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Laser-driven plasma accelerators have attracted attention for their ability to achieve ultra-high gradient acceleration and produce high-quality particle beams. Vacuum-based laser acceleration offers advantages over plasma mediums by eliminating instabilities associated with plasma interactions. This study investigates electron acceleration dynamics using two tightly focused, linearly polarized laser beams with controlled frequency chirp in vacuum. The research aims to optimize parameters for electron energy gain, emphasizing the significance of periodic frequency chirp in enhancing acceleration efficiency. Mathematical analyses elucidate the interaction mechanisms between electrons and tightly focused laser beat waves. Results demonstrate substantial energy gains in the MeV range, with insights into the influence of laser intensity, chirp parameter, and initial phase angle on electron acceleration. The study highlights the importance of precise parameter optimization for maximizing electron energy gain in vacuum-based beat wave acceleration, contributing valuable insights to particle physics and materials science advancements.

The vacuum laser acceleration scheme IFEL has been investigated. We have studied the best conditions for achieving higher energy gain using two laser pulses crossing at an angle in the presence of an undulator. A group of optimized variables for electrons and the laser pulse are employed to numerically investigate the phenomena of the crossing of two lasers using the inverse free electron acceleration (IFELA) mechanism. IFELA mechanism is used to produce a high quality, micro-bunched accelerated electron beam that is used to feed a Compton scattering interaction point, which produce x-rays of directional narrow bandwidth. The effect of linear frequency chirp has been investigated and shown that the final electron energy in the presence of an undulator is strongly dependent on different parameters like the laser’s initial intensity, the crossing angle between the lasers, wiggler magnetic field strength, and the chirping of the laser pulse. It shows that the crossing of lasers plays a crucial role in the final energy gain as compared to the co-propagating lasers. The proportionality of the final energy gain on pre-accelerated electron’s energy is also investigated. Hundreds of MeV energy gain has been obtained in the investigation. Currently these types of lasers are used in scientific research in the field of material science, Chemical engineering, medical science, biophysics, surface studies and solid state physics etc.

A conventional plant flavonoid known as myricetin is well-known for its wide range of effects, including its strong anti-inflammatory, anti-cancer, and antioxidant characteristics. In this study, we examined anti-inflammatory potential of Myricetin (MN) by looking at the expressions of COX-2, IL-6 and TNF-α in leukemia cancer cell lines (THP-1). The THP-1 was cultured in Roswell Park Memorial Institute medium supplemented with 10% foetal bovine serum and penicillin (100 U/ml) for the purposes of the in-vitro investigations. Cell viability and cytotoxicity testing were done using the MTT assay. To prepare the ligand and proteins for the in-silico studies, The structures of the targeted anti-inflammatory proteins COX-2 (PDB ID: 5KIR), TNF- (PDB ID: 1TNF), and IL-6 (PDB ID: 1ALU) were retrieved from Protein Data Bank. Furthermore, docking experiments were carried out using the AutoDock Vina software. In comparison to the reference drug cisplatin (9.46 µg/ml) the IC50 value for MN was found to be 90.161 µg/ml. The cells pretreated with MN showed a significantly lower expression of anti-inflammatory components (COX-2, TNF-α and IL6) upon measured by geometric mean fluorescence intensity as compared to the LPS-induced control cells. Additionally, MN has shown a strong interaction with COX-2, TNF-α and IL-6 in simulation studies. To conclude, MN exhibits a potent anti-inflammatory effect both in-silico and in-vitro studies. Further, in vivo investigations are needed to gain more comprehensive understanding of the molecule.

The effects of two parallel Cosh-Gaussian laser beat waves on electron acceleration in vacuum have been investigated. By using a Cosh-Gaussian (ChG) laser instead of a Gaussian laser, we can achieve higher electron energies. To verify how laser intensities and other parameters affect electron energy, we have also examined the impact of frequency chirp for effective electron acceleration. ChG lasers are excellent for electron acceleration in vacuum due to their special characteristics, including non-diffracting behavior, controlled acceleration gradients, and minimized space charge effects. High-quality, high-energy electron beams can be produced using these lasers for a variety of purposes, such as particle physics research, imaging in medicine, and industrial uses. The electron and laser field can exchange resonant energy due to the chirp-induced phase matching condition. Depending on the chirp properties, the electron may acquire or lose energy. With the use of chirp mechanism, we can achieve more energy gain comparing to without chirp, as the presence of chirp aids in increasing the interaction period between the electron and the laser. Chirped laser pulses help to achieve phase matching between the laser field and accelerated electrons and allow precise control over the electron trajectories. Chirped pulses also help to mitigate the energy spread of the accelerated electrons. We also demonstrated interference at focus in this manuscript caused by two parallel propagated coherent lasers in the z axis, which aids in electron acceleration, resulting higher energy of electron in z-direction. The laser beam width in the transverse direction (perpendicular to the beam propagation) plays a role in focusing the laser field onto the interaction region with the electrons. The chirp and laser beam width of each laser is carefully controlled and synchronized to achieve the desired electron acceleration outcome.

Baccaurea ramifloraLour. syn. Baccaurea sapida(Roxb.) Muell. Arg. widely known as Burmese grape is native to Southeast Asia. Its leaves, fruits, stem, bark, seeds forms an ingredient in many herbal prescriptions which have been used to treat jaundice, constipation, indigestion, cellulitis, as antidote for sanke venome, antiphlogistic and anodyne against rheumatoid arthritis etc. In the recent years, this plant has been largely explored on scientific grounds to identify the chemical constituents and pharmacological activities. The present review work is an effort to revisit the scientific works done to evaluate the scope for bioprospection of B. ramiflora. Based on the study designed, a number of research papers were reviewed, but only about 35 articles having information on B. ramiflorawere evaluated in detail. In total, thirty compounds have been isolated and characterised so far from different parts of this evergreen tree, which accounts for its myriad medicinal value including analgesic, anthelmintic, antioxidant, anti-diarrheal, anti-inflammatory, cytotoxic, haemolytic, hypoglycemic, hypolipidemic, insecticidal, neuropharmacological, thrombocytic, anti-fungal and antimicrobial activities. This compilation of assorted information underpins the basic perceptive of B. ramifloraand opens up new horizon for further phytochemical evaluation, safety efficacy, and clinical trials.

