Real-time self-regulation of emotion networks in patients with depression

Many patients show no or incomplete responses to current pharmacological or psychological therapies for depression. Here we explored the feasibility of a new brain self-regulation technique that integrates psychological and neurobiological approaches through neurofeedback with functional magnetic resonance imaging (fMRI). In a proof-of-concept study, eight patients with depression learned to upregulate brain areas involved in the generation of positive emotions (such as the ventrolateral prefrontal cortex (VLPFC) and insula) during four neurofeedback sessions. Their clinical symptoms, as assessed with the 17-item Hamilton Rating Scale for Depression (HDRS), improved significantly. A control group that underwent a training procedure with the same cognitive strategies but without neurofeedback did not improve clinically. Randomised blinded clinical trials are now needed to exclude possible placebo effects and to determine whether fMRI-based neurofeedback might become a useful adjunct to current therapies for depression.     

Current strategies for cell delivery in cartilage and bone regeneration

Several cell-based tissue-engineering therapies are emerging to regenerate damaged tissues. These strategies use autologous cells in combination with bioresorbable delivery materials. Major functions of a delivery scaffold are to provide initial mechanical stability, homogenous three-dimensional cell distribution, improved tissue differentiation, suitable handling and properties for delivery and fixation into patients. Delivery of cells can be achieved using injectable matrices, soft scaffolds, membranes, solid load-bearing scaffolds or immunoprotective macroencapsulation. Thus, to expand the clinical potential, next generation therapies will depend on smart delivery concepts that make use of the regenerative potential of stem cells, morphogenetic growth factors and biomimetic materials.     

Endpoints,patient selection,and biomarkers in the design of clinical trials for cancer vaccines

Therapeutic cancer vaccines are an emerging and potentially effective treatment modality. Cancer vaccines are usually very well tolerated, with minimal toxicity compared with chemotherapy. Unlike conventional cytotoxic therapies, immunotherapy does not result in immediate tumor shrinkage but may alter growth rate and thus prolong survival. Multiple randomized controlled trials of various immunotherapeutic agents have shown a delayed separation in Kaplan–Meier survival curves, with no evidence of clinical benefit within the first 6–12 months of vaccine treatment. Overall survival benefit is seen in patients with lower disease burden who are not expected to die within those initial 6–12 months. The concept of improved overall survival without marked initial tumor reduction represents a significant shift from the current paradigms established by standard cytotoxic therapies. Future clinical studies of therapeutic vaccines should enroll patients with either lower tumor burden, more indolent disease or both, and must seek to identify early markers of clinical benefit that may correlate with survival. Until then, improved overall survival is the only clear, discriminatory endpoint for therapeutic vaccines as monotherapies.     

Pharmacokinetic considerations for the use of newer antifungal agents

Endogenous commensal yeast and saprophytic molds remain important causes of morbidity and mortality in immunocompromised patients. Treatment options for patients with serious fungal infections have improved over the past decade with the introduction of a novel class of antifungals that target the fungal cell wall (echinocandins) and a new generation of broader-spectrum triazoles (voriconazole, posaconazole). Although these newer therapies provide a number of important advantages in terms of spectrum and safety, their efficacy in some patients can be compromised by limited penetration into some sites of infection or by variable serum concentrations. Hence, pharmacokinetic considerations have become increasingly important for the effective use of these newer antifungals. This article provides a brief overview of the pharmacology and important pharmacokinetic considerations of systemic antifungal therapies, with special focus on newer triazoles and echinocandins.     

