Publications by authors named "Saad Malik"

31 Publications

Overexpression of SlGSNOR impairs in vitro shoot proliferation and developmental architecture in tomato but confers enhanced disease resistance.

J Plant Physiol 2021 Jun 30;261:153433. Epub 2021 Apr 30.

Department of Plant Breeding and Genetics, Faculty of Crop and Food Sciences, PMAS Arid Agriculture University Rawalpindi, Rawalpindi, 46300, Pakistan. Electronic address:

The pervasive presence of nitric oxide (NO) in cells and its role in modifying cystein residues through protein S-nitrosylation is a remarkable redox based signalling mechanism regulating a variety of cellular processes. S-NITROSOGLUTATHIONE REDUCTASE (GSNOR) governs NO bioavailability by the breakdown of S-nitrosoglutathione (GSNO), fine-tunes NO signalling and controls total cellular S-nitrosylated proteins. Most of the published data on GSNOR functional analysis is based on the model plant Arabidopsis with no previous report for its effect on in vitro regeneration of tissue cultured plants. Moreover, the effect of GSNOR overexpression (O.E) on tomato growth, development and disease resistance remains enigmatic. Here we show that SlGSNOR O.E in tomato alters multiple developmental programs from in vitro culture establishment to plant growth and fruit set. Moreover, constitutive SlGSNOR O.E in tomato showed enhanced resistance against early blight (EB) disease caused by Alternaria solani and reduction in hypersensitive response (HR)-mediated cell death after Pseudomonas syringae pv. tomato DC3000 (Pst DC3000) infiltrations. High GSNOR transcript levels led to the inhibition of in vitro shoot proliferation in transformed explants as revealed by the fluorescence microscopy after YFP labelling. Transgenic tomato lines overexpressing SlGSNOR showed defective phenotypes exhibiting stunted plant growth and bushy-type plants due to loss of apical dominance, along with reduced seed germination and delayed flowering. Furthermore, SlGSNOR O.E plants exhibited altered leaf arrangement, fruit shape and modified locules number in tomato fruit. These findings give a novel insight into a multifaceted regulatory role of SlGSNOR in tomato plant development, reproduction and response to pathogens.
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http://dx.doi.org/10.1016/j.jplph.2021.153433DOI Listing
June 2021

A Systematic Review and Network Meta-analysis of Randomized Data on Efficacy of Novel Therapy Combinations in Patients with Lenalidomide-refractory Multiple Myeloma.

Clin Lymphoma Myeloma Leuk 2021 Mar 26. Epub 2021 Mar 26.

Division of Hematologic Malignancies and Cellular Therapeutics, The University of Kansas Medical Center, Kansas City, KS.

Introduction: Lenalidomide use in nearly all induction regimens for multiple myeloma (MM) has led to the treatment of lenalidomide-refractory disease becoming one of the most important clinical questions in its treatment. Given the lack of direct comparisons of treatment regimens for lenalidomide-refractory MM, we used a systematic review to identify randomized controlled trials (RCTs) that included lenalidomide-refractory subgroup analysis.

Methods: We performed a systematic review to identify RCTs for MM that enrolled patients with lenalidomide-refractory disease, then performed a network meta-analysis (NMA) using random effects model to compare regimens.

Results: We identified 123 discrete RCTs, of which 7 reported primary outcomes for lenalidomide-refractory MM. These were linked in 2 discrete networks totaling 1698 lenalidomide-refractory patients. Network 1 compared bortezomib (bort)/dexamethasone (dex) versus other treatments, and analysis showed triplet therapy with pomalidomide (pom)/bort/dex (hazard ratios [HR] 0.65, 95% confidence interval [CI], 0.50-0.84), daratumumab (dara)/bort/dex (HR 0.36, 95% CI, 0.21-0.63), and dara/carfilzomib (carf)/dex (HR 0.38, 95% CI, 0.21-0.69) as more effective than bort/dex. Network 2 compared dex versus other treatments, and analysis showed pom/dex (HR 0.50, 95% CI, 0.40-0.62), isatuximab (isa)/pom/dex (HR 0.30, 95% CI, 0.20-0.44), and elotuzumab (elo)/pom/dex (HR 0.27, 95% CI, 0.16-0.45) as more effective than dex. Within each network, monoclonal antibody (mAb)-containing regimens had lower HRs and higher P-scores than non-mAb regimens, indicating higher likelihood of these regimens being most efficacious.

Conclusion: The results of our NMA demonstrated that for lenalidomide-refractory MM, triplet therapy containing mAbs are superior. There is need for further RCTs to better ascertain the best standard of care for these patients.
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http://dx.doi.org/10.1016/j.clml.2021.03.006DOI Listing
March 2021

Comparative palynology and taxonomic implication of Jasminum L. (Oleaceae) species from Pakistan on the bases of scanning electron microscopy.

Microsc Res Tech 2021 Apr 21. Epub 2021 Apr 21.

Department of Plant Sciences, College of Agricultural and Environmental Sciences, University of California Davis, Davis, California, USA.

Jasminum L. is the largest genus containing ~200 species found wild mostly in the tropical regions of the world. The comparative palynological study of nine Pakistani Jasminum species with SEM showed zonocolpus, trilobate, and tricolpus pollen types with simple endocolpus apertures which are plesiomorphic and conserved in the Jasminum species. The equatorial pollen view was prolate, subprolate, and perprolate with elliptic, lobate, subcircular whereas polar view was subtriangular in all species. Few characters were specific to some species like heteropolarity in Jasminum grandiflorum and foveolate exine ornamentation with rounded heterobrochate in Jasminum angulare whereas reticulate and angular homobrochate character was common in other species. The UPGMA dendrogram based on qualitative characters did not support the phylogenetic classification of the genus Jasminum as these are highly conserved. The quantitative data showed more variation in some characters whereas few characters showed little or no variation. A greater variation in pollen size was observed among the variants of same species, for example, Jasminum humile showed highly variable polar length and equatorial diameter as compared to other species. Minimum variation was observed in colpus length which divided all species in to two groups. The large lumina were specific to Jasminum nitidum and broader muri was the prominent characteristic of Jasminum angulare. Some species like Jasminum sambac and Jasminum azoricum were unable to develop true pollen due to structural or functional disabilities. So, the quantitative characters of pollen are only suitable for palynological based grouping of Jasminum species but less suitable to infer their evolutionary relationship.
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http://dx.doi.org/10.1002/jemt.23787DOI Listing
April 2021

Incidence and Management of Carfilzomib-induced Cardiovascular Toxicity; A Systematic Review and Meta-analysis.

Cardiovasc Hematol Disord Drug Targets 2021 Apr 11. Epub 2021 Apr 11.

Hematology, Oncology, Stem Cell Transplantation, Myeloma program, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH. United States.

Background: The ASPIRE and ENDEAVOUR trials have shown cardiovascular adverse effects in patients treated with carfilzomib-based regimens. Therefore, we conducted this meta-analysis of published clinical trials to identify the cumulative incidence and risk of cardiovascular adverse effects due to carfilzomib.

