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Spinal cord injury (SCI) is a debilitating neurologic condition with tremendous socioeconomic impact on affected individuals and the health care system. The treatment of SCI principally includes surgical treatment and marginal pharmacologic and rehabilitation therapies targeting secondary events with minor clinical improvements. This unsuccessful result mainly reflects the complexity of SCI pathophysiology and the diverse biochemical and physiologic changes that occur in the injured spinal cord. Once the nervous system is injured, cascades of cellular and molecular events are triggered at varying times. Although the cascade of tissue reactions and cell injury develops over a period of days or weeks, the most extensive cell death in SCI occurs within hours of trauma. This situation suggests that early intervention is likely to be the most promising approach to rescue the cord from further and irreversible cell damage. Over the past decades, a wealth of research has been conducted in preclinical and clinical studies with the hope to find new therapeutic strategies. Researchers have identified several targets for the development of potential therapeutic interventions (e.g., neuroprotection, replacement of cells lost, removal of inhibitory molecules, regeneration, and rehabilitation strategies to induce neuroplasticity). Most of these treatments have passed preclinical and initial clinical evaluations but have failed to be strongly conclusive in the clinical setting. This narrative review provides an update of the many therapeutic interventions after SCI, with an emphasis on the underlying pathophysiologic mechanisms.

Background:: The androgen receptor (AR) pathway is a key driver of neoplastic behaviour in the different stages of metastatic prostate cancer (mPCa). Targeting the AR therefore remains the cornerstone for mPCa treatment. We have previously reported that activation of AR signalling affects taxane chemo-sensitivity in preclinical models of castration resistant PCa (CRPC). Here, we explored the anti-tumour efficacy of the AR targeted inhibitor enzalutamide combined with cabazitaxel. Methods:: We used the AR positive CRPC model PC346C-DCC-K to assess the in vitro and in vivo activity of combining enzalutamide with cabazitaxel. Subsequent validation studies were performed using an enzalutamide resistant VCaP model. To investigate the impact of AR signalling on cabazitaxel activity we used quantitative live-cell imaging of tubulin stabilization and apoptosis related nuclear fragmentation. Findings:: Enzalutamide strongly amplified cabazitaxel anti-tumour activity in the patient-derived xenograft models PC346C-DCC-K (median time to humane endpoint 77 versus 48 days, P

The recent years saw the advent of promising preclinical strategies that combat the devastating effects of a spinal cord injury (SCI) that are progressing towards clinical trials. However, individually, these treatments produce only modest levels of recovery in animal models of SCI that could hamper their implementation into therapeutic strategies in spinal cord injured humans. Combinational strategies have demonstrated greater beneficial outcomes than their individual components alone by addressing multiple aspects of SCI pathology. Clinical trial designs in the future will eventually also need to align with this notion. The scenario will become increasingly complex as this happens and conversations between basic researchers and clinicians are required to ensure accurate study designs and functional readouts., This review is comprehensive and timely, and provides to the readers a balanced view of research and clinical findings in spinal cord injury.

Meatballs are widely consumed ready-to-cook meat products due to their favourable tastes and flavours. They can be contaminated with several saprophyte and pathogenic bacteria due to their ingredients. The aim of this study was to investigate the effect of nisin and EDTA treatments in combination with modified atmosphere packaging (ambient air, 80:20:0/O2:CO2:N2 and 0.4:30:69.60/CO:CO2:N2 gas mixtures) on the survival of Salmonella Enteritidis in Turkish type meatballs stored at 4°C. Shelf-life of meatballs containing nisin and/or EDTA was extended compared to control. The efficient inhibition of Salmonella Enteritidis was enhanced with increasing concentrations of EDTA when applied together with nisin (1000 µg/g nisin and 50 mM EDTA). In conclusion, combined effects of nisin and EDTA incorporation with low level of CO packaging appears to be an important strategy to increase food safety; thus, this application can contribute to minimize the incidence of foodborne diseases originated from Salmonella spp.

