The yeast SPT10 gene encodes a putative histone acetyltransferase (HAT) implicated as a global transcription regulator acting through basal promoters. Here we address the mechanism of this global regulation. Although microarray analysis confirmed that Spt10p is a global regulator, Spt10p was not detected at any of the most strongly affected genes in vivo. In contrast, the presence of Spt10p at the core histone gene promoters in vivo was confirmed. Since Spt10p activates the core histone genes, a shortage of histones could occur in spt10⌬ cells, resulting in defective chromatin structure and a consequent activation of basal promoters. Consistent with this hypothesis, the spt10⌬ phenotype can be rescued by extra copies of the histone genes and chromatin is poorly assembled in spt10⌬ cells, as shown by irregular nucleosome spacing and reduced negative supercoiling of the endogenous 2m plasmid. Chromatin structure plays an essential role in gene regulation. The structural unit of chromatin is the nucleosome, which is composed of 147 bp of DNA wrapped in a negative superhelix around a central octamer of core histones (composed of two molecules each of H2A, H2B, H3, and H4) (25). Nucleosomes are separated by linker DNA, forming a "beads on a string" structure. A fifth histone, H1, binds to both the nucleosome and the linker DNA to drive the coiling of the nucleosomal filament to form the 30-nm fiber.The nucleosome presents a problem for regulatory proteins seeking access to DNA because so much of the DNA is protected by histones: the inner surface of the DNA is completely occluded by the central core, the external surface is at least partly protected by the core histone tail domains, and the DNA coils are so close together that their apposed surfaces are also unavailable. To cope with the intrinsically repressive nature of the nucleosome structure, regulatory proteins recruit two types of chromatin remodeling complex to promoters: (i) chromatin remodeling machines, which use ATP to move nucleosomes, effect nucleosomal conformational changes, and exchange core histones with variants (33); and (ii) chromatin modifying enzymes, which catalyze posttranslational modifications of the histones, mostly in their tail domains. These modifications are proposed to represent a "histone code" which is read by regulatory proteins that recognize particular combinations of modifications, resulting in activation or silencing of chromatin (41). Histone acetylation is generally associated with gene activation and is catalyzed by histone acetyltransferases (HATs). The identification of the Gcn5p coactivator as a HAT led to a breakthrough in the field, connecting transcription factors with chromatin (3). The current paradigm is that histone modifying complexes are cofactors recruited to promoters by sequencespecific activators or repressors.Our studies have focused on the CUP1 gene of Saccharomyces cerevisiae as a model for the role of chromatin in gene regulation (35)(36)(37). CUP1 encodes a metallothionein responsible for protecting cell...

SUMMARYToxic epidermal necrolysis (TEN) is a rare but serious dermatological emergency characterised by diffuse exfoliation of the skin and mucous membranes due to immune mediated destruction of the epidermis which can lead to sepsis and respiratory distress. Trimethoprimsulfamethoxazole is a widely used antibiotic which can rarely lead to TEN. Early diagnosis and aggressive medical care is essential for the reduction of high morbidity and mortality associated with this disease. We present a case of successfully recovered TEN due to trimethoprim-sulfamethoxazole in a 62 -year-old woman. BACKGROUND

