Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease

Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer's disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini-Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer's disease, which supports its potential utility as a clinically useful biomarker

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Predictors of Stepping Up to Higher Level of Care Among Eating Disorder Patients in a Partial Hospitalization Program.

Partial hospitalization programming (PHP) is a treatment option available for individuals with eating disorders (ED) who have made insufficient progress in outpatient settings or are behaviorally or medically unstable. Research demonstrates that this level of care yields efficacy for the majority of patients. However, not all patients achieve recovery in PHP and later admit to a higher level of care (HLOC) including residential treatment or inpatient hospitalization. Although PHP is an increasingly common treatment choice for ED, research concerning outcome predictors in outpatient, stepped levels of care remains limited. Thus, the current study sought to identify the predictors of patients first admitted to PHP that later enter residential or inpatient treatment. Participants were 788 patients (after exclusions) enrolled in adolescent or adult partial hospitalization programs in a specialized ED clinic. When compared to patients who maintained treatment in PHP, a significantly greater proportion of patients who discharged to a HLOC had previously received ED residential treatment. Moreover, patients who discharged to a HLOC were diagnosed with a comorbid anxiety disorder and reported greater anxious and depressive symptomatology. A logistic regression model predicting discharge from PHP to a HLOC was significant, and lower body mass index (BMI) was a significant predictor of necessitating a HLOC. Supplemental programming in partial hospitalization settings might benefit individuals with previous ED residential treatment experience, higher levels of anxiety and depression, and lower BMIs. Specialized intervention for these cases is both practically and economically advantageous, as it might reduce the risk of rehospitalization and at-risk patients needing to step up to a HLOC

Measurement of Diphosphine σ‑Donor and π-Acceptor Properties in d⁰ Titanium Complexes Using Ligand K‑Edge XAS and TDDFT

Diphosphines are highly versatile ancillary ligands in coordination chemistry and catalysis because their structures and donor–acceptor properties can vary widely depending on the substituents attached to phosphorus. Experimental and theoretical methods have been developed to quantify differences in phosphine and diphosphine ligand field strength, but experimentally measuring individual σ-donor and π-acceptor contributions to metal–phosphorus bonding remains a formidable challenge. Here we report P and Cl K-edge X-ray absorption spectroscopy (XAS), density functional theory (DFT), and time-dependent density functional theory (TDDFT) studies of a series of [Ph₂P­(CH₂)_<i>n</i>PPh₂]­TiCl₄ complexes, where <i>n</i> = 1, 2, or 3. The d⁰ metal complexes (Ti⁴⁺) revealed both P 1s → Ti–P π and P 1s → Ti–P σ* transitions in the P K-edge XAS spectra, which allowed spectral changes associated with Ti–P σ-bonding and π-backbonding to be evaluated as a function of diphosphine alkane length. DFT and TDDFT calculations were used to assign and quantify changes in Ti–P σ-bonding and π-backbonding. The calculated results for [Ph₂P­(CH₂)₂PPh₂]­TiCl₄ were subsequently compared to electronic structure calculations and simulated spectra for [R₂P­(CH₂)₂PR₂]­TiCl₄, where R = cyclohexyl or CF₃, to evaluate spectral changes as a function of diphosphine ligand field strength. Collectively, our results demonstrate how P K-edge XAS can be used to experimentally measure M-P π-backbonding with a d⁰ metal and corroborate earlier studies showing that relative changes in covalent M-P σ bonding do not depend solely on changes in diphosphine bite angle

Validating the Biphilic Hypothesis of Nontrigonal Phosphorus(III) Compounds

Constraining σ3-P compounds in nontrigonal, entatic geometries has proven to be an effective strategy for promoting biphilic oxidative addition reactions more typical of transition metals. Although qualitative descriptions of the impact of structure and symmetry on σ3-P complexes have been proposed, electronic structure variations responsible for biphilic reactivity have yet to be elucidated experimentally. Reported here are P K-edge XANES data and complementary TDDFT calculations for a series of structurally modified P(N)3 complexes that both validate and quantify electronic structure variations proposed to give rise to biphilic reactions at phosphorus. These data are presented alongside experimentally referenced electronic structure calculations that reveal nontrigonal structures predicted to further enhance biphilic reactivity in σ3-P ligands and catalysts.NIH NIGMS (Grant GM114547)NSF (Grant CHE-1724505

