Praveen Jaiswal - Academia.edu (original) (raw)
Papers by Praveen Jaiswal
Additional file 1. Additional figures and table.
Metastatic disease at baseline was identified in 6/26 patients (5 in lymph nodes and bone, 1 in L... more Metastatic disease at baseline was identified in 6/26 patients (5 in lymph nodes and bone, 1 in LN only) using standard conventional imaging. Neoadjuvant therapy was well-tolerated with 24/26 completing all 3 docetaxel cycles. All patients had multi-focal primary PC detected on pretreatment PSMA pelvic PET/MRI. All patients had a decline in SUVmax after treatment in at least one lesion, but resistant tumor foci on histopathology were noted in a subset of patients. All patients underwent planned surgery (24 robotic and 2 open RP). Mean OR time was 169 minutes and mean blood loss was 226 mL. Mean length of stay was 1.6 days (range 1-7). Grade 3-4 postoperative complications are seen in 7% (2/26). On final pathology, 10 patients had node positive disease, the rate of negative surgical margins was 73%, and 80% had pT3. No patient achieved a complete pathologic response. After follow-up of 9 months, the rate of BCR was 33.3%. CONCLUSIONS: Definitive surgery for high risk localized and/ o...
Cancer Research, 2018
Introduction: Prostate Cancer (PCa) is one of the most common urological malignancies in men in t... more Introduction: Prostate Cancer (PCa) is one of the most common urological malignancies in men in the United States. Tousled Like kinases (TLKs) are involved in numerous cellular functions, including the DNA Damage Response (DDR). Through a novel proteomic approach, we have identified that NIMA kinase NEK1 strongly interacts and co-localizes with TLKs and has a role in the DDR, upstream of ATR and Chk1. In the present study we have tested Thioridazine (THD), an anti-psychotic drug and inhibitor of TLKs in inhibiting the activity of NEK1 in prostate cancer cell lines and LNCaP cell derived xenografts in NOD/SCID mice and the subsequent role of ATR-Chk1 axis following DNA damage. Material & Methods: We have used a prostate cancer cell line viz. LNCaP, C4-2, C4-2b, 22Rv1, DU145 and PC3 and normal prostate cell line RWPE-1. Clonogenic activity was measured by colony formation assay. Immunoblotting was done for TLKs, NEK1, p-ATR and p-Chk1 protein in PCa cell line and tumor xenografts tiss...
PDEF is expressed in luminal epithelial cells of the prostate gland and associates with luminal p... more PDEF is expressed in luminal epithelial cells of the prostate gland and associates with luminal phenotype. Hippo pathway regulates cell growth/proliferation, cellular homeostasis, and organ development by modulating phosphorylation of its downstream effectors. In previous studies, we observed decreased levels of PDEF during prostate cancer progression. In the present studies, we evaluated the effects of PDEF on total and phospho (Ser-127)YAP1 protein(a downstream effector of the Hippo pathway) levels in PC3 cells, a line of castrate resistant prostate cancer. We observed that the expression of PDEF in PC3 cells resulted in increased increased phospho(Ser127) -YAP1 protein levels. Our immunofluorescence analysis for YAP1 revealed an increased cytoplasmic/nuclear ratio of YAP1 in PDEF-PC3 cells as compared to VC-PC3 cells, suggesting PDEF may play a critical role in modulating YAP1 phosphorylation, and by extension in the regulation of the Hippo pathway. We also observed a decrease in...
Experimental and Molecular Therapeutics, 2019
Experimental and Molecular Therapeutics, 2019
Cancer Research, 2018
Introduction: cap-dependent translation is necessary due to high protein requirement in cancer ce... more Introduction: cap-dependent translation is necessary due to high protein requirement in cancer cells. An interaction between EIF4E and EIF4G is crucial for the formation of the EIF4F complex and initiation of cap-dependent translation. In the current study, we analyzed Human prostate cancer tissue microarray (TMA) and mRNA expression data in clinical datasets, and prostate tumor tissue from TRAMP (Transgenic Adenocarcinoma of the Mouse Prostate) model. We also assessed the functional role of EIF4G1 in commonly used PCa cell lines. Methods: Human prostate cancer tissue microarray was used to analyze the EIF4G1 level in patient samples. mRNA expression data for EIF4G1 was analyzed from TCGA and Trento/Cornell/Broad clinical data sets. PCa cells viz. LNCaP, C4-2b, 22Rv1, DU145, PC3 and normal human prostate cell line RWPE-1 were used. For an in-vivo model of PCa, we used TRAMP and wild-type mouse. Loss of function studies was performed by using siRNA/shRNA. Real-time PCR and Western Bl...