This study is the largest analysis of DNA viruses in solid tumors with associated genomics. To achieve this, a novel method for discovery of DNA viruses from matched tumor/normal next-generation sequencing samples was developed and validated. This method performed comparably to reference methods for the detection of high-risk (HR) human papilloma virus (HPV) (area under the receiver operating characteristic curve = 0.953). After virus identification in 48,148 consecutives samples from 42,846 unique patients, novel virus tumor associations were established by segregating tumor types to determine whether each DNA virus was enriched in each of the tumor types compared with the remaining cohort. All firmly established solid tumor-virus associations (eg, HR HPV in cervical cancer) were confirmed, and the novel associations discovered included: human herpes virus 6 in neuroblastoma, human herpes virus 7 in esophagogastric cancer, and HPV42 in digital papillary adenocarcinoma. These associations were confirmed in an independent validation cohort. HR HPV– and Epstein-Barr virus–associated tumors showed newly discovered genomic associations, including a lower tumor mutation burden. The study demonstrated the ability to study the role of DNA viruses in human cancer from clinical genomics data and established the largest cohort that can be utilized as a validation set for future discovery efforts.

Phospholipid nanocarriers have been widely explored for theranostic and nanomedicine applications. These amphiphilic nanocarriers possess outstanding cargo encapsulation efficiency, high water dispersibility, and excellent biocompatibility, which render them promising for drug delivery and bioimaging applications. While the biological applications of phospholipid nanocarriers have been well documented, the fundamental aspects of the phospholipid–cell interactions beyond cytotoxicity have been less investigated. In particular, the effect of phospholipid nanocarriers on collective cell behaviors has not been elucidated. Herein, we evaluate the interactions of phospholipid nanocarriers possessing different functional groups and sizes with normal and cancerous immortalized breast epithelial cell sheets with varying metastatic potential. Specifically, we examine the impact of nanocarrier treatments on the collective migratory dynamics of these cell sheets. We observe that phospholipid nanocarriers induce differential collective cell migratory behaviors, where the migration speed of normal and cancerous breast epithelial cell sheets is retarded and accelerated, respectively. To a certain extent, the nanocarriers are able to alter the migration trajectory of the cancerous breast epithelial cells. Furthermore, phospholipid nanocarriers could modulate the stiffness of the nuclei, cytoplasm, and cell–cell junctions of the breast epithelial cell sheets, remodel their actin filament arrangement, and regulate the expressions of the actin-related proteins. We anticipate that this work will further shed light on nanomaterial–cell interactions and provide guidelines for rational and safer designs and applications of phospholipid nanocarriers for cancer theranostics and nanomedicine.

Cell-free DNA (cfDNA) from cerebrospinal fluid (CSF) offers unique opportunities for genomic profiling of tumors involving the central nervous system but remains uncommonly used in clinical practice. We describe our clinical experience using cfDNA from CSF for routine molecular testing using Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (targeting 468 cancer-related genes). In all, 148 cfDNA samples were assessed, comparing results of cfDNA versus genomic DNA (gDNA; gDNA from cell pellets) derived from the same CSF sample and the primary tumor. Of these, 71.6% (106/148) were successfully sequenced. Somatic alterations (mutations and fusions) were observed in 70.8% (75/106) of the samples; 97.3% (73/75) comprised variants confirming central nervous system involvement by a previously diagnosed tumor, 14.7% (11/75) had additional variants consistent with a therapy-related resistance mechanism, and 2.7% (2/75) had variants that independently diagnosed a new primary. Among samples with paired cfDNA and gDNA sequencing results, cfDNA was more frequently positive for at least one mutation [43.6% (55/126) versus 19.8% (25/126)] and harbored 1.6× more mutations (6.94 versus 4.65; P = 0.005), with higher mean variant allele fractions (41.1% versus 13.0%; P < 0.0001). Among mutation-positive cfDNAs, the corresponding gDNA was frequently negative (44.6%; 25/55) or failed sequencing (17.8%; 9/55). Routine molecular profiling of cfDNA is superior to gDNA from CSF, facilitating the capture of mutations at high variant allele frequency, even in the context of a negative cytology.

Drug Repurposing (DR) is an alternative to the traditional drug discovery process. It is cost and time effective,with high returns and low-risk process that can tackle the increasing need for interventions for varied diseases and new outbreaks. Repurposing of old drugs for other diseases has gained wider attention, as there have been several old drugs approved by the FDA for new diseases. In the global emergency of COVID-19 pandemic, this is one of the strategies implemented in the repurposing of old anti-infective, anti-rheumatic and anti-thrombotic drugs. The goal of the current review is to elaborate the process of DR, its advantages, repurposed drugs for a plethora of disorders, and the evolution of related academic publications. Further, detailed are the computational approaches: literature mining and semantic inference, network-based drug repositioning, signature matching, retrospective clinical analysis, molecular docking and experimental phenotypic screening. We discuss the legal and economic potential barriers in DR, existent collaborative models and recommendations for overcoming these hurdles and leveraging the complete potential of DR in finding new indications.

