SOX11 and TP53 add prognostic information to MIPI in a homogenously treated cohort of mantle cell lymphoma – a Nordic Lymphoma Group study

Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma, where survival has been remarkably improved by use of protocols including high dose cytarabine, rituximab and autologous stem cell transplantation, such as the Nordic MCL2/3 protocols. In 2008, a MCL international prognostic index (MIPI) was created to enable stratification of the clinical diverse MCL patients into three risk groups. So far, use of the MIPI in clinical routine has been limited, as it has been shown that it inadequately separates low and intermediate risk group patients. To improve outcome and minimize treatment‐related morbidity, additional parameters need to be evaluated to enable risk‐adapted treatment selection. We have investigated the individual prognostic role of the MIPI and molecular markers including SOX11, TP53 (p53), MKI67 (Ki‐67) and CCND1 (cyclin D1). Furthermore, we explored the possibility of creating an improved prognostic tool by combining the MIPI with information on molecular markers. SOX11 was shown to significantly add prognostic information to the MIPI, but in multivariate analysis TP53 was the only significant independent molecular marker. Based on these findings, we propose that TP53 and SOX11 should routinely be assessed and that a combined TP53/MIPI score may be used to guide treatment decisions.     

White adipose tissue mitochondrial metabolism in health and in obesity

White adipose tissue is one of the largest organs of the body. It plays a key role in whole‐body energy status and metabolism; it not only stores excess energy but also secretes various hormones and metabolites to regulate body energy balance. Healthy adipose tissue capable of expanding is needed for metabolic well‐being and to prevent accumulation of triglycerides to other organs. Mitochondria govern several important functions in the adipose tissue. We review the derangements of mitochondrial function in white adipose tissue in the obese state. Downregulation of mitochondrial function or biogenesis in the white adipose tissue is a central driver for obesity‐associated metabolic diseases. Mitochondrial functions compromised in obesity include oxidative functions and renewal and enlargement of the adipose tissue through recruitment and differentiation of adipocyte progenitor cells. These changes adversely affect whole‐body metabolic health. Dysfunction of the white adipose tissue mitochondria in obesity has long‐term consequences for the metabolism of adipose tissue and the whole body. Understanding the pathways behind mitochondrial dysfunction may help reveal targets for pharmacological or nutritional interventions that enhance mitochondrial biogenesis or function in adipose tissue.     

Automated GMP production and long-term experience in radiosynthesis of CB1 tracer [18F]FMPEP-d2

Here, we describe the development of an in-house-built device for the fully automated multistep synthesis of the cannabinoid CB₁ receptor imaging tracer (3R,5R)-5-(3-([¹⁸F]fluoromethoxy-d₂)phenyl)-3-(((R)-1-phenylethyl)amino)-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one ([¹⁸F]FMPEP-d₂), following good manufacturing practices. The device is interfaced to a HPLC and a sterile filtration unit in a clean room hot cell. The synthesis involves the nucleophilic ¹⁸F-fluorination of an alkylating agent and its GC purification, the subsequent ¹⁸F-fluoroalkylation of a precursor molecule, the semipreparative HPLC purification of the ¹⁸F-fluoroalkylated product, and its formulation for injection. We have optimized the duration and temperature of the ¹⁸F-fluoroalkylation reaction and addressed the radiochemical stability of the formulated product. During the past 5 years (2013–2018), we have performed a total of 149 syntheses for clinical use with a 90% success rate. The activity yield of the formulated product has been 1.0 ± 0.4 GBq starting from 11 ± 2 GBq and the molar activity 600 ± 300 GBq/μmol at the end of synthesis.     

Surgery for stress urinary incontinence in Finland 1987–2009

Introduction and hypothesis

To estimate the incidence rates of stress urinary incontinence (SUI) surgery among Finnish women from 1987 to 2009 by age, and to evaluate the trends in SUI surgery.

Methods

We conducted a retrospective register-based study. All SUI procedures on adult women over age 18 years in Finland were identified from the nationwide Care Register for Health Care. Age-specific incidence rates per 1,000 women were calculated for each year. The cumulative incidence of SUI surgery was calculated.

