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One in 10 infants are born with a vascular birthmark each year. Some vascular birthmarks, such as infantile hemangiomas, are common, while vascular malformations, such as capillary, lymphatic, venous, and arteriovenous malformations, are less so. Diagnosing uncommon vascular birthmarks can be challenging, given the phenotypic heterogeneity and overlap among these lesions. Both sporadic and germline variants have been detected in various genes associated with vascular birthmarks. Identification of these genetic variants offers insight into both diagnosis and underlying molecular pathways and can be fundamental in the discovery of novel therapeutic approaches. The PIK3/AKT/mTOR and RAS/MEK/ERK signaling pathways, which mediate cell growth and angiogenesis, are activated secondary to genetic variations in vascular malformations. Somatic variants in TEK (TIE2) and PIK3CA cause venous malformations. Variants in PIK3CA also cause lymphatic malformations as well as a number of overgrowth syndromes associated with vascular anomalies. Variants in GNAQ and GNA11 have been identified in both so-called "congenital" hemangiomas and capillary malformations. RASA1 and EPHB4 variants are associated with capillary malformation-arteriovenous malformation syndrome. This review discusses the genetics of vascular birthmarks, including the various phenotypes, genetic variants, pathogenesis, associated syndromes, and new diagnostic techniques.

Background Our purpose is to describe the structure, function and outcomes of our multidisciplinary pediatric thyroid program and to evaluate our experience in comparison to other high-volume centers. Methods We reviewed all thyroid operations performed 10/2012 through 09/2019, and examined number of cases per year, patient demographics, procedures, final diagnoses and results. Primary outcomes were hypoparathyroidism and recurrent laryngeal nerve (RLN) injury at 12 months. Data were analyzed using descriptive statistics and univariate analyses. Results We performed 294 thyroid operations on 279 patients. Seventy-nine percent were female. Median age was 15 years (IQR: 12–17). Operations included total thyroidectomy (65%), lobectomy (30%) and completion thyroidectomy (5%). Most common diagnoses were Graves’ disease (35%), malignancy (29%), and benign nodule (20%). We developed an evidence-based clinical pathway and conducted weekly multidisciplinary meetings. A clinical data specialist reviewed process and outcome measures routinely. Overall, 6 patients (2.0%) had hypoparathyroidism and 2 (0.7%) had unilateral RLN injury at 12 months. Two of the patients with clinical suspicion of permanent hypoparathyroidism were ultimately weaned off calcium. Both patients with RLN injury had extensive locally advanced malignant disease involving the nerve. Conclusions Our multidisciplinary team achieved excellent long-term outcomes for pediatric thyroid surgery comparable to other high-volume pediatric and adult centers. Level of Evidence IV

Rhabdomyosarcoma (RMS) is an aggressive soft tissue malignancy comprised histologically of skeletal muscle lineage precursors that fail to exit the cell cycle and fuse into differentiated syncytial muscle—for which the underlying pathogenetic mechanisms remain unclear. In contrast to myogenic transcription factor signaling, the molecular machinery that orchestrates the discrete process of myoblast fusion in mammals is poorly understood and unexplored in RMS. The fusogenic machinery in Drosophila, however, is understood in much greater detail, where myoblasts are divided into two distinct pools, founder cells (FC) and fusion competent myoblasts (fcm). Fusion is heterotypic and only occurs between FCs and fcms. Here, we interrogated a comprehensive RNA-sequencing database and found that human RMS diffusely demonstrates an FC lineage gene signature, revealing that RMS is a disease of FC lineage rhabdomyoblasts. We next exploited our Drosophila RMS-related model to isolate druggable FC-specific fusogenic elements underlying RMS, which uncovered the EGFR pathway. Using RMS cells, we showed that EGFR inhibitors successfully antagonized RMS RD cells, whereas other cell lines were resistant. EGFR inhibitor–sensitive cells exhibited decreased activation of the EGFR intracellular effector Akt, whereas Akt activity remained unchanged in inhibitor-resistant cells. We then demonstrated that Akt inhibition antagonizes RMS—including RMS resistant to EGFR inhibition—and that sustained activity of the Akt1 isoform preferentially blocks rhabdomyoblast differentiation potential in cell culture and in vivo. These findings point towards selective targeting of fusion- and differentiation-arrest via Akt as a broad RMS therapeutic vulnerability.Significance:EGFR and its downstream signaling mediator AKT1 play a role in the fusion and differentiation processes of rhabdomyosarcoma cells, representing a therapeutic vulnerability of rhabdomyosarcoma.

