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\"Alpha Academy: Where betas get booted. Eccentric billionaire Shira Brazille founded the super-exclusive Alpha Academy on exotic Alpha Island to nurture the next generation of exceptional dancers, writes, musicians, and inventors. It's a dream come true for one hundred lucky girls, but those not measuring up can be sent home at any time, for any reason. The one left standing will win worldwide fame. Who will it be?\"--P. [4] of cover.
Book
Pembrolizumab in men with heavily treated metastatic castrate‐resistant prostate cancer
Background
Pembrolizumab is approved for patients with metastatic, microsatellite instability (MSI)‐high or mismatch repair‐deficient (dMMR) solid tumors. However, very few men with prostate cancer were included in these initial studies.
Methods
We performed a single institution retrospective review of men with metastatic castrate‐resistant prostate cancer (mCRPC) who were treated with pembrolizumab. The primary objective was to describe the clinical efficacy of pembrolizumab associated with patient and genomic characteristics.
Results
We identified 48 men who received ≥1 cycle of pembrolizumab for mCRPC. Of these, 94% (45/48) had ≥3 prior lines of therapy for mCRPC. Somatic tumor sequencing was available in 18/48 men (38%). We found that 17% (8/48) had a ≥50% confirmed PSA decline with pembrolizumab, and 8% (4/48) had a ≥90% PSA decline with durations of response ranging from 3.1 to 16.3 months. Two of these four men had mutations in LRP1b, one of whom also had MSH2 loss and was MSI‐H and TMB‐high. Despite prior progression on enzalutamide, 48% (23/48) of men were treated with concurrent enzalutamide. The median PSA progression‐free‐survival was 1.8 months (range 0.4‐13.7 months), with 31% of patients remaining on pembrolizumab therapy and 54% of men remain alive with a median follow‐up of 7.1 months.
Conclusions
In a heavily pretreated population of men with mCRPC, pembrolizumab was associated with a ≥50% PSA decline in 17% (8/48) of men, including a dramatic ≥90% PSA response in 8% (4/48), two of whom harbored pathogenic LRP1b mutations suggesting that LRP1b mutations may enrich for PD‐1 inhibitor responsiveness in prostate cancer.
A subset of men with heavily treated metastatic castrate resistant prostate cancer derives clinical benefit from treatment with pembrolizumab. Tumor biomarkers such as microsatellite instability are being used to help identify some of these men; more investigation into potential biomarkers such as LRP1b are needed to help identify others who may derive benefit.
Journal Article
PTEN inhibition promotes robust growth of bulbospinal respiratory axons and partial recovery of diaphragm function in a chronic model of cervical contusion spinal cord injury
High spinal cord injury (SCI) leads to persistent and debilitating compromise in respiratory function. Cervical SCI not only causes the death of phrenic motor neurons (PhMNs) that innervate the diaphragm, but also damages descending respiratory pathways originating in the rostral ventral respiratory group (rVRG) located in the brainstem, resulting in denervation and consequent silencing of spared PhMNs located caudal to injury. It is imperative to determine whether interventions targeting rVRG axon growth and respiratory neural circuit reconnection are efficacious in chronic cervical contusion SCI, given that the vast majority of individuals are chronically-injured and most cases of SCI involve contusion-type damage to the cervical region. We therefore employed a clinically-relevant rat model of chronic cervical hemicontusion to test therapeutic manipulations aimed at reconstructing damaged rVRG-PhMN-diaphragm circuitry to achieve recovery of respiratory function. At a chronic time point post-injury, we systemically administered: an antagonist peptide directed against phosphatase and tensin homolog (PTEN), a central inhibitor of neuron-intrinsic axon growth potential; an antagonist peptide directed against receptor-type protein tyrosine phosphatase sigma (PTPσ), another important negative regulator of axon growth capacity; or a combination of these two peptides. PTEN antagonist peptide (PAP4) promoted partial recovery of diaphragm motor activity out to nine months post-injury, while PTPσ peptide did not impact diaphragm function after cervical SCI. Furthermore, PAP4 promoted robust growth of descending bulbospinal rVRG axons caudal to the injury within the denervated portion of the PhMN pool, while PTPσ peptide did not affect rVRG axon growth at this location that is critical to control of diaphragmatic respiratory function. In conclusion, we find that, when PTEN inhibition is targeted at a chronic time point following cervical contusion that is most relevant to the SCI clinical population, our non-invasive PAP4 strategy can successfully promote significant regrowth of damaged respiratory neural circuitry and also partial recovery of diaphragm motor function.Competing Interest StatementThe authors have declared no competing interest.
Paper