Citations

Changes in pituitary-ovarian hormones across the menopausal transition have multiple physiological consequences. However, little is known about how the major types of postmenopausal hormone therapy (HT) affect pituitary-ovarian hormonal relationships. This study evaluated these relationships in recently menopausal women (52.45 ± 2.49 yr of age) in the Kronos Early Estrogen Prevention Study (KEEPS) who were compliant to randomized, double-blinded treatment with oral conjugated equine estrogen (o-CEE; n = 109), transdermal 17β-estradiol (t-E2; n = 107), or placebo ( n = 146). Androstenedione, testosterone, 17β-estradiol, estrone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were measured in serum before (baseline) and 48 mo after randomization to treatment. Descriptive summaries of hormone levels were performed, and multiple regression analyses were used to examine the effects of o-CEE, t-E2, and placebo on these hormone levels at 48 mo, adjusting for baseline levels. A network analysis examined the covariance of changes in hormone levels over the 48 mo within treatment groups. As expected, at 48 mo of treatment, hormone levels differed between women in the two active treatment groups compared with placebo, and network analysis indicated stronger relationships among hormone levels in the t-E2 and o-CEE groups compared with placebo. Associations among testosterone, 17β-estradiol, FSH, and LH differed between the o-CEE group compared with t-E2 and placebo groups. Thus, two common HT regimens differentially alter pituitary-ovarian hormone levels, altering feedback cycles and interhormonal associations in recently menopausal women. These interactions provide the basis for future studies investigating the impact of hormonal modulation of aging, including cognitive decline in women.

Abstract Coccidioides spp. are important pneumonia-causing pathogens of the American southwest, but little is known about their glycobiology and how their glycosylations differ from other pneumonia-causing fungi. There is mounting preliminary evidence to suggest genus or even species-specific glycosylations in the fungal kingdom due to the presence of unique Carbohydrate-Active Enzymes (CAZymes) in fungal genomes (Deshpande and others 2008; Karkowska-Kuleta and Kozik 2015). If Coccidioides spp.-specific glycans can be identified, it may be possible to exploit these differences to develop more specific diagnostic approaches and more effective therapeutics. Herein we i) mined Coccidioides spp. and other pathogenic fungal genomes to identify CAZymes specific for Coccidiodes spp., ii) proteomically determined the Coccidioides spp. “CAZome” produced in vivo and in vitro, and iii) utilized glycomics to differentiate Coccidioides genus-specific N-glycans from other pathogenic fungi. As far as we are aware, this is the first proteomic and glycomic comparison of the N-glycomes and CAZomes of different fungal genera during infection in human hosts.

