Publications by authors named "Rohit Joshi"

76 Publications

Elucidating the Response of Crop Plants towards Individual, Combined and Sequentially Occurring Abiotic Stresses.

Int J Mol Sci 2021 Jun 6;22(11). Epub 2021 Jun 6.

Stress Physiology and Molecular Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India.

In nature, plants are exposed to an ever-changing environment with increasing frequencies of multiple abiotic stresses. These abiotic stresses act either in combination or sequentially, thereby driving vegetation dynamics and limiting plant growth and productivity worldwide. Plants' responses against these combined and sequential stresses clearly differ from that triggered by an individual stress. Until now, experimental studies were mainly focused on plant responses to individual stress, but have overlooked the complex stress response generated in plants against combined or sequential abiotic stresses, as well as their interaction with each other. However, recent studies have demonstrated that the combined and sequential abiotic stresses overlap with respect to the central nodes of their interacting signaling pathways, and their impact cannot be modelled by swimming in an individual extreme event. Taken together, deciphering the regulatory networks operative between various abiotic stresses in agronomically important crops will contribute towards designing strategies for the development of plants with tolerance to multiple stress combinations. This review provides a brief overview of the recent developments in the interactive effects of combined and sequentially occurring stresses on crop plants. We believe that this study may improve our understanding of the molecular and physiological mechanisms in untangling the combined stress tolerance in plants, and may also provide a promising venue for agronomists, physiologists, as well as molecular biologists.
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http://dx.doi.org/10.3390/ijms22116119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201344PMC
June 2021

WRKY transcription factors and plant defense responses: latest discoveries and future prospects.

Plant Cell Rep 2021 Jul 15;40(7):1071-1085. Epub 2021 Apr 15.

Division of Biotechnology, CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh, 176061, India.

Key Message: WRKY transcription factors are among the largest families of transcriptional regulators. In this review, their pivotal role in modulating various signal transduction pathways during biotic and abiotic stresses is discussed. Transcription factors (TFs) are important constituents of plant signaling pathways that define plant responses against biotic and abiotic stimuli besides playing a role in response to internal signals which coordinate different interacting partners during developmental processes. WRKY TFs, deriving their nomenclature from their signature DNA-binding sequence, represent one of the largest families of transcriptional regulators found exclusively in plants. By modulating different signal transduction pathways, these TFs contribute to various plant processes including nutrient deprivation, embryogenesis, seed and trichome development, senescence as well as other developmental and hormone-regulated processes. A growing body of research suggests transcriptional regulation of WRKY TFs in adapting plant to a variety of stressed environments. WRKY TFs can regulate diverse biological functions from receptors for pathogen triggered immunity, modulator of chromatin for specific interaction and signal transfer through a complicated network of genes. Latest discoveries illustrate the interaction of WRKY proteins with other TFs to form an integral part of signaling webs that regulate several seemingly disparate processes and defense-related genes, thus establishing their significant contributions to plant immune response. The present review starts with a brief description on the structural characteristics of WRKY TFs followed by the sections that present recent evidence on their roles in diverse biological processes in plants. We provide a comprehensive overview on regulatory crosstalks involving WRKY TFs during multiple stress responses in plants and future prospects of WRKY TFs as promising molecular diagnostics for enhancing crop improvement.
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http://dx.doi.org/10.1007/s00299-021-02691-8DOI Listing
July 2021

Female breast cancer treatment and survival in South Australia: Results from linked health data.

Eur J Cancer Care (Engl) 2021 Mar 28:e13451. Epub 2021 Mar 28.

Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia.

Objective: We investigated treatment and survival by clinical and sociodemographic characteristics for service evaluation using linked data.

Method: Data on invasive female breast cancers (n = 13,494) from the South Australian Cancer Registry (2000-2014 diagnoses) were linked to hospital inpatient, radiotherapy and universal health insurance data. Treatments ≤12 months from diagnosis and survival were analysed, using adjusted odds ratios (aORs) from logistic regression, and adjusted sub-hazard ratios (aSHRs) from competing risk regression.

Results And Conclusion: Five-year disease-specific survival increased to 91% for 2010-2014. Most women had breast surgery (90%), systemic therapy (72%) and radiotherapy (60%). Less treatment applied for ages 80+ vs <50 years (aOR 0.10, 95% CI 0.05-0.20) and TNM stage IV vs stage I (aOR 0.13, 95% CI 0.08-0.22). Surgical treatment increased during the study period and strongly predicted higher survival. Compared with no surgery, aSHRs were 0.31 (95% CI 0.26-0.36) for women having breast-conserving surgery, 0.49 (95% CI 0.41-0.57) for mastectomy and 0.42 (95% CI 0.33-0.52) when both surgery types were received. Patients aged 80+ years had lower survival and less treatment. More trial evidence is needed to optimise trade-offs between benefits and harms in these older women. Survival differences were not found by residential remoteness and were marginal by socioeconomic status.
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http://dx.doi.org/10.1111/ecc.13451DOI Listing
March 2021

Novel Application of Hot Melt Extrusion Technology for Preparation and Evaluation of Valacyclovir Hydrochloride Ocular Inserts.

AAPS PharmSciTech 2021 Jan 14;22(1):48. Epub 2021 Jan 14.

Department of Pharmaceutics and Drug Delivery, Pii Center for Pharmaceutical Technology, School of Pharmacy, University of Mississippi, University, Mississippi, 38677, USA.

