Search

Lennox-Gastaut syndrome is a severe drug-resistant developmental and epileptic encephalopathy with slow spike and wave on EEG (DEE-SSW) composing about 1–2% of epilepsy patients. Seizures in DEE-SSW are caused by a variety of etiologies, and there is a large unmet treatment need as seizures are usually treatment-resistant and individuals are often unable to function independently. The updated definition by the International League Against Epilepsy has established formal diagnostic criteria allowing for more uniform diagnosis. This article provides a review of typical medication management and treatment strategies, including new and developing surgical approaches. Future directions in treatment include expanding genetic testing with the potential for gene therapy and continuously improving surgical options with the goal to prevent progression to DEE-SSW. [ABSTRACT FROM AUTHOR]

Modern medicine continues to evolve, and the treatment armamentarium for various diseases grows more individualized across a breadth of medical disciplines. Cure rates for infectious diseases that were previously pan-fatal approach 100% because of the identification of the specific pathogen(s) involved and the use of appropriate combinations of drugs, where needed, to completely extinguish infection and hence prevent emergence of resistant strains. Similarly, with the assistance of technologies such as next-generation sequencing and immunomic analysis as part of the contemporary oncology armory, therapies can be tailored to each tumor. Importantly, molecular interrogation has revealed that metastatic cancers are distinct from each other and complex. Therefore, it is conceivable that rational personalized drug combinations will be needed to eradicate cancers, and eradication will be necessary to mitigate clonal evolution and resistance. • Metastatic cancer complexity and heterogeneity requires moving beyond scripted monotherapies to tailored combinations. • Cancer may be akin to the mythical Hydra, whose nine heads must be all severed, as two heads grow back if one is slayed. • Patterns of response and resistance, such as mixed responses, provide clues to underlying molecular heterogeneity. • Customized (N-of-1) combination therapy may hold the key to killing the cancer hydra. [ABSTRACT FROM AUTHOR]

The levels and activities of the DNA/RNA helicase schlafen11 (SLFN11) and the serine/threonine-protein kinase ataxia telangiectasia and Rad3-related protein (ATR) may determine cancer cell sensitivity to DNA damaging agents, including platinum drugs. Here, we studied the roles of SLFN11 and ATR in cisplatin resistance of ovarian cancer using cell lines displaying acquired or intrinsic cisplatin resistance. W1CR, the cisplatin-resistant subline of W1 ovarian cancer cells, displayed reduced SLFN11 levels. HDAC inhibition using entinostat returned an epigenetic downregulation of SLFN11 in W1CR cells, caused SLFN11 re-expression and re-sensitized these cells to cisplatin. Moreover, entinostat also sensitized intrinsically resistant EFO21 ovarian cancer cells to cisplatin by upregulating SLFN11. However, SLFN11 was not involved in cisplatin resistance in all other cell models. Thus, SLFN11 expression is not a general cisplatin resistance marker in ovarian cancer. In contrast, inhibition of the DNA damage repair master regulator ATR using sub-toxic concentrations of elimusertib sensitized parental cell lines as well as intrinsically resistant EFO21 cells to cisplatin, and fully reversed acquired cisplatin resistance in cisplatin-adapted sublines W1CR, A2780cis, and KuramochirCDDP2000. Mechanisms underlying ATR-mediated cisplatin resistance differed between the cell lines and included CHK1/WEE1 signaling and induction of homologous recombination. In conclusion, SLFN11 and ATR are involved in ovarian cancer cisplatin resistance. Although our data identify ATR as key target for tackling cisplatin resistance in ovarian cancer, future studies are needed to identify biomarkers that indicate, which individual ovarian cancers benefit from SLFN11 re-activation and/or ATR inhibition. • Epigenetically induced re-expression of Slfn11 sensitizes cisplatin resistant cells. • ATR is the most critical target in DNA repair pathways for sensitization strategies. • ATR inhibition overcomes intrinsic and acquired cisplatin resistance in ovarian cancer • Downstream regulation of ATR is very heterogeneous among resistant cell lines. [ABSTRACT FROM AUTHOR]

