ALBERT

Description: To interpret molecular dynamics simulations of complex systems, systematic dimensionality reduction methods such as principal component analysis (PCA) represent a well-established and popular approach. Apart from Cartesian coordinates, internal coordinates, e.g., backbone dihedral angles or various kinds of distances, may be used as input data in a PCA. Adopting two well-known model problems, folding of villin headpiece and the functional dynamics of BPTI, a systematic study of PCA using distance-based measures is presented which employs distances between C α -atoms as well as distances between inter-residue contacts including side chains. While this approach seems prohibitive for larger systems due to the quadratic scaling of the number of distances with the size of the molecule, it is shown that it is sufficient (and sometimes even better) to include only relatively few selected distances in the analysis. The quality of the PCA is assessed by considering the resolution of the resulting free energy landscape (to identify metastable conformational states and barriers) and the decay behavior of the corresponding autocorrelation functions (to test the time scale separation of the PCA). By comparing results obtained with distance-based, dihedral angle, and Cartesian coordinates, the study shows that the choice of input variables may drastically influence the outcome of a PCA.

Description: To interpret molecular dynamics simulations of complex systems, systematic dimensionality reduction methods such as principal component analysis (PCA) represent a well-established and popular approach. Apart from Cartesian coordinates, internal coordinates, e.g., backbone dihedral angles or various kinds of distances, may be used as input data in a PCA. Adopting two well-known model problems, folding of villin headpiece and the functional dynamics of BPTI, a systematic study of PCA using distance-based measures is presented which employs distances between C α -atoms as well as distances between inter-residue contacts including side chains. While this approach seems prohibitive for larger systems due to the quadratic scaling of the number of distances with the size of the molecule, it is shown that it is sufficient (and sometimes even better) to include only relatively few selected distances in the analysis. The quality of the PCA is assessed by considering the resolution of the resulting free energy landscape (to identify metastable conformational states and barriers) and the decay behavior of the corresponding autocorrelation functions (to test the time scale separation of the PCA). By comparing results obtained with distance-based, dihedral angle, and Cartesian coordinates, the study shows that the choice of input variables may drastically influence the outcome of a PCA.

Description: We examine vibrational energy flow in dehydrated and hydrated villin headpiece subdomain HP36 by master equation simulations. Transition rates used in the simulations are obtained from communication maps calculated for HP36. In addition to energy flow along the main chain, we identify pathways for energy transport in HP36 via hydrogen bonding between residues quite far in sequence space. The results of the master equation simulations compare well with all-atom non-equilibrium simulations to about 1 ps following initial excitation of the protein, and quite well at long times, though for some residues we observe deviations between the master equation and all-atom simulations at intermediate times from about 1–10 ps. Those deviations are less noticeable for hydrated than dehydrated HP36 due to energy flow into the water.

Description: We examine vibrational energy flow in dehydrated and hydrated villin headpiece subdomain HP36 by master equation simulations. Transition rates used in the simulations are obtained from communication maps calculated for HP36. In addition to energy flow along the main chain, we identify pathways for energy transport in HP36 via hydrogen bonding between residues quite far in sequence space. The results of the master equation simulations compare well with all-atom non-equilibrium simulations to about 1 ps following initial excitation of the protein, and quite well at long times, though for some residues we observe deviations between the master equation and all-atom simulations at intermediate times from about 1–10 ps. Those deviations are less noticeable for hydrated than dehydrated HP36 due to energy flow into the water.

Description: An additional value of the Avogadro constant was obtained by counting the atoms in isotopically enriched Si spheres. With respect to the previous determination, the spheres were etched and repolished to eliminate metal contaminations and to improve the roundness. In addition, all the input quantities—molar mass, lattice parameter, mass, and volume—were remeasured aiming at a smaller uncertainty. In order to make the values given in Andreas et al. [Metrologia 48 , S1 (2011)] and Azuma et al. [Metrologia 52 , 360 (2015)] usable for a least squares adjustment, we report about the estimate of their correlation.

Description: Based on extensive ab initio calculations and the time-propagation of the nuclear Schrödinger equation, we study the vibrational relaxation dynamics and resulting spectral signatures of the OH stretch vibration of a hydrogen-bonded complex, HCO 2 − ⋅ H 2 O . Despite their smallness, it has been shown experimentally by Johnson and coworkers that the gas-phase infrared spectra of these types of complexes exhibit much of the complexity commonly observed for hydrogen-bonded systems. That is, the OH stretch band exhibits a significant red shift together with an extreme broadening and a pronounced substructure, which reflects its very strong anharmonicity. Employing an adiabatic separation of time scales between the three intramolecular high-frequency modes of the water molecule and the three most important intermolecular low-frequency modes of the complex, we calculate potential energy surfaces (PESs) of the ground and the first excited states of the high-frequency modes and identify a vibrational conical intersection between the PESs of the OH stretch fundamental and the HOH bend overtone. By performing a time-dependent propagation of the resulting system, we show that the conical intersection affects a coherent population transfer between the two states, the first step of which being ultrafast (60 fs) and irreversible. The subsequent relaxation of vibrational energy into the HOH bend and ground state occurs incoherently but also quite fast (1 ps), although the corresponding PESs are well separated in energy. Owing to the smaller effective mass difference between light and heavy degrees of freedom, the adiabatic ansatz is consequently less significant for vibrations than in the electronic case. Based on the model, we consider several approximations to calculate the measured Ar-tag action spectrum of HCO 2 − ⋅ H 2 O and achieve semiquantitative agreement with the experiment.

