Publications by authors named "Kiran Vij"

18 Publications

  • Page 1 of 1

Phospho-Ser-VCP Is Required for DNA Damage Response and Is Associated with Poor Prognosis of Chemotherapy-Treated Breast Cancer.

Cell Rep 2020 06;31(10):107745

Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Spatiotemporal protein reorganization at DNA damage sites induced by genotoxic chemotherapies is crucial for DNA damage response (DDR), which influences treatment response by directing cancer cell fate. This process is orchestrated by valosin-containing protein (VCP), an AAA+ ATPase that extracts polyubiquinated chromatin proteins and facilitates their turnover. However, because of the essential and pleiotropic effects of VCP in global proteostasis, it remains challenging practically to understand and target its DDR-specific functions. We describe a DNA-damage-induced phosphorylation event (Ser), which selectively enhances chromatin-associated protein degradation mediated by VCP and is required for DNA repair, signaling, and cell survival. These functional effects of Ser phosphorylation on DDR correlate with a decrease in VCP association with chromatin, cofactors NPL4/UFD1, and polyubiquitinated substrates. Clinically, high phospho-Ser-VCP levels are significantly associated with poor outcome among chemotherapy-treated breast cancer patients. Thus, Ser phosphorylation is a DDR-specific enhancer of VCP function and a potential predictive biomarker for chemotherapy treatments.
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http://dx.doi.org/10.1016/j.celrep.2020.107745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282751PMC
June 2020

Selective targeting of α4β1 integrin attenuates murine graft versus host disease.

Leukemia 2020 11 9;34(11):3100-3104. Epub 2020 Mar 9.

Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, 63110, USA.

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http://dx.doi.org/10.1038/s41375-020-0786-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483240PMC
November 2020

Practical Approaches on CD30 Detection and Reporting in Lymphoma Diagnosis.

Am J Surg Pathol 2020 02;44(2):e1-e14

Departments of Pathology and Dermatology, University of Virginia, Charlottesville, VA.

While our understanding of the biology of CD30 in lymphoma continues to evolve, our need to detect and measure its expression at the protein level remains critically important for diagnosis and patient care. In addition to its diagnostic and prognostic utility, CD30 has emerged as a vehicle for drug targeting through the antibody-drug conjugate brentuximab-vedotin (BV). Given the numerous ways that CD30 is utilized and its emergence as a predictive/prognostic biomarker, pathologists must come to a general consensus on the best reporting structure and methodology to ensure appropriate patient care. In this manuscript, we review the indications for testing, various modalities for testing, technical challenges, pitfalls, and potential standards of reporting. The following questions will try to be addressed in the current review article: What defines a "POSITIVE" level of CD30 expression?; How do we evaluate and report CD30 expression?; What are the caveats in the evaluation of CD30 expression?
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http://dx.doi.org/10.1097/PAS.0000000000001368DOI Listing
February 2020

Reactivity with the EpCAM-specific antibodies MOC-31 and Ber-Ep4 in plasma cell neoplasms: a potential diagnostic pitfall in cytology samples.

J Am Soc Cytopathol 2019 Sep - Oct;8(5):265-269. Epub 2019 Apr 18.

Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, Missouri.

Objective: Epithelial cell adhesion molecule (EpCAM) is a protein expressed on surfaces of healthy epithelia, and is overexpressed in dysplasias and carcinomas. Immunohistochemistry (IHC) utilizing antibodies that react with EpCAM, such as MOC-31 and Ber-EP4, distinguish reactive mesothelial cells from carcinomas in serous effusions. IHC is crucial in effusions with singly dispersed atypical cells, a scenario with a broad differential, including hematopoietic malignancies. Plasma cell neoplasms (PCN) are the second most common hematopoietic malignancy, manifesting as multiple myeloma or plasmacytoma, with 6% of cases developing serous cavity involvement. Most PCNs are readily recognizable; however, variants that deviate from the classic cytomorphology risk erroneous diagnosis. This study demonstrates EpCAM expression in a subset of PCNs, highlighting a potential diagnostic pitfall in serous effusion cytology.