Originally described as mammary analog secretory carcinoma (SC), SC of the salivary gland is a rare malignancy with morphologic and molecular similarities to SC of the breast. We present 2 children with salivary gland SC with the classic ETV6-NTRK3 gene fusion, including 1 with lymph node metastases. Both patients underwent surgical resection and were in remission 24 months postsurgery. One patient was additionally found to have synchronous papillary thyroid carcinoma with a TFG-MET fusion. A review of published cases highlights the expanding molecular profile and confirms the favorable course of salivary gland SC after surgical resection.

In this paper, a new variable step size least mean square adaptive filter-based control algorithm is proposed to generate reference current for voltage source converter of a grid-integrated PV system. The proposed control generates reference current by extracting the fundamental active and reactive component from load current with fast convergence. The proposed control offers better initial transients and dynamic performance than conventional LMS and synchronous reference frame-based control. Grid-integrated PV system is modelled in MATLAB/Simulink and is tested on different loading condition viz. nonlinear load, unbalanced load and variable load. Further, to validate the efficacy of the proposed control, it is also tested in real time on prototype hardware in the laboratory. It has been observed that proposed control provides compensation of harmonic and reactive power of the local load. Distortion at grid side of the system is within the limits as per IEEE-519 standard.

Young males have a unique but rare predilection to develop mediastinal nonseminomatous germ cell tumors (NSGCTs) and concomitant acute megakaryoblastic leukemia (AMKL). Common cytogenetic and molecular abnormalities such as isochromosome 12p and somatic Tumor Protein P53(TP53) and Phosphatase And Tensin Homolog (PTEN) mutations have been reported in the presumed mutual neoplastic clones of origin. We report the case of a 17-year-old male who presented with a mediastinal NSGCT with high-grade sarcomatous transformation and a diagnosis of AMKL approximately 4 months later. Next-generation sequencing revealed identical KRAS Proto-Oncogene, GTPase (KRAS) p.Ala146Thr, TP53 p.Leu257Pro, and PTEN p.Leu181Pro missense mutations at similar variant allele frequencies in both the NSGCT and AMKL samples. Cytogenetic and microarray analyses detected shared copy gains in all chromosomes except chromosomes 9, 13, and Y. Multiple additional clonal chromosomal alterations were detected in the AMKL sample when compared with the NSGCT. This case emphasizes the shared clonal origins of these malignancies and identifies KRAS and other copy number alterations as potential molecular drivers in a subset of these combined diseases.

Ovarian germ cell tumors (GCTs) are rare in adults, but are more common in adolescents and young adults. Contemporary management of ovarian GCTs is evolving as collaboration among pediatric, medical, and gynecologic oncologists increases, and studies increasingly incorporate female adult patients. Despite an improved understanding of ovarian GCT, many questions remain. Areas of continued controversy include which stage I ovarian GCTs and immature teratomas can be observed without adjuvant therapy, appropriate risk classification for ovarian GCT, surveillance strategies, and optimal therapy for recurrence. These topics as well as active areas of clinical investigation are discussed.

