The use of autologous adult, allogenic juvenile, and combined juvenile-adult cartilage fragments for the repair of chondral defects.

Purpose: The goal of the study was to evaluate the repair of chondral lesions treated with combined autologous adult/allogenic juvenile cartilage fragments, compared with isolated adult and isolated juvenile cartilage fragments.

Methods: Fifty-eight adult (>16 week old) and five juvenile (<6 week old) New Zealand White female rabbits were used. A large osteochondral defect was created in the center of the femoral trochlea of adult rabbits.

Selinexor is effective in acquired resistance to ibrutinib and synergizes with ibrutinib in chronic lymphocytic leukemia.

Despite the therapeutic efficacy of ibrutinib in chronic lymphocytic leukemia (CLL), complete responses are infrequent, and acquired resistance to Bruton agammaglobulinemia tyrosine kinase (BTK) inhibition is being observed in an increasing number of patients. Combination regimens that increase frequency of complete remissions, accelerate time to remission, and overcome single agent resistance are of considerable interest. We previously showed that the XPO1 inhibitor selinexor is proapoptotic in CLL cells and disrupts B-cell receptor signaling via BTK depletion.

Characterization of CLL exosomes reveals a distinct microRNA signature and enhanced secretion by activation of BCR signaling.

Multiple studies show that chronic lymphocytic leukemia (CLL) cells are heavily dependent on their microenvironment for survival. Communication between CLL cells and the microenvironment is mediated through direct cell contact, soluble factors, and extracellular vesicles. Exosomes are small particles enclosed with lipids, proteins, and small RNAs that can convey biological materials to surrounding cells.

Effects of self-reported age at nonsurgical menopause on time to first fracture and bone mineral density in the Women's Health Initiative Observational Study.

Objective: Menopause is a risk factor for fracture; thus, menopause age may affect bone mass and fracture rates. We compared bone mineral density (BMD) and fracture rates among healthy postmenopausal women with varying ages at self-reported nonsurgical menopause.

Methods: We compared hazard ratios for fractures and differences in BMD among 21,711 postmenopausal women from the Women's Health Initiative Observational Study cohort who had no prior hysterectomy, oophorectomy, or hormone therapy and had varying self-reported ages at menopause (<40, 40-49, or ≥50 y).

Statins and breast cancer stage and mortality in the Women's Health Initiative.

Purpose: To evaluate the association between statins and breast cancer stage and mortality in the Women's Health Initiative.

Methods: The study population included 128,675 postmenopausal women aged 50-79 years, out of which there were 7,883 newly diagnosed cases of in situ (19%), local (61%)-, regional (19%)- and distant (1%)-stage breast cancer and 401 deaths due to breast cancer after an average of 11.5 (SD = 3.

Up-regulation of CDK9 kinase activity and Mcl-1 stability contributes to the acquired resistance to cyclin-dependent kinase inhibitors in leukemia.

Flavopiridol is a small molecule inhibitor of cyclin-dependent kinases (CDK) known to impair global transcription via inactivation of positive transcription elongation factor b. It has been demonstrated to have significant activity predominantly in chronic lymphocytic leukemia and acute myeloid leukemia in phase I/II clinical trials while other similar CDK inhibitors are vigorously being pursued in pre-clinical and clinical studies. Although flavopiridol is a potent therapeutic agent against blood diseases, some patients still have primary or acquired resistance throughout their clinical course.

Effect of pulmonary hypertension on survival in patients with idiopathic pulmonary fibrosis after lung transplantation: an analysis of the United Network of Organ Sharing registry.

Background: Pulmonary hypertension (PH) is a comorbidity associated with idiopathic pulmonary fibrosis (IPF). There is limited research regarding the effect on survival after lung transplantation (LTx).

Methods: To assess the effect of PH on survival in patients with IPF who received LTx, the United Network for Organ Sharing was queried for eligible patients with recorded mean (PAmean) and systolic (PAsystolic) pulmonary artery pressure.

Effects of bilateral salpingo-oophorectomy at the time of hysterectomy on pelvic organ prolapse: results from the Women's Health Initiative trial.

Objective: This study aims to estimate the effects of bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy and estrogen therapy on vaginal prolapse.

Methods: A retrospective analysis of the Women's Health Initiative estrogen-alone trial was performed. Women who retained their ovaries were compared with women who had BSO at the time of hysterectomy for the presence of cystocele or rectocele at entry into the study.