Mycetoma is a neglected invasive infection endemic in tropical and subtropical regions, presenting as a chronic subcutaneous inflammatory mass that can spread to deeper structures, leading to deformities, disabilities, and potentially mortality. The current treatment of eumycetoma, the fungal form of mycetoma, involves antifungal agents, such as itraconazole, combined with surgical intervention. However, this approach has limited success, with low cure rates and a high risk of recurrence. This study addresses to the urgent need for more effective therapeutics by designing and synthesising 47 diversely pharmacomodulated imidazo [1,2- b ]pyridazine derivatives using a simple synthetic pathway with good yields and purity. Of these, 17 showed promising in vitro activity against Madurella mycetomatis , the prime causative agent of eumycetoma, with IC 50 ≤ 5 μM and demonstrated significantly lower cytotoxicity compared to standard treatments in NIH-3T3 fibroblasts. Notably, compound 14d exhibited an excellent activity with an IC 50 of 0.9 μM, in the same order then itraconazole (IC 50 = 1.1 μM), and achieved a favourable selectivity index of 16 compared to 0.8 for itraconazole. These promising results warrant further research to evaluate the clinical potential of these novel compounds as safer, more effective treatments for eumycetoma, thus addressing a profound gap in current therapeutic strategies. [Display omitted] • Design and synthesis of 47 original imidazo [1,2- b ]pyridazine derivatives. • Antifungal activity against M. mycetomatis , the major cause of eumycetoma. • 17 compounds with in vitro IC 50 ≤ 5 μM against Madurella mycetomatis. • Most active compound 14d with IC 50 of 0.9 μM and selectivity index of 16. • Imidazo [1,2- b ]pyridazines as potential candidates for treating eumycetoma. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract The peripherally expressed voltage-gated sodium Na V 1.7 (gene SCN9A) channel boosts small stimuli to initiate firing of pain-signaling dorsal root ganglia (DRG) neurons and facilitates neurotransmitter release at the first synapse within the spinal cord. Mutations in SCN9A produce distinct human pain syndromes. Widely acknowledged as a "gatekeeper" of pain, Na V 1.7 has been the focus of intense investigation but, to date, no Na V 1.7-selective drugs have reached the clinic. Elegant crystallographic studies have demonstrated the potential of designing highly potent and selective Na V 1.7 compounds but their therapeutic value remains untested. Transcriptional silencing of Na V 1.7 by a naturally expressed antisense transcript has been reported in rodents and humans but whether this represents a viable opportunity for designing Na V 1.7 therapeutics is currently unknown. The demonstration that loss of Na V 1.7 function is associated with upregulation of endogenous opioids and potentiation of mu- and delta-opioid receptor activities, suggests that targeting only Na V 1.7 may be insufficient for analgesia. However, the link between opioid-dependent analgesic mechanisms and function of sodium channels and intracellular sodium-dependent signaling remains controversial. Thus, additional new targets – regulators, modulators – are needed. In this context, we mine the literature for the known interactome of Na V 1.7 with a focus on protein interactors that affect the channel's trafficking or link it to opioid signaling. As a case study, we present antinociceptive evidence of allosteric regulation of Na V 1.7 by the cytosolic collapsin response mediator protein 2 (CRMP2). Throughout discussions of these possible new targets, we offer thoughts on the therapeutic implications of modulating Na V 1.7 function in chronic pain. [ABSTRACT FROM AUTHOR]

CD40 is a TNF receptor superfamily member expressed on both immune and non-immune cells. Interactions between B cell-expressed CD40 and its binding partner, CD40L, predominantly expressed on activated CD4+ T cells, play a critical role in promoting germinal center formation and the production of class-switched antibodies. Non-hematopoietic cells expressing CD40 can also engage CD40L and trigger a pro-inflammatory response. This article will highlight what is known about the biology of the CD40-CD40L axis in humans and describe the potential contribution of CD40 signaling on both hematopoietic and non-hematopoietic cells to autoimmune disease pathogenesis. Additionally, novel therapeutic approaches to target this pathway, currently being evaluated in clinical trials, are discussed. [ABSTRACT FROM AUTHOR]

