Structure-Guided Evolution of Potent and Selective CHK1 Inhibitors through Scaffold Morphing

Pyrazolopyridine inhibitors with low micromolar potency for CHK1 and good selectivity against CHK2 were previously identified by fragment-based screening. The optimization of the pyrazolopyridines to a series of potent and CHK1-selective isoquinolines demonstrates how fragment-growing and scaffold morphing strategies arising from a structure-based understanding of CHK1 inhibitor binding can be combined to successfully progress fragment-derived hit matter to compounds with activity in vivo. The challenges of improving CHK1 potency and selectivity, addressing synthetic tractability, and achieving novelty in the crowded kinase inhibitor chemical space were tackled by multiple scaffold morphing steps, which progressed through tricyclic pyrimido[2,3-b]azaindoles to N-(pyrazin-2-yl)pyrimidin-4-amines and ultimately to imidazo[4,5-c]pyridines and isoquinolines. A potent and highly selective isoquinoline CHK1 inhibitor (SAR-020106) was identified, which potentiated the efficacies of irinotecan and gemcitabine in SW620 human colon carcinoma xenografts in nude mice

An immune dysfunction score for stratification of patients with acute infection based on whole-blood gene expression

Dysregulated host responses to infection can lead to organ dysfunction and sepsis, causing millions of global deaths each year. To alleviate this burden, improved prognostication and biomarkers of response are urgently needed. We investigated the use of whole-blood transcriptomics for stratification of patients with severe infection by integrating data from 3149 samples from patients with sepsis due to community-acquired pneumonia or fecal peritonitis admitted to intensive care and healthy individuals into a gene expression reference map. We used this map to derive a quantitative sepsis response signature (SRSq) score reflective of immune dysfunction and predictive of clinical outcomes, which can be estimated using a 7- or 12-gene signature. Last, we built a machine learning framework, SepstratifieR, to deploy SRSq in adult and pediatric bacterial and viral sepsis, H1N1 influenza, and COVID-19, demonstrating clinically relevant stratification across diseases and revealing some of the physiological alterations linking immune dysregulation to mortality. Our method enables early identification of individuals with dysfunctional immune profiles, bringing us closer to precision medicine in infection.peer-reviewe

Hospital Factors Impact Variation in Emergency Department Length of Stay More Than Physician Factors

Introduction: To analyze the correlation between the many different emergency department (ED) treatment metric intervals and determine if the metrics directly impacted by the physician correlate to the “door to room” interval in an ED (interval determined by ED bed availability). Our null hypothesis was that the cause of the variation in delay to receiving a room was multifactorial and does not correlate to any one metric interval.Methods: We collected daily interval averages from the ED information system, Meditech©. Patient flow metrics were collected on a 24-hour basis. We analyzed the relationship between the time intervals that make up an ED visit and the “arrival to room” interval using simple correlation (Pearson Correlation coefficients). Summary statistics of industry standard metrics were also done by dividing the intervals into 2 groups, based on the average ED length of stay (LOS) from the National Hospital Ambulatory Medical Care Survey: 2008 Emergency Department Summary.Results: Simple correlation analysis showed that the doctor-to-discharge time interval had no correlation to the interval of “door to room (waiting room time)”, correlation coefficient (CC) (CC=0.000, p=0.96). “Room to doctor” had a low correlation to “door to room” CC=0.143, while “decision to admitted patients departing the ED time” had a moderate correlation of 0.29 (p <0.001). “New arrivals” (daily patient census) had a strong correlation to longer “door to room” times, 0.657, p<0.001. The “door to discharge” times had a very strong correlation CC=0.804 (p<0.001), to the extended “door to room” time. Conclusion: Physician-dependent intervals had minimal correlation to the variation in arrival to room time. The “door to room” interval was a significant component to the variation in “door to discharge” i.e. LOS. The hospital-influenced “admit decision to hospital bed” i.e. hospital inpatient capacity, interval had a correlation to delayed “door to room” time. The other major factor affecting department bed availability was the “total patients per day.” The correlation to the increasing “door to room” time also reflects the effect of availability of ED resources (beds) on the patient evaluation time. The time that it took for a patient to receive a room appeared more dependent on the system resources, for example, beds in the ED, as well as in the hospital, than on the physician. [West J Emerg Med. 2014;15(2):158–164.

