Nonlinear coupling of Alfvén and magnetoacoustic waves in partially ionized plasmas: the effect of thermal misbalance on propagating waves.

Partially ionized plasmas constitute an essential ingredient of the solar atmosphere, and ground- and space-based observations have pointed out the presence of oscillations in partially ionized solar plasmas such as chromosphere, photosphere, prominences or spicules, which have been interpreted in terms of magnetohydrodynamic waves. Our aim is to study the spatial behaviour of propagating weakly and fully nonlinear Alfvén waves, and the subsequent excitation of field-aligned motions and perturbations, when dissipative mechanisms, such as ambipolar diffusion and radiative losses, together with parametrized heating mechanisms, are taken into account. When only ambipolar diffusion is taken into account, first-order Alfvén waves as well as ponderomotive-driven perturbations are spatially damped, while field-aligned motions and perturbations representing propagating slow waves are undamped. These perturbations are damped when thermal effects are also considered and their damping lengths can be longer or shorter than those of ponderomotive-driven perturbations. Therefore, after the initial excitation, Alfvén waves and ponderomotive-driven perturbations could be quickly damped while slow waves still remain in the plasma, and vice versa. This article is part of the theme issue 'Partially ionized plasma of the solar atmosphere: recent advances and future pathways'.

Reduction of obstruction related bladder overactivity by the guanylyl cyclase modulators BAY 41-2272 and BAY 60-2770 alone or in combination with a phosphodiesterase type 5 inhibitor.

AIMS: To assess the urodynamic effects of soluble guanylyl cyclase (sGC) stimulator, BAY 41-2272, and activator, BAY 60-2770, (which both are able to induce cGMP synthesis even in the absence of nitric oxide (NO)) alone or in combination with a phosphodiesterase type 5 (PDE5) inhibitor, vardenafil, in a model of partial urethral obstruction (PUO) induced bladder overactivity (BO). METHODS: Fifty-six male Sprague-Dawley rats were used, 31 of them underwent PUO. Fourteen rats were used for Western blots to assess PDE5 and sGC expression. For drug evaluation cystometry without anesthesia was performed three days following bladder catheterization. RESULTS: Obstructed rats showed higher micturition frequency and bladder pressures than non-obstructed animals (Intermicturition Interval, IMI, 2.28 ± 0.55 vs. 3.60 ± 0.60 min (± standard deviation, SD); maximum micturition pressure, MMP, 70.1 ± 8.0 vs. 48.8 ± 7.2 cmH2O; both P < 0.05). In obstructed rats vardenafil, BAY 41-2272, and BAY 60-2770 increased IMI (2.77 ± 1.12, 2.62 ± 0.52, and 3.22 ± 1.04 min; all P < 0.05) and decreased MMP (54.4 ± 2.8, 61.5 ± 11.3, and 51.2 ± 6.3 cmH2O; all P < 0.05). When vardenafil was given following BAY 41-2272 or BAY 60-2770 no further urodynamic effects were observed. PDE5 as well as sGC protein expression was reduced in obstructed bladder tissue. CONCLUSIONS: Targeting sGC via stimulators or activators, which increase the levels of cGMP independent of endogenous NO, is as effective as vardenafil to reduce urodynamic signs of BO. Targeting the NO/cGMP pathway via compounds acting on sGC might become a new approach to treat BO.

Talactoferrin alfa versus placebo in patients with refractory advanced non-small-cell lung cancer (FORTIS-M trial).