Abstract Since the discovery of chlorpromazine in the 1950's, antipsychotic drugs have been the cornerstone of treatment of schizophrenia, and all attenuate dopamine transmission at the dopamine-2 receptor. Drug development for schizophrenia since that time has led to improvements in side effects and tolerability, and limited improvements in efficacy, with the exception of clozapine. However, the reasons for clozapine's greater efficacy remain unclear, despite the great efforts and resources invested therewith. We performed a comprehensive review of the literature to determine the fate of previously tested, non-dopamine-2 receptor experimental treatments. Overall we included 250 studies in the review from the period 1970 to 2017 including treatments with glutamatergic, serotonergic, cholinergic, neuropeptidergic, hormone-based, dopaminergic, metabolic, vitamin/naturopathic, histaminergic, infection/inflammation-based, and miscellaneous mechanisms. Despite there being several promising targets, such as allosteric modulation of the NMDA and α7 nicotinic receptors, we cannot confidently state that any of the mechanistically novel experimental treatments covered in this review are definitely effective for the treatment of schizophrenia and ready for clinical use. We discuss potential reasons for the relative lack of progress in developing non-dopamine-2 receptor treatments for schizophrenia and provide recommendations for future efforts pursuing novel drug development for schizophrenia. [ABSTRACT FROM AUTHOR]

Abstract Mantle cell lymphoma is an incurable, moderately aggressive B cell lymphoma. While a small proportion of patients with indolent disease can be managed expectantly, most patients require treatment. The therapeutic approach is driven by physician recommendation, patient choice, age, fitness and comorbidities. Young, fit patients often receive combination chemoimmunotherapy, including high dose cytarabine, with autologous stem cell transplant. Recent data has indicated benefit from maintenance rituximab following autologous stem cell transplant. Ongoing trials are investigating combinations of chemotherapy and targeted agents as well as the role of minimal residual disease guided therapy. Older, less fit patients often receive bendamustine and rituximab or anthracycline based regimens. Maintenance rituximab is typically administered in older MCL patients after anthracycline based chemotherapy although its use after bendamustine based therapy is not supported by current data. Current trials focus on refining this regimen with the addition of targeted agents. In the relapsed and refractory setting, novel agents have demonstrated activity although durability of responses remains unsatisfactory. [ABSTRACT FROM AUTHOR]

De-regulated cellular energetics is an emerging hallmark of cancer with alterations to glycolysis, oxidative phosphorylation, the pentose phosphate pathway, lipid oxidation and synthesis and amino acid metabolism. Understanding and targeting of metabolic reprogramming in cancers may yield new treatment options, but metabolic heterogeneity and plasticity complicate this strategy. One highly heterogeneous cancer for which current treatments ultimately fail is the deadly brain tumor glioblastoma. Therapeutic resistance, within glioblastoma and other solid tumors, is thought to be linked to subsets of tumor initiating cells, also known as cancer stem cells. Recent profiling of glioblastoma and brain tumor initiating cells reveals changes in metabolism, as compiled here, that may be more broadly applicable. We will summarize the profound role for metabolism in tumor progression and therapeutic resistance and discuss current approaches to target glioma metabolism to improve standard of care. [ABSTRACT FROM AUTHOR]

SL-1-18 (1-(chrysen-6-yl)-3-(4-nitrophenyl)thiourea) is new flexible heteroarotinoid (Flex-Het) analog derived from the parent compound, SHetA2, and our previous study showed comparable activity to SHetA2 in terms of inhibiting ER+ breast cancer cell growth. This current study aims to determine the molecular mechanism underlying SL-1-18's effect on breast cancer cell growth. Our results indicate that SL-1-18 inhibits cell proliferation of ER+ breast cancer cells (MCF-7 and T-47D) by preventing cell cycle progression. SL-1-18 treatment correlated positively with decreased expression of key cell-cycle regulators, such as cyclin D1, as well as other ERα-target genes at both the transcript and protein levels. Interestingly, decreased expression of ERα was also observed, with a significant reduction at the protein level within 2 h of SL-1-18 treatment, while the decrease in mRNA occurred at a later time point. ERα degradation was shown to be mediated by the ubiquitination-proteasome pathway. In summary, this is the first study to show that a Flex-Het- SL-1-18- can promote the degradation of ERα via the ubiquitin-proteasome pathway and should be further developed as a therapeutic option for ER+ breast cancer. [ABSTRACT FROM AUTHOR]