Disease modifying therapy for AD?1

Alzheimer's disease (AD) is the most common form of dementia in industrialized nations. If more effective therapies are not developed that either prevent AD or block progression of the disease in its very early stages, the economic and societal cost of caring for AD patients will be devastating. Only two types of drugs are currently approved for the treatment of AD: inhibitors of acetyl cholinesterase, which symptomatically enhance cognitive state to some degree but are not disease modifying; and the adamantane derivative, memantine. Memantine preferentially blocks excessive NMDA receptor activity without disrupting normal receptor activity and is thought to be a neuroprotective agent that blocks excitotoxicty. Memantine therefore may have a potentially disease modifying effect in multiple neurodegenerative conditions. An improved understanding of the pathogeneses of AD has now led to the identification of numerous therapeutic targets designed to alter amyloid beta protein (Abeta) or tau accumulation. Therapies that alter Abeta and tau through these various targets are likely to have significant disease modifying effects. Many of these targets have been validated in proof of concept studies in preclinical animal models, and some potentially disease modifying therapies targeting Abeta or tau are being tested in the clinic. This review will highlight both the promise of and the obstacles to developing such disease modifying AD therapies.     

Translational research in myelodysplastic syndromes

The myelodysplastic syndromes (MDS) are receiving unusual attention recently as great strides have been made in understanding the biology. Recognition that excessive cytokine-induced apoptosis plays a significant role in the cytopenias of the majority of patients opened the doors to anti-cytokine therapy, with thalidomide being used with success in approximately 20% patients. Other therapies that have emerged include the thalidomide analog lenalidomide which is particularly beneficial for 5q- patients as well as a subset of non-5q- patients with low or intermediate-1 risk MDS. Other targeted therapies include vitamins, agents that are cytoprotective, differentiation inducers, anti-angiogenic, or immune modulatory. In addition, inhibitors of proteasome, methylation, histone deacetylation, farnesylation, receptor tyrosine kinases, topoisomerase, and matrix mettaloproteinases have yielded encouraging responses in subsets of patients. Specific therapies have also been developed for genetic abnormalities that lead to fusion genes (TEL-PDGFR-beta, or FIP1L1-PDGFR-alpha), or abnormal proteins due to mutations/functional inactivation (FLT3), dysregulated expression (EVI-1). In a short span of ten years, the field has evolved from having no effective therapy to offer the majority of MDS patients save chemotherapy, to having one FDA approved drug, several on the way to approval, and a number of novel agents producing exciting clinical results. This chapter summarizes the novel targets and targeted therapies in the rapidly evolving therapeutic landscape of MDS.     

Effectiveness of cell- and colony stimulating factor-based therapy for liver cirrhosis: a network meta-analysis of randomized controlled trials

Background aimsCirrhosis is the 11th leading cause of death worldwide. Because of the limitations of liver transplantation, cell- and granulocyte colony-stimulating factor (G-CSF)-based therapies are considered potential treatment methods. This work analyzes the effectiveness of cell- and G-CSF-based therapies by network meta-analysis.MethodsA literature search was performed in four databases from inception to September 10, 2021. Registered randomized controlled trials (RCTs) evaluating cell-based therapies and/or G-CSF-based therapies for cirrhosis patients were included. Traditional and network meta-analyses were analyzed in terms of survival, model for end-stage liver disease (MELD) score, Child–Turcotte–Pugh (CTP) score, alanine aminotransferase levels and aspartate aminotransferase levels.ResultsTwenty-four studies were included in this analysis. The results showed that G-CSF-based therapies (odds ratio [OR], 2.38, 95% confidence interval [CI], 1.49–3.79, P < 0.01) and cell-based therapies (OR, 1.54, 95% CI, 1.00–2.40, P = 0.048) improved the transplantation-free survival rate compared with standard medical treatment. Network analysis results showed that G-CSF combined with erythropoietin (EPO) and growth hormone (GH) had a therapeutic advantage, and cell-based therapy with mononuclear cell (MNC) hepatic artery injection and intravenous mesenchymal stem cells (MSCs) combined with G-CSF also had a relative advantage in terms of survival outcome. For the MELD score, G-CSF plus GH and MSC portal vein injection had relative advantages. G-CSF plus GH and G-CSF plus EPO had advantages in terms of CTP scores. The included strategies demonstrated no obvious improvement in liver injury indicators.ConclusionsCell-based therapy has potential therapeutic effects for liver cirrhosis. Among cell-based therapies, intravenous MSCs and hepatic artery injection of MNCs have advantageous therapeutic effects. The use of G-CSF was also noted in regimens that improved survival outcomes. However, more well-designed, large-scale RCTs are needed to confirm this conclusion.     