Methods: A 10-year retrospective search for cytology specimens with a diagnosis of PCN was performed. All cases demonstrating CD138/CD38 and monoclonal immunoglobulin expression, and adequately cellular cell block were included. IHC analysis for MOC-31 and Ber-EP4 was performed using Ventana Benchmark Ultra. Scoring was performed as follows: total IHC score equals the positive proportion (0 = no positive tumor cells; 1 = <1%; 2 = 1-10%; 3 =11-33%; 4 = 34-66%; 5 = 67-100%) plus staining intensity (0, no staining; 1, weak; 2, moderate; 3, strong). A score > 4 was considered positive.

Results: 2 of 28 (7%) PCNs demonstrated positivity for MOC-31 and Ber-Ep4.

Conclusion: A subset of PCNs in cytology samples show positivity for MOC-31 and Ber-EP4 which could result in misinterpretation as carcinoma.
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http://dx.doi.org/10.1016/j.jasc.2019.04.003DOI Listing
July 2020

Baricitinib-induced blockade of interferon gamma receptor and interleukin-6 receptor for the prevention and treatment of graft-versus-host disease.

Leukemia 2018 11 2;32(11):2483-2494. Epub 2018 Apr 2.

Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, 63110, USA.

The therapeutic benefits of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are derived from the graft-versus-leukemia (GvL) effects of the procedure. There is a strong association between the GvL effects and graft-versus-host disease (GvHD), a major life-threatening complication of allo-HSCT. The limiting of GvHD while maintaining the GvL effect remains the goal of allo-HSCT. Therefore, identifying optimal therapeutic targets to selectively suppress GvHD while maintaining the GvL effects represents a significant unmet medical need. We demonstrate that the dual inhibition of interferon gamma receptor (IFNγR) and interleukin-6 receptor (IL6R) results in near-complete elimination of GvHD in a fully major histocompatibility complex-mismatched allo-HSCT model. Furthermore, baricitinib (an inhibitor of Janus kinases 1 and 2 (JAK1/JAK2) downstream of IFNγR/IL6R) completely prevented GvHD; expanded regulatory T cells by preserving JAK3-STAT5 signaling; downregulated CXCR3 and helper T cells 1 and 2 while preserving allogeneic antigen-presenting cell-stimulated T-cell proliferation; and suppressed the expression of major histocompatibility complex II (I-Ad), CD80/86, and PD-L1 on host antigen-presenting cells. Baricitinib also reversed established GvHD with 100% survival, thus demonstrating both preventive and therapeutic roles for this compound. Remarkably, baricitinib enhanced the GvL effects, possibly by downregulating tumor PD-L1 expression.
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http://dx.doi.org/10.1038/s41375-018-0123-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168427PMC
November 2018

Serum thymidine kinase 1 activity as a pharmacodynamic marker of cyclin-dependent kinase 4/6 inhibition in patients with early-stage breast cancer receiving neoadjuvant palbociclib.

Breast Cancer Res 2017 Nov 21;19(1):123. Epub 2017 Nov 21.

Division of Oncology, Section of Medical Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, 63110, USA.

Background: Thymidine kinase 1 (TK1) is a cell cycle-regulated enzyme with peak expression in the S phase during DNA synthesis, and it is an attractive biomarker of cell proliferation. Serum TK1 activity has demonstrated prognostic value in patients with early-stage breast cancer. Because cyclin-dependent kinase 4/6 (CDK4/6) inhibitors prevent G/S transition, we hypothesized that serum TK1 could be a biomarker for CDK4/6 inhibitors. We examined the drug-induced change in serum TK1 as well as its correlation with change in tumor Ki-67 levels in patients enrolled in the NeoPalAna trial (ClinicalTrials.gov identifier NCT01723774).

Methods: Patients with clinical stage II/III estrogen receptor-positive (ER+)/HER2-negative breast cancer enrolled in the NeoPalAna trial received an initial 4 weeks of anastrozole, followed by palbociclib on cycle 1, day 1 (C1D1) for four 28-day cycles, unless C1D15 tumor Ki-67 was > 10%, in which case patients went off study owing to inadequate response. Surgery occurred following 3-5 weeks of washout from the last dose of palbociclib, except in eight patients who received palbociclib (cycle 5) continuously until surgery. Serum TK1 activity was determined at baseline, C1D1, C1D15, and time of surgery, and we found that it was correlated with tumor Ki-67 and TK1 messenger RNA (mRNA) levels.