Cancer Letters, 2019
We recently uncovered the critical TLK1>NEK1>ATR>Chk1 axis in mediating the DDR and cell cycle ch... more We recently uncovered the critical TLK1>NEK1>ATR>Chk1 axis in mediating the DDR and cell cycle checkpoint while transiting from Androgen Sensitive to Insensitive growth for LNCaP and TRAMP-C2 cells. However, we did not know the generality of this pathway in PCa progression since there are few cell lines where the transition has been studied. Furthermore, the identification of Nek1, and more importantly the TLK-mediated phosphorylation of T141, has never been studied in PCa biopsies. We now report the first study of a PCa TMA of p-Nek1-T141 and correlation to the Gleason score. In addition we found that TRAMP mice treated with the TLK inhibitor, thioridazine (THD), following castration did not recover cancerous growth of their prostates. Moreover, we recapitulated the process of translational increase in TLK1B expression in a naïve PDX model that was established from an AR+ adenocarcinoma. Therefore, we believe that this TLK1-Nek1 mediated DDR axis is likely to be a common adaptive response during the transition of PCa cells toward androgen-insensitive growth, and hence CRPC progression, which has the potential to be targeted with THD and other TLK or Nek1 inhibitors.
International Journal of Cancer, 2019
Standard therapy for advanced Prostate Cancer (PCa) consists of antiandrogens, which provide resp... more Standard therapy for advanced Prostate Cancer (PCa) consists of antiandrogens, which provide respite from disease progression, but ultimately fail resulting in the incurable phase of the disease: mCRPC. Targeting PCa cells before their progression to mCRPC would greatly improve the outcome. Combination therapy targeting the DNA Damage Response (DDR) has been limited by general toxicity, and a goal of clinical trials is how to target the DDR more specifically. We now show that androgen deprivation therapy (ADT) of LNCaP cells results in increased expression of TLK1B, a key kinase upstream of NEK1 and ATR and mediating the DDR that typically results in a temporary cell cycle arrest of androgen responsive PCa cells. Following DNA damage, addition of the TLK specific inhibitor, thioridazine (THD), impairs ATR and Chk1 activation, establishing the existence of a ADT > TLK1 > NEK1 > ATR > Chk1, DDR pathway, while its abrogation leads to apoptosis. Treatment with THD suppressed the outgrowth of androgen-independent (AI) colonies of LNCaP and TRAMP-C2 cells cultured with bicalutamide. Moreover, THD significantly inhibited the growth of several PCa cells in vitro (including AI lines). Administration of THD or bicalutamide was not effective at inhibiting long-term tumor growth of LNCaP xenografts. In contrast, combination therapy remarkably inhibited tumor growth via bypass of the DDR. Moreover, xenografts of LNCaP cells overexpressing a NEK1-T141A mutant were durably suppressed with bicalutamide. Collectively, these results suggest that targeting the TLK1/NEK1 axis might be a novel therapy for PCa in combination with standard of care (ADT).
Scientific Reports, 2018
eIF4G1, a critical component of the eIF4F complex, is required for cap-dependent mRNA translation... more eIF4G1, a critical component of the eIF4F complex, is required for cap-dependent mRNA translation, a process necessary for tumor growth and survival. However, the role of eIF4G1 has not been evaluated in Prostate Cancer (PCa). We observed an increased eIF4G1 protein levels in PCa tissues as compared to normal tissues. Analysis of the TCGA data revealed that eIF4G1 gene expression positively correlated with higher tumor grade and stage. Furthermore, eIF4G1 was over-expressed and or amplified, in 16% patients with metastatic PCa (SU2C/PCF Dream Team dataset) and in 59% of castration-resistant prostate cancer (CRPC) patients (Trento/Cornell/Broad dataset). We showed for the first time that eIF4G1 expression was increased in PCa and that increased eIF4G1 expression associated with tumor progression and metastasis. We also observed high protein levels of eIF4G1 in PCa cell lines and prostate tissues from the TRAMP model of PCa as compared to normal prostate cell line and prostate tissues from the wild type mice. Knockdown of eIF4G1 in PCa cells resulted in decreased Cyclin D1 and p-Rb protein level, cell cycle delay, reduced cell viability and proliferation, impaired clonogenic activity, reduced cell migration and decreased mRNA loading to polysomes. Treatment with eIF4G complex inhibitor also impaired prostasphere formation. eIF4G1 knockdown or treatment with eIF4G complex inhibitor sensitized CRPC cells to Enzalutamide and Bicalutamide. Our results showed that eIF4G1 plays an important role in PCa growth and therapeutic resistance. These data suggested that eIF4G1 functions as an oncoprotein and may serve as a novel target for intervention in PCa and CRPC. Prostate cancer is the second most frequently diagnosed malignancy in men in the USA 1. Conventional therapies provide a high percentage of the cure for patients with localized prostate cancer, but there is no cure once the disease has spread beyond the prostate and once it fails to respond to androgen deprivation therapies 2. Metastatic castration-resistant prostate cancer (CRPC) is estimated to result in about 26,730 