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Article: Pt(II)-PLGA Hybrid in a pH-Responsive Nanoparticle System Targeting Ovarian Cancer.

Wlodarczyk, Marek T / Dragulska, Sylwia A / Chen, Ying / Poursharifi, Mina / Acosta Santiago, Maxier / Martignetti, John A / Mieszawska, Aneta J

Pharmaceutics

2023 Volume 15, Issue 2

Abstract: Platinum-based agents are the main treatment option in ovarian cancer (OC). Herein, we report a poly(lactic-co-glycolic acid) (PLGA) nanoparticle (NP) encapsulating platinum (II), which is targeted to a cell-spanning protein overexpressed in above 90% of ...

Abstract	Platinum-based agents are the main treatment option in ovarian cancer (OC). Herein, we report a poly(lactic-co-glycolic acid) (PLGA) nanoparticle (NP) encapsulating platinum (II), which is targeted to a cell-spanning protein overexpressed in above 90% of late-stage OC, mucin 1 (MUC1). The NP is coated with phospholipid-DNA aptamers against MUC1 and a pH-sensitive PEG derivative containing an acid-labile hydrazone linkage. The pH-sensitive PEG serves as an off-on switch that provides shielding effects at the physiological pH and is shed at lower pH, thus exposing the MUC1 ligands. The pH-MUC1-Pt NPs are stable in the serum and display pH-dependent PEG cleavage and drug release. Moreover, the NPs effectively internalize in OC cells with higher accumulation at lower pH. The Pt (II) loading into the NP was accomplished via PLGA-Pt (II) coordination chemistry and was found to be 1.62 wt.%. In vitro screening using a panel of OC cell lines revealed that pH-MUC1-Pt NP has a greater effect in reducing cellular viability than carboplatin, a clinically relevant drug analogue. Biodistribution studies have demonstrated NP accumulation at tumor sites with effective Pt (II) delivery. Together, these results demonstrate a potential for pH-MUC1-Pt NP for the enhanced Pt (II) therapy of OC and other solid tumors currently treated with platinum agents.
Language	English
Publishing date	2023-02-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics15020607
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Deep molecular tracking over the 12-yr development of endometrial cancer from hyperplasia in a single patient.

Reid, Katherine / Camacho-Vanegas, Olga / Pandya, Deep / Camacho, Sandra Catalina / Qiao, Rui Fang / Kalir, Tamara / Padron-Rhenals, Maria M / Beddoe, Ann-Marie / Dottino, Peter / Martignetti, John A

Cold Spring Harbor molecular case studies

2024 Volume 9, Issue 4

Abstract: Although the progressive histologic steps leading to endometrial cancer (EndoCA), the most common female reproductive tract malignancy, from endometrial hyperplasia are well-established, the molecular changes accompanying this malignant transformation in ...

Abstract	Although the progressive histologic steps leading to endometrial cancer (EndoCA), the most common female reproductive tract malignancy, from endometrial hyperplasia are well-established, the molecular changes accompanying this malignant transformation in a single patient have never been described. We had the unique opportunity to investigate the paired histologic and molecular features associated with the 12-yr development of EndoCA in a postmenopausal female who could not undergo hysterectomy and instead underwent progesterone treatment. Using a specially designed 58-gene next-generation sequencing panel, we analyzed a total of 10 sequential biopsy samples collected over this time frame. A total of eight pathogenic/likely pathogenic mutations in seven genes,
MeSH term(s)	Humans ; Female ; Hyperplasia ; Progesterone ; Proto-Oncogene Proteins p21(ras)/genetics ; Endometrial Neoplasms/genetics ; Endometrial Neoplasms/therapy ; Endometrial Neoplasms/pathology ; Endometrium ; Mutation
Chemical Substances	Progesterone (4G7DS2Q64Y) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
Language	English
Publishing date	2024-01-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	2835759-0
ISSN	2373-2873 ; 2373-2873
ISSN (online)	2373-2873
ISSN	2373-2873
DOI	10.1101/mcs.a006311
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Article ; Online: Engineering and Validation of a Peptide-Stabilized Poly(lactic-

Dragulska, Sylwia A / Poursharifi, Mina / Chen, Ying / Wlodarczyk, Marek T / Acosta Santiago, Maxier / Dottino, Peter / Martignetti, John A / Mieszawska, Aneta J

Bioconjugate chemistry

2022 Volume 33, Issue 12, Page(s) 2348–2360

Abstract: Developing a biocompatible and biodegradable nanoparticle (NP) carrier that integrates drug-loading capability, active targeting, and imaging modality is extremely challenging. Herein, we report an NP with a core of poly(lactic- ...