BACKGROUND: Talactoferrin alfa is an oral dendritic cell (DC)-mediated immunotherapy (DCMI). We tested whether talactoferrin was superior to placebo in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: An FORTIS-M trial was an international, multicenter, randomized, double-blind comparison of talactoferrin (1.5 g p.o. BID) versus placebo BID, in patients with stage IIIB/IV NSCLC whose disease had failed two or more prior regimens. Treatment was administered for a maximum of five 14-week cycles. The primary efficacy end point was overall survival (OS); secondary end points included 6- and 12-month survival, progression-free survival (PFS), and disease control rate (DCR). RESULTS: Seven hundred and forty-two patients were randomly assigned (2:1) to talactoferrin (497) or placebo (245). The median OS in the intent-to-treat (ITT) population was 7.66 months in the placebo arm and 7.49 months in the talactoferrin arm [hazard ratio (HR), 1.04; 95% CI, 0.873-1.24; P = 0.6602]. The 6-month survival rates were 59.9% (95% CI, 53.4% to 65.8%) and 55.7% (95% CI, 51.1% to 59.9%), respectively. The 12-month survival rates were 32.2% (95% CI, 26.3% to 38.2%) and 30.9% (95% CI, 26.8% to 35%), respectively. The median PFS rates were 1.64 months and 1.68 months, respectively (HR, 0.99; 95% CI, 0.835-1.16; P = 0.8073). The DCRs were 38.4 and 37.6%, respectively [stratified odds ratio (OR), 0.96; 95% CI, 0.698-1.33; P = 0.8336]. The safety profiles were comparable between arms. CONCLUSIONS: There was no improvement in efficacy with talactoferrin alfa in patients with advanced NSCLC whose disease had failed two or more previous regimens.

Disease severity impairs sleep quality in allergic rhinitis (The SOMNIAAR study).

BACKGROUND: Sleep is impaired in allergic rhinitis (AR) patients, with subsequent effects on daytime performance and health-related quality of life (QOL). Sleep quality in AR has rarely been considered through validated tools and consensus classifications. OBJECTIVE: To evaluate sleep quality and daytime somnolence in AR patients, and to estimate its relationship to disease severity according to Allergic Rhinitis and Its Impact on Asthma (ARIA) conventional and modified classifications, as well as in terms of QOL and comorbidities. METHODS: Allergic rhinitis adult patients were evaluated through a prospective, observational, multicentre survey in Spain. Symptoms were assessed using the Total Symptoms Score (TSS), specific QOL by the Rhinitis Quality of Life Questionnaire (RQLQ), sleep quality by Pittsburgh scale, and diurnal somnolence by a scale based on Epworth's, all recorded in a unique visit. RESULTS: A total of 2275 patients were included. According to ARIA criteria, 50.2% had persistent and 49.8% intermittent rhinitis, whereas 87.6% were classified as moderate-severe and 12.4% as mild; 52.8% had poor sleep quality, with a global median score for Pittsburgh scale of 6 (normal < 5) and 21.1% suffered from excessive diurnal somnolence. Correlation between Pittsburgh scale and RQLQ was moderate (r = 0.54). Among symptoms, nasal obstruction and concomitant asthma mainly, contributed to bad sleep quality. In a logistic regression model, moderate-severe rhinitis and nasal obstruction were all associated with a worse sleep quality. CONCLUSIONS AND CLINICAL RELEVANCE: Sleep quality is altered in AR patients. Sleep quality was worse in moderate-severe, and particularly in severe AR. Nasal obstruction and RQLQ deterioration are associated with a poorer sleep quality. Sleep impairment is common in allergic rhinitis, particularly in more severe forms. Nasal obstruction and concomitant asthma should be considered as contributing factors. CAPSULE SUMMARY: This is a large epidemiological survey of patients with allergic rhinitis showing a strong relationship between disease severity, as assessed by a consensus classification, and sleep impairment, as measured by a validated sleep quality tool.

Large scale coherent magnetohydrodynamic oscillations in a sunspot.