deaths in 2017 in the USA 1. There is an urgent and unmet need for identification and characterization of new molecular targets for efficient diagnosis and development of novel therapeutic options in PCa. Cap-dependent translation is essential to maintain high protein synthesis and translation of specific mRNAs that are responsible for various tumorigenic properties in cancer cells. Translational control occurs predominately during a rate-limiting, initiation step which is subjected to extensive regulation 3,4 and is governed by cap-binding complex, eukaryotic initiation factor 4 F (eIF4F) which comprises cap-binding protein eIF4E, eIF4A (helicase) and eIF4G (scaffolding protein). The eIF4F complex recruits ribosomes to mRNA such that the 5′ untranslated region (5′ UTR) can be scanned by ribosomes in search of an initiation codon 4. An interaction between eIF4G and eIF4E is crucial for the formation of the eIF4F complex and initiation of cap-dependent translation 5. The eIF4G family comprises three isoform eIF4G1, eIF4G2 and eIF4G3 6 among
International Journal of Research in Medical Sciences, 2016
from the dual medical conditions; where age-related declined immunity and physiological changes h... more from the dual medical conditions; where age-related declined immunity and physiological changes has led to an increased burden of communicable diseases as well as non-communicable chronic diseases. Equally, defining aging is problematic, and each expert in the field will have his or her own version. We believe that aging is the consequence of two associated, but not identical, processes: the decline in function and the ABSTRACT Background: Chronic kidney disease (CKD) has become a major issue in our nation. CKD does not have a specific target, but individuals with diseases such as diabetes mellitus, cardiovascular disease, and obesity are all at increased risk. The chronic kidney disease (CKD) is associated with many features like hyperkalemia, hypocalcemia, hyponatremia, anaemia, hypoalbuminemia, high blood pressure etc. So if we detect all these features early, we can extend the quality life of CKD patients. Aim and objectives of the study were early detection of CKD in elderly people at Initial stage to prevent progression of disease, to study the clinical and biochemical profile and comorbidities in elderly people with CKD. Methods: This Hospital based descriptive study was done in the Department Of Medicine, NSCB Medical college, Jabalpur from October 2014 to October 2015 including 100 patients of 60+ years of age. Results: In present study the etiology of chronic kidney disease was diabetes in 45.0%, hypertension in 38.0%, obstructive uropathy in 8.0% and undetermined etiology was 9.0%. Cardiovascular disease was present in 28% cases, stroke in 22% cases. Most common clinical features was dyspnoea [63.0% (p<0.001)] pedal oedema (31%), high blood pressure [54.0% (p<0.001)], pallor [49.0% (p<0.001)], and pedal oedema (31.0%).The abnormality in the laboratory profile was dyslipidemia in 73% hypoalbuminemia in 31.0% (p<0.05), albuminuria in 73.0% (p<0.001), hypocalcemia in 54.0% (p<0.001), hyponatremia in 23.0%, hyperkalemia in 14%, anemia in 60.0% (p<0.05). LVH on echocardiography is present in 34.0% (p<0.05) cases. Conclusions: The major causes of CKD in descending order were, type 2 diabetes mellitus, hypertension, and obstructive uropathy. All these features needs prompt detection and correction at earlier stages of CKD to delay progression and reduce associated morbidity and exacerbating factors and to prevent early mortality.
Techniques Hospitalieres, 2010
Environmental Toxicology and Chemistry, 2015
The study evaluates the reduction of As(V) uptake in rice seedlings through individual and combin... more The study evaluates the reduction of As(V) uptake in rice seedlings through individual and combined supplementation of PO4 (3-) , Se(IV) under hydroponic condition. The toxic response in seedlings receiving As(V), manifested as inhibition in physiological parameters such as WUE, Gs, A, E, qp and ETR along with the growth. Arsenic accumulation significantly decreased with Se(IV) treatment (0.5, 1 and 2 µg ml(-1) ) in a dose dependent manner (20%, 35%, 53%, respectively), however, it compromised the PO4 (3-) level and physiological performance. The lower level of Se(IV) (0.5 µg ml(-1) ) was relatively beneficial in terms of reduction in As accumulation than the higher level of Se(IV) (2 µg ml(-1) ) which was rather toxic. Further, decrease in As uptake, replenished the level of PO4 (3-) and physiological performance were observed in the seedlings treated with As + Se + P, compared to the As + Se. However, supplementation of only PO4 (3-) (10 and 20 µg ml(-1) ) along with As(V), was less effective in reduction of As accumulation, as compared to As + Se. The seedlings receiving As + Se + P also exhibited lower TBARS and EC levels as compared to the both As + Se and As + P. Among all the treatments, the activity of antioxidant enzymes was highest in plants treated with As + Se + P. Hence, the higher antioxidant enzymes activity in As + Se + P along with lower levels of TBARS, H2 O2 and As accumulation, are attributed to the competitive reduction in As uptake in presence of Se(IV) and PO4 (3-) . This article is protected by copyright. All rights reserved.
