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Purpose: This phase I trial assessed the safety, tolerability, and preliminary antitumor activity of lifastuzumab vedotin (LIFA), an antibody–drug conjugate of anti-NaPi2b mAb (MNIB2126A) and a potent antimitotic agent (monomethyl auristatin E). Patients and Methods: LIFA was administered to patients with non–small cell lung cancer (NSCLC) and platinum-resistant ovarian cancer (PROC), once every 3 weeks, by intravenous infusion. The starting dose was 0.2 mg/kg in this 3+3 dose-escalation design, followed by cohort expansion at the recommended phase II dose (RP2D). Results: Overall, 87 patients were treated at doses between 0.2 and 2.8 mg/kg. The MTD was not reached; 2.4 mg/kg once every 3 weeks was selected as the RP2D based on overall tolerability profile. The most common adverse events of any grade and regardless of relationship to study drug were fatigue (59%), nausea (49%), decreased appetite (37%), vomiting (32%), and peripheral sensory neuropathy (29%). Most common treatment-related grade ≥3 toxicities among patients treated at the RP2D (n = 63) were neutropenia (10%), anemia (3%), and pneumonia (3%). The pharmacokinetic profile was dose proportional. At active doses ≥1.8 mg/kg, partial responses were observed in four of 51 (8%) patients with NSCLC and 11 of 24 (46%) patients with PROC per RECIST. All RECIST responses occurred in patients with NaPi2b-high by IHC. The CA-125 biomarker assessed for patients with PROC dosed at ≥1.8 mg/kg showed 13 of 24 (54%) had responses (≥50% decline from baseline). Conclusions: LIFA exhibited dose-proportional pharmacokinetics and an acceptable safety profile, with encouraging activity in patients with PROC at the single-agent RP2D of 2.4 mg/kg.

Physical educators play a key role in role modeling to students within the school context. Therefore, there is a need to understand whether current physical education teacher education (PETE) provides sufficient knowledge and practice to prepare preservice educators to be successful. Thirty PETE preservice teachers (23 males, 7 females, aged 19–26) participated in this study. Participants performed tests in physical fitness and motor performance and completed an online questionnaire about cognitive factors (e.g., knowledge and understanding). In addition, a 7-day walking step total was recorded as daily activity in accordance with the Canadian Assessment of Physical Literacy testing battery. Each participant’s performance was compared with the achievement level of a 12-year-old child. Participants had significantly better performance in muscular strength (measured as handgrip test) and flexibility (measured as sit-and-reach test) than a 12-year-old. However, participants had significantly poorer performance in aerobic fitness (measured as PACER), motor performance (measured as obstacle course test), and muscular endurance (measured as plank test) than a 12-year-old. In addition, participants had significantly lower knowledge and understanding of health and physical activity than a 12-year-old. A positive relationship between physical competence (i.e., overall performance in physical fitness and motor performance) and cognitive factor was shown among participants. Growth and maturation may explain participants’ better performance in muscular strength and flexibility. Excessive weight status and low level of knowledge may have contributed to their poor performance in the physical competence domain. The positive relationship may indicate that cognitive factors are a strong predictor of the performance of physical fitness and motor performance. Therefore, for physical educators to promote a healthy lifestyle in education settings, the current PETE curriculum needs to be reviewed and relevant information delivered to promote physical literacy in PETE preservice teachers. Subscribe to TPE

