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MSTPublications: August 2020

Posted by on Wednesday, August 26, 2020 in New Publications .

Changes in peripheral and local tumor immunity after neoadjuvant chemotherapy reshape clinical outcomes in patients with breast cancer.
Axelrod ML, Nixon MJ, Gonzalez-Ericsson PI, Bergman RE, Pilkinton MA, McDonnell WJ, Sanchez V, Opalenik S, Loi S, Zhou J, Mackay S, Rexer BN, Abramson VG, Jansen VM, Mallal SA, Donaldson J, Tolaney SM, Krop I, Garrido-Castro AC, Marotti JD, Shee K, Miller TW, Sanders M, Mayer IA, Salgado R, Balko JM.
Clin Cancer Res. 2020 Aug 21:clincanres.3685.2019. doi: 10.1158/1078-0432.CCR-19-3685. Online ahead of print.

Purpose: The recent approval of anti-PD-L1 immunotherapy in combination with nab-paclitaxel for metastatic triple-negative breast cancer (TNBC) highlights the need to understand the role of chemotherapy in modulating the tumor-immune microenvironment (TIME).
Experimental design: We examined immune-related gene expression patterns before and after neoadjuvant chemotherapy (NAC) in a series of 83 breast tumors, including 44 TNBCs, from patients with residual disease (RD). Changes in gene expression patterns in the TIME were tested for association with recurrence-free (RFS) and overall survival (OS). Additionally, we sought to characterize the systemic effects of NAC through single cell analysis (RNAseq and cytokine secretion) of PD-1HI CD8+ peripheral T cells and examination of a cytolytic gene signature in whole blood.
Results: In non-TNBC, no change in expression of any single gene was associated with RFS or OS, while in TNBC upregulation of multiple immune-related genes and gene sets were associated with improved long-term outcome. High cytotoxic T cell signatures present in the peripheral blood of patients with breast cancer at surgery were associated with persistent disease and recurrence, suggesting active anti-tumor immunity that may indicate ongoing disease burden.
Conclusions: We have characterized the effects of NAC on the TIME, finding that TNBC is uniquely sensitive to the immunologic effects of NAC, and local increases in immune genes/sets are associated with improved outcomes. However, expression of cytotoxic genes in the peripheral blood, as opposed to the TIME, may be a minimally invasive biomarker of persistent micrometastatic disease ultimately leading to recurrence.

Instrument gauge and type in uveal melanoma fine needle biopsy: implications for diagnostic yield and molecular prognostication.
Klofas LK, Bogan CM, Coogan A, Schultenover SJ, Weiss VL, Daniels AB.
Am J Ophthalmol. 2020 Aug 17:S0002-9394(20)30440-2. doi: 10.1016/j.ajo.2020.08.014. Online ahead of print.

Purpose: To systematically evaluate and compare the effects of using small gauge needles and vitrectors on the ability to obtain adequate diagnostic and prognostic uveal melanoma biopsy specimens.
Design: Comparative evaluation of biopsy instruments.
Methods: Survival of uveal melanoma cells was evaluated in vitro following needle aspiration. Five therapeutically enucleated eyes were sampled in triplicate for ex vivo diagnostic biopsy experiments with 25-gauge (25-G) needle, 27-gauge (27-G) needle, and 27-G vitrector. During surgery in eight patients, paired diagnostic transscleral FNABs were performed using both 25-G and 27-G needles. A review of cytologic specimens was performed by a panel of three expert cytopathologists. A retrospective chart review was performed to evaluate 100 consecutive tumors undergoing prognostic biopsy for gene expression profiling to assess the relationship between needle gauge and prognostic adequacy.
Results: No significant cell shearing of uveal melanoma cells occurred in vitro with 25-G, 27-G, or 30-G needles. For ex vivo biopsy samples, diagnostic yield was 100% using 25-G needle (5/5) or 27-G vitrector (5/5), but 60% using a 27-G needle (3/5). For in vivo samples, no difference in diagnostic yield was found between 25-G (75%, 6/8) or 27-G (75%, 6/8) needle sizes. Of 100 molecular prognostic biopsy samples evaluated, 65 were obtained using 27-G needles; for these biopsies, the prognostic yield was 65/65 (100%).
Conclusions: For diagnostic biopsy of uveal melanoma, a larger gauge needle or a 27-G vitrector may have better overall cellularity and diagnostic yield when compared to a 27-G needle. However, for much more common molecular prognostic testing, 27-G needle provided adequate sample in 100% (65/65) of cases, and a larger needle provided no additional benefit.