Annales de pathologie, 1993
BioScience Trends, 2011
p53 is the most frequently mutated gene in all forms of human cancer. It responds to diverse stre... more p53 is the most frequently mutated gene in all forms of human cancer. It responds to diverse stresses including UVR-induced DNA damage and regulates many downstream genes to initiate cell-cycle arrest, DNA repair or apoptosis. p53 gene variants at codon 11, Pro47Ser and codon 248 (exon 7) were evaluated for bladder cancer (BC) risk in North Indians. In the present study, the above encoding regions in p53 genes were analyzed in a hospital based study in 200 BC and 200 healthy controls age and gender matched and of similar ethnicity. The genotyping was assessed by the polymerase chain reaction restriction fragment length polymorphism technique and statistically evaluated using SPSS software ver. 15.0. A significant association was found with p53 codon 248 polymorphism and BC risk whereas p53 codon 11 and p53 Pro47Ser polymorphism showed no association with BC risk. The individuals carrying the heterozygous genotype (Arg/Trp-Arg/Gln) in the p53 codon 248 polymorphism showed high BC risk (p < 0.001). Combinations with heterozygous and variant genotypes also showed a high risk for BC (p < 0.001). The minor allele (Trp/Gln) carriers of the p53 codon 248 demonstrated a 1.7-fold risk for BC. Furthermore, haplotype analysis revealed that the Glu-Pro-Trp/Gln haplotype is associated with a 1.9-fold risk for BC. A protective role was observed with tumor stage/grade of BC patients with p53 codon 248 (p = 0.003; OR = 0.32). Thus, it is evident from our study that of all the 3 single nucleotide polymorphisms evaluated, only p53 codon 248 (exon7) gene polymorphism has an implication for risk in BC in the North Indian population.
Cancer biomarkers : section A of Disease markers
p53 is a major orchestrator of cellular response to a broad array of stress types by regulating a... more p53 is a major orchestrator of cellular response to a broad array of stress types by regulating apoptosis, cell cycle arrest, etc. A few polymorphic sites, one at codon72 of exon4, intron3 16bpdel/ins, intron6G>A have been studied with regard to Bladder cancer (BC) risk in North Indians. Genotypes were assessed in hospital-based case-control study comprising of 200BC cases, 265healthy controls. After extraction of genomic DNA from blood, genotyping was done using PCR Restriction Fragment Length Polymorphism. Individuals with p53R72P G>C, CC genotype demonstrated marginally reduced risk of BC (p=0.053, OR=0.29, 95% 16bp-ins/del.
Indian Journal of Clinical Biochemistry, 2014
Renal cell carcinoma (RCC) is a leading cause of cancer mortality. Characterizing miRNA expressio... more Renal cell carcinoma (RCC) is a leading cause of cancer mortality. Characterizing miRNA expression in RCC by targeting pathways involved in the action of miRNAs, may lead to discovery of some novel prognostic as well as diagnostic biomarkers. In the present study, we aimed at finding the association of various aberrations in miRNAs to be associated with risk of RCC. In this study we selected 100 histologically confirmed RCC patients and 225 healthy unrelated controls with frequency matched age and sex. Genotyping was done by PCR-RFLP for hsa-mir-146aG/C, hsa-mir-27aA/G, hsa-mir-196a2C/T, hsa-mir-499A/G. However, hsa-mir-125aG/T was genotyped by allelic discrimination Taqman Ò assay. Statistical logistic regression and genetic model was used to find out the genetic effects on the risk of RCC and interactions between polymorphism of all four miRNAs and risk factors. The SNP hsa-mir-196aC/T demonstrated significant high risk for heterozygous genotype (CT; p \ 0.001, OR = 3.206, 95 % CI 1.882-5.462) and variant genotype (TT; p = 0.021, OR = 3.57, 95 % CI 1.209-10.54). Similar pattern was seen in the dominant model (CT?TT; p \ 0.001, OR = 2.992, 95 % CI 1.798-4.978) with similar effects at allelic level, T allele (p \ 0.001, OR = 1.902, 95 % CI 1.335-2.709) also for hsa-mir-196aC/T. In case of hsa-mir499T/C SNP, when the three genotypes were compared, the heterozygous genotype (TC) was found to be associated (p = 0.026, OR = 1.61, 95 % CI 1.05-2.45) with RCC risk. Whereas, hsa-mir27aA/G and hsa-mir146aC/G revealed reduced risk to RCC. Our results suggested that the hsa-mir196a2C/T and hsa-mir499T/C perhaps could be used as a predictive marker for RCC in North Indian population if further validated functionally with varied ethnicities.