We have used an integrated computational approach to explore the role of vitamin C and vitamin D in preventing aggregation of Fibrinogen A alpha-chain (FGActer) protein responsible for renal amyloidosis. We modelled structures of E524K / E526K mutants of FGActer protein and examined the potential interactions of these mutants with vitamin C and vitamin D3. Interaction of these vitamins at the amyloidogenic site may prevent the intermolecular interaction required for amyloid formation. The binding free energy values of vitamin C and vitamin D3 for E524K FGActer and E526K FGActer are − 67.12 ± 30.46 kJ/mole and − 79.45 ± 26.12 kJ/mol, respectively. Experimental studies using Congo red absorption, aggregation index studies and AFM imaging show encouraging results. The AFM images of E526K FGActer contained more extensive and higher protofibril aggregates, whereas, in the presence of vitamin D3, small monomeric and oligomeric aggregates were observed. Overall, the works provide interesting results about vitamin C and D role in preventing renal amyloidosis. [Display omitted] • We propose dietary management and therapeutic potential of Vitamin C and Vitamin D3 in cases of FGA renal amyloidosis. • Both Vitamin C and Vitamin D3 has potential to interact C-terminal fragment of FGA mutants (E524K and E526K). • Aggregation index, Congo red absorbance and AFM analysis confirms potential anti-aggregation capacity of these metabolites. • This work opens new areas of potential research into anti-amyloidogenic effects of selective endogenous metabolites. [ABSTRACT FROM AUTHOR]

Posttraumatic stress disorder (PTSD) is a chronic and debilitating psychiatric disorder afflicting millions of individuals across the world. While the availability of robust pharmacologic interventions is quite lacking, our understanding of the putative neurobiological underpinnings of PTSD has significantly increased over the past two decades. Accumulating evidence demonstrates aberrant glutamatergic function in mood, anxiety, and trauma-related disorders and dysfunction in glutamate neurotransmission is increasingly considered a cardinal feature of stress-related psychiatric disorders including PTSD. As part of a PTSD Special Issue, this mini-review provides a concise discussion of (1) evidence of glutamatergic abnormalities in PTSD, with emphasis on human subjects data; (2) glutamate-modulating agents as potential alternative pharmacologic treatments for PTSD; and (3) selected gaps in the literature and related future directions. [ABSTRACT FROM AUTHOR]

Background: Preclinical studies demonstrate poly(ADP-ribose) polymerase (PARP) inhibition augments apoptotic response and sensitizes cervical cancer cells to the effects of cisplatin. Given the use of cisplatin and paclitaxel as first-line treatment for persistent or recurrent cervical cancer, we aimed to estimate the maximum tolerated dose (MTD) of the PARP inhibitor veliparib when added to chemotherapy. Patients and methods: Women with persistent or recurrent cervical carcinoma not amenable to curative therapy were enrolled. Patients had to have received concurrent chemotherapy and radiation as well as possible consolidation chemotherapy; have adequate organ function. The trial utilized a standard 3+3 phase I dose escalation with patients receiving paclitaxel 175mg/m2 on day 1, cisplatin 50mg/m2 on day 2, and escalating doses of veliparib ranging from 50 to 400mg orally two times daily on days 1-7. Cycles occurred every 21 days until progression. Dose-limiting toxicities (DLTs) were assessed at first cycle. Fanconi anemia complementation group D2 (FANCD2) foci was evaluated in tissue specimens as a biomarker of response. Results: Thirty-four patients received treatment. DLTs (n=1) were a grade 4 dyspnea, a grade 3 neutropenia lasting≥3 weeks, and febrile neutropenia. At 400mg dose level (DL), one of the six patients had a DLT, so the MTD was not reached. Across DLs, the objective response rate (RR) for 29 patients with measurable disease was 34% [95% confidence interval (CI), 20%-53%]; at 400mg DL, the RR was 60% (n=3/5; 95% CI, 23%-88%). Median progression-free survival was 6.2 months (95% CI, 2.9-10.1), and overall survival was 14.5 months (95% CI, 8.2-19.4). FANCD2 foci was negative or heterogeneous in 31% of patients and present in 69%. Objective RR were not associated with FANCD2 foci (P=0.53). Conclusions: Combining veliparib with paclitaxel and cisplatin as first-line treatment for persistent or recurrent cervical cancer patients is safe and feasible. [ABSTRACT FROM AUTHOR]

