Publications by authors named "Mamta Gupta"

97 Publications

Mantle cell lymphoma polarizes tumor-associated macrophages into M2-like macrophages, which in turn promote tumorigenesis.

Blood Adv 2021 Jul;5(14):2863-2878

Department of Biochemistry and Molecular Medicine.

Tumor-associated macrophages (TAMs) are recognized as a hallmark of certain solid cancers and predictors of poor prognosis; however, the functional role of TAMs in lymphoid malignancies, including B-cell lymphoma, has not been well defined. We identified infiltration of F4/80+ TAMs in a syngeneic mouse model using the recently generated murine mantle cell lymphoma (MCL) cell line FC-muMCL1. Multicolor flow cytometric analysis of syngeneic lymphoma tumors showed distinct polarization of F4/80+ TAMs into CD206+ M2 and CD80+ M1 phenotypes. Using human MCL cell lines (Mino, Granta, and JVM2), we further showed that MCL cells polarized monocyte-derived macrophages toward an M2-like phenotype, as assessed by CD163+ expression and increased interleukin-10 (IL-10) level; however, levels of the M1 markers CD80 and IL-12 remained unaffected. To show that macrophages contribute to MCL tumorigenesis, we xenografted the human MCL cell line Mino along with CD14+ monocytes and compared tumor growth between these 2 groups. Results showed that xenografted Mino along with CD14+ monocytes significantly increased the tumor growth in vivo compared with MCL cells alone (P < .001), whereas treatment with liposomal clodronate (to deplete the macrophages) reversed the effect of CD14+ monocytes on growth of MCL xenografts (P < .001). Mechanistically, IL-10 secreted by MCL-polarized M2-like macrophages was found to be responsible for increasing MCL growth by activating STAT1 signaling, whereas IL-10 neutralizing antibody or STAT1 inhibition by fludarabine or STAT1 short hairpin RNA significantly abolished MCL growth (P < .01). Collectively, our data show the existence of a tumor microenvironmental network of macrophages and MCL tumor and suggest the importance of macrophages in interventional therapeutic strategies against MCL and other lymphoid malignancies.
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http://dx.doi.org/10.1182/bloodadvances.2020003871DOI Listing
July 2021

Premature adult mortality in India: what is the size of the matter?

BMJ Glob Health 2021 06;6(6)

Gender research project, International Institute for Population Sciences, Mumbai, Maharashtra, India.

Background: Reducing adult mortality by 2030 is a key component of the United Nations Sustainable Development Goals (UNSDGs). Monitoring progress towards these goals requires timely and reliable information on deaths by age, sex and cause. To estimate baseline measures for UNSDGs, this study aimed to use several different data sources to estimate subnational measures of premature adult mortality (between 30 and 70 years) for India in 2017.

Methods: Age-specific population and mortality data were accessed for India and its 21 larger states from the Civil Registration System and Sample Registration System for 2017, and the most recent National Family and Health Survey. Similar data on population and deaths were also procured from the Global Burden of Disease Study 2016 and the National Burden of Disease Estimates Study for 2017. Life table methods were used to estimate life expectancy and age-specific mortality at national and state level from each source. An additional set of life tables were estimated using an international two-parameter model life table system. Three indicators of premature adult mortality were derived by sex for each location and from each data source, for comparative analysis RESULTS: Marked variations in mortality estimates from different sources were noted for each state. Assuming the highest mortality level from all sources as the potentially true value, premature adult mortality was estimated to cause a national total of 2.6 million male and 1.8 million female deaths in 2017, with Bihar, Maharashtra, Tamil Nadu, Uttar Pradesh and West Bengal accounting for half of these deaths. There was marked heterogeneity in risk of premature adult mortality, ranging from 351 per 1000 in Kerala to 558 per 1000 in Chhattisgarh among men, and from 198 per 1000 in Himachal Pradesh to 409 per 1000 in Assam among women.

Conclusions: Available data and estimates for mortality measurement in India are riddled with uncertainty. While the findings from this analysis may be useful for initial subnational health policy to address UNSDGs, more reliable empirical data is required for monitoring and evaluation. For this, strengthening death registration, improving methods for cause of death ascertainment and establishment of robust mortality statistics programs are a priority.
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http://dx.doi.org/10.1136/bmjgh-2020-004451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211056PMC
June 2021

Vegetative Insecticidal Protein (Vip): A Potential Contender From for Efficient Management of Various Detrimental Agricultural Pests.

Front Microbiol 2021 13;12:659736. Epub 2021 May 13.

ICAR-National Institute for Plant Biotechnology, New Delhi, India.

() bacterium is found in various ecological habitats, and has natural entomo-pesticidal properties, due to the production of crystalline and soluble proteins during different growth phases. In addition to Cry and Cyt proteins, this bacterium also produces Vegetative insecticidal protein (Vip) during its vegetative growth phase, which is considered an excellent toxic candidate because of the difference in sequence homology and receptor sites from Cry proteins. Vip proteins are referred as second-generation insecticidal proteins, which can be used either alone or in complementarity with Cry proteins for the management of various detrimental pests. Among these Vip proteins, Vip1 and Vip2 act as binary toxins and have toxicity toward pests belonging to Hemiptera and Coleoptera orders, whereas the most important Vip3 proteins have insecticidal activity against Lepidopteran pests. These Vip3 proteins are similar to Cry proteins in terms of toxicity potential against susceptible insects. They are reported to be toxic toward pests, which can't be controlled with Cry proteins. The Vip3 proteins have been successfully pyramided along with Cry proteins in transgenic rice, corn, and cotton to combat resistant pest populations. This review provides detailed information about the history and importance of Vip proteins, their types, structure, newly identified specific receptors, and action mechanism of this specific class of proteins. Various studies conducted on Vip proteins all over the world and the current status have been discussed. This review will give insights into the significance of Vip proteins as alternative promising candidate toxic proteins from for the management of pests in most sustainable manner.
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http://dx.doi.org/10.3389/fmicb.2021.659736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158940PMC
May 2021

Comparing pattern of musculoskeletal injuries prior to and during COVID-19 lockdown: A time-trend case study from a tertiary level Trauma Center of Northern India.

