So far in this course we have dealt entirely with the evolution of characters that are controlled by simple Mendelian inheritance at a single locus. There are notes on the course website about gametic disequilibrium and how allele frequencies change at two loci simultaneously, but we didn’t discuss them. In every example we’ve considered we’ve imagined that we could understand something about evolution by examining the evolution of a single gene. That’s the domain of classical population genetics. For the next few weeks we’re going to be exploring a field that’s actually older than classical population genetics, although the approach we’ll be taking to it involves the use of population genetic machinery. If you know a little about the history of evolutionary biology, you may know that after the rediscovery of Mendel’s work in 1900 there was a heated debate between the “biometricians” (e.g., Galton and Pearson) and the “Mendelians” (e.g., de Vries, Correns, Bateson, and Morgan). Biometricians asserted that the really important variation in evolution didn’t follow Mendelian rules. Height, weight, skin color, and similar traits seemed to

Human biochemical genetics

https://surfer.nmr.mgh.harvard.edu/ftp/articles/dale99-recon1.pdf

Cortical surface-based analysis. I. Segmentation and surface reconstruction

Co-Planar Stereotaxic Atlas of the Human Brain—3-Dimensional Proportional System: An Approach to Cerebral Imaging, J. Talairach, P. Tournoux. Georg Thieme Verlag, New York (1988), 122 pp., 130 figs. DM 268

https://cogns.northwestern.edu/cbmg/TBSSNI2006.pdf

Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data.

Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association cortices. In turn, new insights into fundamental aspects of protein biology have resulted from research on the disease. This beneficial interplay between basic and applied cell biology is well illustrated by advances in understanding the genotype-to-phenotype relationships of familial Alzheimer's disease. All four genes definitively linked to inherited forms of the disease to date have been shown to increase the production and/or deposition of amyloid β-protein in the brain. In particular, evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the β-amyloid precursor protein by the protease called γ-secretase has spurred progress toward novel therapeutics. The finding that presenilin itself may be the long-sought γ-...

Alzheimer's Disease: Genes, Proteins, and Therapy

Rucaparib is an oral small-molecule poly(ADP-ribose) polymerase inhibitor indicated for patients with recurrent ovarian cancer in the maintenance and treatment settings and for patients with metastatic castration-resistant prostate cancer associated with a deleterious BRCA1 or BRCA2 mutation. Rucaparib has a manageable safety profile; the most common adverse events reported were fatigue and nausea in both indications. Accumulation in plasma exposure occurred after repeated administration of the approved 600-mg twice-daily dosage. Steady state was achieved after continuous twice-daily dosing for a week. Rucaparib has moderate oral bioavailability and can be dosed with or without food. Although a high-fat meal weakly increased maximum concentration and area under the curve, the effect was not clinically significant. A mass balance analysis indicated almost a complete dose recovery of rucaparib over 12 days, with metabolism, renal, and hepatic excretion as the elimination routes. A population pharmacokinetic analysis of rucaparib revealed no effect of age, sex, race, or body weight. No starting dose adjustments were necessary for patients with mild-to-moderate hepatic or renal impairment; the effect of severe organ impairment on rucaparib exposure has not been evaluated. In patients, rucaparib moderately inhibited cytochrome P450 (CYP) 1A2 and weakly inhibited CYP3As, CYP2C9, and CYP2C19. Rucaparib weakly increased systemic exposures of oral contraceptives and oral rosuvastatin and marginally increased the exposure of oral digoxin (a P-glycoprotein substrate). In vitro studies suggested that rucaparib inhibits transporters MATE1, MATE2-K, OCT1, and OCT2. No clinically meaningful drug interactions with rucaparib as a perpetrator were observed. An exposure–response analysis revealed dose-dependent changes in selected clinical efficacy and safety endpoints. Overall, this article provides a comprehensive review of the clinical pharmacokinetics, pharmacodynamics, drug–drug interactions, effects of intrinsic and extrinsic factors, and exposure–response relationships of rucaparib. 

https://link.springer.com/content/pdf/10.1007/s40262-022-01157-8.pdf

Clinical Pharmacokinetics and Pharmacodynamics of Rucaparib

Neural correlates of hedonic response in depressed and healthy subjects: A functional magnetic resonance imaging study