Background Glioblastoma (GBM) is a highly aggressive brain tumor with rapid subclonal diversification, harboring molecular abnormalities that vary temporospatially, a contributor to therapy resistance. Fluorescence-guided neurosurgical resection utilizes the administration of 5-aminolevulinic acid (5-ALA) generating individually fluorescent tumor cells within a background population of non-neoplastic cells in the invasive tumor region. The aim of the study was to specifically isolate and interrogate the invasive GBM cell population using a novel 5-ALA-based method. Methods We have isolated the critical invasive GBM cell population by developing 5-ALA-based metabolic fluorescence-activated cell sorting. This allows purification and study of invasive cells from GBM without an overwhelming background “normal brain” signal to confound data. The population was studied using RNAseq, real-time PCR, and immunohistochemistry, with gene targets functionally interrogated on proliferation and migration assays using siRNA knockdown and known drug inhibitors. Results RNAseq analysis identifies specific genes such as SERPINE1 which is highly expressed in invasive GBM cells but at low levels in the surrounding normal brain parenchyma. siRNA knockdown and pharmacological inhibition with specific inhibitors of SERPINE1 reduced the capacity of GBM cells to invade in an in vitro assay. Rodent xenografts of 5-ALA-positive cells were established and serially transplanted, confirming tumorigenicity of the fluorescent patient-derived cells but not the 5-ALA-negative cells. Conclusions Identification of unique molecular features in the invasive GBM population offers hope for developing more efficacious targeted therapies compared to targeting the tumor core and for isolating tumor subpopulations based upon intrinsic metabolic properties.

Background MUC16 is a tumor-specific antigen overexpressed in ovarian (OC) and pancreatic (PC) cancers. The antibody–drug conjugate (ADC), DMUC5754A, contains the humanized anti-MUC16 monoclonal antibody conjugated to the microtubule-disrupting agent, monomethyl auristatin E (MMAE). Patients and methods This phase I study evaluated safety, pharmacokinetics (PK), and pharmacodynamics of DMUC5754A given every 3 weeks (Q3W, 0.3–3.2 mg/kg) or weekly (Q1W, 0.8–1.6 mg/kg) to patients with advanced recurrent platinum-resistant OC or unresectable PC. Biomarker studies were also undertaken. Results Patients (66 OC, 11 PC) were treated with DMUC5754A (54 Q3W, 23 Q1W). Common related adverse events (AEs) in >20% of patients (all grades) over all dose levels were fatigue, peripheral neuropathy, nausea, decreased appetite, vomiting, diarrhea, alopecia, and pyrexia in Q3W patents, and nausea, vomiting, anemia, fatigue, neutropenia, alopecia, decreased appetite, diarrhea, and hypomagnesemia in Q1W patients. Grade ≥3-related AE in ≥5% of patients included neutropenia (9%) and fatigue (7%) in Q3W patients, and neutropenia (17%), diarrhea (9%), and hyponatremia (9%) in Q1W patients. Plasma antibody-conjugated MMAE (acMMAE) and serum total antibody exhibited non-linear PK across tested doses. Minimal accumulation of acMMAE, total antibody, or unconjugated MMAE was observed. Confirmed responses (1 CR, 6 PRs) occurred in OC patients whose tumors were MUC16-positive by IHC (2+ or 3+). Two OC patients had unconfirmed PRs; six OC patients had stable disease lasting >6 months. For CA125, a cut-off of ≥70% reduction was more suitable for monitoring treatment response due to the binding and clearance of serum CA125 by MUC16 ADC. We identified circulating HE4 as a potential novel surrogate biomarker for monitoring treatment response of MUC16 ADC and other anti-MUC16 therapies in OC. Conclusions DMUC5754A has an acceptable safety profile and evidence of anti-tumor activity in patients with MUC16-expressing tumors. Objective responses were only observed in MUC16-high patients, although prospective validation is required. Clinical Trial Number NCT01335958.

Theories of ageing have suggested that many older adults adopt different strategies to enhance the experience of ageing. The current study was designed to explore the perceived role of religion and spirituality as a person ages. Eight older adults, four men and four women, aged from 67 to 80 years, participated in semi-structured interviews. The results from a thematic analysis revealed three manifest themes (defining religion and spirituality, the spiritual journey and being older but not feeling older) and one latent theme (faith). Religion and spirituality can play an important role in guiding the lives of older adults as well as helping them establish meaning in their lives and to cope with adverse situations. The results show that the participants see older adulthood as a period of spiritual growth and development which provides a means of compensating for losses that can result from physical decline.