Although theoretically predicted, the simultaneous excitation of several resonant modes in sunspots has not been observed. Like any harmonic oscillator, a solar magnetic flux tube can support a variety of resonances, which constitute the natural response of the system to external forcing. Apart from a few single low order eigenmodes in small scale magnetic structures, several simultaneous resonant modes were not found in extremely large sunspots. Here we report the detection of the largest-scale coherent oscillations observed in a sunspot, with a spectrum significantly different from the Sun's global acoustic oscillations, incorporating a superposition of many resonant wave modes. Magnetohydrodynamic numerical modeling agrees with the observations. Our findings not only demonstrate the possible excitation of coherent oscillations over spatial scales as large as 30-40 Mm in extreme magnetic flux regions in the solar atmosphere, but also paves the way for their diagnostic applications in other astrophysical contexts.

Ultrasound arterial anomalies in patients exposed to nilotinib therapy for chronic myeloid leukemia.

INTRODUCTION: Patients exposed to nilotinib for chronic myeloid leukemia (CML) appear to be at risk of arterial complication. The prevalence and aspect of ultrasound asymptomatic arterial lesions are unknown. OBJECTIVE: To describe prevalence and characteristics of ultrasound arterial anomalies in patients treated with nilotinib for CML. METHODS: Patients treated with nilotinib from 2006 to 2015 in the department of the Paoli-Calmettes Institute, Marseille, were included retrospectively. A vascular ultrasound screening was carried out from 2010. The arterial lesions at the first examination were described: plaque and its echogenicity, stenosis or occlusion. A vascular arterial anomaly (VAA) was defined by the presence of a clinical and/or ultrasound anomaly. Patients with or without VAA at initial vascular examination were compared using bivariate and multivariate analysis. RESULTS: 74 patients were included (51.4% men, mean age 54.5 years); 25 patients had ultrasound arterial anomalies (33.8%). Carotid bulb was the most involved territory (44%). Arterial anomalies were: 88% plaques, 44%>50% stenosis and 12% occlusion. 72.7% plaques were echolucent or hypoechogenic. A VAA was present in 25 patients with initial vascular evaluation (33.8%). Patients with VAA at baseline were significantly older (64.9 vs 49.3, P<0.001), older at nilotinib initiation (60.8 vs 46.5, P<0.001), with more arterial hypertension (40% vs 12.2%, P=0.01), with more cardiovascular risk factors (P=0.03). In patient with no cardiovascular risk factor 12.5% had VAA (n=24). CONCLUSION: Nilotinib seems to be associated to arterial lesions of unstable lipid-like appearance. The most involved arterial territory was the carotid bulb and the most common lesion was echolucent or hypoechogenic plaque. VAA can occur in patients without cardiovascular risk factors. This result encourages us to systematically screen and follow all patients exposed to nilotinib even those without cardiovascular risk factors.

[Neuropsychiatric disorders and emotional coping strategies in post-stroke patients. A longitudinal study]. / Trastornos neuropsiquiátricos y estrategias de afrontamiento emocionales en pacientes postictus. Estudio longitudinal.

INTRODUCTION: Between one third and one half of the population that has suffered a stroke present with a neuropsychiatric disorder (NPD), which often goes underdiagnosed. AIM: To study the association between the presence of NPDs and coping strategies in stroke patients. SUBJECTS AND METHODS: Prospective, longitudinal and comparative study in a sample of patients with ischaemic stroke with and without the presence of NPDs. Both sociodemographic and clinical variables were collected. Neurological impairment (National Institute of Health Stroke Scale) and coping (Brief Coping Orientation to Problems Experienced) were assessed at three and 12 months. The period studied was from 2013 to 2017. RESULTS: A total of 82 patients were analysed, with a mean age of 67.6 ± 10.4 years, 52.4% of whom were male. Of them, 14 with NPD and 36 without NPD answered the Brief Coping Orientation to Problems Experienced coping scale, and the remaining 32 were excluded because of aphasia/dysphasia. At three months, dimensions of active coping, social support, denial and behavioural disengagement were observed in the NPD group, and at 12 months, denial and behavioural disengagement persisted, and planning, self-distraction and self-incrimination dimensions appeared. CONCLUSIONS: Results show the need to motivate patients to seek more effective strategies, to identify problems when they arise, to consider them as surmountable and to inhibit impulsive or inappropriate responses, replacing them with emotional responses and appropriate behaviours.

