Synthesis, characterization and photophysical studies of dual-emissive base-modified fluorescent nucleosides.

A straightforward and efficient methodology has been employed for the synthesis of a diverse set of base-modified fluorescent nucleoside conjugates via Cu(I)-catalysed cycloaddition reaction of 5-ethynyl-2',3',5'-tri-O-acetyluridine/3',5'-di-O-acetyl-2'-deoxyuridine with 4-(azidomethyl)-N9-(4'-aryl)-9,10-dihydro-2H,8H-chromeno[8,7-e][1,3]oxazin-2-ones in tBuOH to afford the desired 1,2,3-triazoles in 92-95% yields. Treatment with NaOMe/MeOH resulted in the final deprotected nucleoside analogues. The synthesized 1,2,3-triazoles demonstrated a significant emission spectrum, featuring two robust bands in the region from 350-500 nm (with excitation at 300 nm) in fluorescence studies. Photophysical investigations revealed a dual-emissive band with high fluorescence intensity, excellent Stokes shift (140-164 nm) and superior quantum yields (0.068-0.350). Furthermore, the electronic structures of the synthesized triazoles have been further verified by DFT studies. Structural characterization of all synthesized compounds was carried out using various analytical techniques, including IR, 1H-NMR, 13C-NMR, 1H-1H COSY, 1H-13C HETCOR experiments, and HRMS measurements. The dual-emissive nature of these nucleosides would be a significant contribution to nucleoside chemistry as there are limited literature reports on the same.

Phenyliodine bis(trifluoroacetate) as a sustainable reagent: exploring its significance in organic synthesis.

Iodine-containing molecules, especially hypervalent iodine compounds, have gained significant attention in organic synthesis. They are valuable and sustainable reagents, leading to a remarkable surge in their use for chemical transformations. One such hypervalent iodine compound, phenyliodine bis(trifluoroacetate)/bis(trifluoroacetoxy)iodobenzene, commonly referred to as PIFA, has emerged as a prominent candidate due to its attributes of facile manipulation, moderate reactivity, low toxicity, and ready availability. PIFA presents an auspicious prospect as a substitute for costly organometallic catalysts and environmentally hazardous oxidants containing heavy metals. PIFA exhibits remarkable catalytic activity, facilitating an array of consequential organic reactions, including sulfenylation, alkylarylation, oxidative coupling, cascade reactions, amination, amidation, ring-rearrangement, carboxylation, and numerous others. Over the past decade, the application of PIFA in synthetic chemistry has witnessed substantial growth, necessitating an updated exploration of this field. In this discourse, we present a concise overview of PIFA's applications as a 'green' reagent in the domain of synthetic organic chemistry. A primary objective of this article is to bring to the forefront the scientific community's awareness of the merits associated with adopting PIFA as an environmentally conscientious alternative to heavy metals.

Solvent-free synthesis and in-silico molecular docking study of (E)-3-(ß-C-glycosylmethylidene)-N-aryl/alkyl succinimides.

Globally, human papillomavirus (HPV) infection is the leading cause of mortality associated with cervical cancer, oral cancer (oropharyngeal), and head and neck squamous cell carcinoma (HNSCC). It is essential to explore anti-cancer drugs against life-threatening HPV infections. Aiming to search for potentially better anticancer agents, a small library of ß-C-glycosylated methylidene succinimides have been synthesized under bulk and mechanical grinding conditions using the Wittig olefination reaction. Thus, the reaction of different 2,3,4,6-tetra-O-benzyl-C-glycosyl aldehydes with N-aryl/alkyl maleimides in the presence of PPh3 at 25 °C under bulk and mechanical grinding conditions results in the formation of stereochemically defined (E)-3-(2,3,4,6-tetra-O-benzyl-C-glycosylmethylidene)-N-alkyl/phenyl succinimides, which upon debenzylation with 1 M BCl3 in DCM at -78 °C lead to the synthesis of (E)-3-(C-glycosylmethylidene)-N-alkyl/phenyl succinimides in good to excellent yields. The developed methodology is efficient and environmentally benign because there is no use of organic solvents, and the products are obtained in a stereochemically defined form and in high yields. The aqueous solubility of all synthesized ß-C-glycosylated methylidene succinimides makes them potential candidates for the evaluation of their different biological activities. In the present work, the synthesized glycosylated alkylidine succinimides were subjected to an in-silico molecular docking study against the E6 oncoprotein of high-risk type HPV16, which is responsible for the inactivation of the tumor suppressor p53 protein. Analysis of the molecular docking data revealed that the synthesized compounds are effective inhibitors of HPV infection, which is the cause of oral, head and neck, and cervical cancer. In comparison with the positive control 5-FU, an anti-cancer drug used in chemotherapy, more than fifteen compounds were found to be better E6 protein inhibitors.