Abstract	Developing a biocompatible and biodegradable nanoparticle (NP) carrier that integrates drug-loading capability, active targeting, and imaging modality is extremely challenging. Herein, we report an NP with a core of poly(lactic-
MeSH term(s)	Humans ; Mice ; Animals ; Polylactic Acid-Polyglycolic Acid Copolymer ; Polyglycolic Acid ; Lactic Acid ; Endothelial Cells ; Peptides ; Polyethylene Glycols ; Drug Delivery Systems ; Neoplasms ; Nanoparticles
Chemical Substances	Polylactic Acid-Polyglycolic Acid Copolymer (1SIA8062RS) ; Polyglycolic Acid (26009-03-0) ; Lactic Acid (33X04XA5AT) ; Peptides ; Polyethylene Glycols (3WJQ0SDW1A)
Language	English
Publishing date	2022-11-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1024041-x
ISSN	1520-4812 ; 1043-1802
ISSN (online)	1520-4812
ISSN	1043-1802
DOI	10.1021/acs.bioconjchem.2c00418
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Article ; Online: Treatment-emergent neuroendocrine prostate cancer with a germline

Pandya, Deep / Shah, Myra / Kaplan, Fuat / Martino, Candice / Levy, Gillian / Kazanjian, Mia / Batter, Stephen / Martignetti, John / Frank, Richard C

Cold Spring Harbor molecular case studies

2021 Volume 7, Issue 1

Abstract: Neuroendocrine prostate cancer (NEPC) is a highly aggressive histologic subtype of prostate cancer associated with a poor prognosis. Its incidence is expected to increase as castration-resistant disease emerges from the widespread use of potent androgen ... ...

Abstract	Neuroendocrine prostate cancer (NEPC) is a highly aggressive histologic subtype of prostate cancer associated with a poor prognosis. Its incidence is expected to increase as castration-resistant disease emerges from the widespread use of potent androgen receptor-targeting therapies, such as abiraterone and enzalutamide. Defects in homologous recombination repair genes, such as
MeSH term(s)	Aged ; Androstenes ; Antineoplastic Agents/therapeutic use ; BRCA1 Protein ; BRCA2 Protein/genetics ; Drug Resistance, Neoplasm/genetics ; Drug Therapy ; Genes, BRCA1 ; Genes, BRCA2 ; Germ Cells ; Humans ; Male ; Mutation ; Phthalazines ; Piperazines ; Platinum/therapeutic use ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; Prostatic Neoplasms/drug therapy ; Prostatic Neoplasms/genetics
Chemical Substances	Androstenes ; Antineoplastic Agents ; BRCA1 Protein ; BRCA1 protein, human ; BRCA2 Protein ; BRCA2 protein, human ; Phthalazines ; Piperazines ; Poly(ADP-ribose) Polymerase Inhibitors ; Platinum (49DFR088MY) ; abiraterone (G819A456D0) ; olaparib (WOH1JD9AR8)
Language	English
Publishing date	2021-02-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2835759-0
ISSN	2373-2873 ; 2373-2873
ISSN (online)	2373-2873
ISSN	2373-2873
DOI	10.1101/mcs.a005801
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Article ; Online: Mutations in cancer-relevant genes are ubiquitous in histologically normal endometrial tissue.

Gynecologic oncology

2024 Volume 185, Page(s) 194–201

Abstract: Objective: Endometrial cancer (EndoCA) is the most common gynecologic cancer and incidence and mortality rate continue to increase. Despite well-characterized knowledge of EndoCA-defining mutations, no effective diagnostic or screening tests exist. To ... ...

Abstract	Objective: Endometrial cancer (EndoCA) is the most common gynecologic cancer and incidence and mortality rate continue to increase. Despite well-characterized knowledge of EndoCA-defining mutations, no effective diagnostic or screening tests exist. To lay the foundation for testing development, our study focused on defining the prevalence of somatic mutations present in non-cancerous uterine tissue. Methods: We obtained ≥8 uterine samplings, including separate endometrial and myometrial layers, from each of 22 women undergoing hysterectomy for non-cancer conditions. We ultra-deep sequenced (>2000× coverage) samples using a 125 cancer-relevant gene panel. Results: All women harbored complex mutation patterns. In total, 308 somatic mutations were identified with mutant allele frequencies ranging up to 96.0%. These encompassed 56 unique mutations from 24 genes. The majority of samples possessed predicted functional cancer mutations but curiously no growth advantage over non-functional mutations was detected. Functional mutations were enriched with increasing patient age (p = 0.045) and BMI (p = 0.0007) and in endometrial versus myometrial layers (68% vs 39%, p = 0.0002). Finally, while the somatic mutation landscape shared similar mutation prevalence in key TCGA-defined EndoCA genes, notably PIK3CA, significant differences were identified, including NOTCH1 (77% vs 10%), PTEN (9% vs 61%), TP53 (0% vs 37%) and CTNNB1 (0% vs 26%). Conclusions: An important caveat for future liquid biopsy/DNA-based cancer diagnostics is the repertoire of shared and distinct mutation profiles between histologically unremarkable and EndoCA tissues. The lack of selection pressure between functional and non-functional mutations in histologically unremarkable uterine tissue may offer a glimpse into an unrecognized EndoCA protective mechanism.
Language	English
Publishing date	2024-03-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	801461-9
ISSN	1095-6859 ; 0090-8258
ISSN (online)	1095-6859
ISSN	0090-8258
DOI	10.1016/j.ygyno.2024.02.027
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Article ; Online: A Tripeptide-Stabilized Nanoemulsion of Oleic Acid.

