BRAF-mutant metastatic melanoma [EGFR-mutant [ALK-mutant [BCR–ABL-translocation-positive chronic myelogenous leukemia [The emerging paradigm of precision cancer medicine, in which the use of molecular data at the point of care directly impacts patient treatment and clinical decision-making, has already had a substantial, direct clinical impact on many aspects of medical oncology. Advances in precision cancer medicine include well-established molecularly targeted therapies for patients with melanoma , those wR-mutant  or ALK-mK-mutant  non-smalleukemia . In addileukemia –7 has caHowever, precision cancer medicine remains a promise rather than a solid and robust reality in many areas of clinical oncology. Molecular profiling of tumors is not yet broadly applied in all types of cancer. Furthermore, although the molecular landscapes of many cancers have been revealed using precision oncology approaches, many of the alterations observed in patients remain undruggable, and viable targets are incompletely characterized. In addition, a considerable amount of diversity exists regarding the types of molecular tests being offered clinically ; combineGenome Medicine, original research and reviews from leaders in the field tackle the current challenges in precision oncology. This special issue details technological and analytical advances in tumor characterization, which have provided novel insights into the cancer genome and epigenome. In addition, reports herein explore the integration of molecular profiling into clinical oncology to enable careful assessment of the extent to which prospective clinical sequencing is influencing treatment decisions and improving outcomes, for both adult and pediatric cancers. Furthermore, as new targets are discovered and novel drug resistance mechanisms emerge, combination therapies may prove to be advantageous, and promising therapeutic strategies in immuno-oncology will require new paradigms beyond the assignment of molecularly targeted therapies that are based on a single target lesion [In this special issue of t lesion . Improvet lesion  are esseTo capitalize on these advances and ensure maximal benefit to patients, we advocate expanded access to genomic testing for patients with all types of cancer. Currently, reimbursement for tumor molecular profiling is mostly limited to a small number of tumor types such as lung cancer and melanoma, for which standard-of-care therapies are administered on the basis of molecular aberrations. However, it is now well established that individual targetable alterations may occur across a wide range of histologically defined tumor types and that the same drug may elicit responses across different cancers. Furthermore, broadening the application of molecular profiling will be necessary to establish the evidence base for genomically guided therapy for patients with rare cancers and for patients with common cancers that have rare mutations. Innovative clinical trials such as “basket studies” , which eWith expanded access to genomic profiling, obtaining the necessary data regarding treatment outcomes and carrying out prospective randomized controlled trials may become more feasible at the scale necessary to determine the clinical impact of this approach across cancer types, given the clinically heterogeneous patient populations that would receive such testing. In addition, this approach will highlight areas in which current methodology is insufficient and in which other profiling approaches, such as transcriptome or epigenetic profiling, may provide further clinical impact. Towards that end, studies in prostate  and pediFinally, a complete assessment of the utility of genomic profiling in clinical oncology will require genomic and clinical data to be shared across institutions. Data-sharing is a central tenet of the Cancer Moonshot initiative  advocate


The brain can be viewed as a sophisticated control module for stabilizing blood glucose. A review of classical behavioural evidence indicates that central circuits add predictive (feedforward/anticipatory) control to the reactive (feedback/compensatory) control by peripheral organs. The brain/cephalic control is constructed and engaged, via associative learning, by sensory cues predicting energy intake or expenditure . This allows rapidly measurable sensory information  to control food selection, glucose supply for fight-or-flight responses or preparedness for digestion/absorption. Predictive control is therefore useful for preventing large glucose fluctuations. We review emerging roles in predictive control of two classes of widely projecting hypothalamic neurones, orexin/hypocretin (ORX) and melanin-concentrating hormone (MCH) cells. Evidence is cited that ORX neurones (i) are activated by sensory cues , (ii) drive hepatic production, and muscle uptake, of glucose, via sympathetic nerves, (iii) stimulate wakefulness and exploration via global brain projections and (iv) are glucose-inhibited. MCH neurones are (i) glucose-excited, (ii) innervate learning and reward centres to promote synaptic plasticity, learning and memory and (iii) are critical for learning associations useful for predictive control . This evidence is unified into a model for predictive glucose control. During associative learning, inputs from some glucose-excited neurones may promote connections between the ‘fast’ senses and reward circuits, constructing neural shortcuts for efficient action selection. In turn, glucose-inhibited neurones may engage locomotion/exploration and coordinate the required fuel supply. Feedback inhibition of the latter neurones by glucose would ensure that glucose fluxes they stimulate  are balanced. Estimating nutrient challenges from indirect sensory cues may become more difficult when the cues become complex and variable (e.g. like human foods today). Consequent errors of predictive glucose control may contribute to obesity and diabetes. The brain can influence blood glucose levels independently of food intake and energy expenditure. This is illustrated, for example, by experiments where animals can be trained to lower their blood glucose in response to arbitrary cues  that make glucose shuttle between peripheral organs and the plasma. For example, the firing of sympathetic autonomic nerves can release glucose from liver stores into the blood, while parasympathetic nerves can stimulate the pancreas to produce insulin to lower blood glucose. A distinct property of this neural glucose control is that it is not just a reactive/corrective response to a change in glucose that already occurred. It is an anticipatory action based on an estimation of a future change in glucose level , that isForward-planning actions of the brain  is to change blood glucose level. This requires associative learning, and the ability to refine and update it based on experience . We will discuss a circuit model where predictive control, including associative learning, is linked to glucose-sensing neurones. As background for this model, we first review experimental data on brain glucose-sensing neurones. Our overall intention is to discuss a general systems view  of brainm, m, and so presumably saturate and do not change intracellular energy levels upon glucose fluctuations >1 mm . Recent examinations of neurochemical identities of glucose-sensing neurones revealed diverse cells groups. For example, in the hypothalamus, glucose-inhibited neurones are thought to comprise anatomically and functionally distinct subgroups, for example neurones containing orexin/hypocretin , NPY/AgrP , and SF-1 . Glucose-excited neurones may include POMC neurones (in the arcuate nucleus) and melanin-concentratinghormone,  . Some brIn this review, we will limit our discussion to MCH and orexin neurones of the lateral hypothalamus and attempt to present experimental knowledge about their functions within a broader context of predictive glucose control by the brain. We acknowledge that it is not yet clear whether other glucose-sensing neurones are conceptually similar to the roles of orexin and MCH cells hypothesized here and whether orexin and MCH neurones function as homogenous or heterogenous populations in relation to glucose control.Recent data suggest that MCH neurones are essential for learning to select nutritionally superior foods based on taste, a useful predictive operation  channels  and actual nutrient value of food . Subsequently, detection of a conditioned stimulus can be used for efficient (i.e. rapid) action selection and for preparing the body for subsequent slower arrival of glucose to blood. Recent experimental evidence suggests that MCH neurones are a key part of such associative learning.et al. found that genetic or pharmacological disruption of the MCH receptor (MCH-1R) reduced the ability of a previously learnt conditioned stimulus to serve as a reinforcer in a new instrumental behaviour task  to elicit brain reward and action selection, presumably based on associated changes in energy levels .ORX neurones are activated by diverse stimuli that are of no nutrient value themselves, but may indicate that energy intake or expenditure is imminent [e.g. sounds, sweet taste, stress  still display relatively normal amounts of total sleep and total wake time; however, their wakefulness (and sleep) are fragmented  are balanced . Apart fOur model unifies diverse experimental data with a control framework for improving glucose control. It is hoped that this may produce a clearer view of outstanding questions and discrepancies, and help to generate testable hypotheses. Many unknowns remain. For example, currently available data suggest that MCH cell firing, which enables taste to drive reward  and caloric value are consistent and so can be readily learnt and used for accurate predictive actions (e.g. releasing X amount of insulin upon seeing a red apple). Many of these associations were presumably quite stable on an evolutionary timescale. They are no longer fixed in the modern environment filled with diverse and rapidly changing food packaging and advertising , and artificial flavours mimicking taste without providing caloric value. Presumably, this poses a problem for predictive control, because estimating nutrient challenges from indirect sensory cues becomes different in this complex environment. Frequent errors of predictive control can presumably put a strain on reactive controllers (liver and pancreas) that correct these errors. We hypothesize that predictive control errors may contribute to the development of obesity and diabetes.


