Synthesis and Biological Evaluation of Novel Uracil Derivatives as Thymidylate Synthase Inhibitors.

Cell division is driven by nucleic acid metabolism, and thymidylate synthase (TYMS) catalyzes a rate-limiting step in nucleotide synthesis. As a result, thymidylate synthase has emerged as a critical target in chemotherapy. 5-Fluorouracil (5-FU) is currently being used to treat a wide range of cancers, including breast, pancreatic, head and neck, colorectal, ovarian, and gastric cancers The objective of this study was to establish a new methodology for the low-cost, one-pot synthesis of uracil derivatives (UD-1 to UD-5) and to evaluate their therapeutic potential in BC cells. One-pot organic synthesis processes using a single solvent were used for the synthesis of drug analogues of Uracil. Integrated bioinformatics using GEPIA2, UALCAN, and KM plotter were utilized to study the expression pattern and prognostic significance of TYMS, the key target gene of 5-fluorouracil in breast cancer patients. Cell viability, cell proliferation, and colony formation assays were used as in vitro methods to validate the in silico lead obtained. BC patients showed high levels of thymidylate synthase, and high expression of thymidylate synthase was found associated with poor prognosis. In silico studies indicated that synthesized uracil derivatives have a high affinity for thymidylate synthase. Notably, the uracil derivatives dramatically inhibited the proliferation and colonization potential of BC cells in vitro. In conclusion, our study identified novel uracil derivatives as promising therapeutic options for breast cancer patients expressing the augmented levels of thymidylate synthase.

Correlation of transrectal ultrasonographic findings with histo pathology in prostatic cancer.

OBJECTIVE: To estimate the incidence of hyperechoic, hypoechoic, isoechoic, prostatic cancer in TRUS (transrectal ultrasound guided) guided prostatic specimens. MATERIALS AND METHODS: Four hundred and ninety three patients with raised serum prostatic specific antigen (PSA) and abnormal DRE findings were subjected to TRUS-Guided prostate biopsy. Lateralized sextant biopsy plus prostatic cores from suspicious areas were obtained. RESULTS: Out of 493 patients who were enrolled in the study, 65 (13.18) patients showed hyperechoic lesions on TRUS and 211 (42.79) patients had hypoechoic lesions on TRUS. CONCLUSION: Our study has revealed that hyperechoic lesions on transrectal ultrasonography have more chances of prostatic cancer as reported in previous literature, so we suggest that we should take additional biopsy of hyperechoic lesions and perhaps it should be part of the standard protocol in patients suspected cancer prostate.

Delayed presentation of traumatic diaphragmatic hernia: a diagnosis of suspicion with increased morbidity and mortality.

BACKGROUND: Diaphragmatic rupture due to blunt or penetrating injury may be a missed diagnosis in an acute setting and can present with a delayed complication with significantly increased morbidity and mortality. OBJECTIVES: The objective of this study is to better understand why diaphragmatic tears with delayed presentation and diagnosis are so often missed and why traumatic diaphragmatic tears are difficult to diagnose in emergency settings and how they present with grievous complications. PATIENTS AND METHODS: Eleven patients with diaphragmatic hernias with delayed presentation and delayed diagnosis were operated within the last five years. All patients presented with different complications like gut gangrene or respiratory distress. RESULTS: Out of eleven patients who were operated on for diaphragmatic hernia, three patients (27%) died. Three patients required colonic resection, one patient needed gastrectomy and one patient underwent esophagogastrectomy. CONCLUSIONS: A small diaphragmatic tear due to blunt trauma to the abdomen is difficult to diagnosis in acute settings due to ragged margins and possibly no herniated contents and usually present with a delayed complication. Therefore a careful examination of the entire traumatized area is the best approach in treating delayed presentation of traumatic diaphragmatic hernia prior to development of grievous complications.

The diagnostic efficacy of adenosine deaminase in tubercular effusion.