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant disorder characterized by the asymptomatic presence of a monoclonal protein. It is defined by an M protein < 3 gm/dl, less than 10% clonal plasma cells in the bone marrow, and the absence of anemia, hypercalcemia, renal insufficiency and bone lesions. In 2010 the International Myeloma Working Group (IMWG) advocated for MGUS patients to be stratified into low risk disease, which carries a 5% risk of progression to multiple myeloma at 20 years, and high risk disease, which represents a 20% risk at 20 years. This stratification model categorizes patients as low risk if they have an IgG paraprotein with an M-component < 1.5 g/dl and a normal free light chain (FLC) ratio. As such, it is suggested that the initial workup be comprised of a serum protein electrophoresis (SPEP), an immunofixation (IFE), and a FLC ratio. A bone marrow biopsy (BM) and bone survey should only be performed if anemia, hypercalcemia or an elevated creatinine of unclear etiology is noted. If these studies place a patient into the low risk, it is suggested the patient follow up at 6-months with only an SPEP. If the SPEP is stable, the next follow-up is recommended to occur at 2 to 3 year intervals unless symptoms arise suggestive of a plasma cell dyscrasia. The risk stratification of MGUS patients was validated in 2013 by Turesson et al. in a Swedish cohort (Blood, 2014; 123:338-345). Nevertheless, the risk model is not universally accepted and unnecessary office visits along with laboratory studies are performed on low risk patients. The purpose of this study was to perform an internal retrospective review of our patients diagnosed with low risk MGUS, evaluating excess medical costs incurred when patients were not risk stratified by the IMWG recommendations. Methods: MGUS patients seen in the Hematology Oncology Division of Drexel University between 2014 and 2016 were retrospectively categorized into high and low risk based on the IMWG criteria. Those determined to be low risk were evaluated over two years for extra costs incurred outside the IMWG recommendations. Extra cost was tallied based on initial workup and surveillance studies performed up to two years from diagnosis. Costs per test and follow up visits were based on our office appointment pricing and BM biopsy charges. Laboratory costs were obtained based on pricing from ACCU reference lab. Cost per test (varies by lab/provider) SPEP $67 UPEP $130 Serum IFE $200 Urine IFE $72 IgA $27 IgG $27 IgM $27 K/L ratio $120 B2 microglobulin $42 Office Visit $40 - $100 Bone Survey $500 - $1200 BM biopsy $500- $1000 Results: Sixty patients seen between 2014 and 2016 met the criteria for MGUS. Twenty-eight patients were determined to have low risk disease. Of the 28 patients, five were diagnosed prior to 2010 and were excluded. In the remaining 23 patients, four followed up at exactly six months from diagnosis and only one had an SPEP. The most common test ordered was quantitative immunoglobulins (QI) aside from a CBC and CMP. The total number of excess office visits was 49. Three patients had unnecessary BM biopsies (total cost $1,000 - $2,000), and 11 had unnecessary bone surveys (Total $5,500 - $13,200). The total cost of unnecessary lab tests within 2 years was $6,024 and the total cost of unnecessary office visits within 2 years was $1960 - $4900. Thus, the average excess spent per patient was $630 - $1135, for a total excess cost for the 23 patients of $14,484 - $26,124. Conclusion: This internal review highlights the excess medical costs incurred when patients are not risk stratified by the IMWG recommendations. Ideally, no further health care dollars should be spent for low risk MGUS patients who have a stable SPEP at the 6-month visit until the 2 or 3 year follow up visit. The actual excess amount spent in our office in 2 years for these patients was $14,484 - $26,124 beyond the cost of the standard of care recommended by the IMWG guidelines. Additionally, these values did not include excess basic labs such as a CBC or CMP and it did not include extension of our investigation out to three years which would result in further unnecessary costs. One patient was noted to accumulate excess cost due to his co-morbid condition of prostate cancer, which led to increased surveillance for his low risk MGUS. The risk stratification model allows physicians to offer patients a better understanding of their disease, decrease the patient's burden and reduce the cost on healthcare. Disclosures No relevant conflicts of interest to declare.