The epidermal growth factor receptor (EGFR) is one of the most well-studied signaling pathways in cancer progression. As a result, numerous therapeutics including small-molecule inhibitors and monoclonal antibodies have been developed to target this critical oncogenic driver. Several of these EGFR inhibitors (EGFRi) have been evaluated in metastatic breast cancer, as high-level EGFR expression in primary tumors correlates with the highly aggressive basal-like phenotype and predicts for poor patient prognosis. Surprisingly, these trials have been unanimously unsuccessful at improving patient outcomes. Numerous factors, such as lack of proper patient selection may have contributed to the failure of these trials. However, recent findings suggest that there are fundamental changes in EGFR signaling that take place during primary tumor invasion, dissemination and ultimate metastasis of breast cancer cells. Herein, we review the outcomes of EGFR-targeted clinical trials in breast cancer and explore our current understanding of EGFR signaling within primary mammary tumors and how these events are altered in the metastatic setting. Overall, we put forth the hypothesis that fundamental changes in EGFR signaling between primary and metastatic tumors, a process we term the ‘EGFR paradox,’ contribute to the clinically observed inherent resistance to EGFRi. Furthermore, this hypothesis introduces the possibility of utilizing EGFR agonism as a potential therapeutic approach for the treatment of metastatic breast cancer. ErbB members form homo- and heterodimeric cell-surface receptors with unique extracellular domains yielding ligand-binding specificity. Downstream signaling from these receptors proceeds via tyrosine phosphorylation. Since its discovery, EGFR has been characterized as a mediator of a wide variety of signal transduction events that control cell proliferation, migration and survival. Overexpression of EGFR transforms NIH3T3 fibroblasts in an EGF-dependent manner. Aberrant EGFR activation in tumor cells can result from increased transcriptional expression and/or gene amplification. Increased EGFR protein and transcript levels correlate with poor prognosis in various epithelial cancers, such as colorectal cancer (CRC), non-small cell lung cancer (NSCLC), endometrial cancer, and squamous-cell carcinoma of the head and neck (SCCHN). Another mode of EGFR activation in cancer is activating somatic mutations that result in constitutive kinase activity, and these are particularly prevalent in NSCLC . These findings have led to the development of numerous FDA-approved EGFR inhibitors for many of these cancers  for the treatment of colorectal and head and neck cancers. However, studies are still ongoing to determine other biomarkers that might improve patient selection for these cancers.Epidermal growth factor receptor (EGFR) was the first discovered of the ErbB family of receptor tyrosine kinases which includes a total of four members: Erbb1/EGFR, ErbB2/Her2, ErbB3 and ErbB4. cancers . Gefitin Metastasis is invariably responsible for patient death in BC. The triple negative BC subtype (TNBC) is characterized by metastatic progression, poor patient prognosis, and is identified by the absence of bio-molecules that form the basis for targeted therapies for the other BC subtypes, namely estrogen receptor, progesterone receptor, and Her2 amplification. Thus, there are currently no FDA approved targeted therapies for TNBC. TNBC is initially highly sensitive to chemotherapy, but many TNBC patients rapidly develop resistance, at which point metastatic disease is highly lethal. Although activating mutations and gene amplification of EGFR are rare in BC, EGFR expression can be enhanced by increased gene copy number due to polysomy, and enhanced expression of EGFR in the primary tumor is associated with increased metastasis and decreased survival of TNBC patients. Concomitant with these clinical findings, studies from the Condeelis lab established a paracrine signaling loop in which macrophage-produced EGF supported tumor cell invasion and dissemination from the primary tumor. Experimental findings such as these prompted the initiation of several clinical trials to assess the effectiveness of EGFR inhibition (EGFRi) in metastatic TNBC. The EGFR kinase inhibitor erlotinib was evaluated in a phase II trial of unselected patients with advanced BC having had previously received chemotherapy. In addition, erlotinib was evaluated in combination with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab. Both of these studies determined that erlotinib did not provide clinical benefit to BC patients and erlotinib responsiveness was not predicted by EGFR expression levels in the primary tumor.Breast cancer (BC) is the most commonly diagnosed and the second most lethal cancer in American women. Similarly, gefitinib as a monotherpay in metastatic estrogen receptor alpha (ER-α) negative BC patients did not provide clinical benefit in another phase II clinical trial. Engebraaten et al. tested the efficacy of combining gefitinib with docetaxel in metastatic BC as compared with docetaxel alone. In this study, the combination was associated with lower partial response rate and higher toxicity than chemotherapy alone. In addition to kinase inhibitors, clinical trials have also evaluated the addition of the ligand blocking monoclonal antibody cetuximab to the DNA-alkylating agent carboplatin. Similarly, this study found that fewer than 20% of metastatic TNBC patients responded to cetuximab plus carboplatin. In subsequent studies, the combination of cetuximab with antimicrotubule agents or topoisomerase inhibitors did not increase patient overall survival as compared with these chemotherapies alone, leading to premature trial termination. These findings have been confirmed in more recent trials examining the efficacy of panitumumab, another ligand-blocking anti-EGFR monoclonal antibody, in the treatment of TNBC. As with other EGFRi, panitumumab did not improve progression-free survival over chemotherapy alone when used in metastatic TNBC. In contrast to these adjuvant trials in metastatic disease, use of panitumumab in combination with chemotherapy did appear efficacious as a neoadjuvant therapy for operable stage II–III TNBC. Overall, despite strong pre-clinical data linking high levels of EGFR to increased metastatic progression and decreased patient survival, TNBC in the metastatic setting appears to be unresponsive to EGFRi -driven in vivo metastasis, cells derived from pulmonary metastases are inherently resistant to EGFRi and undergo robust growth inhibition in response to EGF. This idea that growth factors have context dependent dual effects on cell growth has long been proposed. Indeed, growth factors such as interleukin 6 (IL-6) and platelet-derived growth factor (PDGF) are known to paradoxically inhibit the growth of some cell types. Furthermore, the recognized growth-promoting roles of estrogen in BC are coupled with accounts of estrogen-induced apoptosis, termed ‘the estrogen paradox’ nicely reviewed in Jordan and Ford. Another well-established shift in function in BC is that of transforming growth factor-beta (TGF-β) where it functions as a powerful tumor suppressor in primary tumors but drives disease progression in the metastatic setting. Further understanding of this shift in EGFR signaling will likely serve to explain the failure of EGFRi in the treatment of metastatic BC. Furthermore, these findings also present the opportunity to exploit the antimetastatic function of EGFR agonism as a therapeutic approach. Below we review some of the established findings that support the existence of the EGFR paradox during BC growth, dissemination and metastasis.Recently, our lab reported findings that demonstrate a switch in EGFR function between primary and metastatic tumors. This EGFR-driven tumor model forms well-differentiated in situ mammary tumors, but following induction of EMT metastatic tumors derived from these same cells demonstrate reduced expression of EGFR and inherent resistance to erlotinib. Similarly, in vivo metastatic selection of the heterogeneous MDA-MB-231 TNBC cells is associated with a marked loss of EGFR expression. This discordance in EGFR expression is observed clinically and in mouse models of metastatic colorectal cancer, ovarian cancer and lung cancer. The first observation that metastatic BC cells can have low to undetectable levels of EGFR was reported for the DU4475 (cutaneous metastasis) and AlAb 496 (lung metastasis) cell models in 1982. Since then, isogenic BC cell-line series have demonstrated EGFR downregulation through metastatic progression, including the MCF10AT BC progression series and the D2-HAN series. In patient-derived BC tissues, EGFR is downregulated with metastasis and this correlates with resistance to EGFR inhibitors. Similarly, EGFR downregulation through promoter hyper-methylation has been linked to inherent resistance to anti-EGFR therapy in colorectal carcinoma. In BC, however, the mechanism(s) of EGFR attenuation that are responsible for metastatic resistance to EGFRi remain largely unknown.As mentioned above, our lab recently developed a model in which overexpression of WT EGFR transforms normal murine mammary gland (NMuMG) cells. One of the seminal studies reporting EGFR nuclear translocation was done by Lin et al., who described the nuclear function of EGFR as a transcription factor, and established its endogenous target genes, and consensus DNA-binding sequence. Readers seeking an in-depth review on the transport mechanisms and functions of nuclear EGFR are referred to the following. Importantly, increased nuclear transport of EGFR has been suggested as a potential mechanism of acquired resistance to EGFRi. This was shown in studies demonstrating that long-term treatment of a NSCLC cell line with cetuximab generates cell clones that have enhanced nuclear EGFR staining. Similarly in BC, nuclear EGFR has been attributed to inherent resistance to cetuximab and gefitinib using various TNBC cell lines. Retrospective studies using patient-derived samples linking enhanced nuclear EGFR to clinical EGFRi resistance are yet to be performed. These investigations will be essential to confirm the role of nuclear EGFR in resistance to EGFRi therapy. If differential subcellular localization of EGFR is truly at play during inherent resistance to EGFRi, establishing small-molecule inhibitors that specifically localize to these compartments will be essential to understanding and targeting this mechanism in metastatic BC.EGFR is primarily localized to the plasma membrane, but numerous studies have demonstrated nuclear localization of EGFR where it can undergo several poorly understood functions that are both dependent and independent of kinase activity. EGF inhibition of growth has also been demonstrated for human BC cell lines, where higher concentrations of EGF decreased DNA synthesis in MCF-7, SK-Br-3, BT-20, BT-474 cells. MDA-MB-468 is an EGFR amplified BC cell line derived from a pleural effusion that is also known to display marked EGF-induced growth inhibition due to induction of apoptosis. The A431 and MDA-MB-468 cell lines have abnormally high levels of EGFR, and therefore the idea has been purported that the receptor must be present above a critical threshold to induce growth inhibition. However, this does not seem to be solely responsible for this phenomenon as EGF-induced inhibition of cell-growth occurs in various non-EGFR amplified cell-lines. Further, EGF treatment stimulates the growth of several BC cell lines expressing extremely high levels of