Dysregulation of CXCL9 and reduced tumor growth in Egr-1 deficient mice

Advances in the treatment of chronic lymphocytic leukemia (CLL) have improved initial overall response (OR) rates, complete response (CR) rates and progression free survival (PFS). Despite these advances, CLL remains incurable with standard therapies. Thus, there remains a need for more effective therapies in both the upfront and relapsed setting, particularly for patients with high-risk cytogenetic abnormalities such as del(11q22) and del(17p13). The 2008 American Society of Hematology (ASH) Annual Meeting featured several presentations which highlighted the ongoing clinical advances in CLL. The benefit of adding rituximab to purine analog therapy in the upfront setting was demonstrated by a large randomized study which showed that the addition of rituximab to fludarabine and cyclophosphamide (FCR) significantly improved OR, CR and PFS. The improvement in PFS directly resulted from an improved ability to eliminate minimal residual disease (MRD) in the peripheral blood, highlighting the importance of MRD eradication. However, a multi-center study suggested that the high CR rates to chemoimmunotherapy regimens such as FCR obtained in academic centers may not be reproducible when the same regimens are given in the community setting. The immunomodulatory drug lenalidomide is active in relapsed high-risk CLL, but two studies of lenalidomide in previously untreated CLL patients failed to achieve a CR and were associated with significant tumor lysis, tumor flare and hematologic toxicity. In the relapsed setting, a combination study of the bifunctional alkylator bendamustine and rituximab (BR) demonstrated a high OR rate in patients with del(11q22) and del(17p13), indicating that further studies to define's bendamustine activity are warranted in high-risk CLL. Similarly, the CDK inhibitor flavopiridol demonstrated significant clinical activity and durable remissions in heavily treated, refractory CLL patients with high-risk cytogenetic features and bulky lymphadenopathy. The monoclonal anti-CD20 antibody ofatumumab appeared to be superior to rituximab in relapsed CLL patients with bulky nodal disease or high-risk cytogenetic features. Ongoing studies of these agents and other novel therapeutic agents in clinical development hold forth the promise that treatment options for CLL patients will continue to expand and improve.     

Anti-aβ therapeutics in Alzheimer's disease: the need for a paradigm shift

Most current Alzheimer's disease (AD) therapies in advanced phases of development target amyloid β-peptide (Aβ) production, aggregation, or accumulation. Translational models suggest that anti-Aβ therapies may be highly effective if tested as agents to prevent or delay development of the disease or as therapies for asymptomatic patients with very early signs of AD pathology. However, anti-Aβ therapeutics are currently being tested in symptomatic patients where they are likely to be much less effective or ineffective. The lack of alignment between human clinical studies and preclinical studies, together with predictions about optimal trial design based on our understanding of the initiating role of Aβ aggregates in AD, has created a treatment versus prevention dilemma. In this perspective, we discuss why it is imperative to resolve this dilemma and suggest ways for moving forward in the hopes of enhancing the development of truly effective AD therapeutics.     

Injectable cardiac tissue engineering for the treatment of myocardial infarction

Heart disease is a leading cause of morbidity and mortality worldwide. Myocardial infarction leads to permanent loss of cardiac tissue and ultimately heart failure. However, current therapies could only stall the progression of the disease. Thus, new therapies are needed to regenerate damaged hearts to overcome poor prognosis of patients with heart failure. The shortage of heart donors is also a factor for innovating new therapies. Although the cardiac performance by cell-based therapy has improved, unsatisfactory cell retention and transplant survival still plague this technique. Because biomaterials can improve the cell retention, survival and differentiation, cardiac tissue engineering is now being explored as an approach to support cell-based therapies and enhance their efficacy for cardiac disease. In the last decade, cardiac tissue engineering has made considerable progress. Among different kinds of approaches in the cardiac tissue engineering, the approach of injectable cardiac tissue engineering is more minimally invasive than that of in vitro engineered tissue or epicardial patch implantation. It is therefore clinically appealing. In this review, we strive to describe the major progress in the flied of injectable cardiac tissue engineering, including seeding cell sources, biomaterials and novel findings in preclinical studies and clinical applications. The remaining problems will also be discussed.     