The objective of this study was to investigate the processability of hot-melt extrusion (HME) to formulate ocular inserts of valacyclovir hydrochloride and evaluate the in vivo bioavailability of the formulation. To optimize the formulation of this drug, different physical mixtures of the polymers and plasticizer were prepared. The physical mixture was extruded through a co-rotating twin-screw extruder, and the obtained ocular inserts were cut with dimensions of 4 mm × 2 mm × 1 mm to enhance the formulation instillation in the eye. Ocular inserts were evaluated for drug content, weight variation, uniformity of thickness, in vitro drug release, and in vivo drug bioavailability. The ocular inserts were thermally characterized using differential scanning calorimetry (DSC). The attributes observed for the ocular inserts were within the target specifications. The ocular inserts of valacyclovir hydrochloride were successfully prepared using the HME. They provided sustained drug release along with enhanced drug permeation when compared with the eyedrop solution and dissolve completely in 8 h. Additionally, the obtained results demonstrated that the formulation of ocular inserts of valacyclovir hydrochloride using HME was reproducible, robust, and effective method.
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http://dx.doi.org/10.1208/s12249-020-01916-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886274PMC
January 2021

Sensing and signalling in plant stress responses: ensuring sustainable food security in an era of climate change.

New Phytol 2020 11;228(3):823-827

Centre for Plant Sciences, School of Biology, University of Leeds, Leeds, LS2 9JT, UK.

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http://dx.doi.org/10.1111/nph.16893DOI Listing
November 2020

Stacking for future: Pyramiding genes to improve drought and salinity tolerance in rice.

Physiol Plant 2021 Jun 21;172(2):1352-1362. Epub 2020 Nov 21.

Stress Physiology and Molecular Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.

Abiotic stresses, such as drought and salinity, adversely affect rice production and cause a severe threat to food security. Conventional crop breeding techniques alone are inadequate for achieving drought stress tolerance in crop plants. Using transgenic technology, incremental improvements in tolerance to drought and salinity have been successfully attained via manipulation of gene(s) in several crop species. However, achieving the goal via pyramiding multiple genes from the same or different tolerance mechanisms has received little attention. Pyramiding of multiple genes can be achieved either through breeding, by using marker-assisted selection, or by genetic engineering through molecular stacking co-transformation or re-transformation. Transgene stacking into a single locus has added advantages over breeding or re-transformation since the former assures co-inheritance of genes, contributing to more effective tolerance in transgenic plants for generations. Drought, being a polygenic trait, the potential candidate genes for gene stacking are those contributing to cellular detoxification, osmolyte accumulation, antioxidant machinery, and signaling pathways. Since cellular dehydration is inbuilt in salinity stress, manipulation of these genes results in improving tolerance to salinity along with drought in most of the cases. In this review, attempts have been made to provide a critical assessment of transgenic plants developed through transgene stacking and approaches to achieve the same. Identification and functional validation of more such candidate genes is needed for research programs targeting the gene stacking for developing crop plants with high precision in the shortest possible time to ensure sustainable crop productivity under marginal lands.
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http://dx.doi.org/10.1111/ppl.13270DOI Listing
June 2021

Curative therapy for rectal cancer.

Expert Rev Anticancer Ther 2021 Feb 8;21(2):193-203. Epub 2021 Jan 8.

Department of Medical Oncology, The Queen Elizabeth Hospital and University of Adelaide, Adelaide, Australia.

: A comprehensive trimodality approach has become the standard of care for patients with locally advanced rectal cancer. However, the sequencing and duration of chemotherapy and chemoradiotherapy around surgery varies between clinical studies and geographical regions. Growing evidence is also mounting for strategies such as total neoadjuvant therapy and non-operative management for carefully selected patients.: We provide a perspective review of the current evidence and controversies in the treatment of locally advanced rectal cancer including the recent updates from the 2020 ASCO annual conference.: With ongoing advances in the management of locally advanced rectal cancer, a multidisciplinary team approach is necessary as treatments could involve multiple approaches. Chemoradiotherapy whether short or long course followed by at least 3 months of systemic chemotherapy may be the preferred option to balance local and distant disease control. Albeit the choice of doublet or triplet chemotherapy is still controversial. As total neoadjuvant treatment becomes part of the standard of care in rectal cancer, modification of the surveillance schedule is needed to detect early recurrences which may be limited by resources and availability of services.
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http://dx.doi.org/10.1080/14737140.2021.1845145DOI Listing
February 2021

Health-related quality of life in patients with inoperable malignant bowel obstruction: secondary outcome from a double-blind, parallel, placebo-controlled randomised trial of octreotide.

BMC Cancer 2020 Oct 31;20(1):1050. Epub 2020 Oct 31.

IMPACCT, Faculty of Health, University of Technology, Ultimo, New South Wales, Australia.

Background: This analysis aims to evaluate health-related quality of life (HrQoL) (primary outcome for this analysis), nausea and vomiting, and pain in patients with inoperable malignant bowel obstruction (IMBO) due to cancer or its treatments randomised to standardised therapies plus octreotide or placebo over a maximum of 72 h in a double-blind clinical trial.

Methods: Adults with IMBO and vomiting recruited through 12 services spanning inpatient, consultative and community settings in Australia were randomised to subcutaneous octreotide infusion or saline. HrQoL was measured at baseline and treatment cessation (EORTC QLQ-C15-PAL). Mean within-group paired differences between baseline and post-treatment scores were analysed using Wilcoxon Signed Rank test and between group differences estimated using linear mixed models, adjusted for baseline score, sex, age, time, and study arm.