The translation inhibitor silvestrol exhibits direct anti-tumor activity while preserving innate and adaptive immunity against EBV-driven lymphoproliferative disease.

Treatment options for patients with Epstein-Barr Virus-driven lymphoproliferative diseases (EBV-LPD) are limited. Chemo-immunotherapeutic approaches often lead to immune suppression, risk of lethal infection and EBV reactivation, thus it is essential to identify agents that can deliver direct anti-tumor activity while preserving innate and adaptive host immune surveillance. Silvestrol possesses direct anti-tumor activity in multiple hematologic malignancies while causing minimal toxicity to normal mononuclear cells.

Pharmacist-driven renal medication dosing intervention in a primary care patient-centered medical home.

Purpose: The purposes of this population management intervention were to identify patients with stage 3, 4, or 5 chronic kidney disease (CKD) and to improve care in a patient-centered medical home (PCMH). Objectives of the intervention were to (i) increase the identification of CKD, (ii) increase the use of aspirin and angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin II receptor blockers (ARBs) in patients with CKD, and (iii) ensure that all medications prescribed to patients with CKD were dosed appropriately based on renal function.

Setting: This intervention was completed at a National Committee for Quality Assurance tier 3 PCMH associated with a major, academic health system.

OSU-T315: a novel targeted therapeutic that antagonizes AKT membrane localization and activation of chronic lymphocytic leukemia cells.

Aberrant regulation of endogenous survival pathways plays a major role in progression of chronic lymphocytic leukemia (CLL). Signaling via conjugation of surface receptors within the tumor environmental niche activates survival and proliferation pathways in CLL. Of these, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway appears to be pivotal to support CLL pathogenesis, and pharmacologic inhibitors targeting this axis have shown clinical activity.

Fishing with bed nets on Lake Tanganyika: a randomized survey.

Background: Malaria is among the most common causes of death along Lake Tanganyika, a problem which many aid organizations have attempted to combat through the distribution of free mosquito bed nets to high-risk communities. The Lake Tanganyika Floating Health Clinic (LTFHC), a health-based non-governmental organization (NGO), has observed residents of the Lake Tanganyika basin using bed nets to fish small fry near the shoreline, despite a series of laws that prohibit bed net use and other fine-gauge nets for fishing, implemented to protect the near-shore fish ecology. The LTFHC sought to quantify the sources of bed nets and whether they were being used for fishing.

Impact of induction immunosuppression on survival in heart transplant recipients: a contemporary analysis of agents.

Introduction: The impact of induction immunosuppression on long-term survival in heart transplant recipients is unclear. Over the past three decades, practices have varied as induction agents have changed and experiences grew. We sought to evaluate the effect of contemporary induction immunosuppression agents in heart transplant recipients with the primary endpoint of survival, utilizing national registry data.

Ibrutinib treatment ameliorates murine chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is a life-threatening impediment to allogeneic hematopoietic stem cell transplantation, and current therapies do not completely prevent and/or treat cGVHD. CD4+ T cells and B cells mediate cGVHD; therefore, targeting these populations may inhibit cGVHD pathogenesis. Ibrutinib is an FDA-approved irreversible inhibitor of Bruton's tyrosine kinase (BTK) and IL-2 inducible T cell kinase (ITK) that targets Th2 cells and B cells and produces durable remissions in B cell malignancies with minimal toxicity.

IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells.

Chronic lymphocytic leukemia (CLL) displays constitutive phosphatidylinositol 3-kinase (PI3K) activation resulting from aberrant regulation of B-cell receptor (BCR) signaling. Previous studies have shown that an oral PI3K p110δ inhibitor idelalisib exhibits promising activity in CLL. Here, we demonstrate that a dual PI3K p110δ and p110γ inhibitor, IPI-145, antagonizes BCR crosslinking activated prosurvival signals in primary CLL cells.

The impact of tumor deposits on colonic adenocarcinoma AJCC TNM staging and outcome.

The definition of tumor deposits (TDs) in colonic adenocarcinoma has been modified in different editions of the AJCC/TNM staging system. Studies have shown that the presence of TD is associated with advanced tumor growth and poor prognosis. Most of these data were obtained in patients with simultaneous lymph node (LN) metastases.

Activation of the retinoid X receptor modulates angiotensin II-induced smooth muscle gene expression and inflammation in vascular smooth muscle cells.

