The paper reports a new method for three-dimensional observation of the location of focused particle streams along both the depth and width of the channel cross-section in spiral inertial microfluidic systems. The results confirm that particles are focused near the top and bottom walls of the microchannel cross-section, revealing clear insights on the focusing and separation mechanism. Based on this detailed understanding of the force balance, we introduce a novel spiral microchannel with a trapezoidal cross-section that generates stronger Dean vortices at the outer half of the channel. Experiments show that particles focusing in such device are sensitive to particle size and flow rate, and exhibits a sharp transition from the inner half to the outer half equilibrium positions at a size-dependent critical flow rate. As particle equilibration positions are well segregated based on different focusing mechanisms, a higher separation resolution is achieved over conventional spiral microchannels with rectangular cross-section.
NOTCH2 mutations in splenic marginal zone lymphoma are associated with poor prognosis.
Splenic marginal zone lymphoma (SMZL), the most common primary lymphoma of spleen, is poorly understood at the genetic level. In this study, using whole-genome DNA sequencing (WGS) and confirmation by Sanger sequencing, we observed mutations identified in several genes not previously known to be recurrently altered in SMZL. In particular, we identified recurrent somatic gain-of-function mutations in NOTCH2, a gene encoding a protein required for marginal zone B cell development, in 25 of 99 (∼25%) cases of SMZL and in 1 of 19 (∼5%) cases of nonsplenic MZLs. These mutations clustered near the C-terminal proline/glutamate/serine/threonine (PEST)-rich domain, resulting in protein truncation or, rarely, were nonsynonymous substitutions affecting the extracellular heterodimerization domain (HD). NOTCH2 mutations were not present in other B cell lymphomas and leukemias, such as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 15), mantle cell lymphoma (MCL; n = 15), low-grade follicular lymphoma (FL; n = 44), hairy cell leukemia (HCL; n = 15), and reactive lymphoid hyperplasia (n = 14). NOTCH2 mutations were associated with adverse clinical outcomes (relapse, histological transformation, and/or death) among SMZL patients (P = 0.002). These results suggest that NOTCH2 mutations play a role in the pathogenesis and progression of SMZL and are associated with a poor prognosis.
Rationale and Objectives
The purpose of this study was to compare tumor volume in a VX2 rabbit model as calculated using semiautomatic tumor segmentation from C-arm cone-beam computed tomography (CBCT) and multidetector computed tomography (MDCT) to the actual tumor volume.
Materials and Methods
Twenty VX2 tumors in 20 adult male New Zealand rabbits (one tumor per rabbit) were imaged with CBCT (using an intra-arterial contrast medium injection) and MDCT (using an intravenous contrast injection). All tumor volumes were measured using semiautomatic three-dimensional volumetric segmentation software. The software uses a region-growing method using non-Euclidean radial basis functions. After imaging, the tumors were excised for pathologic volume measurement. The imaging-based tumor volume measurements were compared to the pathologic volumes using linear regression, with Pearson’s test, and correlated using Bland-Altman analysis.
Average tumor volumes were 3.5 ± 1.6 cm3 (range, 1.4–7.2 cm3) on pathology, 3.8 ± 1.6 cm3 (range, 1.3–7.3 cm3) on CBCT, and 3.9 ± 1.6 (range, 1.8–7.5 cm3) on MDCT (P < .001). A strong correlation between volumes on pathology and CBCT and also with MDCT was observed (Pearson’s correlation coefficient = 0.993 and 0.996, P < .001, for CBCT and MDCT, respectively). Bland-Altman analysis showed that MDCT tended to overestimate tumor volume, and there was stronger agreement for tumor volume between CBCT and pathology than with MDCT, possibly because of the intra-arterial contrast injection.
Tumor volume as measured using semiautomatic tumor segmentation software showed a strong correlation with the “real volume” measured on pathology. The segmentation software on CBCT and MDCT can be a useful tool for volumetric hepatic tumor assessment.
Tumor segmentation software; C-arm cone-beam CT; multidetector CT; VX2 hepatic tumor
Environment-friendly management of fruit flies involving pheromones is useful in reducing the undesirable pest populations responsible for decreasing the yield and the crop quality. A nanogel has been prepared from a pheromone, methyl eugenol (ME) using a low-molecular mass gelator. This was very stable at open ambient conditions and slowed down the evaporation of pheromone significantly. This enabled its easy handling and transportation without refrigeration, and reduction in the frequency of pheromone recharging in the orchard. Notably the involvement of the nano-gelled pheromone brought about an effective management of Bactrocera dorsalis, a prevalent harmful pest for a number of fruits including guava. Thus a simple, practical and low cost green chemical approach is developed that has a significant potential for crop protection, long lasting residual activity, excellent efficacy and favorable safety profiles. This makes the present invention well-suited for pest management in a variety of crops.
