The association of ABCB1 gene polymorphism with clinical response to carbamazepine monotherapy in patients with epilepsy.

BACKGROUND: Epilepsy is a common neurological disease but around 30% of patients fail to respond to antiepileptic drug (AED) treatment. Genetic variation of the ATP-binding cassette subfamily B, member 1 (ABCB1) gene, a drug efflux transporter may infer treatment resistance by decreasing gastrointestinal absorption and preventing AED entry into the brain. This study examined the impact of ABCB1 genetic variants on carbamazepine responsiveness. MATERIALS AND METHODS: Genomic DNA was extracted from whole blood of 104 epileptic patients. Genotyping of 3 ABCB1 variants (c.C3435T, c.G2677T/A and c.C1236T) was undertaken using validated TaqMan allelic discrimination assays. Plasma carbamazepine levels were measured at 3 and 6 months following the initial dose using high-performance liquid chromatography (HPLC) alongside clinical outcomes evaluation. RESULTS: Nonresponse to carbamazepine (CBZ) was associated significantly with the ABCB1 variants c.C3435T, c.G2677T/A, c.C1236T and TTT, TTC haplotypes (P < 0.05). There was no significant association between variants and plasma CBZ level (P > 0.05). CONCLUSIONS: Our results showed that variant alleles of the ABCB1 gene and TTT, TTC haplotypes were significantly associated with CBZ resistance without affecting the plasma level of carbamazepine. The findings of this study may help to predict patient's response to treatment ultimately it will improve the personalized and evidence based treatment choice of patients with epilepsy.

Immune checkpoint inhibitor therapy for advanced cutaneous squamous cell carcinoma in Australia: a retrospective real world cohort study.

OBJECTIVES: To review the outcomes of immune checkpoint inhibitor (ICI) treatment of advanced cutaneous squamous cell carcinoma (CSCC) outside clinical trials. STUDY DESIGN: Retrospective observational study; review of patient records in fifteen Australian institutions. SETTING, PARTICIPANTS: All Australian adults with locally advanced or metastatic CSCC not amenable to curative surgery or radiotherapy treated with ICIs, 5 May 2017 - 23 May 2022, through a cemiplimab compassionate access scheme (Therapeutic Goods Administration Special Access Scheme) or who personally covered the cost of pembrolizumab prior to the start of the access scheme. MAIN OUTCOME MEASURES: Best overall response rate (ORR) according to standardised assessment criteria using the hierarchy: Response Evaluation Criteria in Solid Tumors (RECIST 1.1), the modified World Health Organization clinical response criteria, and the Positron Emission Tomography Response Criteria (PERCIST 1.0); overall and progression-free survival. RESULTS: A total of 286 people with advanced CSCC received ICI therapy during May 2017 - May 2022 (cemiplimab, 270; pembrolizumab, 16). Their median age was 75.2 years (range, 39.3-97.5 years) and 232 were men (81%); median follow-up time was 12.2 months (interquartile range, 5.5-20.5 months). Eighty-eight people (31%) were immunocompromised, 27 had autoimmune disease, and 59 of 277 (21%) had ECOG performance scores of 2 or 3. The ORR was 60% (166 of 278 evaluable patients): complete responses were recorded for 74 (27%) and partial responses for 92 patients (33%). Twelve-month overall survival was 78% (95% confidence interval [CI], 72-83%); progression-free survival was 65% (95% CI, 58-70%). Poorer ECOG performance status was associated with poorer overall survival (per unit: adjusted hazard ratio [aHR], 3.0; 95% CI, 2.0-4.3) and progression-free survival (aHR, 2.4; 95% CI, 1.8-3.3), as was being immunocompromised (overall: aHR, 1.8; 95% CI, 1.1-3.0; progression-free: aHR, 1.8; 95% CI, 1.2-2.7). Fifty-five people (19%) reported immune-related adverse events of grade 2 or higher; there were no treatment-related deaths. CONCLUSION: In our retrospective study, the effectiveness and toxicity of ICI therapy were similar to those determined in clinical trials. Our findings suggest that ICIs could be effective and well tolerated by people with advanced CSCC who are ineligible for clinical trials.

Impact of haemodialysis on plasma carnitine concentrations in haemodialysis patients.