The retinoid X receptor (RXR) partners with numerous nuclear receptors, such as the peroxisome proliferator activated receptor (PPAR) family, liver X receptors (LXRs), and farnesoid X receptor (FXR). Although each heterodimer can be activated by specific ligands, a subset of these receptors, defined as permissive nuclear receptors, can also be activated by RXR agonists known as rexinoids. Many individual RXR heterodimers have beneficial effects in vascular smooth muscle cells (SMCs).

Mutations in NOTCH1 cause Adams-Oliver syndrome.

Notch signaling determines and reinforces cell fate in bilaterally symmetric multicellular eukaryotes. Despite the involvement of Notch in many key developmental systems, human mutations in Notch signaling components have mainly been described in disorders with vascular and bone effects. Here, we report five heterozygous NOTCH1 variants in unrelated individuals with Adams-Oliver syndrome (AOS), a rare disease with major features of aplasia cutis of the scalp and terminal transverse limb defects.

Diffuse angiopathy in Adams-Oliver syndrome associated with truncating DOCK6 mutations.

Adams-Oliver syndrome (AOS) is a rare malformation syndrome characterized by the presence of two anomalies: aplasia cutis congenita of the scalp and transverse terminal limb defects. Many affected individuals also have additional malformations, including a variety of intracranial anomalies such as periventricular calcification in keeping with cerebrovascular microbleeds, impaired neuronal migration, epilepsy, and microcephaly. Cardiac malformations can be present, as can vascular dysfunction in the forms of cutis marmorata telangiectasia congenita, pulmonary vein stenoses, and abnormal hepatic microvasculature.

PKC-β as a therapeutic target in CLL: PKC inhibitor AEB071 demonstrates preclinical activity in CLL.

Targeting B-cell receptor (BCR) signaling in chronic lymphocytic leukemia (CLL) has been successful with durable remissions observed with several targeted therapeutics. Protein kinase C-β (PKC-β) is immediately downstream of BCR and has been shown to be essential to CLL cell survival and proliferation in vivo. We therefore evaluated sotrastaurin (AEB071), an orally administered potent PKC inhibitor, on CLL cell survival both in vitro and in vivo.

Survival benefit of induction immunosuppression in cystic fibrosis lung transplant recipients.

Background: Despite resistant microbes, induction immunosuppression is used in patients with cystic fibrosis (CF) undergoing lung transplantation (LTx).

Methods: To evaluate the effect of induction immunosuppression on survival, the United Network for Organ Sharing (UNOS) was queried restricting analysis to transplant patients 6-55years old from 2001 to 2012, who received induction agents (INDUCED) or did not (NONE).

Results: A total of 1721 CF patients who underwent LTx were included in the analysis; of these 791 (46%) were INDUCED.

MIF antagonist (CPSI-1306) protects against UVB-induced squamous cell carcinoma.

Unlabelled: Macrophage migration inhibitory factor (MIF) is a homotrimeric proinflammatory cytokine implicated in chronic inflammatory diseases and malignancies, including cutaneous squamous cell carcinomas (SCC). To determine whether MIF inhibition could reduce UVB light-induced inflammation and squamous carcinogenesis, a small-molecule MIF inhibitor (CPSI-1306) was utilized that disrupts homotrimerization. To examine the effect of CPSI-1306 on acute UVB-induced skin changes, Skh-1 hairless mice were systemically treated with CPSI-1306 for 5 days before UVB exposure.

To induce or not to induce: a 21st century evaluation of lung transplant immunosuppression's effect on survival.

Introduction: The impact of induction immunosuppression on long-term survival in lung transplant recipients remains unclear. We sought to evaluate the effect of contemporary induction immunosuppression agents in lung transplant recipients' survival, utilizing national registry data.

Methods: We queried the United Network for Organ Sharing registry from 2001 to 2012 for adult, deceased donor lung transplants who received no antibody-based induction (NONE) or the contemporary agents of basiliximab, alemtuzumab, thymoglobulin, antilymphocyte globulin, or antithymocyte globulin (INDUCED).

Additional post-natal diagnoses following antenatal diagnosis of isolated cleft lip +/− palate.

Introduction: Cleft lip with or without palate (CLP) can be diagnosed antenatally through ultrasound, and may be categorised as apparently isolated versus associated with other malformations. Limited data exist on the long-term outcomes following antenatal diagnosis of apparently isolated CLP.

Aim: This study examined the long-term post-natal outcomes of CLP when found in isolation antenatally, in order to determine the rates of unexpected additional anomalies, developmental delay or genetic syndromes.