Additional file 1. Additional figures and table.
Metastatic disease at baseline was identified in 6/26 patients (5 in lymph nodes and bone, 1 in L... more Metastatic disease at baseline was identified in 6/26 patients (5 in lymph nodes and bone, 1 in LN only) using standard conventional imaging. Neoadjuvant therapy was well-tolerated with 24/26 completing all 3 docetaxel cycles. All patients had multi-focal primary PC detected on pretreatment PSMA pelvic PET/MRI. All patients had a decline in SUVmax after treatment in at least one lesion, but resistant tumor foci on histopathology were noted in a subset of patients. All patients underwent planned surgery (24 robotic and 2 open RP). Mean OR time was 169 minutes and mean blood loss was 226 mL. Mean length of stay was 1.6 days (range 1-7). Grade 3-4 postoperative complications are seen in 7% (2/26). On final pathology, 10 patients had node positive disease, the rate of negative surgical margins was 73%, and 80% had pT3. No patient achieved a complete pathologic response. After follow-up of 9 months, the rate of BCR was 33.3%. CONCLUSIONS: Definitive surgery for high risk localized and/ o...
Cancer Research, 2018
Introduction: Prostate Cancer (PCa) is one of the most common urological malignancies in men in t... more Introduction: Prostate Cancer (PCa) is one of the most common urological malignancies in men in the United States. Tousled Like kinases (TLKs) are involved in numerous cellular functions, including the DNA Damage Response (DDR). Through a novel proteomic approach, we have identified that NIMA kinase NEK1 strongly interacts and co-localizes with TLKs and has a role in the DDR, upstream of ATR and Chk1. In the present study we have tested Thioridazine (THD), an anti-psychotic drug and inhibitor of TLKs in inhibiting the activity of NEK1 in prostate cancer cell lines and LNCaP cell derived xenografts in NOD/SCID mice and the subsequent role of ATR-Chk1 axis following DNA damage. Material & Methods: We have used a prostate cancer cell line viz. LNCaP, C4-2, C4-2b, 22Rv1, DU145 and PC3 and normal prostate cell line RWPE-1. Clonogenic activity was measured by colony formation assay. Immunoblotting was done for TLKs, NEK1, p-ATR and p-Chk1 protein in PCa cell line and tumor xenografts tiss...
PDEF is expressed in luminal epithelial cells of the prostate gland and associates with luminal p... more PDEF is expressed in luminal epithelial cells of the prostate gland and associates with luminal phenotype. Hippo pathway regulates cell growth/proliferation, cellular homeostasis, and organ development by modulating phosphorylation of its downstream effectors. In previous studies, we observed decreased levels of PDEF during prostate cancer progression. In the present studies, we evaluated the effects of PDEF on total and phospho (Ser-127)YAP1 protein(a downstream effector of the Hippo pathway) levels in PC3 cells, a line of castrate resistant prostate cancer. We observed that the expression of PDEF in PC3 cells resulted in increased increased phospho(Ser127) -YAP1 protein levels. Our immunofluorescence analysis for YAP1 revealed an increased cytoplasmic/nuclear ratio of YAP1 in PDEF-PC3 cells as compared to VC-PC3 cells, suggesting PDEF may play a critical role in modulating YAP1 phosphorylation, and by extension in the regulation of the Hippo pathway. We also observed a decrease in...
Experimental and Molecular Therapeutics, 2019
Experimental and Molecular Therapeutics, 2019
Cancer Research, 2018
Introduction: cap-dependent translation is necessary due to high protein requirement in cancer ce... more Introduction: cap-dependent translation is necessary due to high protein requirement in cancer cells. An interaction between EIF4E and EIF4G is crucial for the formation of the EIF4F complex and initiation of cap-dependent translation. In the current study, we analyzed Human prostate cancer tissue microarray (TMA) and mRNA expression data in clinical datasets, and prostate tumor tissue from TRAMP (Transgenic Adenocarcinoma of the Mouse Prostate) model. We also assessed the functional role of EIF4G1 in commonly used PCa cell lines. Methods: Human prostate cancer tissue microarray was used to analyze the EIF4G1 level in patient samples. mRNA expression data for EIF4G1 was analyzed from TCGA and Trento/Cornell/Broad clinical data sets. PCa cells viz. LNCaP, C4-2b, 22Rv1, DU145, PC3 and normal human prostate cell line RWPE-1 were used. For an in-vivo model of PCa, we used TRAMP and wild-type mouse. Loss of function studies was performed by using siRNA/shRNA. Real-time PCR and Western Bl...
