Systematic optimization of cationic surface engineered mucoadhesive vesicles employing Design of Experiment (DoE): A preclinical investigation.

Fungal keratitis (FK) is treated by topical natamycin (Nat) which is an effective antifungal agent. However, it has numerous therapeutic limitations i.e.

Distinctive mechanisms underlie the loss of SMARCB1 protein expression in renal medullary carcinoma: morphologic and molecular analysis of 20 cases.

Renal medullary carcinoma is a rare but highly aggressive type of renal cancer occurring in patients with sickle cell trait or rarely with other hemoglobinopathies. Loss of SMARCB1 protein expression, a core subunit of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, has emerged as a key diagnostic feature of these tumors. However, the molecular mechanism underlying this loss remains unclear.

Cytokine-Regulated Phosphorylation and Activation of TET2 by JAK2 in Hematopoiesis.

Even though the Ten-eleven translocation (TET) enzymes catalyze the generation of 5-hydroxymethylcytosines required for lineage commitment and subsequent differentiation of stem cells into erythroid cells, the mechanisms that link extracellular signals to TET activation and DNA hydroxymethylation are unknown. We demonstrate that hematopoietic cytokines phosphorylate TET2, leading to its activation in erythroid progenitors. Specifically, cytokine receptor-associated JAK2 phosphorylates TET2 at tyrosines 1939 and 1964.

Detection and characterization of an albumin-like protein in Leishmania donovani.

The protozoan parasite, Leishmania donovani, undergoes several molecular adaptations and secretes many effector molecules for host cell manipulation and successful parasitism. The current study identifies an albumin-like secretory protein, expressed in its extracellular promastigote forms. A leishmanial complementary DNA sequence of a partial gene has been cloned, and the encoded peptide (14 kD) is used for the production of polyclonal antibody.

An agent-based model of dengue virus transmission shows how uncertainty about breakthrough infections influences vaccination impact projections.

Prophylactic vaccination is a powerful tool for reducing the burden of infectious diseases, due to a combination of direct protection of vaccinees and indirect protection of others via herd immunity. Computational models play an important role in devising strategies for vaccination by making projections of its impacts on public health. Such projections are subject to uncertainty about numerous factors, however.

PAK Kinase Inhibition Has Therapeutic Activity in Novel Preclinical Models of Adult T-Cell Leukemia/Lymphoma.

Purpose: To evaluate therapeutic activity of PAK inhibition in ATLL and to characterize the role of PAK isoforms in cell proliferation, survival, and adhesion of ATLL cells in preclinical models.

Experimental Design: Frequency and prognostic impact of amplification were evaluated in an ATLL cohort of 370 cases. Novel long-term cultures and xenograft models were developed using primary ATLL cells from North American patients.

Barriers to Allogeneic Hematopoietic Stem Cell Transplantation for Human T Cell Lymphotropic Virus 1-Associated Adult T Cell Lymphoma-Leukemia in the United States: Experience from a Large Cohort in a Major Tertiary Center.

In the United States adult T cell lymphoma-leukemia (ATLL) carries a dismal prognosis and mainly affects immigrants from human T cell lymphotropic virus 1 endemic areas. Allogeneic hematopoietic stem cell transplant (alloHSCT) can be effective and is recommended as an upfront treatment in the National Comprehensive Cancer Network guidelines. We studied the barriers to alloHSCT in one of the largest ATLL populations in the United States.

Diverse Clinical Isolates of Mycobacterium tuberculosis Develop Macrophage-Induced Rifampin Tolerance.

The Mycobacterium tuberculosis lineage 4 strains CDC1551 and H37Rv develop tolerance to multiple antibiotics upon macrophage residence. To determine whether macrophage-induced tolerance is a general feature of clinical M. tuberculosis isolates, we assessed macrophage-induced drug tolerance in strains from lineages 1-3, representing the other predominant M.

Gene Polymorphism and Their Risk Association With Type 2 Diabetes Mellitus.

Background: C-reactive protein (CRP) is an inflammatory marker associated with T2DM, obesity, insulin resistance, and cardiovascular disease.

Aim: The present study evaluates the association of CRP +1059 G/C polymorphism of the gene in 100 T2D cases and 100 healthy controls.

Methods: Present study was done by allele specific PCR method to study the gene polymorphism in study subjects.

Association of Her-2 Expression and Clinicopathological Parameters in Colorectal Carcinoma in Indian Population.