J Family Med Prim Care 2021 Jan 30;10(1):427-431. Epub 2021 Jan 30.

Lead Epidemiologist, Division of Epidemiology and Biostatistics, Alchemist Research and Data Analysis, Chandigarh, India.

Background And Aims: In the COVID-19 times, Indian sub-continent is struggling to contain the epidemic and trying to strengthen the existing health infrastructure, the national level lockdown has raised concerns about the pattern of injuries whether it has remained the same or has changed over this period. This is the first study to compare injury pattern during the two months lockdown period with the data of corresponding months from years 2016-2020. Also we compared the age- and sex-wise distribution patterns of these injuries for the above mentioned period.

Methods: This retrospective cross sectional study was conducted by the Department of Orthopaedics in Guru Gobind Singh Medical College and Hospital (GGSMCH) in Faridkot, Punjab. Secondary data for patient's age and sex, mode of injury, and site of injury was collected through record review for the period of two months (24 March to 24 May) for five consecutive years of 2016-2020. Descriptive analysis and Chi-square test was used to see the association between age and sex with mode and type of injury.

Results: The five year injury trends reflected that the proportion of injuries in 2016 was 16.5% ( = 48) of the total musculoskeletal injuries ( = 291) which rose to 23.4% ( = 68) in 2020. Majority of the patients were males (80%), and belonged to adult age group (69.4%) followed by elderly (17.2%), adolescents (8.6%) and children (4.8%). The proportion of road traffic accidents out of all injuries significantly reduced during the lock down period of two months in 2020 ( = 0.001). On the contrary, the proportion of injuries due to falls as well as unspecified assault increased significantly in 2020 as compared to previous years.

Conclusions: The proportion of musculoskeletal injuries have increased from 2016-2020. Unspecified assault and all types of falls pushed the road traffic accidents to third position during the lockdown period in 2020 as compared to previous four years. Injury surveillance needs to be integrated in routine hospital system for precise information and for more efficient functioning.
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http://dx.doi.org/10.4103/jfmpc.jfmpc_1595_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132754PMC
January 2021

JAK2 activation promotes tumorigenesis in ALK-negative anaplastic large cell lymphoma via regulating oncogenic STAT1-PVT1 lncRNA axis.

Blood Cancer J 2021 Mar 12;11(3):56. Epub 2021 Mar 12.

Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, GW Cancer Center, Washington, DC, USA.

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http://dx.doi.org/10.1038/s41408-021-00447-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955124PMC
March 2021

Comparative evaluation of intracranial oligodendroglioma and astrocytoma of similar grades using conventional and T1-weighted DCE-MRI.

Neuroradiology 2021 Aug 19;63(8):1227-1239. Epub 2021 Jan 19.

Department of Radiology, Fortis Memorial Research Institute, Sector 44, Gurgaon, Haryana, 122002, India.

Purpose: This retrospective study was performed on a 3T MRI to determine the unique conventional MR imaging and T1-weighted DCE-MRI features of oligodendroglioma and astrocytoma and investigate the utility of machine learning algorithms in their differentiation.

Methods: Histologically confirmed, 81 treatment-naïve patients were classified into two groups as per WHO 2016 classification: oligodendroglioma (n = 16; grade II, n = 25; grade III) and astrocytoma (n = 10; grade II, n = 30; grade III). The differences in tumor morphology characteristics were evaluated using Z-test. T1-weighted DCE-MRI data were analyzed using an in-house built MATLAB program. The mean 90th percentile of relative cerebral blood flow, relative cerebral blood volume corrected, volume transfer rate from plasma to extracellular extravascular space, and extravascular extracellular space volume values were evaluated using independent Student's t test. Support vector machine (SVM) classifier was constructed to differentiate two groups across grade II, grade III, and grade II+III based on statistically significant features.

Results: Z-test signified only calcification among conventional MR features to categorize oligodendroglioma and astrocytoma across grade III and grade II+III tumors. No statistical significance was found in the perfusion parameters between two groups and its subtypes. SVM trained on calcification also provided moderate accuracy to differentiate oligodendroglioma from astrocytoma.

Conclusion: We conclude that conventional MR features except calcification and the quantitative T1-weighted DCE-MRI parameters fail to discriminate between oligodendroglioma and astrocytoma. The SVM could not further aid in their differentiation. The study also suggests that the presence of more than 50% T2-FLAIR mismatch may be considered as a more conclusive sign for differentiation of IDH mutant astrocytoma.
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http://dx.doi.org/10.1007/s00234-021-02636-8DOI Listing
August 2021

Cytomorphological pattern analysis of tubercular lymphandenopathies.

Indian J Tuberc 2020 Oct 13;67(4):495-501. Epub 2020 Jul 13.

Department of Pathology, Subharti Medical College, Swami Vivekanand Subharti University, Meerut, India.

Background: The spectrum of morphological pattern in tubercular lymphandenopathies was observed to study the various cytomorphological patterns and their correlation with acid fast bacilli.

Methods: FNAC smears of 210 cases of granulomatous lymphadenitis stained with Giemsa, Pap and haematoxylin and eosin were used to analyze cytomorphological pattern and Zeihl Neelsen stained smears for acid fast bacilli (AFB) detection.

Results: 193 cases with necrotising granulomatous inflammation or positive acid fast bacilli were included. Age group 21-30 years was most common (38.3%) followed by age group 11-20 years (30.05%). Females constituted 66.3% of patients and 33.7% were male. Overall the most common pattern in present study was pattern A (Epitheloid granuloma with caseous necrosis 33.7% followed by pattern B (caseous necrosis with few scattered epitheloid histiocytes and lymphocytes) 31.1% and pattern C (caseous necrosis with suppurative inflammation) 30.6%, followed by pattern D (Caseous necrosis only) (3.6%) and pattern E (non necrotising epitheloid granuloma with positive acid fast bacilli) (1.03%). Acid fast bacilli were demonstrable in 175 cases (90.7%). Amongst the acid fast bacilli positive cases highest bacillary load 3+ grade was seen in pattern C in 6/59 (10.16%) cases.

