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Summary: The treatment landscape of acute myeloid leukaemia (AML) is evolving rapidly. Venetoclax in combination with intensive chemotherapy or doublets or triplets with targeted or immune therapies is the focus of numerous ongoing trials. The development of mutation‐targeted therapies has greatly enhanced the treatment armamentarium, with FLT3 inhibitors and isocitrate dehydrogenase inhibitors improving outcomes in frontline and relapsed/refractory (RR) AML, and menin inhibitors showing efficacy in RR NPM1mut and KMT2A‐rearranged AML. With so many new drugs approved, the number of potential combinatorial approaches to leverage the maximal benefit of these agents has increased dramatically, while at the same time introducing clinical challenges, such as key preclinical and clinical data supporting the development of combinatorial therapy, how to optimally combine or sequence these novel agents, how to optimise dose and duration to maintain safety while enhancing efficacy, the optimal duration of therapy and the role of measurable residual disease in decision‐making in both intensive and low‐intensity therapy settings. In this review, we will outline the evidence leading to the approval of key agents in AML, their on‐label current approvals and how they may be optimally combined in a safe and deliverable fashion to further improve outcomes in AML. [ABSTRACT FROM AUTHOR]

Nonprogrammed cell death (NPCD) and programmed cell death (PCD) are two types of cell death. Cell death is significantly linked to tumor development, medication resistance, cancer recurrence, and metastatic dissemination. Therefore, a comprehensive understanding of cell death is essential for the treatment of cancer. Pyroptosis is a kind of PCD distinct from autophagy and apoptosis in terms of the structure and function of cells. The defining features of pyroptosis include the release of an inflammatory cascade reaction and the expulsion of lysosomes, inflammatory mediators, and other cellular substances from within the cell. Additionally, it displays variations in osmotic pressure both within and outside the cell. Pyroptosis, as evidenced by a growing body of research, is critical for controlling the development of inflammatory diseases and cancer. In this paper, we reviewed the current level of knowledge on the mechanism of pyroptosis and inflammasomes and their connection to cancer and inflammatory diseases. This article presents a theoretical framework for investigating the potential of therapeutic targets in cancer and inflammatory diseases, overcoming medication resistance, establishing nanomedicines associated with pyroptosis, and developing risk prediction models in refractory cancer. Given the link between pyroptosis and the emergence of cancer and inflammatory diseases, pyroptosis‐targeted treatments may be a cutting‐edge treatment strategy. [ABSTRACT FROM AUTHOR]

Summary: For chronic lymphocytic leukaemia (CLL), targeted drugs have become the standard of care, in particular for second‐line treatment. In this study, overall survival (OS), treatment‐free survival (TFS) and adverse events (AE) were registered retrospectively in a Danish population‐based cohort upon second‐line treatment for CLL. Data were collected from medical records and the Danish National CLL register. For 286 patients receiving second‐line treatment, three‐year TFS was higher upon targeted treatment (ibrutinib/venetoclax/idelalisib) [63%, 95% confidence interval (CI) 50%–76%] compared with fludarabine, cyclophosphamide and rituximab or bendamustine and rituximab (FCR/BR) (37%, CI: 26%–48%) and chlorambucil+/−CD20‐antibody (CD20Clb/Clb) (22%, CI: 10%–33%). Upon targeted treatment, three‐year OS estimates were higher for targeted treatment (79%, CI: 68%–91%) compared with FCR/BR (70%, CI: 60%–81%) or CD20Clb/Clb (60%, CI: 47%–74%). The most common AEs were infections and haematological AEs; 92% of patients treated with targeted drugs had AEs, 53% of which were severe. Upon FCR/BR and CD20Clb/Clb, AEs were present for 75% and 53% respectively, of which 63% and 31% were severe. These real‐world data demonstrate higher TFS and a tendency towards higher OS following targeted second‐line treatment for CLL compared to chemoimmunotherapy, also for patients who may be frailer and more comorbid. [ABSTRACT FROM AUTHOR]