Identification and management of adults with asthma prone to exacerbations: can we do better?

Exacerbations are a major cause of morbidity in asthma and generate high health costs. Identification and management of adults with asthma who are prone to exacerbations is of considerable importance as by this means it should be possible to reduce the number of patients who currently experience inadequately controlled disease. Exacerbations occur most frequently in individuals with severe disease. Other risk factors include a history of a recent exacerbation, co-morbidities such as a raised body mass index and psychological problems as well as current smoking and lower socio-economic status. A low FEV₁, particularly if combined with the additional information from questionnaires helps predict exacerbations. Despite the association between these risk factors and exacerbations it remains difficult to accurately predict in an individual patient with asthma whether they will go on to develop an exacerbation in the future. A major aim of international guidelines on the management of asthma is to prevent future risks of exacerbations, but some patients, particularly those with severe disease, respond poorly to current therapies and continue to experience recurrent exacerbations. There is an unmet need for improved management strategies and drugs targeted at preventing asthma exacerbations. Monitoring induced sputum eosinophil cell counts is helpful in preventing exacerbations in some patient with severe asthma. Future developments are likely to include the identification of better biomarkers to predict exacerbations or the cause of exacerbations, augmentation of the immunological response to viruses at the time of the exacerbation, the use of telemonitoring in patients with severe asthma and the development of improved therapies targeted at reducing exacerbations.     

Circadian Rhythms in the Pharmacokinetics and Clinical Effects of Beta-agonist,Theophylline, and Anticholinergic Medications in the Treatment of Nocturnal Asthma

Published asthma consensus reports now acknowledge that asthma is a nocturnal disease in as many as 75% of those afflicted by this medical condition. Nonetheless, the treatment of this chronic obstructive pulmonary disease in the clinic continues to be based primarily on homeostatic considerations in that it relies on long-acting bronchodilator and other therapies formulated and scheduled to ensure constant or near-constant levels of medication during the 24h. The need of asthma patients prone to nighttime attacks is not the same during the day and night; the therapeutic requirements of patients who experience nocturnal asthma, especially ones with the more severe forms of the disease, are often not satisfied by conventional medications. The therapeutic response and patient tolerance to bronchodilator medications can be improved markedly when the medications are proportioned during the 24h as a chronotherapy, that is, when more medication is delivered during nighttime sleep than daytime activity, as verified by numerous studies. This article reviews how the body's circadian rhythms influence the pharmacokinetics and effects of commonly prescribed asthma therapies and addresses why and how they must be taken into consideration to increase the effectiveness of asthma treatment.     

Approaches to the therapy of rheumatoid arthritis

The treatment of RA is generally empirical. While there are many effective agents available, there are no agents that are curative. Progressive disease is frequently seen even in patients who are responsive to current therapies. Newer, more effective therapies are needed. The most promising area for new treatments appears to be specific biologic approaches with monoclonal antibodies or stimulants or inhibitors of lymphocytokines.     