Objective: Inspired by the traditionally clinical application of herb pair Zhimu-Huangbo to treat diabetes, a combination of plant ingredients, timosaponin B2 (TB-2) and berberine (BBR), was evaluated for their anti-diabetic efficacy and cooperative mechanisms. Methods: The efficacy and pharmacokinetics of orally administered TB-2 (33.3 mg/kg/day), BBR (66.7 mg/kg/day), and TB-2+BBR (100 mg/kg/day) were evaluated in spontaneously non-obese diabetic Goto-Kakizaki (GK) rats, and metformin (200 mg/kg/day) was used as a positive control. The comparative exposure of the parent drugs, timosaponin A3 (TB-2 metabolite), and M1-M5 (BBR metabolites) was quantified in the portal vein plasma (before hepatic disposition), liver, and systemic plasma (after hepatic disposition) of normal rats on single and combination treatments. Cooperative mechanism of TB-2 and BBR on intestinal absorption and hepatic metabolism was investigated in Caco-2 cells and primary hepatocytes, respectively. Results: After a 6-week experiment, non-fasting and fasting blood glucose levels and oral glucose tolerance test results showed that TB-2+BBR treatments (100 mg/kg/day) displayed significantly anti-diabetic efficacy in GK rats, comparable to that on metformin treatments. However, no significant improvement was observed on TB-2 or BBR treatments alone. Compared to single treatments, combination treatments led to the increased circulating levels of BBR by 107% in GK rats. In normal rats, the hepatic exposure of BBR, timosaponin A3, and M1-M5 was several hundred folds higher than their circulating levels. Co-administration also improved the levels in the plasma and liver by 41-114% for BBR, 141-230% for TB-2, and 12-282% for M1-M5. In vitro, the interaction between TB-2 and BBR was mediated by intestinal absorption, rather than hepatic metabolism. Conclusion: Combining TB-2 and BBR enhanced the anti-diabetic efficacy by increasing the in vivo variety of effective substances, including the parent compounds and active metabolites, and improving the levels of those substances through intestinal absorption. This study is a new attempt to assess the effects of combined plant ingredients on diabetes by scientifically utilizing clinical experience of an herb pair.

Background: Serotonin reuptake inhibitors (SRIs) and cognitive-behavioral psychotherapy (CBT) are first-line treatments for obsessive-compulsive disorder (OCD). However, a significant proportion of patients do not respond satisfactorily to first-choice treatments. Several options have been investigated for the management of resistant patients. Objective: The aim of the present paper is to systematically review the available literature concerning the strategies for the treatment of resistant adult patients with OCD. Method: We first reviewed studies concerning the definition of treatment-resistant OCD; we then analyzed results of studies evaluating several different strategies in resistant patients. We limited our review to double-blind, placebo-controlled studies performed in adult patients with OCD whose resistance to a first adequate (in terms of duration and dosage) SRI trial was documented and where outcome was clearly defined in terms of decrease in Yale-Brown Obsessive-Compulsive Scale (YBOCS) scores and/or response/ remission rates (according to the YBOCS). Results: We identified five strategies supported by positive results in placebo-controlled randomized studies: 1) antipsychotic addition to SRIs (16 RCTs, of them 10 positive; 4 head-to-head RCTs); among antipsychotics, available RCTs examined the addition of haloperidol (butyrophenone), pimozide (diphenyl-butylpiperidine), risperidone (SDA: serotonin- dopamine antagonist), paliperidone (SDA), olanzapine (MARTA: multi-acting receptor targeted antipsychotic), quetiapine (MARTA) and aripiprazole (partial dopamine agonist); 2) CBT addition to medication (2 positive RCTs); 3) switch to intravenous clomipramine (SRI) administration (2 positive RCTs); 4) switch to paroxetine (SSRI: selective serotonin reuptake inhibitor) or venlafaxine (SNRI: serotonin-norepinephrine reuptake inhibitor) when the first trial was negative (1 positive RCT); and 5) the addition of medications other than an antipsychotic to SRIs (18 RCTs performed with several different compounds, with only 4 positive studies). Conclusion: Treatment-resistant OCD remains a significant challenge to psychiatrists. To date, the most effective strategy is the addition of antipsychotics (aripiprazole and risperidone) to SRIs; another effective strategy is CBT addition to medications. Other strategies, such as the switch to another first-line treatment or the switch to intravenous administration are promising but need further confirmation in double-blind studies. The addition of medications other than antipsychotics remains to be studied, as several negative studies exist and positive ones need confirmation (only 1 positive study).