Methods: A systematic search of PubMed, Embase, Web of Science, and Cochrane library was performed, and we identified 45 prospective trials of carfilzomib with data on 5583 patients. Among all patients being treated with carfilzomib (N=5,583), 8.9% sustained all grade cardiotoxicity, while 4.4% sustained high-grade cardiotoxicity. All-grade hypertension was present in 13.2%, while the incidence of high-grade hypertension was 5.3%.

Result: The observed incidences of all-grade heart failure, edema, and ischemia were 5.1%, 20.7%, and 4.6% respectively. Likewise, for high-grade heart failure and edema observed incidence was 3.2%, and 2.7% respectively. There was no difference in the event rate of all and high-grade cardiotoxicity between newly diagnosed multiple myeloma and relapsed/refractory (p-value 0.42 and 0.86 respectively). Likewise, we did not observe any difference in the event rate of all and high-grade cardiotoxicity when carfilzomib was used as a single agent versus when used in combination therapy with other agents (p-value 0.43 and 0.73 respectively).

Conclusion: Carfilzomib is associated with a significant risk of cardiovascular toxicity and hypertension. With the increasing utilization of carfilzomib, it is critical for primary care physicians, oncologists and cardiologists to be aware of the risk of cardiotoxicity associated with the use of carfilzomib to recognize and treat baseline cardiovascular risk factors in such patients.
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http://dx.doi.org/10.2174/1871529X21666210412113017DOI Listing
April 2021

Emphysematous Gastritis in a Transplant Recipient With Infection.

ACG Case Rep J 2020 Dec 8;7(12):e00488. Epub 2020 Dec 8.

Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.

is a rare infection in poorly controlled diabetic patients with a history of gastroparesis. We present the first documented case in a transplant recipient, who underwent a simultaneous liver kidney transplant. Computed tomography showed emphysematous gastritis, endoscopy revealed gastric necrosis, and microscopy confirmed the diagnosis. Operative intervention was high risk, given the previous liver transplant. Antibiotics and proton pump inhibitor treatment with repeat endoscopy at 4 days showed resolution of gastric necrosis and elimination of microscopic evidence of infection. Combination antibiotic and proton pump inhibitor therapy may be an effective treatment for this rare, life-threatening infection.
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http://dx.doi.org/10.14309/crj.0000000000000488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725253PMC
December 2020

Using oral anticoagulants among chronic kidney disease patients to prevent recurrent venous thromboembolism: A systematic review and meta-analysis.

Thromb Res 2021 02 2;198:103-114. Epub 2020 Dec 2.

Department of Internal Medicine, Marshall University, Huntington, WV, United States of America.

Introduction: Chronic kidney disease (CKD) increases the risk of venous thromboembolism (VTE) among affected patients. Vitamin K antagonists (VKA) and warfarin remains the main stay of its treatment. Due to novelty and unclear risk-to-benefit ratio of direct oral anti-coagulants (DOAC), they remain underutilized in preventing VTE among CKD patients. We aim to assess the efficacy and safety of DOACs and other oral anticoagulants in preventing recurrent VTE among high-risk population.

Material Methods: We conducted a literature search using PubMed, Embase, Cochrane, Web of Science and Clinicaltrials.gov for randomized controlled trials (RCTs) comparing anti-coagulants like DOAC, LMWH or VKA or any oral anti-coagulant (OAC) (This includes VKAs and DOACs) with either placebo or another anti-coagulant. Two independent reviewers screened the retrieved articles and extracted data using a piloted data extraction sheet. The primary outcome of interest was number of recurrent VTE and other side effects among CKD patients receiving respective treatment. Secondary outcomes were risk of major, non-major and intra-cranial bleed.

Results: We retrieved 7244 titles on initial search, reviewed full text of 818 articles, and selected 10 phase III RCTS for quantitative meta-analysis. Out of 36,326 patients in these trials, only 10,840 (29.8%) were evaluable. We stratified patients into four categories based on severity of renal impairment using serum creatinine clearance (SCr) as the marker e.g. mild (>50 - <80) moderate (>30 - ≤50) severe (<30) and any level (from <30 to <80). There was no difference between DOACs vs VKA in decreasing the risk of recurrent VTE among patients with mild (RR:0.86, 95% CI:0.61-1.22, I = 25%) moderate/severe (RR:0.72, 95% CI:0.44-1.17, I = 0%) or any level of renal impairment (RR:0.83, 95% CI:0.60-1.14, I = 34%). No difference in efficacy between LMWH vs VKA among patients with moderate (RR:2.40, 95% CI:0.44-12.96, I = 76%) and any level (RR:2.59, 95% CI:0.66-10.16, I = 71%) of renal impairment respectively. Similarly, no difference in efficacy between LMWH vs any OAC (This includes VKAs and edoxaban) among patients with (RR:2.16, 95% CI:0.66-7.-06, I = 51%) and any level (RR:1.48, 95% CI:0.79-2.78, I = 78%) of renal impairment. DOACs compared to VKAs had significantly lower risk of combined major and non-major bleeding (RR: 0.74, 95% CI:0.65-0.84, I = 26%), major bleeding (RR: 0.51, 95% CI:0.38-0.69, I = 7%) and non-major clinically relevant bleeding (RR: 0.73, 95% CI:0.57-0.94, I = 45%) respectively. Risk of intracranial bleeding was comparable (RR: 0.68, 95% CI:0.19-2.44, I = 0%). There was no difference in the risk of major bleeding between LMWH vs any OAC (RR: 0.83, 95% CI:0.46-1.51, I = 0%).

Conclusion: DOACS and other anticoagulants (VKA and LMWH) showed no statistical difference in preventing recurrent VTEs among CKD patients but DOACs had significantly lower risk of major and non-major clinically relevant bleeding irrespective of the level of renal impairment compared to VKAs. There was no difference in risk of intra-cranial bleeding between DOACs and VKAs.
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http://dx.doi.org/10.1016/j.thromres.2020.11.036DOI Listing
February 2021

A systematic review and meta-analysis of impact of baseline thrombocytopenia on cardiovascular outcomes and mortality in patients undergoing percutaneous coronary intervention.

Catheter Cardiovasc Interv 2021 May 24;97(6):E778-E788. Epub 2020 Nov 24.

Division of Cardiovascular Medicine, Creighton University Medical Center, Omaha, Nebraska, USA.

Background: Thrombocytopenia (TP) is associated with higher incidence of bleeding in the setting of percutaneous coronary intervention (PCI) leading to increased morbidity and mortality. Herein, we report a meta-analysis evaluating the effects of baseline thrombocytopenia (bTP) on cardiovascular outcomes in patients undergoing PCI.

Methods: Literature search was performed using PubMed, Embase, Cochrane library and clinicaltrials.gov from inception till October 2019. Patients were divided into two groups: Patients with (a) no Thrombocytopenia (nTP) (b) bTP before PCI. Primary endpoints were in-hospital, and all-cause mortality rates at the longest follow-up. The main summary estimate was random effects risk ratio (RR) with 95% confidence intervals (CIs).