Presence and frequency of rare circulating tumor cells (CTCs) in bloodstreams of cancer patients are pivotal to early cancer detection and treatment monitoring. Here, we use a spiral microchannel with inherent centrifugal forces for continuous, size-based separation of CTCs from blood (Dean Flow Fractionation (DFF)) which facilitates easy coupling with conventional downstream biological assays. Device performance was optimized using cancer cell lines (> 85% recovery), followed by clinical validation with positive CTCs enumeration in all samples from patients with metastatic lung cancer (n = 20; 5–88 CTCs per mL). The presence of CD133+ cells, a phenotypic marker characteristic of stem-like behavior in lung cancer cells was also identified in the isolated subpopulation of CTCs. The spiral biochip identifies and addresses key challenges of the next generation CTCs isolation assay including antibody independent isolation, high sensitivity and throughput (3 mL/hr); and single-step retrieval of viable CTCs.
Esophageal adenocarcinoma (EAC) arises from Barrett esophagus (BE), intestinal-like columnar metaplasia linked to reflux esophagitis. In a transgenic mouse model of BE, esophageal overexpression of interleukin-1β phenocopies human pathology with evolution of esophagitis, Barrett’s-like metaplasia and EAC. Histopathology and gene signatures resembled closely human BE, with upregulation of TFF2, Bmp4, Cdx2, Notch1 and IL-6. The development of BE and EAC was accelerated by exposure to bile acids and/or nitrosamines, and inhibited by IL-6 deficiency. Lgr5+ gastric cardia stem cells present in BE were able to lineage trace the early BE lesion. Our data suggest that BE and EAC arise from gastric progenitors due to a tumor-promoting IL-1β-IL-6 signaling cascade and Dll1-dependent Notch signaling.
BMI1 is a potent inducer of neural stem cell self-renewal and neural progenitor cell proliferation during development and in adult tissue homeostasis. It is overexpressed in numerous human cancers – including medulloblastomas, in which its functional role is unclear. We generated transgenic mouse lines with targeted overexpression of Bmi1 in the cerebellar granule cell lineage, a cell type that has been shown to act as a cell of origin for medulloblastomas. Overexpression of Bmi1 in granule cell progenitors (GCPs) led to a decrease in cerebellar size due to decreased GCP proliferation and repression of the expression of cyclin genes, whereas Bmi1 overexpression in postmitotic granule cells improved cell survival in response to stress by altering the expression of genes in the mitochondrial cell death pathway and of Myc and Lef-1. Although no medulloblastomas developed in ageing cohorts of transgenic mice, crosses with Trp53−/− mice resulted in a low incidence of medulloblastoma formation. Furthermore, analysis of a large collection of primary human medulloblastomas revealed that tumours with a BMI1high TP53low molecular profile are significantly enriched in Group 4 human medulloblastomas. Our data suggest that different levels and timing of Bmi1 overexpression yield distinct cellular outcomes within the same cellular lineage. Importantly, Bmi1 overexpression at the GCP stage does not induce tumour formation, suggesting that BMI1 overexpression in GCP-derived human medulloblastomas probably occurs during later stages of oncogenesis and might serve to enhance tumour cell survival.
Aberrant signaling through the class I phosphatidylinositol 3-kinase (PI3K)-Akt axis is frequent in human cancer. Here we show that Beclin 1, an essential autophagy and tumor suppressor protein, is a target of the protein kinase Akt. Expression of a Beclin 1 mutant resistant to Akt-mediated phosphorylation increased autophagy, reduced anchorage-independent growth, and inhibited Akt-driven tumorigenesis. Akt-mediated phosphorylation of Beclin 1 enhanced its interactions with 14-3-3 and vimentin intermediate filament proteins, and vimentin depletion increased autophagy and inhibited Akt-driven transformation. Thus, Akt-mediated phosphorylation of Beclin 1 functions in autophagy inhibition, oncogenesis, and the formation of an autophagy-inhibitory Beclin 1/14-3-3/vimentin intermediate filament complex. These findings have broad implications for understanding the role of Akt signaling and intermediate filament proteins in autophagy and cancer.
