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“In spite of a lack of environmental care in the Indian Constitution, India has established a number of important environmental legislation since its independence, despite the lack of environmental concern in the Indian Constitution. However, environmental legislation in India is being developed piecemeal and in response to specific events that have occurred. In the development of Indian environmental legislation, these may be found. The 1972 United Nations Conference on the Human Environment in Stockholm paved the way for future environmental and climate change legislation. On that basis, the Indian parliament adopted many laws and placed environmental measures in the Constitution, such as Articles 48 A and 51 A. (g). Climate change is now having a subtle but profound effect on Indian society. There has been recent progress toward passing a climate change bill under the country's current legislation, while at the UN Lima summit, member nations agreed on cutting Earth-warming greenhouse gas emissions. This year, on the 147th anniversary of Mahatma Gandhi's birth on October 2, 2016, India approved the National Determined Contribution (NDC). Basic climate change law features are explained in this article, with an emphasis on those topics that are likely to be essential for some time to come and on main drivers of climate change law development. Environmental, energy, corporate, and international law all play a role in the development of the evolving climate change legislation. Any attempt to combat climate change raises questions regarding the correct role and relationship of state and federal governments. What follows will serve as a basic overview of an increasingly complicated and dynamic field.”

Maximal safe resection of malignant tissue is associated with improved progression-free survival and better response to radiation and chemotherapy for patients with glioblastoma (GBM). 5-Aminolevulinic acid (5-ALA) is the current FDA-approved standard for intraoperative brain tumor visualization. Unfortunately, autofluorescence in diffuse areas and high fluorescence in dense tissues significantly limit discrimination at tumor margins. This study is the first to compare 5-ALA to an investigational new drug, panitumumab-IRDye800CW, in the same animal model. A patient-derived GBM xenograft model was established in 16 nude mice, which later received injections of 5-ALA, panitumumab-IRDye800CW, IRDye800CW, 5-ALA and IRDye800CW, or 5-ALA and panitumumab-IRDye800CW. Brains were prepared for multi-instrument fluorescence imaging, IHC, and quantitative analysis of tumor-to-background ratio (TBR) and tumor margin accuracy. Statistical analysis was compared with Wilcoxon rank-sum or paired t test. Panitumumab-IRDye800CW had a 30% higher comprehensive TBR compared with 5-ALA (P = 0.0079). SDs for core and margin regions of interest in 5-ALA–treated tissues were significantly higher than those found in panitumumab-IRDye800CW–treated tissues (P = 0.0240 and P = 0.0284, respectively). Panitumumab-IRDye800CW specificities for tumor core and margin were more than 10% higher than those of 5-ALA. Higher AUC for panitumumab-IRDye800CW indicated strong capability to discriminate between normal and malignant brain tissue when compared with 5-ALA. This work demonstrates that panitumumab-IRDye800CW shows potential as a targeting agent for fluorescence intraoperative detection of GBM. Improved margin definition and surgical resection using panitumumab-IRDye800 has the potential to improve surgical outcomes and survival in patients with GBM compared with 5-ALA.

Purpose: Despite reportedly high rates of human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs) among transgender people, laboratory-proven prevalence of these infections in this population has not been systematically reviewed. We performed a systematic review and meta-analysis of the medical literature involving laboratory-proven HIV and STI diagnoses among transgender people. Methods: A systematic review of the English literature regarding laboratory-proven HIV and/or STI testing in transgender populations within the last 50 years was performed. Preliminary meta-analyses assessing the prevalence of HIV and STIs among both transgender men and transgender women were performed. Given the heterogeneity of included studies, these analyses were difficult to interpret and not included in our results. Results: Our literature review identified 25 studies, representing 11 countries. All of these studies included transgender women, with 9 (36%) including data on transgender men. HIV was the most commonly studied STI, with prevalence ranging from 0% to 49.6% in transgender women and 0% to 8.3% in transgender men. For syphilis, gonorrhea, and chlamydia, respectively, prevalence ranged from 1.4% to 50.4%, 2.1% to 19.1%, and 2.7% to 24.7% in transgender women and from 0% to 4.2%, 0% to 10.5%, and 1.2% to 11.1% in transgender men. Site-specific testing practices for gonorrhea and chlamydia were variable. No studies reported prevalence data on trichomoniasis. Conclusion: The literature describing STIs and transgender people primarily focuses on transgender women and HIV. Data involving HIV and STIs among transgender men are lacking. These findings highlight opportunities for the future study of epidemiology of HIV/STIs in transgender men and the relevance of STIs in transgender people.

