The Southwest Respiratory and Critical Care Chronicles, Jan 18, 2019
Despite clear evidence of increased oxidative stress in the blood and tissues of critically ill i... more Despite clear evidence of increased oxidative stress in the blood and tissues of critically ill intensive care unit patients, consistent beneficial effects of many different antioxidants have not been observed, and antioxidant therapy has not yet translated into widely accepted clinical practice. The reasons for this are unclear, likely rooted in the complex and context dependent free radical behavior of antioxidants interacting with the process of lipid peroxidation. Control of lipid peroxidation is a crucial requirement for the beneficial effects of antioxidants, but the interactions of biological antioxidant defenses with the potentially harmful free radical behavior of pharmacological antioxidants complicates the dose and selection of the optimal antioxidants. Glutathione, the primary small molecule antioxidant in biological systems, is the primary enzymatic oxidative stress defense that operates in the context of glutathione-linked antioxidant enzymes to metabolize many harmful products of lipid peroxidation to mercapturic acids. Recently, the mercapturic acid transporter protein, RLIP76 (human RALBP1 gene), has been shown to have a critical role in glutathione linked oxidative stress defenses. These findings provide a rationale for new approaches towards selection and dosing of antioxidant to improve their clinical benefit.
17 Background: According to the World Health Organization GLOBOCAN database, in 2019, approximate... more 17 Background: According to the World Health Organization GLOBOCAN database, in 2019, approximately 1.8 million new colorectal cancer cases were diagnosed, and almost 861,000 deaths were reported. In the United States, CRC is the third most frequent type of cancer and the second leading cause of cancer-related death. Although the overall incidence of CRC among the Hispanic population has been declining over the last decades, recently, a dramatic increase in CRC incidents among Hispanics younger than 50 years of age (early-onset CRC) has been reported. The increase in the incidence of early-onset CRC is markedly more significant in Hispanic-Latino (HL) patients population (45%) than in non-Hispanic Whites (NHW) (27%) and African-Americans (AA) (15%). Additionally, in contrast to NHW, Hispanics have a worse survival rate. The exact reason for these racial disparities and the biology of CRC in the HL population are not well understood. Therefore, we performed this study to better under...
The incidence of malignant melanoma, a neoplasm of melanocytic cells, is increasing rapidly. The ... more The incidence of malignant melanoma, a neoplasm of melanocytic cells, is increasing rapidly. The lymph nodes are often the first site of metastasis and can herald systemic dissemination, which is almost uniformly fatal. RLIP, a multi-specific ATP-dependent transporter that is over-expressed in several types of cancers, plays a central role in cancer cell resistance to radiation and chemotherapy. RLIP appears to be necessary for cancer cell survival because both in vitro cell culture and in vivo animal tumor studies show that the depletion or inhibition of RLIP causes selective toxicity to malignant cells. RLIP depletion/inhibition triggers apoptosis in cancer cells by inducing the accumulation of endogenously formed glutathione-conjugates. In our in vivo studies, we administered RLIP antibodies or antisense oligonucleotides to mice bearing subcutaneous xenografts of SKMEL2 and SKMEL5 melanoma cells and demonstrated that both treatments caused significant xenograft regression with no...
S_ry The efficacy of cisplatin [cis-diamminedichloroplatinum (IT); DDP] is hampered by acquired o... more S_ry The efficacy of cisplatin [cis-diamminedichloroplatinum (IT); DDP] is hampered by acquired or de novo resistance of malignant to its cytotoxic effects. We have previously reported that cisplatin resistance paralklis glutathione S-transferase (GST) activity in several human small-cell lung cancer ce lines. In the presently described studies, we used sala7ine, an inhibitor of GSTs, to evahlate the relative role of GSTs in mediating cisplatin resistan in two human small-cell lung cancer cell lines, NCI H-69 and H-24%. The H-69 cell line, which contained relatively higher GST activity than the H-2496 cell line (317 ± 7 vs 9 ± 1 mU mg-' protein respectively), also displayed a greater degree of cisplatin resistance (IC5o values of 25.0 ± 3.9 vs 4.5 ± 1.0 pi respecively). Western blot and Northern blot analyses of purified GSTs revealed the ecpression of only the s-dass GST in both cell ines. Sulphasalazine inhibited the purified GSTs (IC5u of 10 LM for H-69 and 12fm for H-2496) from both ines in a competitive manner with smilar K vahles (6.5 and 7.9 gM for the H-69 and H-2496 cell lines e). Cytotoxicity studies revealed that sulphasalazne increased the cytotoxicity of cisplatin towards both cel lines. Isobologram analysis showed that lhsalazi synergistically enhanced the cytotoxicity of cisplatin towards both cell lines, the maginitude of synergy being remarkably higher in H-69 cells than in H-2496 cells. Our saudies indicate that clnically achievable concentrations of s salazine may be useful in modulating cisplatin resistance in malignancies with increased GST-x content.