Conclusion: FNAC is a simple useful tool and should be attempted in all cases of lymphandenopathies. It helps in establishing a diagnosis of tubercular etiology based on its morphological patterns however demonstration of acid fast bacilli on aspirated material confirms the diagnosis.
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http://dx.doi.org/10.1016/j.ijtb.2020.07.001DOI Listing
October 2020

Diagnostic Accuracy in Assessment of Depth of Myometrial Invasion in Low-grade Endometrioid Carcinoma: A 2 Center Comparative Study by MRI and Intraoperative Assessment.

Int J Gynecol Pathol 2020 Sep 4. Epub 2020 Sep 4.

Departments of Gynaecology (R.N., H.N.) Pathology (W.G.M.), Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts (T.P., M.G.).

The role of lymphadenectomy in endometrial carcinomas is controversial, especially in low-grade endometrioid carcinomas. In many institutions, lymphadenectomy in the latter neoplasms is undertaken only when there is deep myometrial invasion, defined as invasion involving 50% or more of the myometrium (FIGO stage IB). There has been considerable debate as to the best modality to detect deep myometrial invasion. In Europe, preoperative magnetic resonance imaging (MRI) is the most commonly used modality while in North America, intraoperative assessment (IOA) is undertaken in most, but not all, institutions. The aim of this study was to compare the diagnostic accuracy of these 2 modalities in identifying deep myometrial invasion in low-grade endometrioid carcinomas. Two patient cohorts were studied from Belfast, UK (n=253) and Boston, USA (n=276). With respect to detecting deep myometrial invasion, MRI had a sensitivity of 72.84%, positive predictive value of 75.64% and a positive likelihood ratio of 6.59 (95% confidence interval; 4.23-10.28). IOA had a sensitivity of 78.26%, positive predictive value of 80% and a positive likelihood ratio of 20.00 (95% confidence interval; 10.35-38.63). The superior positive likelihood ratio suggests that IOA is better than MRI in determining deep myometrial invasion and the nonoverlapping 95% confidence intervals suggest this is a significant finding. However, there are significant resource implications associated with IOA and preoperative MRI carries other advantages that are discussed herein.
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http://dx.doi.org/10.1097/PGP.0000000000000703DOI Listing
September 2020

Deregulation of Polycomb Repressive Complex-2 in Mantle Cell Lymphoma Confers Growth Advantage by Epigenetic Suppression of .

Front Oncol 2020 24;10:1226. Epub 2020 Jul 24.

Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, GW Cancer Center, Washington, DC, United States.

The polycomb repressive complex 2 (PRC2) maintains the transcriptional repression of target genes through its catalytic component enhancer of zeste homolog 2 (EZH2). Through modulating critical gene expression, EZH2 also plays a role in cancer development and progression by promoting cancer cell survival and invasion. Mutations in EZH2 are prevalent in certain B-cell lymphoma subtypes such as diffuse large cell lymphoma and follicular lymphoma; while no EZH2 mutation has been reported in the mantle cell lymphoma (MCL). Here we demonstrate that the PRC2 components EZH2, EED and SUZ12 are upregulated in the MCL cells as compared to normal B-cells. Moreover, stably transfected cells with wild-type EZH2 or-EED showed increased cell growth and H3K27-trimehtylation. However, unlike wild-type EZH2, ectopic expression of a deletion construct of EZH2 (EZH2 lacking SET domain) had no growth advantage over control cells. Pharmacological inhibition of EZH2 suppressed H3K27me3 and had significant inhibitory effect on cell growth and colony forming capacity ( < 0.05) of MCL cells, and this effect was more or less comparable to the anti-proliferative effects of EZH2 inhibition in cells harboring EZH2-mutation. Mechanistically, EZH2 appears to downregulate expression of gene via enhanced H3K27me3, a well-known suppressive epigenetic mark, at the promoter region. Overall, these results highlight that deregulation of PRC2/EZH2 is associated with epigenetic suppression of in MCL, and in part responsible for increased cell growth, thus the EZH2 inhibitors may have therapeutic potential in the patients with MCL.
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http://dx.doi.org/10.3389/fonc.2020.01226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396700PMC
July 2020

The civil registration system is a potentially viable data source for reliable subnational mortality measurement in India.

BMJ Glob Health 2020 08;5(8)

Alchemist Research and Data Analysis, Chandigarh, India.

Introduction: The Indian national Civil Registration System (CRS) is the optimal data source for subnational mortality measurement, but is yet under development. As an alternative, data from the Sample Registration System (SRS), which covers less than 1% of the national population, is used. This article presents a comparison of mortality measures from the SRS and CRS in 2017, and explores the potential of the CRS to meet these subnational data needs.

Methods: Data on population and deaths by age and sex for 2017 from each source were used to compute national-level and state-level life tables. Sex-specific ratios of death probabilities in five age categories (0-4, 5-14, 15-29, 30-69, 70-84) were used to evaluate CRS data completeness using SRS probabilities as reference values. The quality of medically certified causes of death was assessed through hospital reporting coverage and proportions of deaths registered with ill-defined causes from each state.

Results: The CRS operates through an extensive infrastructure with high reporting coverage, but child deaths are uniformly under-reported, as are female deaths in many states. However, at ages 30-69 years, CRS death probabilities are higher than the SRS values in 15 states for males and 10 states for females. SRS death probabilities are of limited precision for measuring mortality trends and differentials. Data on medically certified causes of death are of limited use due to low hospital reporting coverage.

Conclusions: The Indian CRS is more reliable than the SRS for measuring adult mortality in several states. Targeted initiatives to improve the recording of child and female deaths, to strengthen the reporting and quality of medically certified causes of death, and to promote use of verbal autopsy methods can establish the CRS as a reliable source of subnational mortality statistics in the near future.
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http://dx.doi.org/10.1136/bmjgh-2020-002586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430426PMC
August 2020

Introgression of productivity enhancing traits, resistance to pod borer and Phytopthora stem blight from to cultivated pigeonpea.