Background: Ameloblastoma may present a significant treatment challenge in the locally advanced, recurrent and metastatic setting. Comprehensive genomic profiling (CGP) can identify targetable genomic alterations to aid in treatment. Methods: Ameloblastoma samples were sequenced using hybrid‐capture based sequencing. A systematic literature review was performed to examine outcomes in studies employing targeted treatment in ameloblastoma. Results: We reviewed 14 cases of Ameloblastoma using CGP. There were six patients with activating BRAF mutations, five with PIK3CA, five with SMO, four with FGFR2, one with EGFR, and one with ROS1. All cases were MSI stable and the median TMB was 2.5 mutations/Mb. A separate literature review of clinical outcomes in ameloblastoma showed a predominance of at least partial response to targeted treatment (7/12 cases). Conclusion: CGP is helpful in identifying specific driver mutations in patients with complex ameloblastoma. Targeted treatment has been employed with success in achieving treatment response. [ABSTRACT FROM AUTHOR]

Triple‐negative breast cancer (TNBC) remains a major challenge in breast cancer management. Continuing research in the past years aimed at understanding the biology of this tumour and developing more effective therapeutic options. It is now clear that TNBC is vastly heterogeneous with diverse histological, molecular, immunological profiles and clinical differences. Current evidence suggested the existence of at least four predominant subtypes based on expression profiling across studies. These subtypes exhibited specific genomic alterations and tumour microenvironment. Subtype‐specific therapeutic strategies were identified. Recognising these subtypes allows not only an improved prognostication but also a better treatment decision. Herein, we provide an overview of the recent findings on TNBC heterogeneity at different levels and corresponding subtyping. The characteristic of subtypes and the implication of these subtypings in therapeutic approaches are also discussed. [ABSTRACT FROM AUTHOR]

Adrenocortical carcinoma (ACC) is a rare, aggressive cancer with still partially unknown pathogenesis, heterogenous clinical behaviour and no effective treatment for advanced stages. Therefore, there is an urgent clinical unmet need for better prognostication strategies, innovative therapies and significant improvement of the management of the individual patients. In this review, we summarize available studies on molecular prognostic markers and markers predictive of response to standard therapies as well as newly proposed drug targets in sporadic ACC. We include in vitro studies and available clinical trials, focusing on alterations at the DNA, RNA and epigenetic levels. We also discuss the potential of biomarkers to be implemented in a clinical routine workflow for improved ACC patient care. [ABSTRACT FROM AUTHOR]

Background: Idiopathic mast cell activation syndrome (MCAS) is characterized by three diagnostic criteria: (1) episodic mast cell (MC)‐driven signs/symptoms of at least two organ systems in the absence of clonal MC expansion and definite triggers, (2) episodic increase in tryptase, and (3) response to MC‐targeted treatment. Many patients believe they have MCAS, but how often this is the case remains unknown. Methods: We prospectively investigated patients with suspected MCAS (n = 100) for the diagnostic criteria including baseline tryptase, KIT D816V mutation, and patient‐reported outcome measures (PROMs) over the course of 12 weeks. Comorbid depression and anxiety were explored with the Hospital Anxiety and Depression Scale (HADS). Results: In 53% of our patients (80% females), suspicion of MCAS was based on self‐evaluation. In total, patients reported 87 different symptoms, mostly fatigue (n = 57), musculoskeletal pain/weakness (n = 49), and abdominal pain (n = 43), with overall high disease activity and impact. Two of 79 patients had increased tryptase (by >20% +2 ng/ml) following an episode. Only 5%, with any of the PROMs used, showed complete response to MC‐targeted treatment. Depression and anxiety disorders were frequent comorbidities (n = 23 each), and 65 patients had pathological HADS values, which were linked to high disease impact and poor symptom control. Conclusion: Mast cell activation syndrome was confirmed in only 2% of patients, which implies that it is not MC activation that drives signs and symptoms in most patients with suspected MCAS. There is a high need for comprehensive research efforts aimed at the identification of the true underlying pathomechanism(s) in patients with suspected MCAS. [ABSTRACT FROM AUTHOR]

