Rutaecarpine-inspired scaffold-hopping strategy and Ullmann cross-coupling based synthetic approach: Identification of pyridopyrimidinone-indole based novel anticancer chemotypes.

Natural products as starting templates have shown historically major contribution to development of drugs. Inspired by the structure-function of an anticancer natural alkaloid Rutaecarpine, the Scaffold-hopped Acyclic Analogues of Rutaecarpine (SAAR) with 'N'-atom switch (1°-hop) and ring-opening (2°-hop) were investigated. A new synthetic route was developed for an effective access to the analogues, i.e. 2-indolyl-pyrido[1,2-a]pyrimidinones, which involved preparation of N-Boc-N'-phthaloyltryptamine/mexamine-bromides and pyridopyrmidinon-2-yl triflate, a nickel/palladium-catalysed Ullmann cross-coupling of these bromides and triflate, deprotection of phthalimide followed by N-aroylation, and Boc-deprotection. Fourteen novel SAAR-compounds were prepared, and they showed characteristic antiproliferative activity against various cancer cells. Three most active compounds (11a, 11b, and 11c) exhibited good antiproliferative activity, IC50 7.7-15.8 µM against human breast adenocarcinoma cells (MCF-7), lung cancer cells (A549), and colon cancer cells (HCT-116). The antiproliferative property was also observed in the colony formation assay. The SAAR compound 11b was found to have superior potency than original natural product Rutaecarpine and an anticancer drug 5-FU in antiproliferative activities with relatively lower cytotoxicity towards normal breast epithelial cells (MCF10A) and significantly higher inhibitory effect on cancer cells' migration. The compound 11b was found to possess favourable in silico physicochemical characteristics (lipophilicity-MLOGP, TPSA, and water solubility-ESOL, and others), bioavailability score, and pharmacokinetic properties (GI absorption, BBB non-permeant, P-gp, and CYP2D6). Interestingly, the compound 11b did not show any medicinal chemistry structural alert of PAINS and Brenk filter. The study represents for the first time the successful discovery of new potent anticancer chemotypes using Rutaecarpine natural alkaloid as starting template and reaffirms the significance of natural product-inspired scaffold-hopping technique in drug discovery research.

Decoding the ubiquitin language: Orchestrating transcription initiation and gene expression through chromatin remodelers and histones.

Eukaryotic transcription is a finely orchestrated process and it is controlled by transcription factors as well as epigenetic regulators. Transcription factors and epigenetic regulators undergo different types of posttranslational modifications including ubiquitination to control transcription process. Ubiquitination, traditionally associated with protein degradation, has emerged as a crucial contributor to the regulation of chromatin structure through ubiquitination of histone and chromatin remodelers. Ubiquitination introduces new layers of intricacy to the regulation of transcription initiation through controlling the equilibrium between euchromatin and heterochromatin states. Nucleosome, the fundamental units of chromatin, spacing in euchromatin and heterochromatin states are regulated by histone modification and chromatin remodeling complexes. Chromatin remodeling complexes actively sculpt the chromatin architecture and thereby influence the transcriptional states of genes. Therefore, understanding the dynamic behavior of nucleosome spacing is critical as it impacts various cellular functions through controlling gene expression profiles. In this comprehensive review, we discussed the intricate interplay between ubiquitination and transcription initiation, and illuminated the underlying molecular mechanisms that occur in a variety of biological contexts. This exploration sheds light on the complex regulatory networks that govern eukaryotic transcription, providing important insights into the fine orchestration of gene expression and chromatin dynamics.

The Use of Preputial Dartos Flap in the Primary Repair of Distal Hypospadias: A Single-centre Experience.

Background: An additional flap during the tubularization of incised urethral plate urethroplasty (TIPU) is believed to minimize the postoperative complications. It is still debatable whether using an additional flap is worth the risk given the hazards associated with doing so. This study aims to re-evaluate the benefits and drawbacks of TIPU with or without a preputial dartos (PD) flap. Materials and Methods: We assessed the results of patients with distal hypospadias who underwent surgery in our institute over the past 2 years. The urethral plate's width, thickness, and depth, the periurethral tissue's quality, and the width of the glans at the mid-glans level determined whether the neourethra was covered with a PD flap or left uncovered. Data on intra-operative blood loss, operating time, length of hospital stay, postoperative complications, and outcome were analysed. Results: There were 96 patients: 58 received an extra PD flap, whereas the other 38 did not. In the flap group, ventral skin necrosis was a prevalent problem, whereas meatal stenosis predominated in the no-flap group. Both the flap group (25.66%) and the no-flap group (23.86%) experienced comparable postoperative complications (P = 0.503). In comparison to the no-flap group, the flap group showed statistically significant differences (P<0.001) in intra-operative blood loss (22.10 ± 6.96 vs. 10.34 ± 3.02 mL), operating time (96.34 ± 6.661 vs. 71.39 ± 9.76 min), and hospital stay (10.04 ± 0.87 vs. 8.47 ± 1.64 days). Conclusion: The additional PD flap does not always affect the result of TIPU in terms of complications.

