Association of Red Cell Distribution Width and Mean Platelet Volume With Disease Activity in Rheumatoid Arthritis Patients.

BACKGROUND: The inner layer of the synovial joints is the primary target of rheumatoid arthritis, or RA, a chronic systemic inflammatory disorder that is linked to increasing disability, early mortality, and economic hardships. The objective is to determine the association of red cell distribution width (RDW) and mean platelet volume (MPV) with disease activity in RA. MATERIAL AND METHODS: A retrospective study was conducted between July 2021 and January 2022 in the outpatient rheumatology clinics at Gulab Devi Teaching Hospital. In this study, 100 consecutive participants with a diagnosis of RA fulfilling the ACR/EULAR 2010 classification criteria were enrolled. Patient's records were reviewed for age, gender, length of illness, smoking status, treatment history, current treatment regimen, concomitant medications, rheumatoid factor (RF), anti-cyclic citrulline peptide (anti-CCP) antibodies, and extra-articular manifestations. Laboratory investigations were reviewed for complete blood count including RDW and MPV, ESR, CRP, liver, and renal functions. Disease activity score DAS 28-ESR was used to quantify disease activity. To determine the relationship between different parameters and the RDW and MPV, linear regression research was conducted. RESULTS: According to the DAS28 score, 12% of patients were in remission, 9% had low, 34% had moderate, and 45% had high disease activity. DAS28 score was 5.01±1.72 (2.45-9.32) and RDW was 16.18±4.42. There was a strong positive correlation (r = 0.653) of RDW with the DAS28 score and it was statistically significant (p<0.001). MPV was 11.30±2.09 fL. There was a moderately positive correlation (r = 0.366) of MPV with the DAS28 score and it was statistically significant (p<0.001). CONCLUSION: Conclusively, both RDW and MPV are positively related to disease activity in patients with RA. These can be used as a simple tool for assessing disease activity and guiding the treatment.

Fault Classification for Cooling System of Hydraulic Machinery Using AI.

Hydraulic systems are used in all kinds of industries. Mills, manufacturing, robotics, and Ports require the use of Hydraulic Equipment. Many industries prefer to use hydraulic systems due to their numerous advantages over electrical and mechanical systems. Hence, the growth in demand for hydraulic systems has been increasing over time. Due to its vast variety of applications, the faults in hydraulic systems can cause a breakdown. Using Artificial-Intelligence (AI)-based approaches, faults can be classified and predicted to avoid downtime and ensure sustainable operations. This research work proposes a novel approach for the classification of the cooling behavior of a hydraulic test rig. Three fault conditions for the cooling system of the hydraulic test rig were used. The spectrograms were generated using the time series data for three fault conditions. The CNN variant, the Residual Network, was used for the classification of the fault conditions. Various features were extracted from the data including the F-score, precision, accuracy, and recall using a Confusion Matrix. The data contained 43,680 attributes and 2205 instances. After testing, validating, and training, the model accuracy of the ResNet-18 architecture was found to be close to 95%.

Role of Ondansetron in Reducing Methotrexate Intolerance in Patients with Inflammatory Arthritis.

OBJECTIVE: To determine the frequency of intolerance to Methotrexate (MTX) in patients with inflammatory arthritis by using MTX intolerance severity score, and evaluate the effects of Ondansetron in reducing MTX intolerance. STUDY DESIGN: Interventional study. PLACE AND DURATION OF STUDY: Rheumatology clinic, Combined Military Hospital (CMH), Lahore, from 1st November 2021 to 30th April 2022. METHODOLOGY: Patients with inflammatory arthritis taking methotrexate regularly for >3 months participated in the study. The patients' age, gender, education level, marital status and smoking history were documented. The disease duration and disease activity was also recorded. Dose/duration/route/frequency and timing of MTX were noted. MTX intolerance was calculated with the use of the Methotrexate intolerance severity score (MISS) questionnaire. Those MTX intolerant patients who reported nausea and vomiting were prescribed ondansetron along with MTX and were followed up for the next 3 consecutive months. RESULTS: Out of 181 patients, 48(26.5%) showed methotrexate intolerance. The predominant symptom was nausea after taking MTX reported in 93.8% of the MTX intolerant patients followed by behavioural symptoms including restlessness and irritability reported among 79% and 77% of intolerant patients respectively. Those methotrexate intolerant patients who mainly had complaints of nausea and vomiting were started on ondansetron on the day of methotrexate and showed a significant reduction in the median of MISS score in the following two consecutive months (p <0.05) while at 3 months the median did not show further reduction as compared to second month (p=0.12). CONCLUSION: Ondansetron prescribed along with methotrexate in patients having complaints of nausea and vomiting with MTX, reduces the intolerance significantly. KEY WORDS: Rheumatoid arthritis, Methotrexate, Ondansetron, Nausea, Arthritis juvenile.