TERTgene promoter mutations are known in multiple cancer types. Other TERTalterations remain poorly characterized. Sequencing data from 30,773 tumors analyzed by a hybridization capture next-generation sequencing assay (Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets) were analyzed for the presence of TERTalterations. Promoter rearrangements (500 bases upstream of the transcriptional start site), hypermethylation (n= 57), and gene expression (n= 155) were evaluated for a subset of cases. Mutually exclusive and recurrent promoter mutations were identified at three hot spots upstream of the transcriptional start site in 11.3% of cases (−124: 74%; −146: 24%; and −138: <2%). Mutually exclusive amplification events were identified in another 2.3% of cases, whereas mutually exclusive rearrangements proximal to the TERTgene were seen in 24 cases. The highest incidence of TERTpromoter mutations was seen in cutaneous melanoma (82%), whereas amplification events significantly outnumbered promoter mutations in well-differentiated/dedifferentiated liposarcoma (14.1% versus 2.4%) and adrenocortical carcinoma (13.6% versus 4.5%). Gene expression analysis suggests that the highest levels of gene expression are seen in cases with amplifications and rearrangements. Hypermethylation events upstream of the TERTcoding sequence were not mutually exclusive with known pathogenic alterations. Studies aimed at defining the prevalence and prognostic impact of TERTalterations should incorporate other pathogenic TERTalterations as these may impact telomerase function.

Organic electronic materials play important roles in modern electronic devices such as light-emitting diodes, solar cells, and transistors. Upon interaction with light, these optically active materials can undergo different photophysical and photochemical pathways, providing unique opportunities for optimization of light emission viaradiative decay, heat generation vianonradiative decay, and singlet oxygen production or phosphorescence emission viaintersystem crossing, all of which open alternative opportunities for their applications in sensing, imaging, and therapy. In this Perspective, we discuss all of the pathways that determine the optical properties of high-performance organic electronic materials, focusing on the optimization of each pathway for photogeneration and relaxation of electronic excited states. We also examine nanoparticle (NP) fabrication techniques tailored to macromolecules and small molecules to render them into NPs with optimized size and distribution for biomedical applications and endow organic electronic materials with water dispersibility and biocompatibility. Lastly, we illustrate the in vitroand in vivoapplications of some representative organic electronic materials after optimization of each relaxation pathway.

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1–3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P< 5.0 × 10−8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P< 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

Immunohistochemistry for mismatch repair protein expression is widely used as a surrogate for microsatellite instability status—an important signature for immunotherapy and germline testing. There are no systematic analyses examining the sensitivity of immunohistochemistry for microsatellite instability-high status. Mismatch repair immunohistochemistry and microsatellite instability testing were performed routinely as clinically validated assays. We classified germline/somatic mutation types as truncating (nonsense, frameshift, and in/del) versus missense and predicted pathogenicity of the latter. Discordant cases were compared with concordant groups: microsatellite instability-high/mismatch repair-deficient for mutation comparison and microsatellite stable/mismatch repair-proficient for immunohistochemical comparison. 32 of 443 (7%) microsatellite instability-high cases had immunohistochemistry. Four additional microsatellite instability-high research cases had discordant immunohistochemistry. Of 36 microsatellite instability-high cases with discordant immunohistochemistry, 30 were mismatch repair-proficient, while six (five MLH1 and one MSH2) retained expression of the defective mismatch repair protein and lost its partner. In microsatellite instability-high tumors with discordant immunohistochemistry, we observed an enrichment in deleterious missense mutations over truncating mutations, with 69% (25/36) of cases having pathogenic germline or somatic missense mutations, as opposed to only 19% (7/36) in a matched microsatellite instability-high group with concordant immunohistochemistry (p= 0.0007).  In microsatellite instability-high cases with discordant immunohistochemistry and MLH1or PMS2abnormalities, less cells showed expression (p= 0.015 and p= 0.00095, respectively) compared with microsatellite stable/mismatch repair-proficient cases. Tumor mutation burden, MSIsensor score, and truncating mismatch repair gene mutations were similar between microsatellite instability-high cases with concordant versus discordant immunohistochemical expression. Approximately 6% of microsatellite instability-high cases have retained mismatch repair protein expression and would be missed by immunohistochemistry-based testing, hindering patient access to immunotherapy. Another 1% of microsatellite instability-high cases show isolated loss of the defective gene’s dimerization partner, which may lead to germline testing of the wrong gene. These cases are enriched for pathogenic mismatch repair missense mutations.

Immunohistochemistry for mismatch repair protein expression is widely used as a surrogate for microsatellite instability status—an important signature for immunotherapy and germline testing. There are no systematic analyses examining the sensitivity of immunohistochemistry for microsatellite instability-high status. Mismatch repair immunohistochemistry and microsatellite instability testing were performed routinely as clinically validated assays. We classified germline/somatic mutation types as truncating (nonsense, frameshift, and in/del) versus missense and predicted pathogenicity of the latter. Discordant cases were compared with concordant groups: microsatellite instability-high/mismatch repair-deficient for mutation comparison and microsatellite stable/mismatch repair-proficient for immunohistochemical comparison. 32 of 443 (7%) microsatellite instability-high cases had immunohistochemistry. Four additional microsatellite instability-high research cases had discordant immunohistochemistry. Of 36 microsatellite instability-high cases with discordant immunohistochemistry, 30 were mismatch repair-proficient, while six (five MLH1 and one MSH2) retained expression of the defective mismatch repair protein and lost its partner. In microsatellite instability-high tumors with discordant immunohistochemistry, we observed an enrichment in deleterious missense mutations over truncating mutations, with 69% (25/36) of cases having pathogenic germline or somatic missense mutations, as opposed to only 19% (7/36) in a matched microsatellite instability-high group with concordant immunohistochemistry (p= 0.0007).  In microsatellite instability-high cases with discordant immunohistochemistry and MLH1or PMS2abnormalities, less cells showed expression (p= 0.015 and p= 0.00095, respectively) compared with microsatellite stable/mismatch repair-proficient cases. Tumor mutation burden, MSIsensor score, and truncating mismatch repair gene mutations were similar between microsatellite instability-high cases with concordant versus discordant immunohistochemical expression. Approximately 6% of microsatellite instability-high cases have retained mismatch repair protein expression and would be missed by immunohistochemistry-based testing, hindering patient access to immunotherapy. Another 1% of microsatellite instability-high cases show isolated loss of the defective gene's dimerization partner, which may lead to germline testing of the wrong gene. These cases are enriched for pathogenic mismatch repair missense mutations.