Resistance to first-line chemotherapies like gemcitabine contributes to high disease lethality in pancreatic cancer. By microarray and qRT-PCR, we observed significant downregulation of microRNA-210 in gemcitabine-resistant cells. The overexpression of microRNA-210 was toxic to gemcitabine-resistant cells and enhanced gemcitabine sensitivity. MicroRNA-210 overexpression induced caspase-3-mediated apoptosis, and inhibited colony formation. Computationally, ABCC5, a highly expressed gene in our array data, was identified as a potential target of microRNA-210 and the overexpression of ABCC5 in gemcitabine-resistant cells was confirmed by qRT-PCR. MicroRNA-210 overexpression reduced ABCC5 mRNA levels and inhibited a luciferase reporter expressing the ABCC5 3' UTR. The expression pattern of microRNA-210 and ABCC5 was mirrored in all of 5 pancreatic cancer cell lines used. Likewise, microRNA-210 transfection nearly totally inhibited tumor xenograft growth, proliferation and metastasis without obvious side effects in vivo. Also, an absence or low expression of microRNA-210 correlated to high ABCC5 expression in the majority of malignant patient tissues from a total of 101 patient tissues examined. Our observations provide at first glance, an important function for microRNA-210 in regulation of gemcitabine responsiveness by it's target gene ABCC5. [ABSTRACT FROM AUTHOR]

Advances in the management of Hodgkin lymphoma in children, adolescents and young adult have resulted in survival outcomes exceeding 90%. The risk of late toxicity, however, remains a significant concern for survivors of HL and the focus of modern trials have been to advance cure rates while reducing long term toxicity. This has been accomplished through response-adapted treatment approaches and the incorporation of novel agents, many of which target the unique interaction between the Hodgkin and Reed Sternberg cells and the tumor microenvironment. In addition, an improved understanding of prognostic markers, risk stratification, and the biology of this entity in children and AYAs may allow us to further tailor therapy. This review focuses on the current management of HL in the upfront and relapsed settings, recent advances in novel agents that target HL and the tumor microenvironment, and promising prognostic markers that may help guide the future management of HL. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus is and continues to be a leading cause of bacterial infections throughout the world. Given the global dissemination of multi-drug resistant (MDR) S. aureus , particularly methicillin-resistant S. aureus (MRSA), novel solutions against S. aureus infections are urgently needed. In our study on the interactions between commonly used photosensitizers and antibiotics in the clinic, we discovered that MRSA can be dramatically destroyed by a simple combination of amoxicillin and light-activated methylene blue (MB). To guide the clinical application of this combination therapy, we quantitatively assessed the interaction between light-activated MB and amoxicillin against S. aureus and its treatment order, dosage, and time length dependence. Furthermore, we evaluated the efficacy of this combination therapy in treating and halting the progression of MRSA infections with the catheter biofilm infection model and the pig skin burn infection model. In the end, we disclosed the antimicrobial mechanisms of this combination therapy to further facilitate its clinical translation. Amoxicillin and light-activated MB can mutually boost each other's uptake in S. aureus , producing up to 8 logs of reduction of MRSA infections when they are co-administrated. Such an anti- S. aureus synergy could be triggered with the currently used MB and amoxicillin clinical administration regimens. It is effective against S. aureus pathogens regardless of their antibiotic resistance backgrounds and does not create significant bacterial resistance with five days of continuous applications. It can lead to more than 99% of reduction of S. aureus infections established not only on the medical devices but also on the body surfaces. Possessing a fusion of effectiveness, safety, sustainability, and broad applicability, this simple combination of light-activated MB and amoxicillin can ultimately reform our treatment against MDR S. aureus pathogens including MRSA, significantly alleviating the health and economic burden of S. aureus infections across the world. • Light-activated MB synergizes with amoxicillin in the killing of S. aureus. • This anti- S. aureus synergism remains effective in multidrug resistant S. aureus. • Medical device sanitation by combing light-activated MB and amoxicillin. • Body surface infection control by combing light-activated MB and amoxicillin. • Amoxicillin and light-activated MB mutually boost each other's uptake in S. aureus. [ABSTRACT FROM AUTHOR]

