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  1. Article: Epigenetic Regulation Towards Acquired Drug Resistance in Cancer.

    Ketkar, Madhura / Dutt, Shilpee

    Sub-cellular biochemistry

    2022  Volume 100, Page(s) 473–502

    Abstract: Therapy resistance remains the most challenging obstacle in cancer treatment. Substantial efforts and evidences have accumulated over decades suggesting not only genetic but non-genomic mechanisms underlying this adaptation of tumor cells. Alterations in ...

    Abstract Therapy resistance remains the most challenging obstacle in cancer treatment. Substantial efforts and evidences have accumulated over decades suggesting not only genetic but non-genomic mechanisms underlying this adaptation of tumor cells. Alterations in epigenome can have a fundamental effect on cellular functions and response to stresses like anticancer therapy. This chapter discusses the principal mechanisms by which epigenetic modifications in the genome and transcriptome aid tumor cells toward acquisition of resistance to chemotherapy.
    MeSH term(s) Humans ; Epigenesis, Genetic ; DNA Methylation ; Neoplasms/drug therapy ; Neoplasms/genetics ; Drug Resistance
    Language English
    Publishing date 2022-10-27
    Publishing country United States
    Document type Journal Article
    ISSN 0306-0225 ; 0096-8757
    ISSN 0306-0225 ; 0096-8757
    DOI 10.1007/978-3-031-07634-3_14
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  2. Article ; Online: Multifaceted luminance gain control beyond photoreceptors in Drosophila.

    Ketkar, Madhura D / Shao, Shuai / Gjorgjieva, Julijana / Silies, Marion

    Current biology : CB

    2023  Volume 33, Issue 13, Page(s) 2632–2645.e6

    Abstract: Animals navigating in natural environments must handle vast changes in their sensory input. Visual systems, for example, handle changes in luminance at many timescales, from slow changes across the day to rapid changes during active behavior. To maintain ...

    Abstract Animals navigating in natural environments must handle vast changes in their sensory input. Visual systems, for example, handle changes in luminance at many timescales, from slow changes across the day to rapid changes during active behavior. To maintain luminance-invariant perception, visual systems must adapt their sensitivity to changing luminance at different timescales. We demonstrate that luminance gain control in photoreceptors alone is insufficient to explain luminance invariance at both fast and slow timescales and reveal the algorithms that adjust gain past photoreceptors in the fly eye. We combined imaging and behavioral experiments with computational modeling to show that downstream of photoreceptors, circuitry taking input from the single luminance-sensitive neuron type L3 implements gain control at fast and slow timescales. This computation is bidirectional in that it prevents the underestimation of contrasts in low luminance and overestimation in high luminance. An algorithmic model disentangles these multifaceted contributions and shows that the bidirectional gain control occurs at both timescales. The model implements a nonlinear interaction of luminance and contrast to achieve gain correction at fast timescales and a dark-sensitive channel to improve the detection of dim stimuli at slow timescales. Together, our work demonstrates how a single neuronal channel performs diverse computations to implement gain control at multiple timescales that are together important for navigation in natural environments.
    MeSH term(s) Animals ; Drosophila ; Contrast Sensitivity ; Vision, Ocular ; Photoreceptor Cells ; Neurons/physiology ; Photic Stimulation/methods
    Language English
    Publishing date 2023-06-06
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1071731-6
    ISSN 1879-0445 ; 0960-9822
    ISSN (online) 1879-0445
    ISSN 0960-9822
    DOI 10.1016/j.cub.2023.05.024
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  3. Article ; Online: Glioblastoma recurrent cells switch between ATM and ATR pathway as an alternative strategy to survive radiation stress.

    Kaur, Ekjot / Ketkar, Madhura / Dutt, Shilpee

    Medical oncology (Northwood, London, England)

    2022  Volume 39, Issue 5, Page(s) 50

    Abstract: Primary treatment modality for glioblastoma (GBM) post-surgery is radiation therapy. Due to increased DNA damage repair capacity of resistant residual GBM cells, recurrence is inevitable in glioblastoma and unfortunately the recurrent tumours are ... ...