We demonstrate rapid mixing of sub-microliter droplets (250nl) using miniaturized magnetic stir bars (400 μm by 200 μm by 15 μm). The stir bars are fabricated using laser micromachining and placed on the substrate on which the drops are manipulated. They are activated by an externally applied magnetic field and used in combination with on-demand drop merging in enthalpy arrays. This technique results in a 10-fold increase in mixing rate, and a mixing time constant of about 2 seconds. Drop mixing times are measured by Förster resonance energy transfer (FRET) and verified by thermodynamic measurements of binding and enzymatic reactions.
Rationale and Objectives
Subtle subject movement during high-resolution 3D μMR imaging of trabecular bone (TB) causes blurring, thereby rendering the data unreliable for quantitative analysis. In this work, the effects of translational and rotational motion displacements have been evaluated qualitatively and quantitatively.
Materials and Methods
In Experiment I, motion was induced by applying various simulated and previously observed in vivo trajectories as phase shifts to k-space or rotation angles to k-space segments of a virtually motion-free data set. In Experiment II, images that were visually free of motion artifacts from two groups of 10 healthy individuals, differing in age, were selected for probing the effects of motion on TB parameters. In both experiments, images were rated for motion severity and the scores were compared to a focus criterion, the normalized gradient squared (NGS).
Strong correlations were observed between the motion quality scores and the corresponding NGS values (R2= 0.52–0.64; p<0.01). The results from Experiment I demonstrated consistently lower image quality and alterations in structural parameters of 9–45% with increased amplitude of displacements. In Experiment II, the significant differences in structural parameter group means of the motion-free images were lost upon motion degradation. Autofocusing, a post-processing correction method, partially recovered the sharpness of the original motion-free images in 13/20 subjects.
Quantitative TB structural measures are highly sensitive to subtle motion-induced degradation which adversely affects precision and statistical power. The results underscore the influence of subject movement in high-resolution 3D μMRI and its correction for TB structure analysis.
3D μMRI; Trabecular bone; Translational and Rotational motion; Virtual bone biopsy
Female mice lacking DEF6 and SWAP70 develop a lupus-like syndrome through dysregulation of IRF4 in activated B cells and plasma cells.
Effective humoral responses to protein antigens require the precise execution of carefully timed differentiation programs in both T and B cell compartments. Disturbances in this process underlie the pathogenesis of many autoimmune disorders, including systemic lupus erythematosus (SLE). Interferon regulatory factor 4 (IRF4) is induced upon the activation of T and B cells and serves critical functions. In CD4+ T helper cells, IRF4 plays an essential role in the regulation of IL-21 production, whereas in B cells it controls class switch recombination and plasma cell differentiation. IRF4 function in T helper cells can be modulated by its interaction with regulatory protein DEF6, a molecule that shares a high degree of homology with only one other protein, SWAP-70. Here, we demonstrate that on a C57BL/6 background the absence of both DEF6 and SWAP-70 leads to the development of a lupus-like disease in female mice, marked by simultaneous deregulation of CD4+ T cell IL-21 production and increased IL-21 B cell responsiveness. We furthermore show that DEF6 and SWAP-70 are differentially used at distinct stages of B cell differentiation to selectively control the ability of IRF4 to regulate IL-21 responsiveness in a stage-specific manner. Collectively, these data provide novel insights into the mechanisms that normally couple and coordinately regulate T and B cell responses to ensure tight control of productive T–B cell interactions.
To evaluate the safety of ranibizumab as a surgical adjunct during cataract surgery in patients with proliferative diabetic retinopathy (PDR) with rubeosis, and to evaluate the efficacy and adverse effects of ranibizumab in treating PDR with rubeosis.
Materials and Methods:
Three intravitreal injections of 0.5 mg ranibizumab were administered on day-1, months-1 and -2 with cataract surgery 6-16 days after first injection. Retreatments with ranibizumab injections and pan-retinal photocoagulation (PRP) were given if recurrence or persistence of PDR was noted between months-3 and -11. Safety observation visits occurred at months-12, -18 and -24. Primary end points were incidence and severity of adverse events (AEs) that were related to both cataract surgery and treatment of PDR with rubeosis through month -12.