Results: One hundred six of the 112 randomised participants were included in the analysis (n = 52 octreotide, n = 54 placebo); 6 participants were excluded due to major protocol violations. Mean baseline HrQoL scores were low (octreotide 22.1, 95% CI 14.3, 29.9; placebo 31.5, 95% CI 22.3, 40.7). There was no statistically significant within-group improvement in the mean HrQoL scores in the octreotide (p = 0.21) or placebo groups (p = 0.78), although both groups reported reductions in mean nausea and vomiting (octreotide p < 0.01; placebo p = 0.02) and pain scores (octreotide p < 0.01; placebo p = 0.03). Although no statistically significant difference in changes in HrQoL scores between octreotide and placebo were seen, an adequately powered study is required to fully assess any differences in HrQoL scores.

Conclusion: The HrQoL of patients with IMBO and vomiting is poor. Further research to formally evaluate the effects of standard therapies for IMBO is therefore warranted.

Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12608000211369 (date registered 18/04/2008).
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http://dx.doi.org/10.1186/s12885-020-07549-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603764PMC
October 2020

Novel β-Coronavirus (SARS-CoV-2): Current and future aspects of pharmacological treatments.

Saudi Pharm J 2020 Oct 27;28(10):1243-1252. Epub 2020 Aug 27.

Biotechnology Division, Council of Scientific & Industrial Research-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh 176061, India.

The novel coronavirus outbreak has reported to be rapidly spreading across the countries and becomes a foremost community health alarm. At present, no vaccine or specific drug is on hand for the treatment of this infectious disease. This review investigates the drugs, which are being evaluated and found to be effective against nCOVID-19 infection. A thorough literature search was performedon the recently published research papers in between January 2020 to May 2020, through various databases like "Science Direct", "Google Scholar", "PubMed","Medline", "Web of Science", and "World Health Organization (WHO)". We reviewed and documented the information related with the current and future aspects for the management and cure of COVID-19. As of 21st July 2020 a total of 14,562,550 confirmed cases of coronavirus and 607,781 deaths have been reported world-wide. The main clinical feature of COVID-19 ranges from asymptomatic disease to mild lower respiratory tract illness to severe pneumonia, acute lung injury, acute respiratory distress syndrome (ARDS), multiple organ dysfunction, and death. The drugs at present used in COVID-19 patients and ongoing clinical trials focusing on drug repurposing of various therapeutic classes of drug e.g. antiviral, anti-inflammatory and/or immunomodulatory drugs along with adjuvant/supportive care. Many drugs on clinical trials shows effective results on preliminary scale and now used currently in patients. Adjuvant/supportive care therapy are used in patients to get the best results in order to minimize the short and long-term complications. However, further studies and clinical trials are needed on large scale of population to reach any firm conclusion in terms of its efficacy and safety.
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http://dx.doi.org/10.1016/j.jsps.2020.08.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449930PMC
October 2020

Sequential activation of Notch and Grainyhead gives apoptotic competence to Abdominal-B expressing larval neuroblasts in Drosophila Central nervous system.

PLoS Genet 2020 08 31;16(8):e1008976. Epub 2020 Aug 31.

Laboratory of Drosophila Neural Development, Centre for DNA Fingerprinting and Diagnostics (CDFD), Inner Ring Road, Uppal, Hyderabad, India.

Neural circuitry for mating and reproduction resides within the terminal segments of central nervous system (CNS) which express Hox paralogous group 9-13 (in vertebrates) or Abdominal-B (Abd-B) in Drosophila. Terminal neuroblasts (NBs) in A8-A10 segments of Drosophila larval CNS are subdivided into two groups based on expression of transcription factor Doublesex (Dsx). While the sex specific fate of Dsx-positive NBs is well investigated, the fate of Dsx-negative NBs is not known so far. Our studies with Dsx-negative NBs suggests that these cells, like their abdominal counterparts (in A3-A7 segments) use Hox, Grainyhead (Grh) and Notch to undergo cell death during larval development. This cell death also happens by transcriptionally activating RHG family of apoptotic genes through a common apoptotic enhancer in early to mid L3 stages. However, unlike abdominal NBs (in A3-A7 segments) which use increasing levels of resident Hox factor Abdominal-A (Abd-A) as an apoptosis trigger, Dsx-negative NBs (in A8-A10 segments) keep the levels of resident Hox factor Abd-B constant. These cells instead utilize increasing levels of the temporal transcription factor Grh and a rise in Notch activity to gain apoptotic competence. Biochemical and in vivo analysis suggest that Abdominal-A and Grh binding motifs in the common apoptotic enhancer also function as Abdominal-B and Grh binding motifs and maintains the enhancer activity in A8-A10 NBs. Finally, the deletion of this enhancer by the CRISPR-Cas9 method blocks the apoptosis of Dsx-negative NBs. These results highlight the fact that Hox dependent NB apoptosis in abdominal and terminal regions utilizes common molecular players (Hox, Grh and Notch), but seems to have evolved different molecular strategies to pattern CNS.
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http://dx.doi.org/10.1371/journal.pgen.1008976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485976PMC
August 2020

Role of glial niche in regulating neural stem cell proliferation in Drosophila central nervous system.

J Neurosci Res 2020 12 18;98(12):2373-2375. Epub 2020 Aug 18.

Centre for DNA Fingerprinting and Diagnostics, Uppal, Hyderabad, India.

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http://dx.doi.org/10.1002/jnr.24713DOI Listing
December 2020

Monitoring TNM stage of female breast cancer and survival across the South Australian population, with national and international TNM benchmarking: A population-based cohort study.

BMJ Open 2020 06 28;10(6):e037069. Epub 2020 Jun 28.

Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia.

Objective: Using linked cancer registry and administrative data to monitor, tumour, node and metastases (TNM) stage and survival from female breast cancer in Australia.