 Background: Fibroblast activation protein (FAP) is a membrane-bound protease that is highly expressed on the surface of cancer-associated fibroblasts (CAFs) present in the tumor microenvironment of most epithelial cancers. With limited expression observed in normal tissues, FAP is a promising therapeutic and imaging target for delivery of radionuclides to cancer tissues. FAP-2286, a low-molecular-weight cyclic peptide that potently and selectively binds to FAP, is attached to a linker and tetraazacyclododecane tetraacetic acid (DOTA) cage that can be used to conjugate radionuclides such as lutetium-177 (177Lu) or gallium-68 (68Ga) for therapeutic or imaging applications, respectively. 177Lu-FAP-2286 has demonstrated antitumor activity in preclinical studies. The LuMIERE study (NCT04939610) is the first phase 1/2 clinical trial of an FAP-targeted radionuclide therapy evaluating 177Lu-FAP-2286 in patients with FAP-expressing solid tumors that are identified with the imaging agent 68Ga-FAP-2286.
 Methods: Eligible adult patients with advanced or metastatic solid tumors and measurable disease (per RECIST v1.1) will be selected for treatment with 177Lu-FAP-2286 on the basis of FAP expression using 68Ga-FAP-2286. In phase 1, tumors must be refractory to or have progressed following prior treatment, with no satisfactory alternative treatment options. Phase 1 includes dose escalation of 177Lu-FAP-2286, starting at 3.7 GBq to a maximum of 9.25 GBq. Patients may receive up to 6 cycles of 177Lu-FAP-2286 administered on day 1 of each 6-week cycle. Three to 12 patients will be treated at each dose level in the dose-escalation portion. Tolerability will be assessed across multiple doses for determination of a recommended phase 2 dose (RP2D), which may be further evaluated in a phase 1 dose-expansion portion. FDG-PET/CT scans will be collected prior to treatment, and patients will be imaged by planar and SPECT/CT scans at multiple time points to calculate organ and tumor dosimetry to determine absorbed radiation dose. Disease status will be assessed per RECIST v1.1 every 6 weeks. The primary objective of phase 1 is to evaluate the safety of 177Lu-FAP-2286 and determine the RP2D. Secondary objectives include the assessment of radiation dosimetry, pharmacokinetics, and preliminary efficacy of 177Lu-FAP-2286 and the evaluation of safety and tumor uptake of 68Ga-FAP-2286. Phase 2 will evaluate the efficacy, safety, and dosimetry of 177Lu-FAP-2286 in patients with select FAP-expressing solid tumors.
 Citation Format: Jonathan McConathy, Mallika Dhawan, Ajit H. Goenka, Emerson A. Lim, Yusuf Menda, Beth Chasen, Moh'd Khushman, Akiva Mintz, Yousef Zakharia, John J. Sunderland, Owen Bowles, Jim Xiao, Andrew D. Simmons, Kenton Wride, Aaron Enke, Thomas A. Hope. LuMIERE: A phase 1/2 study investigating safety, pharmacokinetics, dosimetry, and preliminary antitumor activity of 177Lu-FAP-2286 in patients with advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT251.

Abstract CT251: LuMIERE: A phase 1/2 study investigating safety, pharmacokinetics, dosimetry, and preliminary antitumor activity of 177Lu-FAP-2286 in patients with advanced or metastatic solid tumors

INTRODUCTION
Airway management, including endotracheal intubation, is one of the cornerstones of care of critically ill patients. Internationally, health professionals from varying backgrounds deliver endotracheal intubation as part of their critical care role. This article considers the development of airway management skills within a single advanced critical care practitioner (ACCP) team and uses case series data to analyse the safety profile in performing this aspect of critical care. Skills were acquired during and after the ACCP training pathway. A combination of theoretical teaching, theatre experience, simulation and work-based practice was used. Case series data of all critical care intubations by ACCPs were collected. Audit results: Data collection identified 675 intubations carried out by ACCPs, 589 of those being supervised, non-cardiac arrest intubations requiring drugs. First pass success was achieved in 89.6% of cases. A second intubator was required in 4.3% of cases. Some form of complication was experienced by 42.3% of patients; however, the threshold for complications was set at a low level.


CONCLUSIONS
This ACCP service developed a process to acquire advanced airway management skills including endotracheal intubation. Under medical supervision, ACCPs delivered advanced airway management achieving a first pass success rate of 89.6%, which compares favourably with both international and national success rates. Although complications were experienced in 48.3% of patients, when similar complication cut-offs are compared with published data, ACCPs also matched favourably.

Andrew Simmons

Papers

Clinical Pharmacokinetics and Pharmacodynamics of Rucaparib

Neural correlates of hedonic response in depressed and healthy subjects: A functional magnetic resonance imaging study

Abstract CT251: LuMIERE: A phase 1/2 study investigating safety, pharmacokinetics, dosimetry, and preliminary antitumor activity of 177Lu-FAP-2286 in patients with advanced or metastatic solid tumors

Advanced airway management and drug-assisted intubation skills in an advanced critical care practitioner team.

Effects of estrogen replacement therapy on age-related differenecs in lobar brain volumes