Results: A total of 6,51,543 patients from 10 retrospective studies were included. There was increased in-hospital all-cause mortality (RR 2.58 [1.7-3.8], p < .001) and bleeding (RR 2.37 [1.41-3.98], p < .005), in the bTP group compared to the nTP group. There was no difference for in-hopsital major adverse cardiovascular outcomes (MACE) (RR 1.38 [0.94-2.0], p < .10), post-PCI MI (RR 1.17 [0.9-1.5], p = .19) and TVR (RR 1.65 [0.8-3.6], p = .21), respectively. Outcomes at longest follow-up showed increased incidence of all-cause mortality (RR 1.86 [1.2-2.9], p < .006) and bleeding (RR 1.72 [1.1-2.9], p = .04) in bTP group, while there was no significant difference for post-PCI MI (RR 1.07 [0.91-1.3], p = .42), MACE (RR 1.86 [0.69-1.8], p = .68) and TVR (RR 1.1 [0.9-1.2], p = .93) between both groups.

Conclusions: bTP in patients undergoing PCI is associated with increased mortality and predicts risk of bleeding.
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http://dx.doi.org/10.1002/ccd.29405DOI Listing
May 2021

Fluoroquinolones and the Risk of Aortopathy: A Systematic Review and Meta-Analysis.

WMJ 2020 Sep;119(3):185-189

CHI Health Creighton University, Omaha, Nebraska.

Introduction: Recent studies have raised concerns that fluoroquinolone use is associated with an increased risk of aortopathy, including aortic aneurysm with and without dissection.

Objective: We performed a meta-analysis with a comprehensive literature review to further investigate this association.

Methods: This analysis was conducted per PRISMA guidelines. PubMed, Cochrane Library, ClinicalTrials.gov, Embase, Web of Science, and Google Scholar were searched for studies that included adult patients (age >18 years) exposed to fluoroquinolones or control antibiotics (amoxicillin/any other antibiotic) for urinary tract infection or pneumonia with a primary outcome of aortic aneurysm or dissection. Heterogeneity was calculated using Q statistic I.

Results: A total of 6 studies-comprised of 59% males-were included in our analysis, which showed an increased combined risk of development of aortic aneurysm and aortic dissection with quinolone exposure when compared with controls (relative risk [RR] = 2.11; 95% CI, 1.62 - 2.75; I= 83.700). Individual relative risk for aortic aneurysm (RR = 2.83; 95% CI, 2.02 - 3.95, I = 89.150) and aortic dissection (RR = 1.99; 95% CI, 1.23 - 3.06; I2= 71.33) also were significantly increased.

Conclusion: Compared to other antibiotics, the use of fluoroquinolones was associated with a significantly higher risk of aortic aneurysm and dissection combined.
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September 2020

Impact of Acquired Thrombocytopenia on Cardiovascular Outcomes in Patients With Coronary Artery Disease Undergoing Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis.

Cardiovasc Revasc Med 2021 Jun 24;27:79-87. Epub 2020 Jul 24.

Division of Cardiovascular Medicine, Creighton University Medical Center, Omaha, NE, USA.

Background: Acquired thrombocytopenia (aTP) is associated with a high frequency of bleeding and ischemic complications in patients undergoing percutaneous coronary intervention (PCI). Herein, we report a meta-analysis evaluating the adverse effects of aTP on cardiovascular outcomes and mortality post-PCI.

Methods: A literature search was performed using PubMed, Embase, Cochrane and, clinicaltrials.gov from the inception of these databases through October 2019. Patients were divided into two groups: 1) No Thrombocytopenia (nTP) and 2) Acquired Thrombocytopenia (aTP) after PCI. Primary endpoints were in-hospital, 30-day and all-cause mortality rates at the longest follow-up. The main summary estimate was random effects Risk ratio (RR) with 95% confidence intervals (CIs).

Results: Seven studies involving 57,247 participants were included. There was significantly increased in-hospital all-cause mortality (HR 10.73 [6.82-16.88]), MACE (HR 2.96 [2.24-3.94]), major bleeding (HR 4.78 [3.54-6.47]), and target vessel revascularization (TVR) (HR 7.53 [2.8-20.2]), in the aTP group compared to the nTP group. Similarly, aTP group had a statistically significant increased incidence of 30-day all-cause mortality (HR 6.08), MACE (HR 2.77), post-PCI MI (HR 1.98), TVR (HR 5.2), and major bleeding (HR 12.73). Outcomes at longest follow-up showed increased incidence of all-cause mortality (HR 3.98 [1.53-10.33]) and MACE (HR 1.24 [0.99-1.54]) in aTP group, while there was no significant difference for post-PCI MI (HR 0.94 [0.37-2.39]) and TVR (HR 0.96 [0.69-1.32]) between both groups.

Conclusions: Acquired Thrombocytopenia after PCI is associated with increased morbidity, mortality, adverse bleeding events and the need for in-hospital and 30-day TVR.
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http://dx.doi.org/10.1016/j.carrev.2020.07.014DOI Listing
June 2021

Efficacy of Ibrutinib-Based Regimen in Chronic Lymphocytic Leukemia: A Systematic Review.

J Hematol 2019 Mar 30;8(1):1-10. Epub 2019 Mar 30.

Department of Hematology Oncology, Cleveland Clinic, Cleveland, OH, USA.

Ibrutinib has shown to have better efficacy than standard chemoimmunotherapy in del17 positive chronic lymphocytic leukemia (CLL) patients; however its role in del17 negative patients is less clear. We aim to evaluate the efficacy of ibrutinib-based regimens in CLL. Seven databases were searched in accordance with PRISMA statement guidelines using the following keywords: chronic lymphocytic leukemia, CLL, Bruton tyrosine kinase inhibitor, BTK inhibitor, ibrutinib, and PCI-32765. Data from only prospective clinical trials was included. In a phase 3 trial (n = 136), the overall response rate (ORR) with ibrutinib was 92% whereas 18% patients had a complete response (CR). Progression free survival (PFS) and overall survival (OS) at 2 years were 89% and 95% respectively. Phase 3 trial (n = 195) with single agent ibrutinib showed ORR of 63%. PFS at 6 months and OS at 12 months were 88% and 90% respectively. In a phase 2 trial of relapsed and/or refractory (R/R) or high risk treatment naive (TN) patients, combination of ibrutinib and rituximab (n = 104) achieved an ORR of 100% (CR 28%) as compared to ORR 98% (CR 21%) with ibrutinib monotherapy (n = 102) with no significant difference in PFS. Combination of ibrutinib and ublituximab (n = 64) had an ORR of 78% (CR 7%) in a phase 3 study. In del17p negative R/R patients, combination of bendamustine/rituximab (BR) and ibrutinib (n = 289) achieved an ORR of 83% (CR/CRi 10%) and the 18 month PFS was 79%. In a phase 2 trial treated with ibrutinib (n = 145), patients with del17p R/R disease achieved an ORR of 64% and the 24 month PFS and OS was 63% and 75% respectively. In TN del17p patients (n = 35), ORR was 97% (CR-0) and the 24 month PFS and OS were 82% and 84% respectively with single agent ibrutinib. Ibrutinib is the treatment of choice for patients with del17p mutation and has good efficacy in RR/TN patients without del17p mutation. Ibrutinib is being evaluated in combination with rituximab for del17p mutations. Future prospects include combination of ibrutinib with frontline chemotherapy and other novel agents for TN and RR del17p negative patients.
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http://dx.doi.org/10.14740/jh482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153674PMC
March 2019

Venous thromboembolism risk with contemporary lenalidomide-based regimens despite thromboprophylaxis in multiple myeloma: A systematic review and meta-analysis.