Peptide cargo administration: current state and applications.

Effective delivery of drug molecules to the target site is a challenging task. In the last decade, several innovations in the drug delivery system (DDS) have tremendously improved the therapeutic efficacy of drug molecules. Among various DDS, cell-penetrating peptides (CPPs) based DDS have gathered notable attention owing to their safety, efficacy, selectivity, specificity, and ease of synthesis. CPPs are emerging as an efficient and effective pharmaceutical nanocarriers-based platforms for successful management of various important human health disorders. Failure of several current chemotherapeutic strategies is attributed to low solubility, reduced bioavailability, and off-target delivery of several anti-cancer drugs. Similarly, development of therapeutics for vision-threatening disorders is challenged by the anatomical as well as physiological complexity of the eye. Such therapeutic challenges in cancer and ocular disease management can be overcome by developing cell-penetrating peptide (CPP) based peptide drug conjugates (PDCs). CPPs can be used to deliver various types of cargo molecules including nucleic acids, small molecules, and peptides/proteinaceous agents. In this review, we have briefly introduced CPPs and the linker strategies employed for the development of PDCs. Furthermore, recent studies employing CPP-based PDCs for cancer and ocular disease management have been discussed in detail highlighting their significance over conventional DDS. Later sections of the review are focused on the current status of clinical trials and future implications of CPP-based PDCs in vaccine development. KEY POINTS: • Cell-penetrating peptides (CPPs) can deliver a variety of cargo macromolecules via covalent and non-covalent conjugation. • CPP-based peptide drug conjugates (PDCs) can overcome drawbacks of conventional drug delivery methods such as biocompatibility, solubility, stability, and specificity. • Various PDCs are in clinical trial phase for cancer and ocular therapeutics.

Prevalence of obsessive-Compulsive symptoms and the level of fear due to COVID-19 pandemic among the undergraduate medical students in a tertiary care unit in Southern India.

Background: The emergence of COVID-19 and its consequences is causing widespread fears, anxiety, and worries. To overcome the transmission of COVID-19, people resorted to compulsive behaviors. Objectives: The objectives of this study were to assess the prevalence of obsessive-compulsive symptoms (OCSs) due to COVID-19 pandemic, the prevalence of level of fear due to COVID-19 pandemic, and to assess the factors associated with OCSs due to COVID-19 pandemic among the undergraduate medical students of in tertiary unit in Southern India. Methods: The cross-sectional study was conducted in 250 undergraduate medical students (both MBBS and BDS, from 1st to 4th year) in the institute. Students who had consented in the study were included as study participants. The Yale-Brown Obsessive-Compulsive Scale and Fear of COVID-19 Scale (FCV-19 S) were used in assessing OCSs and the level of fear due to COVID-19. Chi-square test and multiple logistic regression were used to compute the factors associated with OCS. Results: The mean age of the respondents was 21 ± 1.313 years. The prevalence of OCS in undergraduate medical students was 36 (14.4%), and the level of FCV-19 was 107 (42.8%). Male students (17.8%, 44.2%) had higher OCSs and levels of fear as compared to female students (13.6%, 42.4%). Students with FCV-19 were three (adjusted odds ratio-3.418, 95% confidence interval-1.596, 7.319) times more likely to manifest OCSs while factors such as age, gender, and course were not significantly associated with OCS. Conclusion: Psychological counseling for undergraduate students should be pivotal, especially during pandemics and outbreaks.

A double-blind, placebo-controlled randomized clinical trial to evaluate the efficacy of tranexamic acid in irrigant solution on blood loss during percutaneous nephrolithotomy: a pilot study from tertiary care center of North India.

