Publications by authors named "Palak Panchal"

7 Publications

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Molecular Stressors Engender Protein Connectivity Dysfunction through Aberrant N-Glycosylation of a Chaperone.

Cell Rep 2020 06;31(13):107840

Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Stresses associated with disease may pathologically remodel the proteome by both increasing interaction strength and altering interaction partners, resulting in proteome-wide connectivity dysfunctions. Chaperones play an important role in these alterations, but how these changes are executed remains largely unknown. Our study unveils a specific N-glycosylation pattern used by a chaperone, Glucose-regulated protein 94 (GRP94), to alter its conformational fitness and stabilize a state most permissive for stable interactions with proteins at the plasma membrane. This "protein assembly mutation' remodels protein networks and properties of the cell. We show in cells, human specimens, and mouse xenografts that proteome connectivity is restorable by inhibition of the N-glycosylated GRP94 variant. In summary, we provide biochemical evidence for stressor-induced chaperone-mediated protein mis-assemblies and demonstrate how these alterations are actionable in disease.
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http://dx.doi.org/10.1016/j.celrep.2020.107840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372946PMC
June 2020

The epichaperome is a mediator of toxic hippocampal stress and leads to protein connectivity-based dysfunction.

Nat Commun 2020 01 16;11(1):319. Epub 2020 Jan 16.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.

Optimal functioning of neuronal networks is critical to the complex cognitive processes of memory and executive function that deteriorate in Alzheimer's disease (AD). Here we use cellular and animal models as well as human biospecimens to show that AD-related stressors mediate global disturbances in dynamic intra- and inter-neuronal networks through pathologic rewiring of the chaperome system into epichaperomes. These structures provide the backbone upon which proteome-wide connectivity, and in turn, protein networks become disturbed and ultimately dysfunctional. We introduce the term protein connectivity-based dysfunction (PCBD) to define this mechanism. Among most sensitive to PCBD are pathways with key roles in synaptic plasticity. We show at cellular and target organ levels that network connectivity and functional imbalances revert to normal levels upon epichaperome inhibition. In conclusion, we provide proof-of-principle to propose AD is a PCBDopathy, a disease of proteome-wide connectivity defects mediated by maladaptive epichaperomes.
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http://dx.doi.org/10.1038/s41467-019-14082-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965647PMC
January 2020

Experience with antiretroviral electronic adherence monitoring among young African American men who have sex with men living with HIV: findings to inform a triaged real-time alert intervention.

AIDS Care 2020 09 15;32(9):1092-1101. Epub 2020 Jan 15.

Massachusetts General Hospital Center for Global Health, Boston, MA, USA.

We performed a pilot study among young African-American men who have sex with men (AAMSM) of real-time electronic adherence monitoring (EAM) in Chicago to explore acceptability and feasibility of EAM and to inform intervention development. We recruited 40 young AAMSM living with HIV on ART to participate in up to 3 months of monitoring with the Wisepill device. Participants were interviewed at baseline, in response to the first true adjudicated 1-dose, 3-day, and 7-day misses, and at the end of monitoring. Reasons for missing doses and the acceptability and feasibility of electronic monitoring were assessed using mixed methods. The median participant observation time was 90 days ( = 40). For 21 participants with 90 days of follow-up, <90% and <80% adherence occurred in 82% and 79%, respectively in at least one of their monitored months ( = 63 monitored months). The participants generally found the proposed intervention acceptable and useful. Although seven participants said the device attracted attention, none said it led to disclosure of their HIV status. This study found real-time EAM to be generally acceptable and feasible among YAAMSM living with HIV in Chicago. Future work will develop a triaged real-time EAM intervention including text alerts following detection of nonadherence.
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http://dx.doi.org/10.1080/09540121.2020.1713975DOI Listing
September 2020

A triaged real-time alert intervention to improve antiretroviral therapy adherence among young African American men who have sex with men living with HIV: focus group findings.

BMC Public Health 2019 Apr 11;19(1):394. Epub 2019 Apr 11.

University of Illinois at Chicago School of Public Health, Community Outreach Intervention Projects, 1603 W. Taylor Street, Chicago, IL, 60612, USA.

Background: Among persons living with HIV, poorer antiretroviral therapy adherence has been reported in African Americans and disproportionate mortality reported in young African American men who have sex with men (AAMSM) compared to whites. We report the results of focus groups with young AAMSM living with HIV that explore their opinions about the acceptability and feasibility of a triaged real-time missed dose alert intervention to improve treatment adherence. The purpose of this study is to develop a theory-driven triaged real-time adherence monitoring intervention to promote HIV medication adherence in young AAMSM.

