Acute myeloid leukemia (AML) is the most common form of adult acute leukemia with ~20,000 new cases yearly. The disease develops in people of all ages, but is more prominent in the elderly, who due ...to limited treatment options, have poor overall survival rates. Monoclonal antibodies (mAb) targeting specific cell surface molecules have proven to be safe and effective in different haematological malignancies. However, AML target molecules are currently limited so discovery of new targets would be highly beneficial to patients. We examined the C-type lectin receptor CD302 as a potential therapeutic target for AML due to its selective expression in myeloid immune populations. In a cohort of 33 AML patients with varied morphological and karyotypic classifications, 88% were found to express CD302 on the surface of blasts and 80% on the surface of CD34+ CD38- population enriched with leukemic stem cells. A mAb targeting human CD302 was effective in mediating antibody dependent cell cytotoxicity and was internalised, making it amenable to toxin conjugation. Targeting CD302 with antibody limited in vivo engraftment of the leukemic cell line HL-60 in NOD/SCID mice. While CD302 was expressed in a hepatic cell line, HepG2, this molecule was not detected on the surface of HepG2, nor could HepG2 be killed using a CD302 antibody-drug conjugate. Expression was however found on the surface of haematopoietic stem cells suggesting that targeting CD302 would be most effective prior to haematopoietic transplantation. These studies provide the foundation for examining CD302 as a potential therapeutic target for AML.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) significantly reduces the rate of relapse in acute myeloid leukemia (AML) but comes at the cost of significant treatment-related ...mortality. Despite the reduction in relapse overall, it remains common, especially in high-risk groups. The outcomes for patients who relapse after transplant remains very poor. A large proportion of the morbidity that prevents most patients from accessing allo-HSCT is due to toxic nonspecific conditioning agents that are required to remove recipient hematopoietic stem and progenitor cells (HSPCs), allowing for successful donor engraftment. CD300f is expressed evenly across HSPC subtypes. CD300f has transcription and protein expression equivalent to CD33 on AML. We have developed an anti-CD300f antibody that efficiently internalizes into target cells. We have generated a highly potent anti-CD300f antibody-drug conjugate (ADC) with a pyrrolobenzodiazepine warhead that selectively depletes AML cell lines and colony forming units in vitro. The ADC synergizes with fludarabine, making it a natural combination to use in a minimal toxicity conditioning regimen. Our ADC prolongs the survival of mice engrafted with human cell lines and depletes primary human AML engrafted with a single injection. In a humanized mouse model, a single injection of the ADC depletes CD34+ HSPCs and CD34+CD38−CD90+ hematopoietic stem cells. This work establishes an anti-CD300f ADC as an attractive potential therapeutic that, if validated in transplant models using a larger cohort of primary AML samples, will reduce relapse rate and toxicity for patients with AML undergoing allo-HSCT.
•CD300f is expressed in the majority of AML patients and across HSPCs; an anti-CD300f ADC depletes AML cells and HSPCs.•In vitro and in vivo data suggest targeted CD300f therapy enhances efficacy and reduces toxicity of HSCT in AML.
Display omitted
Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) significantly reduces the rate of relapse in Acute Myeloid Leukemia (AML) but comes at the cost of significant Treatment Related ...Mortality (TRM). Despite the reduction in relapse overall, it remains common, especially in high risk groups. There is increasing evidence that many cases of relapse are driven by residual AML that can be detected with minimal residual disease techniques. A large proportion of the morbidity that prevents most patients accessing allo-HSCT is due to nonspecific toxic conditioning agents which are required to remove recipient Hematopoietic Stem and Progenitor Cells (HSPC) allowing for successful engraftment. We propose that a targeted conditioning agent against AML and HSPC can facilitate a reduction in relapse and TRM in allo-HSCT.
CD300f is expressed evenly across HSPC subtypes. CD300f has equivalent transcription and protein expression as CD33 on AML. We have developed an anti-CD300f antibody which efficiently internalises into target cells. Harnessing this ability to internalise, we have generated a highly potent anti-CD300f Antibody Drug Conjugate (ADC) with a pyrrolobenzodiazepine (PBD) warhead which selectively depletes AML cell lines in vitro. Colony Forming Units were inhibited when cultured in the presence of the ADC. The anti-CD300f ADC has a rapid onset of action with >99% cytotoxicity of the AML cell line HL-60 occurring within 24 hours. The ADC synergises with fludarabine, making it a natural combination to use in a minimal toxicity conditioning regimen.