Cancer 2020 04 8;126(8):1640-1650. Epub 2020 Jan 8.

Blood and Marrow Transplant Program, Taussig Cancer Center, Cleveland Clinic, Cleveland, Ohio.

Background: Thromboprophylaxis is routinely used with lenalidomide-based regimens in multiple myeloma because of a substantial risk of venous thromboembolism (VTE). However, little is known about the incidence of VTE with contemporary lenalidomide-based regimens. The objective of the current study was to estimate the incidence of VTE despite thromboprophylaxis with currently used lenalidomide-based regimens in patients with myeloma.

Methods: The Ovid MEDLINE, Embase, and Cochrane databases were queried from study inception to January 2019 for keywords to cover the following concepts: "lenalidomide," "venous thromboembolism," and "multiple myeloma." Phase 1, 2, and 3 clinical trials evaluating lenalidomide-based regimens with thromboprophylaxis were included. The pooled incidence rate of VTE was estimated using a random-effects model.

Results: The search generated 1372 citations, with 51 clinical trials and 9069 patients included for analysis. The most common thromboprophylaxis agents were aspirin, low-molecular-weight heparin or warfarin, administered either per risk-stratification or at investigators' discretion. The pooled incidence of VTE in trials of patients who had newly diagnosed and relapsed/refractory myeloma was 6.2% (95% CI, 5.4%-7.1%) over median treatment durations ranging from 2 to 34 cycles, which translated into 1.2 VTE events per 100 patient-cycles (95% CI, 0.9-1.7 VTE events per 100 patient-cycles). Among contemporary regimens, the risk of VTE was low with combined lenalidomide and low-dose dexamethasone (0.2 [95% CI, 0.1-0.6] events/100 patient-cycles) and lenalidomide maintenance (0.0 [95% CI, 0.0-0.7] events per 100 patient-cycles). VTE risk was higher with combined lenalidomide and low-dose dexamethasone plus proteasome inhibitors (1.3 [95% CI, 0.7-2.3] events per 100 patient-cycles).

Conclusions: Despite adequate thromboprophylaxis, lenalidomide-based regimens have a substantial risk of VTE in controlled clinical trial settings. Further studies are needed on new thromboprophylaxis strategies with regimens that have a high VTE risk.
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http://dx.doi.org/10.1002/cncr.32682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453956PMC
April 2020

Is It Really SUMP Syndrome? A Case Report.

Cureus 2019 Oct 4;11(10):e5837. Epub 2019 Oct 4.

Internal Medicine, Marshall University, Joan C Edwards School of Medicine, Huntington, USA.

Sump syndrome is a rare, long-term complication with a prevalence ranging from 0% to 9.6% in patients with a history of side-to-side choledochoduodenostomy. Choledochoduodenostomy was originally performed to achieve drainage of the common bile duct in high-risk patients with low morbidity, which was commonly done in the pre-endoscopic retrograde cholangiopancreatography era. "Sump" comes from the segment of the common bile duct between the anastomosis and the ampulla of Vater, which acts as a stagnant reservoir for debris, stones, and static bile. This predisposes patients to changes in the biliary tree with signs and symptoms in relation to that area. If left untreated, cholangitis, pancreatitis, hepatic abscesses, and secondary biliary cirrhosis can develop. Here, we have a case of a 77-year-old male with a history significant for choledochoduodenostomy, who presented with the clinical signs and symptoms of pancreatitis, choledocholithiasis, and urinary tract infection. Computed tomography (CT) scan findings revealed choledocholithiasis and an enlarged common bile duct with smaller adjacent calculi along with pneumobilia consistent with sump syndrome. The patient's clinical status improved without invasive measures being taken, i.e. endoscopic retrograde cholangiopancreatography. He was subsequently discharged home after improving clinically and no invasive measures were pursued.
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http://dx.doi.org/10.7759/cureus.5837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827695PMC
October 2019

A role for S-nitrosylation of the SUMO-conjugating enzyme SCE1 in plant immunity.

Proc Natl Acad Sci U S A 2019 08 1;116(34):17090-17095. Epub 2019 Aug 1.

Institute of Molecular Plant Sciences, School of Biological Sciences, University of Edinburgh, EH9 3BF Edinburgh, United Kingdom;

SUMOylation, the covalent attachment of the small ubiquitin-like modifier (SUMO) to target proteins, is emerging as a key modulator of eukaryotic immune function. In plants, a SUMO1/2-dependent process has been proposed to control the deployment of host defense responses. The molecular mechanism underpinning this activity remains to be determined, however. Here we show that increasing nitric oxide levels following pathogen recognition promote S-nitrosylation of the SUMO E2 enzyme, SCE1, at Cys139. The SUMO-conjugating activities of both SCE1 and its human homolog, UBC9, were inhibited following this modification. Accordingly, mutation of Cys139 resulted in increased levels of SUMO1/2 conjugates, disabled immune responses, and enhanced pathogen susceptibility. Our findings imply that S-nitrosylation of SCE1 at Cys139 enables NO bioactivity to drive immune activation by relieving SUMO1/2-mediated suppression. The control of global SUMOylation is thought to occur predominantly at the level of each substrate via complex local machineries. Our findings uncover a parallel and complementary mechanism by suggesting that total SUMO conjugation may also be regulated directly by SNO formation at SCE1 Cys139. This Cys is evolutionary conserved and specifically S-nitrosylated in UBC9, implying that this immune-related regulatory process might be conserved across phylogenetic kingdoms.
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http://dx.doi.org/10.1073/pnas.1900052116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708345PMC
August 2019

Adjuvant Therapy in High-Risk Renal Cell Cancer: A Systematic Review and Meta-analysis.

Mayo Clin Proc 2019 08 11;94(8):1524-1534. Epub 2019 Jul 11.

Department of Oncology, Mayo Clinic, Rochester, MN. Electronic address:

Objective: To perform a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating risk-benefit for adjuvant postoperative treatments in high-risk renal cell carcinoma by assessing reported disease-free survival (DFS), overall survival (OS), toxicity, and quality of life.

Methods: A literature search was performed in PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials to identify relevant RCTs (from database inception through May 15, 2018). The results of the ATLAS trial were published while writing this manuscript, and the manuscript was updated accordingly. A generic variance-weighted random effects model was used to derive estimates for efficacy and common adverse effects. Heterogeneity was assessed using the Cochran Q statistic and was quantified using the I test.