Journal of Community Hospital Internal Medicine Perspectives
On January 30, 2020, the COVID-19 epidemic was declared an international public health emergency ... more On January 30, 2020, the COVID-19 epidemic was declared an international public health emergency by the World Health Organization. Given the growing impact of the pandemic, there is great interest in finding potential targets for treating infected or hospitalized COVID-19 patients. Therapeutic studies have been conducted on pre-existing drugs, which vary by country, including anti-malarial agents, antiviral agents, and convalescent plasma. However, many of these agents are ineffective at reducing mortality or only shorten the severity or duration of COVID-19 illness in hospitalized patients. As such, other alternatives for treating COVID-19 are being investigated. One such target of interest has been clathrin-dependent endocytosis (CDE). Clathrin-dependent endocytosis is the most commonly observed mechanism of viral entry into cells. However, there have been no published studies to date on CDE inhibition strategies against COVID-19. One such target is Rlip or RLIP76 (human gene RALBP1, 18p11.22). Among its many functions, Rlip is a stress-protective, Ral-regulated ATPase of the mercapturic acid pathway that transports glutathione-electrophile conjugates of electrophilic toxins, which are precursors of mercapturic acid that precedes de-glutamylation by gammaglutamyl transferase. Rlip is also regulated by several G-proteins that coordinate movement of cells, organelles, membranes, cytoskeleton, macromolecules, and other small molecules. Previous studies have link Rlip in the pathogenesis of several viral illness. In this paper, we want to propose that RLIP76 (Rlip or RALBP1) may be a novel target for treating SARS-CoV-2 viral infections.
Aggressive fibromatosis (AF) is a rare, benign neoplasm originating from musculoaponeurotic strom... more Aggressive fibromatosis (AF) is a rare, benign neoplasm originating from musculoaponeurotic stromal structures characterized by aggressive growth and infiltration of local tissues. To date, only six previous cases of AF involving the larynx have been reported. The present case was that of a 70-year-old female patient with a 5-year history of hoarseness and an enlarging neck mass consistent with aggressive recurrent fibromatosis. MRI displayed a large, solid mass arising from the left anterior cervical space displacing the trachea and upper airway to the right. At one year after the initial radical resection, the patient presented with recurrence. A second radical excision was performed not including a laryngectomy. Radiation therapy was considered for possible local treatment to prevent subsequent tumor recurrence. According to the literature, AF has recurrence rates of up to 40-70% within 18 months. There is only sparse literature to guide treatment. Using the mutations detected in the patient's AF tissue, an Ingenuity Pathway Analysis (IPA) was used to guide treatment of the recurrence. In the present case, the IPA analysis indicated the use of pazopanib to treat the patient's cancer. In general, surgery appears to be the treatment of choice for head and neck AF, but the management of recurrence is controversial.
Background: Systemic inflammation is an important factor contributing to tumor progression. High ... more Background: Systemic inflammation is an important factor contributing to tumor progression. High neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are markers of host inflammation whose association with worse overall survival (OS) in non-small cell lung cancer (NSCLC) has been shown in various studies. However, there are few studies investigating the association of these, and other haematological parameters of inflammation with prognosis of EGFR mutated NSCLC treated with tyrosine-kinase inhibitors (TKIs). We therefore examined the association between various blood test parameters and prognosis in this group of patients. Method: This retrospective analysis included 74 consecutive advanced lung adenocarcinoma patients of Caucasian descent, stage IIIB or IV, treated with EGFR TKIs in the first line at the Institute for oncology and radiology of Serbia within a five year period. The analysed haematological parameters were derived from the absolute differential counts of a complete blood count (CBC) taken within one week of TKI treatment initiation. Parameters included in this analysis were NLR, PLR, lymphocyte-to-monocyte ratio (LMR), mean platelet volume (MPV), lymphocyte-to-white blood cell ratio (LWR) and neutrophil-to-white blood cell ratio (NWR). Cutoff values were determined using ROC curves. Correlation between each haematological parameter and progression-free survival (PFS) and OS was examined by Kaplan-Meier method and Cox regression Result: Median PFS in the whole group was 13.6 months (10.25-16.95, CI 95%) and median OS was 19.48 months (15.91-23.05, CI 95%). Low LWR (< 0.14) was associated with a shorter PFS in this group of patients (9.2 vs 14.29 months, p¼0.008). High NLR (2.63), high MPV (8.1) and low LWR (< 0.14) were associated with shorter OS (18.0 vs 27.6 months, p¼0.05; 15.57 vs 22.18 months, p¼0.04 and 16.13 vs 22.19, p¼0.038 respectively). No other analysed parameters showed an association with either PFS or OS Conclusion: Pre-treatment NLR, LWR and MPV could be reliable, simple and easy to reproduce parameters for prediction of survival and outcome of targeted therapies in Caucasian EGFR-mutated NSCLC patients. Further prospective trials are needed to definitively confirm this possible prognostic and predictive role
In this article (Cancer Res 2009;69:4244-51), which was published in the May 15, 2009 issue of Ca... more In this article (Cancer Res 2009;69:4244-51), which was published in the May 15, 2009 issue of Cancer Research (1), an incorrect image of the effect of RLIP76 antibody on apoptosis in Caki-2 cells was shown. The corrected Fig. 3A appears below. The conclusions and interpretation of the data in the article are unaltered by this correction.