Methods: We performed five focus groups and two individual interviews among young HIV-positive AAMSM (n = 25) in Chicago guided by the Technology Acceptance Model and explored perceptions regarding the monitoring concept including device issues and concerns about inclusion of support persons whose involvement is triggered by sustained missed doses. The purpose was to inform the development of this intervention in this population.

Results: Generally, the participants found the proposed intervention acceptable and useful. Privacy was a major concern for participants especially with attention to possible disclosure of their HIV status by receiving a medication-related text that someone else might view and could lead to unwanted attention. There was concern that the device could be confused with a taser. Approximately half of the men already had a close personal contact that helped them with medication taking. Some participants acknowledged that the notification might lead to friction.

Conclusions: A triaged real-time alert intervention to improve treatment adherence is acceptable and feasible among young AAMSM living with HIV.
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http://dx.doi.org/10.1186/s12889-019-6689-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458676PMC
April 2019

Prostate-specific membrane antigen cleavage of vitamin B9 stimulates oncogenic signaling through metabotropic glutamate receptors.

J Exp Med 2018 01 15;215(1):159-175. Epub 2017 Nov 15.

Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY

Prostate-specific membrane antigen (PSMA) or folate hydrolase 1 (FOLH1) is highly expressed on prostate cancer. Its expression correlates inversely with survival and increases with tumor grade. However, the biological role of PSMA has not been explored, and its role in prostate cancer remained elusive. Filling this gap, we demonstrate that in prostate cancer, PSMA initiates signaling upstream of PI3K through G protein-coupled receptors, specifically via the metabotropic glutamate receptor (mGluR). PSMA's carboxypeptidase activity releases glutamate from vitamin B9 and other glutamated substrates, which activate mGluR I. Activated mGluR I subsequently induces activation of phosphoinositide 3-kinase (PI3K) through phosphorylation of p110β independent of loss. The p110β isoform of PI3K plays a particularly important role in the pathogenesis of prostate cancer, but the origin of its activation was so far unknown. PSMA expression correlated with PI3K-Akt signaling in cells, animal models, and patients. We interrogated the activity of the PSMA-PI3K axis through positron emission tomography and magnetic resonance imaging. Inhibition of PSMA in preclinical models inhibited PI3K signaling and promoted tumor regression. Our data present a novel oncogenic signaling role of PSMA that can be exploited for therapy and interrogated with imaging.
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http://dx.doi.org/10.1084/jem.20171052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748857PMC
January 2018

The epichaperome is an integrated chaperome network that facilitates tumour survival.

Nature 2016 Oct 5;538(7625):397-401. Epub 2016 Oct 5.

Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.

Transient, multi-protein complexes are important facilitators of cellular functions. This includes the chaperome, an abundant protein family comprising chaperones, co-chaperones, adaptors, and folding enzymes-dynamic complexes of which regulate cellular homeostasis together with the protein degradation machinery. Numerous studies have addressed the role of chaperome members in isolation, yet little is known about their relationships regarding how they interact and function together in malignancy. As function is probably highly dependent on endogenous conditions found in native tumours, chaperomes have resisted investigation, mainly due to the limitations of methods needed to disrupt or engineer the cellular environment to facilitate analysis. Such limitations have led to a bottleneck in our understanding of chaperome-related disease biology and in the development of chaperome-targeted cancer treatment. Here we examined the chaperome complexes in a large set of tumour specimens. The methods used maintained the endogenous native state of tumours and we exploited this to investigate the molecular characteristics and composition of the chaperome in cancer, the molecular factors that drive chaperome networks to crosstalk in tumours, the distinguishing factors of the chaperome in tumours sensitive to pharmacologic inhibition, and the characteristics of tumours that may benefit from chaperome therapy. We find that under conditions of stress, such as malignant transformation fuelled by MYC, the chaperome becomes biochemically 'rewired' to form a network of stable, survival-facilitating, high-molecular-weight complexes. The chaperones heat shock protein 90 (HSP90) and heat shock cognate protein 70 (HSC70) are nucleating sites for these physically and functionally integrated complexes. The results indicate that these tightly integrated chaperome units, here termed the epichaperome, can function as a network to enhance cellular survival, irrespective of tissue of origin or genetic background. The epichaperome, present in over half of all cancers tested, has implications for diagnostics and also provides potential vulnerability as a target for drug intervention.
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http://dx.doi.org/10.1038/nature19807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5283383PMC
October 2016