Circadian Rhythms in the Pharmacokinetics and Clinical Effects of Beta-agonist, Theophylline, and Anticholinergic Medications in the Treatment of Nocturnal Asthma

Published asthma consensus reports now acknowledge that asthma is a nocturnal disease in as many as 75% of those afflicted by this medical condition. Nonetheless, the treatment of this chronic obstructive pulmonary disease in the clinic continues to be based primarily on homeostatic considerations in that it relies on long-acting bronchodilator and other therapies formulated and scheduled to ensure constant or near-constant levels of medication during the 24h. The need of asthma patients prone to nighttime attacks is not the same during the day and night; the therapeutic requirements of patients who experience nocturnal asthma, especially ones with the more severe forms of the disease, are often not satisfied by conventional medications. The therapeutic response and patient tolerance to bronchodilator medications can be improved markedly when the medications are proportioned during the 24h as a chronotherapy, that is, when more medication is delivered during nighttime sleep than daytime activity, as verified by numerous studies. This article reviews how the body's circadian rhythms influence the pharmacokinetics and effects of commonly prescribed asthma therapies and addresses why and how they must be taken into consideration to increase the effectiveness of asthma treatment.     

Clinical application of recombinant human erythropoietin for treatments in patients with head and neck cancer

Summary The therapeutic effects of intravenous recombinant human erythropoietin (r-hEPO) administration on anemia induced by radiation therapy (3 cases), chemotherapy (18 cases) and combined therapies (5 cases) in patients with head and neck malignancies were examined. The effectiveness was evaluated by the changes in the hemoglobin concentration examined before and after the r-hEPO administration. The r-hEPO administration combined with anticancer therapies improved anemia induced by all three treatments. The therapeutic effectiveness of r-hEPO injection was also noted on anemia induced by all of four different chemotherapeutic regimens that have been ordinarily used for head and neck malignancies. Furthermore, the efficacy of the different dose schedules, 3000 IU (12 cases) or 6000 IU (14 cases), three times a week, was compared. Both of the r-hEPO dose schedules were effective for anemia, but the efficacy of 6000 IU was superior to that of 3000 IU. No significant changes were observed in the number of white blood cells and platelets and the results of biochemical examinations after the r-hEPO injection. There were no objective side-effects related to the r-hEPO administration. These results suggest that anemia induced by chemotherapy and/or radiotherapy could be prevented by r-hEPO administration. The addition of r-hEPO to anticancer therapies would make it possible to pursue the planned therapeutic schedules, prevent the decrease of immunity after allogeneic blood transfusion and bring about an improvement in the prognosis of patients with malignancies.     

Grand rounds at the National Institutes of Health: HDAC inhibitors as radiation modifiers, from bench to clinic

Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumour. Patients afflicted with this disease unfortunately have a very poor prognosis, and fewer than 5% of patients survive for 5 years from the time of diagnosis. Therefore, improved therapies to treat this disease are sorely needed. One such class of drugs that have generated great enthusiasm for the treatment of numerous malignancies, including GBM, is histone deacetylase (HDAC) inhibitors. Pre-clinical data have demonstrated the efficacy of various HDAC inhibitors as anticancer agents, with the greatest effects shown when HDAC inhibitors are used in combination with other therapies. As a result of encouraging pre-clinical data, numerous HDAC inhibitors are under investigation in clinical trials, either as monotherapies or in conjunction with other treatments such as chemotherapy, biologic therapy or radiation therapy. In fact, two actively studied HDAC inhibitors, vorinostat and depsipeptide, were recently approved for the treatment of refractory cutaneous T cell lymphoma. In this review, we first present a patient with GBM, and then discuss the pathogenesis, epidemiology and current treatment options of GBM. Finally, we examine the translation of pre-clinical studies that have demonstrated HDAC inhibitors as potent radiosensitizers in in vitro and in vivo models, to a phase II clinical trial combining the HDAC inhibitor, valproic acid, along with temozolomide and radiation therapy for the treatment of GBM.     

