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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., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Tumor heterogeneity is a hallmark of cancer and one of the primary causes of resistance to therapies. Triple-negative breast cancer (TNBC), which accounts for 15-20% of all breast cancers and is the most aggressive subtype, is very diverse, connected to metastatic potential and response to therapy. It is a very diverse disease at the molecular, pathologic, and clinical levels. TNBC is substantially more likely to recur and has a worse overall survival rate following diagnosis than other breast cancer subtypes. Chemokines, low molecular weight proteins that stimulate chemotaxis, have been shown to control the cues responsible for TNBC heterogeneity. In this review, we have focused on tumor heterogeneity and the role of chemokines in modulating tumor heterogeneity, since this is the most critical issue in treating TNBC. Additionally, we examined numerous cues mediated by chemokine networks that contribute to the heterogeneity of TNBC. Recent developments in our knowledge of the chemokine networks that regulate TNBC heterogeneity may pave the way for developing effective therapeutic modalities for effective treatment of TNBC., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest in this research., (Copyright © 2022. Published by Elsevier Ltd.)

The pancreatic β-cells sustain systemic glucose homeostasis by producing and secreting insulin according to the blood glucose levels. Defects in β-cell function are associated with hyperglycemia that can lead to diabetes. During the process of insulin secretion, β-cells experience an influx of Ca 2+ . Thus, imaging the glucose-stimulated Ca 2+ influx using genetically encoded calcium indicators (GECIs) provides an avenue to studying β-cell function. Previously, studies showed that isolated zebrafish islets expressing GCaMP6s exhibit significant Ca 2+ activity upon stimulation with defined glucose concentrations. However, it is paramount to study how β-cells respond to glucose not in isolation, but in their native environment, where they are systemically connected, vascularized, and densely innervated. To this end, the study leveraged the optical transparency of the zebrafish larvae at early stages of development to illuminate β-cell activity in vivo. Here, a detailed protocol for Ca 2+ imaging and glucose stimulation to investigate β-cell function in vivo is presented. This technique allows to monitor the coordinated Ca 2+ dynamics in β-cells with single-cell resolution. Additionally, this method can be applied to work with any injectable solution such as small molecules or peptides. Altogether, the protocol illustrates the potential of the zebrafish model to investigate islet coordination in vivo and to characterize how environmental and genetic components might affect β-cell function.

Berardinelli-Seip congenital lipodystrophy (BSCL) syndrome is a rare genetic disorder caused by dysregulation of glycemic and lipid metabolism. We report five BSCL cases with typical clinical pictures and complications. These, to the best of our knowledge, represent the first case series from Pakistan. BSCL is characterized by marked atrophy of adipose tissue, acromegaly, acanthosis nigricans and tall stature. We could not perform genetics studies in any patient owing to non-availability of genetic laboratory in Pakistan. All the cases presented hypertriglyceridemia. One case developed hyperinsulinism controlled with metformin. There is no curative treatment and the current approach is low-fat diet and management of insulin resistance and diabetes. Recently published studies showed that leptin-replacement therapy is promising in the metabolic correction of complications of BSCL. This highlights the importance of further research in BSCL treatment.

Cancer is a black spot on the face of humanity in this era of science and technology. Presently, several classes of anticancer drugs are available in the market, but issues such as toxicity, low efficacy and solubility have decreased the overall therapeutic indices. Thus, the search for new promising anticancer agents continues, and the battle against cancer is far from over. Imidazole is an aromatic diazole and alkaloid with anticancer properties. There is considerable interest among scientists in developing imidazoles as safe alternatives to anticancer chemotherapy. The present article describes the structural, chemical, and biological features of imidazoles. Several classes of imidazoles as anticancer agents based on their mode of action have been critically discussed. A careful observation has been made into pharmacologically active imidazoles with better or equal therapeutic effects compared to well-known imidazole-based anticancer drugs, which are available on the market. A brief discussion of the toxicities of imidazoles has been made. Finally, the current challenges and future perspectives of imidazole based anticancer drug development are conferred.