PURPOSE: To evaluate the efficacy and safety of 0.1% tranexamic acid in irrigant fluid in reducing blood loss during PCNL. MATERIALS AND METHODS: The study involved 400 patients who were planned for PCNL and were prospectively randomized into two equal groups. In tranexamic group, 0.1% tranexamic acid was given in irrigant fluid, while in placebo group, distilled water was added to irrigant fluid during surgery. Operative data were recorded which included fall in hemoglobin, total blood loss, operative time, irrigation fluid, length of stay in hospital, requirement of blood transfusion, complications related to PCNL and adverse events of tranexamic acid. RESULTS: Baseline parameters were comparable between two groups. The fall in hemoglobin and total blood loss in the tranexamic group was significantly lower than placebo group (1.71 vs. 2.67 gm/dL, 154.55 vs. 212.61 mL, respectively, p < 0.0001). Operative time, amount of irrigation fluid used and hospital stay of tranexamic group were significantly less compared to placebo (p < 0.05). Complete stone clearance rate was 88% in tranexamic group versus 82% in placebo (p = 0.12). The blood transfusion requirement was significantly lower in the tranexamic group versus placebo (5 vs. 12.5%, p = 0.012), as was the complication rate (19 vs. 28%, p = 0.044). The requirement of angioembolization in the tranexamic group was significantly less as compared to placebo (0.5 vs. 4%, p = 0.03). No adverse events related to administration of tranexamic acid were noted. CONCLUSIONS: 0.1% tranexamic acid in irrigant fluid is safe and significantly reduces perioperative blood loss and requirement of blood transfusion during percutaneous nephrolithotomy. It is associated with lower perioperative complication rates.

Predictors of successful trial without catheter following acute urinary retention in benign prostatic enlargement: A single centre, multivariate analysis.

OBJECTIVE: To evaluate the parameters which predict the success or failure of trial without catheter (TWOC) for acute urine retention (AUR). MATERIALS AND METHODS: Medical records of 2 188 patients presenting with first episode of AUR were analyzed. All patients underwent catheterization and were started on α-blocker followed by TWOC. Age, baseline American urological association (AUA) score, prostate volume (PV), residual volume of urine (RV) and intravesical prostatic protrusion (IPP), prostate specific antigen (PSA) were recorded. RESULTS: TWOC was successful in 737 patients (33.7%) and failed in 1 451 patients (66.3%). Patients with successful TWOC had lower mean age, PV, IPP, RV, AUA score, and PSA than those with failed TWOC. On multivariate analysis, the significant independent predictors were IPP, age, AUA score, PV, and RV at odds ratios of 3.11, 1.84, 1.78, 1.53, and 1.23, respectively. From ROC curve, IPP had cut off value of 9 mm and detected success of TWOC with sensitivity (S) of 91% and failure with specificity (s) of 90%. Similarly, cut off value of 64 years for age (S:86%, s:87%), 20 for AUA symptom score (S:83%, s:81%), 56 cc for PV (S:80%, s:74%) and 750 mL for RV (S:71%, s:68%) were obtained. CONCLUSION: Age, baseline AUA score, IPP, PV, and RV independently predict the outcome of TWOC. Patients with IPP > 9 mm, age > 65 years, baseline AUA score > 20, PV > 56 cc, or RV > 750 mL have less probability of successful TWOC in AUR and can be considered for immediate surgery following an episode of AUR.

Natural product inspired diastereoselective synthesis of sugar-derived pyrano[3,2-c]quinolones and their in-silico studies.

Herein, we report the development of a diastereoselective and efficient route to construct sugar-derived pyrano[3,2-c]quinolones utilizing 1-C-formyl glycal and 4-hydroxy quinolone annulation. This methodology will open a route to synthesize nature inspired pyrano[3,2-c]quinolones. This is the first report for the stereoselective synthesis of sugar-derived pyrano[3,2-c]quinolones, where 100% stereoselectivity was observed. A total of sixteen compounds have been synthesized in excellent yields with 100% stereoselectivity. The molecular docking of the synthesized novel natural product analogues demonstrated their binding modes within the active site of type II topoisomerase. The results of the in-silico studies displayed more negative binding energies for the all the synthesized compounds in comparison to the natural product huajiosimuline A, indicating their affinity for the active pocket. Ten out of the sixteen novel synthesized compounds were found to have comparative or relatively more negative binding energy in comparison to the standard anti-cancer drug, doxorubicin. Additionally, the scalability and viability of this protocol was illustrated by the gram scale synthesis.