Calcium-Permeable AMPA Receptors Promote Endocannabinoid Signaling at Parvalbumin Interneuron Synapses in the Nucleus Accumbens Core.
Manz KM, Ghose D, Turner BD, Taylor A, Becker J, Grueter CA, Grueter BA.
Cell Rep. 2020 Jul 28;32(4):107971. doi: 10.1016/j.celrep.2020.107971.

Synaptic plasticity is a key mechanism of learning and memory. Synaptic plasticity mechanisms within the nucleus accumbens (NAc) mediate differential behavioral adaptations. Feedforward inhibition in the NAc occurs when glutamatergic afferents onto medium spiny neurons (MSNs) collateralize onto fast-spiking parvalbumin (PV)-expressing interneurons (PV-INs), which exert GABAergic control over MSN action potential generation. Here, we find that feedforward glutamatergic synapses onto PV-INs in the NAc core selectively express Ca2+-permeable AMPA receptors (CP-AMPARs). Ca2+ influx by CP-AMPARs on PV-INs triggers long-term depression (LTD) mediated by endocannabinoid (eCB) signaling at presynaptic cannabinoid type-1 (CB1) receptors (CB1Rs). Moreover, CP-AMPARs authorize tonic eCB signaling to negatively regulate glutamate release probability. Blockade of CP-AMPARs in the NAc core in vivo is sufficient to disinhibit locomotor output. These findings elucidate mechanisms by which PV-IN-embedded microcircuits in the NAc undergo activity-dependent shifts in synaptic strength.

Characterisation of aortic stenosis severity: a retrospective analysis of echocardiography reports in a clinical laboratory.
Raddatz MA, Gonzales HM, Farber-Eger E, Wells QS, Lindman BR, Merryman WD.
Open Heart. 2020 Aug;7(2):e001331. doi: 10.1136/openhrt-2020-001331.
PMID: 32817269

Objective: To evaluate how common echocardiographic metrics of aortic stenosis (AS) influence the proportion of patients who may be categorised as having severe stenosis and therefore considered for valve replacement.
Methods: Retrospective analysis was performed of all echocardiograms with aortic valve area (AVA) ≤1.2 cm2 and peak jet velocity (Vmax) ≥3 m/s from 1 December 2014 through 30 October 2017 at a single academic medical centre. Echocardiographic indices collected include AVA, Vmax, left ventricular ejection fraction, stroke volume and annotated aortic stenosis severity.
Results: Among 807 patients with AVA ≤1.2 cm2 and Vmax ≥3 m/s (44.0% female, median age 74 years (IQR: 66-81)), 45.6% had Vmax ≥4 m/s, while 75.8% had AVA ≤1 cm2. 40.0% of patients had concordant indices (Vmax ≥4 m/s and AVA ≤1 cm2), and 35.8% had discordant indices (Vmax <4 m/s and AVA ≤1 cm2) of severe AS. Compared with those with concordant indices, patients with discordant indices were more commonly female (54.0% vs 44.3%, p<0.05) and less commonly characterised as severe (42.6% vs 93.8%, p<0.001). Patients with paradoxical low-flow, low-gradient severe AS by echocardiography were disproportionately female (61.5% vs 41.8%, p<0.001), and their disease was characterised as severe only 49.5% of the time.
Conclusions: Patients with discordant indices, who are disproportionately female, are commonly described in clinical echocardiography reports as having less than severe AS. Given the potential benefit of AVR in patients with AVA ≤1 cm2 regardless of Vmax, this could have important clinical implications.

Hippocampal volume and hippocampal neuron density, number and size in schizophrenia: a systematic review and meta-analysis of postmortem studies.
Roeske MJ, Konradi C, Heckers S, Lewis AS.
Mol Psychiatry. 2020 Jul 28. doi: 10.1038/s41380-020-0853-y. Online ahead of print.

Reduced hippocampal volume is a consistent finding in neuroimaging studies of individuals with schizophrenia. While these studies have the advantage of large-sample sizes, they are unable to quantify the cellular basis of structural or functional changes. In contrast, postmortem studies are well suited to explore subfield and cellular alterations, but low sample sizes and subject heterogeneity impede establishment of statistically significant differences. Here we use a meta-analytic approach to synthesize the extant literature of hippocampal subfield volume and cellular composition in schizophrenia patients and healthy control subjects. Following pre-registration (PROSPERO CRD42019138280), PubMed, Web of Science, and PsycINFO were searched using the term: (schizophrenia OR schizoaffective) AND (post-mortem OR postmortem) AND hippocampus. Subjects were adult men and women with schizophrenia or schizoaffective disorder or non-psychiatric control subjects, and key outcomes, stratified by hippocampal hemisphere and subfield, were volume, neuron number, neuron density, and neuron size. A random effects meta-analysis was performed. Thirty-two studies were included (413 patients, 415 controls). In patients, volume and neuron number were significantly reduced in multiple hippocampal subfields in left, but not right hippocampus, whereas neuron density was not significantly different in any hippocampal subfield. Neuron size, averaged bilaterally, was also significantly reduced in all calculated subfields. Heterogeneity was minimal to moderate, with rare evidence of publication bias. Meta-regression of age and illness duration did not explain heterogeneity of total hippocampal volume effect sizes. These results extend neuroimaging findings of smaller hippocampal volume in schizophrenia patients and further our understanding of regional and cellular neuropathology in schizophrenia.