In this study, the development of polydopamine nanoparticle (p‐Dop NP) as a drug carrier system for saponin (Sap) and its use in in vitro targeted cancer therapy was investigated. The average diameter of p‐Dop NP was found as 130 nm with a zeta potential of −18 mV and demonstrated high stability even after 6 weeks. The Sap release and cytotoxicity studies were carried out to reveal the effectiveness of the proposed carrier system. The offered approach demonstrated a high loading capacity of Sap as 81% with a sustainable and controlled release of 75%. To prevent the interaction of the anti‐cancer Sap with other healthy tissue and to enhance the targeting of DLD‐1 cells, anti‐GPA33 was immobilized onto the nanoparticle surface via carbodiimide strategy. The anti‐GPA33 and Sap loaded p‐Dop NPs demonstrated enhanced toxicity and cellular uptake compared to untargeted Sap loaded NPs as expected. The offered carrier system revealed simple and efficient targeted cancer therapy ability in vitro and may provide new ideas for the design of targeted delivery systems in the future. [ABSTRACT FROM AUTHOR]

Inborn errors of immunity consist of over 400 known single gene disorders that may manifest with infection susceptibility, autoimmunity, autoinflammation, hypersensitivity and cancer predisposition. Most patients are treated symptomatically with immunoglobulin replacement, prophylactic antimicrobials or broad immunosuppression pertaining to their disease phenotype. Other than haematopoietic stem cell transplantation, the aforementioned treatments do little to alter disease morbidity or mortality. Further, many patients may not be transplant candidates. In this review, we describe monogenic disorders affecting leucocyte migration, disorders of immune synapse formation and dysregulation of immune cell signal transduction. We highlight the use of off‐label small molecules and biologics mechanistically targeted to altered disease pathophysiology of such diseases. [ABSTRACT FROM AUTHOR]

Background: The development of systemic treatment options leveraging the molecular landscape of advanced thyroid cancer is a burgeoning field. This is a multidisciplinary evidence‐based statement on the definition of advanced thyroid cancer and its targeted systemic treatment. Methods: An expert panel was assembled, a literature review was conducted, and best practice statements were developed. The modified Delphi method was applied to assess the degree of consensus for the statements developed by the author panel. Results: A review of the current understanding of thyroid oncogenesis at a molecular level is presented and characteristics of advanced thyroid cancer are defined. Twenty statements in topics including the multidisciplinary management, molecular evaluation, and targeted systemic treatment of advanced thyroid cancer are provided. Conclusions: With the growth in targeted treatment options for thyroid cancer, a consensus definition of advanced disease and statements regarding the utility of molecular testing and available targeted systemic therapy is warranted. [ABSTRACT FROM AUTHOR]

Current paradigms in emerging treatments encourage clinicians in a position to choose promising, yet unproven, therapies for patients with a lethal disease. This article characterizes the challenge facing clinicians involved in ongoing research and clinical practice, while considering the ethically prescribed path forward. [ABSTRACT FROM AUTHOR]

Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. More than a third of patients do not respond to standard therapy and urgently require alternative treatment options. Due to a high degree of inter‐ and intra‐tumoural genomic heterogeneity and complexity, recurrent molecular alterations that could serve as prognostic predictors or therapeutic targets are still lacking in osteosarcoma. Copy number (CN) gains involving the IGF1R gene, however, have been suggested as a potential surrogate marker for treating a subset of patients with IGF1R inhibitors. In this study, we screened a large set of osteosarcomas and found specific CN gains of the IGF1R gene in 18 of 253 (7.1%) cases with corresponding IGF1R overexpression. Despite the discouraging results observed in clinical trials in other tumours so far, focusing only on selected patients with osteosarcoma that show evidence of IGF pathway activation might represent a promising new and innovative treatment approach. [ABSTRACT FROM AUTHOR]

Cancer is a leading cause of death worldwide. Despite the great advancement in understanding the pharmacology and biology of cancer, it still signifies one of the most serious human‐health related problems. The current treatments for cancer may include surgery, radiotherapy, and chemotherapy, but these procedures have several limitations. Current studies have shown that nanoparticles (NPs) can be used as a novel strategy for cancer treatment. Developing nanosystems that allow lower doses of therapeutic agents, as well as their selective release in tumour cells, may resolve the challenges of targeted cancer therapy. In this review, the authors discuss the role of the size, shape, and surface modifications of NPs in cancer treatment. They also address the challenges associated with cancer therapies based on NPs. The overall purpose of this review is to summarise the recent developments in designing different hybrid NPs with promising therapeutic properties for different types of cancer. [ABSTRACT FROM AUTHOR]