Results

There were 38,340 procedures for SUI in 1987–2009. The overall age-adjusted incidence rate increased 2.6-fold from 0.5/1,000 women in 1987 to 1.3/1,000 in 2002, but declined thereafter by 2009 to 0.8/1,000. There was a six-fold increase in the incidence rate in the age group 60–69 years and a ten-fold increase in the age group 70–79 years from 1987 to 2002. These marked increases in operation rates coincided with the increased use of tension-free vaginal tape (TVT). In 2002, TVT accounted for 96 % of all SUI procedures. Mid-urethral slings with transobturator techniques surpassed TVT in popularity in 2007. The life-long cumulative incidence of SUI surgery was 9.9 % in 2002 and 6.3 % in 2009.

Conclusions

The incidence rates of SUI surgery increased significantly in Finland, especially among women aged 60 to 79 years. Mid-urethral slings have become the dominant procedure.

     

New multifunctional anti-osteolytic releasing bioabsorbable implant

Bioabsorbable devices are a good alternative to metals for bone fixation because of their temporary presence in the body. However, bioabsorbable implants elicit a local foreign-body reaction that may lead to osteolysis. The aim of the current study was to develop and characterize a bioabsorbable implant with anti-osteolytic properties. Poly(lactide-co-glycolide) (PLGA) 80/20, was compounded with clodronic acid disodium salt (CS) to produce rods that were subsequently self-reinforced (SR) and gamma-sterilized. Four different implant types were investigated: 1) PLGA+CS, 2) SR-PLGA+CS, 3) sterilized (s)SR-PLGA+CS, and 4) sSR-PLGA. Drug release was determined using ultraviolet spectrophotometry. Shear strength, bending strength, and Young's modulus in bending were studied for 12 weeks in vitro, and changes in pH of the solution were also evaluated. A burst drug release was detected at the start. Approximately 70% of the drug was released during 10 weeks from SR rods and only 3% from the compounded rods during 12 weeks. gamma-sterilization also accelerated drug release. During the first 6 weeks, CS releasing rods had lower initial mechanical properties than plain rods, whereas they had higher values at 12 weeks because of the more steady and linear strength loss of CS rods. The pH of plain rods leads to a fall in pH at 8 to 12 weeks. A very slight drop in pH was seen with CS rods. In conclusion, it is feasible to develop clodronate-releasing, bioabsorbable PLGA implants that have acceptable mechanical properties. Rods retained suitable mechanical properties for fixation for 6 weeks in vitro. CS rods also prevent a drop in pH in vitro. In vivo studies are needed to evaluate their functionality with the view of clinical application in future.     

A novel mutation in TRIM37 is associated with mulibrey nanism in a Turkish boy

Mulibrey nanism is a rare autosomal-recessive disorder characterized by prenatal onset severe growth retardation and pericardial constriction associated with abnormalities of muscle, liver, brain and eye. More than 80% of previously reported patients are of Finnish origin in whom a founder mutation in the TRIM37 gene have been described. We report on a 7-year-old Turkish boy who presented with classical phenotypic features of mulibrey nanism. Mutation screening of the TRIM37 gene revealed that the proband had a homozygous two base pair deletion, c.1894_1895delGA, resulting in a frame-shift and a premature termination codon. Our proband is one of the rare examples of mulibrey nanism outside Finland and extends the mutation spectrum in this disorder.     

From the Cover: Unlocking adults’ implicit statistical learning by cognitive depletion

Human learning is supported by multiple neural mechanisms that maturate at different rates and interact in mostly cooperative but also sometimes competitive ways. We tested the hypothesis that mature cognitive mechanisms constrain implicit statistical learning mechanisms that contribute to early language acquisition. Specifically, we tested the prediction that depleting cognitive control mechanisms in adults enhances their implicit, auditory word-segmentation abilities. Young adults were exposed to continuous streams of syllables that repeated into hidden novel words while watching a silent film. Afterward, learning was measured in a forced-choice test that contrasted hidden words with nonwords. The participants also had to indicate whether they explicitly recalled the word or not in order to dissociate explicit versus implicit knowledge. We additionally measured electroencephalography during exposure to measure neural entrainment to the repeating words. Engagement of the cognitive mechanisms was manipulated by using two methods. In experiment 1 (n = 36), inhibitory theta-burst stimulation (TBS) was applied to the left dorsolateral prefrontal cortex or to a control region. In experiment 2 (n = 60), participants performed a dual working-memory task that induced high or low levels of cognitive fatigue. In both experiments, cognitive depletion enhanced word recognition, especially when participants reported low confidence in remembering the words (i.e., when their knowledge was implicit). TBS additionally modulated neural entrainment to the words and syllables. These findings suggest that cognitive depletion improves the acquisition of linguistic knowledge in adults by unlocking implicit statistical learning mechanisms and support the hypothesis that adult language learning is antagonized by higher cognitive mechanisms.