Los tratamientos principales aplicados en el ámbito de las adicciones son la farmacoterapia y las terapias psicológicas, siendo escasas las intervenciones en las que se combinan estos dos tipos de terapias. El objetivo de este estudio es revisar y mostrar un resumen de los resultados de las principales investigaciones, que han evaluado la efectividad de la intervención combinada de estas terapias en comparación con la aplicación de los tratamientos administrados de forma aislada. Los resultados muestran que la aplicación combinada de tratamientos farmacológicos y psicológicos, presenta mayor efecto terapéutico y de prevención de recaídas, superando en parte las limitaciones que presentan estos dos tipos de tratamientos en su aplicación aislada The main therapies applied to treat substance abuse or addictions are pharmacotherapy and psychological therapies, with few interventions that combine these two types of therapies. The aim of the present study is to review and to summarize the main results of research devoted to evaluate the effectiveness of the combined action of these therapies, as compared to the effectiveness of each type of treatment administered alone. The results show that the combined application of pharmacological and psychological treatments has a greater therapeutic effect and relapse prevention, thus overcoming some of the limitations of these two types of treatments when administrated alone

Lung cancer is a heterogeneous disease consisting of multiple histological subtypes each driven by unique genetic alterations. Despite the development of targeted therapies that inhibit the oncogenic mutations driving a subset of lung cancer cases, there is a paucity of effective treatments for the majority of lung cancer patients and new strategies are urgently needed. In recent years, the concept of synthetic lethality has been established as an effective approach for discovering novel cancer-specific targets as well as a method to improve the efficacy of existing drugs which provide partial but insufficient benefits for patients. In this review, we discuss the concept of synthetic lethality, the various types of synthetic lethal interactions in the context of oncology and the approaches used to identify these interactions, including recent advances that have transformed the ability to discover novel synthetic lethal combinations on a global scale. Lastly, we describe the specific synthetic lethal interactions identified in lung cancer to date and explore the pharmacological challenges and considerations in translating these discoveries to the clinic.

Background: Serotonin reuptake inhibitors (SRIs) and cognitive-behavioral psychotherapy (CBT) are first-line treatments for obsessive-compulsive disorder (OCD). Since response is often inadequate, in recent years researchers investigated whether combining CBT and SRIs, either ab initio or sequentially, results in a greater reduction of obsessivecompulsive symptoms. Objective: The aims of the present paper are to assess if combination treatment seems adding benefits as compared to either monotherapy alone and if sequential strategies may be effective in converting partial or non responders to a first-line treatment into responders. Method: We reviewed available literature on pharmacological and CBT combination and sequential treatments for adult and pediatric OCD patients and then we conducted a separate analysis for studies concerning these two promising strategies. Search results included openlabel trials and randomized controlled trials (RCTs). Results: We identified ten controlled studies assessing the efficacy of combination treatments ab initio versus CBT alone and six evaluating combination strategies ab initio versus medications alone. Eleven studies, only two of which were RCTs, have been published on sequential treatments. The combination ab initio of CBT and SRIs has not been found to be clearly superior to either monotherapy alone in most studies conducted on this topic, except for patients with severe depression who might benefit more from the combination versus only CBT. A sequential administration of CBT after medications has been found useful in promoting remission in patients who partially responded to drugs and in promoting response in resistant patients. Conclusion: OCD patients with comorbid major depression should receive medication firstly, eventually associated with CBT; for all remaining patients there is clear evidence from the literature of no additive benefits of combining ab initio CBT and medication. Therefore, the routine use of a combination approach in all adult patients affected by OCD is not supported by the literature. The available evidence supports the effectiveness of the sequential addition of CBT to SRIs.