Leukemia is a cancer of the white blood cells, with over 54,000 new cases per year diagnosed worldwide and a 5-year survival rate below 60%. This highlights a need for research into the mechanisms behind its etiology and causes of therapy failure. The bone marrow microenvironment, in which adult stem cells are maintained in healthy individuals, has been implicated as a source of chemoresistance and disease relapse. Here the various ways that the microenvironment can contribute to the resistance and persistence of leukemia are discussed. The targeting of the microenvironment by leukemia cells to create an environment more suitable for cancer progression is described. The role of soluble factors, drug transporters, microvesicles, as well as the importance of direct cell–cell contact, in addition to the effects of inflammation and immune surveillance in microenvironment-mediated drug resistance are discussed. An overview of the clinical potential of translating research findings to patients is also provided. Understanding of and further research into the role of the bone marrow microenvironment in leukemia progression and relapse are crucial towards developing more effective treatments and reduction in patient morbidity. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza. [ABSTRACT FROM AUTHOR]

Recurrent implantation failure is a challenging clinical dilemma, without consensus diagnostic criteria. Current evidence provides a starting point for clinical investigation and treatment, while novel therapeutics are being investigated. Ultimately, a consensus diagnosis is needed to inform clinical management and future investigation. [ABSTRACT FROM AUTHOR]

Despite the large number of novel therapies under basic scientific investigation, the translation of cardioprotective strategies targeting reperfusion injury to improve patient outcomes following percutaneous coronary intervention (PCI) for myocardial infarction (MI) has been disappointing. The varying susceptibility of an individual to reperfusion injury, as well as the narrow window of opportunity in which to intervene, adds significant complexity. Here, we discuss the unmet need and challenges of translating cardioprotective strategies into clinical practice, review the pathophysiology of microvascular dysfunction and lethal reperfusion as they relate to promising novel therapeutics, and evaluate recent and ongoing clinical trials in the field. [ABSTRACT FROM AUTHOR]

Although both surgery and radiation are potential curative options for men with clinically localized prostate cancer, a significant proportion of men with high-risk and locally advanced disease will demonstrate biochemical and potentially clinical progression of their disease. Neoadjuvant systemic therapy before radical prostatectomy (RP) is a logical strategy to improve treatment outcomes for men with clinically localized high-risk prostate cancer. Furthermore, delivery of chemotherapy and other systemic agents before RP affords an opportunity to explore the efficacy of these agents with pathologic end points. Neoadjuvant chemotherapy, primarily with docetaxel (with or without androgen deprivation therapy), has demonstrated feasibility and safety in men undergoing RP, but no study to date has established the efficacy of neoadjuvant chemotherapy or neoadjuvant chemohormonal therapies. Other novel agents, such as those targeting the vascular endothelial growth factor receptor, epidermal growth factor receptor, platelet-derived growth factor receptor, clusterin, and immunomodulatory therapeutics, are currently under investigation. [ABSTRACT FROM AUTHOR]