Of six patients screened, four (mean age 61.3 years) were enrolled. No AEs were noted with either cataract surgery or treatment of PDR. Neovascularization of iris (NVI) promptly regressed by 4 days after first ranibizumab injection, prior to cataract surgery in three of four patients (one had significantly regressed NVI by post-injection day-3 visit); NVI was not noted in any patient at 2 weeks after first ranibizumab injection. Recurrence of rubeosis or NVA after 3 monthly injections was not observed in any. At month-12, PDR was not present when assessed clinically and by fluorescein angiogram (FA). Only one patient developed neovascularization of disc and neovascularization elsewhere and required retreatments at months-5 and -9.
Multiple intravitreal injections of ranibizumab may be a safe, effective treatment adjunct for PDR and diabetes-related rubeosis.
Cataract; diabetic retinopathy; neovascularization; rubeosis iridis; ranibizumab
As preventing cancer with the help of a vaccine is a comparatively new concept, awareness and education about it will have important implication in the implementation of this strategy.
Materials and Methods
Present explorative questionnaire based survey included 618 MBBS students for final analysis.
Majority of participants (89.6%) were well aware of the preventable nature of cervical cancer. Most of them (89.2%) knew that necessary factor responsible for cervical cancer is infection with high risk HPV. Awareness regarding the availability of vaccine against cervical cancer was 75.6%. Females had a better awareness regarding availability of vaccine, target population for vaccination and about the catch up program. Overall acceptance of HPV vaccine among the population studied was 67.8%. Medical teaching had a definitive impact on the understanding of this important public health issue. Females seemed to be more ready to accept the vaccine and recommend it to others. For our study population the most common source of information was medical school teaching. Majority of participants agreed that the most important obstacle in implementation of HPV vaccination program in our country is inadequate information and 86.2% wanted to be educated by experts in this regard.
HPV vaccine for primary prevention of cervical cancer is a relatively new concept. Health professional will be able to play a pivotal role in popularizing this strategy.
Juvenile nasopharyngeal angiofibromas are benign but locally aggressive tumors of nasopharynx seen exclusively in adolescent males. Angiofibromas arising in sites other than nasopharynx is very rare. Maxilla is the most frequent site of origin. Extra nasopharyngeal angiofibromas of adult is extremely rare. We present a case of extra nasopharnygeal angiofibroma arising from maxillary sinus in an adult patient which was excised successfully.
Angiofibroma; Adult; Maxilla
Ribosomes are essential components of the protein translation machinery and are composed of more than 80 unique large and small ribosomal proteins. Recent studies show that in addition to their roles in protein translation, ribosomal proteins are also involved in extra-ribosomal functions of DNA repair, apoptosis and cellular homeostasis. Consequently, alterations in the synthesis or functioning of ribosomal proteins can lead to various hematologic disorders. These include congenital anemias such as Diamond Blackfan anemia and Shwachman Diamond syndrome; both of which are associated with mutations in various ribosomal genes. Acquired uniallelic deletion of RPS14 gene has also been shown to lead to the 5q syndrome, a distinct subset of MDS associated with macrocytic anemia. Recent evidence shows that specific ribosomal proteins are overexpressed in liver, colon, prostate and other tumors. Ribosomal protein overexpression can promote tumorigenesis by interactions with the p53 tumor suppressor pathway and also by direct effects on various oncogenes. These data point to a broad role of ribosome protein alterations in hematologic and oncologic diseases.
Ribosome; MDS; Anemia
Interferon-gamma (IFN-γ) mediates responses to bacterial infection and autoimmune disease but it is also an important tumor suppressor. IFN-γ is upregulated in the gastric mucosa by chronic Helicobacter infection; however, whether it plays a positive or negative role in inflammation-associated gastric carcinogenesis is unexplored. To study this question we generated an H+/K+-ATPase-IFN-γ transgenic mouse that overexpresses murine IFN-γ in the stomach mucosa. In contrast to the expected pro-inflammatory role during infection, we found that IFN-γ overexpression failed to induce gastritis and instead inhibited gastric carcinogenesis induced by IL-1beta (IL-1β) and/or Helicobacter infection. Th1 and Th17 immune responses were inhibited by IFN-γ through Fas induction and apoptosis in CD4 T cells. IFN-γ also induced autophagy in gastric epithelial cells through increased expression of Beclin-1. Lastly, in the gastric epithelium, IFN-γ also inhibited IL-1β- and Helicobacter-induced epithelial apoptosis, proliferation, and Dckl1+ cell expansion. Taken together, our results suggest that IFN-γ coordinately inhibits bacterial infection and carcinogenesis in the gastric mucosa by suppressing putative gastric progenitor cell expansion and reducing epithelial cell apoptosis via induction of an autophagic program.