TITLE: Trastornos neuropsiquiátricos y estrategias de afrontamiento emocionales en pacientes postictus. Estudio longitudinal.Introducción. Entre un tercio y la mitad de la población que ha padecido un ictus presenta un trastorno neuropsiquiátrico (TNp), el cual suele estar infradiagnosticado. Objetivo. Estudiar la asociación entre la presencia de TNp y las estrategias de afrontamiento en pacientes con ictus. Sujetos y métodos. Estudio prospectivo, longitudinal y comparativo en una muestra de pacientes con ictus isquémico con y sin presencia de TNp. Se recogieron variables sociodemográficas y clínicas. Se evaluó la afectación neurológica (National Institute of Health Stroke Scale) y el afrontamiento (Brief Coping Orientation to Problems Experienced) a los tres y a los 12 meses. El período de estudio fue de 2013 a 2017. Resultados. Se analizó a 82 pacientes, con una edad media de 67,6 ± 10,4 años, y eran hombres el 52,4%. De ellos, 14 con TNp y 36 sin TNp respondieron a la escala de afrontamiento Brief Coping Orientation to Problems Experienced, y los 32 restantes fueron excluidos por afasia/disfasia. A los tres meses se observaron dimensiones de afrontamiento activo, apoyo social, negación y desconexión conductual en el grupo TNp, y a los 12 meses persistió la negación y la desconexión conductual, y aparecieron dimensiones de planificación, autodistracción y autoinculpación. Conclusiones. Los resultados muestran la necesidad de motivar a los pacientes a buscar estrategias más eficaces, identificando los problemas cuando aparecen, de considerarlos superables y de inhibir respuestas impulsivas o inadecuadas, sustituyéndolas por respuestas emocionales y conductas adecuadas.

Spontaneous acute hemorrhage within a subependymoma of the lateral ventricle: successful emergent surgical removal through a frontal transcortical approach.

INTRODUCTION. Subependymomas are benign neoplasms intimately related to the ventricular system which only exceptionally associate hemorrhagic events. We present neuroradiological and pathological evidences of intratumoral hemorrhage within a single case of subependymoma operated on at our institution. Additionally we analyze retrospectively the well-defined reports of similar cases published in the scientific literature. CASE REPORT. A 71-year-old man on anticoagulant therapy presented with abrupt and progressive deterioration of his level of consciousness. Emergent computed tomography and magnetic resonance imaging evidenced signs of acute bleeding within a mass located at the frontal horn of the left lateral ventricle, producing obstructive biventricular hydrocephalus. The lesion was immediately and completely removed through a left frontal transcortical approach. Pathological diagnosis was consistent with subependymoma displaying areas of microhemorrhage. After surgery the patient developed global anterograde and retrograde amnesia. CONCLUSIONS. A spontaneous hemorrhagic event within an asymptomatic lateral ventricle subependymoma can result in a surgical emergence as a consequence of sudden obstruction of cerebrospinal fluid pathways. Prompt and radical surgical removal of the mass, which allows a rapid resolution of hydrocephalus and prevents the risk of rebleeding, may constitute the safest management strategy.

In situ revascularization with rifampicin-soaked silver polyester graft for aortic infection: Results of a retrospective monocentric series of 18 cases.