The purpose of our study is to understand the role of the Ralbp1 gene in oxidative stress (OS), m... more The purpose of our study is to understand the role of the Ralbp1 gene in oxidative stress (OS), mitochondrial dysfunction and cognition in Alzheimer’s disease (AD) pathogenesis. The Ralbp1 gene encodes the 76 kDa protein Rlip (aka RLIP76). Previous studies have revealed its role in OS-related cancer. However, Rlip is transcriptionally regulated by EP300, a CREB-binding protein that is important for synaptic plasticity in the brain. Rlip functions as a stress-responsive/protective transporter of glutathione conjugates (GS-E) and xenobiotic toxins. OS causes rapid cellular accumulation of Rlip and its translocation from a tubulin-bound complex to the plasma membrane, mitochondria and nucleus. Therefore, Rlip may play an important role in maintaining cognitive function in the face of OS-related injury. This study is aimed to determine whether Rlip deficiency in mice is associated with AD-like cognitive and mitochondrial dysfunction. Brain tissue obtained from cohorts of wildtype and Rl...
Acetylcholine (ACh), the major parasympathetic neurotransmitter, is released by intrapancreatic n... more Acetylcholine (ACh), the major parasympathetic neurotransmitter, is released by intrapancreatic nerve endings during the preabsorptive and absorptive phases of feeding. In β-cells, ACh binds to muscarinic M3 receptors and exerts complex effects, which culminate in an increase of glucose (nutrient)-induced insulin secretion. Activation of PLC generates diacylglycerol. Activation of PLA2 produces arachidonic acid and lysophosphatidylcholine. These phospholipid-derived messengers, particularly diacylglycerol, activate PKC, thereby increasing the efficiency of free cytosolic Ca2+ concentration ([Ca2+]c) on exocytosis of insulin granules. IP3, also produced by PLC, causes a rapid elevation of [Ca2+]c by mobilizing Ca2+ from the endoplasmic reticulum; the resulting fall in Ca2+ in the organelle produces a small capacitative Ca2+ entry. ACh also depolarizes the plasma membrane of β-cells by a Na+- dependent mechanism. When the plasma membrane is already depolarized by secretagogues such as...
Mutagenic environmental chemical or radiant stresses directly damage DNA and amplify the formatio... more Mutagenic environmental chemical or radiant stresses directly damage DNA and amplify the formation of potent endogenous mutagens from lipid peroxidation, leading to cancers that cause millions of deaths and impose enormous financial and social burdens [...]
2′-hydroxyflavanone (2HF) is a dietary flavonoid with anticancer activity towardsmultiple cancers... more 2′-hydroxyflavanone (2HF) is a dietary flavonoid with anticancer activity towardsmultiple cancers. Here, we report that topically applied 2HF inhibits the growth of intradermalimplants of melanoma in immunocompetent mice. 2HF induced apoptosis and inhibited the growthof the human SK-MEL-24 as well as murine B16-F0 and B16-F10 melanoma cell lines in vitro.Apoptosis was associated with depletion of caspase-3, caspase-9, and PARP1 in B16-F0 and SKMEL-24 cells. Caspase-9 and MEKK-15 were undetected even in untreated B16-F10 cells. Signalingproteins TNFα, and phospho-PDGFR-β were depleted in all three cell lines; MEKK-15 was depletedby 2HF in SK-MEL-24 cells. 2HF enhanced sunitinib (an MEK and PDGFR-β inhibitor) and AZD2461 (a PARP1 inhibitor) cytotoxicity. 2HF also depleted the Ral-regulated, stress-responsive,antiapoptotic endocytic protein RLIP76 (RALBP1), the inhibition of which has previously beenshown to inhibit B16-F0 melanoma growth in vivo. Functional inhibition of RLIP76 was ev...