Expression of p53 Protein in Prostate Carcinoma and its Correlation with Gleason Grade.

OBJECTIVES: To determine the correlation of p53 expression with Gleason score in prostate cancer. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Department of Pathology, Fatima Memorial Hospital, Lahore; from January 2014 to August 2016. METHODOLOGY: Thirty-seven samples of prostate carcinoma were graded using Gleason grading system. p53 expression was detected through routine immunohistochemical staining protocols and assessed semi-quantitatively using four-point scale score. The collected data was analysed statistically using Pearson's correlation coefficient.   Results: Out of a sample of 37, high grade tumours were observed in 21 (57%) cases, making them the most prevalent type; while, p53 positive nuclear staining was observed in 26 (70%) cases. Within the high grade tumours, strong positive p53 expression was observed in 8 (38%) tumours; while, overexpression of p53 protein was seen in 7 (33%) cases. In contrast, overexpression of p53 was absent in low grade tumours. CONCLUSION: A statistically significant correlation was observed between p53 positive expression and high Gleason grade. Key Words: Prostate cancer, Immunohistochemistry, p53 protein, Gleason score.

uPAR antibody (huATN-658) and Zometa reduce breast cancer growth and skeletal lesions.

Urokinase plasminogen activator receptor (uPAR) is implicated in tumor growth and metastasis due to its ability to activate latent growth factors, proteases, and different oncogenic signaling pathways upon binding to different ligands. Elevated uPAR expression is correlated with the increased aggressiveness of cancer cells, which led to its credentialing as an attractive diagnostic and therapeutic target in advanced solid cancer. Here, we examine the antitumor effects of a humanized anti-uPAR antibody (huATN-658) alone and in combination with the approved bisphosphonate Zometa (Zoledronic acid) on skeletal lesion through a series of studies in vitro and in vivo. Treatment with huATN-658 or Zometa alone significantly decreased human MDA-MB-231 cell proliferation and invasion in vitro, effects which were more pronounced when huATN-658 was combined with Zometa. In vivo studies demonstrated that huATN-658 treatment significantly reduced MDA-MB-231 primary tumor growth compared with controls. In a model of breast tumor-induced bone disease, huATN-658 and Zometa were equally effective in reducing skeletal lesions. The skeletal lesions were significantly reduced in animals receiving the combination of huATN-658 + Zometa compared with monotherapy treatment. These effects were due to a significant decrease in osteoclastic activity and tumor cell proliferation in the combination treatment group. Transcriptome analysis revealed that combination treatment significantly changes the expression of genes from signaling pathways implicated in tumor progression and bone remodeling. Results from these studies provide a rationale for the continued development of huATN-658 as a monotherapy and in combination with currently approved agents such as Zometa in patients with metastatic breast cancer.

DNA methylation signatures of breast cancer in peripheral T-cells.

BACKGROUND: Immune surveillance acts as a defense mechanism in cancer, and its disruption is involved in cancer progression. DNA methylation reflects the phenotypic identity of cells and recent data suggested that DNA methylation profiles of T cells and peripheral blood mononuclear cells (PBMC) are altered in cancer progression. METHODS: We enrolled 19 females with stage 1 and 2, nine with stage 3 and 4 and 9 age matched healthy women. T cells were isolated from peripheral blood and extracted DNA was subjected to Illumina 450 K DNA methylation array analysis. Raw data was analyzed by BMIQ, ChAMP and ComBat followed by validation of identified genes by pyrosequencing. RESULTS: Analysis of data revealed ~ 10,000 sites that correlated with breast cancer progression and established a list of 89 CG sites that were highly correlated (p < 0.01, r > 0.7, r < - 0.7) with breast cancer progression. The vast majority of these sites were hypomethylated and enriched in genes with functions in the immune system. CONCLUSIONS: The study points to the possibility of using DNA methylation signatures as a noninvasive method for early detection of breast cancer and its progression which need to be tested in clinical studies.

Methyl donor S-adenosylmethionine (SAM) supplementation attenuates breast cancer growth, invasion, and metastasis in vivo; therapeutic and chemopreventive applications.