Recent advances in the synthesis and utility of thiazoline and its derivatives.

Thiazolines and their derivatives hold significant importance in the field of medicinal chemistry due to their promising potential as pharmaceutical agents. These molecular entities serve as critical scaffolds within numerous natural products, including curacin A, thiangazole, and mirabazole, and play a vital role in a wide array of physiological reactions. Their pharmacological versatility encompasses anti-HIV, neurological, anti-cancer, and antibiotic activities. Over the course of recent decades, researchers have extensively explored and developed analogs of these compounds, uncovering compelling therapeutic properties such as antioxidant, anti-tumor, anti-microbial, and anti-inflammatory effects. Consequently, thiazoline-based compounds have emerged as noteworthy targets for synthetic endeavors. In this review, we provide a comprehensive summary of recent advancements in the synthesis of thiazolines and thiazoline-based derivatives, along with an exploration of their diverse potential applications across various scientific domains.

Advances in chromone-based copper(ii) Schiff base complexes: synthesis, characterization, and versatile applications in pharmacology and biomimetic catalysis.

Chromones are well known as fundamental structural elements found in numerous natural compounds and medicinal substances. The Schiff bases of chromones have a much wider range of pharmacological applications such as antitumor, antioxidant, anti-HIV, antifungal, anti-inflammatory, and antimicrobial properties. A lot of research has been carried out on chromone-based copper(ii) Schiff-base complexes owing to their role in the organometallic domain and promise as potential bioactive cores. This review article is centered on copper(ii) Schiff-base complexes derived from chromones, highlighting their diverse range of pharmacological applications documented in the past decade, as well as the future research opportunities they offer.

Recent advances in synthesis of sugar and nucleoside coumarin conjugates and their biological impact.

Naturally occurring coumarin and sugar molecules have a diverse range of applications along with superior biocompatibility. Coumarin, a member of the benzopyrone family, exhibits a wide spectrum of medicinal properties, such as anti-coagulant, anti-bacterial, anti-tumor, anti-oxidant, anti-cancer, anti-inflammatory and anti-viral activities. The sugar moiety functions as the central scaffold for the synthesis of complex molecules, attributing to their excellent biocompatibility, well-defined stereochemistry, benign nature and outstanding aqueous solubility. When the coumarin moiety is conjugated with the sugar or nucleoside molecule, the resulting conjugates exhibit significant biological properties. Due to the remarkable growth of such bioconjugates in the field of science over the last decade, owing to their future prospect as a potential bioactive core, an update to this area is very much needed. The present review focusses on the synthesis, characterization and the various therapeutic applications of coumarin conjugates, i.e., sugar and nucleoside coumarin conjugates along with their perspective for future research.

Temporal Bone Osteomyelitis Masquerading as Malignancy: A Diagnostic Challenge.

Xanthogranulomatous osteomyelitis is a rare chronic inflammatory disorder. Until now, it has only been reported in long bones. To the best of our knowledge, it has never been reported in temporal bone. We present the case of this rare disease in a 64-year-old male involving the temporal bone, presenting with ear pain, discharge, decreased hearing, and granulation tissue in the external auditory canal, mimicking malignancy clinically and radiologically. The patient was unresponsive to medical management and was taken up for surgical debridement, followed by treatment with systemic and topical antibiotics, with a successful outcome. As this disease has not been reported in the literature yet in the temporal bone and mimics malignancy, it must be differentiated on histopathology to establish a definite diagnosis and provide appropriate management. A long-term follow-up is also necessary to recognize the clinical behavior of this disease, as no treatment protocol has been established yet.

Efficient synthesis of glycosylated imidazo[1,2-a]pyridines via solvent catalysed Groebke-Blackburn-Bienayme reaction.