Cancer Letters, 2019
We recently uncovered the critical TLK1>NEK1>ATR>Chk1 axis in mediating the DDR and cell cycle ch... more We recently uncovered the critical TLK1>NEK1>ATR>Chk1 axis in mediating the DDR and cell cycle checkpoint while transiting from Androgen Sensitive to Insensitive growth for LNCaP and TRAMP-C2 cells. However, we did not know the generality of this pathway in PCa progression since there are few cell lines where the transition has been studied. Furthermore, the identification of Nek1, and more importantly the TLK-mediated phosphorylation of T141, has never been studied in PCa biopsies. We now report the first study of a PCa TMA of p-Nek1-T141 and correlation to the Gleason score. In addition we found that TRAMP mice treated with the TLK inhibitor, thioridazine (THD), following castration did not recover cancerous growth of their prostates. Moreover, we recapitulated the process of translational increase in TLK1B expression in a naïve PDX model that was established from an AR+ adenocarcinoma. Therefore, we believe that this TLK1-Nek1 mediated DDR axis is likely to be a common adaptive response during the transition of PCa cells toward androgen-insensitive growth, and hence CRPC progression, which has the potential to be targeted with THD and other TLK or Nek1 inhibitors.
International Journal of Cancer, 2019
Standard therapy for advanced Prostate Cancer (PCa) consists of antiandrogens, which provide resp... more Standard therapy for advanced Prostate Cancer (PCa) consists of antiandrogens, which provide respite from disease progression, but ultimately fail resulting in the incurable phase of the disease: mCRPC. Targeting PCa cells before their progression to mCRPC would greatly improve the outcome. Combination therapy targeting the DNA Damage Response (DDR) has been limited by general toxicity, and a goal of clinical trials is how to target the DDR more specifically. We now show that androgen deprivation therapy (ADT) of LNCaP cells results in increased expression of TLK1B, a key kinase upstream of NEK1 and ATR and mediating the DDR that typically results in a temporary cell cycle arrest of androgen responsive PCa cells. Following DNA damage, addition of the TLK specific inhibitor, thioridazine (THD), impairs ATR and Chk1 activation, establishing the existence of a ADT > TLK1 > NEK1 > ATR > Chk1, DDR pathway, while its abrogation leads to apoptosis. Treatment with THD suppressed the outgrowth of androgen-independent (AI) colonies of LNCaP and TRAMP-C2 cells cultured with bicalutamide. Moreover, THD significantly inhibited the growth of several PCa cells in vitro (including AI lines). Administration of THD or bicalutamide was not effective at inhibiting long-term tumor growth of LNCaP xenografts. In contrast, combination therapy remarkably inhibited tumor growth via bypass of the DDR. Moreover, xenografts of LNCaP cells overexpressing a NEK1-T141A mutant were durably suppressed with bicalutamide. Collectively, these results suggest that targeting the TLK1/NEK1 axis might be a novel therapy for PCa in combination with standard of care (ADT).
Scientific Reports, 2018
eIF4G1, a critical component of the eIF4F complex, is required for cap-dependent mRNA translation... more eIF4G1, a critical component of the eIF4F complex, is required for cap-dependent mRNA translation, a process necessary for tumor growth and survival. However, the role of eIF4G1 has not been evaluated in Prostate Cancer (PCa). We observed an increased eIF4G1 protein levels in PCa tissues as compared to normal tissues. Analysis of the TCGA data revealed that eIF4G1 gene expression positively correlated with higher tumor grade and stage. Furthermore, eIF4G1 was over-expressed and or amplified, in 16% patients with metastatic PCa (SU2C/PCF Dream Team dataset) and in 59% of castration-resistant prostate cancer (CRPC) patients (Trento/Cornell/Broad dataset). We showed for the first time that eIF4G1 expression was increased in PCa and that increased eIF4G1 expression associated with tumor progression and metastasis. We also observed high protein levels of eIF4G1 in PCa cell lines and prostate tissues from the TRAMP model of PCa as compared to normal prostate cell line and prostate tissues from the wild type mice. Knockdown of eIF4G1 in PCa cells resulted in decreased Cyclin D1 and p-Rb protein level, cell cycle delay, reduced cell viability and proliferation, impaired clonogenic activity, reduced cell migration and decreased mRNA loading to polysomes. Treatment with eIF4G complex inhibitor also impaired prostasphere formation. eIF4G1 knockdown or treatment with eIF4G complex inhibitor sensitized CRPC cells to Enzalutamide and Bicalutamide. Our results showed that eIF4G1 plays an important role in PCa growth and therapeutic resistance. These data suggested that eIF4G1 functions as an oncoprotein and may serve as a novel target for intervention in PCa and CRPC. Prostate cancer is the second most frequently diagnosed malignancy in men in the USA 1. Conventional therapies provide a high percentage of the cure for patients with localized prostate cancer, but there is no cure once the disease has spread beyond the prostate and once it fails to respond to androgen deprivation therapies 2. Metastatic castration-resistant prostate cancer (CRPC) is estimated to result in about 26,730 