DNA hypomethylation coordinately targets various signaling pathways involved in tumor growth and metastasis. At present, there are no approved therapeutic modalities that target hypomethylation. In this regard, we examined the therapeutic plausibility of using universal methyl group donor S-adenosylmethionine (SAM) to block breast cancer development, growth, and metastasis through a series of studies in vitro using two different human breast cancer cell lines (MDA-MB-231 and Hs578T) and in vivo using an MDA-MB-231 xenograft model of breast cancer. We found that SAM treatment caused a significant dose-dependent decrease in cell proliferation, invasion, migration, anchorage-independent growth and increased apoptosis in vitro. These results were recapitulated in vivo where oral administration of SAM reduced tumor volume and metastasis in green fluorescent protein (GFP)-tagged MDA-MB-231 xenograft model. Gene expression analyses validated the ability of SAM to decrease the expression of several key genes implicated in cancer progression and metastasis in both cell lines and breast tumor xenografts. SAM was found to be bioavailable in the serum of experimental animals as determined by enzyme-linked immunosorbent assay and no notable adverse side effects were seen including any change in animal behavior. The results of this study provide compelling evidence to evaluate the therapeutic potential of methylating agents like SAM in patients with breast cancer to reduce cancer-associated morbidity and mortality.

Presentation of parathyroid adenoma with genu valgum and thoracic deformities.

Parathyroid adenoma is the main cause of primary hyperparathyroidism. It is usually asymptomatic and occurs more commonly in adults. It presents with raised parathormone (PTH) and Ca+ levels in serum. Its presentation in adolescence is rare. We report one such incidence of a 14 years old girl who presented with bone pains short stature, and generalized muscle wasting. She was found to have genu valgum at the knee joint, pectus carniatum, scoliosis and cystic changes in pelvis and calvarium. Biochemical investigations and parathyroid Tc-99mMIBI scan confirmed the diagnosis of a parathyroid adenoma. The gland was removed by parathyroidectomy. Till date 12 such cases are reported and none had thoracic, vertebral or calvarium involvement.

A common promoter hypomethylation signature in invasive breast, liver and prostate cancer cell lines reveals novel targets involved in cancer invasiveness.

UNLABELLED: Cancer invasion and metastasis is the most morbid aspect of cancer and is governed by different cellular mechanisms than those driving the deregulated growth of tumors. We addressed here the question of whether a common DNA methylation signature of invasion exists in cancer cells from different origins that differentiates invasive from non-invasive cells. We identified a common DNA methylation signature consisting of hyper- and hypomethylation and determined the overlap of differences in DNA methylation with differences in mRNA expression using expression array analyses. A pathway analysis reveals that the hypomethylation signature includes some of the major pathways that were previously implicated in cancer migration and invasion such as TGF beta and ERBB2 triggered pathways. The relevance of these hypomethylation events in human tumors was validated by identification of the signature in several publicly available databases of human tumor transcriptomes. We shortlisted novel invasion promoting candidates and tested the role of four genes in cellular invasiveness from the list C11orf68, G0S2, SHISA2 and TMEM156 in invasiveness using siRNA depletion. Importantly these genes are upregulated in human cancer specimens as determined by immunostaining of human normal and cancer breast, liver and prostate tissue arrays. Since these genes are activated in cancer they constitute a group of targets for specific pharmacological inhibitors of cancer invasiveness. SUMMARY: Our study provides evidence that common DNA hypomethylation signature exists between cancer cells derived from different tissues, pointing to a common mechanism of cancer invasiveness in cancer cells from different origins that could serve as drug targets.

S-adenosylmethionine blocks osteosarcoma cells proliferation and invasion in vitro and tumor metastasis in vivo: therapeutic and diagnostic clinical applications.

Osteosarcoma (OS) is an aggressive and highly metastatic form of primary bone cancer affecting young children and adults. Previous studies have shown that hypomethylation of critical genes is driving metastasis. Here, we examine whether hypermethylation treatment can block OS growth and pulmonary metastasis. Human OS cells LM-7 and MG-63 were treated with the ubiquitous methyl donor S-adenosylmethionine (SAM) or its inactive analog S-adenosylhomocystine (SAH) as control. Treatment with SAM resulted in a dose-dependent inhibition of tumor cell proliferation, invasion, cell migration, and cell cycle characteristics. Inoculation of cells treated with 150 µmol/L SAM for 6 days into tibia or via intravenous route into Fox Chase severe combined immune deficient (SCID) mice resulted in the development of significantly smaller skeletal lesions and a marked reduction in pulmonary metastasis as compared to control groups. Epigenome wide association studies (EWAS) showed differential methylation of several genes involved in OS progression and prominent signaling pathways implicated in bone formation, wound healing, and tumor progression in SAM-treated LM-7 cells. Real-time polymerase chain reaction (qPCR) analysis confirmed that SAM treatment blocked the expression of several prometastatic genes and additional genes identified by EWAS analysis. Immunohistochemical analysis of normal human bone and tissue array from OS patients showed significantly high levels of expression of one of the identified gene platelet-derived growth factor alpha (PDGFA). These studies provide a possible mechanism for the role of DNA demethylation in the development and metastasis of OS to provide a rationale for the use of hypermethylation therapy for OS patients and identify new targets for monitoring OS development and progression.