Abstract: Prostate cancer is the most common malignancy in Western Europe, of which approximately 10–20% presents with advanced or metastatic disease. Initial response with androgen deprivation therapy is almost universal, but progression to castration resistant prostate cancer (CRPC), an incurable disease, occurs in approximately 2–3years. In recent years, the novel taxane cabazitaxel, the hormonal agents abiraterone and enzalutamide, the immunotherapeutic agent sipuleucel-T and the radiopharmaceutical radium-223 have been shown to prolong survival in large randomised trials, thus widely increasing the therapeutic armamentarium against the disease. Despite these advances, the median survival in the first-line setting of metastatic castration-resistant prostate cancer (mCRPC) is still up to 25months and in the post-docetaxel setting is about 15–18months. There is an urgent need for the development of biomarkers of treatment response, and for a deeper understanding of tumour heterogeneity and the molecular biology underlying the disease. In this review, we attempt to provide insight into the novel molecular targets showing promise in clinical trials. [Copyright &y& Elsevier]

Summary: Mounting evidence from human, animal, and in vitro studies indicates that existing drugs, developed to treat other disorders, also might be effective in preventing or slowing the progression of diabetic nephropathy to end-stage renal disease. Examples of such drugs include the urate-lowering agent allopurinol, the anti–tumor necrosis factor agents etanercept and infliximab, and the immunomodulating drug abatacept. Because some of these medications are already on the market and have been used for a number of years for other indications, they can be tested immediately in human beings for a beneficial effect on renal function in diabetes. Special emphasis should be placed on evaluating the use of these drugs early in the course of diabetic nephropathy when renal damage is most likely to be reversible and interventions can yield the greatest delay to end-stage renal disease. [ABSTRACT FROM AUTHOR]

Abstract: The amplified myeloma centrosome has been identified as a therapeutic target. The present study explored the expression and prognostic significance of the centrosome-associated protein PLK1 in myeloma and the effect of BI 2536, a potent and selective inhibitor of PLK1, on myeloma cells. High plasma cell expression of PLK1 protein in myeloma patient bone marrow biopsies is an independent adverse prognostic factor (HR=2.3, p =0.003 unadjusted; HR=1.9, p =0.03 in multivariable model). BI 2536 inhibits myeloma cell lines at nanomolar concentrations, and is therapeutic for xenografts in NOD/SCID mice. PLK1 inhibition is a potential new strategy for the treatment of multiple myeloma. [Copyright &y& Elsevier]

Abstract: The need for novel anti-inflammatory drugs justifies the search for innovative targets that could satisfy this goal. For quite some time now, we have proposed the study of endogenous anti-inflammation as a distinctive approach to the discovery of new drugs. This approach requires development of new compounds that activate specific receptor targets to downregulate the cellular and tissue pathways operative in the host during inflammation. Here we dwell on a family of G-protein coupled receptors (GPCR) termed FPRs, acronym for formyl-peptide receptors. With three and seven members in man and mouse, respectively, these receptors harness many biological functions, spanning odour perception and hair growth, to the control of multiple facets (pain; cell migration; oxidative burst; xenobiotic engulfment) of the inflammatory reaction. We focus on FPR biology with particular attention to molecules able to produce pharmacological effects by interacting with these GPCRs, describing endogenous agonists of FPRs and, more relevantly, the current development of synthetic agonists. Besides being potential leads for the development of the anti-inflammatory therapeutics of the future, these compounds could also help clarify the properties and roles that each FPR might play in the complex network of pathways that is inflammation. We conclude that FPR2 agonists could be valid warhorses for defining a novel philosophy for anti-inflammatory drug discovery programmes: mimicking – with new compounds – the way our body disposes of inflammation could be a viable approach to regulate aberrant inflammatory responses as in the case of several chronic rheumatic and cardiovascular pathologies. [Copyright &y& Elsevier]

Abstract: Objectives: Review treatment of NMIBC, particularly intermediate-risk NMIBC. Methods: Search of published literature on conventional adjuvant treatment of low-, intermediate-, and high-risk NMIBC, and novel treatment modalities. Results: A considerable percentage of patients with intermediate-risk NMIBC, and especially high-risk NMIBC, are at risk of disease recurrence and progression. Of currently used adjuvant therapies, chemotherapy and especially immunotherapy are effective in reducing the risk of recurrence in the short term, but are suboptimal in the long term. In contrast to chemotherapy, BCG slightly decreases the risk of progression in patients with high-risk tumours. New agents, like gemcitabine and apaziquone, and device-assisted therapies, like thermochemotherapy and EMDA, are promising, but need further evidence on long-term efficacy. Conclusions: There still is a clear need for novel or improved adjuvant treatment modalities for patients with NMIBC. These modalities should be able to better reduce the risk of recurrence of NMIBC and progression to muscle-invasive disease, so as to reduce disease burden, preserve a patient''s bladder, and improve disease-specific survival. [Copyright &y& Elsevier]