Validating the Biphilic Hypothesis of Nontrigonal Phosphorus(III) Compounds

Constraining σ3-P compounds in nontrigonal, entatic geometries has proven to be an effective strategy for promoting biphilic oxidative addition reactions more typical of transition metals. Although qualitative descriptions of the impact of structure and symmetry on σ3-P complexes have been proposed, electronic structure variations responsible for biphilic reactivity have yet to be elucidated experimentally. Reported here are P K-edge XANES data and complementary TDDFT calculations for a series of structurally modified P(N)3 complexes that both validate and quantify electronic structure variations proposed to give rise to biphilic reactions at phosphorus. These data are presented alongside experimentally referenced electronic structure calculations that reveal nontrigonal structures predicted to further enhance biphilic reactivity in σ3-P ligands and catalysts.NIH NIGMS (Grant GM114547)NSF (Grant CHE-1724505

Impact of Coordination Geometry, Bite Angle, and Trans Influence on Metal–Ligand Covalency in Phenyl-Substituted Phosphine Complexes of Ni and Pd

Despite the long-standing use of phosphine and diphosphine ligands in coordination chemistry and catalysis, questions remain as to their effects on metal–ligand bonding in transition metal complexes. Here we report ligand K-edge XAS, DFT, and TDDFT studies aimed at quantifying the impact of coordination geometry, diphosphine bite angle, and phosphine trans influence on covalency in M–P and M–Cl bonds. A series of four-coordinate NiCl₂ and PdCl₂ complexes containing PPh₃ or Ph₂P­(CH₂)_<i>n</i>PPh₂, where <i>n</i> = 1 (dppm), 2 (dppe), 3 (dppp), and 4 (dppb), was analyzed. The XAS data revealed that changing the coordination geometry from tetrahedral in Ni­(PPh₃)₂Cl₂ (<b>1</b>) to square planar in Ni­(dppe)­Cl₂ (<b>2</b>) more than doubles the intensity of pre-edge features assigned to Ni–P and Ni–Cl 1s → σ* transitions. By way of comparison, varying the diphosphine in Pd­(dppm)­Cl₂ (<b>4</b>), Pd­(dppp)­Cl₂ (<b>6</b>), and Pd­(dppb)­Cl₂ (<b>7</b>) yielded Pd–P 1s → σ* transitions with identical intensities, but a 10% increase was observed in the P K-edge XAS spectrum of Pd­(dppe)­Cl₂ (<b>5</b>). A similar observation was made when comparing Ni­(dppe)­Cl₂ (<b>2</b>) to Ni­(dppp)­Cl₂ (<b>3</b>), and DFT and TDDFT calculations corroborated XAS results obtained for both series. Comparison of the spectroscopic and theoretical results to the diphosphine structures revealed that changes in M–P covalency were not correlated to changes in bite angles or coordination geometry. As a final measure, P and Cl K-edge XAS data were collected on <i>trans</i>-Pd­(PPh₃)₂Cl₂ (<b>8</b>) for comparison to the cis diphosphine complex Pd­(dppe)­Cl₂ (<b>5</b>). Consistent with phosphine’s stronger trans influence compared to chloride, a 35% decrease in the intensity of the Pd–P 1s → σ* pre-edge feature and a complementary 34% increase in Pd–Cl 1s → σ* feature was observed for <b>8</b> (trans) compared to <b>5</b> (cis). Overall, the results reveal how coordination geometry, ligand arrangement, and diphosphine structure affect covalent metal–phosphorus and metal–chloride bonding in these late transition metal complexes