Results: Adjuvant therapy with tyrosine kinase inhibitors compared with placebo was observed to have a DFS hazard ratio [HR] of 0.92 (95% CI, 0.83-1.01) and an OS HR of 1.01 (95% CI, 0.89-1.15) (4 RCTs; 4417 patients). Analysis of DFS for sunitinib compared with placebo (n=1909) in the adjuvant setting detected an HR of 0.90 (95% CI, 0.67-1.19). Increased risk of grade 3 or 4 adverse events (relative risk [RR]=2.6; 95% CI, 2.28-2.97), diarrhea (RR=9.89; 95% CI, 4.22-23.14), fatigue (RR=3.11; 95% CI, 1.86-5.18), hypertension (RR=3.63; 95% CI, 2.99-4.41), and palmar/plantar dysesthesia (RR=2.70; 95% CI, 2.47-2.96) was observed.

Conclusion: Adjuvant vascular endothelial growth factor tyrosine kinase inhibitors in high-risk renal cell carcinoma did not improve OS or DFS, and there was a significant increased risk of toxicity in greater than half of the patients, leading to a decline in quality of life.
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http://dx.doi.org/10.1016/j.mayocp.2019.01.045DOI Listing
August 2019

Progressive left lower extremity weakness in a patient with multiple myeloma: A diagnostic dilemma.

SAGE Open Med Case Rep 2019 5;7:2050313X19833506. Epub 2019 Mar 5.

Department of Medicine, Monmouth Medical Center, Long Branch, NJ, USA.

Extramedullary plasmacytoma is a type of plasma cell dyscrasia that can present as solitary tumor or secondary to multiple myeloma. We experienced a case of intramuscular plasmacytoma in the left thigh muscles of a patient secondary to multiple myeloma. A 73-year-old male with relapsed multiple myeloma and bilateral hip arthroplasty complained of lxeft lower limb weakness and hip pain 3 months after relapse. He underwent contrast-enhanced magnetic resonance imaging of lumbar spine and hip which was inconclusive. Subsequently, patient had multiple admissions for progressive lower limb weakness. His clinical course was complicated by a biopsy-proven plasmacytoma of the neck. He received localized radiation therapy to the neck in addition to a change in multiple myeloma chemotherapy regimen, resulting in resolution of the neck mass but his left lower extremity weakness continued to worsen. Repeat magnetic resonance imaging of hip and spine revealed an intramuscular mass in left thigh which was consistent with the diagnosis of extramedullary plasmacytoma on biopsy. Localized radiation to the thigh accompanied with a change in chemotherapy improved his symptoms and a significant reduction in size of plasmacytoma was observed. When an unexplained lower limb weakness is encountered with a history of multiple myeloma, secondary intramuscular plasmacytoma should be considered.
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http://dx.doi.org/10.1177/2050313X19833506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404045PMC
March 2019

Concomitant use of blinatumomab and donor lymphocyte infusion for mixed-phenotype acute leukemia: a case report with literature review.

Immunotherapy 2019 04;11(5):373-378

Department of Hematology, Taussig Cancer Center, Medical Oncology, Cleveland Clinic, Cleveland, OH 44195, USA.

Blinatumomab and donor lymphocyte infusion (DLI) combination is a promising cancer therapy, whereby blinatumomab might achieve an initial reduction in leukemic-cell burden using T cells, and after tumor clearance, DLI can potentially stimulate the donor immune system to achieve longer lasting remission. Here, we present a 51-year-old female with mixed phenotype acute leukemia who had a hematologic relapse 3 months after she received total body irradiation-based myeloablative allogeneic hematopoietic stem cell transplantation from an unrelated human leukocyte antigen matched (10/10) donor and achieved complete remission with minimal residual disease negativity by multi-parameter flow cytometry using the combination of blinatumomab and DLI. To the best of our knowledge, this is the first report to describe the use of blinatumomab and DLI combination therapy in the treatment of B/myeloid mixed phenotype acute leukemia.
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http://dx.doi.org/10.2217/imt-2018-0104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439498PMC
April 2019

Extrapyramidal Symptoms with Administration of Lenalidomide Maintenance Therapy for Multiple Myeloma.

Cureus 2018 Sep 24;10(9):e3349. Epub 2018 Sep 24.

Hematology and Oncology, University of Arizona, Tucson, USA.

Lenalidomide is commonly used as induction or maintenance therapy in multiple myeloma. We report a case of 71-year-old female presenting with tardive dyskinesia-like symptoms one month after starting her lenalidomide maintenance therapy after high-dose chemotherapy and autologous hematopoietic stem cell rescue. Her symptoms evolved over days to pronounced uncontrollable limb movements, tongue smacking, lip-smacking, abnormal sounds, and tongue biting. The patient categorically denied any exposure to other drugs which are known to cause symptoms of tardive dyskinesia. The patient underwent a thorough evaluation, stopped the lenalidomide, and received therapy to control her symptoms with a gradual improvement over a six-week period. There is a paucity of literature on the association of lenalidomide with tardive dyskinesia. Common central nervous system-related side effects include peripheral neuropathy, dizziness, dysgeusia, headache, tremor, somnolence, and memory impairment. Very few studies in the existing literature have reported an association of tardive dyskinesia with lenalidomide therapy. Here, we present a case of an elderly female with multiple myeloma who developed severe tardive dyskinesia while she was on lenalidomide maintenance therapy.
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http://dx.doi.org/10.7759/cureus.3349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255714PMC
September 2018

Significant Risk of Graft-versus-Host Disease with Exposure to Checkpoint Inhibitors before and after Allogeneic Transplantation.

Biol Blood Marrow Transplant 2019 01 6;25(1):94-99. Epub 2018 Sep 6.

Department of Medicine, Hematology/Oncology, Blood and Marrow Transplantation, The University of Arizona, Tucson, Arizona; Department of Hematology, Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, Ohio. Electronic address:

Investigators are using checkpoint inhibitors (CPIs) to treat aggressive hematologic malignancies in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) and in some patients with relapsed disease after allo-HSCT. CTLA-4 inhibitors and PD-1 inhibitors are 2 main types of CPIs, which work through activation of the immune system. On one hand, CPIs can achieve graft-versus-tumor effect, and on the other hand, there is a risk of graft-versus-host disease (GVHD). After a comprehensive literature review, we included data (n = 283) from 24 studies (11 original manuscripts and 13 case reports or case series) and evaluated the results to assess the safety and efficacy of CPI use in conjunction with allo-HSCT. Among the 283 patients, 107 received CPI before allo-HSCT, and 176 received CPI after allo-HSCT. The most common indication for CPI use was for Hodgkin lymphoma. The CPIs used in various studies included ipilimumab, nivolumab, and pembrolizumab. Among the patients exposed to CPI before allo-HSCT, 56% developed acute GVHD and 29% developed chronic GVHD. Investigators reported 20 deaths, 60% of which were GVHD-related. The overall mortality risk with GVHD is 11%. In this group, investigators noted an objective response rate (ORR) in 68% of patients, with complete remission (CR) in 47%, partial remission (PR) in 21%, and stable disease in 11%. Among the patients who received a CPI after allo-HSCT for disease relapse, 14% developed acute GVHD and 9% developed chronic GVHD. Investigators reported 40 deaths, 28% of which were GVHD-related. The mortality risk with GVHD is approximately 7%. Investigators reported ORR in 54% of patients, with CR in 33%, PR in 21%, and disease stabilization in 5%. After careful evaluation of collective data, we found that CPI use both before and after allo-HSCT can be highly effective, but exposure can lead to a significantly increased risk of GVHD-related morbidity and mortality in this patient population. Despite limited availability of data, there is need for extreme caution while making decisions regarding the use of CPIs. Detailed discussions and prospective well-designed clinical trials are needed to explore this issue further.
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http://dx.doi.org/10.1016/j.bbmt.2018.08.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310648PMC
January 2019

Treating Diffuse Large B Cell Lymphoma in the Very Old or Frail Patients.