Objective: To evaluate the impact of haemodialysis on plasma carnitine levels. METHODS: The cross-sectional study was conducted from April 20, 2020 to May 10, 2022, at the dialysis unit of the nephrology ward of Jinnah Postgraduate Medical Centre, Karachi, and the Pakistan Navy Ship Shifa Hospital, Karachi, in collaboration with the Department of Biochemistry, University of Karachi, and comprised patients of either gender aged >18 years. They were divided into chronic kidney disease group A and end-stage renal disease group B. Control group C included subjects from the general population. Free carnitine and total carnitine values were detected using enzyme-linked immunosorbent assay. Acyl carnitine was estimated by applying the standard formula, and the ratio between acyl carnitine and free carnitine was calculated for accurate assessment of the carnitine status. Data was analysed using SPSS 23. RESULTS: Of the 203 subjects, 143(70.44%) were cases and 60(29.55%) were controls. Among the cases, 120(84%) were recruited from Jinnah Postgraduate Medical Centre and 23(16%) from Pakistan Navy Ship Shifa Hospital. There were 60(29.55%) patients in group A, 83(40.88%) in group B and 60(29.55%) in group C. The mean age in group A was 47.90 5.±65 years, it was 44.10 ±8.92 years in group B and 40.90 ± 6.73 years in group C. There was a significant difference related to free carnitine, total carnitine, acyl carnitine values and the ratio between acyl carnitine and free carnitine values in groups A and B compared to control group C (p<0.05). Conclusion: Patients on maintenance haemodialysis developed were found to have developed carnitine deficiency.

Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial.

BACKGROUND: Pembrolizumab prolongs progression-free and overall survival among patients with advanced melanoma and recurrence-free survival in resected stage III disease. KEYNOTE-716 assessed pembrolizumab as adjuvant therapy in patients with completely resected, high-risk, stage II melanoma. We report results from the planned first and second interim analyses for recurrence-free survival. METHODS: In this double-blind, randomised, placebo-controlled phase 3 study, involving 160 academic medical centres and hospitals in 16 countries (Australia, Belgium, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Poland, South Africa, Spain, Switzerland, the UK, and the USA), patients aged 12 years or older with newly diagnosed, completely resected stage IIB or IIC melanoma (TNM stage T3b or T4 with a negative sentinel lymph node biopsy) were recruited. Eligible patients were randomly assigned (1:1), in blocks of four and stratified by T-category (3b, 4a, and 4b) and paediatric status (age 12-17 years vs ≥18 years), using an interactive response technology system to intravenous pembrolizumab 200 mg (2 mg/kg in paediatric patients) or placebo every 3 weeks for 17 cycles or until disease recurrence or unacceptable toxicity. All patients, clinical investigators, and analysts were masked to treatment assignment. The primary endpoint was investigator-assessed recurrence-free survival (defined as time from randomisation to recurrence or death) in the intention-to-treat (ITT) population (ie, all patients randomly assigned to treatment). The primary endpoint was met if recurrence-free survival was significantly improved for pembrolizumab versus placebo at either the first interim analysis (after approximately 128 patients had events) or second interim analysis (after 179 patients had events) under multiplicity control. Safety was assessed in all patients randomly assigned to treatment who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03553836, and is closed to accrual. FINDINGS: Between Sept 23, 2018, and Nov 4, 2020, 1182 patients were screened, of whom 976 were randomly assigned to pembrolizumab (n=487) or placebo (n=489; ITT population). The median age was 61 years (IQR 52-69) and 387 (40%) patients were female and 589 (60%) were male. 874 (90%) of 976 patients were White and 799 (82%) were not Hispanic or Latino. 483 (99%) of 487 patients in the pembrolizumab group and 486 (99%) of 489 in the placebo group received assigned treatment. At the first interim analysis (data cutoff on Dec 4, 2020; median follow-up of 14·4 months [IQR 10·2-18·7] in the pembrolizumab group and 14·3 months [10·1-18·7] in the placebo group), 54 (11%) of 487 patients in the pembrolizumab group and 82 (17%) of 489 in the placebo group had a first recurrence of disease or died (hazard ratio [HR] 0·65 [95% CI 0·46-0·92]; p=0·0066). At the second interim analysis (data cutoff on June 21, 2021; median follow-up of 20·9 months [16·7-25·3] in the pembrolizumab group and 20·9 months [16·6-25·3] in the placebo group), 72 (15%) patients in the pembrolizumab group and 115 (24%) in the placebo group had a first recurrence or died (HR 0·61 [95% CI 0·45-0·82]). Median recurrence-free survival was not reached in either group at either assessment timepoint. At the first interim analysis, grade 3-4 treatment-related adverse events occurred in 78 (16%) of 483 patients in the pembrolizumab groups versus 21 (4%) of 486 in the placebo group. At the first interim analysis, four patients died from an adverse event, all in the placebo group (one each due to pneumonia, COVID-19-related pneumonia, suicide, and recurrent cancer), and at the second interim analysis, one additional patient, who was in the pembrolizumab group, died from an adverse event (COVID-19-related pneumonia). No deaths due to study treatment occurred. INTERPRETATION: Pembrolizumab as adjuvant therapy for up to approximately 1 year for stage IIB or IIC melanoma resulted in a significant reduction in the risk of disease recurrence or death versus placebo, with a manageable safety profile. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA.