IFN-γ; gastric inflammation; gastric carcinogenesis; immune response; autophagy; apoptosis; progenitor cell; H. felis
Barrett’s esophagus, a pre-malignant condition that can lead to esophageal adenocarcinoma, is characterized by histological changes in the normal squamous epithelium of the esophagus. Numerous molecular changes occur during the multistage conversion of Barrett’s metaplasia to dysplasia and frank adenocarcinoma. Epigenetic changes, especially changes in DNA methylation are widespread during this process. Aberrant DNA methylation has been shown to occur at promoters of tumor suppressor genes, adhesion molecules and DNA repair genes during Barrett’s esophagus. These epigenetic alterations can be used as molecular biomarkers for risk stratification and early detection of esophageal adenocarcinoma. We also show that genome wide analysis of methylation surprisingly reveals that global hypomethylation and not hypermethylation is the dominant change during Barrett’s metaplasia. The transformation of Barrett’s esophagus to frank adenocarcinoma is in turn characterized by much smaller wave of selective promoter hypermethylation. These studies reveal many novel, potential targets for new therapies and illustrate the utility of incorporating these epigenetic changes as biomarkers during endoscopic surveillance interval for patients with Barrett’s esophagus.
Barrett’s esophagus; DNA methylation; esophageal adenocarcinoma; global hypomethylation
Altered plasma concentrations of vitamin D and mannose binding lectin (MBL), components of innate immunity, have been shown to be associated with the pathogenesis of viral infections. The objective of the present study was to find out whether plasma concentrations of MBL and vitamin D are different in patients with dengue fever (DF) and dengue hemorrhagic fever (DHF).
The plasma concentrations of vitamin D and MBL were assessed in 48 DF cases, 45 DHF cases and 20 apparently healthy controls using ELISA based methods. Vitamin D concentrations were found to be higher among both DF and DHF cases as compared to healthy controls (P < 0.005 and P < 0.001). Vitamin D concentrations were not different between DF and DHF cases. When the dengue cases were classified into primary and secondary infections, secondary DHF cases had significantly higher concentrations of vitamin D as compared to secondary DF cases (P < 0.050). MBL concentrations were not significantly different between healthy controls and dengue cases. MBL concentrations were observed to be lower in DHF cases as compared to DF cases (P < 0.050). Although MBL levels were not different DF and DHF cases based on immune status, the percentage of primary DHF cases (50%) having MBL levels lower than 500 ng/ml were less compared to primary DF cases (P = 0.038).
The present study suggests that higher concentrations of vitamin D might be associated with secondary DHF while deficiency of MBL may be associated with primary DHF.
Dengue; Vitamin D; Mannose binding lectin; DF; DHF
A Helmholtz-pair local transmit RF coil with an integrated four-element receive array RF coil and foot immobilization platform was designed and constructed for imaging the distal tibia in a whole-body 7 T MRI scanner. Simulations and measurements of the B1 field distribution of the transmit coil are described, along with SAR considerations for operation at 7 T. Results of imaging the trabecular bone of three volunteers at 1.5 T, 3 T and 7 T are presented, using identical 1.5 T and 3 T versions of the 7 T four-element receive array. The spatially registered images reveal improved visibility for individual trabeculae and show average gains in SNR of 2.8x and 4.9x for imaging at 7 T compared to 3 T and 1.5 T, respectively. The results thus display an approximately linear dependence of SNR with field strength and enable the practical utility of 7 T scanners for micro-MRI of trabecular bone.
RF coil; Helmholtz pair; receive array; 7 T; micro-MRI; osteoporosis; trabecular bone; tibia
Diffuse large B-cell lymphoma (DLBCL) is the most common form of human lymphoma. While a number of structural alterations have been associated with the pathogenesis of this malignancy, the full spectrum of genetic lesions that are present in the DLBCL genome, and therefore the identity of dysregulated cellular pathways, remains unknown. By combining next-generation sequencing and copy number analysis, we show that the DLBCL coding genome contains on average more than 30 clonally represented gene alterations/case. This analysis also revealed mutations in genes not previously implicated in DLBCL pathogenesis, including those regulating chromatin methylation (MLL2, 24% of cases) and immune recognition by T cells. These results provide initial data on the complexity of the DLBCL coding genome and identify novel dysregulated pathways underlying its pathogenesis.