Polymeric nanoparticles play important roles in the delivery of a multitude of therapeutic and imaging contrast agents. Although these nanomaterials have shown tremendous potential in disease diagnosis and therapy, there have been many reports on the failure of these nanoparticles in realizing their intended objectives due to an individual or a combination of factors, which have collectively challenged the merit of nanomedicine for disease theranostics. Herein, we investigate the interactions of polymeric nanoparticles with biological entities from molecular to organism levels. Specifically, the protein corona formation, in vitroendothelial uptake, and in vivocirculation time of these nanoparticles are systematically probed. We identify the crucial role of nanocarrier lipophilicity, zeta-potential, and size in controlling the interactions between nanoparticles and biological systems and propose a two-step framework in formulating a single nanoparticle system to regulate multiple biological effects. This study provides insight into the rational design and optimization of the performance of polymeric nanoparticles to advance their theranostic and nanomedicine applications.

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.

Research into food insecurity and energy vulnerability has framed the dilemma of heat or eat as a choice between nutritious food and adequate energy service determined by financial constraints. However, recent reviews of connections between energy poverty and other socio-economic disadvantages have found that the literature lacks an understanding of the nuances and lived experiences of intersecting hardships. In response to this agenda, this paper draws on qualitative work including householder interviews in Australia to explore the nexus of food and fuel poverty. Using the lens of social practice theories, this paper introduces the concept of ontological (in) security to support our argument that food and energy (in) security need to be understood as an outcome of bundling (s) of everyday domestic and coping practices. The paper illustrates that heat or eat is not a choice nor binary, instead, we show that heating and eating are intertwined, interdependent and shaped by coping strategies that seek to balance essential materials requirements and meanings. In addition, the study shows that practice bundles shape the sense of ontological (in) security, therefore, infusing routines and coping practices with new meanings, affects and material arrangements. By doing this, the study highlights how the dynamic co-relations between energy and food social practices, social support services and infrastructures shape wellbeing, through access to retrofits, nutrition, and care and are potential sites of intervention. Finally, we present novel ways of mitigating tensions between food and energy insecurity and alleviating them simultaneously.

Efficacy of several plant extracts in the clinical research for modulating oxidative stress correlated with diabetes mellitus (DM) is well documented. In the present study, we investigated the in vitro antioxidant activity, toxicity, and anti-diabetic activity of methanolic extract of Hippophae salicifolialeaves in normal and alloxan-induced diabetic wistar rats. H. salicifolialeaves were found to be rich in antioxidants. The acute toxicity test of methanolic extract of H. salicifolialeaves revealed that the median lethal dose (LD50) was found to be 3.92 g/kg body weight in mice. Administration of H. salicifolialeaves at 200 mg/kg and 400 mg/kg in alloxan-induced diabetic rats illustrated significant reduction (22% and 39%, respectively) in fasting blood glucose compared to diabetic control. Both the doses were found to be effective when compared to diabetic rats. The Hippophae-treated diabetic rats showed significant increase in the endogenous antioxidant enzymes, superoxide dismutase (50% and 74%, respectively), glutathione peroxidase (57% and 41%, respectively) and decrease in malondialdehyde (33% and 15%, respectively) levels. These results suggested that the methanolic leaf extract of H. salicifoliaenhanced the antioxidant defence against reactive oxygen species produced under hyperglycaemic conditions.

In 2016, non-invasive encapsulated follicular variant of papillary thyroid carcinoma (NI-EFVPTC) was renamed as noninvasive thyroid follicular neoplasm with papillary-like nuclear features (NIFTP). However, as the study cohort did not mention tumors with oncocytic features, such lesions are still labeled by some as FVPTC. It is therefore crucial to evaluate the outcome and molecular profile of oncocytic NI-EFVPTC. A multi-institutional clinico-pathologic review was conducted to select 61 patients having oncocytic NI-EFVPTC. A detailed molecular profile was carried out in 15 patients. Oncocytic NI-EFVPTCs predominantly affected women in their 50s. There was no distant metastasis, lymph node metastases, or structural recurrence in the entire cohort. Among patients with ≥5 years of FU, all 33 individuals did not recur with a median FU of 10.2 years. Oncocytic NI-EFVPTC commonly had RAS(33%) mutations, a high frequency of mitochondrial DNA mutations (67%) and multiple chromosomal gains/losses (53%). No fusion genes were detected. Oncocytic NI-EFVPTC, when stringently selected for, lacks metastasis at presentation and follows an extremely indolent clinical course, even when treated conservatively with lobectomy alone without RAI therapy. These tumors share a similar mutational profile as NIFTP, FVPTC, and follicular neoplasm and are predominantly RAS-related. Like Hurthle cell neoplasms, they harbor a high frequency of mitochondrial DNA mutations, which contribute to the oncocytic cytomorphology. However, they lack the widespread chromosomal alterations observed in Hurthle cell carcinoma. Consideration should be given to include oncocytic NI-EFVPTCs as NIFTP in order to avoid overtreatment of these highly indolent tumors.