Terlipressin in combination with albumin as a therapy for hepatorenal syndrome in patients aged 65 years or older.

INTRODUCTION AND OBJECTIVES: Clinical data for older patients with advanced liver disease are limited. This post hoc analysis evaluated the efficacy and safety of terlipressin in patients aged ≥65 years with hepatorenal syndrome using data from 3 Phase III, randomized, placebo-controlled studies (OT-0401, REVERSE, CONFIRM). PATIENTS AND METHODS: The pooled population of patients aged ≥65 years (terlipressin, n = 54; placebo, n = 36) was evaluated for hepatorenal syndrome reversal-defined as a serum creatinine level ≤1.5 mg/dL (≤132.6 µmol/L) while receiving terlipressin or placebo, without renal replacement therapy, liver transplantation, or death-and the incidence of renal replacement therapy (RRT). Safety analyses included an assessment of adverse events. RESULTS: Hepatorenal syndrome reversal was almost 2-times higher in terlipressin-treated patients compared with patients who received placebo (31.5% vs 16.7%; P = 0.143). Among surviving patients, the need for RRT was significantly reduced in the terlipressin group, with an almost 3-times lower incidence of RRT versus the placebo group (Day 90: 25.0% vs 70.6%; P = 0.005). Among 23 liver-transplant-listed patients, significantly fewer patients in the terlipressin versus placebo group needed RRT by Days 30 and 60 (P = 0.027 each). Fewer patients in the terlipressin group needed RRT post-transplant (P = 0.011). More terlipressin-treated patients who were listed for and received a liver transplant were alive and RRT-free by Day 90. No new safety signals were revealed in the older subpopulation compared with previously published data. CONCLUSIONS: Terlipressin therapy may lead to clinical improvements in highly vulnerable patients aged ≥65 years with hepatorenal syndrome. CLINICAL TRIAL NUMBERS: OT-0401, NCT00089570; REVERSE, NCT01143246; CONFIRM, NCT02770716.

Examination of the Effect of Task Complexity and Coping Capacity on Driving Risk: A Cross-Country and Transportation Mode Comparative Study.

The i-DREAMS project established a 'Safety Tolerance Zone (STZ)' to maintain operators within safe boundaries through real-time and post-trip interventions, based on the crucial role of the human element in driving behavior. This paper aims to model the inter-relationship among driving task complexity, operator and vehicle coping capacity, and crash risk. Towards that aim, data from 80 drivers, who participated in a naturalistic driving experiment carried out in three countries (i.e., Belgium, Germany, and Portugal), resulting in a dataset of approximately 19,000 trips were collected and analyzed. The exploratory analysis included the development of Generalized Linear Models (GLMs) and the choice of the most appropriate variables associated with the latent variables "task complexity" and "coping capacity" that are to be estimated from the various indicators. In addition, Structural Equation Models (SEMs) were used to explore how the model variables were interrelated, allowing for both direct and indirect relationships to be modeled. Comparisons on the performance of such models, as well as a discussion on behaviors and driving patterns across different countries and transport modes, were also provided. The findings revealed a positive relationship between task complexity and coping capacity, indicating that as the difficulty of the driving task increased, the driver's coping capacity increased accordingly, (i.e., higher ability to manage and adapt to the challenges posed by more complex tasks). The integrated treatment of task complexity, coping capacity, and risk can improve the behavior and safety of all travelers, through the unobtrusive and seamless monitoring of behavior. Thus, authorities should utilize a data system oriented towards collecting key driving insights on population level to plan mobility and safety interventions, develop incentives for road users, optimize enforcement, and enhance community building for safe traveling.

Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma (KEYNOTE-716): distant metastasis-free survival results of a multicentre, double-blind, randomised, phase 3 trial.

BACKGROUND: Patients with stage IIB or IIC melanoma who undergo surgery alone are at a substantial risk for disease recurrence. Adjuvant pembrolizumab significantly improved recurrence-free survival versus placebo in stage IIB or IIC melanoma in the first interim analysis of the KEYNOTE-716 trial. Here, we report results from the secondary endpoint of distant metastasis-free survival (prespecified third interim analysis), and recurrence-free survival with longer follow-up. METHODS: KEYNOTE-716 is a multicentre, double-blind, placebo-controlled, crossover or rechallenge, randomised, phase 3 trial done at 160 academic medical centres and hospitals across 16 countries. Eligible patients were aged 12 years and older with newly-diagnosed, completely resected, and histologically confirmed stage IIB (T3b or T4a) or IIC (T4b) cutaneous melanoma; negative sentinel lymph node biopsy; and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) to receive either 200 mg of pembrolizumab (2 mg/kg up to a maximum of 200 mg in paediatric patients) or placebo, both intravenously, every 3 weeks for 17 cycles (part 1) or until disease recurrence or unacceptable toxicity. Eligible patients with disease recurrence could receive further treatment with pembrolizumab in the part 2 crossover or rechallenge phase. Randomisation was done using an interactive response technology system and stratified by T category and paediatric status. The primary endpoint was investigator-assessed recurrence-free survival (assessed here with longer follow-up), and we report the prespecified third interim analysis of distant metastasis-free survival (secondary endpoint). Efficacy analyses were done in the intention-to-treat population (all patients who were randomly assigned, according to assigned group) and safety was assessed in all patients who were randomly assigned and received at least one dose of trial treatment, according to the treatment received. KEYNOTE-716 is registered at ClinicalTrials.gov, NCT03553836, and has completed recruitment. FINDINGS: Between Sept 23, 2018, and Nov 4, 2020, 976 patients were randomly assigned to receive pembrolizumab (n=487) or placebo (n=489). At a median follow-up of 27·4 months (IQR 23·1-31·7), median distant metastasis-free survival was not reached (95% CI not reached [NR]-NR) in either group. Pembrolizumab significantly improved distant metastasis-free survival (hazard ratio [HR] 0·64, 95% CI 0·47-0·88, p=0·0029) versus placebo. Median recurrence-free survival was 37·2 months (95% CI NR-NR) in the pembrolizumab group and not reached in the placebo group (95% CI NR-NR). The risk of recurrence remained lower with pembrolizumab versus placebo (HR 0·64, 95% CI 0·50-0·84). The most common grade 3 or worse adverse events were hypertension (16 [3%] of 483 patients in the pembrolizumab group vs 17 [4%] of 486 patients in the placebo group), diarrhoea (eight [2%] vs one [<1%]), rash (seven [1%] vs two [<1%]), autoimmune hepatitis (seven [1%] vs two [<1%]), and increased lipase (six [1%] vs eight [2%]). Treatment-related serious adverse events occurred in 49 (10%) patients in the pembrolizumab group and 11 (2%) patients in the placebo group. No treatment-related deaths were reported. INTERPRETATION: Adjuvant pembrolizumab is an efficacious treatment option for resected stage IIB and IIC melanoma, with significant improvement in distant-metastasis free survival versus placebo and continued reduction in the risk of recurrence with an adverse event profile consistent with previous studies of pembrolizumab. The overall benefit-risk of pembrolizumab continues to be positive in the adjuvant setting. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.

Detection of clinical progression through plasma ctDNA in metastatic melanoma patients: a comparison to radiological progression.