Physiol Mol Biol Plants 2020 Jul 5;26(7):1399-1410. Epub 2020 Jun 5.

Department of Plant Breeding and Genetics, Punjab Agricultural University, Ludhiana, 141004 India.

The study aimed at introgression of productivity enhancing traits and resistance to pod borer and Phytophthora stem blight from wild to cultivated pigeonpea through an inter-specific cross between (ICP 15683) and (ICPL 20329). Progenies derived from the direct segregating (without backcross) population and backcross population were evaluated for yield and yield contributing traits namely fruiting branches and pods plant and 100-seed weight. Introgressed progenies having higher fruiting branches, pods and yield plant compared to the cultivated parent were identified in both populations. A few progenies with significantly shorter plant height, early flowering and early maturity as compared to both cultivated and wild parents were also recovered in both populations. Progenies from both the populations were identified with higher resistance to pod borer and Phytophthora stem blight. However, some introgressed progenies having lower seed weight and seeds per pod were also recovered. The promising progenies are currently being used in the breeding programme to develop cultivars with improved productivity and resistance to pod borer and Phytophthora stem blight.
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http://dx.doi.org/10.1007/s12298-020-00827-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326853PMC
July 2020

Bromodomain Epigenetic Protein Promotes Metastatic Potential in Melanoma Cells through Increased Invasiveness and Decreased Macrophage-Mediated Phagocytosis.

J Invest Dermatol 2021 Feb 6;141(2):454-458.e2. Epub 2020 Jul 6.

Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, George Washington University, GW Cancer Center, Washington, District of Columbia, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2020.06.016DOI Listing
February 2021

Appropriateness evaluation of Drug Information Center's Facebook page for evidence-based drug information dissemination.

J Am Pharm Assoc (2003) 2020 Nov - Dec;60(6):e129-e132. Epub 2020 Apr 17.

Objective: To assess the characteristics of an unpaid Facebook page for drug information (DI) and its reachability to users.

Methods: In this retrospective observational study over a 6-month duration, a Facebook page for the DI Center was created. One drug-related clinical question recently asked in the DI Center by a hospital clinician and its evidence-based answer along with the appropriate references were framed in a scenario and posted on the Facebook page on working days. The Facebook page likes, consumption, reach, engagement, impressions, and total number of followers were obtained from Facebook insights. The monthly averages of these parameters were assessed using the augmented Dickey-Fuller (ADF) test.

Results: The cointegration (ADF) test revealed a statistically significant time-dependent correlation trend between the mean engaged users and mean monthly reach (ADF, -4.904; P = 0.01). Similarly, a statistically significant time-dependent correlation trend was observed with mean engaged users and mean monthly impressions (ADF, -5.456; P = 0.01).

Conclusion: The knowledge gap between quality DI and evidence-based medicine practice in a developing country can be bridged with a novel DI Center Facebook page initiative.
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http://dx.doi.org/10.1016/j.japh.2020.03.018DOI Listing
June 2021

Urothelial Carcinoma of the Bladder With a Rare Solitary Metastasis to the Ovary.

Urology 2020 Jan 7;135:24-27. Epub 2019 Aug 7.

Department of Surgery, Division of Urology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. Electronic address:

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http://dx.doi.org/10.1016/j.urology.2019.07.028DOI Listing
January 2020

Evaluation of Gall Bladder Stones Using Susceptibility Weighted Imaging.

J Comput Assist Tomogr 2019 Sep/Oct;43(5):747-754

Philips India Limited, Gurgaon, India.

Objective: To evaluate the visualization of gallbladder stones on susceptibility-weighted imaging (SWI).

Materials And Methods: Imaging data from 47 patients who underwent clinically indicated cholecystectomy was reviewed. Breath-hold SWI was added to the magnetic resonance imaging protocol and magnitude and phase data was reviewed for gall-stones visualization. Phase signature, that is, diamagnetic, paramagnetic, or mixed, was also noted in the stones. Magnetic susceptibility value of surgically extracted gallstones were imaged ex vivo (n = 37).

Results: In 45 of 47 cases, gallstones were surgically confirmed. In 43 cases, gallstones were visualized in the SWI. In 1 case, although routine imaging failed, stones were visualized on SWI. In 29 diamagnetic, 7 paramagnetic and 9 cases mixed phase were seen. In an ex vivo study, magnetic susceptibility of stones was found ranging between -0.102 and -0.916 ppm for diamagnetic and 0.203 and 486 ppm for paramagnetic stones.

Conclusions: Gallbladder stones can be visualized with SWI and may be added to the routine magnetic resonance imaging protocol for its evaluation.
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http://dx.doi.org/10.1097/RCT.0000000000000906DOI Listing
October 2019

Targeting MYC activity in double-hit lymphoma with MYC and BCL2 and/or BCL6 rearrangements with epigenetic bromodomain inhibitors.

J Hematol Oncol 2019 07 9;12(1):73. Epub 2019 Jul 9.

Department of Hematology, Mayo Clinic, Rochester, MN, USA.

Double/triple-hit lymphomas (DHL/THL) account for 5-10% of diffuse large B cell lymphoma (DLBCL) with rearrangement of MYC and BCL2 and/or BCL6 resulting in MYC overexpression. Despite the poor prognosis of DHL, R-CHOP chemotherapy remains the treatment backbone and new targeted therapy is needed. We performed comprehensive cytogenetic studies/fluorescence in situ hybridization on DLBCL and Burkitt lymphoma cell lines (n = 11) to identify the DHL/THL DLBCL in vitro model. We identified MYC/IG in Raji and Ramos (single hit); MYC/IG-BCL2 (DHL) in DOHH2, OCI-LY1, SUDHL2, and OCI-LY10; MYC/IG-BCL2/BCL6 (THL) in VAL; and no MYC rearrangement in U2932 and HBL1 (WT-MYC). Targeting MYC in the DHL/THL DLBCLs through bromodomain extra-terminal inhibitors (BETi) (JQ1, I-BET, and OTX015) significantly (p < 0.05) reduced proliferation, similar to WT-MYC cells, accompanied by decreased MYC but not BCL2 protein. Moreover, BETi suppressed MYC transcription and decreased BRD4 binding to MYC promoter in DHL cells. CD47 and PD-L1 are immunoregulatory molecules often expressed on tumors and regulated by MYC. High levels of surface CD47 but not surface PD-L1 was observed in DHL/THL, which was reduced by JQ1 treatment. BETi in combination with Pan-HDAC inhibitor had a limited effect on survival of DHL/THL, while combination of BETi and BCL2 inhibitor (ABT-199) had a significant (p < 0.005) inhibitory effect on survival followed by BCL-XL inhibition. Overall, the data suggests that MYC-expressing DLBCLs are probably addicted to the MYC-oncogenic effect regardless of MYC rearrangements. In summary, we identified an in vitro model for DHL/THL DLBCLs and provide evidence for the therapeutic potential of BET inhibitor alone or in combination with BCL2 inhibitor.
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http://dx.doi.org/10.1186/s13045-019-0761-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617630PMC
July 2019