OBJECTIVE: This study aims to evaluate the diagnostic efficacy of adenosine deaminase in tubercular effusions. METHODS: This study was conducted at the Department of General Medicine and Cardiovascular and Thoracic Surgery, SKIMS, for a period of two years between November 2008 and November 2010. A total of 57 patients presenting with pleural effusions during the two-year study period, who presented with clinical manifestations suggestive of tuberculosis (i.e., the presence of productive cough, low-grade fever, night sweats, weight loss, and chest pain, especially if these symptoms last (3)4 weeks) were included in the study. If the patients presented with less than two of these symptoms, and especially if the clinical manifestations were of <4 weeks duration, they were excluded from the study. RESULTS: The mean adenosine deaminase activity level in all the 57 patients was 109 U/L while the mean adenosine deaminase activity levels in pleural TB patients was 80 U/, and 64 U/L in the controls (p=0.381). Considering 40 U/L as the cut off, the results were positive in 35 out of 39 tuberculosis patients and 9 out of 18 controls. The sensitivity of adenosine deaminase for tubercular effusions worked out to be 90%, with only 50% specificity. CONCLUSION: This study suggests that the estimation of adenosine deaminase activity in pleural fluid is a rapid diagnostic tool for differentiation of tubercular and non tubercular-effusions. The sensitivity and specificity of adenosine deaminase for tubercular effusions in this study was 90% and 50% respectively.

Endorectal coil MRI and MR-spectroscopic imaging in patients with elevated serum prostate specific antigen with negative trus transrectal ultrasound guided biopsy.

BACKGROUND: The aim of this study was to see the efficacy of endorectal coil MRI and MR spectroscopic imaging in patients with elevated serum PSA and negative transrectal ultrasonography (TRUS)-guided biopsy. MATERIALS AND METHODS: This study was conducted on 87 patients presented with: • Elevated prostatic specific antigen levels >5 ng/ml • Symptoms and signs of prostatic carcinoma • Patients with negative TRUS-guided biopsy • Suspicious lesion on TRU. All the patients were subjected to TRUS and followed by TRUS-guided biopsy of the lesion identified on endorectal coil MRI and MR-Spectroscopy. TRUS-guided biopsy of prostate was done with a Siemens Sonoline Adana Scanner. The scanning was performed by mechanical probe 5-7.5 MHz. RESULTS: Out of 87 patients, 43 (49.4%) had hypointense lesion, 11 (12.6%) had hyperintense lesion. Out of 87 patients, MR-spectroscopy showed peak choline-creatine in 74 patients. Normal citrate peak was seen in 13 patients. Patients who had choline-creatine peak, among them 28 (37.8%) had peak in left peripheral zone, 23 (31.1%) had peak in the right peripheral zone, 2 (2.7%) had peak in the central zone, 17 had (23%) peak bilaterally. Four patients (5.4%) had peaks in right and central zones. The difference was statistically significant (P < 0.001). CONCLUSION: Prostatic biopsy directed with endorectal coil MRI and MR-spectroscopic imaging findings in patients with elevated serum PSA and prior negative biopsy, improves the early diagnosis of prostatic carcinoma and accurate localization of prostate cancer within the gland.

The increasing rate of secondary amputation in popliteal arterial injury associated with multi-organ injuries and hypotension.

OBEJECTIVES: To study the role of hypotension and associated injuries in increasing the chances of secondary amputation in lower limb with vascular injuries. METHODS: This study was conducted in the Department of cardiovascular and thoracic surgery( CVTS ), Sher-i- Kashmir Institute of Medical Sciences, ( SKIMS ) Srinagar Kashmir India and comprised all patients sustaining vascular injury due to different causes like road traffic accident, fire arm and blast injuries or falling from height during the last five years. Following admission to our Department, the patients were divided into two groups. The first group with associated injuries was hemodynamically unstable during vascular repair or in post-operative period and the second group had no associated injuries and was hemodynamically stable during vascular repair and in post-operative period. RESULTS: During the past five years, 95 patients were operated for lower limb vascular injury in our department. Of these 25 patients had associated multi-organ injuries and were hemodynamically unstable and needed intensive care monitoring after surgical intervention. Additionally, 10 patients died due to associated multiple organ injuries, 10 needed amputation due to recurrent thrombosis of their anastomosis, and in five patients limb salvage was achieved. Seventy patients who had isolated limb vascular injuries with no associated injuries or hypotension were hemodynamically stable and were kept in low dependency unit after vascular repair. Only Four patients from this group needed amputation for thrombosis of the anastomosis. CONCLUSION: [corrected] Patients with shock and related injuries face significant rate of amputation. These patients whether with multi-organ injuries or isolated vascular injuries need judicious treatment for hypovolumic shock during surgical intervention and in post-operative period.