    Abstract Primary treatment modality for glioblastoma (GBM) post-surgery is radiation therapy. Due to increased DNA damage repair capacity of resistant residual GBM cells, recurrence is inevitable in glioblastoma and unfortunately the recurrent tumours are resistant to the conventional therapy. Here we used our previously described in vitro radiation survival model generated from primary GBM patient samples and cell lines, which recapitulates the clinical scenario of therapy resistance and relapse. Using the parent and recurrent GBM cells from these models, we show that similar to parent GBM, the recurrent GBM cells also elicit a competent DNA damage response (DDR) post irradiation. However, the use of apical DNA damage repair sensory kinase (ATM and/or ATR) is different in the recurrent cells compared to parent cells. Consistently, we demonstrate that there is a differential clonogenic response of parent and recurrent GBM cells to the ATM and ATR kinase inhibitors with recurrent samples switching between these sensory kinases for survival emphasizing on the underlying heterogeneity within and across GBM samples. Taken together, here we report that recurrent tumours utilize an alternate DDR kinase to overcome radiation induced DNA damage. Since there is no effective treatment specifically for recurred GBM patients, these findings provide a rationale for developing newer treatment option to sensitize recurrent GBM samples by detecting in clinics the ability of cells to activate a DNA damage repair kinase different from their parent counterparts.
    MeSH term(s) Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors ; Ataxia Telangiectasia Mutated Proteins/metabolism ; Cell Line, Tumor ; DNA Damage ; DNA Repair ; Glioblastoma/genetics ; Glioblastoma/metabolism ; Glioblastoma/therapy ; Humans ; Neoplasm Recurrence, Local ; Protein Kinase Inhibitors/pharmacology ; Radiation Tolerance/genetics ; Signal Transduction/drug effects ; Signal Transduction/radiation effects
    Chemical Substances Protein Kinase Inhibitors ; ATM protein, human (EC 2.7.11.1) ; ATR protein, human (EC 2.7.11.1) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1)
    Language English
    Publishing date 2022-02-12
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1201189-7
    ISSN 1559-131X ; 0736-0118 ; 1357-0560
    ISSN (online) 1559-131X
    ISSN 0736-0118 ; 1357-0560
    DOI 10.1007/s12032-022-01657-4
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    Zs.A 1899: Show issues Location:
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  4. Article ; Online: First-order visual interneurons distribute distinct contrast and luminance information across ON and OFF pathways to achieve stable behavior.

    Ketkar, Madhura D / Gür, Burak / Molina-Obando, Sebastian / Ioannidou, Maria / Martelli, Carlotta / Silies, Marion

    eLife

    2022  Volume 11

    Abstract: The accurate processing of contrast is the basis for all visually guided behaviors. Visual scenes with rapidly changing illumination challenge contrast computation because photoreceptor adaptation is not fast enough to compensate for such changes. Yet, ... ...

    Abstract The accurate processing of contrast is the basis for all visually guided behaviors. Visual scenes with rapidly changing illumination challenge contrast computation because photoreceptor adaptation is not fast enough to compensate for such changes. Yet, human perception of contrast is stable even when the visual environment is quickly changing, suggesting rapid post receptor luminance gain control. Similarly, in the fruit fly
    MeSH term(s) Animals ; Contrast Sensitivity ; Drosophila ; Interneurons/physiology ; Motion ; Motion Perception/physiology ; Photic Stimulation ; Vision, Ocular ; Visual Pathways/physiology
    Language English
    Publishing date 2022-03-09
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.74937
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  5. Book ; Online: COVID-19

    Ketkar, Madhura / Sarkar, Debashmita / Dutt, Shilpee

    A Compendium of SARS-CoV-2 Invasion and Host Defense

    2020  

    Abstract: Corona Virus Disease (COVID-19) caused by novel SARS-CoV-2 has spread like a wildfire, causing respiratory distress in humans at an alarming rate since its inception at Wuhan, China in December 2019. The mortality rate is 2-3%, causing more complications ...