To assess the efficacy and the safety of Greenlight(TM) high-performance system (HPS) 120-W laser photoselective vaporization of the prostate (PVP) compared with transurethral resection of the prostate (TURP) for treatment of benign prostatic hyperplasia (BPH). The related original studies only including randomized controlled trials were searched by databases MEDLINE, EMBASE, Google Scholar, and the Cochrane Controlled Trial Register. The databases were updated till July 2014. The risk ratio, mean difference, and their corresponding 95% confidence intervals were calculated. Risk of bias of the enrolled trials were assessed according to Cochrane Handbook. A total of four trials involving 559 patients were enrolled. Statistical analysis was performed by software Review Manager (V5.3.3). There was no significant difference in International Prostate Symptom Score (IPSS) and maximum flow rate (Qmax) between PVP and TURP at 6-, 12-, and 24-month follow-up. Patients in the PVP group were associated with significantly lower risk of capsule perforation (risk ratio (RR) = 0.06, 95% confidence interval (95%CI) = 0.01 to 0.46; p = 0.007), significantly lower transfusion requirements (RR = 0.12, 95%CI = 0.03 to 0.43; p = 0.001), a shorter catheterization time (mean difference (MD) = -41.93, 95%CI = -54.87 to -28.99; p < 0.00001), and a shorter duration of hospital stay (MD = -2.09, 95%CI = -2.58 to -1.59; p < 0.00001) than that in the TURP group. In the TURP group, the patients were associated with a lower risk of re-operation (RR = 3.68, 95%CI = 1.04 to 13.00; p = 0.04) and a shorter operative time (MD = 9.28, 95%CI = 2.80 to 15.75; p = 0.005) than those in the PVP group. In addition, no statistically significant differences were detected between groups in terms of the rates of transurethral resection syndrome, urethral stricture, bladder neck contracture, incontinence, and infection. Greenlight(TM) 120-W laser PVP is as effective as TURP for symptom reduction and improvement of the quality of life. Laser PVP shows advantages over TURP in terms of intraoperative safety, whereas TURP is found to have a shorter operative time and lower re-operative risk.

Cancer is the most dangerous disease to haunt the mankind in the world today. Generally, the overall cancer mortality rates are similar in both the sexes. The reasons for most of these deaths are inefficacy and failure of the current methods of treatments or the unavailability of treatment options. The researchers of the world are actively integrating nanotechnology of treating of various cancers. The development of smart nanocarriers is one of the most important innovations in this direction. The nanocarriers of the different materials are being developed to improve the efficacy of current treatments. The present article describes the role of nanotechnology in cancer treatment emphasizing cancer nanotherapy, nanocarriers for drug delivery, types and the mechanisms of the nanocarriers. Besides, the efforts are made to discuss the recent advances in the nanocarriers, current challenges and the future prospective.

Cancer has been cursed for human beings for long time. Millions people lost their lives due to cancer. Despite of the several anticancer drugs available, cancer cannot be cured; especially at the late stages without showing any side effect. Heterocyclic compounds exhibit exciting medicinal properties including anticancer. Some market selling heterocyclic anticancer drugs include 5-flourouracil, methortrexate, doxorubicin, daunorubicin, etc. Besides, some natural products such as vinblastine and vincristine are also used as anticancer drugs. Overall, heterocyclic moeities have always been core parts in the expansion of anticancer drugs. This article describes the importance of heterocyclic nuclei in the development of anticancer drugs. Besides, the attempts have been made to discuss both naturally occurring and synthetic heterocyclic compounds as anticancer agents. In addition, some market selling anticancer heterocyclic compounds have been described. Moreover, the efforts have been made to discuss the mechanisms of actions and recent advances in heterocyclic compounds as anticancer agents. The current challenges and future prospectives of heterocyclic compounds have also been discussed. Finally, the suggestions for syntheses of effective, selective, fast and human friendly anticancer agents are discussed into the different sections.