Method: Analysis of 2000-2014 diagnoses with linked population-based data to investigate: (1) sociodemographic predictors of advanced stage (stages III and IV), using unadjusted and adjusted logistic regression; and (2) sociodemographic factors and stage as predictors of breast cancer survival using competing risk regression.

Design: Population-based registry cohort.

Setting And Participants: 14 759 South Australian women diagnosed in 2000-2014.

Primary And Secondary Outcome Measures: Stage and survival.

Results: At diagnosis, 46% of women were classified as stage I, 39% as stage II, 12% as stage III and 4% as stage IV. After adjusting for sociodemographic factors, advanced stage was more common: (1) for ages <50 years; and although not statistically significant, for ages 80+ years; and (2) in women from socioeconomically disadvantaged areas. Compared with 2000-2004 diagnoses, stage and sociodemographic adjusted risks (sub-HRs (SHRs)) of breast cancer death were lower in 2005-2009 (SHR 0.75, 95% CI 0.67 to 0.83) and 2010-2015 (SHR 0.57, 95% CI 0.48 to 0.67). Compared with stage I, the SHR was 3.87 (95% CI 3.32 to 4.53) for stage II, 10.87 (95% CI 9.22 to 12.81) for stage III, and 41.97 (95% CI 34.78 to 50.65) for stage IV. Women aged 70+ years at diagnosis and those living in the most socioeconomically disadvantaged areas were at elevated risk of breast cancer death, independent of stage and sociodemographic factors.

Conclusions: Stage varied by age, diagnostic period and socioeconomic status, and was a stronger predictor of survival than other statistically significant sociodemographic predictors. Achieving earlier diagnosis outside the original BreastScreen target of 50-69 years (as applying <2014) and in residents of socioeconomically disadvantaged areas likely would increase cancer survival at a population level.
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http://dx.doi.org/10.1136/bmjopen-2020-037069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322288PMC
June 2020

Inferior vena cava thrombectomy following complete response to nivolumab/ipilimumab for metastatic renal cell carcinoma.

ANZ J Surg 2020 07 12;90(7-8):1517-1519. Epub 2019 Dec 12.

Department of Urology, Royal Adelaide Hospital, Adelaide, South Australia, Australia.

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http://dx.doi.org/10.1111/ans.15608DOI Listing
July 2020

Improving chemotherapy outcome in early breast cancer.

Gland Surg 2019 Oct;8(5):585-587

Department of Medical Oncology, Lyell McEwin Hospital, University of Adelaide, Adelaide, South Australia, Australia.

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http://dx.doi.org/10.21037/gs.2019.08.04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842769PMC
October 2019

Enhancing trehalose biosynthesis improves yield potential in marker-free transgenic rice under drought, saline, and sodic conditions.

J Exp Bot 2020 01;71(2):653-668

Plant Stress Biology, International Centre for Genetic Engineering and Biotechnology, New Delhi, India.

Edaphic factors such as salinity, sodicity, and drought adversely affect crop productivity, either alone or in combination. Despite soil sodicity being reported as an increasing problem worldwide, limited efforts have been made to address this issue. In the present study, we aimed to generate rice with tolerance to sodicity in conjunction with tolerance to salinity and drought. Using a fusion gene from E. coli coding for trehalose-6-phosphate synthase/phosphatase (TPSP) under the control of an ABA-inducible promoter, we generated marker-free, high-yielding transgenic rice (in the IR64 background) that can tolerate high pH (~9.9), high EC (~10.0 dS m-1), and severe drought (30-35% soil moisture content). The transgenic plants retained higher relative water content (RWC), chlorophyll content, K+/Na+ ratio, stomatal conductance, and photosynthetic efficiency compared to the wild-type under these stresses. Positive correlations between trehalose overproduction and high-yield parameters were observed under drought, saline, and sodic conditions. Metabolic profiling using GC-MS indicated that overproduction of trehalose in leaves differently modulated other metabolic switches, leading to significant changes in the levels of sugars, amino acids, and organic acids in transgenic plants under control and stress conditions. Our findings reveal a novel potential technological solution to tackle multiple stresses under changing climatic conditions.
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http://dx.doi.org/10.1093/jxb/erz462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946002PMC
January 2020

Time from diagnosis to treatment of colorectal cancer in a South Australian clinical registry cohort: how it varies and relates to survival.

BMJ Open 2019 09 30;9(9):e031421. Epub 2019 Sep 30.

Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia.

Objectives: Some early studies indicated lower survival with longer time from diagnosis to cancer treatment, but others showed the reverse. We investigated time to treatment of colorectal cancer and associations with survival.

Setting And Participants: Clinical registry data for colorectal cancer cases diagnosed in 2000-2010 at four major public hospitals in South Australia and treated by surgery (n=1675), radiotherapy (n=616) and/or systemic therapy (n=1556).

Design: A historic cohort design, with rank-order tests for ordinal clinical and sociodemographic predictors and multiple logistic regression for comparing time from diagnosis to treatment. Unadjusted Kaplan-Meier estimates and adjusted Cox proportional hazards regression were used to investigate disease-specific survival by time to treatment.

Outcome Measures: Time to treatment and survival from diagnosis to death from colorectal cancer.