Resistance to tyrosine kinase inhibitors in clear cell renal cell carcinoma: From the patient's bed to molecular mechanisms

The introduction of anti-angiogenic drugs especially tyrosine kinase inhibitors (TKIs) was a breakthrough in the treatment of renal cell carcinoma (RCC). Although TKIs have significantly improved outcome in patients with metastatic disease, the majority still develop resistance over time. Because different combinations and sequences of TKIs are tested in clinical trials, resistance patterns and mechanisms underlying this phenomenon should be thoroughly investigated. From a clinical point of view, resistance occurs either as a primary phenomenon (intrinsic) or as a secondary phenomenon related to various escape/evasive mechanisms that the tumor develops in response to vascular endothelial growth factor (VEGF) inhibition. Intrinsic resistance is less common, and related to the primary redundancy of available angiogenic signals from the tumor, causing unresponsiveness to VEGF-targeted therapies. Acquired resistance in tumors is associated with activation of an angiogenic switch which leads to either upregulation of the existing VEGF pathway or recruitment of alternative factors responsible for tumor revascularization. Multiple mechanisms can be involved in different tumor settings that contribute both to evasive and intrinsic resistance, and current endeavor aims to identify these processes and assess their importance in clinical settings and design of pharmacological strategies that lead to enduring anti-angiogenic therapies.     

Predictive and prognostic factors in the complex treatment of patients with colorectal cancer

Colon cancer is the second most prevalent lethal cancer. The main cause for high mortality rate is that the prognosis for progressed metastatic colon cancer is most unfavorable. Recent data suggest that disease outcome can be further improved by the addition of targeted biological agents to the first- or second-line treatment. As a result of molecularly targeted anti-EGFR therapies (cetuximab and panitumumab) complementing chemotherapy, liver metastases can reduce in size and become operable in certain patients, which can contribute to the complete recovery of the patient. The main problem, however, is the fact that a positive response only occurs in one third of the patients, even in the case of chemotherapy combined protocol, and the side effects are considerable. For the application of individually tailored treatments, it is an urgent need to develop a system of biomarkers that can predict the effect of treatment and provide information about the optimal selection of both chemotherapy and biological treatment. It should be clarified what the most important requirements of a good and reliable biomarker are. As currently there is no precise predictive molecular diagnostics at our disposal, oncologists have to make one of two choices: they treat a large number of patients with anti-EGFR agents which has negative effects on the quality of life and also reduces the patient's chances of getting appropriate treatment or, if the oncologists refuse to take risks, they omit the use of anti-EGFR treatment in which case those patients for whom this would have been the appropriate treatment are also denied the chance of short-term survival or recovery. Clinical data (response rate, time to progression (TTP) and overall survival (OS)) of 130 colorectal cancer patients have been retrospectively analyzed. Patients have received different chemotherapy protocols in combination with anti-VEGF antibody or with anti-EGFR antibody therapies. EGFR expression was evaluated with immunohistochemistry, KRAS, BRAF and PIK3CA mutations were evaluated by direct sequencing and high resolution melting analysis in the archived formalin-fixed, paraffin-embedded tissue samples. The study found similar efficacy of first-line therapeutic protocols. Protocols combining chemotherapy with biological therapies achieved better overall survival but this difference was not significant (OS: 35.9 versus 36.7 months). The frequency of KRAS mutations was 44% (n=100). None of the KRAS mutant tumors responded to the anti-EGFR monotherapy. TTP in the case of cetuximab monotherapy was twice longer (208 months) than in the KRAS mutant tumors (104 months). One BRAF mutant tumor was also identified (4%) This tumor was also resistant to cetuximab monotherapy. The KRAS and BRAF mutations excluded each other. Except one case, the KRAS status was identical in both the primary tumor and the metastasis. In contrast, PIK3CA mutations were heterogeneous in different tumor samples. In 5 out of 6 cases the mutation status of PIK3CA was different in the primary tumor and the metastasis. New biological therapies provide an additional clinical benefit only for a subset of patients. We need biomarkers to identify these patients. KRAS and most probably BRAF testing can double the efficacy of the anti-EGFR therapies, but we need additional molecular diagnostic tests. PIK3CA is an important candidate but we might need to take biopsy directly from the metastasis or we have to evaluate the circulating tumor cells to judge the molecular status of distant metastasis.