OBJECTIVE: To evaluate the short and long-term results of in situ prosthetic graft treatment using rifampicin-soaked silver polyester graft in patients with aortic infection. MATERIAL AND METHOD: All the patients surgically managed in our center for an aortic infection were retrospectively analyzed. The primary endpoint was the intra-hospital mortality, secondary outcomes were limb salvage, persistent or recurrent infection, prosthetic graft patency, and long-term survival. RESULTS: From January 2004 to December 2015, 18 consecutive patients (12 men and 6 women) were operated on for aortic infection. Six mycotic aneurysms and 12 prosthetic infections, including 8 para-entero-prosthetic fistulas, were treated. In 5 cases, surgery was performed in emergency. During the early postoperative period, we performed one major amputation and two aortic infections were persistent. Intra-hospital mortality was 27.7%. The median follow-up among the 13 surviving patients was 26 months. During follow-up, none of the 13 patients presented reinfection or bypass thrombosis. CONCLUSION: This series shows that in situ revascularization with rifampicin-soaked silver polyester graft for aortic infection have results in agreement with the literature in terms of intra-hospital mortality with a low reinfection rate.

Neuronal survival induced by neurotrophins requires calmodulin.

It has been reported that phosphoinositide 3-kinase (PI 3-kinase) and its downstream target, protein kinase B (PKB), play a central role in the signaling of cell survival triggered by neurotrophins (NTs). In this report, we have analyzed the involvement of Ca2+ and calmodulin (CaM) in the activation of the PKB induced by NTs. We have found that reduction of intracellular Ca2+ concentration or functional blockade of CaM abolished NGF-induced activation of PKB in PC12 cells. Similar results were obtained in cultures of chicken spinal cord motoneurons treated with brain-derived neurotrophic factor (BDNF). Moreover, CaM inhibition prevented the cell survival triggered by NGF or BDNF. This effect was counteracted by the transient expression of constitutive active forms of the PKB, indicating that CaM regulates NT-induced cell survival through the activation of the PKB. We have investigated the mechanisms whereby CaM regulates the activation of the PKB, and we have found that CaM was necessary for the proper generation and/or accumulation of the products of the PI 3-kinase in intact cells.

A role for nuclear lamins in nuclear envelope assembly.

The molecular interactions responsible for nuclear envelope assembly after mitosis are not well understood. In this study, we demonstrate that a peptide consisting of the COOH-terminal domain of Xenopus lamin B3 (LB3T) prevents nuclear envelope assembly in Xenopus interphase extracts. Specifically, LB3T inhibits chromatin decondensation and blocks the formation of both the nuclear lamina-pore complex and nuclear membranes. Under these conditions, some vesicles bind to the peripheral regions of the chromatin. These "nonfusogenic" vesicles lack lamin B3 (LB3) and do not bind LB3T; however, "fusogenic" vesicles containing LB3 can bind LB3T, which blocks their association with chromatin and, subsequently, nuclear membrane assembly. LB3T also binds to chromatin in the absence of interphase extract, but only in the presence of purified LB3. Additionally, we show that LB3T inhibits normal lamin polymerization in vitro. These findings suggest that lamin polymerization is required for both chromatin decondensation and the binding of nuclear membrane precursors during the early stages of normal nuclear envelope assembly.

Allergenic profile of nasal polyposis.

BACKGROUND: Nasal polyposis is highly prevalent in the general population. Its exact origin is unknown, although several factors are involved in the etiology and development of this condition. Clinical patterns, a history of atopy, environmental exposure, eosinophil-mediated inflammation, the presence of inflammatory mediators, and sensitization to some allergens indicate that nasal polyposis is associated with allergic phenomena. The aim of this study was to identify the association between nasal polyposis and allergic factors by examining hypersensitivity reactions to common allergens and environmental exposure that could lead to the development of atopy. METHODS: We conducted a comparative study of 190 patients with nasal polyposis and 190 healthy individuals. The study included clinical and epidemiological variables, environmental exposure factors, and an allergology workup using skin prick tests with 18 inhaled allergens. RESULTS: A total of 121 patients (63.7%) of the 190 were male; 62.1% had a family history of allergy. The incidence of asthma was 48.9% among the patients and only 2.3% among the controls (P < .001). The factor most frequently involved in the patients' symptoms was weather changes (67.4%). Skin prick tests were positive in 63.2% of the patients and 31.1% of the controls. The allergens that most frequently elicited a reaction from the patients in the prick tests were Dermatophagoides pteronyssinus (27.7%), Dermatophagoides farinae (21.3%), and Olea europaea (21.1%). The difference between these results and those of the controls was statistically significant. CONCLUSIONS: Patients with nasal polyposis are sensitive to the most common allergens in our environment and exhibit a clear-cut correlation with other allergic factors, as confirmed by personal and family histories, the presence of chronic rhinitis, and the results of in vivo tests.