Methamphetamine use is a serious public health concern in many countries and is second to cannabis as the most widely abused illicit drug in the world. Effective management for methamphetamine dependence remains elusive and the large majority of methamphetamine users relapse following treatment. Areas covered: Progression in the understanding of the pharmacological basis of methamphetamine use has provided us with innovative opportunities to develop agents to treat dependence. The current review summarizes relevant literature on the neurobiological and clinical correlates associated with methamphetamine use. We then outline agents that have been explored for potential treatments in preclinical studies, human laboratory phase I and phase II trials over the last ten years. Expert opinion: No agent has demonstrated a broad and strong effect in achieving MA abstinence in Phase II trials. Agents with novel therapeutic targets appear promising. Advancement in MA treatment, including translation into practice, faces several clinical challenges.

Synthetic cannabinoids (SCs) have rapidly proliferated as recreational drugs, and may present a substantial health risk to vulnerable populations. However, information on possible effects of long-term use is sparse. This study compared acute and residual effects of the popular indazole carboxamide SC compounds AB-PINACA and AB-FUBINACA in adolescent rats with ∆9-tetrahydrocannabinol (THC) and control treatments. Albino Wistar rats were injected (i.p.) with AB-PINACA or AB-FUBINACA every second day (beginning post-natal day (PND) 31), first at a low dose (0.2 mg/kg on 6 days) followed by a higher dose (1 mg/kg on a further 6 days). THC-treated rats received equivalent doses of 6 × 1 mg/kg and 6 × 5 mg/kg. During drug treatment, THC, AB-PINACA, and AB-FUBINACA decreased locomotor activity at high and low doses, increased anxiety-like behaviours and audible vocalisations, and reduced weight gain. Two weeks after dosing was completed, all cannabinoid pre-treated rats exhibited object recognition memory deficits. These were notably more severe in rats pre-treated with AB-FUBINACA. However, social interaction was reduced in the THC pre-treated group only. Six weeks post-dosing, plasma levels of cytokines interleukin (IL)-1α and IL-12 were reduced by AB-FUBINACA pre-treatment, while cerebellar endocannabinoids were reduced by THC and AB-PINACA pre-treatment. The acute effects of AB-PINACA and AB-FUBINACA were broadly similar to those of THC, suggesting that acute SC toxicity in humans may be modulated by dose factors, including inadvertent overdose and product contamination. However, some lasting residual effects of these different cannabinoid receptor agonists were subtly different, hinting at recruitment of different mechanisms of neuroadaptation.

