Carfilzomib, lenalidomide, and dexamethasone plus transplant in newly diagnosed multiple myeloma.

In this phase 2 multicenter study, we evaluated the incorporation of autologous stem cell transplantation (ASCT) into a carfilzomib-lenalidomide-dexamethasone (KRd) regimen for patients with newly diagnosed multiple myeloma (NDMM). Transplant-eligible patients with NDMM received 4 cycles of KRd induction, ASCT, 4 cycles of KRd consolidation, and 10 cycles of KRd maintenance. The primary end point was rate of stringent complete response (sCR) after 8 cycles of KRd with a predefined threshold of ≥50% to support further study. Seventy-six patients were enrolled with a median age of 59 years (range, 40-76 years), and 35.5% had high-risk cytogenetics. The primary end point was met, with an sCR rate of 60% after 8 cycles. Depth of response improved over time. On intent-to-treat (ITT), the sCR rate reached 76%. The rate of minimal residual disease (MRD) negativity using modified ITT was 70% according to next-generation sequencing (<10-5 sensitivity). After median follow-up of 56 months, 5-year progression-free survival (PFS) and overall survival (OS) rates were 72% and 84% for ITT, 85% and 91% for MRD-negative patients, and 57% and 72% for patients with high-risk cytogenetics. For high-risk patients who were MRD negative, 5-year rates were 77% and 81%. Grade 3 to 4 adverse events included neutropenia (34%), lymphopenia (32%), infection (22%), and cardiac events (3%). There was no grade 3 to 4 peripheral neuropathy. Patients with NDMM treated with KRd with ASCT achieved high rates of sCR and MRD-negative disease at the end of KRd consolidation. Extended KRd maintenance after consolidation contributed to deepening of responses and likely to prolonged PFS and OS. Safety and tolerability were manageable. This trial was registered at www.clinicaltrials.gov as #NCT01816971.

Impact of an Oncology Clinical Pharmacist Specialist in an Outpatient Multiple Myeloma Clinic.

INTRODUCTION: Improvements in cancer treatment and supportive care, as well as the approval of oral chemotherapy medications over the past decade, have resulted in an increasing number of cancer patients being treated in outpatient settings. Transitioning cancer treatments to the outpatient setting places greater emphasis on proper medication counseling and optimal management of adverse effects. We therefore evaluated the clinical and financial impact of an oncology clinical pharmacist specialist in an interdisciplinary multiple myeloma clinic by using a validated scoring tool. METHODS: The oncology clinical pharmacist specialist was available for consult by the multiple myeloma clinic staff. The pharmacist may be consulted for any medication-related inquiry. On the basis of the consult, the pharmacist categorized interventions into 12 predefined intervention categories. RESULTS: Implementation of a clinical pharmacy specialist into a multiple myeloma clinic over 39 clinic days resulted in 241 patient consults and 474 interventions made by the pharmacist. The most frequent interventions made by the pharmacist were medication teaching (n = 97), dose adjustments (n = 82), and medication reconciliation (n = 63). The value of interventions made by the pharmacist during the study period was $189,441, with a predicted annual value of $757,764. CONCLUSION: The addition of an oncology pharmacist to an outpatient multiple myeloma clinic can improve clinical and financial outcomes.

Mitigation of Acetylcholine Esterase Activity in the 1,7-Diazacarbazole Series of Inhibitors of Checkpoint Kinase 1.

Checkpoint kinase 1 (ChK1) plays a key role in the DNA damage response, facilitating cell-cycle arrest to provide sufficient time for lesion repair. This leads to the hypothesis that inhibition of ChK1 might enhance the effectiveness of DNA-damaging therapies in the treatment of cancer. Lead compound 1 (GNE-783), the prototype of the 1,7-diazacarbazole class of ChK1 inhibitors, was found to be a highly potent inhibitor of acetylcholine esterase (AChE) and unsuitable for development. A campaign of analogue synthesis established SAR delineating ChK1 and AChE activities and allowing identification of new leads with improved profiles. In silico docking using a model of AChE permitted rationalization of the observed SAR. Compounds 19 (GNE-900) and 30 (GNE-145) were identified as selective, orally bioavailable ChK1 inhibitors offering excellent in vitro potency with significantly reduced AChE activity. In combination with gemcitabine, these compounds demonstrate an in vivo pharmacodynamic effect and are efficacious in a mouse p53 mutant xenograft model.

Peripheral arterial desaturation is further exacerbated by exercise in adolescents with acute mountain sickness.

OBJECTIVE: Rapid ascent to altitude can result in the development of high altitude illnesses such as acute mountain sickness (AMS). This study aimed to investigate AMS symptoms in adolescents and study basic cardiopulmonary measurements at altitude. METHODS: Thirty-eight adolescents aged 16 to 19 years flew to 3500 m from 215 m and continued over a 23-day period to ascend to a maximum altitude of 5200 m. Each member of the expedition completed a Lake Louise Self-Assessment Questionnaire (LLSAQ) on a daily basis, and AMS was defined as a score of ≥ 3, with an associated headache. Physiology measurements included a step test, and both before and after exercise pulse oximetry, blood pressure, and pulse rate. RESULTS: Oxygen saturation inversely correlated with altitude (P = .001). Mean pulse rate increased from 70 beats/min (± 6.5) at 215 m to 83 beats/min (± 2.2) at 3500 m (P = .01), and a rise in blood pressure with ascent was highlighted (P = .004). The majority of subjects (84%) had an LLSAQ of 3 or more on at least 1 occasion, and they tended to record higher pulse rates (P = .005) and lower oxygen saturations (P = .001). Exercise-induced drops in oxygen saturation and raised pulse rates were more prolonged in subjects with severe AMS compared with subjects not having AMS (P = .046 and P = .005, respectively). CONCLUSIONS: The LLSAQ scoring system appeared to be a simple and effective technique to aid the diagnosis of adolescents who have AMS, and it may help improve the safety of large groups traveling to altitude. The AMS subjects tended to have low oxygen saturations and high pulse rates, highlighting potential areas for further research.