Human learning is thought to be supported by the interactions between two basic memory systems of the brain, namely declarative and nondeclarative memory (1). Declarative memory is characterized by voluntary, explicit, attention-based processes, such as recall and recognition of facts/events, and is mediated by medial-temporal lobe and prefrontal cortex structures (2). Nondeclarative memory, also referred to as procedural memory, on the other hand is part of implicit memory and includes the acquisition of a heterogeneity of skills, habits, and procedures. It is mediated by basal ganglia, cerebellar, and neocortical structures, as well as parts of the prefrontal cortex [e.g., Broca''s area (3–5)].Accumulating evidence supports a competitive relationship between these two memory systems during human skill learning. Suppression of the declarative memory system by interventions like repetitive transcranial magnetic stimulation (TMS), distraction tasks, alcohol consumption, hypnosis, intake of benzodiazepines, or cognitive fatigue, can actually enhance performance in implicit, perceptual-motor learning tasks such as the serial-reaction time task (6–11) or intuitive reasoning tasks (12). These findings suggest that higher-level cognitive functions associated with declarative memory and supported by the prefrontal cortex can interfere with behavior that is naturally driven by implicit learning processes (13). However, it remains unresolved whether competing memory systems also affect implicit statistical learning abilities that are critical for the early, rapid acquisition of language in infants (14). This is an important question, as it could explain why infants and children pick up languages with less effort than adults (cf “What don’t we know?”) (15).Language acquisition involves many different memory and learning processes that are dependent on both procedural and declarative memory (2, 16). The first step for infants acquiring language is to gain knowledge about the phonological structure in one’s spoken language system, the probabilistic constraints on how speech sounds combine (i.e., phonotactic learning), and the segments of continuous speech (i.e., word forms) (17). Word form learning takes place already in the first 12 months of life and is an important precursor to vocabulary acquisition (i.e., mapping form to meaning) and more complex language acquisition (e.g., grammar) later in development (18). In the present study, we focus on statistical learning mechanisms that contribute to word segmentation and thus novel word form learning in the early stages of language acquisition.Statistical learning is generally known as the ability to pick up on patterns in the environment through extraction of frequent regularities and distributional properties. The term was first introduced in the field of cognitive psychology by the work of Saffran, Aslin, and Newport (1996) (19), who demonstrated that infants of only 8-mo-old can extract word boundaries and segment novel word forms from a continuous stream of speech sounds with no other cue than the transitional probabilities between syllables. Later, this learning was also demonstrated in older children and adults (20, 21) and across different domains (e.g., music and grammar) or modalities (e.g., auditory, visual, and motor) (22, 23), indicating that statistical learning is a largely continuous and domain-general learning mechanism for skill acquisition across the human life span.In a typical statistical learning experiment, participants are repeatedly exposed to patterned stimuli such as consonant strings from an artificial grammar, or recurrent syllable triplets. Learning is then typically assessed postexposure by using a two-alternative forced-choice recognition task in which triplets from the exposure stream are pitted against foils. Participants have to indicate which of the two triplets sounded most familiar, and above-chance accuracy is taken as indication of learning. Since statistical learning occurs without any instruction or intention to learn, it is often assumed to result in implicit memory representations (24). This view is also supported by the evidence that statistical learning occurs in infants and even in sleeping neonates (25). However, in recent work, Batterink and colleagues demonstrated that even without intention to learn, adults acquire mainly explicit knowledge of the novel word forms during statistical learning (26–29). This can be derived from the observation that participants’ performance was above chance when they were confident remembering the triplet but at chance when they were unconfident. Knowledge is implicit when participants lack awareness of what they have learned. This means that if participants perform also above chance when they are unconfident, knowledge is inferred to be implicit (30). In contrast, if they perform at chance level when confidence is low, no implicit knowledge is gained. Although statistical learning may produce additional implicit knowledge that cannot be assessed by the recognition and memory judgement tasks (e.g., ref. 28), Batterink’s earlier findings show that adults store the acquired word knowledge mainly in the explicit memory system.We and others have proposed that cognitive development and maturation of the prefrontal areas negatively affect language acquisition, such as word form or grammar learning (31–35). For instance, we showed that children outperform adults on the Hebb repetition learning paradigm (32, 33), a memory paradigm in which participants are asked to immediately recall syllable sequences that consist of hidden repeated word forms. Interestingly, in a follow-up study, we found that cognitive depletion by TMS to the left dorsolateral prefrontal cortex (DLPFC), an area closely related to declarative memory and cognitive control, enhanced Hebb performance in adult participants (34). This suggests that late-developing prefrontal cognitive mechanisms can induce changes in efficiently acquiring sequential language information from the environment, a finding that is largely in line with previously reported evidence in skill learning (13). Recently, we corroborated this idea further by showing enhanced phonotactic constraint learning in adults under cognitive fatigue (35). Based on these findings, we hypothesize that the higher cognitive control system could reduce access to implicit memory processes in adults, thereby making them less efficient in language acquisition relative to infants and children. This idea is in line with the well-known less-is-more hypothesis that attributes developmental changes in language acquisition, such as phonology and grammar, to maturational changes in attention and memory capacities (36–38). In our previous work, participants were explicitly asked to memorize (34) or produce (35) syllable sequences and thus exposure to the novel language was not passive, or “infant like.” Moreover, we did not separate implicit and explicit memory representations. Thus it remains unresolved how higher-order cognitive functions affect acquisition of implicit linguistic knowledge during passive listening to continuous speech using statistical learning mechanisms that support infant language acquisition (23, 39).The aim of the current study was to directly address this question using the auditory statistical learning paradigm. In particular, we aimed to determine whether a temporary depletion of the higher cognitive control system, using two different interventions, can unlock adults’ implicit statistical learning processes that serve infant word segmentation. To investigate this, we exposed young adults to continuous streams of syllables with, unknown to them, repeating three-syllable pseudowords, while watching a silent film. In the first experiment, inhibitory continuous theta-burst stimulation was used to induce a long-lasting disruption in left DLPFC or a control site prior to exposure, similar to the method used in Smalle et al., 2017 (34). In the second experiment, participants first performed an effortful dual working-memory task under high– or low–cognitive-load( HCL and LCL, respectively) conditions, which induces cognitive fatigue that hampers subsequent cognitive performance (7, 35, 40), or did not perform a cognitive load task prior to the language exposure (control or no-load condition). Our primary measure of statistical learning was the offline recognition of the hidden words, which was assessed 15 min after exposure. This was combined with a memory judgement procedure, which measured how confident the participants were that they remembered the hidden words. This task dissociates explicit versus implicit memory representations (e.g., refs. 27–29, 41). In both experiments, electroencephalography (EEG) was also measured during the 20-min language exposure in order to investigate an online perceptual component as second independent measure of statistical learning. Research has shown that the steady-state response of the brain shows a decrease at the frequency of individual syllables and an increase at the rhythm of three-syllable words while listening to continuous sound streams that consist of repeating three-syllable structures. This shift in neural entrainment indicates online statistical learning of novel words as a function of auditory exposure (29). Overall, we predicted that TMS-induced disruption of the DLPFC (in experiment 1) and cognitive fatigue (in experiment 2) would enhance statistical language learning and especially strengthen implicit memory representations for the hidden novel words.     