Results: Despite a significant drop in tumor Ki-67 with anastrozole monotherapy, there was no statistically significant change in TK1 activity. However, a striking reduction in TK1 activity was observed 2 weeks after initiation of palbociclib (C1D15), which then rose significantly with palbociclib washout. At C1D15, TK1 activity was below the detection limit (<20 DiviTum units per liter Du/L) in 92% of patients, indicating a profound effect of palbociclib. There was high concordance, at 89.8% (95% CI: 79.2% - 96.2%), between changes in serum TK1 and tumor Ki-67 in the same direction from C1D1 to C1D15 and from C1D15 to surgery time points. The sensitivity and specificity for the tumor Ki-67-based response by palbociclib-induced decrease in serum TK1 were 94.1% (95% CI 86.2% - 100%) and 84% (95% CI 69.6% -98.4%), respectively. The κ-statistic was 0.76 (p < 0.001) between TK1 and Ki-67, indicating substantial agreement.

Conclusions: Serum TK1 activity is a promising pharmacodynamic marker of palbociclib in ER+ breast cancer, and its value in predicting response to CDK4/6 inhibitors warrants further investigation.

Trial Registration: ClinicalTrials.gov, NCT01723774. Registered on 6 November 2012.
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http://dx.doi.org/10.1186/s13058-017-0913-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5699111PMC
November 2017

HTLV-1 viral oncogene HBZ induces osteolytic bone disease in transgenic mice.

Oncotarget 2017 Sep 27;8(41):69250-69263. Epub 2017 Aug 27.

Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T cell malignancy that occurs in HTLV-1 infected patients. Most ATL patients develop osteolytic lesions and hypercalcemia of malignancy, causing severe skeletal related complications and reduced overall survival. The HTLV-1 virus encodes 2 viral oncogenes, Tax and HBZ. Tax, a transcriptional activator, is critical to ATL development, and has been implicated in pathologic osteolysis. HBZ, HTLV-1 basic leucine zipper transcription factor, promotes tumor cell proliferation and disrupts Wnt pathway modulators; however, its role in ATL induced osteolytic bone loss is unknown. To determine if HBZ is sufficient for the development of bone loss, we established a transgenic Granzyme B HBZ (Gzmb-HBZ) mouse model. Lymphoproliferative disease including tumors, enlarged spleens and/or abnormal white cell counts developed in two-thirds of Gzmb-HBZ mice at 18 months. HBZ positive cells were detected in tumors, spleen and bone marrow. Importantly, pathologic bone loss and hypercalcemia were present at 18 months. Bone-acting factors were present in serum and RANKL, PTHrP and DKK1, key mediators of hypercalcemia and bone loss, were upregulated in Gzmb-HBZ T cells. These data demonstrate that Gzmb-HBZ mice model ATL bone disease and express factors that are current therapeutic targets for metastatic and bone resident tumors.
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http://dx.doi.org/10.18632/oncotarget.20565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642476PMC
September 2017

A Phase II Trial of Neoadjuvant MK-2206, an AKT Inhibitor, with Anastrozole in Clinical Stage II or III -Mutant ER-Positive and HER2-Negative Breast Cancer.

Clin Cancer Res 2017 Nov 5;23(22):6823-6832. Epub 2017 Sep 5.

Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.