RNA m6A methyltransferase METTL3 regulates invasiveness of melanoma cells by matrix metallopeptidase 2.

Melanoma Res 2019 08;29(4):382-389

Department of Biochemistry and Molecular Medicine, School of Medicine and Health Sciences, George Washington University.

The development of immunotherapy has improved the treatment of melanoma; however, resistance and frequent recurrence persist and remain a major problem. N-methyladenosine (mA) is the most abundant epitranscriptomic mark on mRNA and is essential for various physiological processes; however, its role in melanoma is unknown. Utilizing human normal melanocyte and melanoma cell lines, we analyzed the expression of METTL3 by quantitative RT-PCR. We inhibited the METTL3 expression by shRNA and analyzed the effects on melanoma cell proliferation, colony formation ability, and invasion. Finally, we assessed the role of METTL3 by using wild-type and mA catalytic site mutant METTL3. Melanoma cell lines express higher levels of METTL3, as compared with normal melanocytes. Interestingly, silencing of METTL3 gene expression in melanoma cells resulted in decreased mA activity, colony formation and invasiveness, while its overexpression led to increased mA activity, colony formation and invasion. METTL3 overexpression promotes accumulation of MMP2 and N-cadherin in melanoma cells. Strikingly, the overexpression of mA catalytic site mutant METTL3 was unable to produce a similar increase in MMP2 expression, suggesting that mA activity of METTL3 is important for melanoma cell invasiveness. Our results for the first time uncover the role of mA modification in melanoma cell biology. We show that METTL3 is upregulated in human melanoma and plays a role in invasion/migration through MMP2. These findings provide the framework for the development and use of METTL3 inhibitors in melanoma treatment.
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http://dx.doi.org/10.1097/CMR.0000000000000580DOI Listing
August 2019

Prognostic and therapeutic significance of phosphorylated STAT3 and protein tyrosine phosphatase-6 in peripheral-T cell lymphoma.

Blood Cancer J 2018 11 12;8(11):110. Epub 2018 Nov 12.

Division of Hematology, Department of Internal-Medicine Mayo Clinic, Rochester, MN, 55905, USA.

Peripheral T cell lymphomas (PTCL) is a heterogenous group of non-Hodgkin lymphoma and many patients remain refractory to the frontline therapy. Identifying new prognostic markers and treatment is an unmet need in PTCL. We analyzed phospho-STAT3 (pSTAT3) expression in a cohort of 169 PTCL tumors and show overall 38% positivity with varied distribution among PTCL subtypes with 27% (16/59) in PTCL-NOS; 29% (11/38) in AITL, 57% (13/28) in ALK-negative ALCL, and 93% in ALK-pos ALCL (14/15), respectively. Correlative analysis indicated an adverse correlation between pSTAT3 and overall survival (OS). PTPN6, a tyrosine phosphatase and potential negative regulator of STAT3 activity, was suppressed in 62% of PTCL-NOS, 42% of AITL, 60% ALK-neg ALCL, and 86% of ALK-pos ALCL. Loss of PTPN6 combined with pSTAT3 positivity predicted an infwere considered significantferior OS in PTCL cases. In vitro treatment of TCL lines with azacytidine (aza), a DNA methyltransferase inhibitor (DNMTi), restored PTPN6 expression and decreased pSTAT3. Combining DNMTi with JAK3 inhibitor resulted in synergistic antitumor activity in SUDHL1 cell line. Overall, our results suggest that PTPN6 and activated STAT3 can be developed as prognostic markers, and the combination of DNMTi and JAK3 inhibitors as a novel treatment for patients with PTCL subtypes.
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http://dx.doi.org/10.1038/s41408-018-0138-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232096PMC
November 2018

Anti-Inflammatory Drug Use and Ovarian Cancer Risk by COX1/COX2 Expression and Infiltration of Tumor-Associated Macrophages.

Cancer Epidemiol Biomarkers Prev 2018 12 30;27(12):1509-1517. Epub 2018 Oct 30.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

Background: Nonsteroidal anti-inflammatory drug (NSAID) use may affect ovarian cancer risk via prostaglandin synthesis and tumor-associated macrophage (TAM) infiltration. We evaluated if associations between aspirin or non-aspirin NSAID use and ovarian cancer risk differed by tumor expression of prostaglandin-related (COX1, COX2) and TAM-related (CD68, CD163) markers.

Methods: We evaluated cases and matched controls from the Nurses' Health Study (NHS), NHSII, and New England Case-Control Study (NECC). Cases with IHC data on COX1 and COX2 ( = 532) or CD68 and CD163 ( = 530) were included. We used polytomous logistic regression, adjusted for ovarian cancer risk factors, to estimate OR for NSAID use and ovarian cancer risk by marker level.

Results: Recent aspirin use had a nonsignificant inverse association and recent non-aspirin NSAID use had no association with ovarian cancer risk. NSAID use was not differentially associated with ovarian cancer by COX1 or COX2 expression. However, recent aspirin use was associated with lower ovarian cancer risk for high [OR 0.54; 95% confidence interval (CI), 0.37-0.78], but not low (OR 1.50; 95% CI, 0.97-2.31), CD163 density ( < 0.001). Similar results were observed for aspirin duration and tablets and for recent non-aspirin NSAID use. Results were not clearly different by macrophage density defined by the less specific macrophage marker, CD68.