deaths in 2017 in the USA 1. There is an urgent and unmet need for identification and characterization of new molecular targets for efficient diagnosis and development of novel therapeutic options in PCa. Cap-dependent translation is essential to maintain high protein synthesis and translation of specific mRNAs that are responsible for various tumorigenic properties in cancer cells. Translational control occurs predominately during a rate-limiting, initiation step which is subjected to extensive regulation 3,4 and is governed by cap-binding complex, eukaryotic initiation factor 4 F (eIF4F) which comprises cap-binding protein eIF4E, eIF4A (helicase) and eIF4G (scaffolding protein). The eIF4F complex recruits ribosomes to mRNA such that the 5′ untranslated region (5′ UTR) can be scanned by ribosomes in search of an initiation codon 4. An interaction between eIF4G and eIF4E is crucial for the formation of the eIF4F complex and initiation of cap-dependent translation 5. The eIF4G family comprises three isoform eIF4G1, eIF4G2 and eIF4G3 6 among
International Journal of Research in Medical Sciences, 2016
from the dual medical conditions; where age-related declined immunity and physiological changes h... more from the dual medical conditions; where age-related declined immunity and physiological changes has led to an increased burden of communicable diseases as well as non-communicable chronic diseases. Equally, defining aging is problematic, and each expert in the field will have his or her own version. We believe that aging is the consequence of two associated, but not identical, processes: the decline in function and the ABSTRACT Background: Chronic kidney disease (CKD) has become a major issue in our nation. CKD does not have a specific target, but individuals with diseases such as diabetes mellitus, cardiovascular disease, and obesity are all at increased risk. The chronic kidney disease (CKD) is associated with many features like hyperkalemia, hypocalcemia, hyponatremia, anaemia, hypoalbuminemia, high blood pressure etc. So if we detect all these features early, we can extend the quality life of CKD patients. Aim and objectives of the study were early detection of CKD in elderly people at Initial stage to prevent progression of disease, to study the clinical and biochemical profile and comorbidities in elderly people with CKD. Methods: This Hospital based descriptive study was done in the Department Of Medicine, NSCB Medical college, Jabalpur from October 2014 to October 2015 including 100 patients of 60+ years of age. Results: In present study the etiology of chronic kidney disease was diabetes in 45.0%, hypertension in 38.0%, obstructive uropathy in 8.0% and undetermined etiology was 9.0%. Cardiovascular disease was present in 28% cases, stroke in 22% cases. Most common clinical features was dyspnoea [63.0% (p<0.001)] pedal oedema (31%), high blood pressure [54.0% (p<0.001)], pallor [49.0% (p<0.001)], and pedal oedema (31.0%).The abnormality in the laboratory profile was dyslipidemia in 73% hypoalbuminemia in 31.0% (p<0.05), albuminuria in 73.0% (p<0.001), hypocalcemia in 54.0% (p<0.001), hyponatremia in 23.0%, hyperkalemia in 14%, anemia in 60.0% (p<0.05). LVH on echocardiography is present in 34.0% (p<0.05) cases. Conclusions: The major causes of CKD in descending order were, type 2 diabetes mellitus, hypertension, and obstructive uropathy. All these features needs prompt detection and correction at earlier stages of CKD to delay progression and reduce associated morbidity and exacerbating factors and to prevent early mortality.
Techniques Hospitalieres, 2010
Environmental Toxicology and Chemistry, 2015
The study evaluates the reduction of As(V) uptake in rice seedlings through individual and combin... more The study evaluates the reduction of As(V) uptake in rice seedlings through individual and combined supplementation of PO4 (3-) , Se(IV) under hydroponic condition. The toxic response in seedlings receiving As(V), manifested as inhibition in physiological parameters such as WUE, Gs, A, E, qp and ETR along with the growth. Arsenic accumulation significantly decreased with Se(IV) treatment (0.5, 1 and 2 µg ml(-1) ) in a dose dependent manner (20%, 35%, 53%, respectively), however, it compromised the PO4 (3-) level and physiological performance. The lower level of Se(IV) (0.5 µg ml(-1) ) was relatively beneficial in terms of reduction in As accumulation than the higher level of Se(IV) (2 µg ml(-1) ) which was rather toxic. Further, decrease in As uptake, replenished the level of PO4 (3-) and physiological performance were observed in the seedlings treated with As + Se + P, compared to the As + Se. However, supplementation of only PO4 (3-) (10 and 20 µg ml(-1) ) along with As(V), was less effective in reduction of As accumulation, as compared to As + Se. The seedlings receiving As + Se + P also exhibited lower TBARS and EC levels as compared to the both As + Se and As + P. Among all the treatments, the activity of antioxidant enzymes was highest in plants treated with As + Se + P. Hence, the higher antioxidant enzymes activity in As + Se + P along with lower levels of TBARS, H2 O2 and As accumulation, are attributed to the competitive reduction in As uptake in presence of Se(IV) and PO4 (3-) . This article is protected by copyright. All rights reserved.