Interleukin 2 (IL-2) is a growth factor for T and natural killer cells, promotes proinflammatory ... more Interleukin 2 (IL-2) is a growth factor for T and natural killer cells, promotes proinflammatory cytokines, and can lead to durable responses in patients with melanoma. Vascular endothelial growth factor (VEGF) promotes angiogenesis and modulates host innate and adaptive immunity. High VEGF levels were found to be associated with nonresponse to IL-2. Ziv-aflibercept may deplete VEGF and thereby enhance antitumor T-cell responses, thus supporting a combination immunotherapeutic strategy with IL-2. NCI 8628 was a phase 2 trial of ziv-aflibercept and IL-2 (arm A) versus IL-2 alone (arm B) randomized at 2:1, respectively. Eligible patients had inoperable American Joint Committee on Cancer stage III or stage IV melanoma. The primary endpoint was progression-free survival (PFS). A total of 89 patients were enrolled and 84 patients were treated. The median follow-up was 41.4 months. Among treated patients (55 patients in arm A and 29 patients in arm B), PFS was significantly improved in fa...
Talimogene laherparepvec is a genetically modified herpes simplex virus-1-based oncolytic immunot... more Talimogene laherparepvec is a genetically modified herpes simplex virus-1-based oncolytic immunotherapy for the local treatment of unresectable cutaneous, subcutaneous, and nodal tumors in patients with melanoma recurrence following surgery. We aim to describe the safety of talimogene laherparepvec. Intralesional talimogene laherparepvec was administered at less than or equal to 4 ml×10 PFU/ml at protocol day 1, then less than or equal to 4 ml×10 PFU/ml 21 days later, and then every 14 days. Treatment continued until complete response, absence of injectable tumors, progressive disease, intolerance, or US Food and Drug Administration approval. Adverse events were graded during and 30 days after the end of treatment. Lesions suspected to have herpetic origin were tested for talimogene laherparepvec DNA by quantitative PCR (qPCR). Between September 2014 and October 2015, 41 patients were enrolled with stage IIIB (22%), IIIC (37%), IVM1a (34%), IVM1b (5%), and IVM1c (2%) melanoma. The m...
Lung cancer is still a major cause of cancer deaths in spite of considerable efforts in its syste... more Lung cancer is still a major cause of cancer deaths in spite of considerable efforts in its systemic therapy. Chemotherapy, along with local irradiation is frequently employed but as a palliative therapy. Inherent and acquired resistance in NSCLC and SCLC towards chemotherapeutic agents further makes chemotherapy an incommodious problem. The resistance mechanisms responsible for inherent DOX-resistance of NSCLC and acquired DOX-resistance in SCLC have been the subject of numerous investigations. This review will focus on the recent studies done for understanding the mechanism(s) of inherent and acquired resistance in NSCLC and SCLC and how these can be exploited for the future development of more effective novel biologic agents for the treatment of lung cancer. Contents 1. Introduction 2. RLIP76: a non-ABC transporter 3. Physiological significance of RLIP76 4. Doxorubicin resistance in lung cancer 5. RLIP76 is a major DOX transporter 6. Impairment of transport of RLIP76 sensitizes lung cancer cells to doxorubicin 7. Role of PKC• and RLIP76 in transport-mediated DOXresistance in lung cancer 8. RLIP76 is essential for PKC• mediated DOX-resistance 9. RLIP76 inhibition by POB1 and Hsf-1 induces DOX sensitivity 10. Conclusions
RLIP76, a stress-responsive, multi-functional protein with multi-specific transport activity towa... more RLIP76, a stress-responsive, multi-functional protein with multi-specific transport activity towards glutathioneconjugates (GS-E) and chemotherapeutic agents is frequently overexpressed in malignant cells. Our recent studies suggest that it plays a prominent anti-apoptotic role selectively in cancer cells. The present studies were performed to compare RLIP76 activity towards glutathione-conjugates in recombinant and K562 human erythroleukemia cells. The purity and identity of recombinant and K562 RLIP76 was established by SDS-PAGE and Western blot analysis. These studies confirmed the origin of the 38 kDa protein, previously referred to as DNP-SG ATPase, from RLIP76. Comparison of ATPase activity and transport kinetics for DNP-SG and GS-HNE between recombinant vs. K562 RLIP76 revealed higher specific activity of ATPase and transport for recombinant purified RLIP76, indicating that additional factors present in recombinant purified RLIP76 can modulate its transport activity.
Primary lymphoma of the liver. Report of a case with diagnosis by fine needle aspiration
Acta cytologica
In a 69-year-old man with hepatomegaly, a diagnosis of primary non-Hodgkin's lymphoma (NHL) o... more In a 69-year-old man with hepatomegaly, a diagnosis of primary non-Hodgkin's lymphoma (NHL) of the liver was made by fine needle aspiration (FNA). At the time of presentation there was no evidence of involvement of the lymph nodes, bone marrow or any other organ. Although hepatic involvement is common in advanced stages of Hodgkin's disease and NHL, primary lymphoma of the liver is rare. The purpose of this paper is to report a rare occurrence of primary lymphoma of the liver and to demonstrate the possibility of making this diagnosis by FNA.