Fungal sensitization in nasal polyposis.

BACKGROUND: There are indications that polyposis is somehow related to allergic phenomena. Fungal sensitization in substantial proportions of patients has been cited as a trigger of inflammatory mechanisms involving either an immunoglobulin (Ig) E-mediated reaction to fungal colonization or fungal invasion of tissues. OBJECTIVE: To confirm whether fungi were involved in the development of polyposis by examining sensitivity to fungal allergens and potential local contamination by fungal species. METHODS: We performed a study of 190 patients with polyposis and 190 controls in which we compared the results of skin prick tests to 12 fungi, total IgE, and specific IgE to 15 fungal extracts and nasal fungal cultures. RESULTS: The specific fungi eliciting a reaction from the largest proportion of patients in the skin prick tests were Fusarium solani (13.7%), Penicillium frequentans (12.6%), Trichophyton mentagrophytes (11.1%), and Candida albicans (8.4%) (P < .001). The proportion of individuals that tested positive for fungal-specific IgE was 22.4% (38/170) for patients and 10.1% (19/189) for controls (P = .04). The respective proportions of positive responses to fungal cultures were 58.7% and 60%. Furthermore, no significant differences between patients and controls were found for the results of in vitro tests with cultured fungal allergens. CONCLUSIONS: Although the patients with polyposis exhibited sensitization to fungal allergens, we found that nasal colonization by fungi was similar in patients and the general population. We were also unable to find a correlation between a positive response to the cultures and the presence of fungal allergen-specific IgE. It therefore seems that nasal colonization by fungi does not induce fungal sensitization.

Prediction of massive bleeding in a prehospital setting: validation of six scoring systems. / Predicción de hemorragia masiva a nivel extrahospitalario: validación de seis escalas.

OBJECTIVE: To validate the diagnostic ability of six different scores to predict massive bleeding in a prehospital setting. DESIGN: Retrospective cohort. SETTING: Prehospital attention of patients with severe trauma. SUBJECTS: Subjects with more than 15 years, a history of severe trauma (defined by code 15 criteria), that were initially assisted in a prehospital setting by the emergency services between January 2010 and December 2015 and were then transferred to a level one trauma center in Madrid. VARIABLES: To validate: 1. Trauma Associated Severe Haemorrhage Score. 2. Assessment of Blood Consumption Score. 3. Emergency Transfusión Score. 4. Índice de Shock. 5. Prince of Wales Hospital/Rainer Score. 6. Larson Score. RESULTS: 548 subjects were studied, 76,8% (420) were male, median age was 38 (interquartile range [IQR]: 27-50). Injury Severity Score was 18 (IQR: 9-29). Blunt trauma represented 82,5% (452) of the cases. Overall, frequency of MB was 9,2% (48), median intensive care unit admission days was 2,1 (IQR: 0,8 - 6,2) and hospital mortality rate was 11,2% (59). Emergency Transfusión Score had the highest precisions (AUC 0,85), followed by Trauma Associated Severe Haemorrhage score and Prince of Wales Hospital/Rainer Score (AUC 0,82); Assessment of Blood Consumption Score was the less precise (AUC 0,68). CONCLUSION: In the prehospital setting the application of any the six scoring systems predicts the presence of massive hemorrhage and allows the activation of massive transfusion protocols while the patient is transferred to a hospital.