Charles B Pull1, Cristian Damsa21Department of Neurosciences, Centre Hospitalier de Luxembourg, Luxembourg; 2Department of Psychiatry, Clinical Investigation Program, University of Colorado Health Sciences Center, USAAbstract: Panic disorder (PD) is a common, persistent and disabling mental disorder. It is often associated with agoraphobia. The present article reviews the current status of pharmacotherapy for PD with or without agoraphobia as well as the current status of treatments combing pharmacotherapy with cognitive behavior therapy (CBT). The review has been written with a focus on randomized controlled trials, meta-analyses, and reviews that have been published over the past few years. Effective pharmacological treatments include tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and various benzodiazepines. Treatment results obtained with CBT compare well with pharmacotherapy, with evidence that CBT is at least as effective as pharmacotherapy. Combining pharmacotherapy with CBT has been found to be superior to antidepressant pharmacotherapy or CBT alone, but only in the acute-phase treatment. Long term studies on treatments combining pharmacotherapy and CBT for PD with or without agoraphobia have found little benefit, however, for combination therapies versus monotherapies. New investigations explore the potential additional value of sequential versus concomitant treatments, of cognitive enhancers and virtual reality exposure therapy, and of education, self management and Internet-based interventions.Keywords: Panic disorder, agoraphobia, pharmacotherapy, cognitive-behavioral therapy, combination treatments.

Triple negative breast cancers (TNBC) are characterized by aggressive tumor biology, lack of targetedtreatments and poor prognosis. Anthracyclins were shown to induce immunogenic death in target cells, potentially leading to “endogenous” vaccination. We comparatively assessed expression of cancer testisantigens (CTA) and topoisomerase 2-alpha (TOPO2A), a well defined molecular target of anthracyclins, in TNBC fully characterized for basal-like (BL) immunophenotype, BL morphology and conventional clin-icopathological factors. The study included 83 patients undergoing surgery between January 2003 andDecember 2009. Tissue sections were stained with CK5/6, CK14, EGFR, Ki-67, TOPO2A, MAGE-A1, MAGE-A10, NY-ESO and multi-MAGE-A specific reagents. Of the 83 TNBC, >66.3% had BL immunophenotype and48.2% had BL morphology. MAGE-A1 specific staining was most frequently detectable (69.2%), followedby multi-MAGE-A (58%), NY-ESO (27.1%) and MAGE-A10 (16%) specific staining. MAGE-A10 expressionsignificantly correlated with tumor size (p = 0.026). Furthermore, MAGE-A1, MAGE-A10 and multi-MAGE-A specific stainings significantly correlated with advanced clinical stage (p = 0.024, p = 0.041, p = 0.031, respectively). We found no significant association between CTA expression and disease free (DFS) oroverall survival (OS). Most interestingly, a significant correlation was observed between expression ofMAGE-A10 and NY-ESO and expression of TOPO2A (p = 0.005, p = 0.013). Expression of defined CTA andTOPO2A are significantly correlated in TNBC. Considering the limited therapeutic options for TNBC, thesefindings might suggest novel forms of combination therapies that should be further explored.