Atypical presentations of hydatid cyst in children and their management.

Hydatid cyst (HC) is uncommon in children and usually involves a single organ, the lung being the most common site followed by the liver. A series of 18 children who presented with HC at different organs of the body managed at our institute over a period of 5 years is presented here. The clinico-radiological evaluation was done in all patients followed by pharmacotherapy/surgery and was followed up for 2 years. Demographic data, organs of involvement, clinical presentations and investigations, response to oral albendazole therapy, surgical procedures, operative findings, perioperative clinical courses, and surgical outcomes were recorded. The mean age of presentation was 7.7 years with a male:female ratio of 11:7. All patients were symptomatic at presentation and four (22.22%) had atypical symptoms (obstructive jaundice, bladder outlet obstruction, and acute abdominal pain). Liver HC was more common than lung HC. Three patients (16.6%) had synchronous involvement of the lung and liver/spleen. All the patients underwent surgical excision of the cyst as none of them responded to preoperative pharmacotherapy. Open surgery was done in 15 patients and laparoscopic excision was carried out in three (16.6%). Two patients had abnormal communications (cysto-biliary/cysto-bronchial), which were managed successfully. Neither any major perioperative morbidity nor mortality was nor any recurrence was seen in a 2-year clinical follow-up, no significant perioperative morbidity or mortality occurred, and no recurrence was noted. In conclusion, single organ HC is more common in children, with more prevalence of hepatic than pulmonary HC. Early surgical excision of the cyst should be considered (preferably laparoscopic whenever possible) instead of pharmacotherapy.

Esophageal Atresia and Tracheoesophageal Fistula: A Retrospective Review from a Tertiary Care Institute.

Background: A survey of neonates with esophageal atresia and tracheoesophageal fistula (EA ± TEF) to determine additional factors responsible for poor surgical outcomes in our institution where employing an improved standard of care can ameliorate the outcome. Materials and Methods: We carried out a retrospective review of 54 neonates, who underwent surgical repair of EA± TEF over a 5-year period. We collected data regarding the patients' demographics, perioperative findings, records of neonatal intensive care, and ascertained the effects of gender, gestational age, birth weight, age at operation, type of anomaly, coexisting major anomalies, preoperative inotrope therapy, and duration of postoperative ventilation on the surgical outcome. Results: The mortality rate was 51.9%, out of which, 42.8% of neonates succumbed to ventilator-associated conditions. Age at the time of surgery, gestational age, preoperative inotrope support, presence of coexisting anomalies, and duration of postoperative ventilation were determined as the significant variables predicting mortality(P < 0.05). The area under the Receiver Operating Curve showed the duration of postoperative ventilation as the best indicator of mortality. The Logistic regression model (χ2 = 11.204, P = 0.019) with the above-mentioned variables showed that neonates who were operated before 2.5 days and who required <74.5 hours of postoperative ventilation were 3.91 and 48.30 times more likely to survive respectively, than their counterparts. Conclusion: A delay in surgery due to delayed diagnosis and or delayed transportation to tertiary centres and prolonged ventilatory support have an additional detrimental effect on the surgical outcomes of EA ± TEF.

Empyema Thoracis in Children: A 5-Year Experience in a Tertiary Care Institute.

OBJECTIVE: Empyema thoracis (ET) in children is a disease of significant morbidity and mortality. In the event of failure to resolute following intercostal chest tube drainage (ICD), thoracotomy decortication (TDC) remains the treatment of choice. We have reviewed the outcome of management of 96 cases of ET with the intent to establish the scope of ICD as primary form of the management. MATERIALS AND METHODS: This is a retrospective study of 96 patients of ET who were managed in pediatric surgery department over a period of 5 years (April 2013 - March 2018). Ninety-six patients at a single center met inclusion criteria for having ET and underwent ICD. We excluded the cases where video-assisted thoracoscopic surgery was provided as primary treatment. The patients were categorized into complicated and uncomplicated groups. Those with pyopneumothorax, encysted empyema, multiloculated empyema, and bilateral ET were assigned as complicated group. There were two treatment groups: (I) those responded with ICD alone (II) those with ICD followed by TDC. RESULTS: All 96 cases received ICD as primary management. There were 54 uncomplicated cases and 42 complicated cases. Out of 42 complicated cases, 26 patients recovered with ICD alone and 16 patients needed TDC. A total of 80 (83.33%) patients (54 uncomplicated ± 26 complicated) recovered with ICD alone. Significant complications were encountered in follow-up of patients who underwent delayed thoracotomy in the form of overriding of the ribs (n = 3) and postoperative air leak (n = 4). There was no mortality in our series. CONCLUSION: Early initiation of management of ET with intercostal tube drainage is simple, safe, effective even in complicated cases, and has less complications. Thoracotomy with decortication should be reserved for ICD failure cases.