PURPOSE: There is a clinical need for agents that target glioma cells for non-invasive and intraoperative imaging to guide therapeutic intervention and improve the prognosis of glioma. Matrix metalloproteinase (MMP)-14 is overexpressed in glioma with negligible expression in normal brain, presenting MMP-14 as an attractive biomarker for imaging glioma. In this study, we designed a peptide probe containing a near-infrared fluorescence (NIRF) dye/quencher pair, a positron emission tomography (PET) radionuclide, and a moiety with high affinity to MMP-14. This novel substrate-binding peptide allows dual modality imaging of glioma only after cleavage by MMP-14 to activate the quenched NIRF signal, enhancing probe specificity and imaging contrast. METHODS: MMP-14 expression and activity in human glioma tissues and cells were measured in vitro by immunofluorescence and gel zymography. Cleavage of the novel substrate and substrate-binding peptides by glioma cells in vitro and glioma xenograft tumors in vivo was determined by NIRF imaging. Biodistribution of the radiolabeled MMP-14-binding peptide or substrate-binding peptide was determined in mice bearing orthotopic patient-derived xenograft (PDX) glioma tumors by PET imaging. RESULTS: Glioma cells with MMP-14 activity showed activation and retention of NIRF signal from the cleaved peptides. Resected mouse brains with PDX glioma tumors showed tumor-to-background NIRF ratios of 7.6–11.1 at 4 h after i.v. injection of the peptides. PET/CT images showed localization of activity in orthotopic PDX tumors after i.v. injection of (68)Ga-binding peptide or (64)Cu-substrate-binding peptide; uptake of the radiolabeled peptides in tumors was significantly reduced (p < 0.05) by blocking with the non-labeled-binding peptide. PET and NIRF signals correlated linearly in the orthotopic PDX tumors. Immunohistochemistry showed co-localization of MMP-14 expression and NIRF signal in the resected tumors. CONCLUSIONS: The novel MMP-14 substrate-binding peptide enabled PET/NIRF imaging of glioma models in mice, warranting future image-guided resection studies with the probe in preclinical glioma models.

Supplemental Digital Content is Available in the Text., Background: To assess the performance and suitability of dried blood spot (DBS) sampling using filter paper to collect blood for viral load (VL) quantification under routine conditions. Methods: We compared performance of DBS VL quantification using the Biocentric method with plasma VL quantification using Roche and Biocentric as reference methods. Adults (≥18 years) were enrolled at 2 health facilities in Eswatini from October 12, 2016 to March 1, 2017. DBS samples were prepared through finger-prick by a phlebotomist (DBS-1), and through the pipetting of whole venous blood by a phlebotomist (DBS-2) and by a laboratory technologist (DBS-3). We calculated the VL-testing completion rate, correlation, and agreement, as well as diagnostic accuracy estimates at the clinical threshold of 1000 copies/mL. Results: Of 362 patients enrolled, 1066 DBS cards (DBS-1: 347; DBS-2: 359; DBS-3: 360) were tested. Overall, test characteristics were comparable between DBS-sampling methods, irrespective of the reference method. The Pearson correlation coefficients ranged from 0.67 to 0.82 (P < 0.001) for different types of DBS sampling using both reference methods, and the Bland–Altman difference ranged from 0.15 to 0.30 log10 copies/mL. Sensitivity estimates were from 85.3% to 89.2% and specificity estimates were from 94.5% to 98.6%. The positive predictive values were between 87.0% and 96.5% at a prevalence of 30% VL elevations, and negative predictive values were between 93.7% and 95.4%. Conclusions: DBS VL quantification using the newly configured Biocentric method can be part of contextualized VL-testing strategies, particularly for remote settings and populations with higher viral failure rates.