IMPORTANCE: The anti–programmed cell death protein 1 (PD-1) antibody pembrolizumab is approved by the US Food and Drug Administration for the treatment of microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) solid tumors, but the prevalence of MSI-H/dMMR prostate cancer and the clinical utility of immune checkpoint blockade in this disease subset are unknown. OBJECTIVE: To define the prevalence of MSI-H/dMMR prostate cancer and the clinical benefit of anti–PD-1/programmed cell death 1 ligand 1 (PD-L1) therapy in this molecularly defined population. DESIGN, SETTING, AND PARTICIPANTS: In this case series, 1551 tumors from 1346 patients with prostate cancer undergoing treatment at Memorial Sloan Kettering Cancer Center were prospectively analyzed using a targeted sequencing assay from January 1, 2015, through January 31, 2018. Patients had a diagnosis of prostate cancer and consented to tumor molecular profiling when a tumor biopsy was planned or archival tissue was available. For each patient, clinical outcomes were reported, with follow-up until May 31, 2018. MAIN OUTCOMES AND MEASURES: Tumor mutation burden and MSIsensor score, a quantitative measure of MSI, were calculated. Mutational signature analysis and immunohistochemistry for MMR protein expression were performed in select cases. RESULTS: Among the 1033 patients who had adequate tumor quality for MSIsensor analysis (mean [SD] age, 65.6 [9.3] years), 32 (3.1%) had MSI-H/dMMR prostate cancer. Twenty-three of 1033 patients (2.2%) had tumors with high MSIsensor scores, and an additional 9 had indeterminate scores with evidence of dMMR. Seven of the 32 MSI-H/dMMR patients (21.9%) had a pathogenic germline mutation in a Lynch syndrome–associated gene. Six patients had more than 1 tumor analyzed, 2 of whom displayed an acquired MSI-H phenotype later in their disease course. Eleven patients with MSI-H/dMMR castration-resistant prostate cancer received anti–PD-1/PD-L1 therapy. Six of these (54.5%) had a greater than 50% decline in prostate-specific antigen levels, 4 of whom had radiographic responses. As of May 2018, 5 of the 6 responders (5 of 11 total [45.5%]) were still on therapy for as long as 89 weeks. CONCLUSIONS AND RELEVANCE: The MSI-H/dMMR molecular phenotype is uncommon yet therapeutically meaningful in prostate cancer and can be somatically acquired during disease evolution. Given the potential for durable responses to anti–PD-1/PD-L1 therapy, these findings support the use of prospective tumor sequencing to screen all patients with advanced prostate cancer for MSI-H/dMMR. Because not all patients with the MSI-H/dMMR phenotype respond, further studies should explore mechanisms of resistance.

Photothermal therapy (PTT) has shown great promise to spatiotemporally ablate cancer cells, and further understanding of the immune system response to PTT treatment would contribute to improvement in therapeutic outcomes. Herein, we utilize microfluidic technology to prepare biocompatible conjugated polymer nanoparticles (CP NPs) as PTT agents and assess the immune response triggered by CP-based PTT treatment in vitro and in vivo. Through careful control of the antisolvent, CP NPs with a uniform diameter of 52 nm were obtained. The c-RGD-functionalized CP NPs exhibit high photothermal conversion efficiency, inducing effective cancer cell death under an 808 nm laser illumination. Using macrophage cells as the model, CP NPs demonstrate effective activation of proinflammatory immune response. Furthermore, in tumor-bearing mice model, a single round of CP NP-assisted PTT could efficiently induce antitumor immunity activation and ultimately inhibit tumor growth. The study provides detailed understanding of both microfluidic technology for CP NP fabrication and photothermal-triggered antitumor immune responses.

Organic particles have attracted extensive attention due to their broad scientific and industrial applications. Solvents play important roles in producing organic particles with fine-tuned sizes, shapes, and surface morphologies, thus the advancement of microfluidic devices with a thorough understanding of solvent miscibility offers additional opportunities to fabricate organic particles in large quantities. In this issue of ACS Nano, Chen et al.report that solvents could play a seemingly magical role in switching both reaction directions and particle morphologies from the same starting materials. Through monitoring the particle formulation kinetics, both social self-sorting and narcissistic self-sorting mechanisms have been proposed, which offer powerful methods to yield organic particles with desirable shapes and compositions.

The G-coupled receptors seen on the cell surface are composites with a lipid bilayer. The chemokines are kind of G-coupled receptor which majorly involved in the activation and downstream signalling of the cell. In general, many G-coupled receptors lack their 3D structures which become a hurdle in the drug designing process. In this study, comparative modelling of the CXCR3 receptor was carried out, structure evaluation was done using various tools and softwares. Additionally, molecular dynamics and docking were performed to prove the structural quality and architecture. Interestingly, the studies like toggle switch mechanism, lipid dynamics, virtual screening were carried out to find the potent antagonist for the CXCR3 receptor. During virtual screening 14,303 similar molecules were retrieved among them only four compounds have an ability to interact with a crucial amino acid residue of an antagonist. Hence, these screened compounds can serve as a drug candidate for a CXCR3 receptor, but further in vitroand in vivostudies are ought to do to prove its same efficacy.