Dragulska, Sylwia A / Wlodarczyk, Marek T / Poursharifi, Mina / Martignetti, John A / Mieszawska, Aneta J

Journal of visualized experiments : JoVE

2019 , Issue 144

Abstract: We describe a method to produce a nanoemulsion composed of an oleic acids-Pt(II) core and a lysine-tyrosine-phenylalanine (KYF) coating (KYF-Pt-NE). The KYF-Pt-NE encapsulates Pt(II) at 10 wt. %, has a diameter of 107 ± 27 nm and a negative surface ... ...

Abstract	We describe a method to produce a nanoemulsion composed of an oleic acids-Pt(II) core and a lysine-tyrosine-phenylalanine (KYF) coating (KYF-Pt-NE). The KYF-Pt-NE encapsulates Pt(II) at 10 wt. %, has a diameter of 107 ± 27 nm and a negative surface charge. The KYF-Pt-NE is stable in water and in serum, and is biologically active. The conjugation of a fluorophore to KYF allows the synthesis of a fluorescent nanoemulsion that is suitable for biological imaging. The synthesis of the nanoemulsion is performed in an aqueous environment, and the KYF-Pt-NE forms via self-assembly of a short KYF peptide and an oleic acids-platinum(II) conjugate. The self-assembly process depends on the temperature of the solution, the molar ratio of the substrates, and the flow rate of the substrate addition. Crucial steps include maintaining the optimal stirring rate during the synthesis, permitting sufficient time for self-assembly, and pre-concentrating the nanoemulsion gradually in a centrifugal concentrator.
MeSH term(s)	Emulsions/chemistry ; Lysine/chemistry ; Nanostructures/chemistry ; Oleic Acid/chemistry ; Peptides/chemistry ; Phenylalanine/chemistry ; Platinum/chemistry ; Tyrosine/chemistry
Chemical Substances	Emulsions ; Peptides ; Oleic Acid (2UMI9U37CP) ; Tyrosine (42HK56048U) ; Phenylalanine (47E5O17Y3R) ; Platinum (49DFR088MY) ; Lysine (K3Z4F929H6)
Language	English
Publishing date	2019-02-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Video-Audio Media
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/59034
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Article: Five (un)easy pieces: the MYH9-related giant platelet syndromes.

Martignetti, John

Haematologica

2002 Volume 87, Issue 9, Page(s) 897–898

MeSH term(s)	Bernard-Soulier Syndrome/genetics ; Bernard-Soulier Syndrome/metabolism ; Blood Platelets/metabolism ; Blood Platelets/pathology ; Humans ; Molecular Motor Proteins/genetics ; Molecular Motor Proteins/metabolism ; Myosin Heavy Chains/genetics ; Myosin Heavy Chains/metabolism
Chemical Substances	MYH9 protein, human ; Molecular Motor Proteins ; Myosin Heavy Chains (EC 3.6.4.1)
Language	English
Publishing date	2002-09
Publishing country	Italy
Document type	Comment ; Editorial
ZDB-ID	2333-4
ISSN	1592-8721 ; 0390-6078 ; 0017-6567
ISSN (online)	1592-8721
ISSN	0390-6078 ; 0017-6567
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Comparative Serum Analyses Identify Cytokines and Hormones Commonly Dysregulated as Well as Implicated in Promoting Osteolysis in MMP-2-Deficient Mice and Children.

Sarker, Hassan / Hardy, Eugenio / Haimour, Ayman / Karim, Mahmoud A / Scholl-Bürgi, Sabine / Martignetti, John A / Botto, Lorenzo D / Fernandez-Patron, Carlos

Frontiers in physiology

2020 Volume 11, Page(s) 568718

Abstract: Deficiency of matrix metalloproteinase 2 (MMP-2) causes a complex syndrome characterized by multicentric osteolysis, nodulosis, and arthropathy (MONA) as well as cardiac valve defects, dwarfism and hirsutism. MMP-2 deficient ( ...