Application of distinct positron emission tomography (PET) scan reconstruction algorithms can lead to statistically significant differences in measuring lesion functional properties. We looked at the influence of two-dimensional filtered back projection (2D FBP), two-dimensional ordered subset expectation maximization (2D OSEM), three-dimensional ordered subset expectation maximization (3D OSEM) without 3D maximum a posteriori and with (3D OSEM MAP) on lesion hypoxia tracer uptake using a pre-clinical PET scanner.Reconstructed images of a rodent tumor model bearing P22 carcinosarcoma injected with hypoxia tracer Copper-64-Diacetyl-bis (N4-methylthiosemicarbazone) (i.e. Cu-64 ATSM) were analyzed at 10 minute intervals till 60 minute post injection. Lesion maximum standardized uptake values (SUVmax) and SUVmax/background SUVmean (T/B) were recorded and investigated after application of multiple algorithm and reconstruction parameters to assess their influence on Cu-64 ATSM measurements and associated trends over time.SUVmax exhibited convergence for OSEM reconstructions while ANOVA results showed a significant difference in SUVmax or T/B between 2D FBP, 2D OSEM, 3D OSEM and 3D OSEM MAP reconstructions across all time frames. SUVmax and T/B were greatest in magnitude for 2D OSEM followed by 3D OSEM MAP, 3D OSEM and then 2D FBP at all time frames respectively. Similarly SUVmax and T/B standard deviations (SD) were lowest for 2D OSEM in comparison with other algorithms.Significantly higher magnitude lesion SUVmax and T/B combined with lower SD were observed using 2D OSEM reconstruction in comparison with 2D FBP, 3D OSEM and 3D OSEM MAP algorithms at all time frames. Results are consistent with other published studies however more specimens are required for full validation.Amaç: Farklı pozitron emisyon tomografisi (PET) rekonstrüksiyon algoritmalarının uygulanması lezyonun fonksiyonel özelliklerinde istatistiksel olarak anlamlı farklılıklara neden olabilir. Bu çalışmada iki-boyutlu filtreli geri projeksiyon (2D FBP), iki-boyutlu düzenli subset expectation maksimizasyonu (2D OSEM), 3D maksimum a posteriori olmaksızın (3D OSEM) ve 3D maksimum a posteriori ile (3D OSEM MAP) üç-boyutlu düzenli subset expectation maksimizasyonu kullanımının pre-klinik bir PET tarayıcısı ile lezyon hipoksisini izleyen maddenin (tracer) tutulumu üzerine etkisi incelenmiştir. Yöntem: P22 karsinosarkomlu bir kemirgen tümör modelinde hipoksi izleyen maddenin Copper-64-Diacetyl-bis (N4- methylthiosemicarbazone) (Cu-64 ATSM) enjeksiyonu ile 60. dakikaya kadar her 10 dakikada bir elde edilen rekonstrükte görüntüler incelendi. Lezyonun maksimum standardize tutulum değeri (SUV max ) ve SUV max /taban SUV ortalama (T/B) değerleri kaydedildi, ve multipl algoritma ve rekonstrüksiyon parametresi uygulanmasından sonra bunların Cu-64 ATSM ölçümleri üzerindeki etkisi ve farklı zaman dilimlerindeki seyri araştırıldı. Bulgular: SUV max OSEM rekonstrüksiyonları için konverjans gösterirken ANOVA sonuçları tüm zaman dilimlerinde 2D FBP, 2D OSEM, 3D OSEM ve 3D OSEM MAP rekonstrüksiyonları arasında SUV max veya T/B de anlamlı farklılık tespit etti. En yüksek SUV max ve T/B değerleri tüm zaman dilimlerinde 2D OSEM’de saptandı, bunu sırasıyla 3D OSEM MAP, 3D OSEM ve 2D FBP takip etti. Benzer şekilde SUV max ve T/B standart deviasyonları (SD) diğer algoritmalara kıyasla 2D OSEM’de en düşüktü. Sonuç: 2D OSEM rekonstrüksiyonu ile 2D FBP, 3D OSEM ve 3D OSEM MAP algoritmalarına kıyasla tüm zaman dilimlerinde anlamlı olarak daha yüksek lezyon SUV max ve T/B ile birlikte daha düşük SD gözlemlendi. Sonuçlar daha önce yayınlanmış çalışmalarla uyumlu olmakla birlikte tam onaylama için daha fazla veri gerekmektedir.

Synthetic cannabinoid (SC) designer drugs based on indole and indazole scaffolds and featuring l-valinamide or l-tert-leucinamide side chains are encountered with increasing frequency by forensic researchers and law enforcement agencies and are associated with serious adverse health effects. However, many of these novel SCs are unprecedented in the scientific literature at the time of their discovery, and little is known of their pharmacology. Here, we report the synthesis and pharmacological characterization of AB-FUBINACA, ADB-FUBINACA, AB-PINACA, ADB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA, ADBICA, 5F-ADBICA, and several analogues. All synthesized SCs acted as high potency agonists of CB1 (EC50 = 0.24-21 nM) and CB2 (EC50 = 0.88-15 nM) receptors in a fluorometric assay of membrane potential, with 5F-ADB-PINACA showing the greatest potency at CB1 receptors. The cannabimimetic activities of AB-FUBINACA and AB-PINACA in vivo were evaluated in rats using biotelemetry. AB-FUBINACA and AB-PINACA dose-dependently induced hypothermia and bradycardia at doses of 0.3-3 mg/kg, and hypothermia was reversed by pretreatment with a CB1 (but not CB2) antagonist, indicating that these SCs are cannabimimetic in vivo, consistent with anecdotal reports of psychoactivity in humans.