Distortion correction of diffusion weighted MRI without reverse phase-encoding scans or field-maps.
Schilling KG, Blaber J, Hansen C, Cai L, Rogers B, Anderson AW, Smith S, Kanakaraj P, Rex T, Resnick SM, Shafer AT, Cutting LE, Woodward N, Zald D, Landman BA.
PLoS One. 2020 Jul 31;15(7):e0236418. doi: 10.1371/journal.pone.0236418. eCollection 2020.

Hyperoxia Injury in the Developing Lung Is Mediated by Mesenchymal Expression of Wnt5A.
Sucre JMS, Vickers KC, Benjamin JT, Plosa EJ, Jetter CS, Cutrone A, Ransom M, Anderson Z, Sheng Q, Fensterheim BA, Ambalavanan N, Millis B, Lee E, Zijlstra A, Königshoff M, Blackwell TS, Guttentag SH.
Am J Respir Crit Care Med. 2020 May 15;201(10):1249-1262. doi: 10.1164/rccm.201908-1513OC.

Modeling Monogenic Diabetes using Human ESCs Reveals Developmental and Metabolic Deficiencies Caused by Mutations in HNF1A.
Cardenas-Diaz FL, Osorio-Quintero C, Diaz-Miranda MA, Kishore S, Leavens K, Jobaliya C, Stanescu D, Ortiz-Gonzalez X, Yoon C, Chen CS, Haliyur R, Brissova M, Powers AC, French DL, Gadue P.
Cell Stem Cell. 2019 Aug 1;25(2):273-289.e5. doi: 10.1016/j.stem.2019.07.007.

The S. pombe adaptor protein Bbc1 regulates localization of Wsp1 and Vrp1 during endocytic actin patch assembly.
MacQuarrie CD, Mangione MC, Carroll R, James M, Gould KL, Sirotkin V.
J Cell Sci. 2019 Sep 11;132(17):jcs233502. doi: 10.1242/jcs.233502.

Neanderthal introgression reintroduced functional ancestral alleles lost in Eurasian populations.
Rinker DC, Simonti CN, McArthur E, Shaw D, Hodges E, Capra JA.
Nat Ecol Evol. 2020 Jul 27. doi: 10.1038/s41559-020-1261-z. Online ahead of print.

Fine-Needle Aspiration-Based Patient-Derived Cancer Organoids.
Vilgelm AE, Bergdorf K, Wolf M, Bharti V, Shattuck-Brandt R, Blevins A, Jones C, Phifer C, Lee M, Lowe C, Hongo R, Boyd K, Netterville J, Rohde S, Idrees K, Bauer JA, Westover D, Reinfeld B, Baregamian N, Richmond A, Rathmell WK, Lee E, McDonald OG, Weiss VL.
iScience. 2020 Aug 21;23(8):101408. doi: 10.1016/j.isci.2020.101408. Epub 2020 Jul 24.

Throwing the bones to diagnose HIV: Views of rural South African traditional healers on undertaking HIV counselling and testing.
Audet CM, Clemens EM, Ngobeni S, Mkansi M, Sack DE, Wagner RG.
AIDS Care. 2020 Aug 17:1-5. doi: 10.1080/09540121.2020.1808568. Online ahead of print.

Medicaid Expansion and Hospitalization for Ambulatory Care-Sensitive Conditions Among Nonelderly Adults With Diabetes.
Mondesir FL, Kilgore ML, Shelley JP, Levitan EB, Huang L, Riggs KR, Pisu M, Li Y, Bronstein JM, Agne A, Cherrington AL.
J Ambul Care Manage. 2019 Oct/Dec;42(4):312-320. doi: 10.1097/JAC.0000000000000280.

Selective inhibition of mTORC1 in tumor vessels increases antitumor immunity.
Wang S, Raybuck A, Shiuan E, Cho SH, Wang Q, Brantley-Sieders DM, Edwards D, Allaman MM, Nathan J, Wilson KT, DeNardo D, Zhang S, Cook R, Boothby M, Chen J.
JCI Insight. 2020 Aug 6;5(15):139237. doi: 10.1172/jci.insight.139237.