Background: Human epidermal growth factor receptor 2 (HER-2) is an oncogenic gene and a well-established therapeutic target in several cancers including breast and ovary.

Aim: The present study aimed to compare HER-2 expression status with histological grades as well as Clinicopathological parameters including age, bleeding per rectum, pain/burning sensation in defecation and exercise.

Methods: Her-2 status was assessed by immunohistochemistry (IHC).

Ascorbic acid-induced TET activation mitigates adverse hydroxymethylcytosine loss in renal cell carcinoma.

Although clear cell renal cell carcinoma (ccRCC) has been shown to result in widespread aberrant cytosine methylation and loss of 5-hydroxymethylcytosine (5hmC), the prognostic impact and therapeutic targeting of this epigenetic aberrancy has not been fully explored. Analysis of 576 primary ccRCC samples demonstrated that loss of 5hmC was strongly associated with aggressive clinicopathologic features and was an independent adverse prognostic factor. Loss of 5hmC also predicted reduced progression-free survival after resection of nonmetastatic disease.

Sinusoidal Obstruction Syndrome (SOS) in Multiple Myeloma with Renal Failure.

SOS is a rare complication of stem cell transplantation and has significant morbidity and mortality. We present three cases of SOS and highlight underlying risk factors for its development, such as impaired clearance of alkylating agents (especially melphalan) in patients with renal failure and prolonged infection. Although, melphalan and cyclophosphamide cause SOS less commonly than alkylating agents such as busulfan, physicians must use caution when administering these drugs to patients with underlying comorbidities such as renal failure that may increase the likelihood of development of SOS.

Frequency of I655V SNP of HER-2/ in colorectal cancer: a study from India.

The present study was conducted to determine the prognostic significance of I655V SNP (rs1136201) is a genetic one in HER-2 oncoprotein in cases of colorectal cancer (CRC). We conducted a case-control study analysing 83 subjects (naïve primary CRC cases) who underwent CRC biopsy/colectomy and included 57 healthy control subjects. Analysis of HER-2 polymorphism was done by PCR-RFLP technique.

The expanding world of plant J-domain proteins.

Plants maintain cellular proteostasis during different phases of growth and development despite a barrage of biotic and abiotic stressors in an ever-changing environment. This requires a collaborative effort of a cadre of molecular chaperones. Hsp70s and their obligate co-chaperones, J-domain proteins (JDPs), are arguably the most ubiquitous and formidable components of the cellular chaperone network, facilitating numerous and diverse cellular processes and allowing survival under a plethora of stressful conditions.

Publisher Correction: Myelodysplastic syndrome progression to acute myeloid leukemia at the stem cell level.

In the version of this article originally published, Ulrich Steidl's name was listed as "and Ulrich Steidl." His name has been updated to "Ulrich Steidl." The error has been fixed in the print, PDF and HTML versions of this article.

Myelodysplastic syndrome progression to acute myeloid leukemia at the stem cell level.

Myelodysplastic syndromes (MDS) frequently progress to acute myeloid leukemia (AML); however, the cells leading to malignant transformation have not been directly elucidated. As progression of MDS to AML in humans provides a biological system to determine the cellular origins and mechanisms of neoplastic transformation, we studied highly fractionated stem cell populations in longitudinal samples of patients with MDS who progressed to AML. Targeted deep sequencing combined with single-cell sequencing of sorted cell populations revealed that stem cells at the MDS stage, including immunophenotypically and functionally defined pre-MDS stem cells (pre-MDS-SC), had a significantly higher subclonal complexity compared to blast cells and contained a large number of aging-related variants.

Ventricular Pseudoaneurysms After Perventricular Closure of Ventricular Septal Defect.

Perventricular ventricular septal defect closure has become an accepted method for treatment of some muscular and perimembranous ventricular septal defects. This report describes the case of a child who had left ventricular pseudoaneurysms after perventricular closure of a ventricular septal defect performed at 3 months of age. At 18 months, the ventricular pseudoaneurysms were closed surgically.

Co-culture development and bioformulation efficacy of psychrotrophic PGPRs to promote growth and development of Pea (Pisum sativum) plant.

Numerous microbes reside in the rhizosphere having plant growth promoting activity, and enhancing the property by increasing plant yield. Plant growth promoting rhizobacteria (PGPR) has gradually increased in agriculture and offers an attractive way to replace chemical fertilizers, pesticides and supplements. Soil was collected from the rhizosphere of an agricultural farm and the psychrotrophic bacterial strains STA (KY888133) and RM (KY888134) were successfully isolated, and screened on the basis of phosphate solubilization.