A solvent catalysed and metal catalyst-free Groebke-Blackburn-Bienayame three component reaction (GBB-3CR) has been developed for the synthesis of 2-(ß-D-glycal-1-yl)-3-N-alkylamino-1-azaindolizines and 2-alkyl/aryl/heteroaryl-3-N-alkylamino-1-azaindolizines. The modified GBB reaction protocol is highly efficient, versatile, atom economic and has been performed in hexafluoroisopropanol (HFIP) without any added catalyst. The GBB-3CR showed high tolerance for a large no of substrates in term of aldehydes, differently substituted 2-aminopyridines and isocyanides without being affected by the presence of electron donating and electron withdrawing substituents at either aldehydes or 2-aminopyridines.

Autistic traits and individual brain differences: functional network efficiency reflects attentional and social impairments, structural nodal efficiencies index systemising and theory-of-mind skills.

BACKGROUND: Autism is characterised not only by impaired social cognitive 'empathising' but also by superior rule-based 'systemising'. These cognitive domains intertwine within the categorical diagnosis of autism, yet behavioural genetics suggest largely independent heritability, and separable brain mechanisms. We sought to determine whether quantitative behavioural measures of autistic traits are dimensionally associated with structural and functional brain network integrity, and whether brain bases of autistic traits vary independently across individuals. METHODS: Thirty right-handed neurotypical adults (12 females) were administered psychometric (Social Responsiveness Scale, Autism Spectrum Quotient and Systemising Quotient) and behavioural (Attention Network Test and theory-of-mind reaction time) measures of autistic traits, and structurally (diffusion tensor imaging) and functionally (500 s of 2 Hz eyes-closed resting fMRI) derived graph-theoretic measures of efficiency of information integration were computed throughout the brain and within subregions. RESULTS: Social impairment was positively associated with functional efficiency (r = .47, p = .006), globally and within temporo-parietal and prefrontal cortices. Delayed orienting of attention likewise was associated with greater functional efficiency (r = - .46, p = .0133). Systemising was positively associated with global structural efficiency (r = .38, p = 0.018), driven specifically by temporal pole; theory-of-mind reaction time was related to structural efficiency (r = - .40, p = 0.0153) within right supramarginal gyrus. LIMITATIONS: Interpretation of these relationships is complicated by the many senses of the term 'connectivity', including functional, structural and computational; by the approximation inherent in group functional anatomical parcellations when confronted with individual variation in functional anatomy; and by the validity, sensitivity and specificity of the several survey and experimental behavioural measures applied as correlates of brain structure and function. CONCLUSIONS: Functional connectivities highlight distributed networks associated with domain-general properties such as attentional orienting and social cognition broadly, associating more impaired behaviour with more efficient brain networks that may reflect heightened feedforward information flow subserving autistic strengths and deficits alike. Structural connectivity results highlight specific anatomical nodes of convergence, reflecting cognitive and neuroanatomical independence of systemising and theory-of-mind. In addition, this work shows that individual differences in theory-of-mind related to brain structure can be measured behaviourally, and offers neuroanatomical evidence to pin down the slippery construct of 'systemising' as the capacity to construct invariant contextual associations.

Detection of SAR-CoV-2 on surfaces in food retailers in Ontario.

The COVID-19 pandemic has generated increased interest in potential transmission routes. In food retail settings, transmission from infected customers and workers and customers through surfaces has been deemed plausible. However, limited information exists on the presence and survival of SARS-CoV-2 on surfaces, particularly outside laboratory settings. Therefore, the purpose of this project was to assess the presence of the virus at commonly found surfaces at food retail stores and the potential role that these spaces play in virus transmission. Samples (n=957) were collected twice a week for a month in food-retail stores within Ontario, Canada. High-touch surfaces were identified and surveyed in 4 zones within the store (payment stations, deli counters, refrigerated food section and carts and baskets). The samples were analyzed using a molecular method, i.e., reverse transcriptase quantitative Polymerase Chain Reaction (RT-qPCR). Regardless of the store's location, the sampling day or time, the location of the surface within the store or the surface material, all samples tested negative for SARS-CoV-2. These results suggest that the risk of exposure from contaminated high-touch surfaces within a food retailer store is low if preventive measures and recommended sanitizing routines are maintained.

What's in a Hub?-Representing Identity in Language and Mathematics.