Background: Salivary gland cancers (SGCs) are rare. The approach to metastatic patients is histology‐dependent. There is little evidence on whether next‐generation sequencing (NGS) findings translate to tumor control in SGCs. Methods: We analyzed all patients with histologically confirmed SGC who underwent NGS. Results: Twenty‐seven patients were identified, 14 (51.8%) had targetable findings in NGS: 5 ERBB2 amplifications, 3 PIK3CA mutations, 2 RUNX1 mutations, 1 TRIM33‐RET fusion, 1 FGFR3‐TACC3 fusion, 1 microsatellite instability‐high, and 2 high mutational burden. Ten patients were treated accordingly. Median progression‐free survival for targeted treatment was 8.4 months. Of five patients who achieved durable responses of 8.4 to 31.3 months, two are ongoing. The overall median survival was not reached for patients receiving targeted treatment and was 40.4 months for patients treated conventionally (P =.18). Conclusions: In the absence of a well‐established therapeutic approach, NGS may detect clinically significant genetic alterations and benefit patients with advanced SGC. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Fragile X syndrome (FXS) is a common monogenetic cause of intellectual disability, autism spectrum features, and a broad range of other psychiatric and medical problems. FXS is caused by the lack of the fragile X mental retardation protein (FMRP), a translational regulator of specific mRNAs at the postsynaptic compartment. The absence of FMRP leads to aberrant synaptic plasticity, which is believed to be caused by an imbalance in excitatory and inhibitory network functioning of the synapse. Evidence from studies in mice demonstrates that GABA, the major inhibitory neurotransmitter in the brain, and its receptors, is involved in the pathogenesis of FXS. Moreover, several FXS phenotypes, including social behavior deficits, could be corrected in Fmr1 KO mice after acute treatment with GABAB agonists. Methods: As FXS would probably require a lifelong treatment, we investigated the effect of chronic treatment with the GABAB agonist baclofen on social behavior in Fmr1 KO mice on two behavioral paradigms for social behavior: the automated tube test and the three‐chamber sociability test. Results: Unexpectedly, chronic baclofen treatment resulted in worsening of the FXS phenotypes in these behavior tests. Strikingly, baclofen treatment also affected wild‐type animals in both behavioral tests, inducing a phenotype similar to that of untreated Fmr1 KO mice. Conclusion: Altogether, the disappointing results of recent clinical trials with the R‐baclofen enantiomer arbaclofen and our current results indicate that baclofen should be reconsidered and further evaluated before its application in targeted treatment for FXS. [ABSTRACT FROM AUTHOR]

The introduction of omalizumab to the management of chronic spontaneous urticaria (CSU) has markedly improved the therapeutic possibilities for both, patients and physicians dealing with this disabling disease. But there is still a hard core of patients who do not tolerate or benefit from existing therapies and who require effective treatment. Novel approaches include the use of currently available drugs off-licence, investigational drugs currently undergoing clinical trials and exploring the potential for therapies directed at pathophysiological targets in CSU. Off-licence uses of currently available drugs include rituximab and tumour necrosis factor inhibitors. Ligelizumab (anti-IgE), canakinumab (anti-IL-1), AZD1981 (a PGD2 receptor antagonist) and GSK 2646264 (a selective Syk inhibitor) are currently in clinical trials for CSU. Examples of drugs that could target potential pathophysiological targets in CSU include substance P antagonists, designed ankyrin repeat proteins, C5a/C5a receptor inhibitors, anti-IL-4, anti-IL-5 and anti-IL-13 and drugs that target inhibitory mast cell receptors. Other mediators and receptors of likely pathogenic relevance should be explored in skin profiling and functional proof of concept studies. The exploration of novel therapeutic targets for their role and relevance in CSU should help to achieve a better understanding of its etiopathogenesis. [ABSTRACT FROM AUTHOR]