Results: Treatment (any type) commenced for 87% of surgical cases 60 days of diagnosis, with 80% having surgery within this period. Of those receiving radiotherapy, 59% began this treatment 60 days, and of those receiving systemic therapy, the corresponding proportion was 56%. Adjusted analyses showed treatment delay >60 days was more likely for rectal cancers, 2006-2010 diagnoses, residents of northern than other metropolitan regions and for surgery, younger ages <50 years and unexpectedly, those residing closer to metropolitan services. Adjusting for clinical and sociodemographic factors, and diagnostic year, better survival occurred in 2 years from diagnosis for time to treatment >30 days. Survival in the 3-10 years postdiagnosis generally did not differ by time to treatment, except for lower survival for any treatment >90 days for surgical cases.

Conclusions: The lower survival 2 years from diagnosis for treatment 30 days of diagnosis is consistent with other studies attributed to preferencing more complicated cases for earlier care. Lower 3-10 years survival for surgical cases first treated >90 days from diagnosis is consistent with previously reported U-shaped relationships.
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http://dx.doi.org/10.1136/bmjopen-2019-031421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797269PMC
September 2019

The Hox gene uses Doublesex as a cofactor to promote neuroblast apoptosis in the central nervous system.

Development 2019 08 22;146(16). Epub 2019 Aug 22.

Laboratory of Drosophila Neural Development, Centre for DNA Fingerprinting and Diagnostics (CDFD), Inner Ring Road, Uppal, Hyderabad 500039, India

Highly conserved DM domain-containing transcription factors (Doublesex/MAB-3/DMRT1) are responsible for generating sexually dimorphic features. In the central nervous system, a set of Doublesex (Dsx)-expressing neuroblasts undergo apoptosis in females whereas their male counterparts proliferate and give rise to serotonergic neurons crucial for adult mating behaviour. Our study demonstrates that the female-specific isoform of Dsx collaborates with Hox gene () to bring about this apoptosis. Biochemical results suggest that proteins AbdB and Dsx interact through their highly conserved homeodomain and DM domain, respectively. This interaction is translated into a cooperative binding of the two proteins on the apoptotic enhancer in the case of females but not in the case of males, resulting in female-specific activation of apoptotic genes. The capacity of AbdB to use the sex-specific isoform of Dsx as a cofactor underlines the possibility that these two classes of protein are capable of cooperating in selection and regulation of target genes in a tissue- and sex-specific manner. We propose that this interaction could be a common theme in generating sexual dimorphism in different tissues across different species.
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http://dx.doi.org/10.1242/dev.175158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737903PMC
August 2019

CO uptake and chlorophyll a fluorescence of Suaeda fruticosa grown under diurnal rhythm and after transfer to continuous dark.

Photosynth Res 2019 Nov 17;142(2):211-227. Epub 2019 Jul 17.

Stress Physiology and Molecular Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.

Although only 2-4% of absorbed light is emitted as chlorophyll (Chl) a fluorescence, its measurement provides valuable information on photosynthesis of the plant, particularly of Photosystem II (PSII) and Photosystem I (PSI). In this paper, we have examined photosynthetic parameters of Suaeda fruticosa L. (family: Amaranthaceae), surviving under extreme xerohalophytic conditions, as influenced by diurnal rhythm or continuous dark condition. We report here CO gas exchange and the kinetics of Chl a fluorescence of S. fruticosa, made every 3 hours (hrs) for 3 days, using a portable infra-red gas analyzer and a Handy PEA fluorimeter. Our measurements on CO gas exchange show the maximum rate of photosynthesis to be at 08:00 hrs under diurnal condition and at 05:00 hrs under continuous dark. From the OJIP phase of Chl a fluorescence transient, we have inferred that the maximum quantum yield of PSII photochemistry must have increased during the night under diurnal rhythm, and between 11:00 and 17:00 hrs under constant dark. Overall, our study has revealed novel insights into how photosynthetic reactions are affected by the photoperiodic cycles in S. fruticosa under high salinity. This study has further revealed a unique strategy operating in this xero-halophyte where the repair mechanism for damaged PSII operates during the dark, which, we suggest, contributes to its ecological adaptation and ability to survive and reproduce under extreme saline, high light, and drought conditions. We expect these investigations to help in identifying key genes and pathways for raising crops for saline and dry areas.
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http://dx.doi.org/10.1007/s11120-019-00659-0DOI Listing
November 2019

Nivolumab-induced myocarditis complicated by complete atrioventricular block in a patient with metastatic non-small cell lung cancer.

BMJ Case Rep 2019 Jul 11;12(7). Epub 2019 Jul 11.

University of Adelaide School of Medicine, Adelaide, South Australia, Australia.

We report a case of a 74-year-old man who developed myocarditis complicated by atrioventricular (AV) block following two doses of nivolumab for the treatment of non-small cell lung cancer. A diagnosis of drug-induced acute myocarditis with complete AV block was considered on the basis of elevated troponin, new onset left ventricular (LV) systolic dysfunction, absence of acute myocardial infarction and some findings suggestive of myocarditis on cardiac magnetic resonance. The patient was commenced on glucocorticoids, perindopril and carvedilol. AV block and LV dysfunction persisted despite 2 weeks of treatment. He ultimately became hypotensive which prompted an implantation of a cardiac resynchronisation therapy pacemaker. Follow-up echocardiogram at 6 weeks showed resolution of LV systolic dysfunction. However, he continued to have AV block.
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http://dx.doi.org/10.1136/bcr-2019-229963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626443PMC
July 2019

Soft substrate maintains proliferative and adipogenic differentiation potential of human mesenchymal stem cells on long-term expansion by delaying senescence.

Biol Open 2019 Apr 25;8(4). Epub 2019 Apr 25.