The growth of subcutaneous tumours in mice engrafted with the AML cell line U937 was significantly reduced by a single dose of our ADC (at 150 μg/kg or 300 μg/kg). In a bone marrow engraftment model with HL-60, our ADC prolongs the survival at a single dose of 300 μg/kg (Fig 1A). In a humanised mouse model, 85% of all CD34+ cells and 90% of the primitive CD34+ CD38- CD90+ population were depleted with a single injection of our ADC at 300 μg/kg (Fig1 B). There was significant reduction in primary AML cells with a single injection of our ADC at 300 μg/kg (Fig 1C).
This proof of principle work establishes an anti-CD300f ADC as an attractive potential therapeutic to develop which will reduce the toxicity of allo-HSCT and the relapse rate afterwards. We have demonstrated that CD300f is expressed across HSPC and AML. Our antibody to CD300f is efficiently internalised and capable of delivering a PBD warhead. Our ADC synergised with fludarabine and has a rapid onset of action. We have demonstrated that our ADC prolongs survival in mouse cell line models as well as depletes both HSPC and primary AML in vivo. A targeted conditioning agent has the potential to reduce relapse risk and toxicity of allo-HSCT in AML.
Hypertension is of frequent occurrence in the elderly population.Isolated systolic hypertension(ISH) accounts for the majority of cases of hypertension in the elderly.ISH is associated with a ...2-4-fold increase in the risk of myocardial infarction,left ventricular hypertrophy,renal dysfunction,stroke,and cardiovascular mortality.There have been many studies to determine the optimal treatment for hypertension in the elderly. Why,when and how to treat hypertension in the elderly was the scope of the majority of these trials.Despite countless efforts many aspects remain obscure.While a number of novel drugs are being developed,the issue of whether all antihypertensive drugs bestow parallel benefits or whether some agents offer a therapeutic advantage beyond blood pressure control remains of crucial importance.Furthermore,the response of theelderly to different antihypertensive agents also differs from that of younger patients and may explain some of the disparities in outcomes of trials conducted in elderly patients with hypertension.
The aims of this study were to identify resistance to spot form of net blotch (SFNB) in spring barley and to investigate the stability of SFNB resistance in Morocco. The seedling resistance to SFNB ...was evaluated by inoculating 340 barley genotypes with the
Pyrenophora teres F. maculata
(Ptm) isolate FGOB10Ptm-1 (FGO) in the greenhouse. The same barely genotypes were evaluated for adult-stage plant resistance to SFNB in field trials in Morocco. All experiments were conducted in alpha-lattices with two replicates. SFNB disease severity was estimated on barley leaves using double digit scale. To investigate the stability of both qualitative and quantitative resistance to SFNB, 104 barley genotypes were subjected to AMMI analysis. Differential responses of SFNB barley resistance to FGO were found at the seedling stage in the greenhouse. Twelve genotypes showing scores of <1.5, at the seedling stage, were determined to be highly resistant to FGO. The ANOVA showed highly significant (
p
< 0.001) effects of genotype (G) and G × E (E-Pathotypes of SFNB) interaction on SFNB severity among the 340 barley genotypes at the adult plant stage. The AMMI ANOVA showed that IPCA1, IPCA2 and IPCA3 accounted for 77.9% of the variation of the G × E interaction for SFNB severity. The G × E interaction consisted of divergent genotypic responses to SFNB severity due to different pathotypes prevalent in hot-spot environments. The AMMI stability value demonstrated that barley genotypes AM-14, 30, 31, 68, 107, 108, 112, 149, 170, 185, 204, 240, 304, 326, 326 and 337 were resistant and stable across hot-spot environments against SFNB. Divergent environmental responses of SFNB were recorded in MCH_2015, SE_2015, AT_2016, SE_2016 and JS_2015. Stable SFNB resistant genotypes are valuable resources for the introgression of qualitative and quantitative resistance to barley in Morocco.
This study was conducted to identify stable resistance to net form of net blotch (NFNB) in spring barley in Moroccan environments. Seedling resistance to NFNB was evaluated by inoculating 336 barley ...genotypes with two NFNB isolates LDNH04Ptt‐19 and TD‐10 in the greenhouse. These genotypes were evaluated for adult plant resistance to NFNB under seven environments in Morocco in 2015 and 2016. The disease severity was estimated at GS 77–87 on barley leaves using a double‐digit scale. To investigate stability of resistance, 149 barley genotypes were subjected to AMMI analysis. At the seedling stage, differential responses of barley genotypes to different NFNB isolates were identified, whereas genotypes had variable stability to NFNB resistance at the adult stages. Five genotypes, AM‐68, AM‐95, AM‐250, AM‐267 and AM‐322, were resistant to both NFNB isolates at the seedling stage. There were significant (p < .001) effects of genotype (G) and G × E interaction on NFNB severity for barley genotypes at the adult stage. The principal components, IPCA1 and IPCA2, accounted for 48.4% and 18.7% variation for NFNB severity, respectively. The AMMI stability values (ASVs) ranged from 0.01 to 15.5, and fifty‐nine barley genotypes had stable responses (ASV ≤ 0.05) across all seven environments. Specifically, two stable genotypes, AM‐187 and AM‐244, had lower mean NFNB severities across all environments, suggesting a quantitative resistance in these genotypes. Divergent environmental responses of NFNB severity were measured in Sidi El Ayedi 2015 and Sidi Allal Tazi 2016, suggesting that these environments may be suitable to capture resistance to diverse pathotypes. These stable genotypes are valuable resources for introgression of both qualitative resistance and quantitative resistance to NFNB in future.