    Abstract Corona Virus Disease (COVID-19) caused by novel SARS-CoV-2 has spread like a wildfire, causing respiratory distress in humans at an alarming rate since its inception at Wuhan, China in December 2019. The mortality rate is 2-3%, causing more complications in elderly people, males with pre-existing medical conditions like diabetes, asthma, cardiac anomalies. Self-isolation is the best strategy to effectively contain the virus and prevent the spread. Like the SARS and MERS outbreaks in previous decades, this transmission has also been from animals to humans. However, due to novel alterations in spike protein, SARS-CoV-2 has a high affinity towards host cell Angiotensin Converting Enzyme (ACE2) receptor, which has allowed for its rapid human to human transmission. Therefore, it is of the utmost importance to gain knowledge about the virus in detail and our own immune system proficiency in combating the infection. In the present review, we focus on the genomic and proteomic features of SARS-CoV-2, the infection mechanism and immune response of the host to the virus along with potential therapeutic interventions. Understanding the crux of infection will aid in devising therapeutic strategies to control the COVID-19 pandemic.
    Keywords COVID-19 ; SARS-CoV-2 entry ; Coronavirus pathogenesis ; Host immune response ; Immunotherapy ; Pandemic ; Global health ; covid19
    Subject code 572
    Language English
    Publishing date 2020-05-02
    Publisher AIJR Preprints
    Publishing country in
    Document type Book ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Book ; Online ; Thesis: Strategies for dynamic vision in the Drosophila peripheral visual system

    Ketkar, Madhura D. [Verfasser] / Silies, Marion [Akademischer Betreuer] / Silies, Marion [Gutachter] / Gollisch, Tim [Gutachter] / Priesemann, Viola [Gutachter]

    2022  

    Author's details Madhura D. Ketkar ; Gutachter: Marion Silies, Tim Gollisch, Viola Priesemann ; Betreuer: Marion Silies
    Keywords Psychologie ; Psychology
    Subject code sg150
    Language English
    Publisher Niedersächsische Staats- und Universitätsbibliothek Göttingen
    Publishing place Göttingen
    Document type Book ; Online ; Thesis
    Database Digital theses on the web

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  7. Article ; Online: Luminance Information Is Required for the Accurate Estimation of Contrast in Rapidly Changing Visual Contexts.

    Ketkar, Madhura D / Sporar, Katja / Gür, Burak / Ramos-Traslosheros, Giordano / Seifert, Marvin / Silies, Marion

    Current biology : CB

    2020  Volume 30, Issue 4, Page(s) 657–669.e4

    Abstract: Visual perception scales with changes in the visual stimulus, or contrast, irrespective of background illumination. However, visual perception is challenged when adaptation is not fast enough to deal with sudden declines in overall illumination, for ... ...

    Abstract Visual perception scales with changes in the visual stimulus, or contrast, irrespective of background illumination. However, visual perception is challenged when adaptation is not fast enough to deal with sudden declines in overall illumination, for example, when gaze follows a moving object from bright sunlight into a shaded area. Here, we show that the visual system of the fly employs a solution by propagating a corrective luminance-sensitive signal. We use in vivo 2-photon imaging and behavioral analyses to demonstrate that distinct OFF-pathway inputs encode contrast and luminance. Predictions of contrast-sensitive neuronal responses show that contrast information alone cannot explain behavioral responses in sudden dim light. The luminance-sensitive pathway via the L3 neuron is required for visual processing in such rapidly changing light conditions, ensuring contrast constancy when pure contrast sensitivity underestimates a stimulus. Thus, retaining a peripheral feature, luminance, in visual processing is required for robust behavioral responses.
    MeSH term(s) Animals ; Contrast Sensitivity/physiology ; Drosophila melanogaster/physiology ; Pattern Recognition, Visual/physiology ; Photic Stimulation ; Visual Perception/physiology
    Language English
    Publishing date 2020-01-30
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1071731-6
    ISSN 1879-0445 ; 0960-9822
    ISSN (online) 1879-0445
    ISSN 0960-9822
    DOI 10.1016/j.cub.2019.12.038
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3208: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  8. Article ; Online: Combined fMRI- and eye movement-based decoding of bistable plaid motion perception.