Route Designer: a retrosynthetic analysis tool utilizing automated retrosynthetic rule generation.

Route Designer, version 1.0, is a new retrosynthetic analysis package that generates complete synthetic routes for target molecules starting from readily available starting materials. Rules describing retrosynthetic transformations are automatically generated from reaction databases, which ensure that the rules can be easily updated to reflect the latest reaction literature. These rules are used to carry out an exhaustive retrosynthetic analysis of the target molecule, in which heuristics are used to mitigate the combinatorial explosion. Proposed routes are prioritized by an empirical rating algorithm to present a diverse profile of the most promising solutions. The program runs on a server with a web-based user interface. An overview of the system is presented together with examples that illustrate Route Designer's utility.

Biomimetic synthesis of resorcylate natural products utilizing late stage aromatization: concise total syntheses of the marine antifungal agents 15G256iota and 15G256beta.

Diketo-1,3-dioxin-2-ones underwent retro-Diels-Alder reaction on heating in toluene at 110 degrees C to generate alpha,gamma,-triketo-ketenes. These were trapped with alcohols to provide 2,4,6-triketocarboxylates, which were smoothly aromatized by sequential reaction with potassium carbonate and methanolic hydrogen chloride to give resorcylate esters. The reaction was applied in the total synthesis of the marine antifungal agents 15G256beta (1), 15G256iota (2), and 15G256pi (3) and the mycotoxin S-(-)-zearalenone (4).

The closely related estrogen-regulated trefoil proteins TFF1 and TFF3 have markedly different hydrodynamic properties, overall charge, and distribution of surface charge.

The human trefoil proteins TFF1 and TFF3 are expressed predominantly in the gastrointestinal tract. They are also expressed and regulated by estrogens in malignant breast epithelial cells. TFF1 and TFF3 are small cysteine-rich acidic secreted proteins of 60 and 59 amino acids with similar isoelectric points of 4.75 and 3.94, respectively. Each contains one trefoil domain that is characterized by several conserved features including six cysteine residues with conserved spacing. TFF1 and TFF3 form intermolecular disulfide bonds via an extra-trefoil domain cysteine residue and are present in vivo as monomers and homodimers and as complexes with other proteins. The TFF1 dimer is more active than the TFF1 monomer. In the present study the hydrodynamic and charge properties of TFF1 and TFF3 monomers and homodimers have been compared and shown to differ markedly. Notably, TFF1 is significantly more asymmetric than TFF3 (frictional coefficients 1.25 and 1.12, respectively, p < 0.001), and homodimerization of TFF1 results in a greater increase in asymmetry than for TFF3. The overall charges of TFF1 and TFF3 are very different at neutral pH. Titration curves predicted significant differences in charge across a wide pH range that agreed well with experimental data. The locations of charged amino acids in the primary sequences and in the tertiary structures of TFF1 and TFF3 were examined. This revealed interesting divergence in both the distribution and local topology of charged amino acid side chains. The significant differences between the shape, size, and surface charge of these two closely related molecules may account for their divergent biological activities.

Role of dimerization in KH/RNA complexes: the example of Nova KH3.

The K homology module, one of the most common RNA-binding motifs, is present in multiple copies in both prokaryotic and eukaryotic regulatory proteins. Increasing evidence suggests that self-aggregation of KH modules has a functional role. We have used a combination of techniques to characterize the behavior in solution of the third KH domain of Nova-1, a paradigmatic KH protein. The possibility of working on the isolated module allowed us to observe specifically the homodimerization and RNA-binding properties of KH domains. We provide conclusive evidence that self-association of Nova-1 KH3 occurs in solution even in the absence of RNA. Homodimerization involves a specific protein/protein interface. We also studied the dynamical behavior of Nova-1 KH3 in isolation and in complex with RNA. These data provide a model for the mechanism of KH/RNA recognition and suggest functional implications of dimerization in KH complexes. We discuss our findings in the context of the whole KH family and suggest a generalized mode of interaction.

Molecular interactions between desmosomal cadherins.

Desmocollins (Dscs) and desmogleins (Dsgs) are cell-adhesion molecules involved in the formation of desmosome cell-cell junctions and share structural similarities to classical cadherins such as E-cadherin. In order to identify and provide quantitative information on the types of protein-protein interactions displayed by the type 2 isoforms and investigate the role of Ca(2+) in this process, we have developed an Escherichia coli expression system to generate recombinant proteins containing the first two extracellular domains, namely Dsg2(1-2) and Dsc2(1-2). Analytical ultracentrifugation, chemical cross-linking, CD, fluorescence and BIAcore have been used to provide the first direct evidence of Ca(2+) binding to desmosomal cadherins. These studies suggest that Dsc2(1-2) not only exhibits homophilic interactions in solution, but can also form heterophilic interactions with Dsg2(1-2). The latter, on the other hand, shows much weaker homophilic association. Our results further demonstrate that heterophilic interactions are Ca(2+)-dependent, whereas the Ca(2+)-dependence of homophilic association is less clear. Our data indicate that the functional properties of Dsc2(1-2) are more similar to those of classical cadherins, consistent with the observation that Dsc shares a higher level of sequence homology with classical cadherins than does Dsg. In addition to corroborating the conclusions of previously reported transfection studies which suggest the formation of lateral heterodimers and homodimers, our results also provide direct quantitative information on the strength of these interactions which are essential for understanding the adhesion mechanism.