Objective: To compare the efficacy of ondansetron alone and combination of ondansetron and dexamethasone in preventing post-operative nausea and vomiting in patients undergoing laparoscopic cholecystectomy., Methods: The randomised control trial was conducted from April 23 to August 22, 2009, at the Liaquat National Hospital, Karachi, and comprised 100 American Society of Anaesthesiology I and II patients undergoing laparoscopic cholecystectomy. Half of the subjects comprised Group A and received ondansetron alone, while Group B received combination of ondansetron and dexamethasone. They were randomised by opaque envelope method. Group A received ondansetron 4 mg while Group B received ondansetron 4 mg with dexamethasone 8 mg, 1 minute before induction. Post-operatively patients were observed for six hours for any episode of nausea or vomiting, or whether the patients required any rescue anti emetic. SPSS 19 was used for statistical analysis., Results: Patients receiving ondansetron alone showed 14 (28%) with incidence of nausea or vomiting while the other group showed 6 (12%). This difference was statistically significant (p < 0.046)., Conclusion: Combination of ondansetron and dexamethasone was more efficacious compared to ondansetron alone in the prevention of postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy.

Objective: To assess the role of sonography as an adjunct to mammography in women with dense breast tissue by determining yield and validity of sonography using histopathology/follow-up mammography as gold standard., Methods: It was a descriptive analytical study conducted at the Radiology Department of Aga Khan University Hospital, from September 2005 to April 2007. A total of 76, mammographically dense breasts were evaluated with ultrasound. Of these 32 had palpable lumps on mammography, and were excluded from the study. A total of 44 patients had either symptoms of vague nodularity, nipple discharge, mastalgia or had no symptoms and the mammograms showed dense breast parenchyma without any focal abnormality. All these patients underwent whole breast ultrasound. The findings on ultrasound and subsequent histopathology and follow-up mammography were used to calculate the sensitivity, specificity, positive and negative predictive value of whole breast ultrasound as an adjunct to mammography., Results: The age range of patients was 35 to 56 years, mean age was 42 +/- 7.33 years. Of the 44 patients included, 37 had normal ultrasound examinations and had the same findings on one year follow-up mammograms and ultrasound examinations. The remaining, seven patients were categorized as BI RADS category 4 due to presence of suspicious findings on ultrasound examination. They underwent ultrasound guided biopsy of the detected lesions. Out of seven solid lesions biopsied six were benign and one was reported malignant on histopathological examination. The sensitivity, specificity, positive and negative predictive values were 100%, 85%, 14% and 86% respectively., Conclusion: Breast ultrasound can be a useful adjunct to mammography in women with dense breast by detecting small cancers not identified on mammography or clinical breast examination. Larger studies will be required to suggest that ultrasound could be used as an adjunct.

Background: Hydatid disease is endemic in the cattle grazing areas. It is a parasitic infection caused by the Echinoccocus Granulosus. Dogs are the definitive host and humans get infected either by contact with the definitive host or by consuming hydatid ova contaminated vegetables., Methods: A 42 yr old lady presented with shortness of breath on exertion, orthopnea and progressively increasing abdominal distention. She had past history of hydatid disease and had three laparatomies and a right thoracotomy, in the past five years. On physical examination, she had a distended, non-tender abdomen.. Her routine laboratory investigations were normal. Echinococcus antibody titres were 1:64 (Normal 1:32). Computed Tomography (CT) scan revealed multiple, well defined cysts throughout the abdomen. Laparotmy and right thoracotomy was planned., Results: Patient refused to undergo any further surgical procedure. She was discharged from the clinic with a prescription ofAlbendazole 400 mg twice a day for an indefinite period., Conclusion: Symptomatic or large cysts should be surgically treated. In cases suspected of having peritoneal spillage, antihelminthic drugs should be administered. In addition, small asymptomatic cysts, some daughter cysts, and peritoneal secondary cysts and splenic cysts may also be effectively treated with Albendazole.