In this paper, solar photovoltaic (SPV)-based microgrid has been connected to grid. Modified synchronous reference frame control of PV inverter has been proposed to estimate reference current for power quality improvement. Conventionally, DC link voltage of the PV inverter is regulated using proportional integral (PI) controller, which suffers from undershoot/overshoot and long settling time during load variation. Intelligent control technique can be the better solution with more accuracy and fast dynamic response. In the present work, interval type-2 (IT-2)-based fuzzy logic controller (FLC) has been proposed to control inverter’s DC link voltage. Performance of the grid-connected SPV system is analyzed using proposed IT-2 FLC and compared with conventional PI as well as type-1 FLC. It compensates the harmonics of the nonlinear load and maintains the grid at unity power factor by supplying the reactive demand of the load. Total harmonic distortion at grid side of the system is within the limits as per IEEE-519 standard. To test the efficacy of the proposed IT-2 FLC for grid-connected SPV system MATLAB software2016(a) has been used.

Clinicians are regularly confronted with different choices after failure of root canal treatment. In present scenario patient prefer to retain their original teeth thats why non-surgical retreatment should be the treatment of choice. The new generation of endodontic instruments, magnification, materials and technology with the basic principles of endodontic retreatment have helped in retention of the patients natural tooth structure to form and function decreasing the need for extensively expensive prosthetic replacement in the area of implant dentistry. Surgical approach can be adopted in obstructed, calcified or non-negotiable canals.

Abdominal lymphatic malformations (LM) have been historically managed with surgical resection; however, sclerotherapy and sirolimus have emerged as effective therapies. The purpose of our study is to evaluate our institutional change in management and outcomes for abdominal LM over the past decade.A retrospective cohort study was performed for all children with an abdominal LM managed at our multidisciplinary Vascular Anomalies Center from 2011 to 2020. Patient demographics, symptoms, treatment, treatment response, and complications were analyzed with descriptive statistics.Twenty-nine patients with abdominal LM were identified with a median age at treatment of 6 y (interquartile range 3-14). A majority of lesions were identified as macrocystic (n = 18, 62%). The most common intervention was surgery alone (n = 14, 48%) followed by sirolimus alone (n = 4, 14%), and sclerotherapy + sirolimus (n = 4, 14%). Five patients were observed due to lack of symptoms at presentation. Prior to 2017, 91% (10/11) of LM were treated with surgery alone. Following 2017, only 31% (4/13) were treated with surgery alone. Sixty-seven percent (16/24) of treated patients had95% reduction in LM maximum diameter. A majority of patients (23/24) who received treatment had improvement or resolution of symptoms at median 9-mo follow-up. Only three patients had post-treatment complications, including a drain site infection, small bowel obstruction, and an aspiration event. Complications only occurred after sclerotherapy sessions.Over the study period, our institution has transitioned to initial management of symptomatic abdominal LM with sclerotherapy and/or sirolimus with almost all treated patients having excellent or satisfactory treatment response. Post-treatment complications were rare.

Chylothorax can be a presenting symptom of complex lymphatic anomaly in children and is associated with significant respiratory morbidity. Historically, the traditional pharmacological treatment has been octreotide. There are several treatments that have been utilized in the past few years including sirolimus; however, data regarding their efficacy and outcomes is limited. Furthermore, sirolimus has proven efficacy in complex vascular malformations, and hence, its utility/efficacy in infantile primary chylous effusions warrants further investigation.In this retrospective study at Texas Children's Hospital, data were extracted for all infants with chylothorax who were treated with sirolimus between 2009 and 2020. Details regarding underlying diagnosis, comorbidities, and number of days from sirolimus initiation to resolution of effusion were collected.Initially a total of 12 infants were identified. Among them, seven patients had complete data and were included in the study. Reasons for chylous effusions include presumed complex lymphatic anomaly, generalized lymphatic anomaly, and complex congenital lymphatic anomaly. The mean duration of sirolimus treatment needed for chest tube removal was 16 days, with a median of 19 days and range of 7-22 days. No patients had progression of effusions while on sirolimus.With close monitoring, sirolimus appears to be an effective therapy for pediatric lymphatic effusions even in critically ill infants. The study also demonstrates shorter duration of chest tube requirement after initiation of sirolimus compared to previous studies. Larger multi-institutional studies are needed to further support our findings.