Background Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening conditions that may present with similar findings to other severe dermatologic diseases. Objective The primary objective of this exploratory study was to explore factors associated with SJS/TEN and develop a model that provides the predicted probability of SJS/TEN for patients for whom the diagnosis of SJS/TEN is considered. Methods Retrospective review of consultations for patients with suspected SJS, TEN, or overlap at 4 academic dermatology consultation services. Results Overall, 208 patients were included; 59 (28.4%) had a final diagnosis of SJS/TEN, and 149 (71.6%) were given a different diagnosis. The most common mimickers were drug hypersensitivity syndrome (n = 21, 10.1%), morbilliform drug eruption (n = 18, 8.7%), erythema multiforme (n = 15, 7.2%), and acute generalized exanthematous pustulosis (n = 13, 6.2%). Nikolsky sign, atypical targets, fever, and lymphopenia were included in a model for predicting the probability of SJS/TEN. Limitations All cases were obtained from academic centers, which may limit the generalization of findings to community-based settings. This was an exploratory study with a small number of cases, and external validation of the model performance is needed. Conclusion Early dermatologic evaluation of patients with suspected SJS/TEN is key to separating patients with this condition from those who ultimately receive diagnoses of other serious skin diseases.

UVA irradiation is known to cause photoaging via production of reactive oxygen species (ROS) and activation of inflammatory processes. Previously, we have demonstrated that baicalin, a plant-derived flavonoid possessing both antioxidant and anti-inflammatory activity, protects mouse keratinocytes against damage from UVB irradiation. However, the role of baicalin in vivo has not been well studied, particularly in the setting of UVA irradiation. To explore the protective effects and mechanisms of baicalin treatment in mice after UVA irradiation, mice were exposed to acute and chronic doses of UVA irradiation with or without baicalin or vehicle. Skin samples were collected for histological staining, RNA isolation, flow cytometry, and protein extraction. Our results demonstrate the protective effect of baicalin against UVA-induced oxidative damage and inflammation in mouse skin. These effects are likely mediated via the TLR4 pathway, which may serve as a target for photochemoprevention against skin inflammation.

Background The transgender (TG) population is under-researched. Despite reportedly high rates of HIV and sexually transmitted infections (STIs) among TGs, prevalence of these in TGs has not been systematically reviewed. Our primary objective was to perform a systematic review of the literature for studies reporting laboratory test proven prevalence data of HIV and other STIs among male-to-female (MTF) and female-to-male (FTM) TGs. Given the sexual risk factors traditionally associated with MTFs (e.g. commercial sex work), we hypothesized that HIV/STI prevalence would be higher among MTFs compared to FTMs. Methods A systematic review of the literature on original English-language research involving HIV and/or STI laboratory testing in TG populations within the last 50 years was performed. Results Of 32 eligible studies, most focused on MTFs, with only 10 (31%) including data on FTMs. MTFs were exclusively investigated in 22 (69%) of studies. The majority of studies including MTFs were focused on sex workers, with 7 (22%) exclusively evaluated sex workers. HIV data was reported in 31 (97%) of studies. Syphilis data was presented in 18 (56%) studies. Regarding gonorrhea and chlamydia, 15 (47%) studies presented testing data, but only 7 reported urogenital and extragenital results. No studies evaluated trichomoniasis. In MTFs, prevalence of HIV, syphilis, gonorrhea, and chlamydia ranged from 0%–70.3%, 1.4%–50.4%, 0%–29.4%, and 2.7%–24.7%, respectively. In FTMs, prevalence of HIV, syphilis, gonorrhea, and chlamydia ranged from 0%–8.3%, 0%–4.2%, 0%–10.5%, and 0–11.1%, respectively. Conclusion Literature involving STIs in TG people focuses on the MTF community and HIV. Testing patterns for bacterial STIs are variable, especially for gonorrhea and chlamydia. Per current literature, STIs appear to be more prevalent in MTFs compared to FTMs. Data for STIs in FTMs is limited. These gaps present opportunities for further study involving the epidemiology of STIs in the FTM population and the relevance of extragenital bacterial and parasitic STIs in all TGs. Disclosure No significant relationships.