Conclusions: NSAID use was inversely associated with risk of ovarian cancer with high density CD163, a marker for M2-type, immunosuppressive macrophages. However, the relationship did not differ by prostaglandin synthesis markers.

Impact: Future research should explore prostaglandin-independent mechanisms for the association between NSAID use and ovarian cancer risk, including immune mechanisms.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-0346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6415678PMC
December 2018

Production of Deuterated Cyanidin 3--Glucoside from Recombinant .

ACS Omega 2018 Sep 24;3(9):11643-11648. Epub 2018 Sep 24.

Department of Chemical and Biological Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180, United States.

Anthocyanins are plant secondary metabolites that, despite their chemical instability, have found many applications as natural food colorants. They are also known for their beneficial health effects because of their antioxidant and anticancer properties. More stable versions of these molecules, particularly at neutral pH conditions, are required to study the anthocyanin pharmacokinetic properties and obtain effective therapeutic results. In the present report, a cost-effective technique was developed to prepare the deuterated anthocyanin using recombinant as a production host and deuterated glycerol and DO in the culture media. This approach resulted in the formation of endogenous deuterated uridine 5'-diphosphate-glucose that was further incorporated by the recombinant anthocyanin pathway, resulting in the formation of deuterated cyanidin 3--glucoside (C3G). The deuterium exchange of O-D and C-D were studied by liquid chromatography (LC)-mass spectrometry and NMR analysis. The labeled C3G, purified by high-performance LC showed a stable nature at pH 7.0 as compared to nondeuterated C3G.
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http://dx.doi.org/10.1021/acsomega.8b01134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173498PMC
September 2018

Metabolic engineering of Corynebacterium glutamicum for anthocyanin production.

Microb Cell Fact 2018 Sep 14;17(1):143. Epub 2018 Sep 14.

Department of Chemical and Biological Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, 12180, USA.

Background: Anthocyanins such as cyanidin 3-O-glucoside (C3G) have wide applications in industry as food colorants. Their current production heavily relies on extraction from plant tissues. Development of a sustainable method to produce anthocyanins is of considerable interest for industrial use. Previously, E. coli-based microbial production of anthocyanins has been investigated extensively. However, safety concerns on E. coli call for the adoption of a safe production host. In the present study, a GRAS bacterium, Corynebacterium glutamicum, was introduced as the host strain to synthesize C3G. We adopted stepwise metabolic engineering strategies to improve the production titer of C3G.

Results: Anthocyanidin synthase (ANS) from Petunia hybrida and 3-O-glucosyltransferase (3GT) from Arabidopsis thaliana were coexpressed in C. glutamicum ATCC 13032 to drive the conversion from catechin to C3G. Optimized expression of ANS and 3GT improved the C3G titer by 1- to 15-fold. Further process optimization and improvement of UDP-glucose availability led to ~ 40 mg/L C3G production, representing a > 100-fold titer increase compared to production in the un-engineered, un-optimized starting strain.

Conclusions: For the first time, we successfully achieved the production of the specialty anthocyanin C3G from the comparatively inexpensive flavonoid precursor catechin in C. glutamicum. This study opens up more possibility of C. glutamicum as a host microbe for the biosynthesis of useful and value-added natural compounds.
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http://dx.doi.org/10.1186/s12934-018-0990-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138892PMC
September 2018

Social autopsy for identifying causes of adult mortality.

PLoS One 2018 31;13(5):e0198172. Epub 2018 May 31.

School of Public Health, Post Graduate Institute of Medical Education & Research, Chandigarh, India.

Verbal autopsy methods have been developed to determine medical causes of deathforprioritizing disease control programs. Additional information on social causesmay facilitate designing of more appropriate prevention strategies. Use of social autopsy in investigations of causes of adult deaths has been limited. Therefore, acommunity-based study was conducted in NandpurKalour Block of Fatehgarh Sahib District in Punjab (India)for finding social causes of adult deaths. An integrated verbal and social autopsy toolwas developed and verbal autopsies of 600 adult deaths, occurring over a reference period of one year, were conducted in 2014. Quantitative analysis described the socio-demographic characteristics of the deceased, number and type of consultations from health care providers, and type of care received during illness. Qualitative data was analyzed to find out social causes of death by thematic analysis. The median duration of illness from symptom onset till death was 9 days (IQR = 1-45 days). At the onset of illness, 72 (12%) deceased utilized home remedies and 424 (70.7%)received care from a clinic/hospital, and 104 (17.3%) died withoutreceiving any care. The number of medical consultations varied from one to six (median = 2). The utilization of government health facilities and qualified allopathic doctor increased with each consultation (p value<0.05). The top five social causes of adult deaths in a rural area of Punjab in India. (1) Non availability of medical practitioner in the vicinity, (2) communication gaps between doctor and patient on regular intake of medication, (3) delayed referral by service provider, (4) poor communication with family on illness, and (5) perception of illness to be 'mild' by the family or care taker. To conclude, social autopsy tool should be integrated with verbal autopsy tool for identification of individual, community, and health system level factors associated with adult mortality.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198172PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5978887PMC
November 2018

Assessment of a Chemotherapy Response Score (CRS) System for Tubo-Ovarian High-Grade Serous Carcinoma (HGSC).

Int J Gynecol Pathol 2019 May;38(3):230-240

Department of Pathology, Women's and Perinatal Pathology Division (H.M.D., K.C.S., E.E.M., W.R.W., M.S.H., B.J.Q., K.R.L., C.P.C., G.L.M., M.R.N., B.E.H.) Division of Gynecologic Oncology and Reproductive Biology (M.G.M., J.F.L., C.F., N.H., R.S.B.), Brigham and Women's Hospital Department of Pathology, Beth Israel Deaconess Medical Center (M.G., J.L.H., D.I.L.) Medical Gynecologic Oncology Program, Dana-Farber Cancer Institute (E.S., P.A.K., U.A.M.), Harvard Medical School, Boston, Massachusetts Department of Pathology, Duke University Medical Center, Durham, North Carolina (K.C.S.) Department of Gynecology and Obstetrics, Odense University Hospital, University of Southern Denmark, Odense, Denmark (K.M.J.) Department of Pathology, Stanford University, Stanford, California (B.E.H.).