Department of Chemical Engineering, Indian Institute of Technology Bombay (IITB), Mumbai 400076, India

Human mesenchymal stem cells (hMSCs), during expansion, gradually lose their distinct spindle morphology, self-renewal ability, multi-lineage differentiation potential and enter replicative senescence. This loss of cellular function is a major roadblock for clinical applications which demand cells in large numbers. Here, we demonstrate a novel role of substrate stiffness in the maintenance of hMSCs over long-term expansion. When serially passaged for 45 days from passage 3 to passage 18 on polyacrylamide gel of Young's modulus =5 kPa, hMSCs maintained their proliferation rate and showed nine times higher population doubling in comparison to their counterparts cultured on plastic Petri-plates. They did not express markers of senescence, maintained their morphology and other mechanical properties such as cell stiffness and cellular traction, and were significantly superior in adipogenic differentiation potential. These results were demonstrated in hMSCs from two different sources, umbilical cord and bone marrow. In summary, our result shows that a soft gel is a suitable substrate to maintain the stemness of mesenchymal stem cells. As preparation of polyacrylamide gel is a well-established, and well-standardized protocol, we propose that this novel system of cell expansion will be useful in therapeutic and research applications of hMSCs.
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http://dx.doi.org/10.1242/bio.039453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503999PMC
April 2019

Patterns of care for stage III non-small cell lung cancer in Australia.

Asia Pac J Clin Oncol 2019 Jun 14;15(3):93-100. Epub 2019 Mar 14.

St Vincent's Hospital and Kinghorn Cancer Centre, Darlinghurst, NSW, Australia.

Stage III non-small cell lung cancer (NSCLC) makes up a third of all NSCLC cases and is potentially curable. Despite this 5-year survival rates remain between 15% and 20% with chemoradiation treatment alone given with curative intent. With the recent exciting breakthroughs in immunotherapy use (durvalumab) for stage III NSCLC, further improvements in patient survival can be expected. Most patients with stage III NSCLC present initially to their general practitioner (GP). The recommended time from GP referral to first specialist appointment is less than 14 days with treatment initiated within 42 days. Our review found that there is a shortfall in meeting these recommendations, however a number of initiatives have been established in Australia to improve timely and accurate diagnosis and treatment patterns. The lung cancer multidisciplinary team (MDT) is critical to consistency of evidence-based diagnosis and treatment and can improve patient survival. We aimed to review current patterns of care and clinical practice recommendations for stage III NSCLC across Australia and identify opportunities to improve practice in referral, diagnosis and treatment pathways.
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http://dx.doi.org/10.1111/ajco.13140DOI Listing
June 2019

Transcriptional regulation of osmotic stress tolerance in wheat (Triticum aestivum L.).

Plant Mol Biol 2018 Aug 14;97(6):469-487. Epub 2018 Aug 14.

Guru Gobind Singh Indraprastha University, New Delhi, India.

Key Message: The current review provides an updated, new insights into the regulation of transcription mediated underlying mechanisms of wheat plants to osmotic stress perturbations. Osmotic stress tolerance mechanisms being complex are governed by multiple factors at physiological, biochemical and at the molecular level, hence approaches like "OMICS" that can underpin mechanisms behind osmotic tolerance in wheat is of paramount importance. The transcription factors (TFs) are a class of molecular proteins, which are involved in regulation, modulation and orchestrating the responses of plants to a variety of environmental stresses. Recent reports have provided novel insights on the role of TFs in osmotic stress tolerance via direct molecular links. However, our knowledge on the regulatory role TFs during osmotic stress tolerance in wheat remains limited. The present review in its first part sheds light on the importance of studying the role of osmotic stress tolerance in wheat plants and second aims to decipher molecular mechanisms of TFs belonging to several classes, including DREB, NAC, MYB, WRKY and bHLH, which have been reported to engage in osmotic stress mediated gene expression in wheat and third part covers the systems biology approaches to understand the transcriptional regulation of osmotic stress and the role of long non-coding RNAs in response to osmotic stress with special emphasis on wheat. The current concept may lead to an understanding in molecular regulation and signalling interaction of TFs under osmotic stress to clarify challenges and problems for devising potential strategies to improve complex regulatory events involved in plant tolerance to osmotic stress adaptive pathways in wheat.
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http://dx.doi.org/10.1007/s11103-018-0761-6DOI Listing
August 2018

An actin-depolymerizing factor from the halophyte smooth cordgrass, Spartina alterniflora (SaADF2), is superior to its rice homolog (OsADF2) in conferring drought and salt tolerance when constitutively overexpressed in rice.

Plant Biotechnol J 2019 01 28;17(1):188-205. Epub 2018 Jun 28.

School of Plant, Environmental and Soil Sciences, Louisiana State University Agricultural Center, Baton Rouge, LA, USA.

Actin-depolymerizing factors (ADFs) maintain the cellular actin network dynamics by regulating severing and disassembly of actin filaments in response to environmental cues. An ADF isolated from a monocot halophyte, Spartina alterniflora (SaADF2), imparted significantly higher level of drought and salinity tolerance when expressed in rice than its rice homologue OsADF2. SaADF2 differs from OsADF2 by a few amino acid residues, including a substitution in the regulatory phosphorylation site serine-6, which accounted for its weak interaction with OsCDPK6 (calcium-dependent protein kinase), thus resulting in an increased efficacy of SaADF2 and enhanced cellular actin dynamics. SaADF2 overexpression preserved the actin filament organization better in rice protoplasts under desiccation stress. The predicted tertiary structure of SaADF2 showed a longer F-loop than OsADF2 that could have contributed to higher actin-binding affinity and rapid F-actin depolymerization in vitro by SaADF2. Rice transgenics constitutively overexpressing SaADF2 (SaADF2-OE) showed better growth, relative water content, and photosynthetic and agronomic yield under drought conditions than wild-type (WT) and OsADF2 overexpressers (OsADF2-OE). SaADF2-OE preserved intact grana structure after prolonged drought stress, whereas WT and OsADF2-OE presented highly damaged and disorganized grana stacking. The possible role of ADF2 in transactivation was hypothesized from the comparative transcriptome analyses, which showed significant differential expression of stress-related genes including interacting partners of ADF2 in overexpressers. Identification of a complex, differential interactome decorating or regulating stress-modulated cytoskeleton driven by ADF isoforms will lead us to key pathways that could be potential target for genome engineering to improve abiotic stress tolerance in agricultural crops.
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http://dx.doi.org/10.1111/pbi.12957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330539PMC
January 2019