The nutgrass, Cyperus rotundusL. (Family: Cyperaceae), is a colonial, perennial herb considered to have originated in India 2000 years ago and widely used in Ayurveda to treat several ailments. In addition to its prehistoric uses, it is used in several systems of medicine for treating variety of diseases. The synergistic actions of the Cyperus’ compounds have added advantage over that of a single constituent. In the past decade, numerous studies proved analgesic, anti-allergic, anti-arthritic, anti-candida, anti-cariogenic, anti-convulsant, anti-diarrheal, anti-emetic, anti-helminthic, anti-histamine, anti-hyperglycemic, anti-hypertensive, anti-inflammatory, anti-malarial, anti-obesity, antioxidant, anti-platelet, anti-pyretic, anti-ulcer, anti-viral, cardioprotective, cytoprotective, cytotoxic, gastroprotective, hepatoprotective, neuroprotective, ovicidal, and larvicidal, wound healing and inhibition of brain Na+K+ATPase activities of C. rotundusand its chemical constituents. However, the exact the mechanism of action is not very clear and requires further evaluation. These properties strongly suggest an extensive use of C. rotundusfor clinical applications. In this review, we attempted to provide information about the pharmacological effects of Cyperusand its proposed mechanisms of actions.

ABSTRACTThis article uses ‘food selfies’ posted on social media as a means of exploring the changing spatio-temporal characteristics of eating practices. It is inspired by a research that views the digital practice of posting food selfies on social media as a complex socio-cultural phenomenon. In this research, images of food and eating or ‘food selfies’, posted on Facebook were used to follow the eating practices of university students on and off campus. This article argues that such digital methods not only offer an innovative means of capturing social practices in motion, but they also reveal hidden or ignored aspects of practices that may not be evident from conventional methods. In particular, I argue that the affordances of social media platforms such as Facebook enable privileged access to people’s everyday social practices. The article proposes that such digital practices provide an on-going method of research that may offer institutions access to real time and archival data that is neither spatially nor temporally constrained.

Approximately 1–2% of pancreatic neoplasms are acinar cell carcinomas. Recently, BRAF gene rearrangements were identified in over 20% of acinar-type neoplasms, which included both pure acinar cell carcinomas and mixed carcinomas with acinar differentiation, using next-generation sequencing-based platforms, providing a potential therapeutic target for patients with these neoplasms. Thus, it is clinically important to develop a rapid, cost- and material-efficient assay to screen for BRAF gene fusions in pancreatic acinar-type neoplasms. We developed a dual color, break-apart FISH assay to detect BRAF gene rearrangements in these neoplasms and evaluated its performance in comparison to next-generation sequencing-based studies. A blinded BRAF rearrangement FISH investigation was performed on 31 acinar-type neoplasms that had been studied previously by next-generation sequencing-based analysis as well as on 18 additional acinar-type neoplasms that were accrued over the past 2 years. In total, BRAF fusions were identified in 12/49 (24%) acinar-type neoplasms by FISH. BRAF fusion partners were uncovered by using targeted next-generation sequencing studies in 11 FISH-positive cases that had sufficient material for next-generation sequencing studies. SND1 was the most frequent fusion partner involved in BRAF-fusion acinar-type neoplasms (50%), followed by HERPUD1 (18%). No BRAF fusions were identified by next-generation sequencing in any of the FISH-negative cases investigated. FISH analysis showed that BRAF rearrangements were diffusely present across tumor-rich areas in BRAF-fusion acinar-type neoplasms, which is consistent with an oncogenic driver alteration pattern. Thus, we demonstrated that, in comparison to targeted next-generation sequencing-based technologies, the FISH assay is highly sensitive and specific as well as time- and cost-efficient in the detection of BRAF fusions in acinar-type neoplasms. The FISH assay can be easily implemented in diagnostic settings to identify acinar-type neoplasms patients potentially suitable for targeted therapy to inhibit MAPK pathway activity.

Approximately 1–2% of pancreatic neoplasms are acinar cell carcinomas. Recently, BRAFgene rearrangements were identified in over 20% of acinar-type neoplasms, which included both pure acinar cell carcinomas and mixed carcinomas with acinar differentiation, using next-generation sequencing-based platforms, providing a potential therapeutic target for patients with these neoplasms. Thus, it is clinically important to develop a rapid, cost- and material-efficient assay to screen for BRAFgene fusions in pancreatic acinar-type neoplasms. We developed a dual color, break-apart FISH assay to detect BRAFgene rearrangements in these neoplasms and evaluated its performance in comparison to next-generation sequencing-based studies. A blinded BRAFrearrangement FISH investigation was performed on 31 acinar-type neoplasms that had been studied previously by next-generation sequencing-based analysis as well as on 18 additional acinar-type neoplasms that were accrued over the past 2 years. In total, BRAFfusions were identified in 12/49 (24%) acinar-type neoplasms by FISH. BRAFfusion partners were uncovered by using targeted next-generation sequencing studies in 11 FISH-positive cases that had sufficient material for next-generation sequencing studies. SND1was the most frequent fusion partner involved in BRAF-fusion acinar-type neoplasms (50%), followed by HERPUD1(18%). No BRAFfusions were identified by next-generation sequencing in any of the FISH-negative cases investigated. FISH analysis showed that BRAFrearrangements were diffusely present across tumor-rich areas in BRAF-fusion acinar-type neoplasms, which is consistent with an oncogenic driver alteration pattern. Thus, we demonstrated that, in comparison to targeted next-generation sequencing-based technologies, the FISH assay is highly sensitive and specific as well as time- and cost-efficient in the detection of BRAFfusions in acinar-type neoplasms. The FISH assay can be easily implemented in diagnostic settings to identify acinar-type neoplasms patients potentially suitable for targeted therapy to inhibit MAPK pathway activity.