The introduction of omalizumab to the management of chronic spontaneous urticaria (CSU) has markedly improved the therapeutic possibilities for both, patients and physicians dealing with this disabling disease. But there is still a hard core of patients who do not tolerate or benefit from existing therapies and who require effective treatment. Novel approaches include the use of currently available drugs off‐licence, investigational drugs currently undergoing clinical trials and exploring the potential for therapies directed at pathophysiological targets in CSU. Off‐licence uses of currently available drugs include rituximab and tumour necrosis factor inhibitors. Ligelizumab (anti‐IgE), canakinumab (anti‐IL‐1), AZD1981 (a PGD2 receptor antagonist) and GSK 2646264 (a selective Syk inhibitor) are currently in clinical trials for CSU. Examples of drugs that could target potential pathophysiological targets in CSU include substance P antagonists, designed ankyrin repeat proteins, C5a/C5a receptor inhibitors, anti‐IL‐4, anti‐IL‐5 and anti‐IL‐13 and drugs that target inhibitory mast cell receptors. Other mediators and receptors of likely pathogenic relevance should be explored in skin profiling and functional proof of concept studies. The exploration of novel therapeutic targets for their role and relevance in CSU should help to achieve a better understanding of its etiopathogenesis. [ABSTRACT FROM AUTHOR]

Quantum advances have occurred in the field of human genetics in the six decades since Watson and Crick expressed their 'wish to suggest a structure for the salt of deoxyribose nucleic acid.' These culminated with the human genome project, which has opened up myriad possibilities, including that of individualized genetic medicine, the ability to deliver medical advice, management, and therapy tailored to an individual's genetic blueprint. Advances in genetic diagnostic capabilities have been rapid, to the point where the genome can be sequenced for several thousand dollars. Crucially, it has facilitated the identification of targets for 'precision' treatments to combat genetic diseases at their source. This manuscript will review the innovative, pathogenesis-based therapies that are revolutionizing management of skeletal dysplasias, giving patients and families new options and outcomes. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

HOX genes are vital for all aspects of mammalian growth and differentiation, and their dysregulated expression is related to ovarian carcinogenesis. The aim of the current study was to establish the prognostic value of HOX dysregulation as well as its role in platinum resistance. The potential to target HOX proteins through the HOX/PBX interaction was also explored in the context of platinum resistance. HOX gene expression was determined in ovarian cancer cell lines and primary EOCs by QPCR, and compared to expression in normal ovarian epithelium and fallopian tube tissue samples. Statistical analysis included one-way ANOVA and t-tests, using statistical software R and GraphPad. The analysis identified 36 of the 39 HOX genes as being overexpressed in high grade serous EOC compared to normal tissue. We detected a molecular HOX gene-signature that predicted poor outcome. Overexpression of HOXB4 and HOXB9 was identified in high grade serous cell lines after platinum resistance developed. Targeting the HOX/PBX dimer with the HXR9 peptide enhanced the cytotoxicity of cisplatin in platinum-resistant ovarian cancer. In conclusion, this study has shown the HOX genes are highly dysregulated in ovarian cancer with high expression of HOXA13, B6, C13, D1 and D13 being predictive of poor clinical outcome. Targeting the HOX/PBX dimer in platinum-resistant cancer represents a potentially new therapeutic option that should be further developed and tested in clinical trials. [ABSTRACT FROM AUTHOR]

BACKGROUND Targeting a single pathway in pancreatic adenocarcinoma (PC) is unlikely to affect its natural history. We tested the hypothesis that simulataneous targeting of the epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor-1 (IGF-1R) pathways would significantly improve progression-free survival (PFS) by abrogating reciprocal signaling that promote drug resistance METHODS This was a phase Ib/II study testing cixutumumab, combined with erlotinib and gemcitabine (G) in patients with untreated metastatic PC. The control arm was erlotinib plus G. The primary end point was PFS. Eligibility included performance status 0/1 and normal fasting blood glucose. Polymorphisms in genes involved in G metabolism and in the EGFR pathway were also studied RESULTS The phase I results (n = 10) established the safety of cixutumumab 6 mg/kg/week intravenously, erlotinib 100 mg/day orally, and G 1000 mg/m2 intravenously on days 1, 8, and 15 of a 28-day cycle. In the RP2 portion (116 eligible patients; median age, 63), the median PFS and overall survival (OS) were 3.6 and 7.0 months, respectively, on the cixutumumab arm, and 3.6 and 6.7 months, respecively, on the control arm. Major grades 3 and 4 toxicities with cixutumumab and control were elevation of transaminases, 12% and 6%, respectively; fatigue, 16% and 12%, respectively; gastrointestinal, 35% and 28%, respectively; neutropenia, 21% and 10%, respectively; and thrombocytopenia, 16% and 7%, respecively. Grade 3/4 hyperglycemia was seen in 16% of patients on cixutumumab. Grade 3 or 4 skin toxicity was similar in both arms of the study (< 5%). No significant differences in PFS by genotype were seen for any of the polymorphisms. CONCLUSIONS Adding the IGF-1R inhibitor cixutumumab to erlotinib and G did not lead to longer PFS or OS in metastatic PC. Cancer 2014;120:2980-2985. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