Hubs emerge in structural and resting state network analysis as areas highly connected to other parts of the brain and have been shown to respond to several task domains in functional imaging studies. A cognitive explanation for this multi-functionality is still wanting. We propose, that hubs subserve domain-general meta-cognitive functions, relevant to a variety of domain-specific networks and test this hypothesis for the example of processing explicit identity information. To isolate this meta-cognitive function from the processing of domain-specific context, we investigate the overlapping activations to linguistic identity processes (e.g. Mr. Dietrich is the dentist) on the one hand and numerical identity processes (e.g. do "3 × 8" and "36-12" give the same number) on the other hand. The main question was, whether these overlapping activations would fall within areas, consistently identified as hubs by network-based analyses. Indeed, the two contrasts showed significant conjunctions in the left inferior parietal lobe (IPL), precuneus (PC), and posterior cingulate. Accordingly, identity processing may well be one domain-general meta-cognitive function that hub-areas provide to domain-specific networks. For the parietal lobe we back up our hypothesis further with existing reports of activation peaks for other tasks that depend on identity processing, e.g., episodic recollection, theory of mind, and visual perspective taking.

Increased Expression of Oct4, Nanog and CD24 Predicts Poor Response to Chemo-Radiotherapy and Unfavourable Prognosis in Locally Advanced Oral Squamous Cell Carcinoma.

BACKGROUND: Current study investigates the role of Oct4, Nanog and CD24 in locally-advanced oral squamous cell carcinoma (OSCC), to evaluate whether the expression of these markers can predict efficacy of neoadjuvant-chemo-radiotherapy and survival of patients. METHODS: Biomarker expression was evaluated in 50 homogenously treated patients of locally-advanced OSCC. RESULTS: Clinical response was complete in 30% (n=15), partial response in 46% (n=23), no response in 24% (n=12). Pathologically, 74% patents (n=37) were responders and 26% were non-responders (n=13). Biomarker-overexpression was seen in 46% cases for Oct4, 54% cases for Nanog and 58% cases for CD24. Oct4, Nanog and CD24 expression showed significant correlation with clinical and pathological response (p <0.05). Three year recurrence-free survival was 71%, overall survival was 66%. Post-treatment advanced pathological N (ypN), post treatment advanced pathological TNM (ypTNM) stage, clinical non-response, pathologic non-response, positive/high expression of all three biomarkers had a significant negative impact on recurrence-free and overall survival. CONCLUSIONS: Expressions of Oct4, Nanog and CD24 have significant association with treatment response and survival in patients with locally advanced OSCC treated with neoadjuvant chemo-radiation. Survival of these patients is significantly affected by ypN stage, ypTNM stage, expression of all three biomarkers, clinical and pathological response to neoadjuvant therapy.
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Validation of the Brandwein Gensler Risk Model in Patients of Oral Cavity Squamous Cell Carcinoma in North India.

India has one of the highest incidences of oral squamous cell carcinoma (OSCC), with 75,000-80,000 new cases a year. The outcome in early oral cancer is better, but a significant proportion (12-14%) of these patients still relapses and dies due to locoregional or distant recurrences. Several clinicopathological and molecular factors have been used to prognosticate and predict outcomes in these patients of OSCC. The present study aims to validate Brandwein Gensler (BG) risk predictive model in surgically treated OSCC patients in a tertiary care centre in North India. All oral cavity cancer patients, treated in the Department of Surgical Oncology, King George's Medical University, between 2013 and 2017, were reviewed. Patients with histologically diagnosed OSCC, aged > 18 years undergoing primary surgical resection were included in the study. The final histopathological evaluation was done by a dedicated pathologist to categorize patients according to BG model risk categories. This model comprises of three factors, lymphocytic host response, perineural invasion and worst pattern of invasion, scored by the method described by Brandwein Gensler et al. The sum of these scores is used to define low, moderate and high risk categories. The study, conducted during 2013-2017, included 149 patients. Median age was 45 years (range 25-75 years). Tobacco use was noted in 143 patients. Buccal mucosa was the most common site (51%). Surgical margins were clear (> 5 mm) in 97.9% cases. Postoperative radiotherapy was given in 47.7% patients. Locoregional recurrences (LRR) (primary site and neck) were documented in 17 of the 149 patients (11.4%). There was no synchronous or metachronous distant metastasis noted in any of the study patients. Six patients had disease specific mortality. Among the 17 patients with LRR, majority (11) belonged to the high risk category of the BG risk model. Adjuvant radiotherapy had been administered in 10 of these 11 recurrent patients belonging to the high risk category. The Brandwein Gensler risk model is predictive of locoregional recurrences (p = 0.02) for OSCC undergoing primary surgery. It can be used to devise strategies to prevent recurrences or identification of recurrences at an earlier point for salvage. The benefit of further escalation of adjuvant therapy in the high risk category needs further studies, as 90% patients in this group recurred despite complete adjuvant treatment.