BACKGROUND: The validity of circulating tumour DNA (ctDNA) as an indicator of disease progression compared to medical imaging in patients with metastatic melanoma requires detailed evaluation. METHODS: Here, we carried out a retrospective ctDNA analysis of 108 plasma samples collected at the time of disease progression. We also analysed a validation cohort of 66 metastatic melanoma patients monitored prospectively after response to systemic therapy. RESULTS: ctDNA was detected in 62% of patients at the time of disease progression. For 67 patients that responded to treatment, the mean ctDNA level at progressive disease was significantly higher than at the time of response (P < 0.0001). However, only 30 of these 67 (45%) patients had a statistically significant increase in ctDNA by Poisson test. A validation cohort of 66 metastatic melanoma patients monitored prospectively indicated a 56% detection rate of ctDNA at progression, with only two cases showing increased ctDNA prior to radiological progression. Finally, a correlation between ctDNA levels and metabolic tumour burden was only observed in treatment naïve patients but not at the time of progression in a subgroup of patients failing BRAF inhibition (N = 15). CONCLUSIONS: These results highlight the low efficacy of ctDNA to detect disease progression in melanoma when compared mainly to standard positron emission tomography imaging.

Diversity and distribution of thermophilic microorganisms and their applications in biotechnology.

Hot springs ecosystem is the most ancient continuously inhabited ecosystem on earth which harbors diverse thermophilic bacteria and archaea distributed worldwide. Life in extreme environments is very challenging so there is a great potential biological dark matter and their adaptation to harsh environments eventually producing thermostable enzymes which are very vital for the welfare of mankind. There is an enormous need for a new generation of stable enzymes that can endure harsh conditions in industrial processes and can either substitute or complement conventional chemical processes. Here, we review at the variety and distribution of thermophilic microbes, as well as the different thermostable enzymes that help them survive at high temperatures, such as proteases, amylases, lipases, cellulases, pullulanase, xylanases, and DNA polymerases, as well as their special properties, such as high-temperature stability. We have documented the novel isolated thermophilic and hyperthermophilic microorganisms, as well as the discovery of their enzymes, demonstrating their immense potential in the scientific community and in industry.

Flavonoids as Antidiabetic and Anti-Inflammatory Agents: A Review on Structural Activity Relationship-Based Studies and Meta-Analysis.

Flavonoids are a group of naturally occurring polyphenolic secondary metabolites which have been reported to demonstrate a wide range of pharmacological properties, most importantly, antidiabetic and anti-inflammatory effects. The relationship between hyperglycaemia and inflammation and vascular complications in diabetes is now well established. Flavonoids possessing antidiabetic properties may alleviate inflammation by reducing hyperglycaemia through different mechanisms of action. It has been suggested that the flavonoids' biochemical properties are structure-dependent; however, they are yet to be thoroughly grasped. Hence, the main aim of this review is to understand the antidiabetic and anti-inflammatory properties of various structurally diverse flavonoids and to identify key positions responsible for the effects, their correlation, and the effect of different substitutions on both antidiabetic and anti-inflammatory properties. The general requirement of flavonoids for exerting both anti-inflammatory and antidiabetic effects is found to be the presence of a C2-C3 double bond (C-ring) and hydroxyl groups at the C3', C4', C5, and C7 positions of both rings A and B of a flavonoid skeleton. Furthermore, it has been demonstrated that substitution at the C3 position of a C-ring decreases the anti-inflammatory action of flavonoids while enhancing their antidiabetic activity. Correlation is discussed at length to support flavonoids possessing essential pharmacophores to demonstrate equipotent effects. The consideration of these structural features may play an important role in synthesizing better flavonoid-based drugs possessing dual antidiabetic and anti-inflammatory effects. A meta-analysis further established the role of flavonoids as antidiabetic and anti-inflammatory agents.

Prevalence of antibiotic resistance pattern in shigella isolates procured from pediatric patients at Faisalabad - Pakistan.

Shigella infection (shigellosis) is an intestinal disease caused by a shigella isolates belongs to a family Enterobacteriacea. Watery diarrhea, abdominal pain and tenesmus are the prominent symptoms of shigella infection. The present study was designed to determine period prevalence and antimicrobial susceptibility of Shigella species recovered from stool specimens obtained from diarrheal paediatric patients under 5 years of age. This cross-sectional study was carried out for a period of six months (Jan to June, 2016). All Shigella isolates were identified based on colony morphology, microscopic characteristics, and biochemical characteristics. After applying Kirby Baur disc diffusion method only 22 (18.96%) stool specimens were found positive for Shigella isolates among the 116 stool specimens. The isolates were also found susceptible to Levofloxacin (72.72%), Azithromycin (59.09%), and Cefotaxime (40.90%). However, the said isolates were resistant to Lincomycin (100%) and Penicillin-G (100%), followed by Amoxicillin (95.45%) and Oxacillin (95.45%). The chi-square test was used to check the close association among antimicrobial agents used and as highly significant (p-value < 2.2e-16). Based on antimicrobial susceptibility findings, Levofloxacin, Azithromycin and Cefotoxime were found effective for the control of shigellosis.