Abstract	Deficiency of matrix metalloproteinase 2 (MMP-2) causes a complex syndrome characterized by multicentric osteolysis, nodulosis, and arthropathy (MONA) as well as cardiac valve defects, dwarfism and hirsutism. MMP-2 deficient (
Language	English
Publishing date	2020-09-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2020.568718
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Article ; Online: Loss of MMP-2 in murine osteoblasts upregulates osteopontin and bone sialoprotein expression in a circuit regulating bone homeostasis.

Mosig, Rebecca A / Martignetti, John A

Disease models & mechanisms

2012 Volume 6, Issue 2, Page(s) 397–403

Abstract: Multicentric osteolysis with arthropathy (MOA; MIM 605156) is an inherited osteolyses and arthritis syndrome resulting from loss of matrix metalloproteinase 2 (MMP-2). We recently demonstrated that Mmp2(-/-) mice represent a unique model for the study of ...

Abstract	Multicentric osteolysis with arthropathy (MOA; MIM 605156) is an inherited osteolyses and arthritis syndrome resulting from loss of matrix metalloproteinase 2 (MMP-2). We recently demonstrated that Mmp2(-/-) mice represent a unique model for the study of the human disease, sharing many features of the human syndrome including skeletal dysplasia and defects in osteoblast behavior. We therefore sought to explore the secondary molecular effects of MMP-2 loss, which coexist with the underlying skeletal and osteoblast phenotypes. We used quantitative real-time RT-PCR (qRT-PCR) to measure osteoblast-related gene expression through ex vivo osteoblast differentiation of bone marrow stromal cells (BMSC) from Mmp2(-/-) and Mmp2(+/+) mice. We used western blot to measure osteopontin (OPN) serum levels and immunohistochemical staining to examine bone expression. MMP-2 expression was inhibited in SaOS2 cells using siRNA, and decreased MMP-2 expression at both RNA and protein levels was confirmed by qRT-PCR and western blot, respectively. Mmp2(-/-) BMSC induced to differentiate into osteoblasts were shown to significantly upregulate OPN and bone sialoprotein (BSP) expression levels compared with controls. Transcriptional upregulation was maintained in vivo, as demonstrated by increased levels of OPN in serum and bone in Mmp2(-/-) mice. These effects are generalizable because siRNA-mediated inhibition in cultured cells also upregulated OPN and BSP. OPN and BSP are known to affect MMP-2 expression and activity but have not previously been shown to be regulated by MMP-2. Identification of this newly defined circuitry provides insight into the potential molecular landscape underlying the MOA phenotype and highlights a pathway that might play a role in normal bone homeostasis.
MeSH term(s)	Animals ; Bone and Bones/cytology ; Bone and Bones/metabolism ; Cell Line, Tumor ; Gene Knockdown Techniques ; Homeostasis/genetics ; Humans ; Integrin-Binding Sialoprotein/genetics ; Integrin-Binding Sialoprotein/metabolism ; Matrix Metalloproteinase 2/deficiency ; Matrix Metalloproteinase 2/metabolism ; Mesenchymal Stem Cells/metabolism ; Mice ; Osteoblasts/cytology ; Osteoblasts/enzymology ; Osteopontin/blood ; Osteopontin/genetics ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA, Small Interfering/metabolism ; Up-Regulation
Chemical Substances	Integrin-Binding Sialoprotein ; RNA, Messenger ; RNA, Small Interfering ; Osteopontin (106441-73-0) ; Matrix Metalloproteinase 2 (EC 3.4.24.24) ; Mmp2 protein, mouse (EC 3.4.24.24)
Language	English
Publishing date	2012-08-23
Publishing country	England
Document type	Journal Article
ZDB-ID	2451104-3
ISSN	1754-8411 ; 1754-8403
ISSN (online)	1754-8411
ISSN	1754-8403
DOI	10.1242/dmm.007914
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Article: Protein-losing enteropathy and joint contractures caused by a novel homozygous ANTXR2 mutation.

Schussler, Edith / Linkner, Rita V / Levitt, Jacob / Mehta, Lakshmi / Martignetti, John A / Oishi, Kimihiko

Advances in genomics and genetics

2018 Volume 8, Page(s) 17–21

Abstract: Infantile systemic hyalinosis (ISH) is a rare autosomal recessive disorder and an allelic form of hyaline fibromatosis syndrome that is caused by mutations in ... ...

Abstract	Infantile systemic hyalinosis (ISH) is a rare autosomal recessive disorder and an allelic form of hyaline fibromatosis syndrome that is caused by mutations in the
Language	English
Publishing date	2018-06-27
Publishing country	New Zealand
Document type	Journal Article
ZDB-ID	2673404-7
ISSN	1179-9870
ISSN	1179-9870
DOI	10.2147/AGG.S159077
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