Improvements in cancer genomics and tumor biology have reinforced the evidence of cancer development driven by numerous genomic alterations. Advanced genomics technology can be used to characterize genomic alterations that potentially drive tumor growth. With the possibility of screening thousands of genes simultaneously, personalized molecular medicine has become an option. New treatments are being investigated in phase 1 trials around the world. Traditionally, the goal of phase 1 studies was to determine the optimal dose and assess dose-limiting toxicity of a potential new experimental drug. Only a limited number of patients will benefit from the treatment. However, introducing genomic mapping to select patients for early clinical trials with targeted molecular therapy according to the genomic findings, may lead to a better outcome for the patient, an enrichment of phase 1 trials, and thereby accelerated drug development. The overall advantage is to determine which mutation profiles correlate with sensitivity or lack of resistance to specific targeted therapies. The utility and current limitations of genomic screening to guide selection to Phase 1 clinical trial will be discussed. [ABSTRACT FROM AUTHOR]

Equine gastrointestinal nematodes are ubiquitous; in horses that graze contaminated pasture and that are not treated appropriately, large numbers of worms can accumulate, which can lead to serious clinical disease. Nematode control has traditionally followed interval treatment regimens, which involve regular anthelmintic administration to all horses based on the strongyle egg reappearance periods of each drug, usually defined around the time of licensing. Interval treatment programmes have resulted in substantial reductions in large strongyle disease, but have made major contributions to the development of anthelmintic resistance, particularly in cyathostomins. Cyathostomin resistance to 2 of the 3 available anthelmintic classes is widespread, and resistance to both classes in single populations is not uncommon. Reduced efficacy of the most commonly used macrocyclic lactone anthelmintics, as measured by shortened egg reappearance periods after treatment, is emerging in cyathostomins. Macrocyclic lactone resistance is also now commonly reported in Parascaris equorum on stud farms. Faecal worm egg counts ( FWEC) are increasingly being used as part of targeted approaches to parasite control, whereby only those horses with moderate to high FWEC within a group are treated with an anthelmintic. The objective of this approach is to reduce environmental contamination, while leaving a proportion of the worm population in some horses unexposed to selection pressure for anthelmintic resistance. This article reviews recent findings in equine parasitology research that will underpin guidelines for control, with a particular focus on how to optimise the value of FWEC methodologies and anthelmintic efficacy analyses. [ABSTRACT FROM AUTHOR]

Aims: Insulin-like growth factor receptor-1 (IGFR-1) and its signalling axis promote tumorigenesis, metastasis, and resistance to existing forms of cancer therapy, and have become a major focus for the development of anticancer drugs. As oncological management options for triple-negative breast cancers (TNBCs) are limited, there is potential for the rapid development of novel selective anticancer agents specifically targeting components of the PTEN-phospholinositide 3-kinase-AKT pathway, including the phosphorylated form of AKT (pAKT) and the tumour suppressor molecule PTEN. The aim of this study was to conduct immunohistochemical analyses to examine the levels of PTEN, IGFR-1 and pAKT expression in TNBCs, and determine whether these levels correlated with poor prognosis in this subset of aggressive breast cancers. Methods and results: Immunohistochemistry was performed on paraffin-embedded tumour tissues from a consecutive cohort of 144 female patients diagnosed with TNBC. Associations of IGFR-1, PTEN and pAKT expression with clinicopathological parameters, disease-free survival (DFS) and overall survival (OS) were evaluated. There were significant increases in IGFR-1 expression (99%) and pAKT expression (92%) with concomitant loss of PTEN expression in the majority of cases (63%). Increased IGFR-1 expression and loss of PTEN expression were associated with reduced OS and DFS, respectively. pAKT expression showed a strong correlation with basal-like expression. Combinatorial immunophenotypic analyses showed that loss of PTBN expression with concomitant IGFR-1 expression correlated with poor DFS. Conclusions: A high percentage of PTEN loss with overexpression of IGFR-1 and pAKT in TNBC indicates the potential of these molecules for predicting early recurrence and/or as targets in the formulation of effective alternative therapy regimens. [ABSTRACT FROM AUTHOR]