RF-amide related peptide-3 (RFRP-3): a novel neuroendocrine regulator of energy homeostasis, metabolism, and reproduction.

A hypothalamic neuropeptide, RF-amide related peptide-3 (RFRP-3), the mammalian ortholog of the avian gonadotropin-inhibitory hormone (GnIH) has inhibitory signals for reproductive axis via G-protein coupled receptor 147 in mammals. Moreover, RFRP-3 has orexigenic action but the mechanism involved in energy homeostasis and glucose metabolism is not yet known. Though, the RFRP-3 modulates orexigenic action in co-operation with other neuropeptides, which regulates metabolic cues in the hypothalamus. Administration of GnIH/RFRP-3 suppresses plasma luteinizing hormone, at the same time stimulates feeding behavior in birds and mammals. Likewise, in the metabolically deficient conditions, its expression is up-regulated suggests that RFRP-3 contributes to the integration of energy balance and reproduction. However, in many other metabolic conditions like induced diabetes and high-fat diet obesity, etc. its role is still not clear while, RFRP-3 induces the glucose homeostasis by adipocytes is reported. The physiological role of RFRP-3 in metabolic homeostasis and the metabolic effects of RFRP-3 signaling in pharmacological studies need a detailed discussion. Further studies are required to find out whether RFRP-3 is associated with restricted neuroendocrine function observed in type II diabetes mellitus, aging, or sub-fertility. In this context, the current review is focused on the role of RFRP-3 in the above-mentioned mechanisms. Studies from search engines including PubMed, Google Scholar, and science.gov are included after following set inclusion/exclusion criteria. As a developing field few mechanisms are still inconclusive, however, based on the available information RFRP-3 seems to be a putative tool in future treatment strategies towards metabolic disease.

Detection and prognostic role of heterogeneous populations of melanoma circulating tumour cells.

BACKGROUND: Circulating tumour cells (CTCs) can be assessed through a minimally invasive blood sample with potential utility as a predictive, prognostic and pharmacodynamic biomarker. The large heterogeneity of melanoma CTCs has hindered their detection and clinical application. METHODS: Here we compared two microfluidic devices for the recovery of circulating melanoma cells. The presence of CTCs in 43 blood samples from patients with metastatic melanoma was evaluated using a combination of immunocytochemistry and transcript analyses of five genes by RT-PCR and 19 genes by droplet digital PCR (ddPCR), whereby a CTC score was calculated. Circulating tumour DNA (ctDNA) from the same patient blood sample, was assessed by ddPCR targeting tumour-specific mutations. RESULTS: Our analysis revealed an extraordinary heterogeneity amongst melanoma CTCs, with multiple non-overlapping subpopulations. CTC detection using our multimarker approach was associated with shorter overall and progression-free survival. Finally, we found that CTC scores correlated with plasma ctDNA concentrations and had similar pharmacodynamic changes upon treatment initiation. CONCLUSIONS: Despite the high phenotypic and molecular heterogeneity of melanoma CTCs, multimarker derived CTC scores could serve as viable tools for prognostication and treatment response monitoring in patients with metastatic melanoma.

PD-L1 Expression on Circulating Tumor Cells May Be Predictive of Response to Pembrolizumab in Advanced Melanoma: Results from a Pilot Study.