Hospital Factors Impact Variation in Emergency Department Length of Stay More Than Physician Factors

Introduction: To analyze the correlation between the many different emergency department (ED) treatment metric intervals and determine if the metrics directly impacted by the physician correlate to the “door to room” interval in an ED (interval determined by ED bed availability). Our null hypothesis was that the cause of the variation in delay to receiving a room was multifactorial and does not correlate to any one metric interval.Methods: We collected daily interval averages from the ED information system, Meditech©. Patient flow metrics were collected on a 24-hour basis. We analyzed the relationship between the time intervals that make up an ED visit and the “arrival to room” interval using simple correlation (Pearson Correlation coefficients). Summary statistics of industry standard metrics were also done by dividing the intervals into 2 groups, based on the average ED length of stay (LOS) from the National Hospital Ambulatory Medical Care Survey: 2008 Emergency Department Summary.Results: Simple correlation analysis showed that the doctor-to-discharge time interval had no correlation to the interval of “door to room (waiting room time)”, correlation coefficient (CC) (CC=0.000, p=0.96). “Room to doctor” had a low correlation to “door to room” CC=0.143, while “decision to admitted patients departing the ED time” had a moderate correlation of 0.29 (p &lt;0.001). “New arrivals” (daily patient census) had a strong correlation to longer “door to room” times, 0.657, p&lt;0.001. The “door to discharge” times had a very strong correlation CC=0.804 (p&lt;0.001), to the extended “door to room” time. Conclusion: Physician-dependent intervals had minimal correlation to the variation in arrival to room time. The “door to room” interval was a significant component to the variation in “door to discharge” i.e. LOS. The hospital-influenced “admit decision to hospital bed” i.e. hospital inpatient capacity, interval had a correlation to delayed “door to room” time. The other major factor affecting department bed availability was the “total patients per day.” The correlation to the increasing “door to room” time also reflects the effect of availability of ED resources (beds) on the patient evaluation time. The time that it took for a patient to receive a room appeared more dependent on the system resources, for example, beds in the ED, as well as in the hospital, than on the physician. [West J Emerg Med. 2014;15(2):158–164.

Cerebral white matter rarefaction has both neurodegenerative and vascular causes and may primarily be a distal axonopathy

Cerebral white matter rarefaction (CWMR) was considered by Binswanger and Alzheimer to be due to cerebral arteriolosclerosis. Renewed attention came with CT and MR brain imaging, and neuropathological studies finding a high rate of CWMR in Alzheimer disease (AD). The relative contributions of cerebrovascular disease and AD to CWMR are still uncertain. In 1181 autopsies by the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), large-format brain sections were used to grade CWMR and determine its vascular and neurodegenerative correlates. Almost all neurodegenerative diseases had more severe CWMR than the normal control group. Multivariable logistic regression models indicated that Braak neurofibrillary stage was the strongest predictor of CWMR, with additional independently significant predictors including age, cortical and diencephalic lacunar and microinfarcts, body mass index, and female sex. It appears that while AD and cerebrovascular pathology may be additive in causing CWMR, both may be solely capable of this. The typical periventricular pattern suggests that CWMR is primarily a distal axonopathy caused by dysfunction of the cell bodies of long-association corticocortical projection neurons. A consequence of these findings is that CWMR should not be viewed simply as small vessel disease or as a pathognomonic indicator of vascular cognitive impairment or vascular dementia

Structure-Guided Evolution of Potent and Selective CHK1 Inhibitors through Scaffold Morphing

Pyrazolopyridine inhibitors with low micromolar potency for CHK1 and good selectivity against CHK2 were previously identified by fragment-based screening. The optimization of the pyrazolopyridines to a series of potent and CHK1-selective isoquinolines demonstrates how fragment-growing and scaffold morphing strategies arising from a structure-based understanding of CHK1 inhibitor binding can be combined to successfully progress fragment-derived hit matter to compounds with activity in vivo. The challenges of improving CHK1 potency and selectivity, addressing synthetic tractability, and achieving novelty in the crowded kinase inhibitor chemical space were tackled by multiple scaffold morphing steps, which progressed through tricyclic pyrimido­[2,3-<i>b</i>]­azaindoles to <i>N</i>-(pyrazin-2-yl)­pyrimidin-4-amines and ultimately to imidazo­[4,5-<i>c</i>]­pyridines and isoquinolines. A potent and highly selective isoquinoline CHK1 inhibitor (SAR-020106) was identified, which potentiated the efficacies of irinotecan and gemcitabine in SW620 human colon carcinoma xenografts in nude mice