Surgery is the only chance for cure in pancreatic ductal adenocarcinoma. In unresectable, locally advanced pancreatic cancer (LAPC), the National Comprehensive Cancer Network (NCCN) suggests chemotherapy and consideration for radiation in cases of unresectable LAPC. Here we present a rare case of unresectable LAPC with a complete histopathological response after chemoradiation followed by surgical resection. A 54-year-old female presented to our clinic in December 2013 with complaints of abdominal pain and 30-pound weight loss. An MRI demonstrated a mass in the pancreatic body measuring 6.2 × 3.2 cm; biopsy revealed proven ductal adenocarcinoma. Due to splenic vein/artery and contiguous celiac artery encasement, she was deemed surgically unresectable. She was started on FOLFIRINOX therapy (three cycles), intensity modulated radiation to a dose of 54 Gy in 30 fractions concurrent with capecitabine, followed by FOLFIRI, and finally XELIRI. After 8 cycles of ongoing XELIRI completed in March 2015, restaging showed a remarkable decrease in tumor size, along with PET-CT revealing no FDG-avid uptake. She was reevaluated by surgery and taken for definitive resection. Histopathological evaluation demonstrated a complete R0 resection and no residual tumor. Based on this patient and literature review, this strategy demonstrates potential efficacy of neoadjuvant chemoradiation with prolonged chemotherapy, followed by surgery, which may improve outcomes in patients deemed previously unresectable.

Background: Induction chemotherapy followed by autologous stem cell transplantation (ASCT) is considered a standard of care for appropriate patients with newly diagnosed multiple myeloma (MM), but with the rapid expansion of available treatments, the role of ASCT has been questioned. Numerous studies have shown an improvement in complete response (CR) and progression free survival (PFS) with ASCT but our study is a cost comparison between novel agents and ASCT. We aimed to compare the cost effectiveness of ASCT versus non-transplant regimens in relation to PFS. Methods: We queried the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample (NIS) between 2008 and 2013 using the ICD-9 code 203.00 for MM and V42.81 for ASCT in the primary and secondary diagnosis fields. The analysis included patients who were 18 years or older. We monitored the trends in ASCT with regards to cost of a transplant admission and length of stay (LOS). Cost of hospitalization was adjusted for inflation in reference to the year 2011 and cost to charge ratio. Literature regarding common treatment regimens, response rates, duration of treatment, and PFS was reviewed. The assumption was made that transplant eligible patients that did not undergo transplant would be treated as though they were transplant ineligible. Gay et al 2015 showed a 43.4-month (mo) median PFS with 4 cycles of Rd followed by ASCT and lenalidomide maintenance until progression or toxicity. The cost of novel regimens was estimated using the one month commercial cost described by Roy et al and wholesale acquisition costs for new agents not described by the study which were adjusted using adjunct cost described by the study. A standard weight of 70 kg was used for agents requiring dose calculations. The cost of novel agents for an equivalent duration of 43.4 mo was estimated. Results: A total of 44778 (weighted n=9039) hospitalizations for MM (Male 55.9%, Caucasian 57.9%, peak incidence 65-79 yrs) occurred from 2008-2013. The average length of stay during ASCT admission was 11.4 +/- 0.4 days with a cost of $109,856 +/-5749.83. There has been a 16.89% decrease in LOS and 1.99% increase in the cost of ASCT (p<0.05). Gay et al showed a 43.4 mo PFS with 4 cycles Rd ($46,216) followed by ASCT ($109,856) and lenalidomide maintenance (~35.4 mo $564,453 adjusted for cost of office visits and lab work) for a total of $720,525 Conclusion: Rd + ASCT + R maintenance is efficacious for the treatment of newly diagnosed MM. The cost associated with the induction and transplant represents only 22% of the total cost, whereas lenalidomide maintenance makes up 78%. Considering secondary risks and the cost involved with lenolidomide maintenance, further investigation is warranted regarding the optimal duration of maintenance therapy and resultant progression free survival. It also raises the need for alternative options for maintenance therapy. Bortezomib and ixazomib are both more cost effective options and studies are in progress to assess their efficacy in PFS in the maintenance setting. Studies using novel agents for induction prior to ASCT are ongoing and have yet to reach an optimal duration of therapy. Table 1 shows that most of the novel agents used in combination regimens are more expensive that ASCT. Although most patients would not remain on one of these regimens for 43.4 mo, they would presumably progress through multiple lines of therapy during the 43.4 mo of PFS that ASCT provides. In an era of cost consciousness, ASCT should continue to be an integral component of MM treatment. Disclosures No relevant conflicts of interest to declare.