Hyperactivation of AKT is common and associated with endocrine resistance in estrogen receptor-positive (ER) breast cancer. The allosteric pan-AKT inhibitor MK-2206 induced apoptosis in -mutant ER breast cancer under estrogen-deprived condition in preclinical studies. This neoadjuvant phase II trial was therefore conducted to test the hypothesis that adding MK-2206 to anastrozole induces pathologic complete response (pCR) in mutant ER breast cancer. Potential eligible patients with clinical stage II/III ER/HER2 breast cancer were preregistered and received anastrozole (goserelin if premenopausal) for 28 days in cycle 0 pending tumor sequencing. Patients positive for mutation in the tumor were eligible to start MK-2206 (150 mg orally weekly, with prophylactic prednisone) on cycle 1 day 2 (C1D2) and to receive a maximum of four 28-day cycles of combination therapy before surgery. Serial biopsies were collected at preregistration, C1D1 and C1D17. Fifty-one patients preregistered and 16 of 22 with -mutant tumors received study drug. Three patients went off study due to C1D17 Ki67 >10% ( = 2) and toxicity ( = 1). Thirteen patients completed neoadjuvant therapy followed by surgery. No pCRs were observed. Rash was common. MK-2206 did not further suppress cell proliferation and did not induce apoptosis on C1D17 biopsies. Although AKT phosphorylation was reduced, PRAS40 phosphorylation at C1D17 after MK-2206 persisted. One patient acquired an mutation at surgery. MK-2206 is unlikely to add to the efficacy of anastrozole alone in -mutant ER breast cancer and should not be studied further in the target patient population. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392430PMC
November 2017

Allogeneic hematopoietic cell transplantation in morphologic leukemia-free aplastic state.

Am J Hematol 2017 Sep 19;92(9):E549-E552. Epub 2017 Jul 19.

Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.

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http://dx.doi.org/10.1002/ajh.24804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736150PMC
September 2017

Azacitidine Mitigates Graft-versus-Host Disease via Differential Effects on the Proliferation of T Effectors and Natural Regulatory T Cells In Vivo.

J Immunol 2017 05 22;198(9):3746-3754. Epub 2017 Mar 22.

Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110

Azacitidine (AzaC) mitigates graft-versus-host disease (GvHD) in both murine preclinical transplant models and in human clinical trials while maintaining a robust graft-versus-leukemia effect. Previous studies have failed to investigate the role of natural regulatory T cells (nTregs) on the mitigation of GvHD by AzaC, instead focusing on the generation of suppressive Tregs (CD4CD25FOXP3) through the in vivo conversion of alloreactive donor T effectors (Teffs; CD4CD25FOXP3) and the direct antiproliferative effects of AzaC on allogeneic T cells. Using B6. mice in which Tregs can be specifically ablated through administration of diphtheria toxin, we demonstrate that natural Tregs are required in the donor graft for AzaC to optimally protect against GvHD and that nTregs, unlike Teffs (CD3FOXP3), are resistant to the antiproliferative effects of AzaC. Gene expression analysis identified the potent cell cycle inhibitor, p21, was significantly upregulated in Teffs but not nTregs after treatment with AzaC. Furthermore, we demonstrate that Teffs deficient in p21 are less sensitive to the antiproliferative effects of AzaC. These results demonstrate that nTregs are essential for AzaC to fully protect against GvHD and have important clinical implications for future clinical trials testing AzaC as a novel method of GvHD prophylaxis in man.
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http://dx.doi.org/10.4049/jimmunol.1502399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5541679PMC
May 2017

NeoPalAna: Neoadjuvant Palbociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor, and Anastrozole for Clinical Stage 2 or 3 Estrogen Receptor-Positive Breast Cancer.

Clin Cancer Res 2017 Aug 7;23(15):4055-4065. Epub 2017 Mar 7.

Pfizer Pharmaceuticals, New York, New York.