Isolated Mediastinal Pseudocyst of the Pancreas.

BACKGROUND: Mediastinal pancreatic pseudocyst is a rare complication of pancreatitis. CASE CHARACTERISTICS: An 8-year-old boy with chest pain and shortness of breath. Computed tomography of chest showed a cystic mass in the mediastinum. The cyst aspirate revealed high amylase and lipase levels, suggestive of pancreatic pseudocyst. OUTCOME: The patient gradually recovered after Roux-en-Y cystojejunostomy. MESSAGE: Cysto-jejunostomy is a viable treatment option for mediastinal pancreatic pseudocyst, especially with failure of medical therapy.

Laparoscopy in the Evaluation of Impalpable Testes and Its Short-term Outcomes: A 7 Years' Experience.

AIMS: The aim of this study is to report and analyze results of laparoscopy in impalpable testes performed between 2009 and 2016 and its short-term outcomes. MATERIALS AND METHODS: Demographic data, laterality, laparoscopic findings, operative time, procedure, hospital stay, complications, and follow-up data of 76 patients with 79 impalpable testes from 2009 to 2016 were retrospectively collected and analyzed. Successful outcome was defined as maintenance of intrascrotal position with no atrophy at a follow-up of at least 6 months. RESULTS: Impalpable testes constituted 24% of undescended testes in our series. Mean age was 3.9 years. Forty-two patients had left-sided, 31 right-sided, and three bilateral impalpable testes. Of the 79 clinically impalpable testes, on laparoscopy, 3 were vanishing testes, 52 were intra-abdominal (6 high-lying and 46 low-lying), 18 canalicular and 6 nubbin testes. Ultimately, 52 underwent laparoscopic orchiopexy: 46 single-staged orchiopexy and 6 two-staged Fowler-Stephens procedure. Mean operating time was 77 min. Complications were few and mostly minor. Eleven patients were lost in follow-up. On a mean follow-up of 23 months, one testis that underwent single-staged laparoscopic orchiopexy atrophied whereas good size and intrascrotal position were maintained in the rest. CONCLUSIONS: Laparoscopy in impalpable testes was safe, feasible, and effective. Overall outcome was good which was obtained by minimal use of electrocautery, dissection with wide strip of peritoneum and extensive retroperitoneal dissection for mobilization. There is a need for wide reporting of cases from high-volume pediatric surgery centers in India.

Delayed primary end-to-end anastomosis for traumatic long segment urethral stricture and its short-term outcomes.

BACKGROUND:: The purpose of this study is to evaluate the aetiology of posterior urethral stricture in children and analysis of results after delayed primary repair with extensive distal urethral mobilisation. MATERIALS AND METHODS: This was a retrospective study carried out in a tertiary care centre from January 2009 to December 2013. RESULTS:: Eight children with median age 7.5 years (range 4-11 years), underwent delayed anastomotic urethroplasty: Six through perineal and two through combined perineal and transpubic approach. All the eight children had long-segment >2 cm stricture: Three posterior and five anterior urethral stricture. On a mean follow-up period of 33 months (range 24-48 m), all were passing urine with good flow and stream. CONCLUSION:: End-to-end anastomosis in post-traumatic long segment posterior urethral stricture between prostatic and penile urethra in children is possible by perineal or combined perineal and transpubic approach with good results without any urethral replacement.

Prolapsing cystitis cystica causing bladder outlet obstruction: An unusual complication.

Cystitis cystica (CC) is aproliferative disorder of bladder urothelium and usually subsides with medical therapy. However, this is not true for severe CC where surgical intervention is required to control breakthrough urinary tract infection (UTI). It may be mistaken as bladder neoplasm or posterior urethral valve, especially in children. Here, we report a case of CC in a 2-year-old boy where we had to excise the large pedunculated intravesical lesion to control breakthrough UTI and ongoing renal damage.

Intragastric pressure: Useful indicator in the management of congenital diaphragmatic hernia.