The Southwest Respiratory and Critical Care Chronicles, Jan 18, 2019
Despite clear evidence of increased oxidative stress in the blood and tissues of critically ill i... more Despite clear evidence of increased oxidative stress in the blood and tissues of critically ill intensive care unit patients, consistent beneficial effects of many different antioxidants have not been observed, and antioxidant therapy has not yet translated into widely accepted clinical practice. The reasons for this are unclear, likely rooted in the complex and context dependent free radical behavior of antioxidants interacting with the process of lipid peroxidation. Control of lipid peroxidation is a crucial requirement for the beneficial effects of antioxidants, but the interactions of biological antioxidant defenses with the potentially harmful free radical behavior of pharmacological antioxidants complicates the dose and selection of the optimal antioxidants. Glutathione, the primary small molecule antioxidant in biological systems, is the primary enzymatic oxidative stress defense that operates in the context of glutathione-linked antioxidant enzymes to metabolize many harmful products of lipid peroxidation to mercapturic acids. Recently, the mercapturic acid transporter protein, RLIP76 (human RALBP1 gene), has been shown to have a critical role in glutathione linked oxidative stress defenses. These findings provide a rationale for new approaches towards selection and dosing of antioxidant to improve their clinical benefit.
17 Background: According to the World Health Organization GLOBOCAN database, in 2019, approximate... more 17 Background: According to the World Health Organization GLOBOCAN database, in 2019, approximately 1.8 million new colorectal cancer cases were diagnosed, and almost 861,000 deaths were reported. In the United States, CRC is the third most frequent type of cancer and the second leading cause of cancer-related death. Although the overall incidence of CRC among the Hispanic population has been declining over the last decades, recently, a dramatic increase in CRC incidents among Hispanics younger than 50 years of age (early-onset CRC) has been reported. The increase in the incidence of early-onset CRC is markedly more significant in Hispanic-Latino (HL) patients population (45%) than in non-Hispanic Whites (NHW) (27%) and African-Americans (AA) (15%). Additionally, in contrast to NHW, Hispanics have a worse survival rate. The exact reason for these racial disparities and the biology of CRC in the HL population are not well understood. Therefore, we performed this study to better under...
The incidence of malignant melanoma, a neoplasm of melanocytic cells, is increasing rapidly. The ... more The incidence of malignant melanoma, a neoplasm of melanocytic cells, is increasing rapidly. The lymph nodes are often the first site of metastasis and can herald systemic dissemination, which is almost uniformly fatal. RLIP, a multi-specific ATP-dependent transporter that is over-expressed in several types of cancers, plays a central role in cancer cell resistance to radiation and chemotherapy. RLIP appears to be necessary for cancer cell survival because both in vitro cell culture and in vivo animal tumor studies show that the depletion or inhibition of RLIP causes selective toxicity to malignant cells. RLIP depletion/inhibition triggers apoptosis in cancer cells by inducing the accumulation of endogenously formed glutathione-conjugates. In our in vivo studies, we administered RLIP antibodies or antisense oligonucleotides to mice bearing subcutaneous xenografts of SKMEL2 and SKMEL5 melanoma cells and demonstrated that both treatments caused significant xenograft regression with no...
S_ry The efficacy of cisplatin [cis-diamminedichloroplatinum (IT); DDP] is hampered by acquired o... more S_ry The efficacy of cisplatin [cis-diamminedichloroplatinum (IT); DDP] is hampered by acquired or de novo resistance of malignant to its cytotoxic effects. We have previously reported that cisplatin resistance paralklis glutathione S-transferase (GST) activity in several human small-cell lung cancer ce lines. In the presently described studies, we used sala7ine, an inhibitor of GSTs, to evahlate the relative role of GSTs in mediating cisplatin resistan in two human small-cell lung cancer cell lines, NCI H-69 and H-24%. The H-69 cell line, which contained relatively higher GST activity than the H-2496 cell line (317 ± 7 vs 9 ± 1 mU mg-' protein respectively), also displayed a greater degree of cisplatin resistance (IC5o values of 25.0 ± 3.9 vs 4.5 ± 1.0 pi respecively). Western blot and Northern blot analyses of purified GSTs revealed the ecpression of only the s-dass GST in both cell ines. Sulphasalazine inhibited the purified GSTs (IC5u of 10 LM for H-69 and 12fm for H-2496) from both ines in a competitive manner with smilar K vahles (6.5 and 7.9 gM for the H-69 and H-2496 cell lines e). Cytotoxicity studies revealed that sulphasalazne increased the cytotoxicity of cisplatin towards both cel lines. Isobologram analysis showed that lhsalazi synergistically enhanced the cytotoxicity of cisplatin towards both cell lines, the maginitude of synergy being remarkably higher in H-69 cells than in H-2496 cells. Our saudies indicate that clnically achievable concentrations of s salazine may be useful in modulating cisplatin resistance in malignancies with increased GST-x content.