Background: While rare in children, chylothorax is a significant cause of respiratory morbidity and can lead to malnutrition and immunodeficiency. Historically, the traditional pharmacological treatment has been octreotide. There are several treatments that have been utilized in the past few years including sirolimus, however data regarding their efficacy and outcomes is limited. Furthermore, sirolimus has proven efficacy in complex vascular malformations, and hence, its utility/efficacy in pediatric chylous effusions warrants further investigation. Methods: In this retrospective study at Texas Children’s Hospital, data were extracted for all patients with chylothorax who were treated with sirolimus between 2009 and 2020. Details regarding underlying diagnosis, co-morbidities and number of days from sirolimus initiation to resolution of effusion were collected. Descriptive statistics were used to analyze the study cohort. Results: Initially a total of twelve infants were identified. Among them, seven patients had complete data and were included in the study. The mean duration of sirolimus treatment needed for chest tube removal was 16 days, with a median of 19 days and range of 7- 22 days. Chest tube output corresponded with sirolimus serum trough levels and trended down prior to chest tube removal. Conclusion: With close monitoring, sirolimus is a safe and effective therapy for pediatric lymphatic effusions even in critically-ill infants. The study also demonstrates shorter duration of chest tube requirement after initiation of sirolimus compared to previous studies. Our conclusion is based on a small case series due to the rare incidence of the condition.

Rhabdomyosarcoma (RMS) is an aggressive soft tissue malignancy comprised histologically of skeletal muscle lineage precursors that fail to exit the cell cycle and fuse into differentiated syncytial muscle—for which the underlying pathogenetic mechanisms remain unclear. In contrast to myogenic transcription factor signaling, the molecular machinery that orchestrates the discrete process of myoblast fusion in mammals is poorly understood and unexplored in RMS. The fusogenic machinery in Drosophila, however, is understood in much greater detail, where myoblasts are divided into two distinct pools, founder cells (FC) and fusion competent myoblasts (fcm). Fusion is heterotypic and only occurs between FCs and fcms. Here, we interrogated a comprehensive RNA-sequencing database and found that human RMS diffusely demonstrates an FC lineage gene signature, revealing that RMS is a disease of FC lineage rhabdomyoblasts. We next exploited our Drosophila RMS-related model to isolate druggable FC-specific fusogenic elements underlying RMS, which uncovered the EGFR pathway. Using RMS cells, we showed that EGFR inhibitors successfully antagonized RMS RD cells, whereas other cell lines were resistant. EGFR inhibitor–sensitive cells exhibited decreased activation of the EGFR intracellular effector Akt, whereas Akt activity remained unchanged in inhibitor-resistant cells. We then demonstrated that Akt inhibition antagonizes RMS—including RMS resistant to EGFR inhibition—and that sustained activity of the Akt1 isoform preferentially blocks rhabdomyoblast differentiation potential in cell culture and in vivo. These findings point towards selective targeting of fusion- and differentiation-arrest via Akt as a broad RMS therapeutic vulnerability. Significance: EGFR and its downstream signaling mediator AKT1 play a role in the fusion and differentiation processes of rhabdomyosarcoma cells, representing a therapeutic vulnerability of rhabdomyosarcoma.

