Marrow transplantation from HLA-identical siblings for treatment of aplastic anemia: is exposure to marrow donor blood products 24 hours before high-dose cyclophosphamide needed for successful engraftment?

The present study in patients with aplastic anemia was undertaken to determine whether exposure of recipients to donor blood products 24 hr before preparation with cyclophosphamide (1) enhanced the rate of sustained engraftment of marrow from HLA-identical siblings as suggested by animal experiments, (2) increased the rejection rate, in particular in transfused patients who may already have been exposed to donor antigens by blood products, or (3) was of no relevance to the outcome of transplantation of marrow from HLA-identical siblings. One- hundred fifty-five patients were studied, of whom 78 received blood products from the marrow donor 24 hr before cyclophosphamide and 77 did not. A binary logistic regression analysis was applied to the data, simultaneously considering five previously known risk factors for rejection. Results showed that preceding transfusion of donor blood products had neither a significant beneficial nor detrimental effect on the incidence of sustained engraftment.     

A monokine regulates colony-stimulating activity production by vascular endothelial cells

Human umbilical vein endothelial cells were cultured in supernatants of peripheral blood monocytes that had been cultured for 3 days with and without lactoferrin. Colony-stimulating activity (CSA) was measured in supernatants of the endothelial cell cultures and appropriate control cultures using normal, T-lymphocyte-depleted, phagocyte-depleted, low- density bone marrow cells in colony growth (CFU-GM) assays. Monocyte- conditioned medium contained a nondialyzable, heat labile factor that enhanced 4-15--fold the production of CSA by endothelial cells. The addition of lactoferrin to monocyte cultures reduced the activity of this monokine by 69%. Lactoferrin did not inhibit CSA production by monokine-stimulated endothelial cells. Therefore, vascular endothelial cells are potent sources of CSA, the production of CSA by these cells is regulated by a stimulatory monokine, and the production and/or release of the monokine is inhibited by lactoferrin, a neutrophil- derived putative feedback inhibitor of granulopoiesis. Inasmuch as a similar monokine is known to stimulate CSA production by fibroblasts and T lymphocytes, we suggest that mononuclear phagocytes play a pivotal role in the regulation of granulopoiesis by recruiting a variety of cell types to produce CSA.     

The impact of hospital volume on perioperative outcomes of rectal cancer

Background

The purpose of this study was to investigate the impact of hospital volume on perioperative outcomes of clinical tumour stage (cT)1-3 and cT4 rectal cancer.

Face shape of unaffected parents with cleft affected offspring: combining three‐dimensional surface imaging and geometric morphometrics

Authors – Weinberg SM, Naidoo SD, Bardi KM, Brandon CA, Neiswanger K, Resick JM, Martin RA, Marazita ML Objective – Various lines of evidence suggest that face shape may be a predisposing factor for non‐syndromic cleft lip with or without cleft palate (CL/P). In the present study, 3D surface imaging and statistical shape analysis were used to evaluate face shape differences between the unaffected (non‐cleft) parents of individuals with CL / P and unrelated controls. Methods – Sixteen facial landmarks were collected from 3D captures of 80 unaffected parents and 80 matched controls. Prior to analysis, each unaffected parent was assigned to a subgroup on the basis of prior family history (positive or negative). A geometric morphometric approach was utilized to scale and superimpose the landmark coordinate data (Procrustes analysis), test for omnibus group differences in face shape, and uncover specific modes of shape variation capable of discriminating unaffected parents from controls. Results – Significant disparity in face shape was observed between unaffected parents and controls (p < 0.01). Notably, these changes were specific to parents with a positive family history of CL / P. Shape changes associated with CL / P predisposition included marked flattening of the facial profile (midface retrusion), reduced upper facial height, increased lower facial height, and excess interorbital width. Additionally, a sex‐specific pattern of parent‐control difference was evident in the transverse dimensions of the nasolabial complex. Conclusions – The faces of unaffected parents from multiplex cleft families displayed meaningful shape differences compared with the general population. Quantitative assessment of the facial phenotype in cleft families may enhance efforts to discover the root causes of CL /P.     

Modulation of human motor cortex excitability by valproate

Rationale  

Valproate is widely used in the treatment of epilepsy, bipolar disorder, and chronic pain disorders, but its exact mechanisms of action is still incompletely understood.     

Disulfiram, and disulfiram derivatives as novel potential anticancer drugs targeting the ubiquitin-proteasome system in both preclinical and clinical studies

Disulfiram is a FDA approved drug for the treatment of alcoholism and available for clinical use since over 5 decades. Despite data from the 1970s and 80s that showed that disulfiram and analogs are able to enhance the activity of anticancer cytotoxic drugs and might be useful chemopreventative agents, the underlying molecular mechanisms remained unknown until recently. Large scale screening efforts for agents that can inhibit the proteasome and be used as novel anticancer drugs, revealed that disulfiram has proteasome inhibitory activity. Moreover, disulfiram was also found to have specific activity against zinc fingers and RING-finger ubiquitin E3 ligases that play an important role in cancer development. Here, we review the preclinical and clinical studies exploring disulfiram as an anticancer agent as well as research programs that focus on the development of disulfiram derivatives as inhibitors of the ubiquitin-proteasome system.