Abstract: Experimental mouse allergic asthma is a reliable, clinically relevant facsimile of human disease. The focus here is to demonstrate that antigen-induced mouse allergic asthma is a useful model for testing novel therapeutics. Furthermore, it is especially crucial to treat mice during established disease, either during ongoing clinically manifest disease or to prevent disease relapses. In addition, our results indicate that lung Th2 resting memory cells are important targets for the treatment of allergic asthma. [Copyright &y& Elsevier]

New drug approvals now afford AML physicians a wider choice of initial treatment options than ever before. Although chemotherapy for AML is by no means ready to be replaced entirely by novel agents, the role of traditional cytotoxics in AML therapy is rapidly changing. In particular, biologically targeted agents such as the BCL2 inhibitor venetoclax and inhibitors of FLT3 and IDH mutations stand out as drugs likely to take AML therapy in important new directions. Maximum response and survival benefits likely require combinations of novel agents and chemotherapy or multiple novel agents together. The recently-published phase 3 VIALE-A study demonstrates a very successful example of a new combination approach, which led to venetoclax plus azacitidine establishing itself as the new standard of care for patients unfit for intensive chemotherapy. One could reasonably expect other subsets of AML to benefit from this regimen or other applications of venetoclax combinations. Building on this experience, venetoclax-based regimens also have the potential to replace standard intensive cytarabine/anthracycline "7&3" induction approach for some if not many patients who are fit for induction. This review will describe novel agents with the greatest potential for impactful frontline applications that will change the AML treatment paradigm. [ABSTRACT FROM AUTHOR]

Abstract: Recent advances behind the understanding of the molecular mechanisms of bladder tumorigenesis have contributed towards the identification of molecules that can act as potential therapeutic targets for novel agents. Concurrently, this has also led to the understanding that effective therapy for superficial and invasive bladder cancers will entail a combination of therapeutic agents that target multiple tumorigenic pathways. Management of bladder cancer patients, as is the case in many other solid tumors, may witness radical transformations in the coming years as we translate our molecular understanding of the disease into novel clinical trial designs and screening techniques. [Copyright &y& Elsevier]

ETV6 (translocation-Ets-leukemia virus) gene is a transcriptional repressor mainly involved in haematopoiesis and maintenance of vascular networks and has developed to be a major oncogene with the potential ability of forming fusion partners with many other genes with carcinogenic consequences. ETV6 fusions function primarily by constitutive activation of kinase activity of the fusion partners, modifications in the normal functions of ETV6 transcription factor, loss of function of ETV6 or the partner gene and activation of a proto-oncogene near the site of translocation. The role of ETV6 fusion gene in tumorigenesis has been well-documented and more variedly found in haematological malignancies. However, the role of the ETV6 oncogene in solid tumors has also risen to prominence due to an increasing number of cases being reported with this malignancy. Since, solid tumors can be well-targeted, the diagnosis of this genre of tumors based on ETV6 malignancy is of crucial importance for treatment. This review highlights the important ETV6 associated fusions in solid tumors along with critical insights as to existing and novel means of targeting it. A consolidation of novel therapies such as immune, gene, RNAi, stem cell therapy and protein degradation hitherto unused in the case of ETV6 solid tumor malignancies may open further therapeutic avenues. Unlabelled Image • ETV6 gene has the potential to form fusion partners with several genes with carcinogenic consequences. • Fusion genes are significant as they often are the driver mutations and are easily targetable, being organ specific. • ETV6 gene aberrations have long been studied in haematological cancers, but they also play a major role in solid tumors. • New therapeutic avenues need to be found to target fusion genes along with advanced detection techniques. [ABSTRACT FROM AUTHOR]