A chemotherapy response score (CRS) system was recently described to assess the histopathologic response and prognosis of patients with tubo-ovarian high-grade serous carcinoma (HGSC) receiving neoadjuvant chemotherapy. The current study was performed as an independent assessment of this CRS system. We retrospectively identified advanced stage HGSC patients who received neoadjuvant chemotherapy and underwent interval debulking. If available, a hemotoxylin and eosin slide from the omentum and the adnexa was selected for the study. Slides were independently scored by 13 pathologists using the 3-tiered CRS system. Reviewers then received web-based training and rescored the slides. Overall survival and progression-free survival were estimated using the Kaplan-Meier method and compared using the log-rank test. A total of 68 patients with omental (n=65) and/or adnexal (n=59) slides were included in the study. Interobserver reproducibility was moderate for omentum (κ, 0.48) and poor for adnexa (κ, 0.40), which improved for omentum (κ, 0.62) but not for adnexa (κ, 0.38) after online training. For omental slides, a consensus CRS of 1/2 was associated with a shorter median progression-free survival (10.9 mo; 95% confidence interval, 9-14) than a CRS of 3 (18.9 mo; 95% CI, 18-24; P=0.020). In summary, a 3-tiered CRS system of hemotoxylin and eosin-stained omental deposits can yield prognostic information for HGSC patients receiving neoadjuvant chemotherapy, and web-based training improved reproducibility but did not alter determination of clinical outcomes. The CRS system may allow oncologists to identify potential nonresponders and triage HGSC patients for heightened observation and/or clinical trials.
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http://dx.doi.org/10.1097/PGP.0000000000000513DOI Listing
May 2019

Longitudinal changes in gray matter regions after cranial radiation and comparative analysis with whole body radiation: a DTI study.

Int J Radiat Biol 2018 06 27;94(6):532-541. Epub 2018 Apr 27.

a NMR Research Centre , Institute of Nuclear Medicine and Allied Sciences , Delhi , India.

Purpose: Radiation-induced white matter changes are well known and vastly studied. However, radiation-induced gray matter alterations are still a research question. In the present study, these changes were assessed in a longitudinal manner using Diffusion Tensor Imaging (DTI) and further compared for cranial and whole body radiation exposure.

Materials And Methods: Male mice (C57BL/6) were irradiated with cranial or whole body radiation followed by DTI study at 7T animal MRI system during predose, subacute and early delayed phases of radiation sickness. Fractional anisotropy (FA) and mean diffusivity (MD) values were obtained from brain's gray matter regions.

Results: Decreased FA with increased MD was observed prominently in animals exposed to cranial radiation showing most changes at 8 months post irradiation. However, whole body radiation induced FA changes were mostly observed at 1 month post irradiation as compared to controls.

Conclusions: The differential response after whole body and cranial irradiation observed in the study depicts that radiation exposure of 5 Gy could induce permanent alterations in gray matter regions prominently as observed in Caudoputamen region at all the time points. Thus, our study has bolstered the role of DTI to probe microstructural changes in gray matter regions of brain after radiation exposure.
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http://dx.doi.org/10.1080/09553002.2018.1466064DOI Listing
June 2018

Predictors of adverse outcome in uterine smooth muscle tumours of uncertain malignant potential (STUMP): a clinicopathological analysis of 22 cases with a proposal for the inclusion of additional histological parameters.

Histopathology 2018 Aug 21;73(2):284-298. Epub 2018 May 21.

Harvard Medical School, Boston, MA, USA.

Aims: The current World Health Organisation classification defines smooth muscle tumours of uncertain malignant potential (STUMPs) as neoplasms that cannot be diagnosed reliably as benign or malignant according to generally accepted criteria. This has led to the application of various sets of criteria; consequently, consistent and reliable outcome data are lacking. The aims of this study were: (i) to compare the frequency of adverse outcome in STUMP on the basis of enhanced criteria; and (ii) to perform failure analysis to identify feature(s) helpful in predicting outcome METHODS AND RESULTS: Cases of STUMP diagnosed between 1994 and 2009 were retrieved and follow-up data were collected. Morphological parameters were scored and correlated with outcome. Twenty-two subjects with a median follow-up of 74.5 months (range, 26-166 months) formed the study group. Their age ranged from 31.9 years to 51.8 years (median, 45.3 years). Sixteen subjects underwent hysterectomy and six underwent myomectomy. Adverse outcomes were noted in eight (36.4%) cases. In cases with adverse outcomes, notable features included moderate-severe nuclear atypia (seven), epithelioid features (one), infiltrative or irregular margins (five), atypical mitoses (two), and vascular intrusion (three) CONCLUSIONS: The frequency of adverse outcomes in our series (36.4%) was higher than that in previously published reports (7-26.7%), suggesting that the use of more stringent criteria can exclude some patients from further follow-up. Although 'significant' nuclear atypia was not discriminatory, its frequent association with adverse outcomes has pathobiological implications. The presence of necrosis was not particularly associated with adverse outcomes. Atypical mitoses, epithelioid differentiation, vascular involvement and infiltrative/irregular margins appear to herald adverse outcomes, and therefore merit inclusion in the diagnostic regimen.
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http://dx.doi.org/10.1111/his.13515DOI Listing
August 2018

Elevated GLI3 expression in germinal center diffuse large B cell lymphoma.

Leuk Lymphoma 2018 11 21;59(11):2743-2745. Epub 2018 Feb 21.

a Department of Molecular, Cellular and Biomedical Sciences , University of New Hampshire , Durham , NH , USA.

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http://dx.doi.org/10.1080/10428194.2018.1439169DOI Listing
November 2018

Epigenetic Reprogramming Strategies to Reverse Global Loss of 5-Hydroxymethylcytosine, a Prognostic Factor for Poor Survival in High-grade Serous Ovarian Cancer.