EGFR. Overall, the strongest body of literature supports that the growth-inhibitory action of EGF is largely due to induction of apoptosis. The mechanisms of EGF-induced apoptosis are still not fully understood, but seem to involve signaling events that take place following receptor internalization potentially resulting in endosomal accumulation. In addition, EGFR-mediated activation of signal transducer and activator of transcription-1 (STAT1) has been shown to induce apoptosis via activation of caspases, induction of elements of the interferon pathway, or by mediating cell cycle arrest by activation of p21.The first observation that EGF inhibits cancer-cell growth at concentrations that are stimulatory to other cells was reported for the rat pituitary GH4CI tumor cell line and the human epidermoid carcinoma A431 cell line. In NSCLC, the amplification of hepatocyte growth factor receptor (c-MET) has been implicated in resistance to EGFR kinase inhibition by reactivating ErbB signaling through the ErbB3 receptor. Studies in NSCLC also suggest the Axl receptor can facilitate resistance to erlotinib. Similarly, Axl has been found to interact with and transactivate signaling from EGFR and other receptors independent of ligand engagement in TNBC cells. Clearly this mechanism would contribute to resistance to ligand-blocking EGFR antibodies. In our EGFR-driven metastatic BC model, the diminution and functional switch of EGFR in metastatic lesions is associated with an increase in fibroblast growth factor receptor 1 splice variant β (FGFR1-β) expression. Indeed, recent studies from our lab and others highlight the value of FGFR targeting therapies in TNBC and lapatinib-resistant BC models. Interestingly, separate studies point to the role of β3 integrin in mediating NFκB signaling and resistance to erlotinib. Along these lines, we find that β3 integrin is absolutely required for FGFR signaling in BC. Further mechanistic understanding of how BC cancer cells upregulate alternative growth pathways to replace the driver function of EGFR will expand the therapeutic options for BC patients in the metastatic setting.The above mechanisms of inherent resistance to EGFRi dictate the emergence of alternative signaling pathways that sustain tumor cell survival and metastatic growth. In esophageal cancer, resistance to EGFRi is associated with fibroblast growth factor receptor 2 (FGFR2) amplification and overexpression. Thus, it is tempting to speculate a model where cell surface EGFR signaling has a crucial role for the initial invasion of BC. However, following systemic dissemination, tumor cells will increase EGFR internalization and/or decrease its expression as part of an adaptation response to the metastatic microenvironment. Thus, established macrometastases evolve to become EGFR independent and are therefore inherently resistant to targeted inhibition of EGFR (EGFR is a critical signaling molecule involved in a myriad of biological processes and carcinogenic events. In various cancers, aberrant EGFR activation contributes to the initial oncogenic transformation of cells and their subsequent invasion and exit from the primary tumor. These canonical signaling events generated from plasma membrane localized receptors drive the well-established oncogenic effects of EGFR. In contrast, progression of disseminated BC cells into macrometastases is associated with downregulation of EGFR, shunting of EGFR away from the cell surface, and non-canonical pro-apoptotic signaling through STAT1. Although a precise mechanism that unifies these observations remains unknown, EGFR induction of apoptosis has previously been demonstrated to result from intracellular signaling from endosomes. of EGFR .Inhibition of EGFR signaling via kinase inhibitors and monoclonal antibodies has resulted in fundamental changes in patient care for some tumor types. However, numerous attempts to apply these therapies to metastatic BC patients have been unsuccessful. We believe the literature as a whole supports a paradoxical shift in EGFR function during BC metastasis to a STAT1-dominated pro-apoptotic signaling mechanism. Other STAT1-activating cytokines are heavily used therapeutically, yet EGFR–STAT1 signaling is virtually unexplored in cancer treatment. We conclude that EGFR agonism could be pursued as a potential adjuvant therapy for metastatic BC. Despite the potential utility of EGFR agonism as a therapeutic approach in metastatic BC, predicting patient groups that might benefit from EGFR agonists versus inhibitors faces many challenges. Paramount to these challenges includes the design of effective biomarkers to predict the pro- versus anti-tumorigenic effect of EGFR. Although EGFR expression and cellular localization can be assessed in primary mammary tumor biopsies, these types of analyses would need to be standardized into reproducible diagnostics that could be introduced to the clinic. Furthermore, these detection methods may not be feasible on metastatic BC tissues. Similarly, patients pretreated and resistant to endocrine inhibition therapies do show antitumor responses when switched to high-dose estrogen. Therefore, one potential course of therapy for patients who present with metastatic lesions and display EGFR expression in their primary tumor would be to initiate EGFRi treatment, and at the point of disease progression, abruptly switch to a high-dose EGFR agonist. Indeed, a recent study using the A431 model of EGF-induced growth inhibition has established proof-of-concept for in vivo tumor inhibition upon systemic administration of supraphysiologic levels of recombinant EGF. Overall, more thorough preclinical and clinical studies will establish if we will be able to harness the power of the EGFR paradox for the therapeutic benefit of metastatic BC patients.However, using the estrogen paradox as a model, estrogen treatment has demonstrated growth inhibitory effects on BC cells in culture and in mouse models.


Several photocatalytic nanoparticles are synthesized and studied for potential application for the degradation of organic and biological wastes. Although these materials degrade organic compounds by advance oxidation process, the exact mechanisms of microbial decontamination remains partially known. Understanding the real mechanisms of these materials for microbial cell death and growth inhibition helps to fabricate more efficient semiconductor photocatalyst for large-scale decontamination of environmental wastewater or industries and hospitals/biomedical labs generating highly pathogenic bacteria and toxic molecules containing liquid waste by designing a reactor. Recent studies on microbial decontamination by photocatalytic nanoparticles and their possible mechanisms of action is highlighted with examples in this mini review. In some instances, the contaminated water and foods caused severe epidemics and pandemics due to super-bacteria resistant to almost all drugs. In another hand, the genetic disorders caused by chemical mutagens leaving thousands of people with deadly non-transmissible diseases such as cancers, reproductive disorders and adverse pregnancy outcomes, physical disorders, and disabilities . Thus, the environment protection is always crucial to secure the human life and animals on the planet. Though governments of different nations issued standard guidelines to discharge treated effluents, sewerage, and other wastages to the environment, yet excessive discharge of waste is maltreating the environment and the ecosystem. Hence, there is an urgent need for a highly efficient system to treat waste for complete degradation of toxic molecules into simpler non-toxic forms while inactivating highly pathogenic multidrug-resistant superbugs to make water free of pathogens.The natural ecosystem is being deteriorated continuously because of unrestrained flow of wastewater from various industries, hospital wastes, and laboratories due to rapid and poorly-planned urbanization in developing countries and development of mega cities. The urban population is rising unprecedentedly. The socio-economic disparities is exacerbating while creating unsanitary conditions that facilitates the outbreaks. The natural water bodies are contaminated with (i) pathogens originated from hospitals and biomedical laboratories, (ii) different hazardous materials such as organic dyes, chemicals, and toxins from industries. Meanwhile, fertile agricultural lands are also affected with those chemicals and excessively used hazardous pesticides, herbicides, and plastics while unduly used fertilizers are causing algal blooms in natural water bodies  physical methods- sedimentation, floatation, filtration; (2) biological oxidation methods- includes trickling filters, rotating biological contractor, activated sludge, lagoons, and various aerobic and anaerobic methods; and (3) chemical treatment methods such as coagulation and flocculation by lime added with ferric chloride and lime added with aluminum sulfate. Hospitals and biomedical laboratories treat microbially contaminated wastes by either physical means such as autoclaving and irradiation, or chemical treatment methods using organic solvents and detergents to remove or inactivate pathogens prior to discharge. All these methods have their own merits and demerits. The major demerit lies in the incomplete removal of these wastage products as well as the formation of intermediates which are more toxic than the parent pollutants.4 visible light active semiconductor and showed efficient removal of ibuprofen and Escherichia coli in water. Recently, the synthesis of Bi2MoO6 on g-C3N4 nanosheet is reported with enhanced photocatalytic hydrogen evolution and disinfection of E. coli under the visible light  and is capable of generating different reactive species such as reactive oxygen species (ROS), reactive nitrogen species (RNS), oxygen radicals  can act as a photocatalytic substrate by producing highly reactive radicals that can that can degrade indiscriminately micropollutants including harmful micro-organism present in wastewater  are generated by NPs by reducing O2 molecules  tuning the morphology, (2) incorporating transition metal ions such as Ag, Au, Cu, Fe, or Ni and (3) designing heterojunction photocatalysts capable of utilizing efficient energy source such as sunlight (Guo et al., CR, BJ, SR, GG, and RP wrote the manuscript. CR and BJ equally contributed to this article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Vector control using long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) accounts for most of the malaria burden reductions achieved recently in low and middle-income countries (LMICs). LLINs and IRS are highly effective, but are insufficient to eliminate malaria transmission in many settings because of operational constraints, growing resistance to available insecticides and mosquitoes that behaviourally avoid contact with these interventions. However, a number of substantive opportunities now exist for rapidly developing and implementing more diverse, effective and sustainable malaria vector control strategies for LMICs. For example, mosquito control in high-income countries is predominantly achieved with a combination of mosquito-proofed housing and environmental management, supplemented with large-scale insecticide applications to larval habitats and outdoor spaces that kill off vector populations en masse, but all these interventions remain underused in LMICs. Programmatic development and evaluation of decentralised, locally managed systems for delivering these proactive mosquito population abatement practices in LMICs could therefore enable