Synchronous Cervical Minimal Deviation Adenocarcinoma, Gastric Type Adenocarcinoma and Lobular Endocervical Glandular Hyperplasia Along with STIL in Peutz-Jeghers Syndrome: Eliciting Oncogenesis Pathways.

We describe an unusual case of a Peutz-Jeghers syndrome associated with a composite synchronous cervical neoplasia comprising precursor "lobular endocervical glandular hyperplasia (LEGH)", "minimal deviation adenocarcinoma (MDA)" and "gastric-type adenocarcinoma (GTA)" along with a serous tubal intraepithelial lesion (STIL) in the right fallopian tube. A 24-year-old woman presented with a white mucoid discharge and bleeding per vaginum for one year. Histopathological evaluation showed MDA & GTA in FIGO grade III with pelvic lymph node metastasis despite a deceptively bland tumour morphology and low Ki-67 index, indicating an aggressive tumour course and poor prognosis. Diagnostic marker profile in the cervix showed gastric type mucin and positive expression of CK-7, CK-20 (patchy), CEA, and negative CDX-2, p16, ER and PR. Further an attempt at eliciting the oncogenesis pathway in view of the p16 and HPV negative nature of the gastric type cervical adenocarcinoma showed negativity for p53 but activation of cyclin D1. Growth factors including Her2 and EGFR were negative while VEGFR was over-expressed. She was treated by radical hysterectomy and pelvic radiation. She was free from recurrence at the 12-month follow-up. This is a first-time report of a STIL in the fallopian tube which was validated by a unilateral mutant type p53 expression and increased Ki67 index, associated with synchronous gastric type adenocarcinoma of the cervix in all stages of evolution.

Investigation of targetable predictive and prognostic markers in gallbladder carcinoma.

BACKGROUND: Gallbladder carcinoma, uncommon in most of the world, is frequent in South East Asia. It presents in advanced stages with limited therapeutic options. We investigated targetable predictive and prognostic Markers in 268 cases including 233 primary site lesions and 35 metastatic gallbladder carcinoma. METHODS: EGFR, VEGF, HER2/Neu and p53 were assessed using immunohistochemistry. HER2/Neu was validated in a subset by fluorescent in situ hybridization (FISH) using tissue microarray (TMA). Broader spectrum of gene variation was screened in NGS in representative FFPE tissue using the Ion AmpliSeq cancer hotspot panel V2. RESULTS: Mean age was 49.5 years with female predominance (77.6%). Histological types included 221 cases of adenocarcinoma not otherwise specified (NOS), 23 invasive papillary carcinoma, 11 mucinous adenocarcinoma, 8 adenosquamous, 1 signet ring, 3 neuroendocrine and 1 undifferentiated carcinoma. Majority (76.1%) presented with stage 3/4 disease. Overall positive expression of p53 was 44.8%, VEGF 79.4%, HER2/Neu 27.3% and EGFR 34.6%. Intratumoral heterogeneity was evident in HER2/Neu. Marker expression was not significantly associated with stage, grade, type and metastasis except VEGF which correlated with histological type (P=0.018) and tumor grade (P=0.027). NGS using Ion AmpliSeq cancer hotspot panel V2 revealed multiple non synonymous mutations, most frequent being TP53 and CDKN2A mutations and mutations in MET, KDR, PIK3CA, VHL, MPL, HER2 and SMARCB1 genes. CONCLUSIONS: Predictive targetable markers like HER2/Neu, VEGF and EGFR are expressed in high proportion of gallbladder carcinoma. Significant expression of RAS pathway molecules suggests that interactions take place among the different members of the ErbB family during tumor development.