Journal of Community Hospital Internal Medicine Perspectives
On January 30, 2020, the COVID-19 epidemic was declared an international public health emergency ... more On January 30, 2020, the COVID-19 epidemic was declared an international public health emergency by the World Health Organization. Given the growing impact of the pandemic, there is great interest in finding potential targets for treating infected or hospitalized COVID-19 patients. Therapeutic studies have been conducted on pre-existing drugs, which vary by country, including anti-malarial agents, antiviral agents, and convalescent plasma. However, many of these agents are ineffective at reducing mortality or only shorten the severity or duration of COVID-19 illness in hospitalized patients. As such, other alternatives for treating COVID-19 are being investigated. One such target of interest has been clathrin-dependent endocytosis (CDE). Clathrin-dependent endocytosis is the most commonly observed mechanism of viral entry into cells. However, there have been no published studies to date on CDE inhibition strategies against COVID-19. One such target is Rlip or RLIP76 (human gene RALBP1, 18p11.22). Among its many functions, Rlip is a stress-protective, Ral-regulated ATPase of the mercapturic acid pathway that transports glutathione-electrophile conjugates of electrophilic toxins, which are precursors of mercapturic acid that precedes de-glutamylation by gammaglutamyl transferase. Rlip is also regulated by several G-proteins that coordinate movement of cells, organelles, membranes, cytoskeleton, macromolecules, and other small molecules. Previous studies have link Rlip in the pathogenesis of several viral illness. In this paper, we want to propose that RLIP76 (Rlip or RALBP1) may be a novel target for treating SARS-CoV-2 viral infections.
Aggressive fibromatosis (AF) is a rare, benign neoplasm originating from musculoaponeurotic strom... more Aggressive fibromatosis (AF) is a rare, benign neoplasm originating from musculoaponeurotic stromal structures characterized by aggressive growth and infiltration of local tissues. To date, only six previous cases of AF involving the larynx have been reported. The present case was that of a 70-year-old female patient with a 5-year history of hoarseness and an enlarging neck mass consistent with aggressive recurrent fibromatosis. MRI displayed a large, solid mass arising from the left anterior cervical space displacing the trachea and upper airway to the right. At one year after the initial radical resection, the patient presented with recurrence. A second radical excision was performed not including a laryngectomy. Radiation therapy was considered for possible local treatment to prevent subsequent tumor recurrence. According to the literature, AF has recurrence rates of up to 40-70% within 18 months. There is only sparse literature to guide treatment. Using the mutations detected in the patient's AF tissue, an Ingenuity Pathway Analysis (IPA) was used to guide treatment of the recurrence. In the present case, the IPA analysis indicated the use of pazopanib to treat the patient's cancer. In general, surgery appears to be the treatment of choice for head and neck AF, but the management of recurrence is controversial.
Background: Systemic inflammation is an important factor contributing to tumor progression. High ... more Background: Systemic inflammation is an important factor contributing to tumor progression. High neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are markers of host inflammation whose association with worse overall survival (OS) in non-small cell lung cancer (NSCLC) has been shown in various studies. However, there are few studies investigating the association of these, and other haematological parameters of inflammation with prognosis of EGFR mutated NSCLC treated with tyrosine-kinase inhibitors (TKIs). We therefore examined the association between various blood test parameters and prognosis in this group of patients. Method: This retrospective analysis included 74 consecutive advanced lung adenocarcinoma patients of Caucasian descent, stage IIIB or IV, treated with EGFR TKIs in the first line at the Institute for oncology and radiology of Serbia within a five year period. The analysed haematological parameters were derived from the absolute differential counts of a complete blood count (CBC) taken within one week of TKI treatment initiation. Parameters included in this analysis were NLR, PLR, lymphocyte-to-monocyte ratio (LMR), mean platelet volume (MPV), lymphocyte-to-white blood cell ratio (LWR) and neutrophil-to-white blood cell ratio (NWR). Cutoff values were determined using ROC curves. Correlation between each haematological parameter and progression-free survival (PFS) and OS was examined by Kaplan-Meier method and Cox regression Result: Median PFS in the whole group was 13.6 months (10.25-16.95, CI 95%) and median OS was 19.48 months (15.91-23.05, CI 95%). Low LWR (< 0.14) was associated with a shorter PFS in this group of patients (9.2 vs 14.29 months, p¼0.008). High NLR (2.63), high MPV (8.1) and low LWR (< 0.14) were associated with shorter OS (18.0 vs 27.6 months, p¼0.05; 15.57 vs 22.18 months, p¼0.04 and 16.13 vs 22.19, p¼0.038 respectively). No other analysed parameters showed an association with either PFS or OS Conclusion: Pre-treatment NLR, LWR and MPV could be reliable, simple and easy to reproduce parameters for prediction of survival and outcome of targeted therapies in Caucasian EGFR-mutated NSCLC patients. Further prospective trials are needed to definitively confirm this possible prognostic and predictive role
In this article (Cancer Res 2009;69:4244-51), which was published in the May 15, 2009 issue of Ca... more In this article (Cancer Res 2009;69:4244-51), which was published in the May 15, 2009 issue of Cancer Research (1), an incorrect image of the effect of RLIP76 antibody on apoptosis in Caki-2 cells was shown. The corrected Fig. 3A appears below. The conclusions and interpretation of the data in the article are unaltered by this correction.