broader scale-up. Furthermore, a diverse range of emerging or repurposed technologies are becoming available for targeting mosquitoes when they enter houses, feed outdoors, attack livestock, feed on sugar or aggregate into mating swarms. Global policy must now be realigned to mobilise the political and financial support necessary to exploit these opportunities over the decade ahead, so that national malaria control and elimination programmes can access a much broader, more effective set of vector control interventions. Vector control in low and middle-income countries (LMICs), using long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS), accounts for most of the unprecedented malaria burden reductions achieved in the 21st century.LLINs and IRS are highly effective in LMICs, but are insufficient to eliminate malaria transmission in many settings because of operational constraints, mosquitoes that behaviourally avoid contact with them inside houses and growing resistance to available insecticides.However, mosquito control in high-income countries (HICs) is predominantly achieved with a combination of long-standing high coverage with mosquito-proofed housing and environmental management, supplemented with proactive, large-scale insecticide applications to larval habitats and outdoor spaces that kill off vector populations en masse.In contrast with the prescriptive, centralised global recommendation of LLINs and IRS as ubiquitous first-choice vector control tools for LMICs, the more aggressive, area-wide population suppression practices of HICs are idiosyncratically tailored to local conditions by decentralised mosquito abatement programmes, which are governed, funded and managed at the local level.A number of existing technologies are available that remain underdeveloped or underexploited, which could be rapidly mobilised to enable implementation of far more diverse, effective and sustainable malaria vector control strategies in LMICs.Where sufficient implementation capacity exists, and human population density is high enough to make the cost per person protected affordable, systems for vertical, proactive, locally managed delivery of mosquito population abatement technologies already used extensively in HICs should be developed and evaluated in LMICs. Experiences from programmes in HICs may be selectively leveraged wherever appropriate in LMIC contexts.Furthermore, a diverse range of repurposed and emerging technologies for targeting mosquitoes when they enter houses, feed outdoors, attack livestock, feed on sugar or aggregate into mating swarms are becoming available. These new technological options could all be developed into programmatically scalable vector control tools within the decade ahead and provide unprecedented opportunities for more effective suppression of malaria transmission in LMICs. Many of these technologies could be delivered horizontally, making them practically applicable even in settings with weak implementation capacity.Global policy must now fully and consistently realign with both the programmatic needs and biological realities of malaria vector control, to prioritise accelerated development of these diverse options for malaria vector control in LMICs.Developing such an expanded toolbox for malaria vector control will require investment in product and system development, high-quality evaluations of efficacy and effectiveness, and operational research to define best practices for programmatic use of these additional interventions.Vector control with long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) accounts for an estimated 78% of the 663 million malaria cases averted globally since 2000.LLINs and IRS have been highly effective interventions in LMICs,19Resistance to all four classes of insecticide available for public health, especially the pyrethroids we rely on for LLINs, is now prevalent across Africa.2residual transmission  to prevent emergence of adult mosquitoes: The mainstay of most mosquito control programmes in high-income countries (HICs) is aggressive control of immature mosquitoes in aquatic habitats through LSM, which includes all forms of environmental management, biological control and/or regular larvicide application that prevent immature aquatic stages of mosquitoes from emerging as adults.few, fixed and findable, a situation for which supporting evidence of success in LMICs already exists.Space spraying to kill flying and resting adult mosquitoes: Ground or aerial delivery of insecticides in the form of fine sprays, with small droplet sizes that remain suspended in the air for long periods, can kill mosquitoes which are resting or flying in the targeted time and place.space spraying or fogging, and is a mainstay of HIC mosquito control programmes as a response to disease outbreaks and/or increase in mosquito abundance.Anopheles populations and reduce malaria transmission, and ground-based space spraying has been employed successfully for malaria vector control in India, Tanzania and El Salvador.47–49Many well-established and highly effective mosquito control technologies that have been applied in HICs for decadesThe LSM and space-spraying interventions these programmes rely on are both area-wide interventions, so their application costs depend on the size of the catchment to be treated. Thus, the denser the human population, the more cost-efficient these measures become per person protected. With ongoing population growth, urbanisation and democratisation, development of such vertical but decentralised mosquito control programmes becomes an increasingly viable solution for many LMICs. Even now, ∼25% of the world's at-risk population already lives at densities of at least 1000 people per square kilometre, matching the sparsest population density at which LSM has already proven efficacious in Africa, albeit in the form of a district-scale research project rather than a larger programmatic evaluation.38The remaining 75% of the world's malaria-prone population is probably too sparsely distributed to support specialist vertical programmes for active mosquito abatement. Therefore, other technological solutions requiring less advanced delivery capacity will also be needed.Box 2Improving and extending physical protection of houses and peridomestic spaces:Extending coverage with solid-phase contact insecticides by treating clothing: Treating even the most basic garments and bed clothes with contact insecticides has long been known to protect against malaria exposure indoors and outdoors.irritants rather than repellents in the strict sense,63Vapour-phase insecticides for protecting open spaces: Devices which emanate vapour from volatile insecticides or repellents into the air are already widely used in HICs for protection of open spaces where people are usually awake and active.spatial repellents,vapour-phase insecticides, to distinguish them from repellents and irritants in the strict sense, which may be associated with considerable limitations, disadvantages and risks.61–63Odour-baited traps targeting host-seeking mosquitoes: Recent large-scale epidemiological trials have conclusively demonstrated mass suppression of the notoriously efficient African vector Anopheles funestus, and dramatically reduced malaria transmission by this widely distributed mosquito.72Veterinary insecticides to target vectors feeding on livestock: Most malaria vector species prefer animals over humans77Fortunately, a number of existing technologies are available for targeting adult mosquito blood-feeding behaviours, which could be readily adapted or repurposed for malaria vector control, and conveniently delivered through existing, non-specialist, horizontal distribution systems in LMICs . While IBeyond the well-understood blood-feeding behaviours that are most obvious as targets for mosquito control, other behaviours that are critical to mosquito survival can be targets for malaria vector control . While f39Box 3Attractive toxic sugar baits (ATSBs): All mosquito species exploit sugar as a source of adult nutrition, so existing ATSB products designed for other insects may be highly effective for population control of malaria vectors. Additionally, home-made prototypes, constructed in situ with materials that are readily available in most African villages, have performed remarkably well against malaria vector populations in the few small-scale trails completed until now.80Targeted space spraying of mating swarms: Male mosquitoes aggregate in swarms, where they compete for the attention of female mosquitoes visiting them in search of a mate, usually for an hour or less at dusk or dawn. Mating swarms have been documented for several important malaria vector species all across Africa.Box 4Against malaria vectors specifically:Numerous larval source management (LSM) programmes in the first half of the 20th century, including several successes in tropical of Africa, Asia and Latin America.10Indoor residual spraying (IRS) against malaria vectors as the primary vector control measure of the Global Malaria Eradication Program in the second half of the 20th century, which enabled elimination of malaria from dozens of previously endemic countries.82Largely spontaneous and horizontal uptake of mosquito-proofed housing to protect many populations of the world during the first half of the 20th century, including expatriates living in what we now call low-income and middle-income countries (LMICs), canal workers in Panama and residents of southern USA.33The systematic, vertical, proactive and decentralised local mosquito population abatement programmes established in high-income countries, especially the USA and Australia,Against vectors of other pathogens:The Onchocerciasis Control Program spanning 10 west African countries in the latter quarter of the 20th century, which relied primarily on LSM of blackflies in rivers.83Southern Cone Initiative to eliminate American trypanosomiasis through IRS against triatomine bugs living inside houses.84Several large-scale, vertical Tsetse control programmes scattered across Africa, deploying varying combinations of attractive traps and targets with area-wide, outdoor space and surface spraying.85While sugar-feeding and mating behaviours are attractive targets for developing new vector control strategies , these bA range of existing products and promising prototypes are now available that could be rapidly adapted for malaria vector control in LMICs . After d19Importantly, none of these exciting new vector control interventions will provide a universally applicable panacea; one size will not fit all. Different combinations of approaches will be needed in different geographies based on local ecology and vector biology, malaria epidemiology and operational capacity. While the need for national malaria control programmes to record epidemiological indicators of impact is obvious, programmes should also measure simple but robust indicators of mosquito and human behaviours that create these intervention opportunities, so that the best options can be selected, optimised and combined.42Ambitions to provide vertical mosquito population control services already have political support in some LMICs, to the extent that they finance them from predominantly domestic sources.residual transmission was only formally defined in 2016,Malaria control is at an important historical juncture, as global progress over recent years is documentedAt present, the evidence base relating to these additional vector control options is lacking both in quantity and quality with respect to their application to prevention of malaria and other mosquito-borne pathogens.