[Nursing students voice their opinions regarding their profession]. / Los estudiantes de enfermería opinan sobre su profesión.

The authors research the opinions of first year nursing students about why the nursing profession does not receive the same degree of consideration which similar academic professionals receive. At the same time, the authors studied to see if this lower professional consideration is due to the predominant presence of females in the nursing profession. To collect data, the authors ran a transversal, descriptive, qualitative study by means of nominal group and discussion group techniques. Among the main results, the authors highlight that Nursing is considered a socially unknown profession and receives little acknowledgment inside the new health care model; furthermore, the fact that the majority of nurses are female does bear an influence on the vision of the nursing field and this female predominance harms competitiveness in the profession since nurses must conciliate their family lives with their professional lives.

Nerve growth factor activation of the extracellular signal-regulated kinase pathway is modulated by Ca(2+) and calmodulin.

Nerve growth factor is a member of the neurotrophin family of trophic factors that have been reported to be essential for the survival and development of sympathetic neurons and a subset of sensory neurons. Nerve growth factor exerts its effects mainly by interaction with the specific receptor TrkA, which leads to the activation of several intracellular signaling pathways. Once activated, TrkA also allows for a rapid and moderate increase in intracellular calcium levels, which would contribute to the effects triggered by nerve growth factor in neurons. In this report, we analyzed the relationship of calcium to the activation of the Ras/extracellular signal-regulated kinase pathway in PC12 cells. We observed that calcium and calmodulin are both necessary for the acute activation of extracellular signal-regulated kinases after TrkA stimulation. We analyzed the elements of the pathway that lead to this activation, and we observed that calmodulin antagonists completely block the initial Raf-1 activation without affecting the function of upstream elements, such as Ras, Grb2, Shc, and Trk. We have broadened our study to other stimuli that activate extracellular signal-regulated kinases through tyrosine kinase receptors, and we have observed that calmodulin also modulates the activation of such kinases after epidermal growth factor receptor stimulation in PC12 cells and after TrkB stimulation in cultured chicken embryo motoneurons. Calmodulin seems to regulate the full activation of Raf-1 after Ras activation, since functional Ras is necessary for Raf-1 activation after nerve growth factor stimulation and calmodulin-Sepharose is able to precipitate Raf-1 in a calcium-dependent manner.

Emerging treatment using tubulin inhibitors in advanced non-small cell lung cancer.

INTRODUCTION: Tubulin inhibitors including taxanes and vinca alkaloids are important components of chemotherapy regimens used in advanced non-small cell lung cancer (NSCLC). Despite a treatment paradigm shift due to molecularly-targeted therapies and immunotherapy, a majority of patients will receive chemotherapy during their treatment course. Either used alone or in combination, tubulin inhibitors have demonstrated clinical benefits in different settings of lung cancer management. Areas covered: This review first discusses FDA-approved tubulin inhibitors for NSCLC, such as paclitaxel, docetaxel, vinorelbine, and nab-paclitaxel. The article then provides a summary of novel tubulin inhibitors, including cabazitaxel, eribulin, ixabepilone, patupilone, plinabulin, new colchicine analogues and others. It also discusses new tubulin inhibitor combinations with immunotherapy (PD-1/PD-L1 inhibitors) and molecularly-targeted therapies (e.g. anti-angiogenic agents, mTOR inhibitors, heat shock protein 90 inhibitors, MEK inhibitors, and anti-HER3 agents). Lastly, emerging data on potential resistance mechanisms and predictive biomarkers for tubulin inhibitors are explored. Expert opinion: Tubulin inhibitors will likely continue to play important roles in NSCLC management due to the advent of novel agents and combinations. Through further understanding of tumor biology, investigation of drug resistance, and development of predictive biomarkers, we will be better positioned to incorporate microtubule inhibition into patient specific treatment strategies.