Computer-Aided Drug Designing (CADD) has gained a wide popularity among biologists and chemists as a part of interdisciplinary drug discovery approach. It plays a vital role in the discovery, design and analysis of drugs in pharmaceutical industry. It is extensively used to reduce cost, time and speed up the early stage development of biologically new active molecules. In the current review we presented a brief review of CADD, merits and demerits, DNA, protein and enzyme as targets, types of CADD: Structure Based Drug Designing (SBDD), Ligand Based Drug Designing (LBDD), Pharmacophore based drug designing (PBDD) and Fragment Based Drug Designing (FBDD), theory behind the types of CADD and their applications. The review also focuses on the in-silico pharmokinetic, pharmacodynamic and toxicity filters or predictions that play a major role in identifying the drug like molecules. Currently in pharmaceutical sciences computational tools and software are exhibiting imperative role in the different stages of drug discovery hence the review throws light on various commercial and freeware available for each step of CADD.

With about 136 species, India is one among the richest countries in bamboo resources that help mankind in more than 1500 diverse ways. Although the utilization of juvenile shoots of bamboo in tribal diet of Northeast India is a very old observable fact, its numerous health benefits and potentiality remains uncharted. Apart from being delicious, the bamboo shoots are also rich in minerals and nutrient components such as carbohydrates, proteins, fiber and are low in fat and sugar which could be helpful in mitigating the problem of malnutrition. Few studies also revealed the health benefits of bamboo shoots for the treatment of cancer and cardiovascular diseases, weight loss and to improve digestion. Over and above the nutritional values of different species of bamboo shoots, the increasing inclinations towards health awareness among the consumers have emphasized its utilization in modern diet as a health food for boosting the nutritional security. Thus, in the present review, the nutraceutical potentiality of bamboo shoots is explored alongside its various qualities.

Bambusa balcooa(Poaceae) is native to India and has been used traditionally by the tribes of Northeast India to treat diabetes. The present investigation was aimed to evaluate the toxicity, anti-diabetic activity along with in vitro antioxidant activity of the leaf of B. balcooain alloxan-induced diabetic rats and also identify active compounds by using HPLC. The acute toxicity test of aqueous extract of B. balcooaleaf revealed that the median lethal dose (LD50) of B. balcooaaqueous extract (BAQE) was 5.18 g/kg body weight in mice. Administration of BAQE at 100 and 200 mg/kg in alloxan-induced diabetic rats showed significant reduction in fasting blood glucose and glycated hemoglobin while plasma insulin level was elevated compared to diabetic control. Both the doses were effective when compared to diabetic glibenclamide rats. The BAQE treated diabetic rats showed significant increase in the endogenous antioxidant enzymes superoxide dismutase, glutathione peroxidase and decrease in malondialdehyde levels. HPLC analysis of BAQE showed the presence of rutin, gallic acid and β sitosterol. Thus, it can be inferred from this study that BAQE possess antidiabetic and in vivo antioxidant activity. The overall activity might be possibly due to the presence of potential antioxidants.

Tumor molecular profiling is a fundamental component of precision oncology, enabling the identification of genomic alterations in genes and pathways that can be targeted therapeutically. The existence of recurrent targetable alterations across distinct histologically defined tumor types, coupled with an expanding portfolio of molecularly targeted therapies, demands flexible and comprehensive approaches to profile clinically relevant genes across the full spectrum of cancers. We established a large-scale, prospective clinical sequencing initiative using a comprehensive assay, MSK-IMPACT, through which we have compiled tumor and matched normal sequence data from a unique cohort of more than 10,000 patients with advanced cancer and available pathological and clinical annotations. Using these data, we identified clinically relevant somatic mutations, novel noncoding alterations, and mutational signatures that were shared by common and rare tumor types. Patients were enrolled on genomically matched clinical trials at a rate of 11%. To enable discovery of novel biomarkers and deeper investigation into rare alterations and tumor types, all results are publicly accessible.

The Cancer Genome Atlas data on colorectal carcinoma have provided a comprehensive view of the tumor’s genomic alterations and their tumorigenic roles. Tumor morphology, however, has not been fully integrated into the analysis. The aim of this study was to explore relevant associations between tumor morphology and the newly characterized genomic alterations in colorectal carcinoma. Two hundred and seven colorectal carcinomas that had undergone whole-exome sequencing as part of The Cancer Genome Atlas project and had adequate virtual images in the cBioPortal for Cancer Genomics constituted our study population. Upon analysis, a tight association between ‘microsatellite instability-high histology’ and microsatellite instability-high (P<0.001) was readily detected and helped validate our image-based histology evaluation. Further, we showed, (1) among all histologies, the not otherwise specified type had the lowest overall mutation count (P<0.001 for entire cohort, P<0.03 for the microsatellite-instable group), and among the microsatellite-instable tumors, this type also correlated with fewer frameshift mutations in coding mononucleotide repeats of a defined set of relevant genes (P<0.01); (2) cytosine phosphate guanine island methylator phenotype-high colorectal cancers with or without microsatellite instability tended to have different histological patterns: the former more often mucinous and the latter more often not otherwise specified; (3) mucinous histology was associated with more frequent alterations in BRAF, PIK3CA, and the transforming growth factor-β pathway when compared with non-mucinous histologies (P<0.001, P=0.01, and P<0.001, respectively); and (4) few colorectal cancers (<9%) exhibited upregulation of immune-inhibitory genes including major immune checkpoints; these tumors were primarily microsatellite-instable (up to 43%, vs <3% in microsatellite-stable group) and had distinctly non-mucinous histologies with a solid growth. These morphology–molecular associations are interesting and propose important clinical implications. The morphological patterns associated with alterations of immune checkpoint genes bear the potential to guide patient selection for clinical trials that target immune checkpoints in colorectal cancer, and provide directions for future studies.