Language offers a privileged view into the mind; it is the basis by which we infer others’ thoughts. Subtle language disturbance is evident in schizophrenia prior to psychosis onset, including decreases in coherence and complexity, as measured using clinical ratings in familial and clinical high-risk (CHR) cohorts. Bearden et al previously used manual linguistic analysis of baseline speech transcripts in CHR to show that illogical and referential thinking, and poverty of content, predict later psychosis onset. Then, Bedi et al used automated natural language processing (NLP) of CHR transcripts to show that decreased semantic coherence and reduction in syntactic complexity predicted psychosis onset. To determine validity and reproducibility, we have applied automated NLP methods, with machine learning, to Bearden’s original CHR transcripts to identify a language profile predictive of psychosis.Participants in the Bearden UCLA cohort include 59 CHR, of whom 19 developed psychosis (CHR+) within 2 years, whereas 40 did not (CHR-), as well as 16 recent-onset psychosis and 21 healthy individuals, similar in demographics; speech was elicited using Caplan’s “Story Game. Participants in the Bedi NYC cohort include 34 CHR (29 CHR+), with speech elicited using open-ended interview. Speech was audiotaped, transcribed, de-identified and then subjected to latent semantic analysis to determine coherence and part-of-speech tagging to characterize syntactic structure and complexity. A machine-learning speech classifier of psychosis onset was derived from the UCLA CHR cohort, and then applied both to the NYC CHR cohort and to the UCLA psychosis/control comparison, with convex hull (three-dimension depiction of model) and receiver operating characteristics analyses. Correlational analyses with demographics, symptoms and manual linguistic features were also done.A four-factor model language classifier derived from the UCLA CHR cohort that comprised three semantic coherence variables and one syntax (usage of possessive pronouns) predicted psychosis t with accuracy of 83% (intra-protocol) for UCLA CHR, 79% (cross-protocol) for NYC CHR, and 72% for discriminating psychosis from normal speech (UCLA psychosis/control). Convex hulls were defined as the smallest space containing all datapoints within a set for CHR- or healthy controls: these convex hulls showed substantial overlap, with CHR+ and psychosis speech datapoints largely outside these convex hulls. Coherence was associated with age, but speech variables did not vary by gender, race, or socioeconomic status in this study. While automated text features were unrelated to prodromal symptom severity, they were highly correlated with manual text features .In this small preliminary study, we identified and cross-validated a robust language classifier of psychosis risk that comprised measures of semantic coherence (flow of meaning in language) and syntactic usage (usage of possessive pronouns). This classifier had utility in discriminating speech in individuals with recent-onset psychosis from the norm. It demonstrated concurrent validity in that it was highly correlated with manual linguistic features previously identified by Bearden et al, important as automated methods are fast and inexpensive. Automated language features were unrelated to sex, ethnicity or social class in these small samples, and semantic coherence increased with age, consistent with prior studies of normal language development. Of interest, overlapping convex hulls could be defined for groups of individuals without psychosis , suggesting a constrained hull of normal language in respect to syntax and semantics, from which pre-psychosis and psychosis speech deviates. The RDoC linguistic corpus-based variables of semantic coherence and syntactic structure hold promise as biomarkers of psychosis risk and expression, with initial validation and reproducibility. Next steps in biomarker development include larger multisite studies with standardization of protocols for speech elicitation, test-retest, and attention to traction/feasibility, acceptability, cost, and utility. Mechanistic studies can also yield neural and physiological correlates of abnormal semantic coherence and syntax.


Introduction: The transition from paediatric to adult care poses risks to the health of young adults living with HIV if unsuccessful, including interruptions in care and poor health outcomes. Evolving best practices in HIV healthcare transition should ideally be informed by real-world qualitative and quantitative clinical healthcare transition outcomes. There has been a recent proliferation of HIV healthcare transition outcome research, largely from Europe and North America.Methods: A literature search was undertaken using the online databases PubMed, Web of Science, and Google Scholar. Medical subject and text word searches were combined for terms relating to HIV, paediatric transition outcomes, and internal and external factors were used to identify peer-reviewed articles.Results: In this paper, we review data on HIV healthcare transition outcomes in North America and Europe. Internal and external factors which may impact the success of HIV healthcare transition are examined. We describe ongoing research efforts to capture transition outcomes in the North America and Europe. Clinical, operational, and implementation science research gaps that exist to date are highlighted. Efforts to improve HIV healthcare transition research through country-level surveillance networks and large multicentre cohorts, including data integration and linkage between paediatric and adult cohorts are discussed.Conclusions: We identified the need for a comprehensive approach to implementing empirically supported protocols to support healthcare transition for ALHIV. While there is limited prospective longitudinal cohort data available at this time, cohorts linking the paediatric and adolescent with ongoing surveillance into adulthood are being developed. Through a review of existing qualitative and quantitative healthcare transition outcomes studies, we identify emerging areas of consensus surrounding healthcare transition research implementation. Successful healthcare transition programmes in Europe and North America often share several characteristics, including implementation of a youth friendly multidisciplinary approach, consistent communication and integration between paediatric and adult care teams, and an individualized approach which is attuned the adolescent’s transition readiness. Moving forward, the voices of youth and young adults living with HIV should be included in the development and evaluation of healthcare transition protocols to ensure that the definition of successful transition reflects all of the stakeholders in the transition process. Early in the HIV epidemic, mother-to-child HIV transmission (MTCT) contributed significantly to the numbers of children living with HIV in Europe and the United States. Prevention of mother-to-child HIV transmission (PMTCT) and expanded access to combination antiretroviral therapy (cART) in the 1990s led to sharp declines in MTCT in these countries, and current rates of MTCT in these regions are <1% . The con“…few studies have evaluated the impact of transition interventions for adolescents and young adults with chronic illness on the outcome of transfer from pediatric to adult centered care, and… the few studies that have reported on this outcome have been limited by methodological challenges including non-randomization and convenience sampling [”.Adolescence is a time of great change and challenge, bridging the chasm between childhood and adult life. For adolescents with living with HIV (ALHIV), this period may be fraught with even greater adversity. One of the distinct challenges faced by emerging adults with chronic illnesses is the transition of their medical care from their long-term paediatric specialty provider to care within the adult healthcare system. Unfortunately, despite the complexity of the healthcare transition process, there is limited evidence in the medical literature to support specific approaches to successful transition. In a recent systematic review of the impact of transition interventions for adolescents with chronic illness, Chu and colleagues summarized the state of the field, sampling ”.It is accepted that successful transitions from paediatric to adult healthcare for ALHIV will improve the health outcomes, increase health literacy and self-care skills of emerging adults, which will ultimately result in optimal quality of life. However, the evidence base to support which transition approaches work best is limited by inadequate methodology, challenges with the definition of transition outcomes, a lack of comparison groups, and a paucity of implementation science research. Despite these challenges, a small number of HIV healthcare transition outcomes studies have been published, some of which reveal concerning health consequences to ALHIV as they transition to adult care.In this paper, we explore the challenges encountered by adolescents and young adults living with HIV, their caregivers and healthcare providers engaging in healthcare transition in Europe and North America. The published outcomes of HIV transition programmes reported in Europe and North America are examined, and we highlight early lessons from these studies and identify evolving clinical, operational, and implementation science research gaps that exist. We discuss efforts to improve HIV healthcare transition research through country-level surveillance networks and large multicentre cohorts, including proposed data integration and linkage between current paediatric and adult cohorts.A literature search was undertaken using the online databases PubMed, Web of Science, and Google Scholar. No restrictions were set on language or publication date; articles were only included if indexed up to 15 January 2017. Medical subject and text word searches were combined for terms relating to HIV, healthcare transition, and paediatric transition outcomes and were used to identify relevant peer-reviewed publications. The abstracts of identified articles were evaluated for relevance. In addition, this procedure was utilized to search for relevant abstracts presented at internationally recognized HIV conferences since 2015.Sociodemographic Characteristics of Transitioning ALHIV in Europe and North AmericaIn Europe, healthcare transition most often occurs at or near 18 years of age, and adolescent-specific HIV clinics are uncommon ,5. HowevIn the United States, HIV healthcare transition usually occurs at a somewhat older age; often when youth have reached their mid-twenties. As a result, the transitioning population includes higher relative proportions of behaviourally HIV-infected youth, populations which may differ from those with perinatally-acquired HIV in meaningful ways. Though mostly native-born, a large proportion of ALHIV with perinatally acquired HIV in the US are ethnic minorities living in urban, socio-economically disadvantaged communities. In a US-based prospective, multicentre surveillance study of long-term outcomes in HIV-infected children and adolescents (IMPAACT P1074), among 1173 patients alive as of 2014 , 58% were African American, 28% were Hispanic, and 11% were White . In addiHealthcare transition challenges across these populations may be broadly conceptualized as comprising internal factors, which are unique to an individual adolescent and/or sub-population, and external factors, or provider and/or structural circumstances over which the adolescent has little or no control. ALHIV likely experience healthcare transition challenges derived from unique combinations of these internal and external factors.At the time of healthcare transition, most adolescents and young adults living with HIV have navigated years of life stressors, including serious illness and hospitalization, HIV disclosure to partners and friends, often the loss of one or both parents, and trauma associated with living in limited-resource communities affected by violence. The scope of parental loss in the perinatal HIV population cannot be overstated. Forty-six per cent of ALHIV in the French