BackgroundA major obstacle to using recombinant adenoviral vectors in gene therapy is the natural ability of human adenovirus to activate the classical and alternate complement pathways. These innate immune responses contribute to hepatic adenoviral uptake following systemic delivery and enhance the humoral immune responses associated with adenoviral infection.MethodsA recombinant Ad5 vector was genetically modified to display a peptide sequence ("rH17d'"), a known inhibitor of the classical complement pathway. The replication-defective vectors Ad5.HVR2-rH17d' and Ad5.HVR5-rH17d' were constructed by engineering the rH17d' peptide into the hypervariable region (HVR)-2 or HVR5 of their major capsid protein hexon. Control Ad5 vectors were created by incorporation of a 6-histidine (His6)-insert in either HVR2 or HVR5 (Ad5.HVR2-His6 and Ad5.HVR5-His6, respectively). All vectors encoded CMV promoter-controlled firefly luciferase (Luc). The four vectors were evaluated in TIB76 mouse liver cells and immunocompetent mice to compare infectivity and liver sequestration, respectively.ResultsIn vitro studies demonstrated that preincubation of all the Ad5 vectors with fresh serum significantly increased their gene transfer relative to preincubation with PBS except Ad5.HVR5-rH17d', whose infectivity of liver cells showed no serum-mediated enhancement. In line with that, mice injected with Ad5.HVR2-rH17d' or Ad5.HVR5-rH17d' showed significantly lower luciferase expression levels in the liver as compared to the respective control vectors, whereas efficiency of tumor transduction by rH17d' and His6 vectors following their intratumoral injection was similar.ConclusionsDisplaying a complement-inhibiting peptide on the Ad5 capsid surface by genetic modification of the hexon protein could be a suitable strategy for reducing Ad5 liver tropism (Ad5 sequestration by liver), which may be applicable to other gene therapy vectors with natural liver tropism.

Objective: Although fluorescence imaging is being applied to a wide range of cancers, it remains unclear which disease populations will benefit greatest. Therefore, we review the potential of this technology to improve outcomes in surgical oncology with attention to the various surgical procedures while exploring trial endpoints that may be optimal for each tumor type. Background: For many tumors, primary treatment is surgical resection with negative margins, which corresponds to improved survival and a reduction in subsequent adjuvant therapies. Despite unfavorable effect on patient outcomes, margin positivity rate has not changed significantly over the years. Thus, patients often experience high rates of re-excision, radical resections, and overtreatment. However, fluorescence-guided surgery (FGS) has brought forth new light by allowing detection of subclinical disease not readily visible with the naked eye. Methods: We performed a systematic review of clinicatrials.gov using search terms "fluorescence," "image-guided surgery," and "near-infrared imaging" to identify trials utilizing FGS for those received on or before May 2016. Inclusion criteria: fluorescence surgery for tumor debulking, wide local excision, whole-organ resection, and peritoneal metastases. Exclusion criteria: fluorescence in situ hybridization, fluorescence imaging for lymph node mapping, nonmalignant lesions, nonsurgical purposes, or image guidance without fluorescence. Results: Initial search produced 844 entries, which was narrowed down to 68 trials. Review of literature and clinical trials identified 3 primary resection methods for utilizing FGS: (1) debulking, (2) wide local excision, and (3) whole organ excision. Conclusions: The use of FGS as a surgical guide enhancement has the potential to improve survival and quality of life outcomes for patients. And, as the number of clinical trials rise each year, it is apparent that FGS has great potential for a broad range of clinical applications.