Curr Treat Options Oncol 2018 09 1;19(10):50. Epub 2018 Sep 1.

Department of Medicine, Hematology/Oncology, Blood and Marrow Transplantation, University of Arizona, Tucson, AZ, 85724, USA.

Opinion Statement: R-CHOP has been the standard of care for diffuse large B cell lymphoma (DLBCL), curing approximately 60% of patients for more than 2 decades. However, the optimal treatment of patients who are too frail to tolerate this regimen and/or are not candidates for anthracycline therapy continues to be debated. MInT and GELA trials established addition of rituximab to CHOP in DLBCL but excluded patients older than 80 years. Multiple regimens have been tried with varying success in the very elderly, including R-mini-CHOP, R-mini CEOP, R-split CHOP, pre-phase strategies, and R-GCVP. However, there has not been a randomized trial among these strategies. Although addition of novel agents including ibrutinib, brentuximab vedotin, lenalidomide, and many others on the horizon holds promise in this population, none have been tested in a randomized setting or have results awaited. There is also a lack of a validated and easy to use clinical tool in this population to predict patients who will not tolerate R-CHOP. Identifying patients who will not tolerate R-CHOP early with the help of tools like CGA, along with integrating biology-based treatment (ibrutinib, lenalidomide in activated B cell type DLBCL) is being investigated in this population.
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http://dx.doi.org/10.1007/s11864-018-0565-6DOI Listing
September 2018

Spindle Cell Carcinoma of the Lung/Pleura: An Incidental Finding.

Cureus 2018 Jun 20;10(6):e2848. Epub 2018 Jun 20.

Internal Medicine, Monmouth Medical Center, Long Branch, USA.

A 59-year-old male with a medical history of abdominal aortic dissection underwent a follow-up computed tomography (CT) scan abdomen, which showed an incidental pleural-based mass in the left lung base. The patient underwent an ultrasound (US)-guided biopsy and the histology was consistent with spindle cell carcinoma (SpCC). Staging workup was concerning for a metastatic lesion on the adrenal gland. The patient refused surgery and was subsequently started on chemotherapy. SpCC is a rare histological variant of sarcomatoid carcinoma. The prognosis is generally poor and treatment is the same as for other non-small cell lung cancers (NSCLC). The literature on disease progression and treatment is limited.
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http://dx.doi.org/10.7759/cureus.2848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103392PMC
June 2018

Possible Predictive Factors for In-hospital Cardiac Arrest in Patients with Cancer: A Retrospective Single Center Study.

Cureus 2018 Jun 18;10(6):e2828. Epub 2018 Jun 18.

Internal Medicine, Monmouth Medical Center, Long Branch, USA.

Background: Despite cancer being the second most common cause of death in the United States, more people are living longer after the diagnosis of cancer than before. Healthcare workers will be treating an increasing number of patients with cancer. Various studies have identified predictors of cardiac arrest in the general population, however, none have been done to identify such factors in cancer patients who form a more vulnerable group with lower survival rate following cardiac arrest.

Methods: We retrospectively analysed charts of all patients with active cancer who experienced in-hospital cardiac arrest (IHCA) and underwent cardio-pulmonary resuscitation (CPR) from January 2015 to December 2017 at our hospital (n=44, group A). We compared this group to 44 consecutive patients with active cancer admitted to the oncology unit who did not experience cardiac arrest (n=44, group B). We excluded patients in remission.

Results: Both the groups were comparable in terms of age (69 ± 14 vs 68 ± 15, p=0.776) and gender distribution (50% vs 56% males, p=0.521). Prevalence of coronary artery disease (CAD) (25% vs 11%, p=0.097), hypertension (68% vs 66%, p=0.821), hyperlipidaemia (34% in both groups, p=1.000), tobacco abuse (18% vs 27%, p=0.308), and diabetes mellitus (34% vs 23%, p=0.237) was not significantly different between the two groups. Group with cardiac arrest had significantly higher alanine aminotransferase (100 U/L ± 150 vs 47 U/L ± 87, p=0.043), alkaline phosphatase (288 U/L ± 512 vs 118 U/L ± 80, p=0.032), creatinine (1.8 mg/dl ± 1.74 vs 1.1 mg/dl ± 0.76, p=0.023), international normalised ratio (INR) (2.1 ± 1.5 vs 1.2 ± 0.5, p=0.005), and lower estimated -glomerular filtration rate (43 mL/min/1.73m ± 17 vs 51 mL/min/1.73m ± 15, p=0.022) on admission. Group A also had significantly higher incidence of sepsis during the hospital course as compared to group B (30% vs 2%, p<0.001). In group A, 11.4% survived to discharge as compared to 95.5% in group B. Significantly higher number of patients in group B were taking chemotherapy (77.27% vs 34.09%, p=0.000046) and radiation therapy (65.9% vs 22.72%, p=0.000046) as compared to group A.

Conclusion: Cancer patients who experienced IHCA had worse renal and hepatic function; they were frequently diagnosed with sepsis and had similar cardiovascular risk factors as compared to cancer patients who did not experience cardiac arrest. Furthermore, a higher number of patients with active cancer who did not experience cardiac arrest were on chemotherapy, immunotherapy or radiation therapy.
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http://dx.doi.org/10.7759/cureus.2828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6101448PMC
June 2018

Disease Milestones through Bibliometric Analysis of the Top 100 Cited Articles in Multiple Myeloma.

Cureus 2018 Apr 5;10(4):e2438. Epub 2018 Apr 5.

Hematology and Oncology, University of Arizona, Tucson, USA.

Multiple myeloma (MM) accounts for 1.6% of all cancers and 5%-10% of all hematologic malignancies in the United States (US). Despite marked progress in disease management, it remains incurable with high rates of relapse. We conducted a bibliographic analysis on the Web of Science (WOS) from July 25, 2017 and July 29, 2017. Among the top 100 most-cited articles (1901-2012), the most cited article received 2404 citations and least cited article received 336 citations. Forty-four of 100 articles were published in journals with impact factors greater than 20. We observed that over the years, the focus of research has shifted from diagnosis, staging, and pathogenesis to better treatment outcomes. A subgroup analysis of the top 100 cited articles published in the last five years (2012-2017) demonstrated that several landmark studies, which will likely change the landscape of treating multiple myeloma, were not included in the top 100 list. Interestingly, most of these articles were focused on novel therapeutic agents. This bibliographic analysis provides a list of the 100 top-cited articles in multiple myeloma along with the captivating comprehension of the history and development in various aspects of disease processes. The landscape of this disease is rapidly evolving, and bibliometric studies such as the one presented provide a valuable tool that can highlight the important transitions in the field.
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http://dx.doi.org/10.7759/cureus.2438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988170PMC
April 2018

Psoriasis and Psoriatic Spectrum Disease: A Primer for the Primary Care Physician.