Phase IB/II Study of Second-Line Therapy with Panitumumab, Irinotecan, and Everolimus (PIE) in Wild-Type Metastatic Colorectal Cancer.

Clin Cancer Res 2018 08 8;24(16):3838-3844. Epub 2018 May 8.

The Queen Elizabeth Hospital, Adelaide, South Australia, Australia.

Inhibition of mTOR in addition to EGFR may overcome resistance to EGFR inhibitors in metastatic colorectal cancer (mCRC). This phase Ib/II study evaluated the safety and efficacy of the combination of irinotecan, panitumumab, and everolimus. Patients with exon 2 wild-type (WT) mCRC following failure of fluoropyrimidine-based therapy received i.v. irinotecan and panitumumab every 2 weeks, and everolimus orally throughout a 14-day cycle. The primary endpoint of the phase II study was response rate (RR). Secondary survival outcomes were calculated using the Kaplan-Meier method, and results were analyzed as intention to treat. A preplanned exploratory biomarker analysis was performed. Forty-nine patients were enrolled. Dose level 1 (irinotecan 200 mg/m, panitumumab 6 mg/kg, and everolimus 5 mg alternate day) was declared the MTD with no dose-limiting toxicities in six patients. Forty patients were treated at dose level 1: median age, 60 years (37-76); 65% male; 45% and 52.5%, respectively, with Eastern Cooperative Oncology Group values of 0/1. Median dose intensity was 85%. Grade 3 toxicities were diarrhea (23%), mucositis (18%), rash (13%), fatigue (8%), dehydration (5%), neutropenia (20%), febrile neutropenia (8%), hypomagnesemia (20%), and hypokalemia (8%). Grade 4 toxicities were hypomagnesemia (5%) and neutropenia (3%). RR was 48%, and stable disease was 43%. Median progression-free survival (PFS) was 5.6 months, and median overall survival (OS) was 10.8 months. Twenty-five patients were WT and had an RR of 60%, median PFS of 6.4 months, and OS of 11.8 months. The toxicity of the panitumumab, irinotecan, and everolimus regimen is as expected and manageable. The RR of 60% in all WT supports further study of this combination. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3590DOI Listing
August 2018

Understanding the regulation of neural stem cell proliferation in Drosophila central nervous system.

J Neurosci Res 2018 06 25;96(6):1119-1120. Epub 2018 Mar 25.

Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India.

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http://dx.doi.org/10.1002/jnr.24234DOI Listing
June 2018

Engineering abiotic stress response in plants for biomass production.

J Biol Chem 2018 04 16;293(14):5035-5043. Epub 2018 Jan 16.

From the Stress Physiology and Molecular Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India,

One of the major challenges in today's agriculture is to achieve enhanced plant growth and biomass even under adverse environmental conditions. Recent advancements in genetics and molecular biology have enabled the identification of a complex signaling network contributing toward plant growth and development on the one hand and abiotic stress response on the other hand. As an outcome of these studies, three major approaches have been identified as having the potential to improve biomass production in plants under abiotic stress conditions. These approaches deal with having changes in the following: (i) plant-microbe interactions; (ii) cell wall biosynthesis; and (iii) phytohormone levels. At the same time, employing functional genomics and genetics-based approaches, a very large number of genes have been identified that play a key role in abiotic stress tolerance. Our Minireview is an attempt to unveil the cross-talk that has just started to emerge between the transcriptional circuitries for biomass production and abiotic stress response. This knowledge may serve as a valuable resource to eventually custom design the crop plants for higher biomass production, in a more sustainable manner, in marginal lands under variable climatic conditions.
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http://dx.doi.org/10.1074/jbc.TM117.000232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892563PMC
April 2018

Combinatorial action of Grainyhead, Extradenticle and Notch in regulating Hox mediated apoptosis in Drosophila larval CNS.

PLoS Genet 2017 Oct 12;13(10):e1007043. Epub 2017 Oct 12.

Laboratory of Drosophila Neural Development, Centre for DNA Fingerprinting and Diagnostics (CDFD), Tuljaguda Complex, Nampally, Hyderabad, India.

Hox mediated neuroblast apoptosis is a prevalent way to pattern larval central nervous system (CNS) by different Hox genes, but the mechanism of this apoptosis is not understood. Our studies with Abdominal-A (Abd-A) mediated larval neuroblast (pNB) apoptosis suggests that AbdA, its cofactor Extradenticle (Exd), a helix-loop-helix transcription factor Grainyhead (Grh), and Notch signaling transcriptionally contribute to expression of RHG family of apoptotic genes. We find that Grh, AbdA, and Exd function together at multiple motifs on the apoptotic enhancer. In vivo mutagenesis of these motifs suggest that they are important for the maintenance of the activity of the enhancer rather than its initiation. We also find that Exd function is independent of its known partner homothorax in this apoptosis. We extend some of our findings to Deformed expressing region of sub-esophageal ganglia where pNBs undergo a similar Hox dependent apoptosis. We propose a mechanism where common players like Exd-Grh-Notch work with different Hox genes through region specific enhancers to pattern respective segments of larval central nervous system.
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http://dx.doi.org/10.1371/journal.pgen.1007043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5667929PMC
October 2017

Female breast cancer management and survival: The experience of major public hospitals in South Australia over 3 decades-trends by age and in the elderly.