Effects on the monocyte-macrophage system and antitumor activity against L1210 leukemia of cis-bis-cyclopentenecarboxylato-trans-R,R-1,2-diaminocyclohexane -platinum (II) encapsulated in multilamellar vesicles.

Multilamellar vesicles (MLVs) composed of dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol at a molar ratio of 7:3 were used as carriers of cis-bis-cyclopentenecarboxylato-trans-R,R-1,2-diaminocyclohexane-p latinum (II) (CPDP). The encapsulation efficiency of liposomal CPDP (L-CPDP) was 87.6%, and its stability in normal saline at 14 days was 94.4%. The in vitro and in vivo effects on the function of the monocyte-macrophage system and the antitumor activity against L1210 leukemia were investigated in CD-1 and (C57BL/6J X DBA/2J)F1 mice. L-CPDP and cisplatin (CDDP) caused a comparable inhibition of murine-resident peritoneal macrophage (PM) protein and RNA synthesis and superoxide anion release. PM-mediated tumor cell cytotoxicity was completely inhibited at a concentration of 10 micrograms CDDP and L-CPDP/ml but not at concentrations of 1 and 5 micrograms/ml. The differences in plasma clearance of 99mTc-labeled MLV and phagocytic capacity of the liver among animals pretreated with the maximum tolerated doses of L-CPDP (25 mg/kg), empty liposomes, or CDDP (10 mg/kg) were not statistically significant (plasma clearance % of control: 105, 110, and 100, respectively: P greater than .05; liver uptake % of control: 87, 96, and 104, respectively: P greater than .05). At the maximum tolerated doses, the antitumor activity of L-CPDP against L1210 leukemia was similar to that of CDDP when a single dose was administered [median survival of treated mice/median survival of control mice X 100 (%T/C): 181 vs. 175] and slightly higher with the use of a triple-dose schedule (%T/C: 275 vs. 225). L-CPDP is easy to prepare, has a high-encapsulation efficiency and stability, is not more toxic than CDDP to the monocyte-macrophage system, and is at least as effective as CDDP against L1210 leukemia.

Effective treatment of early endobronchial cancer with regional administration of liposome-p53 complexes.

BACKGROUND: Lung cancer originates in a diffusely damaged bronchial epithelium as a result of sequential and cumulative genetic alterations. We investigated the feasibility of in vivo gene replacement in endobronchial precancerous and cancerous cells by a regionally administered nonviral delivery system. METHODS: After evaluating the in vitro transfection efficiency and cytotoxicity of a variety of cationic liposome-p53 formulations, a specific formulation, DP3-p53, was selected for further in vitro and in vivo evaluation. The ability of DP3-p53 to introduce the p53 gene in the normal bronchial epithelium was studied in transgenic mice that lack the p53 gene. The therapeutic effect of DP3-p53 administered intratracheally was studied in two nude mouse models of endobronchial human lung cancer by use of H358 (p53-null) and H322 (p53-mutant) cells. RESULTS: DP3-p53 was able to effectively introduce and express the p53 gene and induce G1 arrest and apoptosis in H358 cells in vitro and to introduce and transcribe the p53 gene in the bronchial epithelium of transgenic mice that lack the p53 gene in vivo. In therapeutic experiments using groups of four or five mice each, administration of five intratracheal doses of DP3-p53 (2 microg or 8 microg DNA per dose) on days 4, 8, 12, 16, and 20 after intratracheal tumor inoculation significantly inhibited lung tumor formation and prolonged by approximately twofold the survival of mice bearing H358 or H322 endobronchial tumor cells in contrast to the survival among untreated mice and mice treated with the DP3-empty vector (P = .007 [two-sided logrank test] for mice bearing H358 cells and P = .008 [two-sided logrank test] for those bearing H322 cells). CONCLUSIONS/IMPLICATIONS: Liposome-based p53 delivery through the airways is a potentially effective strategy for the treatment of early endobronchial cancer. These results have important implications for the gene therapy and prevention of human lung cancer.