Am J Med 2018 10 2;131(10):1146-1154. Epub 2018 Jun 2.

Complex Medical Dermatology Clinic, St. Elizabeth Physicians, Florence, Ky.

Psoriasis is a chronic, immune-mediated disorder that affects approximately 7.5 million people in the United States. Individuals with psoriasis may develop cutaneous, articular, and systemic manifestations, which are a source of significant morbidity and a heightened risk of mortality, and may adversely impact patient-reported quality of life measures. Psoriasis is now recognized as a risk factor for cardiovascular disease, metabolic syndrome, peripheral vascular disease, inflammatory bowel disease, certain malignancies, and chronic renal disease. Therefore, it has become increasingly relevant that primary care physicians have a basic working knowledge and an understanding of fundamental management principles of psoriasis. This review highlights the salient clinical features of psoriasis and psoriatic spectrum disease, emphasizing key updates with respect to systemic disease and associated conditions, and briefly outlines a therapeutic algorithm for the primary care physician.
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http://dx.doi.org/10.1016/j.amjmed.2018.05.013DOI Listing
October 2018

Prophylaxis for Hepatitis B Virus Reactivation after Allogeneic Stem Cell Transplantation in the Era of Drug Resistance and Newer Antivirals: A Systematic Review and Meta-Analysis.

Biol Blood Marrow Transplant 2018 07 12;24(7):1483-1489. Epub 2018 Mar 12.

Department of Medicine, Hematology/Oncology, Blood and Marrow Transplantation, University of Arizona, Tucson, Arizona. Electronic address:

Patients undergoing allogenic hematopoietic stem cell transplantation (allo-HSCT) are at a very high risk of hepatitis B virus reactivation (HBVr). Lamivudine is commonly used as prophylaxis against HBVr in high-risk patients undergoing allo-HSCT. Unfortunately, its efficacy is diminishing due to the development of HBV mutant drug-resistant strains. With the availability of newer antiviral agents such as entecavir, telbivudine, adefovir, and tenofovir, it is important to assess their role in HBVr prophylaxis. A comprehensive search of 7 databases was performed to evaluate efficacy of antiviral prophylaxis against HBVr in allo-HSCT patients (PubMed/Medline, Embase, Scopus, Cochrane Library, Web of Science, CINAHL, and ClinicalTrials.gov (June 21, 2017)). We identified 10 studies, with 2067 patients undergoing allo-HSCT; these primarily evaluated the use of lamivudine and entecavir as prophylaxis against HBVr in patients undergoing allo-HSCT because there were little or no data about adefovir, telbivudine, or tenofovir as prophylaxis in this specific patient population. Thus, included studies were categorized into 2 main prophylaxis groups: lamivudine and entecavir. Results of our meta-analysis suggest that entecavir is very effective against HBVr, although further clinical trials are required to test efficacy of new antivirals and explore the emerging threat of drug resistance.
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http://dx.doi.org/10.1016/j.bbmt.2018.02.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045972PMC
July 2018

Comparison of Knowledge and Attitudes Regarding Hepatitis B Among Healthcare Professionals in Pakistan.

Cureus 2017 Feb 23;9(2):e1049. Epub 2017 Feb 23.

Department of Psychiatry and Mental Health, Rush University Medical Center.

Aim: Hepatitis B virus (HBV) is a blood-borne infectious disease. It is one of the most common causes of end-stage liver disease, including cirrhosis and hepatocellular carcinoma. Healthcare professionals, including medical and dental students, are at a high risk of acquiring this infection. The aim of this study was to compare and contrast the knowledge and attitudes toward HBV infection amongst doctors, dentists, nurses, and undergraduate final year medical and dental students.

Subjects And Method: A cross-sectional study was carried out on a sample size of 381 medical professionals, which included doctors (59), dentists (77), nurses (71), final year medical students (126), and final year dental students (48) at Combined Military Hospital Lahore Medical College and Institute of Dentistry (CMH LMC). A questionnaire comprising 27 multiple choice questions was distributed amongst the groups mentioned above. The questionnaire aimed to assess basic knowledge, attitudes towards those infected, and knowledge about vaccination against HBV.

Results: The total response rate was 88.8% (382/430 respondents returned the questionnaire). The mean ± standard deviation (SD) score for all healthcare professionals in knowledge was 15.54 ± 3.69 and attitude were 4.67 ± 1.37, which indicated that majority of the healthcare professionals were well informed about hepatitis B and generally exhibited positive attitudes. However, results revealed that medical students lacked adequate knowledge about various aspects of HBV infection, including modes of transmission and prevention methods against the disease. On the other hand, dental students were better informed and exhibited a more positive attitude towards the disease.

Conclusion: According to the results of our study, medical students showed poor knowledge about hepatitis B disease, including its modes of transmission and the option of vaccination. Lack of knowledge contributed significantly to their negative attitudes towards those suffering from the disease, which has the potential to considerably affect the quality of patient care and the doctor-patient relationship. Major steps should be taken towards improving the curriculum followed at medical colleges in Pakistan. More emphasis should be laid on providing knowledge during early academic years and increasing the amount of clinical exposure. Frequent workshops and seminars should be organized in order to provide up-to-date knowledge about HBV infection and means of prevention to both healthcare professionals and students.
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http://dx.doi.org/10.7759/cureus.1049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5364084PMC
February 2017

A Combination of MUC5AC and CA19-9 Improves the Diagnosis of Pancreatic Cancer: A Multicenter Study.

Am J Gastroenterol 2017 01 15;112(1):172-183. Epub 2016 Nov 15.

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA.

Objectives: Pancreatic cancer (PC) is a lethal malignancy that lacks specific diagnostic markers. The present study explores the diagnostic potential of the most differentially overexpressed secretory mucin MUC5AC alone and in combination with CA19-9 using multi-center training and validation sets.

Methods: The expression of MUC5AC in benign pancreatic pathologies, PC precursor lesions, primary PC tissues and metastatic lesions was evaluated by immunohistochemistry. Circulating MUC5AC levels were measured using sandwich ELISA assay developed in-house, and CA19-9 was measured using radioimmunoassay. A combined training set (n=346) was used to evaluate the diagnostic (n=241) and predictive (n=105, total samples 201 from pre- and post-surgical and chemotherapy set) significance of MUC5AC. Results were further validated with a pre-defined cut-off value using independent sets from the Mayo Clinic (n=94) and the University of Pittsburgh Medical Center (n=321).