AIMS: To assess the role of measuring of intragastric pressure (IGP) during closure of congenital diaphragmatic hernia. MATERIALS AND METHODS: Thirty-two cases were included in the study (August 2008 to February 2014), and IGP has been measured intraoperatively during closure. RESULT: Patients were categorized in group A (15 patients), group B (14 patients) and group C (3 patients). In group C, IGP was more than 30 cm of water pressure and all of tehm required creation of ventral hernia and ventilator support. CONCLUSION: Measurement of IGP as an objective, noninvasive and simple method to evaluate intra-abdominal pressure and prevention of abdominal compartment syndrome and intraoperative IGP value determines the types of abdominal closure.

Uncommon renal tumors in children: A single center experience.

AIMS: Scrutiny over the clinical behaviors, management, and the final outcome of some rare renal neoplasm in order to find out some hidden facts about these tumors which are playing an important role in the disease course and its management. MATERIALS AND METHODS: Retrospective evaluation of uncommon (non-Wilms') renal neoplasm in the pediatric population in a tertiary care center. Fifteen cases of uncommon renal tumors were treated in our institution over the last 5 years (January 2008 to December 2012). The cases were tabulated in the form of age, sex, mode of presentation, preoperative investigations, intraoperative grading, pathological type, postoperative management and the final outcome. The patients were followed up for 2 years (clinically every 3 months and ultrasonography abdomen in every 6 months for first 2 years) in order to see any evidence of recurrence and complications related to postoperative chemotherapy. RESULTS: Out of 15 cases, four cases were clear cell sarcoma (CCS) (26.6%), three cases were rhabdoid tumor (20%), three cases were congenital mesoblastic nephroma (20%), two cases were multilocular cystic nephroma (13.3%), two cases were renal teratoma (13.3%), and one case of teratoid Wilms' tumor (6.6%). There were two deaths (one CCS and one rhabdoid tumor) due to chemotherapy-related toxicity but no recurrence. Three patients were lost during postoperative follow-up; ten patients are doing well and getting a regular visit in the follow-up clinic. CONCLUSION: The clinical presentations of these uncommon renal tumors are similar to that of Wilms' tumor. Thus, preoperative diagnosis is difficult even with modern imaging techniques. Some of these tumors (CCS, rhabdoid tumor) are rapidly progressing and have a poor outcome. Hence, early intervention in the form of complete surgical resection of the tumor (whenever possible) and postoperative chemo/radiotherapy are imperative for fruitful outcome.

Shanghai Fever: A Fatal Form of Pseudomonas Aeruginosa Enteric Disease.

BACKGROUND: Outcome of pseudomonas enteric fever is unpredictable as multiple systemic lethal complications occur abruptly. CASE CHARACTERISTICS: A 9-month-old girl with multiple ileal perforations, leukocoria, ecthyma gangrenosum, hemiplegia and a perforated ulcer in the soft palate. Blood culture suggested Pseudomonas aeruginosa infection. Operative repair of multiple ileal perforations and multidisciplinary management was provided. OUTCOME: On 10th post-operative day, patient succumbed to multiple organ dysfunction syndrome. MESSAGE: Early detection and management of complications of P. aeruginosa enteric disease is important.

Colonic atresia associated with annular pancreas: An extremely rare and previously unreported association.

Colonic atresia is the rarest entity among the all intestinal atresias and may be associated with anterior abdominal wall defect, small intestinal atresia, Hirschsprung's disease, and other anomalies. Here, we are reporting a case of colonic atresia associated with annular pancreas, which has not been reported previously to the best of our knowledge.

Congenital cystic lesions of lung in the paediatric population: A 5-year single institutional study with review of literature.

BACKGROUND: The aim was to evaluate the clinical presentation, investigation modalities, operative management, pathology, outcome (morbidity and mortality) and short term follow-up of congenital cystic lesions of the lung. MATERIALS AND METHODS: This is a retrospective study. Study period was 5 years (December 2008-November 2013) in the Department of paediatric surgery, Nil Ratan Sircar Medical College. STUDY POPULATION: Total number = 10 patients. Age range: 2 days-7 years. (Neonate-4). Male and female ratio = 1:1. RESULT: Among 10 cases of lung cyst four having congenital lobar emphysema, four having congenital pulmonary airway malformation, one sequestration and one teratoma. All patients have undergone surgical excision in terms of lobectomy or excision of the lesion. Post-operative histopathology confirmed the diagnosis. Recovery was uneventful. CONCLUSION: Although our experience is limited, operative management of lung cysts seems to be safe with rewarding results. However we are yet to encounter many of the other varieties of the cysts found in the lung, which may be associated with other congenital anomalies and have an impact on prognosis.

Patent Urachus in a Neonate: a Rarity.

Here, we present a pictorial description of a rare case of patent urachus in a neonate and its management.