NF-E2-related factor 2 activation boosts antioxidant defenses and ameliorates inflammatory and amyloid properties in human Presenilin-1 mutated Alzheimer's disease astrocytes

Alzheimer's disease (AD) is a common dementia affecting a vast number of individuals and significantly impairing quality of life. Despite extensive research in animal models and numerous promising treatment trials, there is still no curative treatment for AD. Astrocytes, the most common cell type of the central nervous system, have been shown to play a role in the major AD pathologies, including accumulation of amyloid plaques, neuroinflammation, and oxidative stress. Here, we show that inflammatory stimulation leads to metabolic activation of human astrocytes and reduces amyloid secretion. On the other hand, the activation of oxidative metabolism leads to increased reactive oxygen species production especially in AD astrocytes. While healthy astrocytes increase glutathione (GSH) release to protect the cells, Presenilin-1-mutated AD patient astrocytes do not. Thus, chronic inflammation is likely to induce oxidative damage in AD astrocytes. Activation of NRF2, the major regulator of cellular antioxidant defenses, encoded by the NFE2L2 gene, poses several beneficial effects on AD astrocytes. We report here that the activation of NRF2 pathway reduces amyloid secretion, normalizes cytokine release, and increases GSH secretion in AD astrocytes. NRF2 induction also activates the metabolism of astrocytes and increases the utilization of glycolysis. Taken together, targeting NRF2 in astrocytes could be a potent therapeutic strategy in AD.