Novel targeting approaches and signaling pathways of colorectal cancer: An insight.

Colorectal cancer (CRC) is the third most common cancer of mortality in the world. Chemotherapy based treatment leads to innumerable side effects as it delivers the anticancer drug to both normal cells besides cancer cells. Sonic Hedgehog (SHH), Wnt wingless-type mouse mammary tumor virus/β-catenin, transforming growth factor-β/SMAD, epidermal growth factor receptor and Notch are the main signaling pathways involved in the progression of CRC.

Azacitidine with or without eltrombopag for first-line treatment of intermediate- or high-risk MDS with thrombocytopenia.

Azacitidine treatment of myelodysplastic syndromes (MDSs) generally exacerbates thrombocytopenia during the first treatment cycles. A Study of Eltrombopag in Myelodysplastic Syndromes Receiving Azacitidine (SUPPORT), a phase 3, randomized, double-blind, placebo-controlled study, investigated the platelet supportive effects of eltrombopag given concomitantly with azacitidine. International Prognostic Scoring System intermediate-1, intermediate-2, or high-risk MDS patients with baseline platelets <75 × 10/L were randomized 1:1 to eltrombopag (start, 200 mg/d [East Asians, 100 mg/d], maximum, 300 mg/d [East Asians, 150 mg/d]) or placebo, plus azacitidine (75 mg/m subcutaneously once daily for 7 days every 28 days).

Antisense STAT3 inhibitor decreases viability of myelodysplastic and leukemic stem cells.

Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are associated with disease-initiating stem cells that are not eliminated by conventional therapies. Transcriptomic analysis of stem and progenitor populations in MDS and AML demonstrated overexpression of STAT3 that was validated in an independent cohort. STAT3 overexpression was predictive of a shorter survival and worse clinical features in a large MDS cohort.

controls MDS-associated chronic TGF-β signaling, aberrant splicing, and stem cell fitness.

The transforming growth factor beta (TGF-β) signaling pathway controls hematopoietic stem cell (HSC) behavior in the marrow niche; however, TGF-β signaling becomes chronic in early-stage myelodysplastic syndrome (MDS). Although TGF-β signaling normally induces negative feedback, in early-stage MDS, high levels of microRNA-21 (miR-21) contribute to chronic TGF-β signaling. We found that a TGF-β signal-correlated gene signature is sufficient to identify an MDS patient population with abnormal RNA splicing (eg, ) independent of splicing factor mutations and coincident with low HNRNPK activity.

Thrombopoietin receptor-independent stimulation of hematopoietic stem cells by eltrombopag.

Eltrombopag (EP), a small-molecule thrombopoietin receptor (TPO-R) agonist and potent intracellular iron chelator, has shown remarkable efficacy in stimulating sustained multilineage hematopoiesis in patients with bone marrow failure syndromes, suggesting an effect at the most immature hematopoietic stem and multipotent progenitor level. Although the functional and molecular effects of EP on megakaryopoiesis have been studied in the past, mechanistic insights into its effects on the earliest stages of hematopoiesis have been limited. We investigated the effects of EP treatment on hematopoietic stem cell (HSC) function using purified primary HSCs in separation-of-function mouse models, including a TPO-R-deficient strain, and stem cells isolated from patients undergoing TPO-R agonist treatment.

North American ATLL has a distinct mutational and transcriptional profile and responds to epigenetic therapies.

Adult T-cell leukemia lymphoma (ATLL) is a rare T cell neoplasm that is endemic in Japanese, Caribbean, and Latin American populations. Most North American ATLL patients are of Caribbean descent and are characterized by high rates of chemo-refractory disease and worse prognosis compared with Japanese ATLL. To determine genomic differences between these 2 cohorts, we performed targeted exon sequencing on 30 North American ATLL patients and compared the results with the Japanese ATLL cases.

A novel synthesis of 2-arylbenzimidazoles in molecular sieves-MeOH system and their antitubercular activity.

Arylbenzimidazoles have been synthesized as antimycobacterial agents. An efficient synthesis has been developed for 2-arylbenzimidazoles from o-phenylenediamines and aromatic aldehydes in molecular sieves-methanol system. The methodology is straightforward to get 2-arylbenzimidazoles (3a-3z) in excellent yields with high chemoselectivity over 2-aryl-1-benzylbenzimidazoles (4a-4z).