CoA reductase (Hmgcr^m–/m–), which is the rate-limiting enzyme in cholesterol biosynthesis, protects against atherosclerosis by inhibiting macrophage migration in mice. We hypothesized that ATMs are harder to accumulate in Hmgcr^m–/m– mice than in control Hmgcr^fl/fl mice in the setting of obesity. To test this hypothesis, we fed Hmgcr^m–/m– and Hmgcr^fl/fl mice a high-fat diet (HFD) for 24 weeks and compared plasma glucose metabolism as well as insulin signaling and histology between the two groups. Myeloid cell–specific reduction of Hmgcr improved glucose tolerance and insulin sensitivity without altering body weight in the HFD-induced obese mice. The improvement was due to a decrease in the number of ATMs. The ATMs were reduced by decreased recruitment of macrophages as a result of their impaired chemotactic activity. These changes were associated with decreased expression of proinflammatory cytokines in adipose tissues. Myeloid cell–specific reduction of Hmgcr also attenuated hepatic steatosis. In conclusion, reducing myeloid HMGCR may be a promising strategy to improve insulin resistance and hepatic steatosis in obesity.

Steven M Haffner
Jun 1, 1992; 41:715-722
Original Article