To describe and compare dynamic distance direct ophthalmoscopy (DDDO) with dynamic retinoscopy (DR) in assessment of accommodation in children.
Materials and Methods:
This prospective observational study had four components. Component 1: to understand the characteristic digital images of DDDO. Component 2: to compare DDDO with DR for detection of accommodative defects in children (1–16 years). Component 3: to compare DDDO with DR for the detection of completeness of pharmacologically induced cycloplegia in children (5–16 years) and Component 4: to assess which one of the two techniques was more sensitive to detect onset of cycloplegia after instillation of 1% cyclopentolate eye drops.
Component 1: image analysis of DDDO on two subjects (7 years and 35 years) demonstrated superior pupillary crescent that progressively disappeared with increasing accommodation. Concurrently an inferior crescent appeared that became bigger in size with increasing accommodation. Component 2: the prevalence of defects in accommodation was 3.3% (33/1000 children). Three had unilateral accommodation failure. Sensitivity of DDDO was 94%, specificity 100%, positive predictive value 100%, negative predictive value 99%, and clinical agreement (kappa) 0.97. Component 3: in the detection of completeness of pharmacologically induced cycloplegia (n=30), the sensitivity of DDDO was 94%, specificity 96%, positive predictive value 97%, negative predictive value 93% and kappa 0.9. DR had two false positives. DDDO had one false negative. Component 4: DDDO detected onset of pharmacologically induced cycloplegia 5 min earlier than DR (n=5).
DDDO is a novel, simple, clinical and reliable method to assess accommodation in young children. This test can assess the accommodative response of both eyes simultaneously.
Accommodation; dynamic retinoscopy; ophthalmoscopy; photorefraction; photoretinoscopy
Children with medical complexity (CMC) have medical fragility and intensive care needs that are not easily met by existing health care models. CMC may have a congenital or acquired multisystem disease, a severe neurologic condition with marked functional impairment, and/or technology dependence for activities of daily living. Although these children are at risk of poor health and family outcomes, there are few well-characterized clinical initiatives and research efforts devoted to improving their care. In this article, we present a definitional framework of CMC that consists of substantial family-identified service needs, characteristic chronic and severe conditions, functional limitations, and high health care use. We explore the diversity of existing care models and apply the principles of the chronic care model to address the clinical needs of CMC. Finally, we suggest a research agenda that uses a uniform definition to accurately describe the population and to evaluate outcomes from the perspectives of the child, the family, and the broader health care system.
medical complexity; special needs; chronic illness/conditions; delivery of care; definitions
Even though myelodysplastic syndromes are characterized by ineffective hematopoiesis, the molecular alterations that lead to marrow failure have not been well elucidated. We have previously shown that the myelosuppressive TGF-β pathway is constitutively activated in MDS progenitors. Since there is conflicting data about upregulation of extracellular TGF-b levels in MDS, we wanted to determine the molecular basis of TGF-β pathway overactivation and consequent hematopoietic suppression in this disease. We observed that SMAD7, a negative regulator of TGF-β receptor I (TBRI) kinase is markedly decreased in a large meta-analysis of gene expression studies from MDS marrow derived CD34+ cells. SMAD7 protein was also found to be significantly decreased in MDS marrow progenitors when examined immunohistochemically in a bone marrow tissue microarray. Reduced expression of SMAD7 in hematopoietic cells led to increased TGF-β mediated gene transcription and enhanced sensitivity to TGF-β mediated suppressive effects. The increased TGF-β signaling due to SMAD7 reduction could be effectively inhibited by a novel clinically relevant TBRI (ALK5 kinase) inhibitor, LY-2157299. LY-2157299 could inhibit TGF-β mediated SMAD2 activation and hematopoietic suppression in primary hematopoietic stem cells. Furthermore, in vivo administration of LY-2157299 ameliorated anemia in a TGF-β overexpressing transgenic mouse model of bone marrow failure. Most importantly, treatment with LY-2157199 stimulated hematopoiesis from primary MDS bone marrow specimens. These studies demonstrate that reduction in SMAD7 is a novel molecular alteration in MDS that leads to ineffective hematopoiesis by activating of TGF-β signaling in hematopoietic cells. These studies also illustrate the therapeutic potential of TBRI inhibitors in MDS.
Myelodysplasia; TGF; SMAD7; LY-2157299