The purpose of our study is to understand the role of the Ralbp1 gene in oxidative stress (OS), m... more The purpose of our study is to understand the role of the Ralbp1 gene in oxidative stress (OS), mitochondrial dysfunction and cognition in Alzheimer’s disease (AD) pathogenesis. The Ralbp1 gene encodes the 76 kDa protein Rlip (aka RLIP76). Previous studies have revealed its role in OS-related cancer. However, Rlip is transcriptionally regulated by EP300, a CREB-binding protein that is important for synaptic plasticity in the brain. Rlip functions as a stress-responsive/protective transporter of glutathione conjugates (GS-E) and xenobiotic toxins. OS causes rapid cellular accumulation of Rlip and its translocation from a tubulin-bound complex to the plasma membrane, mitochondria and nucleus. Therefore, Rlip may play an important role in maintaining cognitive function in the face of OS-related injury. This study is aimed to determine whether Rlip deficiency in mice is associated with AD-like cognitive and mitochondrial dysfunction. Brain tissue obtained from cohorts of wildtype and Rl...
Acetylcholine (ACh), the major parasympathetic neurotransmitter, is released by intrapancreatic n... more Acetylcholine (ACh), the major parasympathetic neurotransmitter, is released by intrapancreatic nerve endings during the preabsorptive and absorptive phases of feeding. In β-cells, ACh binds to muscarinic M3 receptors and exerts complex effects, which culminate in an increase of glucose (nutrient)-induced insulin secretion. Activation of PLC generates diacylglycerol. Activation of PLA2 produces arachidonic acid and lysophosphatidylcholine. These phospholipid-derived messengers, particularly diacylglycerol, activate PKC, thereby increasing the efficiency of free cytosolic Ca2+ concentration ([Ca2+]c) on exocytosis of insulin granules. IP3, also produced by PLC, causes a rapid elevation of [Ca2+]c by mobilizing Ca2+ from the endoplasmic reticulum; the resulting fall in Ca2+ in the organelle produces a small capacitative Ca2+ entry. ACh also depolarizes the plasma membrane of β-cells by a Na+- dependent mechanism. When the plasma membrane is already depolarized by secretagogues such as...
Mutagenic environmental chemical or radiant stresses directly damage DNA and amplify the formatio... more Mutagenic environmental chemical or radiant stresses directly damage DNA and amplify the formation of potent endogenous mutagens from lipid peroxidation, leading to cancers that cause millions of deaths and impose enormous financial and social burdens [...]
2′-hydroxyflavanone (2HF) is a dietary flavonoid with anticancer activity towardsmultiple cancers... more 2′-hydroxyflavanone (2HF) is a dietary flavonoid with anticancer activity towardsmultiple cancers. Here, we report that topically applied 2HF inhibits the growth of intradermalimplants of melanoma in immunocompetent mice. 2HF induced apoptosis and inhibited the growthof the human SK-MEL-24 as well as murine B16-F0 and B16-F10 melanoma cell lines in vitro.Apoptosis was associated with depletion of caspase-3, caspase-9, and PARP1 in B16-F0 and SKMEL-24 cells. Caspase-9 and MEKK-15 were undetected even in untreated B16-F10 cells. Signalingproteins TNFα, and phospho-PDGFR-β were depleted in all three cell lines; MEKK-15 was depletedby 2HF in SK-MEL-24 cells. 2HF enhanced sunitinib (an MEK and PDGFR-β inhibitor) and AZD2461 (a PARP1 inhibitor) cytotoxicity. 2HF also depleted the Ral-regulated, stress-responsive,antiapoptotic endocytic protein RLIP76 (RALBP1), the inhibition of which has previously beenshown to inhibit B16-F0 melanoma growth in vivo. Functional inhibition of RLIP76 was ev...