Previous studies have shown that about 90% of adult Amblyomma variegatum Fabricius (Acari: Ixodidae) picked up daily by grazing cattle are still attached to the interdigital areas in the evening, when the animals return from pasture. It was therefore postulated that a targeted treatment, designed to kill the ticks attached to the feet, would limit infestation of the predilection sites. Footbaths filled with various pyrethroid formulations were used over 3 years, at the beginning of the rainy season (from mid-May to the end of July), to assess the efficacy of such a control method. It proved efficient in preventing the ticks from attaching to the predilection sites. Although five to 12 A. variegatum adults attached to each treated animal daily, and although the tick burden of the predilection sites of control cattle increased each day by four to 10 ticks, the average infestation of the predilection sites of treated cattle that were initially highly infested (over 100 ticks/animal) continuously decreased to reach a level of about 10–30 ticks/animal after 6–8 weeks of treatment. In herds with a lower initial tick burden (40–70 ticks/animal) this level was obtained within 2–3 weeks and the mean infestation subsequently remained consistently low. Footbath treatment carried out every other day during the adult peak infestation period should therefore greatly limit losses due to ticks. This method was appreciated by traditional livestock farmers, essentially because it is not time-consuming and because it requires only c. 200 mL aqueous formulation per animal at each passage. The cost of the acaricide needed to treat one animal during the peak infestation period was assessed at c. € 0.20. This control method might also have an impact on some species of tsetse flies and mosquitoes, thereby contributing to trypanosomiasis and malaria control. [ABSTRACT FROM AUTHOR]

Biologic medications are systemic therapeutic options for inflammatory dermatoses. Local forms of administration are less well-studied. To provide a summary of intralesional (IL) administration of biologics for various non-malignant inflammatory dermatologic conditions reported in the literature. A systematic review was performed in the PubMed and Embase databases from 2000 to 2020. Inclusion criteria included the local use of biologic medications for non-malignant cutaneous conditions. Quality was assessed with the modified Oxford Centre for Evidence-Based Medicine ratings. A total of 19 articles describing the use of 5 biologic medications in 9 dermatologic conditions were identified, comprising 172 patients. Conditions successfully treated with intralesional biologics included pemphigus vulgaris (rituximab), granuloma faciale (rituximab), perianal Crohn's disease (infliximab), lichen sclerosus (adalimumab), and necrobiosis lipoidica (etanercept and infliximab). Intralesional etanercept reduced pruritus associated with keloids. A case report of the use of infliximab for pyoderma gangrenosum did not demonstrate any efficacy. There was no consistent effect noted with treatments for sarcoidosis (infliximab) or cutaneous lymphoid hyperplasia (rituximab). Local administration of biologic medications may offer an additional method of treating refractory inflammatory dermatoses, but further study is needed to develop standardized dosing protocols, clarify efficacy rates, and identify optimal treatment candidates., (© 2021 Wiley Periodicals LLC.)

Background: The majority of individuals with fragile X syndrome (FXS) have intellectual disability, behavioral problems, autism, and language deficits. IQ typically declines with age in boys with the full mutation. The results of preclinical studies demonstrated that metformin, a biguanide used to treat type 2 diabetes, rescues multiple phenotypes of FXS in both Drosophila and mouse models. Preliminary studies of patients with FXS demonstrated improvements in behavior. Methods: Here, we present two cases of individuals who have been treated with metformin clinically for one year. Results: Both patients demonstrated significant cognitive and behavioral improvements. They also improved eating habits and normalization of their weight percentiles. Conclusion: Metformin may be a candidate drug for treatment of several types of symptoms in individuals with FXS. [ABSTRACT FROM AUTHOR]