Abstract Introduction: AITL is a distinct clinicopathologic entity among the mature T-cell and NK-cell lymphomas, accounting for approximately 1-2% of all non-Hodgkin lymphomas. Although autologous HCT (auto-HCT) provides high response rates, there is a high relapse risk associated with this procedure. Allo-HCT may result in a lower risk of relapse in part due to a graft-versus-lymphoma effect mediated by alloreactive donor cells. The role of allo-HCT in AITL with advanced disease (prior auto-HCT failure, or chemorefractory state) is not well described. Using the CIBMTR registry, we report here the outcomes of AITL patients undergoing an allo-HCT. Methods: We evaluated 249 adult (≥18years) patients with AITL who received a first allo-HCT during 2000-2016. Patients receiving mismatched unrelated donor, cord blood or haploidentical donor transplantation were excluded due to small numbers. The primary end-point was overall survival (OS). Secondary endpoints included cumulative incidence of acute graft-versus-host disease (GVHD), chronic GVHD, non-relapse mortality (NRM), relapse/progression (R/P) and progression-free survival (PFS). Results: Baseline patient characteristics are summarized in Table. The median patient age was 56 years (range=21-77 years). The graft source was mainly peripheral blood. Median follow-up of survivors was 49 months (range=4-170 months). The cumulative incidence of grade 2-4 and grade 3-4 acute GVHD at day 180 were 36% (95% CI=30-42)% and 12 (95% CI=8-17)%, respectively. The cumulative incidence of chronic GVHD at 2 years was 58% (95% CI=51-64)%. The 1-year NRM was 19% (95% CI=14-24)%, while the 4-year R/P, PFS, and OS were 21% (95% CI=16-27)%, 49% (95% CI=42-56)% and 56% (95% CI=49-63)%, respectively [Figure]. On multivariate analysis, chemoresistant status at allo-HCT was associated with a significantly higher risk for progression (RR=1.73 95% CI=1.08-2.77), while KPS <90% was associated with a significantly higher risk of mortality (RR=3.46 95% CI=1.75 - 6.87). Subgroup analysis looking at the effect of prior auto-HCT (no prior auto-HCT vs prior auto-HCT), the 4-year PFS (50% vs 47%, p=0.60) and OS (57% vs 54%, p=0.70) were not significantly different. Similarly, on comparing the disease status at allo-HCT (CR1 vs CR>1 vs PR vs refractory), there was no significant difference in the 4-year PFS (58% vs 45% vs 47% vs 38%, p=0.41) or OS (70% vs 54% vs 50% vs 52%, p=0.27). The 1-year NRM was 24%, while the 4-year R/P, PFS, and OS in patients with refractory AITL were 32%, 38%, and 52%, respectively. The most common cause of death was organ failure. Conclusion: In this largest series of mostly advanced AITL patients, allo-HCT was shown to provide durable disease control (4-year PFS=47%) with a clear plateau in relapse at 1-year post-transplantation. Allo-HCT provided durable disease control even in patients with a failed prior auto-HCT and those subjects with refractory disease at the time of allografting. Disclosures Kharfan-Dabaja: Alexion Pharmaceuticals: Speakers Bureau; Incyte Corp: Speakers Bureau; Seattle Genetics: Speakers Bureau. Smith:BMS: Consultancy; Portola: Honoraria. Sureda:Sanofi: Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria; Roche: Honoraria; BMS: Consultancy, Honoraria. Hamadani:Merck: Research Funding; Celgene Corporation: Consultancy; ADC Therapeutics: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Ostuka: Research Funding; Janssen: Consultancy; MedImmune: Consultancy, Research Funding; Takeda: Research Funding; Cellerant: Consultancy.

Abstract Quiescin sulfhydryl oxidase 1 (QSOX1) is an enzyme overexpressed by many different tumor types. QSOX1 catalyzes the formation of disulfide bonds in proteins. Because short hairpin knockdowns (KD) of QSOX1 have been shown to suppress tumor growth and invasion in vitro and in vivo, we hypothesized that chemical compounds inhibiting QSOX1 enzymatic activity would also suppress tumor growth, invasion, and metastasis. High throughput screening using a QSOX1-based enzymatic assay revealed multiple potential QSOX1 inhibitors. One of the inhibitors, known as “SBI-183,” suppresses tumor cell growth in a Matrigel-based spheroid assay and inhibits invasion in a modified Boyden chamber, but does not affect viability of nonmalignant cells. Oral administration of SBI-183 inhibits tumor growth in 2 independent human xenograft mouse models of renal cell carcinoma. We conclude that SBI-183 warrants further exploration as a useful tool for understanding QSOX1 biology and as a potential novel anticancer agent in tumors that overexpress QSOX1.

Introduction. Some patients with head and neck cancers have pain refractory to aggressive multimodal therapies. Herein, we report the use of an intrathecal targeted drug delivery (TDD) system catheter tip placed at C1 for the treatment of recalcitrant oropharyngeal cancer pain. Case Report. A patient with recurrent metastatic squamous cell tongue cancer reported severe pain not controlled despite high-dose opioids and nonopioid adjuvants. It was elected to proceed with an intrathecal TDD system with the catheter tip placed at the C1 level. After pump placement, we were able to decrease her daily oral morphine equivalents (OME) from nearly 1000 mg to 300 mg over the course of two months while titrating her TDD from 0.3 mg/day to 0.7 mg/day of intrathecal hydromorphone. Unfortunately, her improvement was limited secondary to aggressive cancer-directed treatments likely contributing to device infection and explant. Conclusions. In this patient, high cervical placement of an intrathecal TDD catheter was associated with a decrease in OME. While used in clinical practice on occasion, the use of high cervical TDD placement such as this implantable C1 intrathecal TDD system for cancer-associated pain is underreported in the literature. Further studies on this intervention within this challenging population are warranted.