Results: Tissue expression analyses indicated the de novo expression of MUC5AC in pancreatic intraepithelial precursor lesions 1A (PanIN1A); the expression was maintained through all stages of progression to invasive adenocarcinoma. The median circulating MUC5AC levels in patients with resectable early-stage PC (EPC) (stage 1/2; 67.2 ng/ml, IQR: 23.9-382.1) and unresectable late-stage PC (LPC) (stage 3/4; 389.7 ng/ml, IQR: 87.7-948.6) were significantly higher compared with (P-value ≤0.0001) benign controls (BC) (7.2 ng/ml, IQR: 0.4-26.5) and (P-value ≤0.0001) chronic pancreatitis (CP) controls (8.4 ng/ml, IQR: 1.5-19.2). In the diagnostic training set (n=241), MUC5AC efficiently differentiated EPC from healthy controls (HC) (83%/80% sensitive (SN)/specific (SP)), BC (67%/87% SN/SP), and CP (83%/77% SN/SP). Independent validation sets from the Mayo Clinic and UPMC confirmed the diagnostic potential of MUC5AC to differentiate EPC from BC (68%/73%; 65%/83%) and CP (68%/79%; 65%/72%). Furthermore, MUC5AC and CA19-9 combination significantly improved (p-value < 0.001) the diagnostic accuracy for differentiating resectable cases from controls.

Conclusions: MUC5AC is a valuable diagnostic biomarker, either alone or in combination with CA19-9, to differentiate PC from CP and benign controls.
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http://dx.doi.org/10.1038/ajg.2016.482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5365072PMC
January 2017

The attitudes and beliefs of Pakistani medical practitioners about depression: a cross-sectional study in Lahore using the Revised Depression Attitude Questionnaire (R-DAQ).

BMC Psychiatry 2016 Oct 18;16(1):349. Epub 2016 Oct 18.

CMH Lahore Medical College and Institute of Dentistry, Lahore, Pakistan.

Background: Mental disorders such as depression are common and rank as major contributors to the global burden of disease. Condition recognition and subsequent management of depression is variable and influenced by the attitudes and beliefs of clinicians as well as those of patients. Most studies examining health professionals' attitudes have been conducted in Western nations; this study explores beliefs and attitudes about depression among doctors working in Lahore, Pakistan.

Methods: A cross-sectional survey conducted in 2015 used a questionnaire concerning demographics, education in psychiatry, beliefs about depression causes, and attitudes about depression using the Revised Depression Attitude Questionnaire (R-DAQ). A convenience sample of 700 non-psychiatrist medical practitioners based in six hospitals in Lahore was approached to participate in the survey.

Results: Six hundred and one (86 %) of the doctors approached consented to participate; almost all respondents (99 %) endorsed one of various biopsychosocial causes of depression (38 to 79 % for particular causes), and 37 % (between 13 and 19 % for particular causes) noted that supernatural forces could be responsible. Supernatural causes were more commonly held by female doctors, those working in rural settings, and those with greater psychiatry specialist education. Attitudes to depression were mostly less confident or optimistic and less inclined to a generalist perspective than those of clinicians in the UK or European nations, and deterministic perspectives that depression is a natural part of aging or due to personal failings were particularly common. However, there was substantial confidence in the efficacy of antidepressants and psychological therapy. More confident and therapeutically optimistic views and a more generalist perspective about depression management were associated with a rejection of supernatural explanations of the origin of depression.

Conclusions: Non-psychiatrist medical practitioners in Pakistan hold a range of views about the causes of depression, with supernatural explanations held by more than a third. Depression attitudes appear less positive than among UK and European clinicians, with the notions that depression is due to a lack of stamina and will-power and a natural part of growing old being especially commonly held; more positive attitudes appear to be associated with a rejection of supernatural explanatory models of depression.
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http://dx.doi.org/10.1186/s12888-016-1069-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070008PMC
October 2016

Abdominal cocoon (sclerosing encapsulating peritonitis): a rare cause of intestinal obstruction.

J Coll Physicians Surg Pak 2012 Mar;22(3):171-3

Department of Surgery, Combined Military Hospital, Lahore.

A 24 years old lady presented with classical history of acute intestinal obstruction. There was a background history of chronic abdomen for 9 years. There was asymmetrical abdominal distension. On laparotomy, the entire small intestine was cocooned and enclosed in a yellowish white thick fibrotic membrane resulting in obstruction of the small intestine. When the membrane was carefully peeled off the small intestine, the underlying small gut was found to be absolutely healthy. The histopathology report was consistent with non-specific dense fibrosis. Based on these findings, a diagnosis of abdominal cocoon or sclerosing encapsulating peritonitis was made which is an extremely rare cause of small bowel obstruction.
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http://dx.doi.org/02.2012/JCPSP.171173DOI Listing
March 2012

GSNOR-mediated de-nitrosylation in the plant defence response.

Plant Sci 2011 Nov 21;181(5):540-4. Epub 2011 Apr 21.

Institute of Molecular Plant Sciences, School of Biological Sciences, University of Edinburgh, King's Buildings, Mayfield Road, Edinburgh EH9 3JR, United Kingdom.

A key feature of the plant defence response is the transient engagement of a nitrosative burst, resulting in the synthesis of reactive nitrogen intermediates (RNIs). Specific, highly reactive cysteine (Cys) residues of low pK(a) are a major site of action for these intermediates. The addition of an NO moiety to a Cys thiol to form an S-nitrosothiol (SNO), is termed S-nitrosylation. This redox-based post-translational modification is emerging as a key regulator of protein function in plant immunity. Here we highlight recent advances in our understanding of de-nitrosylation, the mechanism that depletes protein SNOs, with a focus on S-nitrosoglutathione reductase (GSNOR). This enzyme controls total cellular S-nitrosylation indirectly during the defence response by turning over S-nitrosoglutathione (GSNO), a major cache of NO bioactivity.
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http://dx.doi.org/10.1016/j.plantsci.2011.04.004DOI Listing
November 2011

Activation tagging of ADR2 conveys a spreading lesion phenotype and resistance to biotrophic pathogens.

New Phytol 2009 22;183(4):1163-1175. Epub 2009 Jun 22.

Institute of Molecular Plant Sciences, School of Biological Sciences, University of Edinburgh, King's Buildings, Edinburgh EH9 3JR, UK.

An Arabidopsis PR1::luciferase (LUC) transgenic line was transformed with activation T-DNA tags and the resulting population screened for dominant gain-of-function mutants exhibiting constitutive LUC activity. LUC imaging identified activated disease resistance 2 (adr2), which exhibited slowly spreading lesions in the absence of pathogen challenge. Molecular, genetic and histochemical analysis was employed to characterize this mutant in detail. adr2 plants constitutively expressed defence-related and antioxidant genes. Moreover, this line accrued increased quantities of salicylic acid (SA) and exhibited heightened mitogen-activated protein kinase activity. adr2 plants exhibited increased resistance against numerous biotrophic but not necrotrophic pathogens. The adr2 phenotype resulted from the overexpression of a Toll interleukin receptor (TIR) nucleotide binding site (NBS) leucine rich repeat (LRR) gene (At1g56510). Constitutive PR1 expression was completely abolished in adr2 nahG, adr2 npr1 and adr2 eds1 double mutants. Furthermore, heightened resistance against Hyaloperonospora arabidopsis Noco2 was compromised in adr2 nahG and adr2 eds1 double mutants but not in adr2 npr1, adr2 coi1 or adr2 etr1 plants. These data imply that adr2-mediated resistance operates through an Enhanced Disease Susceptibility (EDS) and SA-dependent defence signalling network which functions independently from COI1 or ETR1.
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http://dx.doi.org/10.1111/j.1469-8137.2009.02902.xDOI Listing
December 2009