Apoptosome activation, an important molecular instigator in 6-mercaptopurine induced Leydig cell death.

Leydig cells are crucial to the production of testosterone in males. It is unknown if the cancer chemotherapeutic drug, 6-mercaptopurine (6 MP), produces Leydig cell failure among adult survivors of childhood acute lymphoblastic leukemia. Moreover, it is not known whether Leydig cell failure is due to either a loss of cells or an impairment in their function. Herein, we show, in a subset of childhood cancer survivors, that Leydig cell failure is related to the dose of 6 MP. This was extended, in a murine model, to demonstrate that 6 MP exposure induced caspase 3 activation, and the loss of Leydig cells was independent of Bak and Bax activation. The death of these non-proliferating cells was triggered by 6 MP metabolism, requiring formation of both cytosolic reactive oxygen species and thiopurine nucleotide triphosphates. The thiopurine nucleotide triphosphates (with physiological amounts of dATP) uniquely activated the apoptosome. An ABC transporter (Abcc4/Mrp4) reduced the amount of thiopurines, thereby providing protection for Leydig cells. The studies reported here demonstrate that the apoptosome is uniquely activated by thiopurine nucleotides and suggest that 6 MP induced Leydig cell death is likely a cause of Leydig cell failure in some survivors of childhood cancer

Maintenance of head and neck tumor on-chip: gateway to personalized treatment?

Aim: Head and neck squamous cell carcinomas (HNSCC) are solid tumors with low overall survival (40–60%). In a move toward personalized medicine, maintenance of tumor biopsies in microfluidic tissue culture devices is being developed. Methodology/ results: HNSCC (n = 15) was dissected (5–10 mg) and either analyzed immediately or cultured in a microfluidic device (37°C) for 48 h. No difference was observed in morphology between pre- and postculture specimens. Dissociated samples were analyzed using trypan blue exclusion (viability), propidium iodide flow cytometry (death) and MTS assay (proliferation) with no significant difference observed highlighting tissue maintenance. Computational fluid dynamics showed laminar flow within the system. Conclusion: The microfluidic culture system successfully maintained HNSCC for 48 h, the culture system will allow testing of different treatment modalities with response monitoring. Lay abstract: Head and neck cancers often have a poor treatment outcome. In order to study the response of the tissue, a miniaturized culture system has been developed to keep a small piece of tumor alive. In the current study, we show that small pieces of cancer tissue can be maintained in the system, using tissue structure and viability of single cells as a guide. In future work, patient equivalent treatments can be applied to these microculture systems to investigate individual patient tumor responses, which could help to guide treatment selection

On the Significance of Absorption Features in HST/COS Data

We present empirical scaling relations for the significance of absorption features detected in medium resolution, far-UV spectra obtained with the Cosmic Origins Spectrograph (COS). These relations properly account for both the extended wings of the COS line spread function and the non-Poissonian noise properties of the data, which we characterize for the first time, and predict limiting equivalent widths that deviate from the empirical behavior by \leq 5% when the wavelength and Doppler parameter are in the ranges \lambda = 1150-1750 A and b > 10 km/s. We have tested a number of coaddition algorithms and find the noise properties of individual exposures to be closer to the Poissonian ideal than coadded data in all cases. For unresolved absorption lines, limiting equivalent widths for coadded data are 6% larger than limiting equivalent widths derived from individual exposures with the same signal-to-noise. This ratio scales with b-value for resolved absorption lines, with coadded data having a limiting equivalent width that is 25% larger than individual exposures when b \approx 150 km/s.Comment: 25 pages, 3 tables, 7 figures, accepted for publication in PAS

Intraoperative suprachoroidal hemorrhage during Xen gel stent implantation

Purpose: To report a rare case of intraoperative suprachoroidal hemorrhage during Xen gel stent implantation with accompanying surgical video and subsequent 6-month follow-up. Observations: Our patient required incisional glaucoma surgery after inadequate pressure reduction with four classes of topical medication, methazolamide, and selective laser trabeculoplasty. The patient underwent Xen gel stent implantation and developed an intraoperative suprachoroidal hemorrhage, which was managed in the operating room. The patient recovered his baseline visual acuity with a functioning bleb out to 6 months postoperatively. Conclusions and Importance: Micro-invasive glaucoma surgeries offer a new repertoire of surgical options, purportedly with safer and less invasive techniques. Xen gel stent implantation may be a promising alternative to traditional trabeculectomies and tube shunt implants, providing similar IOP lowering results with potentially lower risk for complications. However, rare and severe complications such as suprachoroidal hemorrhage may still occur. Recognizing a suprachoroidal bleed, particularly intraoperatively, will still be necessary to help minimize the potential vision threatening sequelae often associated with this severe complication

The Wife of the Alcoholic; Sexist Stereotypes in the Alcoholism Literature

Current alcoholism literature, alcoholism education, and alcoholism treatment suggests that the wife of the alcoholic is every bit as sick (physically, mentally, and spiritually) as her practicing alcoholic husband. How did we come to this view of the wife of the alcoholic? This paper will review 1) how the wife of the alcoholic has been regarded over the years; 2) how these portraits of the wife of the alcoholic that appeared in the scholarly literature have influenced current thinking and treatment, and 3) how this body of literature and the popular concepts of the wife of the alcoholic that evolved from it, carry sexual biases and stereotyping that can potentially interfere with optimum treatment, full recovery, and effective marital and family functioning

The Apparent Host Galaxy of PKS 1413+135: HST, ASCA and VLBA Observations

PKS 1413+135 (z=0.24671) is one of very few radio-loud AGN with an apparent spiral host galaxy. Previous authors have attributed its nearly exponential infrared cutoff to heavy absorption but have been unable to place tight limits on the absorber or its location in the optical galaxy. In addition, doubts remain about the relationship of the AGN to the optical galaxy given the observed lack of re-emitted radiation. We present new HST, ASCA and VLBA observations which throw significant new light on these issues. The HST observations reveal an extrremely red color (V-H = 6.9 mag) for the active nucleus of PKS 1413+135, requiring both a spectral turnover at a few microns due to synchrotron aging and a GMC-sized absorber. We derive an intrinsic column N_H = 4.6^{+2.1}_{-1.6} times 10^{22}cm^{-2} and covering fraction f = 0.12^{+0.07}_{-0.05}. As the GMC is likely in the disk of the optical galaxy, our sightline is rather unlikely (P ~ 2 times 10^{-4}). The properties of the GMC typical of GMCs in our own galaxy. The HI absorber appears centered 25 milliarcseconds away from the nucleus, while the X-ray and nearly all of the molecular absorbers must cover the nucleus, implying a complicated geometry and cloud structure, with a molecular core along our line of sight to the nucleus. Interestingly, the HST/NICMOS data require the AGN to be decentered relative to the optical galaxy by 13 +/- 4 milliarcseconds. This could be interpreted as suggestive of an AGN location far in the background compared to the optical galaxy, but it can also be explained by obscuration and/or nuclear structure, which is more consistent with the observed lack of multiple images.Comment: 27 pages, 8 figures; accepted to A