The Cancer Genome Atlas data on colorectal carcinoma have provided a comprehensive view of the tumor's genomic alterations and their tumorigenic roles. Tumor morphology, however, has not been fully integrated into the analysis. The aim of this study was to explore relevant associations between tumor morphology and the newly characterized genomic alterations in colorectal carcinoma. Two hundred and seven colorectal carcinomas that had undergone whole-exome sequencing as part of The Cancer Genome Atlas project and had adequate virtual images in the cBioPortal for Cancer Genomics constituted our study population. Upon analysis, a tight association between ‘microsatellite instability-high histology' and microsatellite instability-high (P<0.001) was readily detected and helped validate our image-based histology evaluation. Further, we showed, (1) among all histologies, the not otherwise specified type had the lowest overall mutation count (P<0.001 for entire cohort, P<0.03 for the microsatellite-instable group), and among the microsatellite-instable tumors, this type also correlated with fewer frameshift mutations in coding mononucleotide repeats of a defined set of relevant genes (P<0.01); (2) cytosine phosphate guanine island methylator phenotype-high colorectal cancers with or without microsatellite instability tended to have different histological patterns: the former more often mucinous and the latter more often not otherwise specified; (3) mucinous histology was associated with more frequent alterations in BRAF, PIK3CA, and the transforming growth factor-β pathway when compared with non-mucinous histologies (P<0.001, P=0.01, and P<0.001, respectively); and (4) few colorectal cancers (<9%) exhibited upregulation of immune-inhibitory genes including major immune checkpoints; these tumors were primarily microsatellite-instable (up to 43%, vs<3% in microsatellite-stable group) and had distinctly non-mucinous histologies with a solid growth. These morphology–molecular associations are interesting and propose important clinical implications. The morphological patterns associated with alterations of immune checkpoint genes bear the potential to guide patient selection for clinical trials that target immune checkpoints in colorectal cancer, and provide directions for future studies.

Endometrial stromal sarcomas (ESS) are often underpinned by recurrent chromosomal translocations resulting in the fusion of genes involved in epigenetic regulation. To date, only YWHAE-NUTM2rearrangements are associated with distinctive high-grade morphology and aggressive clinical behavior. We identified 3 ESS morphologically mimicking myxoid leiomyosarcoma of the uterus and sought to describe their unique histopathologic features and identify genetic alterations using next-generation sequencing. All cases displayed predominantly spindled cells associated with abundant myxoid stroma and brisk mitotic activity. Tumors involved the endometrium and demonstrated tongue-like myometrial infiltration. All 3 were associated with an aggressive clinical course, including multisite bony metastases in 1 patient, progressive peritoneal disease after chemotherapy in another, and metastases to the lung and skin in the last patient. All 3 ESS were found to harbor ZC3H7B-BCORgene fusions by targeted sequencing and fluorescence in situ hybridization. On the basis of the review of these cases, we find that ESS with ZC3H7B-BCORfusion constitutes a novel type of high-grade ESS and shares significant morphologic overlap with myxoid leiomyosarcoma.

An in vitro protocol has been established for clonal propagation of Nothapodytes nimmonianawhich is an important source of Camptothecin (CPT). Elite source was identified based on the chemical potency to accumulate the optimum level of CPT. Different types and concentrations of plant growth regulators were used to study their effect on inducing multiple shoots from the explants regenerated from embryos of N. nimmoniana. Of these, a combination of N6-benzyladenine (0.2 mg L−1) and Indole-3-butyric acid (IBA) (0.1 mg L−1) proved optimum for differentiating multiple shoots in 90.6 % of the cultures with an average of 10.24 shoots per explant obtained within 8 weeks of inoculation. Nearly, 92 % of the excised in vitro shoots rooted on half strength Murashige and Skoog (MS) medium containing 0.05 % activated charcoal, supplemented with 1-naphthaleneacetic acid and IBA at 0.1 mg L−1each. The micropropagated plants were evaluated for their genetic fidelity by employing inter simple sequence repeats (ISSR) markers. Ten individuals, randomly chosen from a population of 145 regenerants, were compared with the donor plant. The regenerated plants were also evaluated for their chemical potency using high-performance liquid chromatography (HPLC) analysis of CPT content. The true-to-type nature of the micropropagated plants was confirmed based on their monomorphic banding profiles with that of the mother plants using ISSR markers. Besides, HPLC evaluation of the CPT content confirmed the existence of chemical uniformity among the regenerated plants and the elite mother plant.

Malarial parasite P. falciparum, an apicomplexan protozoan has a 23.3MB nuclear genome and encodes ~5600 transcripts. The genetic diversity of the parasite within and across geographical zones is a challenge to gene expression studies which are essential for understanding of disease process, outcome and developing markers for diagnostics and prognostics. Here, we describe the strategy involved in designing a custom P. falciparum15K array using the Agilent platform and Genotypic's Right Design methodology to study the transcriptome of Indian field isolates for which genome sequence information is limited. The array contains probes representing genome sequences of two distinct geographical isolates (i.e. 3D7 and HB3) and sub-telomeric vargene sequences of a third isolate (IT4) known to adhere in culture condition. Probes in the array have been selected based on their efficiency to detect transcripts through a 244K array experimentation. Array performance for the 15K array, was evaluated and validated using RNA materials from P. falciparumclinical isolates. A large percentage (91%) of the represented transcripts was detected from Indian P. falciparumpatient isolates. Replicated probes and multiple probes representing the same gene showed perfect correlation between them suggesting good probe performance. Additional transcripts could be detected due to inclusion of unique probes representing HB3 strain transcripts. Variant surface antigen (VSA) transcripts were detected by optimized probes representing the VSA genes of three geographically distinct strains. The 15K cross strain P. falciparumarray has shown good efficiency in detecting transcripts from P. falciparumparasite samples isolated from patients. The low parasite loads and presence of host RNA makes arrays a preferred platform for gene expression studies over RNA-Seq.