Among morphological characteristics that differentiate a male from a female, tooth size has also been evaluated in various populations for its applicability in anthropologic and forensic ...investigations to identify the gender from dental remains. The present study was undertaken to investigate the accuracy of mesio-distal width of the mandibular canines, inter-canine arch width, and Mandibular Canine Index (MCI) with which gender can be differentiated in Moradabad population and to correlate the results with other available data.
A cross-sectional study was conducted on the casts of 30 males and 30 females between the age group of 19-30 years.
The mean right and left canine dimension (RCW and LCW) for females was between 6.28 mm and 6.54 mm while that of males was 7.06 mm and 7.45 mm. The mean inter-canine arch width (ICW) in males was 27.64 mm, whereas in females was 23.42 mm. Area under curve (AUC) of ICW, RCW, and LCW had 100%, 98%, and 99.7%. The predicted sensitivity and specificity observed of three criteria was 100% for ICW, 93.3% and 93.3% for RCW, and 96.7% and 100% for LCW, which were found to be highly statistically significant. The mean values of right and left CMI were significantly higher in females as compared to males (P < 0.001).
The MCI parameter in the present study was a quick and reliable method for sexual identification and showed sexual dimorphism by both the RMCI and LMCI with greater significance in identifying females by using RMCI.
In the Czochralski growth of GGG/Nd:GGG, the percentage of oxygen flowing in the growth chamber plays an important role in eliminating or controlling a number of growth problems. In this paper we ...report the growth of Nd3+:Gd3Ga5O12 (Nd:GGG) crystal at different flow rates of argon and oxygen percentages (1–2%) and concluded that the optimum percentage is 1.0–1.2%. No effect on the crystal growth was observed while increasing the argon flow rate from 240LPH to 420LPH and by keeping same percentage of oxygen. The growth of Nd:GGG crystal by the Czochralski technique with a flat crystal/melt interface was also studied using different crucible sizes and under the same crystal growth conditions. In this study, it was found that the critical Reynolds number, which measures the flow driven by crystal rotation to achieve flat crystal/melt interface, is directly proportional to the crucible diameter. And the crucible diameter (D) is related with the crystal diameter (d) by equation D=Kωd2, where K is the proportionality constant and ω is the crystal rotation rate. We also found that for a given crucible, the critical Reynolds number remains the same even for different crystal diameters.
► This paper reports the growth of Nd:GGG crystal at different gas flows and crucibles. ► Optimum oxygen percentage is 1.0–1.2% and no effect by increasing argon. ► For flat interface, the critical Re is proportional to the crucible diameter. ► Crucible diameter (D) is related with crystal diameter (d) by D=Kωd2. ► For a given crucible and thermal condition, the critical Re remains constant.
Nd:GGG crystals (GGG is gadolinium gallium garnet) grown with different crystal/melt interface shapes (convex/flat/concave) by varying the seed rotation rate while using the Czochralski technique ...were studied for their optical homogeneity and crystalline perfection by optical polarization microscopy (OPM) and high‐resolution X‐ray diffractometry (HRXRD), respectively. It was found that there is a remarkable effect of seed rotation rate, which decides the shape of the crystal/melt interface, on the optical homogeneity and crystalline perfection. It was found experimentally that, as the rotation rate increases, the crystal/melt interface changes from convex to flat. If the rate further increases the interface becomes concave. With a steep convex interface (for low rotation rates), certain facets are concentrated in the small central portion of the crystal, and as the rate increases, these facets slowly move outward, leading to improved optical homogeneity and crystalline perfection as observed from the OPM and HRXRD results. The strain developed in the crystalline matrix as a result of segregation of oxygen in the crystals at low seed rotation rates as observed from HRXRD seems to be the reason for the observed optical inhomogeneity. The correlation between optical inhomogeneity and crystalline perfection for a variety of specimens with different shapes of the crystal/liquid interface obtained at different seed rotation rates is reported.
PDF