BACKGROUND: PD-1 inhibitors are routinely used for the treatment of advanced melanoma. This study sought to determine whether PD-L1 expression on circulating tumor cells (CTCs) can serve as a predictive biomarker of clinical benefit and response to treatment with the PD-1 inhibitor pembrolizumab. METHODS: Blood samples were collected from patients with metastatic melanoma receiving pembrolizumab, prior to treatment and 6-12 weeks after initiation of therapy. Multiparametric flow cytometry was used to identify CTCs and evaluate the expression of PD-L1. RESULTS: CTCs were detected in 25 of 40 patients (63%). Patients with detectable PD-L1+ CTCs (14/25, 64%) had significantly longer progression-free survival (PFS) compared with patients with PD-L1- CTCs (26.6 months vs. 5.5 months; p = .018). The 12-month PFS rates were 76% versus 22% in the PD-L1+ versus PD-L1- CTCs groups (p = .012), respectively. A multivariate linear regression analysis confirmed that PD-L1+ CTC is an independent predictive biomarker of PFS (hazard ratio, 0.229; 95% confidence interval, 0.052-1.012; p = .026). CONCLUSION: Our results reveal the potential of CTCs as a noninvasive real-time biopsy to evaluate PD-L1 expression in patients with melanoma. PD-L1 expression on CTCs may be predictive of response to pembrolizumab and longer PFS. IMPLICATIONS FOR PRACTICE: The present data suggest that PD-L1 expression on circulating tumor cells may predict response to pembrolizumab in advanced melanoma. This needs further validation in a larger trial and, if proven, might be a useful liquid biopsy tool that could be used to stratify patients into groups more likely to respond to immunotherapy, hence leading to health cost savings.

Enhanced tunable plasmonic resonance in crumpled graphene resonators loaded with gate tunable metamaterials.

Graphene devices have been widely explored for photonic applications, as they serve as promising candidates for controlling light interactions resulting in extreme confinement and tunability of graphene plasmons. The ubiquitous presence of surface crumples in graphene, very less is known on how the crumples in graphene can affect surface plasmon resonance and its absorption properties. In this article, a novel approach based on the crumpled graphene is investigated to realize broadband tunability of plasmonic resonance through the mechanical reconfiguration of crumpled graphene resonators. The mechanical reconfiguration of graphene crumples combined with dual electrostatic gating (i.e. raising the Fermi level from 0.2-0.4 eV) of graphene serves as a tuning knob enabling broad spectral tunability of plasmonic resonance in the wavelength range of 14-24 µm. The crumpled region in the resonators exhibits an effective trapping potential where it extremely confines the surface plasmonic field on the surfaces of crumples providing localized surface plasmon resonance at the apices of these crumples. Finally, to achieve near-unity absorption >99% at the resonance wavelengths (17 µm and 22 µm) crumpled graphene resonators are loaded with four ring shaped metamaterials which result in the enhanced near-field intensity of ≈1.4×106. This study delivers insight into the tunability of crumpled graphene and their coupling mechanism by providing a new platform for the flexible and gate tunable graphene sensors at the infrared region.

A Fully-Printed CRLH Dual-Band Dipole Antenna Fed by a Compact CRLH Dual-Band Balun.

In this paper, a new design method is proposed for a planar and compact dual-band dipole antenna. The dipole antenna has arms as a hybrid CRLH (Composite right- and left-handed) transmission-line comprising distributed and lumped elements for the dual-band function. The two arms are fed by the outputs of a compact and printed CRLH dual-band balun which consists of a CRLH hybrid coupler and an additional CRLH phase-shifter. Its operational frequencies are 2.4 and 5.2 GHz as popular mobile applications. Verifying the method, the circuit approach, EM (Electromagnetics) simulation and measurement are conducted and their results turn out to agree well with each other. Additionally, the CRLH property is shown with the dispersion diagram and the effective size-reduction is mentioned.

RF Channel-Selectivity Sensing by a Small Antenna of Metamaterial Channel Filters for 5G Sub-6-GHz Bands.

In this paper, a new small antenna is suggested for 5G Sub-6-GHz band mobile communication. It can change the channel among the three given bands (called the 3.5-GHz area), as a wide-band antenna is connected to a small multiplexer comprising three metamaterial channel filters. The function of channel selection of this antenna system is experimentally demonstrated to prove the validity of the presented scheme. The channel selection for 5G mobile communication is conducted from f1 (channel 1) through f2 (channel 2) to f3 (channel 3), when TX and RX antennas with gains over 0 dBi and S11 less than -10 dB are located far-field apart (RFar ≫ 2.1 cm), and result in the transmission coefficient (S21) being the greatest at the selected channel, which is detected by a vector network analyzer.