Background: Children with hematologic malignancies, especially those who receive intensive chemotherapy, are at high risk for invasive mold infections (IMI) that confer substantial mortality. Randomized controlled trials support the use of anti-fungal prophylaxis with anti-mold activity as an optimal strategy for risk reduction in this population, but studies outlining the practical application of evidence-based recommendations are lacking. Procedure: We conducted a 15-year, single-institution retrospective review of children with hematologic malignancies treated with chemotherapy to determine the incidence of proven or probable IMI diagnosed between 2006 and 2020 and to identify the host and disease factors associated with IMI risk. We then compared the incidence and type of IMI and related factors before and after 2016 implementation of an evidence-based, risk-adapted anti-fungal prophylaxis algorithm that broadened coverage to include molds in patients at highest risk for IMI. Multivariable linear regression was used to determine factors related to IMI risk. Results: We identified 61 cases of proven or probable IMI in 1,456 patients diagnosed with hematologic malignancies during the study period (4.2%). Implementation of an anti-fungal prophylaxis algorithm reduced the IMI incidence in this population from 4.8% to 2.9%. After multivariable analysis, both Hispanic ethnicity and cancer diagnosis prior to 2016 were significantly associated with risk for IMI. Conclusion: An evidence-based, risk-adapted approach to anti-fungal prophylaxis for children with hematologic malignancies is an effective strategy to reduce incidence of IMI.

Neuroendocrine tumors (NETs) of the pancreas and midgut are extremely rare in children, and patients presenting with metastatic disease have poor survival. Given this rarity, treatments are extrapolated from guidelines for adults with NET. Recent clinical trials in adults with NETs have shown that the addition of peptide receptor radionuclide therapy (PRRT) with 177 Lu-DOTATATE resulted in a disease control rate of nearly 80%, with minimal side effects. We report our experience using 177 Lu-DOTATATE to treat two pediatric patients with metastatic NET.

Originally described as mammary analog secretory carcinoma (SC), SC of the salivary gland is a rare malignancy with morphologic and molecular similarities to SC of the breast. We present 2 children with salivary gland SC with the classic ETV6-NTRK3 gene fusion, including 1 with lymph node metastases. Both patients underwent surgical resection and were in remission 24 months postsurgery. One patient was additionally found to have synchronous papillary thyroid carcinoma with a TFG-MET fusion. A review of published cases highlights the expanding molecular profile and confirms the favorable course of salivary gland SC after surgical resection.

Multifocal lymphangioendotheliomatosis with thrombocytopenia (MLT) is a recently recognized disorder characterized by vascular lesions marked by distinct endothelial proliferation. Lesions affect multiple tissues, and MLT can be associated with refractory thrombocytopenia resulting in life-threatening bleeding. Diagnosing MLT may be challenging given its rarity and phenotypic variability. There is no consensus on the optimal management or treatment duration. We report a 4-month-old male who presented with multiple vascular malformations involving the gastrointestinal tract, lung, bones, choroid plexus, and spleen, with minimal cutaneous involvement and no thrombocytopenia. Wedge resection of a pulmonary nodule was strongly positive for lymphatic vessel endothelial hyaluronan receptor 1 favoring MLT despite the lack of thrombocytopenia. The patient's clinical symptoms and vascular lesions improved on sirolimus therapy. We review the literature to highlight the clinical variability of MLT and discuss the diagnostic and therapeutic options for MLT.

With the increased penetration of photovoltaic (PV) based distributed generation (DG), power quality (PQ) at the point of common coupling (PCC) becomes a major concern mainly due to harmonics. Harmonics, generated by nonlinear loads in the system, are multiples of fundamental frequency. This paper presents the comparative analysis and discussion of various control techniques for VSC of a grid connected PV based micro grid to mitigate the harmonics. The mitigation of harmonics is achieved using control techniques viz. conventional and adaptive of reference generation. Simulation of the developed model is carried out on MATLAB/Simulink. Performance of the system is evaluated under IEEE-519 standard.

Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal tumor of intermediate malignant potential that predominantly affects children, adolescents and young adults. IMT has a predilection for the lung, abdomen, pelvis, and retroperitoneum, however, can affect any part of the body. IMT is typically localized, and multifocal or metastatic disease is uncommon. Complete surgical resection is the treatment of choice when feasible. There is no established standard of care for unresectable and advanced IMT. Approximately half of IMTs harbor anaplastic lymphoma kinase (ALK) gene rearrangements, and fusions involving ROS1, PDGFRβ, RET and NTRK have also been described. Given the molecular landscape of IMT, management of these tumors has evolved to include tyrosine kinase inhibitors and novel targeted therapeutics. This review highlights the molecular characteristics, evolution of targeted therapies and the remaining challenges in the management of IMT.

This paper consists of an analysis of technical and economical aspects of the installation of piezoelectric pads on the railway tracks. The lead zirconate titanate (PZT) has been used as piezoelectric material in this paper. For harvesting electrical energy, the two types of piezoelectric energy harvesting system, namely compression-type piezoelectric harvester and cantilever-type piezoelectric harvester are considered. The technical analysis included the sensitivity analysis of the energy produced by both types of piezoelectric system. The physical dimensions, frequency of vibrations, and amount of charge produced are the basic parameters of the piezoelectric energy harvesting system. Further, to get an idea about the economic aspect of the project, the cost analysis of single units of both the system has also been done. It has been observed that compression-type piezoelectric harvester is technically and economically superior to cantilever-type energy harvesting system in terms of electrical power generation for railway tracks.

In the present paper, authors have developed stand-alone solar photovoltaic (PV) system tied with battery energy storage system (BESS). The system continuously supplies power to the load by the inclusion of another source that is battery energy storage system. Perturb & Observe (P&O) has been used for tracking the maximum power of PV array. PV system supplies power to the load and is also used to charge the battery. In case PV is not able to supply the load power then deficit power will be supplied by BESS as well as DC link voltage has been maintained. The PV system connected to battery energy storage system for commercial applications has been modelled using MATLAB/Simulink. Test results has taken for variable irradiation and load demand, voltage across dc-link are shown are verified through simulation model.

In this paper, an analysis of two methods of harvesting the electrical power from the two different piezoelectric systems in railway traction system is carried out. The two piezoelectric systems used for analysis are compression type piezoelectric system and cantilever beam type piezoelectric system. These systems are suggested to be embedded on the railway track and attached to the rail tracks to produce the electrical output. The lead zirconate titanate (PZT), which is one of the recent piezoelectric, which accumulates more charge on mechanical disturbance, is used in both the cases. The compression type piezoelectric system is excited by the force applied by the train, and cantilever beam type system is excited by the ground vibrations of the track. The output of two systems is compared for a single unit, and according to this comparison, the array of compression type system has been designed.

Background Pediatric papillary thyroid carcinoma (PTC) is clinically and biologically distinct from adult PTC. We sequenced a cohort of clinically annotated pediatric PTC cases enriched for high-risk tumors to identify genetic alterations of relevance for diagnosis and therapy. Methods Tumor DNA and RNA were extracted from FFPE tissue and subjected to next-generation sequencing (NGS) library preparation using a custom 124-gene hybridization capture panel and the 75-gene Archer Oncology Research Panel, respectively. NGS libraries were sequenced on an Illumina MiSeq. Results Thirty-six pediatric PTC cases were analyzed. Metastases were frequently observed to cervical lymph nodes (29/36, 81%), with pulmonary metastases less commonly found (10/36, 28%). Relapsed or refractory disease occurred in 18 patients (18/36, 50%). DNA sequencing revealed targetable mutations in 8 of 31 tumors tested (26%), most commonly BRAF p.V600E (n = 6). RNA sequencing identified targetable fusions in 13 of 25 tumors tested (52%): RET (n = 8), NTRK3 (n = 4), and BRAF. Mutually exclusive targetable alterations were discovered in 15 of the 20 tumors (75%) with both DNA and RNA analyzed. Fusion-positive PTC was associated with multifocal disease, higher tumor staging, and higher American Thyroid Association risk levels. Both BRAF V600E mutations and gene fusions were correlated with the presence of cervical metastases. Conclusions Targetable alterations were identified in 75% of pediatric PTC cases with both DNA and RNA evaluated. Inclusion of RNA sequencing for detection of fusion genes is critical for evaluation of these tumors. Patients with fusion-positive tumors were more likely to have features of high-risk disease.