Interleukin 2 (IL-2) is a growth factor for T and natural killer cells, promotes proinflammatory ... more Interleukin 2 (IL-2) is a growth factor for T and natural killer cells, promotes proinflammatory cytokines, and can lead to durable responses in patients with melanoma. Vascular endothelial growth factor (VEGF) promotes angiogenesis and modulates host innate and adaptive immunity. High VEGF levels were found to be associated with nonresponse to IL-2. Ziv-aflibercept may deplete VEGF and thereby enhance antitumor T-cell responses, thus supporting a combination immunotherapeutic strategy with IL-2. NCI 8628 was a phase 2 trial of ziv-aflibercept and IL-2 (arm A) versus IL-2 alone (arm B) randomized at 2:1, respectively. Eligible patients had inoperable American Joint Committee on Cancer stage III or stage IV melanoma. The primary endpoint was progression-free survival (PFS). A total of 89 patients were enrolled and 84 patients were treated. The median follow-up was 41.4 months. Among treated patients (55 patients in arm A and 29 patients in arm B), PFS was significantly improved in fa...
Talimogene laherparepvec is a genetically modified herpes simplex virus-1-based oncolytic immunot... more Talimogene laherparepvec is a genetically modified herpes simplex virus-1-based oncolytic immunotherapy for the local treatment of unresectable cutaneous, subcutaneous, and nodal tumors in patients with melanoma recurrence following surgery. We aim to describe the safety of talimogene laherparepvec. Intralesional talimogene laherparepvec was administered at less than or equal to 4 ml×10 PFU/ml at protocol day 1, then less than or equal to 4 ml×10 PFU/ml 21 days later, and then every 14 days. Treatment continued until complete response, absence of injectable tumors, progressive disease, intolerance, or US Food and Drug Administration approval. Adverse events were graded during and 30 days after the end of treatment. Lesions suspected to have herpetic origin were tested for talimogene laherparepvec DNA by quantitative PCR (qPCR). Between September 2014 and October 2015, 41 patients were enrolled with stage IIIB (22%), IIIC (37%), IVM1a (34%), IVM1b (5%), and IVM1c (2%) melanoma. The m...
Lung cancer is still a major cause of cancer deaths in spite of considerable efforts in its syste... more Lung cancer is still a major cause of cancer deaths in spite of considerable efforts in its systemic therapy. Chemotherapy, along with local irradiation is frequently employed but as a palliative therapy. Inherent and acquired resistance in NSCLC and SCLC towards chemotherapeutic agents further makes chemotherapy an incommodious problem. The resistance mechanisms responsible for inherent DOX-resistance of NSCLC and acquired DOX-resistance in SCLC have been the subject of numerous investigations. This review will focus on the recent studies done for understanding the mechanism(s) of inherent and acquired resistance in NSCLC and SCLC and how these can be exploited for the future development of more effective novel biologic agents for the treatment of lung cancer. Contents 1. Introduction 2. RLIP76: a non-ABC transporter 3. Physiological significance of RLIP76 4. Doxorubicin resistance in lung cancer 5. RLIP76 is a major DOX transporter 6. Impairment of transport of RLIP76 sensitizes lung cancer cells to doxorubicin 7. Role of PKC• and RLIP76 in transport-mediated DOXresistance in lung cancer 8. RLIP76 is essential for PKC• mediated DOX-resistance 9. RLIP76 inhibition by POB1 and Hsf-1 induces DOX sensitivity 10. Conclusions
RLIP76, a stress-responsive, multi-functional protein with multi-specific transport activity towa... more RLIP76, a stress-responsive, multi-functional protein with multi-specific transport activity towards glutathioneconjugates (GS-E) and chemotherapeutic agents is frequently overexpressed in malignant cells. Our recent studies suggest that it plays a prominent anti-apoptotic role selectively in cancer cells. The present studies were performed to compare RLIP76 activity towards glutathione-conjugates in recombinant and K562 human erythroleukemia cells. The purity and identity of recombinant and K562 RLIP76 was established by SDS-PAGE and Western blot analysis. These studies confirmed the origin of the 38 kDa protein, previously referred to as DNP-SG ATPase, from RLIP76. Comparison of ATPase activity and transport kinetics for DNP-SG and GS-HNE between recombinant vs. K562 RLIP76 revealed higher specific activity of ATPase and transport for recombinant purified RLIP76, indicating that additional factors present in recombinant purified RLIP76 can modulate its transport activity.
Primary lymphoma of the liver. Report of a case with diagnosis by fine needle aspiration
Acta cytologica
In a 69-year-old man with hepatomegaly, a diagnosis of primary non-Hodgkin's lymphoma (NHL) o... more In a 69-year-old man with hepatomegaly, a diagnosis of primary non-Hodgkin's lymphoma (NHL) of the liver was made by fine needle aspiration (FNA). At the time of presentation there was no evidence of involvement of the lymph nodes, bone marrow or any other organ. Although hepatic involvement is common in advanced stages of Hodgkin's disease and NHL, primary lymphoma of the liver is rare. The purpose of this paper is to report a rare occurrence of primary lymphoma of the liver and to demonstrate the possibility of making this diagnosis by FNA.
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Papers by Sanjay Awasthi