EPF/ANRS CO10 cohort had a deceased mother, and one-third lived with non-relative caregivers . Thirty-The caregiver’s role in the HIV healthcare transition process is notable among youth living with perinatally acquired HIV. The parents and/or caregivers of adolescents living with perinatally acquired HIV have been closely involved in all aspects of their care since their diagnosis. As a result, these adolescents may not fully understand their healthcare options as someone else had been making the decisions for them, and their voice may have not been solicited or heard. Adolescents living with perinatally acquired HIV may feel passively involved in their healthcare decisions given their caregiver’s historical role in healthcare decisions .As a result of their longstanding relationship, perinatally infected adolescents and their families may view the paediatric care team as extended members of their family, especially in the context when family members have been lost . LeavingHealthcare transition occurs during the dynamic period of adolescent development. The normal developmental process of adolescence involves physical, cognitive, and psychosocial changes during which identity is formed, autonomy is established (including completing education and establishing a vocation), intimate relationships are developed, and abstract thought is incorporated into cognitive reasoning ,24. ImpoHIV is a highly stigmatized illness and many ALHIV report that HIV-associated stigma and disclosure to sexual partners, friends, and family is a barrier to engagement in adult care and quality of life ,26,27. HMany adolescents and young adults with perinatally acquired HIV experience high rates of neurodevelopmental deficits, particularly among those were born prior to the inception of cART . These dAdolescents with both behaviourally and perinatally acquired HIV have higher rates of mental health diagnoses when compared to their HIV-negative peers ,35, in pALHIV face similar sexual health challenges as their non-HIV-infected peers, including pregnancy. In a study examining transition practices in an Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) clinic, it was observed that young women with HIV who had been pregnant appeared to have an easier transition to adult medical care. It was suggested that the experience of receiving prenatal care in a different clinic, as well as additional social services offered to the pregnant woman, facilitated the movement from paediatric to adult care for this group of transition aged patients .Given the development of autonomy, limited self-perception of risk, and close dependence on peer groups, adolescence is a time of increased risk for substance use. In addition, HIV-infected adolescents with mental health disorders have a higher risk for substance abuse . Among tYouth living in economically disadvantaged areas are less likely to make appointments and demonstrate consistent adherence to antiretroviral therapy . PovertyPaediatric and adolescent HIV care is characterized by an emphasis on multidisciplinary on-site care with a youth friendly environment, a family-centred focus, and psychosocial support which attends to adolescent developmental needs . Many adTypically, paediatric and adult HIV clinic environments differ significantly. Adult HIV clinics are often more formal and business like in approach, with limited scheduling flexibility, more patient- and disease-focused care, less co-located specialty care, and fewer youth-friendly services . These cThe degree to which the adult and paediatric healthcare teams communicate and collaborate may affect the success of HIV transition. In a qualitative study establishing HIV healthcare transition best practices, providers cited paediatric/adult communication as an essential element of successful transition . UnfortuThough provider-directed guidelines on HIV healthcare transition exist in the US , and HIVHistorically, limitations of HIV transition research have included relatively small samples sizes, varying methodologies, and a heavy reliance on only qualitative research. In addition, most studies examined outcomes exclusively among perinatally infected adolescents and young adults. Studies of outcomes of HIV transition can be categorized into three basic areas: studies examining barriers and expectations prior to transition, descriptive analyses of provider practice during transition, and retrospective qualitative and quantitative descriptions of transition outcomes. As qualitative outcomes associated with expectations pre-transition and provider practices have been published elsewhere , we willWiener et al. interviewed 59 post-transition youth in the US about their healthcare transition experience. Forty-five per cent of the youth who participated in the interviews reported finding the transition more challenging than anticipated . Miles eThough there remains no consensus on what outcomes constitute a successful transition, researchers have identified several potential clinical outcomes to quantitatively measure transition success, including retention in adult care, ART adherence, HIV viral suppression, immunological (CD4) stability, and mortality in adult care. Studies which have examined one or more of these healthcare transition outcomes are described below and outlined in Fish et al. described the clinical characteristics of fourteen perinatally infected young adults previously enrolled in the CHIPS cohort and who died in adult care after transition in fourteen clinics in the UK . The medHope, et al. examined post-transition outcomes among 211 adolescents with perinatally acquired HIV in the UK-based CHIPS programme, 57% of who transitioned within the same hospital, and 55% of who had a staged transition between one or more clinics. They found that those who changed hospitals for adult transfer had higher odds of clinic non-attendance or death . EncouraRighetti et al. described survey-based post-transition outcomes among 45 HIV+ adolescents attending a multidisciplinary programme which was transitioned to an adult programme in Genoa, Italy . Due to Weijsenfeld et al. captured post-transition outcomes in a cohort of 59 Dutch adolescents with predominantly behaviourally acquired HIV . Like thSainz et al. performed a cross-sectional study examining pre- and post-transition immunologic and virologic outcomes among the Spanish Cohort of the Spanish Paediatric HIV Network (CoRISpe) ,64. VariWestling et al. performed a pre-transition cross-sectional study and 2-year follow up among 34 HIV+ adolescents  who underwent transfer to adult care following the development of the Treatment Outpatient Clinic, a co-located paediatric and adult multidisciplinary clinic in Sweden, after which youth may stay in adult care in the same physical space . In thisMaturo et al. provided the first description of post-transition outcomes in a US-based cohort of 38 patients with behaviourally acquired HIV attending a youth-friendly adolescent clinic with a formal healthcare transition protocol . This 5-Ryscavage et al. examined clinic retention, ART use, viral suppression, and CD4 trends following transition among 50  HIV-infected young adults . Though Kakkar et al. interviewed 45 patients who had transferred from a Montreal-based paediatric HIV programme to adult HIV care. These interviews were conducted a median of 3.6 years post-transfer. Of these 45 patients, 25 consented to the study, 8 were lost to follow up, 8 declined participation, and 4 had died  . SeventyDespite the relatively small sample sizes, variable methodology, disparate transition success measures, retrospective designs, lack of representation from behaviourally infected adolescents, and limited external validity due to variations in transition practice, the emerging literature on HIV healthcare transition has focused on several outcomes. The two most commonly utilized transition outcomes have been retention in adult care (eight of nine studies cited above) and HIV suppression (eight of nine studies cited above). CD4 + T cell changes and cART adherence have been less frequently examined, and the results of those studies which did include these outcomes suggest that they may be less useful instruments for gauging transition success. Mortality, though rare, appears to be an important transition variable, specifically as a means to examine predictors of the most catastrophic healthcare transition outcomes. Additionally, pre-transition outcomes, including retention in paediatric care and viral suppression, may be markers of the likelihood of post-transition success ,63,64. FIn addition to transition categorical outcomes, choices, there are several meaningful lessons from the emerging HIV healthcare transition literature. First, the transitioning ALHIV population is complex and heterogeneous, and the possible consequences of poor transition include lack of viral suppression, immune deterioration, and death ,60. SecoDespite the growth of the literature on HCT outcomes, there is an urgent need to study transition outcomes and transition models for behaviourally infected adolescents, particularly as there is incompletely explored evidence that behaviourally infected adolescents may be less likely to be retained in adult care either alone or compared to those with perinatally acquired HIV ,67. In aThere is a recognized need for improved surveillance of paediatric and adult cohorts through the transition process. Linkage of these cohorts will allow for long term, seamless monitoring of clinical and transition outcomes in order to inform HIV clinical and policy-level decisions in the future. Among paediatric and adolescent cohorts, researchers have identified the need for HIV disclosure in the consent process as a potential barrier to enrolment of adolescent participants . In the A recent survey study of HIV cohort studies participating in the EuroCoord Network of Excellence was performed in order to ascertain the number and distribution of patients with perinatally acquired HIV, as well as to examine the degree of seamless linkage between individual European paediatric and adult HIV cohorts . This stThe UK has had a comprehensive observational active surveillance system for paediatric HIV for the last 25 years through the National Study of HIV in Pregnancy and Childhood (NSHPC) . In addiProspective longitudinal cohorts of older adolescents transitioning into adulthood are now being followed in the US. The Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) has developed the CATCH (Comprehensive Assessment of Transition and Coordination for HIV-Positive Youth as They Move From Adolescent to Adult Care) cohort (ATN 135), which will capture medical and appointment records data across the transition spectrum, and prospectively explore pre- and post-transition experiences of ALHIV (age 18–24 years) . In addiWe have identified the need for a comprehensive approach to planning and implementing rigorous empirically supported protocols to support transition for ALHIV. Published studies point to several potential key measures which could serve as markers of successful healthcare transition models including viral load suppression and long-term retention in adult care. While not all are empirically supported, we have identified programmatic approaches which have been shown to improve the transition process for ALHIV. These approaches include: a youth friendly multidisciplinary approach, early and integrated involvement of an adult care team, optimal communication between paediatric and adult care teams, and an individualized approach which is attuned the adolescent’s transition readiness. While there is limited prospective longitudinal cohort data available at this time, cohorts linking the paediatric and adolescent with ongoing surveillance are being developed. These diverse multicentre cohorts of ALHIV will allow programmes to systematically evaluate the efficacy of models of transition that work best for specific populations of ALHIV. The voices of youth and young adults living with HIV should be included in the development and evaluation of transition protocols to ensure that the definition of successful transition reflects all of the stakeholders in the transition process.