Genome-wide study of hypomethylated and induced genes in patients with liver cancer unravels novel anticancer targets.

PURPOSE: We utilized whole-genome mapping of promoters that are activated by DNA hypomethylation in hepatocellular carcinoma (HCC) clinical samples to shortlist novel targets for anticancer therapeutics. We provide a proof of principle of this approach by testing six genes short-listed in our screen for their essential role in cancer growth and invasiveness. EXPERIMENTAL DESIGN: We used siRNA- or shRNA-mediated depletion to determine whether inhibition of these genes would reduce human tumor xenograft growth in mice as well as cell viability, anchorage-independent growth, invasive capacities, and state of activity of nodal signaling pathways in liver, breast, and bladder cancer cell lines. RESULTS: Depletion of EXOSC4, RNMT, SENP6, WBSCR22, RASAL2, and NENF effectively and specifically inhibits cancer cell growth and cell invasive capacities in different types of cancer, but, remarkably, there is no effect on normal cell growth, suggesting a ubiquitous causal role for these genes in driving cancer growth and metastasis. Depletion of RASAL2 and NENF in vitro reduces their growth as explants in vivo in mice. RASAL2 and NENF depletion interferes with AKT, WNT, and MAPK signaling pathways as well as regulation of epigenetic proteins that were previously demonstrated to drive cancer growth and metastasis. CONCLUSION: Our results prove that genes that are hypomethylated and induced in tumors are candidate targets for anticancer therapeutics in multiple cancer cell types. Because these genes are particularly activated in cancer, they constitute a group of targets for specific pharmacologic inhibitors of cancer and cancer metastasis. Clin Cancer Res; 20(12); 3118-32. ©2014 AACR.

Meningioma like tumour of thyroid: a rare variant of follicular adenoma.

Spindle cell lesions of thyroid are uncommon. Meningioma like tumour of thyroid is a rare variant of follicular adenoma, which can easily be misdiagnosed. One such case is being reported here with detailed histological, histochemical and immunohistochemical findings.

Association of raised intraocular pressure and its correlation to the energy used with raised versus normal intraocular pressure following Nd: YAG laser posterior capsulotomy in pseudophakes.

OBJECTIVE: To determine the frequency of raised intraocular pressure (IOP) after Nd: YAG laser posterior capsulotomy and its association with the energy used with raised versus normal intraocular pressure in pseudophakes. STUDY DESIGN: Comparative, cross-sectional study. PLACE AND DURATION OF STUDY: Ophthalmology Department, PNS Shifa Hospital, Karachi, from August 2008 to February 2009. METHODOLOGY: Pseudophakes having poor vision due to posterior capsular opacification (PCO) in an otherwise normal looking eye and intraocular pressure between 10-20 mmHg were included in the study. Patients with diabetic retinopathy, corneal diseases, inflammatory eye diseases, posterior segment surgery, glaucoma, trabeculectomy, maculopathy and any systemic disease were excluded from the study. Particulars of the eligible patients and pre-laser intraocular pressure were entered in specially designed proforma. Nd: YAG laser posterior capsulotomy was done. Laser energy used was noted and then their post-laser intraocular pressure was checked after 4 hours. Unpaired t-test was used for comparison of means of IOP and energy levels. Chi-square test was applied to compare the proportions of patients with raised and the normal IOP with YAG laser energy used during posterior capsulotomy. RESULTS: Raised intraocular pressure (IOP>or=5 mmHg from the baseline) after Nd: YAG laser posterior capsulotomy was noted in both the 'low energy' and the 'high energy' groups but it was more common in the 'high energy' group (p<0.001, r=0.512). CONCLUSION: Higher YAG laser energy has significantly higher chances of raising IOP. Hence, it was recommended that each patient undergoing Nd: YAG laser capsulotomy should receive minimum possible laser energy and must be followed up for raised intraocular pressure.

Central mucoepidermoid carcinoma, a case report with molecular analysis of the TORC1/MAML2 gene fusion.

Mucoepidermoid carcinoma is the most common salivary gland malignancy. The majorities of these tumors arise in the parotid and minor salivary glands, but may rarely develop intraosseously. The latter is not uncommonly associated with diagnostic and management difficulties. We report an example of intraosseous mucoepidermoid carcinoma with positive TORC1/MAML2 gene fusion transcript and discuss the clinical implications.