Annales de pathologie, 1993
BioScience Trends, 2011
p53 is the most frequently mutated gene in all forms of human cancer. It responds to diverse stre... more p53 is the most frequently mutated gene in all forms of human cancer. It responds to diverse stresses including UVR-induced DNA damage and regulates many downstream genes to initiate cell-cycle arrest, DNA repair or apoptosis. p53 gene variants at codon 11, Pro47Ser and codon 248 (exon 7) were evaluated for bladder cancer (BC) risk in North Indians. In the present study, the above encoding regions in p53 genes were analyzed in a hospital based study in 200 BC and 200 healthy controls age and gender matched and of similar ethnicity. The genotyping was assessed by the polymerase chain reaction restriction fragment length polymorphism technique and statistically evaluated using SPSS software ver. 15.0. A significant association was found with p53 codon 248 polymorphism and BC risk whereas p53 codon 11 and p53 Pro47Ser polymorphism showed no association with BC risk. The individuals carrying the heterozygous genotype (Arg/Trp-Arg/Gln) in the p53 codon 248 polymorphism showed high BC risk (p < 0.001). Combinations with heterozygous and variant genotypes also showed a high risk for BC (p < 0.001). The minor allele (Trp/Gln) carriers of the p53 codon 248 demonstrated a 1.7-fold risk for BC. Furthermore, haplotype analysis revealed that the Glu-Pro-Trp/Gln haplotype is associated with a 1.9-fold risk for BC. A protective role was observed with tumor stage/grade of BC patients with p53 codon 248 (p = 0.003; OR = 0.32). Thus, it is evident from our study that of all the 3 single nucleotide polymorphisms evaluated, only p53 codon 248 (exon7) gene polymorphism has an implication for risk in BC in the North Indian population.
Cancer biomarkers : section A of Disease markers
p53 is a major orchestrator of cellular response to a broad array of stress types by regulating a... more p53 is a major orchestrator of cellular response to a broad array of stress types by regulating apoptosis, cell cycle arrest, etc. A few polymorphic sites, one at codon72 of exon4, intron3 16bpdel/ins, intron6G>A have been studied with regard to Bladder cancer (BC) risk in North Indians. Genotypes were assessed in hospital-based case-control study comprising of 200BC cases, 265healthy controls. After extraction of genomic DNA from blood, genotyping was done using PCR Restriction Fragment Length Polymorphism. Individuals with p53R72P G>C, CC genotype demonstrated marginally reduced risk of BC (p=0.053, OR=0.29, 95% 16bp-ins/del.
Indian Journal of Clinical Biochemistry, 2014
Renal cell carcinoma (RCC) is a leading cause of cancer mortality. Characterizing miRNA expressio... more Renal cell carcinoma (RCC) is a leading cause of cancer mortality. Characterizing miRNA expression in RCC by targeting pathways involved in the action of miRNAs, may lead to discovery of some novel prognostic as well as diagnostic biomarkers. In the present study, we aimed at finding the association of various aberrations in miRNAs to be associated with risk of RCC. In this study we selected 100 histologically confirmed RCC patients and 225 healthy unrelated controls with frequency matched age and sex. Genotyping was done by PCR-RFLP for hsa-mir-146aG/C, hsa-mir-27aA/G, hsa-mir-196a2C/T, hsa-mir-499A/G. However, hsa-mir-125aG/T was genotyped by allelic discrimination Taqman Ò assay. Statistical logistic regression and genetic model was used to find out the genetic effects on the risk of RCC and interactions between polymorphism of all four miRNAs and risk factors. The SNP hsa-mir-196aC/T demonstrated significant high risk for heterozygous genotype (CT; p \ 0.001, OR = 3.206, 95 % CI 1.882-5.462) and variant genotype (TT; p = 0.021, OR = 3.57, 95 % CI 1.209-10.54). Similar pattern was seen in the dominant model (CT?TT; p \ 0.001, OR = 2.992, 95 % CI 1.798-4.978) with similar effects at allelic level, T allele (p \ 0.001, OR = 1.902, 95 % CI 1.335-2.709) also for hsa-mir-196aC/T. In case of hsa-mir499T/C SNP, when the three genotypes were compared, the heterozygous genotype (TC) was found to be associated (p = 0.026, OR = 1.61, 95 % CI 1.05-2.45) with RCC risk. Whereas, hsa-mir27aA/G and hsa-mir146aC/G revealed reduced risk to RCC. Our results suggested that the hsa-mir196a2C/T and hsa-mir499T/C perhaps could be used as a predictive marker for RCC in North Indian population if further validated functionally with varied ethnicities.