    Wilbertz, Gregor / Ketkar, Madhura / Guggenmos, Matthias / Sterzer, Philipp

    NeuroImage

    2017  Volume 171, Page(s) 190–198

    Abstract: The phenomenon of bistable perception, in which perception alternates spontaneously despite constant sensory stimulation, has been particularly useful in probing the neural bases of conscious perception. The study of such bistability requires access to ... ...

    Abstract The phenomenon of bistable perception, in which perception alternates spontaneously despite constant sensory stimulation, has been particularly useful in probing the neural bases of conscious perception. The study of such bistability requires access to the observer's perceptual dynamics, which is usually achieved via active report. This report, however, constitutes a confounding factor in the study of conscious perception and can also be biased in the context of certain experimental manipulations. One approach to circumvent these problems is to track perceptual alternations using signals from the eyes or the brain instead of observers' reports. Here we aimed to optimize such decoding of perceptual alternations by combining eye and brain signals. Eye-tracking and functional magnetic resonance imaging (fMRI) was performed in twenty participants while they viewed a bistable visual plaid motion stimulus and reported perceptual alternations. Multivoxel pattern analysis (MVPA) for fMRI was combined with eye-tracking in a Support vector machine to decode participants' perceptual time courses from fMRI and eye-movement signals. While both measures individually already yielded high decoding accuracies (on average 86% and 88% correct, respectively) classification based on the two measures together further improved the accuracy (91% correct). These findings show that leveraging on both fMRI and eye movement data may pave the way for optimized no-report paradigms through improved decodability of bistable motion perception and hence for a better understanding of the neural correlates of consciousness.
    MeSH term(s) Adult ; Brain Mapping/methods ; Eye Movements ; Female ; Humans ; Image Processing, Computer-Assisted/methods ; Magnetic Resonance Imaging ; Male ; Motion Perception/physiology ; Photic Stimulation ; Support Vector Machine ; Young Adult
    Language English
    Publishing date 2017-12-30
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1147767-2
    ISSN 1095-9572 ; 1053-8119
    ISSN (online) 1095-9572
    ISSN 1053-8119
    DOI 10.1016/j.neuroimage.2017.12.094
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    Zs.A 3664: Show issues Location:
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    Zs.MO 7: Show issues

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  9. Article ; Online: Down-regulation of metabolic pathways could offset the poor prognosis conferred by co-existent diabetes mellitus in pancreatic (head) adenocarcinoma.

    Gardi, Nilesh / Ketkar, Madhura / McKinnon, Ross A / Pandol, Stephen J / Dutt, Shilpee / Barreto, Savio G

    ANZ journal of surgery

    2021  Volume 91, Issue 11, Page(s) 2466–2474

    Abstract: Background: Pancreatic ductal adenocarcinoma (PDAC) patients with diabetes mellitus (DM) have poor overall survival. Underlying mechanisms have not been fully clarified. This presents an opportunity for precision-oncology for which we systematically ... ...

    Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) patients with diabetes mellitus (DM) have poor overall survival. Underlying mechanisms have not been fully clarified. This presents an opportunity for precision-oncology for which we systematically analysed publicly-available PDAC transcriptome data.
    Methods: PDAC TCGA RNASeq data were used. Analyses were restricted to only 'high purity' and 'head' as anatomical site. Patients were characterised by: (1) Gene expression classification, and (2) Weighted gene correlation network analysis (WGCNA) to identify co-expression patterns of genes. Newly identified gene signature subclasses of pancreatic head PDAC were associated with clinical and functional characteristics of patients.
    Results: Consensus clustering identified two patient subclasses within PDAC involving pancreatic head. WGCNA identified 11 distinct networks of gene expression patterns across two sub-classes. Class 1 patients demonstrated a significant upregulation of Module 5 and Module 6 gene expression compared to Class 2. Class 1 predominantly expressed the acinar, ductal and islet cell gene signatures. There were significantly less patients with DM in Class 1 subclass compared to Class 2 (p < 0.037). Patients with DM had significant downregulation of pathways involved in cellular metabolism, hormone secretion and paucity of islet cell markers with no reduced survival compared with non-diabetics.
    Conclusions: A significant proportion of patients with PDAC of pancreatic head and DM exhibit downregulation of pathways involved in cellular metabolism, hormone secretion and signalling accompanied by a paucity of islet expression. Investigating the relationship between DM and gene expression profiles in patients with PDAC presents opportunities to improve overall survival in diabetics with PDAC.
    MeSH term(s) Adenocarcinoma/genetics ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Carcinoma, Pancreatic Ductal/genetics ; Diabetes Mellitus/genetics ; Down-Regulation ; Gene Expression Regulation, Neoplastic ; Humans ; Metabolic Networks and Pathways ; Pancreatic Neoplasms/genetics ; Prognosis
    Chemical Substances Biomarkers, Tumor
    Language English
    Publishing date 2021-09-13
    Publishing country Australia
    Document type Journal Article
    ZDB-ID 2050749-5
    ISSN 1445-2197 ; 1445-1433 ; 0004-8682
    ISSN (online) 1445-2197
    ISSN 1445-1433 ; 0004-8682
    DOI 10.1111/ans.17194
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    Zs.A 180: Show issues Location:
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  10. Article ; Online: DUSP6 regulates radiosensitivity in glioblastoma by modulating the recruitment of phosphorylated DNAPKcs at DNA double-strand breaks.

    Nair, Jyothi / Basha Syed, Safiulla / Mahaddalkar, Tejashree / Ketkar, Madhura / Thorat, Rahul / Sastri Goda, Jayant / Dutt, Shilpee

    Journal of cell science

    2021  Volume 134, Issue 24

    Abstract: Glioblastoma (GBM) has poor median survival due to its resistance to chemoradiotherapy, which results in tumor recurrence. Recurrent GBMs currently lack effective treatments. DUSP6 is known to be pro-tumorigenic and is upregulated in GBM. We show that ... ...

    Abstract Glioblastoma (GBM) has poor median survival due to its resistance to chemoradiotherapy, which results in tumor recurrence. Recurrent GBMs currently lack effective treatments. DUSP6 is known to be pro-tumorigenic and is upregulated in GBM. We show that DUSP6 expression is significantly higher in recurrent GBM patient biopsies compared to expression levels in primary GBM biopsies. Importantly, although it has been reported to be a cytoplasmic protein, we found nuclear localization of DUSP6 in primary and recurrent patient samples and in parent and relapse populations of GBM cell lines generated from an in vitro radiation survival model. DUSP6 inhibition using BCI resulted in decreased proliferation and clonogenic survival of parent and relapse cells. Pharmacological or genetic inhibition of DUSP6 catalytic activity radiosensitized primary and, importantly, relapse GBM cells by inhibiting the recruitment of phosphorylated DNAPKcs (also known as PRKDC), subsequently downregulating the recruitment of phosphorylated histone H2AX (γH2AX) and 53BP1 (also known as TP53BP1). This resulted in decreased cell survival and prolonged growth arrest upon irradiation in vitro and significantly increased the progression-free survival in orthotopic mouse models of GBM. Our study highlights a non-canonical function of DUSP6, emphasizing the potential application of DUSP6 inhibitors in the treatment of recurrent GBM.
    MeSH term(s) Animals ; Brain Neoplasms/genetics ; Cell Line, Tumor ; DNA ; DNA Breaks, Double-Stranded ; DNA-Activated Protein Kinase ; Dual Specificity Phosphatase 6 ; Glioblastoma/genetics ; Glioblastoma/radiotherapy ; Humans ; Mice ; Radiation Tolerance/genetics
    Chemical Substances DNA (9007-49-2) ; DNA-Activated Protein Kinase (EC 2.7.11.1) ; PRKDC protein, human (EC 2.7.11.1) ; DUSP6 protein, human (EC 3.1.3.48) ; Dual Specificity Phosphatase 6 (EC 3.1.3.48)
    Language English
    Publishing date 2021-12-15
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2993-2
    ISSN 1477-9137 ; 0021-9533
    ISSN (online) 1477-9137
    ISSN 0021-9533
    DOI 10.1242/jcs.259520
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