Clin Cancer Res 2018 03 20;24(6):1389-1401. Epub 2017 Dec 20.

Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

A major challenge in platinum-based cancer therapy is the clinical management of chemoresistant tumors, which have a largely unknown pathogenesis at the level of epigenetic regulation. We evaluated the potential of using global loss of 5-hydroxymethylcytosine (5-hmC) levels as a novel diagnostic and prognostic epigenetic marker to better assess platinum-based chemotherapy response and clinical outcome in high-grade serous tumors (HGSOC), the most common and deadliest subtype of ovarian cancer. Furthermore, we identified a targetable pathway to reverse these epigenetic changes, both genetically and pharmacologically. This study shows that decreased 5-hmC levels are an epigenetic hallmark for malignancy and tumor progression in HGSOC. In addition, global 5-hmC loss is associated with a decreased response to platinum-based chemotherapy, shorter time to relapse, and poor overall survival in patients newly diagnosed with HGSOC. Interestingly, the rescue of 5-hmC loss restores sensitivity to platinum chemotherapy and , decreases the percentage of tumor cells with cancer stem cell markers, and increases overall survival in an aggressive animal model of platinum-resistant disease. Consequently, a global analysis of patient 5-hmC levels should be included in future clinical trials, which use pretreatment with epigenetic adjuvants to elevate 5-hmC levels and improve the efficacy of current chemotherapies. Identifying prognostic epigenetic markers and altering chemotherapeutic regimens to incorporate DNMTi pretreatment in tumors with low 5-hmC levels could have important clinical implications for newly diagnosed HGSOC disease. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951622PMC
March 2018

Differential expression of c-Met between primary and metastatic sites in clear-cell renal cell carcinoma and its association with PD-L1 expression.

Oncotarget 2017 Nov 23;8(61):103428-103436. Epub 2017 Oct 23.

Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.

In preclinical models, c-Met promotes survival of renal cancer cells through the regulation of programmed death-ligand 1 (PD-L1). However, this relationship in human clear cell renal cell carcinoma (ccRCC) is not well characterized. We evaluated c-Met expression in ccRCC patients using paired primary and metastatic samples and assessed the association with PD-L1 expression and other clinical features. Areas with predominant and highest Fuhrman nuclear grade (FNG) were selected. c-Met expression was evaluated by IHC using an anti-Met monoclonal antibody (MET4 Ab) and calculated by a combined score (CS, 0-300): intensity of c-Met staining (0-3) x % of positive cells (0-100). PD-L1 expression in tumor cells was previously assessed by IHC and PD-L1+ was defined as PD-L1 > 0% positive cells. Our cohort consisted of 45 pairs of primary and metastatic ccRCC samples. Overall, c-Met expression was higher in metastatic sites compared to primary sites (average c-Met CS: 55 vs. 28, = 0.0003). Higher c-Met expression was associated with higher FNG (4 vs. 3) in primary tumors (average c-Met CS: 52 vs. 20, = 0.04). c-Met expression was numerically greater in PD-L1+ vs. PD-L1- tumors. Higher c-Met expression in metastatic sites compared to primary tumors suggests that testing for biomarkers of response to c-Met inhibitors should be conducted in metastases. While higher c-Met expression in PD-L1+ tumors requires further investigation, it supports exploring these targets in combination clinical trials.
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http://dx.doi.org/10.18632/oncotarget.21952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732739PMC
November 2017

Prediction of Delivery in Women with Threatening Preterm Labour using Phosphorylated Insulin-Like Growth Factor Binding Protein-1 and Cervical Length using Transvaginal Ultrasound.

J Clin Diagn Res 2017 Sep 1;11(9):QC01-QC04. Epub 2017 Sep 1.

Senior Specialist and Head, Department of Obstetrics and Gynaecology, Hindu Rao Hospital and Associated NDMC Medical College, Delhi, India.

Introduction: Preterm delivery remains a challenge in Obstetrics as it is responsible for significant cause of perinatal morbidity and mortality. At present there is no standard test for prediction of preterm labour for timely referral to a center with NICU facilities.

Aim: To evaluate the effectiveness of the cervical phosphorylated insulin like growth factor binding protein-1(phIGFBP-1), cervical length measurement and combination of phIGFBP-1 with cervical length for Predicting Preterm Labour (PTL).

Materials And Methods: It was a observational prospective study done from January 2014 to April 2015 in Department of Obstetrics and Gynaecology, NDMC Medical College and Hindu Rao Hospital, Delhi, India. A total of 100 women with singleton pregnancy, between 24 and 36 weeks of gestation with complaint of uterine contractions were randomly selected. These women were subjected to detect phIGFBP-1 in cervical secretions and cervical length measurement by Transvaginal Sonography (TVS). Result of the test, cervical length and time lapse between test and delivery was noted and the results were analysed. The cervical length less than 25 mm was used as a cut off point for predicting pre-term delivery. Data was analysed using SPSS software version 20.0.

Results: The Negative Predictive Value (NPV) of phIGFBP-1 and cervical length was similar (95.2% vs 94.05%) respectively for prediction of preterm labour within one week of admission and 93.92% vs 94.80% at 37 weeks of gestational age. Combined test had higher NPV of 96.38% at 34 weeks of gestation and 94% within two days of admission. Positive Predictive Value (PPV) was low for both the test and combining the two-test did not have any advantage as far as PPV was concerned. Receiver Operating Characteristic (ROC) curve showed that the combined test had a superior result in predicting PTL compared to either phIGFBP-1 or cervical length. The combined test had steepest ROC curve at < 34 weeks of gestation (AUC-0.83 with 95% CI).

Conclusion: The phIGFBP-1 test and cervical length have an almost equivalent ability to predict preterm delivery independently. The combined use of phIGFBP-1 and TVS for cervical length shows an increase in efficacy in predicting preterm labour.
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http://dx.doi.org/10.7860/JCDR/2017/28794.10585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5713804PMC
September 2017
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