Differentiated thyroid cancer (DTC) is the most common childhood thyroid malignancy. The standard of care for pediatric DTC is total thyroidectomy followed by radioactive iodine (RAI) treatment when indicated. Molecular changes and potential therapeutic targets have been recently described in pediatric thyroid cancer. Pediatric oncologists are increasingly involved in the evaluation of thyroid nodules in childhood cancer survivors and in the management of advanced thyroid cancer. In 2015, the American Thyroid Association published management guidelines for children with DTC. We provide an overview of the current standard of care and highlight available targeted therapies for progressive or RAI refractory DTC.

Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy in children and adolescents. Infrequently, children with PTC may present with or develop disease not amenable to surgery or radioactive iodine (RAI), and systemic therapy may be an option. Lenvatinib is an oral tyrosine kinase inhibitor that is approved by the Food and Drug Administration for the treatment of adults with locally recurrent or metastatic, progressive, RAI-refractory well-differentiated thyroid carcinoma. The effect of lenvatinib in children with PTC has not been reported.Three children with metastatic PTC not amenable or refractory to RAI who responded to lenvatinib are reported. All of them developed respiratory distress requiring oxygen caused by extensive bilateral metastatic pulmonary disease. The first patient is a 14-year-old female who was initially treated with sorafenib for extensive PTC not amenable to upfront surgery or RAI. She had progressive pulmonary disease after five months, and was subsequently treated with oral lenvatinib (14 mg/mThree pediatric patients are reported with metastatic PTC not amenable or refractory to RAI who achieved a response on lenvatinib.Lenvatinib therapy is well tolerated and demonstrated clinical activity in children with advanced PTC. Lenvatinib should be considered in children with PTC that is refractory or not amenable to conventional management.

A strategy for construction of medicinally important 1,4-substituted 1H-1,2,3-triazolo-quinazolin-4(3H)-ones has been devised and presented here. The compounds have been synthesized using one-pot multicomponent strategy under microwave assisted conditions. Triazolyl-quinazolinone based D-ring modified analogs are designed based on IC87114 scaffold, which is first known isoform selective inhibitor of PI3Kδ. Herein, we identified two triazolyl-quinazolinone compounds (5a and 5l) based on same scaffold with PI3Kγ specific inhibitory potential, the selectivity towards this isoform is well supported by in silico results, wherein, these compounds show better interaction and affinity and inhibitory activity for PI3Kγ rather than PI3Kδ. This repositioning of scaffold from PI3Kδ to PI3Kγ isoform can be very useful from medicinal chemistry and drug discovery perspective to unravel molecular interactions of this new scaffold in different cellular pathways.

l-Vasicine is a quinazoline alkaloid with an electron dense ring and additional functionalities in its structure. Employing target oriented synthesis (TOS) based on in silico studies, molecules with significant docking scores containing different derivatives of l-vasicine as caps were synthesized. Interestingly, one molecule, i.e., 4a, which contained 3-hyroxypyrrolidine as a cap group and a six carbon long aliphatic chain as a linker was found to inhibit HDACs. 4a showed more specificity toward class I HDAC isoforms. Also 4a was found to be less cytotoxic toward normal cell lines as compared to cancer cell lines. 4a inhibited cancer cell growth and induced cell death by various mechanisms. However, 4a was found to induce cell death independent of ROS generation, and unlike many natural product based HDAC inhibitors, 4a was found to be nontoxic under in vivo conditions. Importantly, we for the first time report the possibility of using a 3-hydroxypyrrolidine cap for the synthesis of HDAC inhibitors with good potency.