Ionizing radiation (IR) is a powerful therapeutic modality for cancer, commonly used for its capacity to kill cancer cells. In this Frontiers Research Topic Book radiotherapy effects are re-visited, from the point of view of the host's immune system (IS). An introductory article from Golden et al. (2012) examines the consequences of the many types of radiation-induced tumor cell death and how these coalesce to generate the key signals that define an immunogenic cell death (ICD). Cancer cells dying by ICD deliver a cascade of signals to the IS that culminates in the generation of anti-tumor T cells by providing a source of antigen for cross-presentation coupled with maturation signals to dendritic cells (DC). The ability of IR to induce an ICD is exploited by novel cancer therapies that have, for instance, shown the benefit of intra-tumoral injection of DC post-radiotherapy in preclinical models. Finkelstein and Fishman (2012) discuss this approach and the emergence of encouraging results from clinical pilot studies. Burnette et al. (2012) provide an overview of the immunological environment existing in tumor-bearing hosts, emphasizing the challenge of overcoming tolerance and immunosuppression to achieve tumor rejection. To overcome this barrier, combinations of IR with specific immunotherapies have been tested by several labs and shown to be effective at eliciting robust anti-tumor immunity. One such strategy, discussed by Mason and Hunter (2012), is the combination of IR with intra-tumoral synthetic oligodeoxynucleotides such as CpG. The preclinical success of this combination was translated to the clinic where it has demonstrated to induce rejection of the irradiated tumor as well as tumors outside the radiation field (abscopal effect). Another strategy, which is in earlier stage of investigation but holds great potential, is nanovectorized radiotherapy discussed by Vanpouille-Box and Hindre (2012). Delivery of radionuclides using nanoparticles has the advantage of providing targeting specificity to the tumor as well as exploiting the intrinsic immunostimulatory properties of nanoparticles. Importantly, IR effects exceed the classical cytocidal properties by also causing phenotypic changes in the fraction of surviving cells, markedly enhancing their susceptibility to T cell-mediated elimination. Kwilas et al. (2012) define these effects of IR as “immunogenic modulation” and illustrate the examples of IR-induced Major Histocompatibility Complex antigens and death receptors, which improve tumor rejection by T cells adoptively transferred or activated by vaccination. However, not all IR-induced modifications of the tumor and its microenvironment favor immune rejection. Chiang et al. (2012) provide novel evidence for accumulation of pro-tumorigenic M2 macrophages in areas of hypoxia present in irradiated tumors. Schaue et al. (2012) discuss the increase of regulatory T cells post-radiotherapy, potentially hindering the development of effective anti-tumor T cell responses. Intriguingly, the dose and fractionation of radiotherapy may play a role in modulating the expansion of effector versus regulatory T cells. This aspect is critically addressed by Demaria and Formenti (2012). Since much of the available preclinical data come from experiments testing single IR doses, further exploration of fractionated regimens is warranted. Overall, the book provides an overview of the available data and evolving concepts in support of a novel use of radiotherapy: that of an immune modulator and optimal partner for immunotherapy. While enthusiasm for the combination of IR and immunotherapy was enhanced by recent anecdotal reports in some cancer patients, much work remains to be done. Hopefully, the book will inspire more investigators to explore this new area, and encourage more discovery of the interaction of IR and immunity.

The clinical success of small-molecule vascular disrupting agents (VDAs) depends on their combination with conventional therapies. Scheduling and sequencing remain key issues in the design of VDA-chemotherapy combination treatments. This study examined the antitumour activity of ZD6126, a microtubule destabilising VDA, in combination with paclitaxel (PTX), a microtubule-stabilising cytotoxic drug, and the influence of schedule and sequence on the efficacy of the combination. Nude mice bearing MDA-MB-435 xenografts received weekly cycles of ZD6126 (200 mg kg(-1) i.p.) administered at different times before or after PTX (10, 20, and 40 mg kg(-1) i.v.). ZD6126 given 2 or 24 h after PTX showed no significant benefit, a result that was attributed to a protective effect of PTX against ZD6126-induced vascular damage and tumour necrosis, a hallmark of VDA activity. Paclitaxel counteracting activity was reduced by distancing drug administrations, and ZD6126 given 72 h after PTX potentiated the VDA's antitumour activity. Schedules with ZD6126 given before PTX improved therapeutic activity, which was paralleled by a VDA-induced increase in cell proliferation in the viable tumour tissue. Paclitaxel given 72 h after ZD6126 yielded the best response (50% tumours regressing). A single treatment with ZD6126 followed by weekly administration of PTX was sufficient to achieve a similar response (57% remissions). These findings show that schedule, sequence and timing are crucial in determining the antitumour efficacy of PTX in combination with ZD6126. Induction of tumour necrosis and increased proliferation in the remaining viable tumour tissue could be exploited as readouts to optimise schedules and maximise therapeutic efficacy.