Cyclin-dependent kinase (CDK) 4/6 drives cell proliferation in estrogen receptor-positive (ER) breast cancer. This single-arm phase II neoadjuvant trial (NeoPalAna) assessed the antiproliferative activity of the CDK4/6 inhibitor palbociclib in primary breast cancer as a prelude to adjuvant studies. Eligible patients with clinical stage II/III ER/HER2 breast cancer received anastrozole 1 mg daily for 4 weeks (cycle 0; with goserelin if premenopausal), followed by adding palbociclib (125 mg daily on days 1-21) on cycle 1 day 1 (C1D1) for four 28-day cycles unless C1D15 Ki67 > 10%, in which case patients went off study due to inadequate response. Anastrozole was continued until surgery, which occurred 3 to 5 weeks after palbociclib exposure. Later patients received additional 10 to 12 days of palbociclib (Cycle 5) immediately before surgery. Serial biopsies at baseline, C1D1, C1D15, and surgery were analyzed for Ki67, gene expression, and mutation profiles. The primary endpoint was complete cell cycle arrest (CCCA: central Ki67 ≤ 2.7%). Fifty patients enrolled. The CCCA rate was significantly higher after adding palbociclib to anastrozole (C1D15 87% vs. C1D1 26%, < 0.001). Palbociclib enhanced cell-cycle control over anastrozole monotherapy regardless of luminal subtype (A vs. B) and status with activity observed across a broad range of clinicopathologic and mutation profiles. Ki67 recovery at surgery following palbociclib washout was suppressed by cycle 5 palbociclib. Resistance was associated with nonluminal subtypes and persistent E2F-target gene expression. Palbociclib is an active antiproliferative agent for early-stage breast cancer resistant to anastrozole; however, prolonged administration may be necessary to maintain its effect. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-3206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555232PMC
August 2017

Tissue polymerase chain reaction for the diagnosis of cytomegalovirus disease after allogeneic hematopoietic cell transplantation.

Am J Hematol 2017 02;92(2):E19-E20

Bone Marrow Transplantation and Leukemia Section, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.

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http://dx.doi.org/10.1002/ajh.24609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211556PMC
February 2017

Aberrant expression of alpha-fetoprotein in intrahepatic cholangiocarcinoma: an exceptional occurrence.

Int J Surg Pathol 2008 Apr;16(2):194-8

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

A high level of serum alpha-fetoprotein (AFP) is typically indicative of hepatocellular carcinoma in patients with liver lesions. In this article, we describe an exceptional case of intrahepatic cholangiocarcinoma that occurred in a 36-year-old man with a markedly elevated serum AFP level (12310.7 ng/mL). Histopathologic examination of surgically resected liver mass showed classic morphologic features of cholangiocarcinoma, with no hepatocellular carcinoma component identified. Immunohistochemically, the tumor cells were strongly and diffusely positive for AFP, CA19-9, and cytokeratin 19 and were negative for hepatocyte antigen. The patient's serum AFP level declined to 46.2 ng/mL 1 month after surgery. To the best of our knowledge, this is the first documented case of AFP-producing intrahepatic cholangiocarcinoma with immunohistochemical evidence confirming the tumor cells to be the source of high-level AFP production.
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http://dx.doi.org/10.1177/1066896907304519DOI Listing
April 2008

Mice expressing a dominant-negative Ret mutation phenocopy human Hirschsprung disease and delineate a direct role of Ret in spermatogenesis.

Development 2004 Nov 6;131(21):5503-13. Epub 2004 Oct 6.

Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.

The Ret receptor tyrosine kinase mediates physiological signals of glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) and is essential for postnatal survival in mice. It is implicated in a number of human diseases and developmental abnormalities. Here, we describe our analyses of mice expressing a Ret mutant (RetDN) with diminished kinase activity that inhibits wild-type Ret activity, including its activation of AKT. All RetDN/+ mice died by 1 month of age and had distal intestinal aganglionosis reminiscent of Hirschsprung disease (HSCR) in humans. The RetDN/+ proximal small intestine also had severe hypoganglionosis and reduction in nerve fiber density, suggesting a potential mechanism for the continued gastric dysmotility in postsurgical HSCR patients. Unlike Ret-null mice, which have abnormalities in the parasympathetic and sympathetic nervous systems, the RetDN/+ mice only had defects in the parasympathetic nervous system. A small proportion of RetDN/+ mice had renal agenesis, and the remainder had hypoplastic kidneys and developed tubulocystic abnormalities postnatally. Postnatal analyses of the testes revealed a decreased number of germ cells, degenerating seminiferous tubules, maturation arrest and apoptosis, indicating a crucial role for Ret in early spermatogenesis.
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http://dx.doi.org/10.1242/dev.01421DOI Listing
November 2004
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