Moreover, the ways of overcoming disadvantages of phytoremediation using genetic transformation approachare proposed. The knowledge gathered here could be useful for designing new research aimed at biotechnological improvement of phytoremediation efficiency.Avoidance and reduction of soil contamination with heavy metals is one of the most serious global challenges. Nowadays, science offers us new opportunities of utilizing plants to extract toxic elements from the soil by means of phytoremediation. Plant abilities to uptake, translocate, and transform heavy metals, as well as to limit their toxicity, may be significantly enhanced via genetic engineering. This paper provides a comprehensive review of recent strategies aimed at the improvement of plant phytoremediation potential using plant transformation and employing current achievements in nuclear and cytoplasmic genome transformation. Strategies for obtaining plants suitable for effective soil clean-up and tolerant to excessive concentrations of heavy metals are critically assessed. Promising directions in genetic manipulations, such as gene silencing and  Dynamic development of industrial, urban, and agricultural aspects of human activities in the 20th century resulted in chemical pollution of the environment  growing naturally in contaminated sites  family, a large group of genes encoding proteins responsible for detoxification and ion-regulation processes  in tobacco stimulated hyperaccumulation of cadmium and enhanced tolerance and accumulation of arsenic upon exogenous. As stress, indicating broad substrate specificity of OsMTP1  family encode various types of proteins called metal tolerance/transport protein (MTP), that enable cells to exclude excessive amounts of ions from cytoplasm. Plants overexpressing CDF genes produce elevated amounts of thiol compounds and, therefore, are able to efficiently sequester metal ions in the vacuoles by chelating them.This may result in hyperaccumulation of toxic ions in plant biomass. It was recently reported that during external Cd stress, overexpression of OsMTP1 gene from indica rice , which are engaged in the regulation of cytoplasmic transport of zinc and iron. In wild-type plants, these high affinity uptake systems are induced at transcriptional level by Zn or Fe deficiency , which are peptides enzymatically synthesized from glutathione, low molecular organic acids and amino acids (LMWOA), and metallothioneins (MT). Among these compounds, only metallothioneins are direct products of gene expression. In contrast, the level of phytochelatins and organic and amino acids depends on the activity of enzymes involved in their biosynthesis, and thus genes encoding these enzymes should be manipulated.c-glutamyl cysteine synthetase (c-GCS)  were either capable of greater accumulation of Cd and Pb, or were simply more tolerant to Cd, although without enhanced accumulation of this element  and o et al.  proved tHordeum vulgare into Arabidopsis, reported by Kim et al.  are ubiquitous cysteine-rich proteins capable of high affinity coordination of heavy metal ions via cysteine residues gathered in Cys–X–Cys or Cys–Cys motifs. Plant metallothioneins are currently categorized into four types that slightly differ in a structure of cysteine-rich domains  . Damaging effects of ROS to biomolecules, such as DNA, proteins, and lipids, can be minimized by antioxidant defense system including enzymatic mechanisms based mainly on superoxide dismutase (SOD), ascorbate peroxidase (APX), catalase (CAT), and glutathione S-transferase (GST) genes in plants subjected to heavy metal stress. These enzymes, possessing glutathione peroxidase activity, catalyze conjugation reactions between glutathione and a number of xenobiotics, and thereby contribute to the detoxification of free radicals  line was produced overexpressing apple spermidine synthase MdSPDS1 gene. After exposure to Cd and Zn, the transformants responded with enhanced synthesis and accumulation of polyamines as compared with wild-type plants. Beneficial effects were attributed to antioxidant activity of spermidine and its ability to bind free metal ions , and glutathione reductase (GR). Although transplastomic plants were less sensitive to various stress conditions, such as increased salinity and chilling, chloroplast transformation did not ameliorate plants response to heavy metal exposure. This illustrates the fact that in some cases, nuclear transformation has more pronounced impact on antioxidant system than chloroplast transformation. Therefore, screening for appropriate genes is essential to successfully transform plastids towards heavy metal tolerance. A good candidate gene is BrMT1 encoding Brassica rapa type-1 metallothionein. This gene was successfully targeted to the chloroplasts of Arabidopsis and its overexpression in either the chloroplasts or the cytosol allowed for effective detoxification of cadmium in transplastomic plants (Kim et al. 2O2. Considering efficiency of plastid transformation, there are some concerns about the functioning of transgenic chloroplasts in the roots, where are naturally absent. Since root system plays a crucial role in phytoremediation, Davison (Nicotiana plants exhibiting elevated tolerance to multiple biotic and abiotic stresses (Chen et al. Small chloroplast genome can be modified by genetic transformation, generating cells and plants with transgenic plastid genomes, which are referred to as transplastomic plants. A specific feature of plastid transformation is homologous recombination that facilitates the site-specific alteration of endogenous plastid genes as well as the precisely targeted insertion of foreign genes into the plastid DNA Bock . This en Davison  doubts wChlamydomonas, in the genome of which at least 11 unique gene families known to encode metal transporters were described (Rubinelli et al. Algal species, especially microalga, have great ability to absorb and transform pollutants, including heavy metals. These organisms synthesize both phytochelatins and metallothioneins, and, therefore, are capable of chelating and efficiently detoxifying toxic elements (Perales-Vela et al. Arabidopsis plants silenced for arsenate reductase gene were capable of efficiently translocating arsenic to the shoots, in contrast with wild-type plants (Dhankher et al. An emerging transformation approach for increased heavy metal resistance may become gene silencing. Biological basis for this process is RNA interference, a conserved defense mechanism, in which small RNA molecules suppress gene expression by interfering with the translation of target mRNA (Saurabh et al. Arabidopsis or Thlaspi, are good candidates for genetic modifications due to scientific knowledge on their genetics and their close phylogenetic relationships. Genetic foundations of heavy metal tolerance were extensively studied in this family and several ecotypes of hyperaccumulator species were identified (Marmiroli et al. Genetic engineering is a powerful tool that may accelerate development of new plant lines with traits desirable in phytoremediation. However, there have been public concerns about testing transgenic lines in field conditions, and therefore, no genetically modified plants have been tested in large-scale field experiments for their specific potential in heavy metal remediation. Thus, also the potential risks associated with outcrossing with any wild relatives or uncontrolled spread due to higher tolerance level have never been clearly evaluated. The risk of gene escape with engineered hyperaccumulator lines can be reduced if plant material is applied in isolated industrial districts instead of agricultural areas. A novel solution can be an application of cisgenesis and intragenesis in genetic engineering of phytoremediating plants. These new tools in plant genetic modification were successfully applied in improving crop quality and enhancing tolerance to biotic stresses (Espinoza et al. In this review, we have comprehensively discussed recent achievements and novel directions of plant transformation towards enhanced heavy metal tolerance and phytoremediation. We also proposedsome potential transformation-based solutions to the most important phytoremediation drawbacks. In this view, plant transformation may facilitate soil clean-up for sustainable environmental protection. Since genetic engineering may be extremely powerful tool in environmental studies, especially taking into account that new technologies, such as genome editing and genome engineering, are still emerging, the knowledge gathered here could be useful in designing new research towards biotechnological improvement of phytoremediation efficiency.


Telomeres are tandem repeat DNA sequences present at the ends of each eukaryotic chromosome to stabilize the genome structure integrity. Telomere lengths progressively shorten with each cell division. Inflammation and oxidative stress, which are implicated as major mechanisms underlying cardiovascular diseases, increase the rate of telomere shortening and lead to cellular senescence. In clinical studies, cardiovascular risk factors such as smoking, obesity, sedentary lifestyle, and hypertension have been associated with short leukocyte telomere length. In addition, low telomerase activity and short leukocyte telomere length have been observed in atherosclerotic plaque and associated with plaque instability, thus stroke or acute myocardial infarction. The aging myocardium with telomere shortening and accumulation of senescent cells limits the tissue regenerative capacity, contributing to systolic or diastolic heart failure. In addition, patients with ion-channel defects might have genetic imbalance caused by oxidative stress-related accelerated telomere shortening, which may subsequently cause sudden cardiac death. Telomere length can serve as a marker for the biological status of previous cell divisions and DNA damage with inflammation and oxidative stress. It can be integrated into current risk prediction and stratification models for cardiovascular diseases and can be used in precise personalized treatments. In this review, we summarize the current understanding of telomeres and telomerase in the aging process and their association with cardiovascular diseases. In addition, we discuss therapeutic interventions targeting the telomere system in cardiovascular disease treatments. Aging is a major risk factor for cardiovascular diseases (CVDs), including myocardial infarction (MI), stroke, hypertension, and chronic heart failure (HF). The prevalence of CVDs significantly increases with age, and CVDs are a major cause of chronic disability and the leading cause of death worldwide. Although the prevention and treatment of CVDs have substantially progressed during the previous two decades, morbidity and mortality rates associated with CVDs remain high and impose a tremendous burden on the national healthcare system. According to heart disease and stroke statistics, CVDs account for 30.8% of deaths ; that isSeveral epidemiologic surveys have reported an association of short telomere length (TL) with CVD ,4,5,6 anIn humans, telomeres consist of hundreds to thousands of repetitive sequences of TTAGGG at chromosomal ends for maintaining genomic integrity . BecauseThe human telomerase is responsible for maintaining and elongating TL and consists of the telomerase RNA component (TERC) and telomerase reverse transcriptase (TERT), the catalytic component. The TERT uses the TERC as a template to synthesize new telomeric DNA repeats at a single-stranded overhang to maintain TL. Some cells such as germ cells, stem cells, hematopoietic progenitor cells, activated lymphocytes, and most cancer cells have a high level of telomerase activity to overcome telomere shortening and maintain limitless cell division. However, somatic cells generally have a low or undetectable