Description: Background: Disease relapse remains the primary cause of mortality following allogeneic hematopoietic cell transplantation (alloHCT). One important mechanism of disease relapse in this setting is failure of the graft-versus-tumor (GvT) effect, and the PD-1/PD-L1 axis may diminish GvT after alloSCT. We hypothesized that PD-1/PD-L1 interactions prevent donor-derived T cells from eliminating malignant cells expressing minor histocompatibility antigens, and that blocking PD-1/PD-L1 interactions with the anti-PD-1 antibody, pembrolizumab (pem), might restore GvT and induce clinical responses in patients (pts) with relapsed hematologic malignancies following alloHCT. However, PD-1 blockade therapy has been associated with severe graft-versus-host disease (GVHD) in murine models, and GVHD has been reported in humans treated with anti-PD-1 therapy after alloHCT. Thus, we developed a prospective clinical study to test the tolerability and preliminary efficacy of pembrolizumab in patients with relapsed leukemia/lymphoma after alloSCT. Methods: Pts with AML, MDS, or B cell lymphomas with biopsy-proven recurrence after alloSCT were eligible, as long as no active acute GVHD 〉 grade 1 or chronic GVHD was present. Pts were treated with pem 200 mg IV q3 weeks for up to 2 years, provided that neither intolerable side-effects nor disease progression occurred. Pem could be delayed for treatment-limiting toxicities (TLT), defined as immune-related adverse events (irAEs) not meeting criteria for a dose-limiting toxicity (DLT). DLT was defined as the development of grade 3 or 4 acute GVHD/irAE, any unexpected grade 〉 2 toxicity related to pem, or development of 〉 grade 2 vital organ dysfunction secondary to an irAE within 90 days of pem initiation. A two-stage mini-max design was chosen, with an early stopping rule for DLT after the first 11 patients were enrolled. Results: 11 pts (7 male, 4 female), mean age 49.5 yrs (range, 27-62 yrs) have been enrolled. 8 pts had AML and 3 had lymphoma (DLBCL - 2, cHL - 1). 6 pts had matched-related donors (MRD) and 5 pts had haploidentical/umbilical cord blood (haplo-cord) donors. Pts with MRD were conditioned with fludarabine, melphalan, and alemtuzumab, or fludarabine and busulfan. Pts with haplo-cord donors were conditioned with fludarabine, melphalan, and ATG. 5 pts had prior acute GVHD. Pts relapsed following alloHCT at a median of 453 days (range, 101-1021 days). A median of 2 cycles of pembrolizumab (range, 1-8) was administered. 3 pts are receiving ongoing treatment. 3 pts experienced a DLT due to an irAE (grade 3-4 pneumonitis 2 pts; grade 3 hyperthyroidism 1 pt), all of which occurred after 1-2 cycles of pem, and resolved after pem discontinuation and corticosteroid treatment. 1 pt experienced a TLT (grade 2 rash), but resumed pem treatment. Among all pts, irAEs of any grade occurred in 7 pts. 7 pts were evaluable for response. 3 pts (2 AML, 1 DLBCL) experienced progressive disease (PD), 2 pts (AML) had stable disease (SD), and 2 pts achieved CR (DLBCL, cHL). 1 pt with AML (myeloid sarcoma) in whom pem was discontinued for PD by PET/CT imaging had a concurrent tumor biopsy that revealed marked T cell infiltration and PD-L1 expression on a significant fraction of malignant myeloid cells, suggestive of possible inflammatory "pseudo-progression". 1 pt in CR developed therapy-related AML unrelated to pem. Notably, both patients with CR following pem had PD-L1 gene-amplified lymphomas by FISH, and diffuse PD-L1 protein expression on pre-treatment biopsies. Currently, 4 pts have died, all due to disease progression, and 7 are alive. A total of 26 patients are expected to be enrolled. Conclusions: Treatment with pem in the post-alloHCT disease relapse setting is feasible, but can induce early and severe irAEs, requiring vigilant monitoring. To date, objective responses were seen in 2/3 lymphoma patients treated with pem. In AML, pem may be less effective, where a best response of SD was observed in 2 pts, and possible "pseudo-progression" in a patient with myeloid sarcoma. This study continues to accrue pts, and correlative analyses are underway. To our knowledge, these are the first prospective data of PD-1 blockade therapy in the post-alloHCT setting. Disclosures Kline: iTeos: Research Funding; Merck: Honoraria, Research Funding. Liu:BMS: Research Funding. Curran:Merck: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Smith:BMS: Consultancy; Portola: Honoraria. Bishop:Juneau Therapeutics: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; United Healthcare: Employment; Novartis Pharmaceuticals Corporation: Speakers Bureau.