Background and Objectives Optical imaging to guide cancer resections is rapidly transitioning into the operating room. However, the sensitivity of this technique to detect subclinical disease is yet characterized. The purpose of this study was to determine the minimum range of cancer cells that can be detected by antibody-based fluorescence imaging. Methods 2LMP (breast), COLO-205 (colon), MiaPaca-2 (pancreas), and SCC-1 (head and neck) cells incubated in vitro with cetuximab-IRDye800CW (dose range 8.6-86 nM) were implanted subcutaneously in mice (n = 3 mice, 5 tumors/mouse). Following incubation with 8.6 × 10−2 µM of cetuximab-IRDye800CW in vitro, serial dilutions of each cell type (1 × 103–1 × 106) were implanted subcutaneously (n = 3, 5 tumors/mouse). Tumors were imaged with Pearl Impulse and Xenogen IVIS 100 imaging systems. Scatchard analysis was performed to determine receptor density and kinetics for each cell line. Results Under conditions of minimal cetuximab-IRDye800CW exposure to low cellular quantity, closed-field fluorescence imaging theoretically detected a minimum of 4.2 × 104-9.5 × 104 2LMP cells, 1.9 × 105-4.5 × 105 MiaPaca-2 cells, and 2.4 × 104-6.7 × 104 SCC-1 cells; COLO-205 cells could not be identified. Higher EGFR-mediated uptake of cetuximab correlated with sensitivity of detection. Conclusion This study supports the clinical utility of cetuximab-IRDye800CW to sensitively localize subclinical disease in the surgical setting.

The advent of fluorescence imaging (FI) for cancer cell detection in the field of oncology is promising for both cancer screening and surgical resection. Particularly, FI in cancer screening and surveillance is actively being evaluated in many new clinical trials with over 30 listed on Clinical Trials.gov . While surgical resection forms the foundation of many oncologic treatments, early detection is the cornerstone for improving outcomes and reducing cancer-related morbidity and mortality. The applications of FI are twofold as it can be applied to high-risk patients in addition to those undergoing active surveillance. This technology has the promise of highlighting lesions not readily detected by conventional imaging or physical examination, allowing disease detection at an earlier stage of development. Additionally, there is a persistent need for innovative, cost-effective imaging modalities to ameliorate healthcare disparities and the global burden of cancer worldwide. In this review, we outline the current utility of FI for screening and detection in a range of cancer types.

OBJECTIVES/SPECIFIC AIMS: Interleukin-23 (IL-23) promotes differentiation of naïve T-cells into Th17 cells, which drive the pathogenesis of autoinflammatory conditions such as psoriasis. IL-23-neutralizing antibody therapies are now in use for treatment of psoriasis, with promising results. Studies in mice have shown that IL-23 plays a role in inhibiting the growth, progression, and metastasis of melanomas. Thus, therapeutic neutralization of IL-23 in patients may inadvertently increase their susceptibility to development of melanoma. In this study, we aim to characterize expression of IL-23 receptors (IL-23R) in human melanocytes and melanoma cells and tissue and to study the effect of IL-23 on growth, proliferation, and tumorigenicity of these cells. METHODS/STUDY POPULATION: IL-23R expression was characterized using immunofluorescence staining, Western blot, and flow cytometric analysis. Response of melanoma and melanocytes to recombinant IL-23 treatment will be studied through similar methods in addition to assays of cell proliferation and tumorigenicity. RESULTS/ANTICIPATED RESULTS: Preliminary immunofluorescence staining and flow cytometry results indicate that both human melanoma and primary melanocytes express IL-23 receptors. Western blot analysis showed that melanoma cell line A375 expressed nearly twice the amount of IL-23R versus normal melanocytes (p