level of telomerase activity with limited longevity. The TL and integrity are regulated through the interplay between the telomerase and shelterin proteins . TelomerWhen a telomere is shortened to a critical length, the cell enters cellular senescence, which initiates a series of changes in the gene expression of replicative cell-cycle inhibitors and inhibits proliferation and then finally into apoptosis  as knownAtherosclerosis is developed through a complex multifactorial process and contributes to major CVDs . EndotheThe functional integrity of endothelial cells is essential for vascular health and preventing the development of atherosclerosis. Substantial evidence indicated that a biological relationship is present among shortened TL, cellular senescence, and atherosclerosis . MoleculTelomerase activity is repressed in endothelial cells freshly isolated from intact endothelia, as in most somatic cells with low proliferative activity. However, telomerase activity is present in cultured endothelial cells and has been shown to be reversibly upregulated by fibroblast growth factor-2 (FGF-2)  and nitrIn human atherosclerosis study , VSMCs iRegarding the role of telomerase in the proliferation of VSMCs, Minamino et al. demonstrated that VSMC proliferation is closely correlated with increased telomerase activity and that the protein kinase inhibitor H7 suppresses the activation of telomerase in the cytoplasm and nucleus, as well as reducing the growth of VSMCs . They prInflammation is believed to play a crucial role in atherosclerosis. The presence of short LTL in human atherosclerosis can be mainly attributed to the increased leukocyte consumption in inflammatory processes and accelerated telomere loss per replication in enhanced oxidative stress. Similarity, short TL in T lymphocytes are also exhibited in patients with chronic infection  and infl+ T cells and associated immune responses to acute inflammation. Spyridopoulos et al. reported TL in granulocytes, monocytes, peripheral blood stem cells and progenitor cells was consistently 500 bases shorter in leukocytes from patients with CAD than in control subjects. However, only cytotoxic CD8+ T cells in CMV-seropositive CAD patients were found to have increased TL loss of 1000 bases than in control subjects [+ T cells in CMV-seropositive patients through programmed cell death-1-dependent apoptosis processes during acute myocardial infarction [+ T cells left blood circulation and migrated into the target organ during acute inflammation in CMV-seropositive patients. The activated CD8+ T cells exhibit cytotoxic damage in the target organ and then were depleted spontaneously via an apoptosis mechanism. Homeostatic proliferation of T cells after acute stage accelerated TL shortening of CD8+ T cells and immunosenescence in CMV-seropositive patients. It could serve as a model of further investigations about the regulatory mechanisms of leukocytes telomere shortening in circumstances of acute inflammation.Telomere loss is a marker of leukocyte senescence. Immunosenescence is generally used to described the age-associated functional decline of immune system [+ CD28− T cells with features of replicative senescence, such as shortened telomeres, loss of telomerase activity, and enhanced secretion of inflammatory cytokines [+ T cells is believed to be a causative factor in numerous age-related conditions, including atherosclerosis, cardiovascular diseases, metabolic syndrome, obesity, type 2 diabetes, osteoporosis, and osteoarthritis [−/− mice, which entails loss of repressive regulation of proinflammatory gene transcription, results in premature aging with telomere dysfunction, cell senescence, and impaired tissue regeneration in multiple organ systems. This phenomenon can be reversed by anti-inflammatory or antioxidant treatment [For example, chronic cytomegalovirus (CMV) infection was reported to be associated with atherosclerosis in humans , which msubjects . In theifarction . Furtherfarction . Differee system , which iytokines . Accumulrthritis . In animreatment .−/− mice model, generation four TERC−/− ApoE−/− mice developed fewer atherosclerotic lesions compared with generation four TERC+/+ ApoE−/− mice, which implies that the absence of telomerase activity is protective for atherosclerotic disease. This conflicting result might be explained by replicative senescence in immune cells. In this study, the proliferative capacity of macrophages and lymphocytes was decreased in generation four TERC−/− ApoE−/− mice compared with generation four TERC+/+ ApoE−/− [−/− mice have been observed to have more severe structural defects than earlier generation TERC−/− mice, including spleen atrophy and bone marrow proliferative defects, which limits differentiation and proliferation of functional immunocompetent cells and thus restricts atheroma progression. Therefore, telomere attrition might consistently cause cellular senescence, and apoptosis in difference cell types, but have variable effects on complex disease processes, such as atherogenesis or tumorigenesis in tissues or species and disease-specific patterns.However, in TERC ApoE−/− . In addi−/−) have progressively shortened telomeres in the later generation along with attenuation in myocyte proliferation and an increase in apoptosis [An experimental study reported that telomerase knockout mice , which originate from hematopoietic stem cells (HSCs) in the bone marrow . The shoFurthermore, we observed mutations in circadian gene Per2 caused vascular senescence and impaired impairs ischemia-induced revascularization through the alteration of EPC function , which mPeripheral leukocyte DNA has been most commonly used in epidemiological studies to measure TL because a blood sample can be easily obtained. A consistent synchrony exists between LTL and somatic cells, including vascular cells, within people . The twoTL is largely inherited ,61 and iThe amount of telomere lost during each cell division varies among people. Previous evidence indicated that increased oxidative stress and chronic inflammation are associated with a higher telomere loss and accelerated telomere shortening . Several−/− and endothelial nitric oxide synthase (eNOS)−/− mice, indicating the beneficial effects are medicated by TERT and eNOS [However, some dietary and lifestyle factors such as marine omega-3 fatty acid , antioxiand eNOS . A humanand eNOS .Consequently, telomere shortening is a reflection of cellular aging and a marker of the health status of the aging population . AbsolutSeveral studies in diverse populations have reported an association of shorter telomeres in circulating leukocytes with CAD ,90,91,92However, many studies are cross-sectional design and because most cardiovascular risk factors also affect LTL, the causal or consequential relationship between shorter TL and CAD remains controversial. Recently, some prospective longitudinal studies may support the hypothesis that telomere shortening causes CAD, rather than telomere shortening is a consequence of CAD. In a large prospective WOSCOPS study , compareLTL in patients with CAD has prognostic value. A prospective cohort study of 780 patients conducted for a follow-up period of 4.4 years reported an association of decreased LTL with all-cause mortality, with an adjusted hazard ratio of 1.8 in the lowest TL quartile compared with the highest TL quartile . MoreoveIn the coronary intervention field, researchers observed shorter LTL and increased proinflammatory activity in high-risk unstable plaque  on virtual histology intravascular ultrasound in patients with acute coronary syndrome also . FurtherIn a clinical study of 803 patients, LTL was decreased by approximately 40% in patients with HF, and TL in the patients with HF was related to the disease severity . A studyHF with a normal ejection fraction was not well recognized until the two previous decades. Approximately half of patients hospitalized for HF have a normal ejection fraction, and outcomes in these patients are equivalent to those in patients with a lower ejection fraction . Aging lThe association of stroke and peripheral artery disease (PAD) ,111,112 Sudden cardiac death (SCD) has been attributed to some genetic variations in the DNA sequence of ion channels. However, it is hypothesized that changes in the gene copy number of potassium  and calcium  channels cause genetic instability and SCD. Moreover, a case-control study reported that patients who experienced SCD had shorter telomeres and changes in the gene copy number of ion channels . This maIn idiopathic pulmonary arterial hypertension, an increase in the proliferation of pulmonary artery smooth muscle cells contributes to the fundamental disease mechanism. A study reported that telomeres in pulmonary arterial smooth muscle cells are longer in patients with idiopathic pulmonary arterial hypertension than in controls and that TL is positively correlated with pulmonary vascular resistance . HoweverIn patients with degenerative aortic valve stenosis, decreased regenerative capacity and a decreased number of EPCs, caused by cellular senescence, were associated with the progression of degenerative aortic valve stenosis .From the implications of current understanding of telomere biology, potential therapeutic interventions such as the maintenance of TL and modulation of telomerase activity to reverse telomere attrition and cellular senescence, is emerging as a novel strategy for treating atherosclerosis and CVD . Experim+) than in the CD8-positive (CD8+) T-cell subsetSeveral studies demonstrated the effects of TL maintenance and senescence prevention in certain drugs, which have been used for decades exert clinically beneficial on CVD. For example, statins, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, exert various pleiotropic effects to prevent the development of atherosclerotic plaque. They mitigate the genomic damage through potentiation of the DNA repair capacity  and upreAngiotensin II has been reported to induce oxidative DNA damage and accelerate cellular senescence in cultured human VSMCs . TherefoTelomere shortening and dysfunction play a crucial role in the pathogenesis of aging-associated CVDs. Critically short telomeres can lead to cellular senescence and apoptosis, which contribute to the development of atherosclerosis and predispose people to plaque instability. Both genetic and environmental factors have been associated with individual variations in TL. Cardiovascular risk factors such as smoking, diabetes mellitus, hypertension, obesity, sedentary lifestyle, and stress have been considered to increase oxidative stress or inflammation, consequently accelerating TL shortening. However, healthy lifestyle and physical activity are protective factors and maintain TL. In clinical practice, shorter LTL reflects the burden of oxidative stress and inflammation, and might be an effective biomarker for risk stratification for atherosclerosis and CVDs. The association of LTL with CAD has been reported in several prospective epidemiological studies, although conclusive evidence of causal relationship is still lacing. However, for subclinical atherosclerosis, ischemic stroke, and PAD, available data are controversial. The role of telomeres in disease pathogenesis should be explored according to some crucial clinical implications of pilot studies, such as coronary artery stenting, SCD, idiopathic pulmonary hypertension, and degenerative aortic stenosis. Furthermore, targeting telomerase or additional telomere-associated proteins may provide a novel therapeutic strategy for neovascularization in patients with ischemic heart diseases and for restoring replicative capacity in those with HF. Additional basic and well-designed clinical studies are required to validate these observations and further expand our knowledge the complexities of telomere dynamics in humans.