Description: Introduction: Hematopoietic cell transplantation (HCT) advances in reduced intensity conditioning, donor identification, and supportive care have led to its increased use over the last few decades. HCT is a complex process that requires coordination at multiple levels, and there may be disparities in its utilization. To better understand these access disparities, we conducted a systematic review of studies that assessed barriers to referral and/or receipt of HCT. Additionally, we focused on a subgroup of older patients (aged ≥65 at transplant), who we hypothesized would be at higher risk for access barriers to HCT. Methods: A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched for articles published in English from PubMed, Embase, Cumulative Index for Nursing and Allied Health, and Cochrane Central Register of Controlled Trials between the database inception and January 12th, 2018. Inclusion criteria were: 1) clinical trials, observational, qualitative, cross-sectional, or mixed-method study designs; 2) study assessed barriers to HCT or factors associated with referral for or receipt of HCT (except for country-specific economic factors as these are less likely to be targetable), 3) included patients ≥18 years with cancer. Narrative review articles and abstracts without full text were excluded. Two authors independently reviewed all titles and abstracts (N=3,262) and assessed studies for full-text eligibility (N=153). A third reviewer resolved any discrepancies. Eighteen studies met eligibility criteria and an additional 5 studies (not identified on our search strategy) were included on review of the bibliographies. Literature on subgroup of patients aged ≥65 was also assessed. Results: Among the 23 studies included, 16 were published after 2010. Studies were retrospective (N=18; 14 from registry data), cross-sectional (N=4; 2 from registry data), and mixed-method (N=1), and primarily conducted in the US (N=21). Barriers were assessed at the patient level (N=19; sample size ranged from 350 to 38,420), healthcare professional level (N=3; 1 study assessed both patients and healthcare professionals), or country level (N=2). Fourteen studies included some information on age of the patients and 10 studies included some patients aged 60 and above. Seventeen studies only included patients with hematologic malignancies. Age was the most common barrier identified (N=16 out of 16 studies identified older age as a barrier). Fourteen studies showed that older age was associated with lower odds of referral for or receipt of HCT, and the remaining 2 studies provided descriptive data showing lower percentages of patients receiving HCT compared to the younger age groups. Table 1 shows other potential barriers or factors associated with lower referral for or receipt of HCT at the patient, disease, physician, and organizational levels. These included race (N=14 out of 16 studies identified non-white race as a barrier), insurance or financial capacity (N=11/12), comorbidity (N=8/9), gender (N=7/17; primarily female), disease status (N=5/5), patient preferences (N=5/5), time of diagnosis (N=5/5), cancer type (N=4/6), and socioeconomic status (N=4/5). Only one study evaluated factors associated with receipt of HCT in a subgroup of patients ≥65 years. Older age, female gender, and a diagnosis of leukemia other than acute myeloid leukemia were associated with lower odds of receiving HCT. Conclusions: There are limited prospective studies evaluating access barriers to HCT in adult patients with cancer. Older age is the most commonly reported barrier to both autologous and allogeneic HCT, although studies have not addressed specific mechanisms for this disparity. In addition, other potential barriers identified such as gender, race, insurance status, and comorbidity have not been well studied in the context of older age. While some barriers may be difficult to intervene upon (e.g. comorbidity, disease status, performance status), many are amenable to interventions (e.g. socioeconomic status, distance to transplant center, social support). With the increasing trend for HCT in older patients, there is a critical need for prospective studies that better describe these access barriers and their mechanisms in order to design future interventions to reduce disparities in HCT access. Figure. Figure. Disclosures Liesveld: Onconova: Other: DSMB; Abbvie: Honoraria. Aljitawi:Medpace: Consultancy; The University of Rochester Medical Center: Patents & Royalties: Pending patent related to decellularized Wharton's jelly matrix. Klepin:Genentech Inc: Consultancy. Stock:Jazz Pharmaceuticals: Consultancy. Wildes:Janssen: Research Funding. Majhail:Incyte: Honoraria; Anthem, Inc.: Consultancy; Atara: Honoraria.

Description: Background: Inotuzumab ozogamicin (InO), a humanized anti-CD22 antibody-calicheamicin conjugate, produced a superior response compared with standard of care (SOC) for relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) in an intent-to-treat (ITT) analysis of the first 218 of 326 patients (pts) randomized (ITT218) in the INO-VATE trial (complete remission [CR], including CR with incomplete hematologic recovery [CRi], 80.7% [95% CI, 72-88] vs 29.4% [21-39]; 1-sided P