J Eval Clin Pract 2017 Dec 8;23(6):1433-1443. Epub 2017 Oct 8.

Haematology and Medical Oncology, The Queen Elizabeth Hospital, Woodville, South Australia, Australia.

Background: Clinical registry data from major South Australian public hospitals were used to investigate trends in invasive breast-cancer treatment and survival by age.

Methods: Disease-specific survival was calculated for the 1980 to 2013 diagnostic period using Kaplan-Meier product-limit estimates, with a censoring of live cases on December 31, 2014. Cox proportional hazards regression was used to examine differences in survival by age and tumour characteristic. First-round treatments following diagnosis were analysed, using multiple logistic regression to adjust for confounding.

Results: Five-year survival increased from 75% in the 1980s to 87% in 2000 to 2013, consistent with national trends, and with increases occurring irrespective of age. There was an increased use of breast conserving surgery, radiotherapy, chemotherapy, and hormone treatments. Five-year survival was lower for women aged 80+ years, increasing from 65% in the 1980s to 74% in 2000 to 2013. Lower survival in these older women persisted after adjusting for TNM stage, other clinical variables, and diagnostic year, without evidence of a reduced disparity over time. Older women were less likely to have surgery, radiotherapy, and chemotherapy throughout 1980 to 2013. By comparison, their use of hormone therapy was elevated. The adjusted relative odds of mastectomy (as opposed to breast conserving surgery) were lower for the 80+ year age range.

Conclusions: Breast-cancer survival increases applied to all ages, including 80+ years, but poorer outcomes persisted in this older group and the gap did not reduce. A key question is whether the best trade-off now exists between optimally therapeutic cancer treatment and accommodations for frailty and co-morbidity in the aged, or whether opportunities exist for better trade-offs and better survival. Local registry data are important for describing local service activity and outcomes by age for local service providers, health administrations and consumer groups; monitoring disparities; and indicating effects of local initiatives.
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http://dx.doi.org/10.1111/jep.12819DOI Listing
December 2017

Overview of Methods for Assessing Salinity and Drought Tolerance of Transgenic Wheat Lines.

Methods Mol Biol 2017 ;1679:83-95

Stress Physiology and Molecular Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, Delhi, India.

Salinity and drought are interconnected, causing phenotypic, physiological, biochemical, and molecular changes in a cell. These stresses are the major factors adversely affecting growth and productivity in cereals. Genetic engineering methods have advanced to enable development of genotypes with improved salinity and drought tolerance. The resulting transgenic plant produces a group of progenies which includes moderate to high-stress tolerant transgenic lines. Development of reproducible screening methods to identify high-stress tolerant germplasm under laboratory, greenhouse, or field conditions is must. Further, field level demonstration of improved phenotypes and yield under salinity and drought stress conditions is both challenging and expensive. Fast and efficient screening techniques that could be used to screen transgenic lines under greenhouse conditions, for salt and drought stress tolerance, may contribute toward the identification of promising lines for field conditions. This chapter provides information on various approaches which can be developed during different stages of plant development for selecting salinity and drought tolerant plants in cereals, especially wheat.
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http://dx.doi.org/10.1007/978-1-4939-7337-8_5DOI Listing
May 2018

A pragmatic, phase III, multisite, double-blind, placebo-controlled, parallel-arm, dose increment randomised trial of regular, low-dose extended-release morphine for chronic breathlessness: Breathlessness, Exertion And Morphine Sulfate (BEAMS) study protocol.

BMJ Open 2017 Jul 17;7(7):e018100. Epub 2017 Jul 17.

Discipline, Palliative and Supportive Services, Flinders University, Adelaide, Australia.

Introduction: Chronic breathlessness is highly prevalent and distressing to patients and families. No medication is registered for its symptomatic reduction. The strongest evidence is for regular, low-dose, extended- release (ER) oral morphine. A recent large phase III study suggests the subgroup most likely to benefit have chronic obstructive pulmonary disease (COPD) and modified Medical Research Council breathlessness scores of 3 or 4. This protocol is for an adequately powered, parallel-arm, placebo-controlled, multisite, factorial, block-randomised study evaluating regular ER morphine for chronic breathlessness in people with COPD.

Methods And Analysis: The primary question is what effect regular ER morphine has on worst breathlessness, measured daily on a 0-10 numerical rating scale. Uniquely, the coprimary outcome will use a FitBit to measure habitual physical activity. Secondary questions include safety and, whether upward titration after initial benefit delivers greater net symptom reduction. Substudies include longitudinal driving simulation, sleep, caregiver, health economic and pharmacogenetic studies. Seventeen centres will recruit 171 participants from respiratory and palliative care. The study has five phases including three randomisation phases to increasing doses of ER morphine. All participants will receive placebo or active laxatives as appropriate. Appropriate statistical analysis of primary and secondary outcomes will be used.

Ethics And Dissemination: Ethics approval has been obtained. Results of the study will be submitted for publication in peer-reviewed journals, findings presented at relevant conferences and potentially used to inform registration of ER morphine for chronic breathlessness.

Trial Registration Number: NCT02720822; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2017-018100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5726102PMC
July 2017