A Review on the Development of Tunable Graphene Nanoantennas for Terahertz Optoelectronic and Plasmonic Applications.

Exceptional advancement has been made in the development of graphene optical nanoantennas. They are incorporated with optoelectronic devices for plasmonics application and have been an active research area across the globe. The interest in graphene plasmonic devices is driven by the different applications they have empowered, such as ultrafast nanodevices, photodetection, energy harvesting, biosensing, biomedical imaging and high-speed terahertz communications. In this article, the aim is to provide a detailed review of the essential explanation behind graphene nanoantennas experimental proofs for the developments of graphene-based plasmonics antennas, achieving enhanced light-matter interaction by exploiting graphene material conductivity and optical properties. First, the fundamental graphene nanoantennas and their tunable resonant behavior over THz frequencies are summarized. Furthermore, incorporating graphene-metal hybrid antennas with optoelectronic devices can prompt the acknowledgment of multi-platforms for photonics. More interestingly, various technical methods are critically studied for frequency tuning and active modulation of optical characteristics, through in situ modulations by applying an external electric field. Second, the various methods for radiation beam scanning and beam reconfigurability are discussed through reflectarray and leaky-wave graphene antennas. In particular, numerous graphene antenna photodetectors and graphene rectennas for energy harvesting are studied by giving a critical evaluation of antenna performances, enhanced photodetection, energy conversion efficiency and the significant problems that remain to be addressed. Finally, the potential developments in the synthesis of graphene material and technological methods involved in the fabrication of graphene-metal nanoantennas are discussed.

Dynamic Absorption Enhancement and Equivalent Resonant Circuit Modeling of Tunable Graphene-Metal Hybrid Antenna.

Plasmonic antennas are attractive optical components of the optoelectronic devices, operating in the far-infrared regime for sensing and imaging applications. However, low optical absorption hinders its potential applications, and their performance is limited due to fixed resonance frequency. In this article, a novel gate tunable graphene-metal hybrid plasmonic antenna with stacking configuration is proposed and investigated to achieve tunable performance over a broad range of frequencies with enhanced absorption characteristics. The hybrid graphene-metal antenna geometry is built up with a hexagon radiator that is supported by the Al2O3 insulator layer and graphene reflector. This stacked structure is deposited in the high resistive Si wafer substrate, and the hexagon radiator itself is a sandwich structure, which is composed of gold hexagon structure and two multilayer graphene stacks. The proposed antenna characteristics i.e., tunability of frequency, the efficiency corresponding to characteristics modes, and the tuning of absorption spectra, are evaluated by full-wave numerical simulations. Besides, the unity absorption peak that was realized through the proposed geometry is sensitive to the incident angle of TM-polarized incidence waves, which can flexibly shift the maxima of the absorption peak from 30 THz to 34 THz. Finally, an equivalent resonant circuit model for the investigated antenna based on the simulations results is designed to validate the antenna performance. Parametric analysis of the proposed antenna is carried out through altering the geometric parameters and graphene parameters in the Computer Simulation Technology (CST) studio. This clearly shows that the proposed antenna has a resonance frequency at 33 THz when the graphene sheet Fermi energy is increased to 0.3 eV by applying electrostatic gate voltage. The good agreement of the simulation and equivalent circuit model results makes the graphene-metal antenna suitable for the realization of far-infrared sensing and imaging device containing graphene antenna with enhanced performance.

Heavy Metals Assessment in Water, Sediments, Algae and Two Fish Species from River Swat, Pakistan.

The heavy metals were studied in water, sediments, algae, and various tissues of Glyptosternon reticulatum and Cyprinus carpio from River Swat, Pakistan, using flame atomic absorption spectrophotometer. The Zn, Cu, Pb and Ni were higher in water at sewage site compared to upstream and downstream sites. In sediments, the Ni and Cd were not detected whereas Cu, Pb and Zn were higher at downstream followed by sewage and upstream sites. The Ni and Zn in algae were higher at upstream and sewage sites compared to downstream site whereas Pb and Cd were higher at upstream site compared to sewage and downstream sites and Cu was found same at all the three sites. The heavy metals (Zn > Cu > Pb and Ni) in tissues (liver > gills > skin > muscles) of G. reticulatum was higher than in C. carpio. This study recommends the proper monitoring of River Swat in order to save its water and inhabitant aquatic life.